Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][C:8]([OH:10])=[O:9])[CH2:3][CH2:2]1.[C:11](OC(=O)C)(=[O:13])[CH3:12]>CO>[C:11]([N:1]1[CH2:6][CH2:5][CH:4]([CH2:7][C:8]([OH:10])=[O:9])[CH2:3][CH2:2]1)(=[O:13])[CH3:12]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(O)CC1CCNCC1
Solvent: CO
Product: CC(=O)N1CCC(CC(=O)O)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 98.7 %

Procedure:
4-Piperidinylacetic acid (5 grams) (35.0 mmoles) was reacted with acetic anhydride (10.7 grams) (105.0 mmoles) in MeOH (100 ml.) and the mixture was stirred at 25° C. for 24 hours. The mixture was evaporated to dryness and the residue was azeotroped with toluene to give the title compound (Yield: 6.4 grams, 99%, MH+ 185).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[C:8]([N:15]([CH2:17][C:18]1([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)[CH3:16])[N:7]=[C:6]2[NH2:30].[O:31]1[CH2:35][CH2:34][CH2:33][CH:32]1[C:36](O)=[O:37].C(N(CC)CC)C.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F>ClCCl>[NH2:30][C:6]1[C:5]2[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=2)[N:9]=[C:8]([N:15]([CH2:17][C:18]2([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:19][CH2:20][N:21]([C:36]([CH:32]3[CH2:33][CH2:34][CH2:35][O:31]3)=[O:37])[CH2:22][CH2:23]2)[CH3:16])[N:7]=1
Reactant: O=C(O)C1CCCO1
Reactant: COc1cc2nc(N(C)CC3(c4ccccc4)CCNCC3)nc(N)c2cc1OC
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc2nc(N(C)CC3(c4ccccc4)CCN(C(=O)C4CCCO4)CC3)nc(N)c2cc1OC
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 6,7-dimethoxy-N2-(4-phenyl-piperidin-4-ylmethyl)-N2-methyl-quinazoline-2,4-diamine 11 (210 mg), tetrahydro-2-furoic acid (70 mg) and triethylamine (180 μL) in dichloromethane was added BOP reagent (benzotriazol -1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate) (250 mg). The mixture was stirred at room temperature for 20 hours, evaporated to dryness, and distributed between ethyl acetate and water. The organic phase was washed with sodium bicarbonate, brine, and dried over sodium sulfate. The crude product was purified by flash chromatography to provide 1-(4-{[(4-Amino-6,7-dimethoxy-quinazolin-2-yl)-methyl-amino]-methyl}-4-phenyl-piperidin-1-yl)-1-(tetrahydro-furan-2-yl)-methanone 14, MS: 506 ([M+H]+), which was converted into the HCl salt: 180 mg as white crystals.
Reaction SMILES: C[O-].[Na+].[CH2:4]([O:6][CH:7]([O:10][CH2:11][CH3:12])[C:8]#[N:9])[CH3:5].[C:13](=O)=[O:14]>CO>[CH2:4]([O:6][CH:7]([O:10][CH2:11][CH3:12])[C:8](=[NH:9])[O:14][CH3:13])[CH3:5]
Reactant: O=C=O
Reactant: CCOC(C#N)OCC
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCOC(OCC)C(=N)OC
Temperature: 25 °C
Reaction time: 4 h
Yield: 92 %

Procedure:
To a solution of sodium methoxide (3.54 ml of a 25% wt. solution in methanol, 15.5 mmol) in methanol (80 ml) was added diethoxyacetonitrile (215 ml, 155 mmol) and the reaction mixture stirred for 4 hours at room temperature. Solid carbon dioxide was added and most of the methanol was removed in vacuo. Diethyl ether (30 ml) was added and the sodium carbonate removed by filtration. The residue was concentrated to afford methyl diethoxyacetimidate as a colourless oil (22 g, 92% yield) which was used with no further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[F:10])[CH:5]=O.[Cl-].[F:12][C:13]1[CH:14]=[CH:15][C:16]([O:39]COC)=[C:17]([CH:38]=1)[CH2:18][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1CCN2C(=NCCC2)CC1>C(#N)C.C(O)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl-].[Rh]>[F:1][C:2]1[CH:3]=[C:4]([CH2:5][CH2:18][C:17]2[CH:38]=[C:13]([F:12])[CH:14]=[CH:15][C:16]=2[OH:39])[CH:7]=[CH:8][C:9]=1[F:10]
Reactant: O=Cc1ccc(F)c(F)c1
Reactant: COCOc1ccc(F)cc1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Rh]
Agent: [Cl-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCO
Solvent: CC#N
Product: Oc1ccc(F)cc1CCc1ccc(F)c(F)c1
Temperature: 60 °C
Reaction time: 14 h

Procedure:
610 mg of 3,4-difluorobenzaldehyde, 2000 mg of 5-fluoro-2-methoxymethoxybenzyltriphenylphosphonium chloride and 0.64 ml of DBU were allowed to react together in 20 ml of acetonitrile, subsequently treated, and purified by silica gel column chromatography, using a 15:1 by volume mixture of hexane and ethyl acetate as the eluent, in the same manner as described in Preparation 2, to give 1230 mg of an oily substance. This oily substance was dissolved in 10 ml of ethanol, and 300 mg of tris-(triphenylphosphine)rhodium(I) chloride were added to the resulting solution. The resulting mixture was then stirred under a hydrogen atmosphere at atmospheric pressure and at 60° C. for 14 hours. At the end of this time, the reaction solution was filtered with a Celite (trade mark) filter aid. The filtrate was concentrated by evaporation under reduced pressure, and allowed to adsorb on a silica gel column for some time. The filtrate was then allowed to elute slowly, using a 4:1 by volume mixture of hexane and ethyl acetate as the eluent, to give an eluate containing the title compound. This eluate was concentrated by evaporation under reduced pressure, and dried in vacuo, to give 1010 mg (yield 93%) of the title compound as a solid substance.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][CH2:11][C:12]1[C:13](=[O:29])[NH:14][C:15]([CH2:20][O:21]CC2C=CC=CC=2)=[C:16]([CH2:18][CH3:19])[CH:17]=1.B(Br)(Br)Br.CCCCCC.C(OCC)C>C(Cl)Cl>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][CH2:11][C:12]1[C:13](=[O:29])[NH:14][C:15]([CH2:20][OH:21])=[C:16]([CH2:18][CH3:19])[CH:17]=1
Reactant: CCc1cc(CCc2nc3ccccc3o2)c(=O)[nH]c1COCc1ccccc1
Agent: BrB(Br)Br
Solvent: CCOCC
Solvent: ClCCl
Solvent: CCCCCC
Product: CCc1cc(CCc2nc3ccccc3o2)c(=O)[nH]c1CO
Reaction time: 1 h

Procedure:
A solution of 3-[2-(benzoxazol-2-yl)ethyl]-5-ethyl-6-benzyloxymethyl-2(1H)-pyridinone (198 mg, 0.51 mmol) in dry methylene chloride (6 mL) was cooled in an ice/acetone bath and 1M boron tribromide/hexane (1.5 mL, 1.5 mmol) was added dropwise to give a white precipitate. This suspension was stirred for one hour and then the reaction was quenched by addition of saturated aqueous NaHCO3 (10 mL). After stirring for 0.5 hours, the product was extracted into CH2Cl2, dried, filtered and the solvent evaporated to give a solid. Trituration with diethyl ether gave product as a tan solid. Recrystallization from ethyl acetate afforded a light yellow solid with m.p. of 155°-156° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C:10]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([CH2:13][CH2:14]OS(C)(=O)=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:26]([O:28][CH2:29][CH2:30][N:31]1[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=2[N:33]=[C:32]1[NH:40][CH:41]1[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1)[CH3:27].C(N(CC)C(C)C)(C)C>C(#N)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:13][CH2:14][N:44]2[CH2:45][CH2:46][CH:41]([NH:40][C:32]3[N:31]([CH2:30][CH2:29][O:28][CH2:26][CH3:27])[C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=4[N:33]=3)[CH2:42][CH2:43]2)([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOCCn1c(NC2CCNCC2)nc2ccccc21
Reactant: CC(C)(C)OC(=O)N1CCC(CCOS(C)(=O)=O)(c2ccccc2)C1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCOCCn1c(NC2CCN(CCC3(c4ccccc4)CCN(C(=O)OC(C)(C)C)C3)CC2)nc2ccccc21
Reaction time: 18 h

Procedure:
Combine 1-(t-butoxycarbonyl)-3-phenyl-3-(2-methanesulfonyloxyethyl)pyrrolidine (25 mmol), (1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)(piperidin-4-yl)amine (30 mmol), and N,N-diisopropylethylamine (18 mL, 101 mmol) in acetonitrile (300 mL). Heat to reflux. After 18 hours, evaporate in vacuo to give a residue. Chromatograph the residue on silica gel to give 1-(t-butoxycarbonyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl-amino)piperidin-1-yl)ethyl)-3-phenylpyrrolidine.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[CH:13]=[C:12]([CH2:16][NH:17][S:18]([C:21]2[CH:22]=[C:23]([CH3:27])[CH:24]=[CH:25][CH:26]=2)(=[O:20])=[O:19])[N:11]([CH3:28])[C:10]=1[C:29](O)=[O:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:32]([NH:35]C(C1N(C)C(CNS(C2C=CC=CC=2)(=O)=O)=CC(=O)C=1OCC1C=CC=CC=1)=O)([CH3:34])[CH3:33]>>[CH:32]([NH:35][C:29]([C:10]1[N:11]([CH3:28])[C:12]([CH2:16][NH:17][S:18]([C:21]2[CH:22]=[C:23]([CH3:27])[CH:24]=[CH:25][CH:26]=2)(=[O:20])=[O:19])=[CH:13][C:14](=[O:15])[C:9]=1[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:30])([CH3:34])[CH3:33]
Reactant: Cc1cccc(S(=O)(=O)NCc2cc(=O)c(OCc3ccccc3)c(C(=O)O)n2C)c1
Reactant: CC(C)NC(=O)c1c(OCc2ccccc2)c(=O)cc(CNS(=O)(=O)c2ccccc2)n1C
Product: Cc1cccc(S(=O)(=O)NCc2cc(=O)c(OCc3ccccc3)c(C(=O)NC(C)C)n2C)c1
Yield: 45.7 %

Procedure:
3-Benzyloxy-1-methyl-4-oxo-6-[(toluene-3-sulfonylamino)-methyl]-1,4-dihydro-pyridine-2-carboxylic acid isopropylamide (17-04) (250.0 mg, 45.70%) was synthesized as a white solid from 3-benzyloxy-1-methyl-4-oxo-6-[(toluene-3-sulfonylamino)-methyl]-1,4-dihydro-pyridine-2-carboxylic acid (13-04) (500.0 mg, 1.13 mmol) following the procedure described for 6-(benzenesulfonylamino-methyl)-3-benzyloxy-1-methyl-4-oxo-1,4-dihydro-pyridine-2-carboxylic acid isopropylamide (17-01).
Reaction SMILES: [C:1](#[N:4])[CH:2]=[CH2:3].C1(P(C(C)(C)C)C(C)(C)C)C=CC=CC=1.[F:20][C:21]([F:34])([F:33])[C:22]1[CH:23]=[C:24](Cl)[CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1.C1(C(N)C2CCCCC2)CCCCC1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.CC(N(C)C)=O>[F:20][C:21]([F:33])([F:34])[C:22]1[CH:23]=[C:24]([CH:25]=[C:26]([C:28]([F:29])([F:30])[F:31])[CH:27]=1)[CH:3]=[CH:2][C:1]#[N:4]
Reactant: FC(F)(F)c1cc(Cl)cc(C(F)(F)F)c1
Reactant: C=CC#N
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(c1ccccc1)C(C)(C)C
Solvent: CC(=O)N(C)C
Solvent: O
Product: N#CC=Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reaction time: 4 h
Yield: 69 %

Procedure:
0.382 g (7.2 mmol) of acrylonitrile, 38.7 mg (120 μmol) of NBu4Br, 6.7 mg (30 μmol) of palladium acetate and 26.7 mg (120 μmol) of phenyldi(t-butyl)phosphine are weighed into a Schlenk vessel. 1.49 g (6 mmol) of 3,5-bis(trifluoromethyl)chlorobenzene and 1.53 ml (7.2 mmol) of dicyclohexylmethylamine and also 3.5 ml of dimethylacetamide are then added. The Schlenk vessel is placed in a heating bath at 130° C. and the contents are stirred. After 4 hours, the contents are poured into 30 ml of water and the product is extracted by shaking with t-butyl methyl ether. After drying the organic phase over MgSO4, the solvent is removed under reduced pressure and the product is isolated. Orange oil, yield: 69%.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6](Br)[CH:5]=1.[F:13][C:14]([F:25])([F:24])[C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1.C(=O)(O)[O-].[K+].ClCCl>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:1][O:2][C:3]([C:4]1[CH:5]=[C:6]([C:18]2[CH:19]=[CH:20][C:15]([C:14]([F:25])([F:24])[F:13])=[CH:16][CH:17]=2)[C:7]([OH:10])=[CH:8][CH:9]=1)=[O:12]
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: COC(=O)c1ccc(O)c(Br)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])O
Solvent: C1COCCO1
Solvent: ClCCl
Product: COC(=O)c1ccc(O)c(-c2ccc(C(F)(F)F)cc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.9 %

Procedure:
To a solution of 3-bromo-4-hydroxy-benzoic acid methyl ester (4.50 g, 19.5 mmol) and 4-trifluoromethylbenzene boronic acid (4.07 g, 21.4 mmol) in dioxane (75 mL) was added 2 M potassium bicarbonate solution (29.2 mL, 58.4 mmol) and a second portion of dioxane (75 mL, 150 mL total volume added). This mixture was then degassed by bubbling dry nitrogen through the mixture for 5 minutes. After degassing, [1,1′-bis(diphenylphosphino)-ferrocene]dichloro palladium (II), complex 1:1 with dichloromethane (DPPF; 0.40 g, 0.49 mmol) was added and the reaction mixture was stirred at ambient temperature for 1 hour. The mixture was then heated to reflux for 5 hours, allowed to cool back to ambient temperature for 14 hours and then refluxed for an additional 5 hours. After cooling back to ambient temperature, the mixture was partitioned between 1 M hydrochloric acid (100 mL) and ethyl acetate. The layers were separated and the aqueous layer was adjusted to pH 3. The aqueous layer was extracted with two additional portions of ethyl acetate. The organics were combined, dried over anhydrous magnesium sulfate, filtered through Celite and concentrated under reduced pressure. The crude material was purified by flash chromatography through silica gel using diethyl ether/hexanes (0/100 gradient to 20/80) to give 6-hydroxy-4′-trifluoromethyl-biphenyl-3-carboxylic acid methyl ester (3.40 g, 76%) as a white powder. 1H NMR (400 MHz, DMSO-d6); δ 10.76 (s, 1H), 7.87 (s, 1H), 7.84 (d, 1H), 7.76 (s, 4H), 7.06 (d, 1H), 3.79 (s, 3H).
Reaction SMILES: [CH3:1][N:2]([CH3:11])[S:3]([N:6]1[CH:10]=[CH:9][CH:8]=[N:7]1)(=[O:5])=[O:4].O1CCCC1.C([Li])CCC.[CH3:22][S:23]SC>CCCCCC.O>[CH3:1][N:2]([CH3:11])[S:3]([N:6]1[C:10]([S:23][CH3:22])=[CH:9][CH:8]=[N:7]1)(=[O:4])=[O:5]
Reactant: CSSC
Reactant: CN(C)S(=O)(=O)n1cccn1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: O
Product: CSc1ccnn1S(=O)(=O)N(C)C
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To a mixture of 4.0 g of N,N-dimethyl-1H-pyrazole-1-sulfonamide and 45 ml of tetrahydrofuran was added dropwise 15.7 ml of a 1.6M n-butyl lithium solution in hexane at −78° C., and the mixture was stirred at −78° C. for 10 minutes. After 2.3 ml of dimethyl disulfide was added to the mixture, the mixture was stirred for 4 hours while the reaction temperature was gradually returned to room temperature. Water was poured into the reaction mixture, and the mixture was extracted with methyl t-butyl ether three times. The combined organic layer was washed successively with a 1N aqueous sodium hydroxide solution and an aqueous saturated sodium chloride solution, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography to obtain 4.87 g of N,N-dimethyl-5-methylthio-1H-pyrazole-1-sulfonamide of the formula:
Reaction SMILES: C(OC)(=O)C(C)=C.[C:8]([O:12][CH2:13][CH2:14]CC)(=[O:11])C=C.C(O)(=O)C=C.CC(CC([NH:29][C:30]([CH:32]=[CH2:33])=[O:31])(C)C)=O.C(NN)(=O)CCCCC(NN)=O>O.C(N(CC)CC)C.CC(O)C.CCC(C)=O>[C:30]([NH:29][C:8]([O:12][CH2:13][CH3:14])=[O:11])([CH:32]=[CH2:33])=[O:31]
Reactant: C=CC(=O)NC(C)(C)CC(C)=O
Reactant: C=CC(=O)OCCCC
Agent: C=C(C)C(=O)OC
Agent: C=CC(=O)O
Agent: NNC(=O)CCCCC(=O)NN
Solvent: CCC(C)=O
Solvent: CC(C)O
Solvent: O
Product: C=CC(=O)NC(=O)OCC
Temperature: 75 °C

Procedure:
In the dropping tank of a reaction vessel (tank) equipped with a stirrer, a thermometer, a nitrogen-sealing tube, a condenser and a dropping tank were placed 30.0 parts of PA-1, 22.0 parts of methyl methacrylate (referred to hereinafter as MMA), 10.0 parts of n-butyl acrylate (referred to hereinafter as BA), 0.5 part of acrylic acid (referred to hereinafter as AA), 2.5 parts of diacetoneacrylamide (referred to hereinafter as DAAA), 1.0 part of 2,2′-azobis-2-isobutyronitrile (referred to hereinafter as AIBN), 25 parts of MEK and 25 parts of IPA, and then well mixed. Separately, in the reaction tank were placed 30.0 parts of PA-1, 22.0 parts of MMA, 10.0 parts of BA, 0.5 part of AA, 2.5 parts of DAAA, 10 parts of MEK and 10 parts of IPA, and then uniformly mixed. Subsequently, the reaction tank was heated to 75° C. and the liquid mixture in the dropping tank was dropped into the reaction tank over 5 hours. Thereafter, the resulting mixture was further subjected to reaction at the same temperature for 4 hours. Thereafter, 2.0 parts of triethylamine (referred to hereinafter as TEA) was added to the reaction mixture to sufficiently neutralize the same, after which aqueous hydrazide consisting of 149 parts of distilled water and 2.6 parts of adipic acid dihydrazide (referred to hereinafter as ADH) was added and the reaction mixture was emulsified. Thereafter, the MEK and the IPA present in the system were removed at 60° C. at 100 Torr to obtain an aqueous emulsion of a self-emulsifiable acryl-urethane copolymer having a solid content of 40.1% (the emulsion is referred to hereinafter as EA-1).
Reaction SMILES: [F:1][C:2]([F:44])([F:43])[C:3]1[CH:4]=[C:5]([N:13]([CH3:42])[C:14]([N:16]([CH3:41])[C@H:17]2[C@H:21]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)[CH2:20][N:19]([C:29](OC3C=CC([N+]([O-])=O)=CC=3)=[O:30])[CH2:18]2)=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[F:45][C:46]1([F:52])[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]1>>[F:12][C:9]([F:10])([F:11])[C:7]1[CH:6]=[C:5]([N:13]([CH3:42])[C:14]([N:16]([C@H:17]2[C@H:21]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)[CH2:20][N:19]([C:29]([N:49]3[CH2:50][CH2:51][C:46]([F:52])([F:45])[CH2:47][CH2:48]3)=[O:30])[CH2:18]2)[CH3:41])=[O:15])[CH:4]=[C:3]([C:2]([F:1])([F:43])[F:44])[CH:8]=1
Reactant: FC1(F)CCNCC1
Reactant: CN(C(=O)N(C)[C@@H]1CN(C(=O)Oc2ccc([N+](=O)[O-])cc2)C[C@H]1c1ccc(F)cc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Product: CN(C(=O)N(C)[C@@H]1CN(C(=O)N2CCC(F)(F)CC2)C[C@H]1c1ccc(F)cc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
By reaction and purification in the same manner as in the method described in Example 420 and using the compound obtained in Example 362 and 4,4-difluoropiperidine, the title compound was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH:17]3[CH:22]=[CH:21][N:20](C(OCC)=O)[N:19]=[CH:18]3)=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[N:10]=2)[N:7]=1.C1(Cl)C(Cl)=C(Cl)C(=O)C(=O)C=1Cl.[OH-].[Na+]>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:17]3[CH:22]=[CH:21][N:20]=[N:19][CH:18]=3)=[C:9]([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:10]=2)[N:7]=1
Reactant: CCOC(=O)N1C=CC(c2c(-c3ccccc3)nc3ccc(Cl)nn23)C=N1
Agent: O=C1C(=O)C(Cl)=C(Cl)C(Cl)=C1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: Clc1ccc2nc(-c3ccccc3)c(-c3ccnnc3)n2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.2 %

Procedure:
22.3 g (58.4 mmol) of ethyl 4-[6-chloro-2-phenylimidazo[1,2-b]pyridazin-3-yl]-4H-pyridazine-1-carboxylate are dissolved in 450 ml of chloroform and 15.1 g (61.3 mmol) of ortho-chloranil are added portionwise. The reaction medium is stirred for 30 minutes at ambient temperature and then poured into a 2N aqueous solution of sodium hydroxide. The product is extracted with chloroform. The organic phase is dried over sodium sulfate and then concentrated under reduced pressure. The dark beige residue is crystallized from a mixture of 80 ml of isopropanol and 60 ml of diisopropyl ether under hot conditions, to give 12.8 g of a beige powder after cooling, isolation by filtration and drying.
Reaction SMILES: [OH:1][C:2]1[N:11]=[C:10]([OH:12])[C:9]2[C:4](=[CH:5][C:6]([O:18][CH3:19])=[C:7]([O:16][CH3:17])[C:8]=2[N+:13]([O-])=O)[N:3]=1>[Pd].C(O)(=O)C.CO.C(Cl)Cl.[OH-].[Na+]>[NH2:13][C:8]1[C:7]([O:16][CH3:17])=[C:6]([O:18][CH3:19])[CH:5]=[C:4]2[C:9]=1[C:10]([OH:12])=[N:11][C:2]([OH:1])=[N:3]2
Reactant: COc1cc2nc(O)nc(O)c2c([N+](=O)[O-])c1OC
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Solvent: ClCCl
Product: COc1cc2nc(O)nc(O)c2c(N)c1OC
Yield: 73.6 %

Procedure:
A mixture of the product of step (b) (35.0 g, 0.13 mol) and 10% palladium on carbon (4.0 g) was suspended in glacial acetic acid (200 ml) and hydrogenated at 50 psi (3.4 atm) and 5° C. for 2.5 days. The reaction was then cooled, suspended in MeOH/CH2Cl2 (1/1 v/v, 1 L) and filtered. The residue was transferred to a soxhlet apparatus and continually extracted with MeOH for 3 days. Evaporation afforded a grey solid which was dissolved in 2N NaOH, filtered through a pad of silica, washing with H2O. The filtrate was then acidified with concentrated HCl. The resulting precipitate was isolated by filtration, washing sequentially with H2O and acetone, then dried in vacuo at 60° C. to give the subtitle compound as a white solid (22.7 g, 73%). Rf 0.42 (EtOAc/MeOH 95/5, v/v). MS m/z 238 (MH+).
Reaction SMILES: [P:1](=[O:5])([OH:4])([OH:3])[OH:2].O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Zn+2:18]>O>[P:1]([O-:5])([O-:4])([O-:3])=[O:2].[Zn+2:18].[P:1]([O-:5])([O-:4])([O-:3])=[O:2].[Zn+2:18].[Zn+2:18]
Reactant: O=P(O)(O)O
Agent: O=S(=O)([O-])[O-]
Agent: [Zn+2]
Solvent: O
Product: O=P([O-])([O-])[O-]

Procedure:
7,000 g of water and 484 g of 85% phosphoric acid were mixed, and 1,150 g of zinc sulfate heptahydrate was dissolved therein to obtain an aqueous zinc phosphate solution having a phosphorus/zinc molar ratio of 1.05.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:7])[CH2:4][N+:5]#[C-:6].[C:8]1([C:14](=[CH2:17])[CH:15]=[O:16])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>>[CH3:1][O:2][C:3]([CH:4]1[CH:15]([C:14]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH2:17])[O:16][CH:6]=[N:5]1)=[O:7]
Reactant: C=C(C=O)c1ccccc1
Reactant: [C-]#[N+]CC(=O)OC
Product: C=C(c1ccccc1)C1OC=NC1C(=O)OC

Procedure:
By reaction of isocyanoacetic acid methyl ester with 2-phenylacrolein in a manner analogous to that described in Example 1, and after purification by column chromatography (silica gel; dichloromethane/methanol 97.5:2.5), 5-(1-phenyl-vinyl)-2-oxazoline-4-carboxylic acid methyl ester is obtained in the form of a pale yellow oil. 1H-NMR (CDCl3) 3.80 (s, 3H, CH3); 4.45 (dd, 1H, C(4)-H); 5.76 (d, 1H, C(5)-H).
Reaction SMILES: [BH4-].[K+].[CH3:3][O:4][C:5]1[N:14]=[C:13]2[C:8]([CH:9]=[CH:10][C:11]([N:15]3[CH:23]([CH2:24][C:25](=[O:31])[CH2:26][CH2:27][CH:28]([CH3:30])[CH3:29])[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[C:16]3=[O:32])=[N:12]2)=[CH:7][CH:6]=1.ClCCl>O.C(O)C>[OH:31][CH:25]([CH2:26][CH2:27][CH:28]([CH3:30])[CH3:29])[CH2:24][CH:23]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16](=[O:32])[N:15]1[C:11]1[CH:10]=[CH:9][C:8]2[C:13](=[N:14][C:5]([O:4][CH3:3])=[CH:6][CH:7]=2)[N:12]=1
Reactant: COc1ccc2ccc(N3C(=O)c4ccccc4C3CC(=O)CCC(C)C)nc2n1
Agent: [BH4-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Solvent: CCO
Product: COc1ccc2ccc(N3C(=O)c4ccccc4C3CC(O)CCC(C)C)nc2n1
Temperature: 20 °C
Reaction time: 16 h
Yield: 66.3 %

Procedure:
Potassium borohydride (0.41 g) dissolved in distilled water (12 cc) is added at a temperature in the region of 20° C. to a suspension of 2-(7-methoxy-1,8-naphthyridin-2-yl)-3-(5-methyl-2-oxohexyl)-1-isoindolinone (3.0 g) in ethanol (50 cc), and the suspension is stirred for 16 hours at a temperature in the region of 20° C. The reaction mixture is then poured into a mixture of distilled water (300 cc) and dichloromethane (150 cc) which has been cooled to a temperature in the region of 0° C. The aqueous phase is separated after settling has occurred, and re-extracted with dichloromethane (2×150 cc). The organic phases are combined, washed with distilled water (3×25 cc), dried over magnesium sulphate, filtered and then concentrated to dryness under reduced pressure (2.7 kPa) at 40° C. The product obtained is recrystallized twice in diisopropyl ether. 3-(2-Hydroxy-5-methylhexyl)-2-(7-methoxy-1,8-naphthyridin-2-yl)-1-isoindolinone (2.0 g), m.p. 110° C., is thereby obtained.