Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[C:4]2([CH2:7][NH:6][CH2:5]2)[CH2:3][O:2]1.C[O:9][C:10]([C:12]1[C:16]([NH:17][C:18]([C:20]2[C:25]([NH:26][C:27]3[CH:28]=[N:29][CH:30]=[N:31][CH:32]=3)=[CH:24][CH:23]=[C:22]([CH:33]3[CH2:35][CH2:34]3)[N:21]=2)=[O:19])=[CH:15][N:14]([CH3:36])[N:13]=1)=O>>[CH3:36][N:14]1[CH:15]=[C:16]([NH:17][C:18]([C:20]2[C:25]([NH:26][C:27]3[CH:32]=[N:31][CH:30]=[N:29][CH:28]=3)=[CH:24][CH:23]=[C:22]([CH:33]3[CH2:34][CH2:35]3)[N:21]=2)=[O:19])[C:12]([C:10]([N:6]2[CH2:7][C:4]3([CH2:3][O:2][CH2:1]3)[CH2:5]2)=[O:9])=[N:13]1
Reactant: COC(=O)c1nn(C)cc1NC(=O)c1nc(C2CC2)ccc1Nc1cncnc1
Reactant: C1NCC12COC2
Product: Cn1cc(NC(=O)c2nc(C3CC3)ccc2Nc2cncnc2)c(C(=O)N2CC3(COC3)C2)n1
Yield: 5 %

Procedure:
According to the general method described in step 5 of example 27, reaction of 2-oxa-6-aza-spiro[3.3]heptane with 4-{[6-cyclopropyl-3-(pyrimidin-5-ylamino)-pyridine-2-carbonyl]-amino}-1-methyl-1H-pyrazole-3-carboxylic acid methyl ester provided the title compound (5%) as sticky yellow solid.
Reaction SMILES: [Si:1](Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[OH:9][C:10]1[C:11]([CH3:28])=[C:12]2[C:17](=[C:18]([CH3:21])[C:19]=1[CH3:20])[O:16][C:15]([CH3:27])([CH2:22][C:23]([O:25][CH3:26])=[O:24])[CH2:14][CH2:13]2.N1C=CN=C1>CN(C=O)C.C(=O)([O-])O.[Na+].C(OCC)C>[O:9]([C:10]1[C:11]([CH3:28])=[C:12]2[C:17](=[C:18]([CH3:21])[C:19]=1[CH3:20])[O:16][C:15]([CH3:27])([CH2:22][C:23]([O:25][CH3:26])=[O:24])[CH2:14][CH2:13]2)[Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: COC(=O)CC1(C)CCc2c(C)c(O)c(C)c(C)c2O1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: CCOCC
Solvent: CN(C)C=O
Product: COC(=O)CC1(C)CCc2c(C)c(O[Si](C)(C)C(C)(C)C)c(C)c(C)c2O1
Temperature: 0 °C
Reaction time: 20 h

Procedure:
Under nitrogen, 5.41 g (35.9 mM) of tert-butyldimethylsilyl chloride was added to a solution of 7.69 g (27.63 mM) of methyl 6-hydroxy-2,5,7,8-tetramethylchroman-2-acetate and 2.82 g (41.4 mM) of imidazole in DMF (54 ml) at room temperature and the mixture was stirred at 0° C. for 20 hours. This reaction mixture was poured in saturated aqueous sodium hydrogen carbonate-diethyl ether under intense agitation to stop the reaction and, then, extracted with diethyl ether. The organic layer was washed with water and saturated aqueous solution of sodium chloride and dried over MgSO4. The resulting crude product was purified by column chromatography (ethyl acetate-hexane: 10%) to provide the title compound as yellow oil.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([O:10][CH2:11][CH:12]3[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[ClH:25].O1CCOCC1>>[ClH:25].[ClH:25].[NH:15]1[CH2:16][CH2:17][CH:12]([CH2:11][O:10][C:6]2[CH:5]=[C:4]3[C:9](=[CH:8][CH:7]=2)[NH:1][N:2]=[CH:3]3)[CH2:13][CH2:14]1
Reactant: CC(C)(C)OC(=O)N1CCC(COc2ccc3[nH]ncc3c2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: c1cc2[nH]ncc2cc1OCC1CCNCC1
Reaction time: 1 h
Yield: 95 %

Procedure:
To tert-butyl 4-[(1H-indazol-5-yloxy)methyl]piperidine-1-carboxylate (81.2 mg, 0.245 mmol) was added 4N-hydrochloric acid-dioxane (1 ml). After 1 hour, the resulting mixture was concentrated under reduced pressure, and the resulting residue was dissolved in methanol (0.5 ml) and crystallized from diethyl ether (10 ml). The crystals were filtered and then dried under reduced pressure to obtain 5-(piperidin-4-ylmethoxy)-1H-indazole dihydrochloride (71 mg, 95%).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1O)[C:6]([O:8][CH3:9])=[O:7])=[O:2].[CH2:14]([C:16]1[CH:21]=[CH:20][C:19]([Li])=[CH:18][CH:17]=1)[CH3:15].C([Li])(C)(C)C.BrC1C=CC(CC)=CC=1.[Cl-].[NH4+]>O1CCCC1>[CH2:14]([C:16]1[CH:21]=[CH:20][C:19]([CH:1]([OH:2])[C:3]2[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=2)[C:6]([O:8][CH3:9])=[O:7])=[CH:18][CH:17]=1)[CH3:15]
Reactant: COC(=O)c1ccc(O)c(C=O)c1
Reactant: [Li]c1ccc(CC)cc1
Agent: CCc1ccc(Br)cc1
Agent: [Cl-]
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: CCc1ccc(C(O)c2cccc(C(=O)OC)c2)cc1
Reaction time: 1 h
Yield: 46 %

Procedure:
To a mixture of methyl 3-formyl-4-hydroxybenzoate (4.0 g, 22.2 mmol) and tetrahydrofuran (100 mL), 4-ethylphenyllithium [which had been prepared by stirring t-butyllithium (66 mmol) into a mixture of 1-bromo-4-ethylbenzene (12.3 g, 66 mmol) and tetrahydrofuran (200 mL) at −70° C. for 30 minutes] was added at −70° C. and stirred for 1 hour. After addition of saturated aqueous ammonium chloride, the reaction mixture was extracted with ethyl acetate, and the organic phase was washed with saturated aqueous sodium chloride and then dried over anhydrous magnesium sulfate. After the solvent was distilled off under reduced pressure, the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=65:35–50:50) to give methyl 3-[(4-ethylphenyl)hydroxymethyl]benzoate (2.92 g, 46%) as a light-yellow gum.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[C:8]([O:10][CH2:11][CH3:12])=[O:9].[NH2:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[NH:19][N:18]=[CH:17]2.C(=O)([O-])O.[Na+]>CO>[NH:19]1[C:20]2[C:16](=[CH:15][C:14]([NH:13][CH:2]3[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]3[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:22][CH:21]=2)[CH:17]=[N:18]1
Reactant: Nc1ccc2[nH]ncc2c1
Reactant: CCOC(=O)C1CCCCC1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: CCOC(=O)C1CCCCC1Nc1ccc2[nH]ncc2c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 105.8 %

Procedure:
Ethyl 2-oxocyclohexanecarboxylate (0.85 g) and 5-aminoindazole (0.60 g) were dissolved in methanol (10 ml), and a borane-pyridine complex (0.81 ml) was added dropwise to the solution at room temperature. The reaction mixture was stirred at room temperature for 18 hr. A saturated aqueous sodium hydrogencarbonate solution (10 ml) was then added thereto, and the mixture was extracted with chloroform-propanol (3/1). The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed by distillation under the reduced pressure. The residue was purified by chromatography on silica gel [chloroform/methanol] to give the title compound (1.37 g) as substantially 1:1 enantiomers.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][CH:9]1[CH:22]=[C:21]([CH:23]=[CH:24][C:25]#[N:26])[CH:20]=[C:19]([CH3:27])[C:10]1(C(O)=O)CNC1C=CC=CC=1.[NH3:31]>O>[CH3:8][C:9]1[CH:22]=[C:21]([CH:23]=[CH:24][C:25]#[N:26])[CH:20]=[C:19]([CH3:27])[C:10]=1[NH2:31]
Reactant: N
Reactant: CC1=CC(C=CC#N)=CC(C)C1(CNc1ccccc1)C(=O)O
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C=CC#N)cc(C)c1N
Temperature: 52.5 °C

Procedure:
Trifluoroacetic acid (600 ml) was slowly added to the residue of 2,6-dimethyl-4-(2-cyanoethenyl)-1-carboxybenzyl phenylamine obtained from example 2 (161 gms) at 25 to 30° C. and the reaction mass was stirred at 45-60° C. till completion of reaction as monitored by TLC. After completion of the reaction, water (1800 ml) was added to the reaction mass, neutralized with aqueous ammonia and extracted with toluene. The organic layer was separated and concentrated to give 2,6-dimethyl-4-(2-cyanoethenyl)phenylamine. The residue was admixed with 1:1 mixture of isopropanol and diisopropyl ether (1000 ml) and treated with HCl dissolved in isopropanol to yield 2,6-dimethyl-4-(2-cyanoethenyl)phenylamine hydrochloride salt (II) which was cooled to 25-30° C., filtered and dried.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.Cl.Cl.[CH3:23][C:24]1([NH2:28])[CH2:27][NH:26][CH2:25]1.C(N(CC)CC)C>N1C=CC=CC=1>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11]([N:26]4[CH2:27][C:24]([CH3:23])([NH2:28])[CH2:25]4)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Reactant: CC1(N)CNC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: CC1(N)CN(c2c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)C1

Procedure:
A mixture of 0.23 g (0.82 mmoles) of 1-cyclopropyl-6,7,8-trifluoro-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid, 0.26 g (1.64 mmoles) of 3-methyl-3-aminoazetidine dihydrochloride and 0.5 ml of triethylamine is refluxed in 10 ml of pyridine for 2 hours. Filtering and washing with water and ethanol yield 0.250 g (87%) of 1-cyclopropyl-6,8-difluoro-1,4-dihydro-7-(3-methyl-3-amino-1-azetidinyl)-4-oxo-3-quinolinecarboxylic acid having a melting point and spectroscopic data identical to those of the derivative obtained by Method E.
Reaction SMILES: [NH2:1][CH2:2][C:3]([OH:5])=[O:4].[OH-].[Na+].[F:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=1[F:18])[C:12](Cl)=[O:13].Cl>C1COCC1.CCOC(C)=O>[F:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=1[F:18])[C:12]([NH:1][CH2:2][C:3]([OH:5])=[O:4])=[O:13]
Reactant: NCC(=O)O
Reactant: O=C(Cl)c1ccc(F)c(F)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(O)CNC(=O)c1ccc(F)c(F)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 101.4 %

Procedure:
Glycine (8.26 g, 110 mmol) was dissolved in 2M NaOH (125 ml, 250 mmol). The resulting colorless solution was cooled to 0° C. and 3,4-difluorobenzoyl chloride (12 mL, 95 mmol) in 60 mL of THF was added dropwise over 10 minutes. The reaction was stirred for 1 hour at 0° C. and allowed to warm to room temperature over 2 hours. The reaction was acidified to pH 1 with concentrated HCl while cooling in an ice bath. 100 mL of EtOAc was added and the mixture was poured into a separatory funnel and the layers separated. The aqueous layer was extracted with EtOAc (2×50 mL). The combined organic layers were washed with water and brine (50 mL each), dried with sodium sulfate, filtered and concentrated in vacuo to about 30 mL whereupon a solid began to crystallize. The mixture was allowed to stand overnight. The solid residue was concentrated on a rotary evaporator to remove the remaining EtOAc and then dried in a vacuum oven at 40° C. to provide the desired product, 2-(3,4-difluorobenzamido)acetic acid as an off-white solid (20.73 grams, 96%). LCMS (+ESI) m/z 216.2 [M+H]+. 1H-NMR (CDCl3) δ 12.70 (br s, 1H), 9.00 (t, 1H), 7.90 (m, 1H), 7.75 (m, 1H), 7.55 (m, 1H), 3.90 (s, 2H).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5](Br)[C:6]2[O:10][CH:9]=[CH:8][C:7]=2[CH:11]=1.[C:15]([O:19][C:20]([N@@:22]1[CH2:24][CH:23]1[CH3:25])=[O:21])([CH3:18])([CH3:17])[CH3:16]>>[C:15]([O:19][C:20]([NH:22][C@H:23]([CH3:25])[CH2:24][C:5]1[C:6]2[O:10][CH:9]=[CH:8][C:7]=2[CH:11]=[C:3]([C:2]([F:14])([F:13])[F:1])[CH:4]=1)=[O:21])([CH3:18])([CH3:17])[CH3:16]
Reactant: CC1CN1C(=O)OC(C)(C)C
Reactant: FC(F)(F)c1cc(Br)c2occc2c1
Product: C[C@H](Cc1cc(C(F)(F)F)cc2ccoc12)NC(=O)OC(C)(C)C
Yield: 24.9 %

Procedure:
Beginning with 0.256 gm (0.97 mMol) 5-trifluoromethyl-7-bromobenzofuran and 0.142 gm (0.90 mMol) (R)-(−)-N-tert-butoxycarbon-yl-2-methylaziridine, 0.077 gm (23%) of the desired compound were prepared essentially as described in Example 10.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[CH:4][N:3]=1.C(N(CC)C(C)C)(C)C.[F:18][C:19]([F:30])([F:29])[C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=1)[C:23](Cl)=[O:24]>ClCCl>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:23](=[O:24])[C:22]2[CH:26]=[CH:27][CH:28]=[C:20]([C:19]([F:18])([F:29])[F:30])[CH:21]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Nc1ccnc(Cl)c1
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccnc(Cl)c1)c1cccc(C(F)(F)F)c1
Temperature: 0 °C

Procedure:
Into a 100-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 2-chloropyridin-4-amine (1.0 g, 7.78 mmol, 1.00 equiv) and N,N-Diisopropylethylamine (1.0 mL) in dichloromethane (30.0 mL). This was followed by the addition of a solution of 3-(trifluoromethyl)benzoyl chloride (2.6 g, crude) in dichloromethane (5.0 mL) dropwise with stirring at 0° C. The resulting solution was stirred for 2 h at room temperature. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (0˜1:2). This resulted in 2.2 g (92%) of N-(2-chloropyridin-4-yl)-3-(trifluoromethyl)benzamide as a light-yellow syrup
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[N:11]1[C:20]2[C:15](=[CH:16][C:17]([CH2:21][C:22]([O:24][CH3:25])=[O:23])=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1.[CH3:26]I>C1COCC1>[N:11]1[C:20]2[C:15](=[CH:16][C:17]([CH:21]([CH3:26])[C:22]([O:24][CH3:25])=[O:23])=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: CI
Reactant: COC(=O)Cc1ccc2ncccc2c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)C(C)c1ccc2ncccc2c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 84.5 %

Procedure:
To a 250 ml round-bottomed flask was added lithium bis(trimethylsilyl)amide (2.0 g, 12 mmol) and tetrahydrofuran (75 ml). The mixture was cooled to −78° C. and methyl 2-(quinolin-6-yl)acetate (2.0 g, 9.9 mmol) was added as a solution in 1 ml THF. This was stirred at −78° C. for 30 min and then methyl iodide (0.75 ml, 12 mmol) was added. This was stirred for 30 min at −78° C. and then allowed to warm to rt. The mixture was quenched with sat NH4Cl (40 mL) and diluted with water (200 mL). The mixture was concentrated in vacuo to remove the THF and then was extracted with EtOAc (2×100 ml). The combined extracts were washed with brine (50 ml), dried (Na2SO4) and concentrated onto silica. Purification by silica gel chromatography (20 to 60% EtOAc/hexane) afforded the title compound as a brown oil (1.8 g, 85%). MS (ESI, pos. ion) m/z: 216 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9](=[O:16])[N:10]2[CH2:13][CH:14]=C)=[N:5][CH:4]=1.I([O-])(=O)(=O)=[O:18].[Na+]>O1CCOCC1.O.[Os](=O)(=O)(=O)=O>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9](=[O:16])[N:10]2[CH2:13][CH:14]=[O:18])=[N:5][CH:4]=1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=CCn1c(=O)ccc2ncc(OC)cc21
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: COc1cnc2ccc(=O)n(CC=O)c2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
7-(Methoxy)-1-(2-propen-1-yl)-1,5-naphthyridin-2(1H)-one (5.046 g, 23.361 mmol) was dissolved in 1,4-dioxane (100 mL) and water (100 mL). Sodium periodate (12.49 g, 58.402 mmol) was added, followed by osmium tetroxide (5 mL of 4% aqueous solution). The mixture stirred at rt for 1 h, water (200 ml) was added the mixture was stirred for a further 1 h. The reaction was concentrated to about 300 ml and extracted with 20% MeOH/DCM (3×400 ml). The organic extracts were combined, dried over anhydrous magnesium sulphate, filtered and evaporated under reduced pressure to give [7-(methoxy)-2-oxo-1,5-naphthyridin-1(2H)-yl]acetaldehyde (as the methyl hemiacetal) as a yellow solid (3.807 g, 75%).
Reaction SMILES: [C:1]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:24]=[C:23]3[C:19]([CH2:20][N:21]([C@@H:26]([CH:31]([CH3:33])[CH3:32])[C:27]([O:29][CH3:30])=[O:28])[C:22]3=[O:25])=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N[C:35]1[CH:40]=[CH:39][C:38]([C:41]2C=C3C(CN([C@@H](C(C)C)C(OC)=O)C3=O)=[CH:43][CH:42]=2)=[CH:37][CH:36]=1.C(C1C=CC(C(Cl)=O)=CC=1)CCCCCCCC>>[CH3:32][CH:31]([CH3:33])[C@H:26]([N:21]1[CH2:20][C:19]2[C:23](=[CH:24][C:16]([C:13]3[CH:12]=[CH:11][C:10]([NH:9][C:1](=[O:8])[C:2]4[CH:3]=[CH:4][C:5]([CH2:39][CH2:40][CH2:35][CH2:36][CH2:37][CH2:38][CH2:41][CH2:42][CH3:43])=[CH:6][CH:7]=4)=[CH:15][CH:14]=3)=[CH:17][CH:18]=2)[C:22]1=[O:25])[C:27]([O:29][CH3:30])=[O:28]
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4ccccc4)cc3)cc2C1=O
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(N)cc3)cc2C1=O
Agent: CCCCCCCCCc1ccc(C(=O)Cl)cc1
Product: CCCCCCCCCc1ccc(C(=O)Nc2ccc(-c3ccc4c(c3)C(=O)N([C@H](C(=O)OC)C(C)C)C4)cc2)cc1
Yield: 76 %

Procedure:
The compound of example 185 was prepared analogous to compound of example 97 by reaction of compound of example 6 with 4-(n-nonyl)benzoyl chloride.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:9]([N:12]2[CH2:16][CH:15]([C:17]([OH:19])=O)[N:14]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:13]2=[O:26])(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1.[CH3:27][C:28]1[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][C:29]=1[N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C>O1CCCC1>[CH3:27][C:28]1[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][C:29]=1[N:35]1[CH2:36][CH2:37][N:38]([C:17]([CH:15]2[CH2:16][N:12]([S:9]([C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=3)(=[O:11])=[O:10])[C:13](=[O:26])[N:14]2[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[O:19])[CH2:39][CH2:40]1
Reactant: COc1cccc(S(=O)(=O)N2CC(C(=O)O)N(c3ccccc3)C2=O)c1
Reactant: Cc1ccc(C)c(N2CCNCC2)c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1cccc(S(=O)(=O)N2CC(C(=O)N3CCN(c4cc(C)ccc4C)CC3)N(c3ccccc3)C2=O)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 111.5 %

Procedure:
To a solution of (RS)-1-(3-methoxy-benzenesulfonyl)-2-oxo-3-phenyl-imidazolidine-4-carboxylic acid (0.040 g) in tetrahydrofuran (2 ml) were added 1-(2,5-dimethylphenyl)-piperazine (0.030 g), (benzotriazol-1-yloxy)-tris-(dimethylamino)-phosphonium-hexafluorophosphate (BOP reagent, 0.071 g) and N-ethyl-diisopropylamine (0.041 g). The mixture was stirred at room temperature for 4 h. The solvent was evaporated and the product was purified by chromatography (SiO2, cyclohexane/ethyl acetate 4:1=>1:1) to give (RS)-4-[4-(2,5-dimethyl-phenyl)-piperazine-1-carbonyl]-1-(3-methoxy-benzenesulfonyl)-3-phenyl-imidazolidin-2-one (0.065 g) as a colorless solid. MS: 549.0 ([M+H]+)
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[OH:11])(=[O:4])=[O:3].C([O-])([O-])=O.[K+].[K+].Br[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21]>CC#N.O>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[O:11][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])(=[O:3])=[O:4]
Reactant: CS(=O)(=O)c1ccccc1O
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CCOC(=O)COc1ccccc1S(C)(=O)=O
Temperature: 80 °C
Yield: 94 %

Procedure:
To a solution of 2-(methylsulfonyl)phenol (100 mg, 0.58 mmol) and K2CO3 (276 mg, 2 mmol) in CH3CN (10 mL) was added ethyl 2-bromoacetate (115.2 mg, 0.69 mmol) at 25° C. The mixture was heated at 80° C. for 4 h, diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated. The crude product was used in the next step without further purification. (140 mg, yield 94%).
Reaction SMILES: [CH2:1]([NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([Br:18])=[C:13]2[N:12]=[CH:11][C:10]=1[C:19]([OH:21])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>>[CH2:1]([NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([Br:18])=[C:13]2[N:12]=[CH:11][C:10]=1[C:19]([N:32]1[CH2:33][CH2:34][N:29]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[CH3:22])[CH2:30][CH2:31]1)=[O:21])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccccc1N1CCNCC1
Reactant: O=C(O)c1cnc2c(Br)cnn2c1NCc1ccccc1
Product: Cc1ccccc1N1CCN(C(=O)c2cnc3c(Br)cnn3c2NCc2ccccc2)CC1
Yield: 84.1 %

Procedure:
In the same manner as in Example 21, step 5 and using 7-benzylamino-3-bromopyrazolo[1,5-a]pyrimidine-6-carboxylic acid (0.150 g, 0.400 mmol) obtained in Example 22, step 3 and 1-(2-methylphenyl)piperazine (0.084 g, 0.480 mmol), the title compound (0.170 g, 79%) was obtained.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][NH:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.C(=O)([O-])[O-].[Na+].[Na+].CN(C)C=O>O>[F:12][C:9]1[CH:10]=[CH:11][C:6]([NH:5][CH2:4][CH2:3][CH2:2][N:24]2[CH2:23][CH2:22][N:21]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[O:14][CH3:13])[CH2:26][CH2:25]2)=[CH:7][CH:8]=1
Reactant: Fc1ccc(NCCCCl)cc1
Reactant: COc1ccccc1N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccccc1N1CCN(CCCNc2ccc(F)cc2)CC1

Procedure:
A mixture of 1.9 g of N-(3-chloropropyl)-p-fluoroaniline, 1.9 g of 1-(o-methoxyphenyl)piperazine, 0.5 g of sodium carbonate and 50 ml of dimethylformamide was heated at 80°-90° C for 15 hours. After cooling, the reaction mixture was poured into water and extracted with benzene. The extract was washed with water, dried over sodium sulfate and evaporated under reduced pressure to give 1-{3-(p-fluoroanilino)propyl}-4-(o-methoxyphenyl)piperazine, m.p. 79°-80° C; recrystallized from cyclohexane, m.p. 84°-84.5° C.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]1([C:15]3=[CH:16][C:17]4[O:21][CH2:20][O:19][C:18]=4[CH:22]=[C:14]3[O:13][CH2:12]1)[C:5](=[O:11])[NH:6]2.BrC1C=[CH:31][CH:30]=[C:29]2[C:25]=1[C:26]1([C:42]3=[CH:43][C:44]4OCO[C:45]=4[CH:49]=[C:41]3[O:40][CH2:39]1)C(=O)N2CCCCC.C1C2C3C=CC=CC=3OC=2C(B(O)O)=CC=1.CN(C)C1N=CC(B(O)O)=CC=1>>[CH:43]1[C:42]2[C:26]3[CH:25]=[CH:29][CH:30]=[CH:31][C:39]=3[O:40][C:41]=2[C:49]([C:2]2[CH:10]=[CH:9][CH:8]=[C:7]3[C:3]=2[C:4]2([C:15]4=[CH:16][C:17]5[O:21][CH2:20][O:19][C:18]=5[CH:22]=[C:14]4[O:13][CH2:12]2)[C:5](=[O:11])[NH:6]3)=[CH:45][CH:44]=1
Reactant: CCCCCN1C(=O)C2(COc3cc4c(cc32)OCO4)c2c(Br)cccc21
Reactant: O=C1Nc2cccc(Br)c2C12COc1cc3c(cc12)OCO3
Agent: CN(C)c1ccc(B(O)O)cn1
Agent: OB(O)c1cccc2c1oc1ccccc12
Product: O=C1Nc2cccc(-c3cccc4c3oc3ccccc34)c2C12COc1cc3c(cc12)OCO3

Procedure:
Following the procedure as described in EXAMPLE 4, and making non-critical variations using 4′-bromospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one to replace 4′-bromo-1′-pentylspiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one, and dibenzo[b,d]furan-4-ylboronic acid to replace [6-(dimethylamino)pyridin-3-yl]boronic acid, the title compound was obtained (10%) as a colorless solid: mp>230° C.; 1H NMR (300 MHz, DMSO-d6) δ 10.77 (s, 1H), 8.04 (d, 1H), 7.97 (dd, 1H), 7.43-7.42 (m, 3H), 7.34-7.29 (m, 3H), 7.16 (t, 1H), 6.98 (d, 1H), 6.89 (d, 1H), 6.25 (s, 1H), 5.69 (d, 2H), 4.41 (ABq, 2H); MS (ES+) m/z 448.5 (M+1).
Reaction SMILES: [O:1]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17][NH:16][CH2:15][CH2:14][O:13][CH2:12][CH2:11][O:10][CH2:9][CH2:8][O:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH3:22][C:23]([CH3:29])([CH3:28])[CH2:24][C:25](Cl)=[O:26]>>[CH3:22][C:23]([CH3:29])([CH3:28])[CH2:24][C:25]([N:4]1[CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][N:16]([C:25](=[O:26])[CH2:24][C:23]([CH3:29])([CH3:28])[CH3:22])[CH2:17][CH2:18][O:19][CH2:20][CH2:21][O:1][CH2:2][CH2:3]1)=[O:26]
Reactant: C1COCCOCCNCCOCCOCCOCCN1
Reactant: CC(C)(C)CC(=O)Cl
Product: CC(C)(C)CC(=O)N1CCOCCOCCOCCN(C(=O)CC(C)(C)C)CCOCCOCC1

Procedure:
Analogously to Example 2 from 1,7,10,13,19-pentaoxa-4,16-diazacycloheneicosane and 3,3-dimethylbutyryl chloride.
Reaction SMILES: [OH-].[Na+].[CH2:3]([NH2:7])[CH:4]([CH3:6])[CH3:5].[Br:8][CH:9]([CH2:13][CH2:14]Cl)[C:10](Cl)=[O:11].O>C([N+](CCCC)(CCCC)CCCC)CCC.S([O-])(O)(=O)=O.ClCCl>[CH2:3]([N:7]1[CH2:14][CH2:13][CH:9]([Br:8])[C:10]1=[O:11])[CH:4]([CH3:6])[CH3:5]
Reactant: CC(C)CN
Reactant: O=C(Cl)C(Br)CCCl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CC(C)CN1CCC(Br)C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 0.1 %

Procedure:
In a 1.5-liter 4-necked flask, equipped with a stirrer, reflux condenser, thermometer and argon inlet, 54.4 g NaOH pearls (1.36 mol) and 9.26 g tetrabutylammonium-hydrogensulfate (27.3 mmol) were suspended at room temperature under argon in 500 ml dichloromethane. To this suspension 36.6 g isobutylamine (500 mol) were added. Under stirring 100.0 g 2-bromo-4-chlorobutyric acid chloride (400 mol, product of Example 1) in 100 ml dichloromethane were added in 10 min. After the first three minutes of addition reflux of the mixture was reached and maintained during the addition. Reflux of the mixture was continued for 2.0 h. After the first 10 minutes, the initially yellowish suspension turned purple, then gradually faded into gray. After completed reflux, the mixture was allowed to cool to room temperature during 15 min., a mixture of 50 g ice in 250 ml deionized water was added under stirring during 1 min., and the phases were separated. The organic phase was first washed with a solution of 60 g ammonium chloride in 300 ml deionized water, then with 300 ml deionized water, and finally evaporated to yield 84.3 g of N-isobutyl-3-bromopyrrolidine-2-one as a dark oil.