Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[C:2]1([CH3:21])[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:20]2[C:19]3[CH2:18][CH2:17][NH:16][CH2:15][C:14]=3[CH:13]=[N:12][C:11]=2[NH:10][N:9]=1.C(N(CC)CC)C.[C:29]1([N:35]=[C:36]=[O:37])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>O1CCCC1>[C:29]1([NH:35][C:36]([N:16]2[CH2:15][C:14]3[CH:13]=[N:12][C:11]4[NH:10][N:9]=[C:8]([C:3]5[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=5[CH3:21])[C:20]=4[C:19]=3[CH2:18][CH2:17]2)=[O:37])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: Cc1ccccc1-c1n[nH]c2ncc3c(c12)CCNC3
Reactant: O=C=Nc1ccccc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1ccccc1-c1n[nH]c2ncc3c(c12)CCN(C(=O)Nc1ccccc1)C3
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To the crude 1-o-tolyl-6,7,8,9-tetrahydro-3H-pyrazolo[3,4-c][2,7]naphthyridine hydrochloride salt obtained from step 2 was added anhydrous tetrahydrofuran (1.5 mL) and triethylamine (50 μL) followed by 400 mM solution of phenyl isocyanate (0.25 mL) in tetrahydrofuran. The reaction mixture was shaken at room temperature for 6 hours. The solvent was then removed under reduced pressure and the crude product was purified using reverse phase HPLC to give the pure desired product, N-phenyl-1-o-tolyl-8,9-dihydro-3H-pyrazolo[3,4-c][2,7]naphthyridine-7(6H)-carboxamide. LCMS [M+H]: 384.
Reaction SMILES: CS(C)=O.Cl.Cl.[NH2:7][CH:8]1[CH2:11][NH:10][CH2:9]1.[NH2:12][C:13]1[CH:14]=[C:15]([N:20]2[C:29]3[C:24](=[CH:25][C:26]([F:32])=[C:27](F)[C:28]=3[Cl:30])[C:23](=[O:33])[C:22]([C:34]([OH:36])=[O:35])=[CH:21]2)[CH:16]=[N:17][C:18]=1[Cl:19]>C(N(CC)CC)C>[NH2:7][CH:8]1[CH2:11][N:10]([C:27]2[C:28]([Cl:30])=[C:29]3[C:24]([C:23](=[O:33])[C:22]([C:34]([OH:36])=[O:35])=[CH:21][N:20]3[C:15]3[CH:16]=[N:17][C:18]([Cl:19])=[C:13]([NH2:12])[CH:14]=3)=[CH:25][C:26]=2[F:32])[CH2:9]1
Reactant: Nc1cc(-n2cc(C(=O)O)c(=O)c3cc(F)c(F)c(Cl)c32)cnc1Cl
Reactant: NC1CNC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: Nc1cc(-n2cc(C(=O)O)c(=O)c3cc(F)c(N4CC(N)C4)c(Cl)c32)cnc1Cl
Yield: 49.6 %

Procedure:
To dimethylsulfoxide solution 1 ml of 53 mg of 3-aminoazetidine dihydrochloride and 146 mg of triethylamine at 80° C. was added 80 mg of 1-(5-amino-6-chloropyridine-3-yl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid with stirring, and the mixture was stirred at 80° C. for 1 hour. The reaction solution was allowed to cool and decanted with diethylether. Ethanol was added to the residue to disperse the solid content, aisd the solid content was collected by filtration, washed with ethanol, and dried to obtain 45 mg of the title compound as a pale yellow powder.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:18]=[N:17][CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=O.[CH2:19]([O:26][NH2:27])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH2:19]([O:26][NH:27][C:12](=[O:14])[C:11]1[CH:15]=[CH:16][N:17]=[CH:18][C:10]=1[NH:9][C:3]1[CH:4]=[CH:5][C:6]([I:8])=[CH:7][C:2]=1[F:1])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(O)c1ccncc1Nc1ccc(I)cc1F
Reactant: NOCc1ccccc1
Product: O=C(NOCc1ccccc1)c1ccncc1Nc1ccc(I)cc1F

Procedure:
N-(benzyloxy)-3-[(2-fluoro-4-iodophenyl)amino]isonicotinamide was synthesized according to the procedure for General Method 1, outlined above, starting with 0.5 mmol of 3-[(2-fluoro-4-iodophenyl)amino]isonicotinic acid (intermediate 1) and 0.72 mmol of O-benzyl-hydroxylamine. LC/MS [9.50 min; 464 (M+1)]
Reaction SMILES: [CH3:1][Si:2]([CH3:28])([CH3:27])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][NH:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=1.[C:29]([OH:34])(=[O:33])[CH:30]([CH3:32])O.C1(C)C(S(O)(=O)=O)=CC=CC=1>C1(C)C=CC=CC=1>[CH3:28][Si:2]([CH3:1])([CH3:27])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][NH:17][C:18]1[CH:19]=[CH:20][C:21]([C:22]([O:24][CH:30]([C:29]([OH:34])=[O:33])[CH3:32])=[O:23])=[CH:25][CH:26]=1
Reactant: CC(O)C(=O)O
Reactant: C[Si](C)(C)CCCCCCCCCCCCCCNc1ccc(C(=O)O)cc1
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: Cc1ccccc1
Product: CC(OC(=O)c1ccc(NCCCCCCCCCCCCCC[Si](C)(C)C)cc1)C(=O)O

Procedure:
A flask containing 10.0 g. 4-[14-(trimethylsilyl)tetradecylamino]benzoic acid, 3.4 g. lactic acid, 500 mg. toluenesulfonic acid and 500 ml. toluene is equipped with a Soxhlet extractor charged with activated 4A Linde molecular sieves. The solution is refluxed for 24 hours, during which time the Soxhlet extractor is charged twice more with fresh sieves. The hot solution is filtered and allowed to cool, whereupon the product separates as off-white crystals.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[C@H:10]([O:12][C:13]1[C:14]([NH2:28])=[N:15][CH:16]=[C:17](B2OC(C)(C)C(C)(C)O2)[CH:18]=1)[CH3:11].[C:29]([O:33][C:34]([N:36]1[CH2:41][CH2:40][CH:39]([N:42]2[CH:46]=[C:45](Br)[CH:44]=[N:43]2)[CH2:38][CH2:37]1)=[O:35])([CH3:32])([CH3:31])[CH3:30].C([O-])([O-])=O.[Na+].[Na+]>COCCOC.O>[C:29]([O:33][C:34]([N:36]1[CH2:37][CH2:38][CH:39]([N:42]2[CH:46]=[C:45]([C:17]3[CH:16]=[N:15][C:14]([NH2:28])=[C:13]([O:12][C@@H:10]([C:3]4[C:4]([Cl:9])=[CH:5][CH:6]=[C:7]([F:8])[C:2]=4[Cl:1])[CH3:11])[CH:18]=3)[CH:44]=[N:43]2)[CH2:40][CH2:41]1)=[O:35])([CH3:32])([CH3:30])[CH3:31]
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(Br)cn2)CC1
Reactant: C[C@@H](Oc1cc(B2OC(C)(C)C(C)(C)O2)cnc1N)c1c(Cl)ccc(F)c1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: C[C@@H](Oc1cc(-c2cnn(C3CCN(C(=O)OC(C)(C)C)CC3)c2)cnc1N)c1c(Cl)ccc(F)c1Cl
Temperature: 87 °C
Reaction time: 16 h
Yield: 62.1 %

Procedure:
To a stirred solution of 3-[(R)-1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-2-ylamine (4.2711 g, 10.0 mmol) and 4-(4-bromo-pyrazol-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (3.9628 g, 12.0 mmol) in DME (40 mL) was added a solution of Na2CO3 (3.1787 g, 30.0 mmol) in water (10 mL). The solution was degassed and charged with nitrogen three times. To the solution was added Pd(PPh3J2CI2 (351 mg, 0.50 mmol). The reaction solution was degassed and charged with nitrogen again three times. The reaction solution was stirred at 87° C. oil bath for about 16 hours (or until consumption of the borane pinacol ester), cooled to ambient temperature and diluted with EtOAc (200 mL). The reaction mixture was filtered through a pad of celite and washed with EtOAc. The EtOAc solution was washed with brine, dried over Na2SO4, and concentrated. The crude product was purified on a silica gel column eluting with EtOAc/hexane system (0% EtOAc to 100% EtOAc) to afford 4-(4-{6-amino-5-[(R)-1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-pyrazol-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (3.4167 g, 65% yield, −95% purity) with a Rf of 0.15 (50% EtOAc/Hexanes). MS m/e 550 (M+1)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][CH2:17][C:18]([O:20]CC)=O)=[O:15])[CH2:10][CH2:9]2)=[N:6][CH:7]=1.[CH3:23][NH2:24].C(OC(C)C)(C)C>O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:9][CH2:10][N:11]([C:14]([O:16][CH2:17][C:18]([NH:24][CH3:23])=[O:20])=[O:15])[CH2:12][CH2:13]2)=[N:6][CH:7]=1
Reactant: CN
Reactant: CCOC(=O)COC(=O)N1CCN(c2ccc(Br)cn2)CC1
Solvent: C1CCOC1
Solvent: CC(C)OC(C)C
Product: CNC(=O)COC(=O)N1CCN(c2ccc(Br)cn2)CC1

Procedure:
The process is performed as described in Example 1 (step 1.4.). Starting with 2.20 g (5.91 mmol) of 2-(ethyloxy)-2-oxoethyl 4-(5-bromo-2-pyridyl)-1-piperazinecarboxylate, obtained in step 3.3. of Example 3, and 14.80 ml (29.55 mmol) of a solution of methylamine (2M) in tetrahydrofuran, and after crystallization from diisopropyl ether, 1.974 g of pure product are obtained in the form of a white solid.
Reaction SMILES: Br[C:2]1[S:10][C:9]2[C:8](=[O:11])[N:7]([C:12]3[CH:17]=[CH:16][C:15]([N:18]4[CH2:22][CH2:21][C@@H:20]([N:23]([CH3:25])[CH3:24])[CH2:19]4)=[CH:14][CH:13]=3)[CH:6]=[N:5][C:4]=2[CH:3]=1.[NH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1.O>C(OCC)(=O)C>[CH3:24][N:23]([CH3:25])[C@@H:20]1[CH2:21][CH2:22][N:18]([C:15]2[CH:16]=[CH:17][C:12]([N:7]3[C:8](=[O:11])[C:9]4[S:10][C:2]([N:26]5[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]5)=[CH:3][C:4]=4[N:5]=[CH:6]3)=[CH:13][CH:14]=2)[CH2:19]1
Reactant: CN(C)[C@@H]1CCN(c2ccc(-n3cnc4cc(Br)sc4c3=O)cc2)C1
Reactant: C1CCNCC1
Solvent: O
Solvent: CCOC(C)=O
Product: CN(C)[C@@H]1CCN(c2ccc(-n3cnc4cc(N5CCCCC5)sc4c3=O)cc2)C1
Temperature: 100 °C

Procedure:
A mixture of 6-bromo-3-[4-((R)-3-dimethylaminopyrrolidin-1-yl)phenyl]-3H-thieno[3,2-d]pyrimidin-4-one (40 mg) and piperidine (492 mg) was heated at 100° C. for 2 days. Water and ethyl acetate were then added, and the organic phase was washed twice with water. The ethyl acetate phase was dried over sodium sulfate and the solvent was removed in vacuo. The residue was purified by preparative HPLC. The product with the molecular weight of 423.58 (C23H29N50S) was obtained in this way; MS (ESI): 424 (M+H+).
Reaction SMILES: [CH3:1][CH2:2][CH:3]([NH:6][CH2:7][C:8]1[CH:9]=[C:10]([CH:30]=[CH:31][CH:32]=1)[C:11]([NH:13][C:14]1[S:15][C:16]2[CH2:29][CH2:28][CH2:27][CH2:26][C:17]=2[C:18]=1[C:19]([O:21]C(C)(C)C)=[O:20])=O)[CH2:4][CH3:5].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:5][CH2:4][CH:3]([NH:6][CH2:7][C:8]1[CH:9]=[C:10]([C:11]2[O:21][C:19](=[O:20])[C:18]3[C:17]4[CH2:26][CH2:27][CH2:28][CH2:29][C:16]=4[S:15][C:14]=3[N:13]=2)[CH:30]=[CH:31][CH:32]=1)[CH2:2][CH3:1]
Reactant: CCC(CC)NCc1cccc(C(=O)Nc2sc3c(c2C(=O)OC(C)(C)C)CCCC3)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCC(CC)NCc1cccc(-c2nc3sc4c(c3c(=O)o2)CCCC4)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 93.6 %

Procedure:
To a mixture of 8.99 g of tert-butyl 2-({3-[(pentan-3-ylamino)methyl]benzoyl}amino)-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxylate and 100 mL of methylene chloride was added 30 mL of TFA, followed by stirring for 15 hours at room temperature. The reaction mixture was concentrated under reduced pressure, and azeotropy was performed using toluene. 4.3 mL of thionyl chloride and 50 mL of toluene were added to the residue, and 0.10 mL of DMF was added dropwise thereto, followed by stirring for 1 hour at 60° C. The reaction mixture was concentrated under reduced pressure, a saturated aqueous sodium hydrogen carbonate solution was added thereto, followed by extraction with ethyl acetate. The organic layer was washed with saturated brined and dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:2), thereby obtaining 7.05 g of 2-{3-[(pentan-3-ylamino)methyl]phenyl}-5,6,7,8-tetrahydro-4H-[1]benzothieno[2,3-d][1,3]oxazin-4-one.
Reaction SMILES: CO.Cl.[CH3:4][O:5][NH2:6].[CH3:7][CH:8]1[O:12][CH:11](O)[CH:10]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:9]1>C(N(CC)CC)C>[CH3:4][O:5][N:6]=[CH:11][CH:10]([O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:9][CH:8]([OH:12])[CH3:7]
Reactant: CON
Reactant: CC1CC(Oc2ccccc2)C(O)O1
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: CON=CC(CC(C)O)Oc1ccccc1
Temperature: 25 °C
Reaction time: 5.5 h
Yield: 88.2 %

Procedure:
20 mL of methanol and 1.8 g of O-methylhydroxylamine hydrochloride were added to 3.6 g of 5-methyl-3-phenoxyoxolan-2-ol that was a colorless oily product, and thereafter, 2.79 mL of triethylamine was added dropwise to the mixture. The thus obtained mixture was stirred at room temperature for 5.5 hours. Thereafter, methanol was distilled away under reduced pressure, 100 mL of ethyl acetate and 100 mL of water were then added to the residue, and the water layer was then removed. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was then distilled away under reduced pressure, so as to obtain 3.65 g of 5-(methoxyimino)-4-phenoxypentan-2-ol in the form of a colorless oily product.
Reaction SMILES: [N+:1]([C:4]1[CH:16]=[CH:15][C:7]([CH:8]=[CH:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:6](OCC)[CH:5]=1)([O-])=O.[C:20](OCC)(=[O:22])[CH3:21]>[Pd]>[CH2:20]([O:22][CH:9]([CH2:8][C:7]1[CH:6]=[CH:5][C:4]([NH2:1])=[CH:16][CH:15]=1)[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH3:21]
Reactant: CCOC(C)=O
Reactant: CCOC(=O)C=Cc1ccc([N+](=O)[O-])cc1OCC
Agent: [Pd]
Product: CCOC(=O)C(Cc1ccc(N)cc1)OCC
Yield: 60 %

Procedure:
Ethyl 4-nitro-2-ethoxycinnamate obtained in step (i) was hydrogenated using Pd (10%)/C—H2 (60 psi) (11 g) in ethyl acetate (150 ml) at RT and chromatographed using ethyl acetate/hexane to yield the title compound as viscous oil (9.41 g, yield 60%).
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[Cl:9][C:10]1[C:15]([F:16])=[CH:14][CH:13]=[CH:12][N:11]=1.[I:17]I>O1CCCC1>[Cl:9][C:10]1[C:15]([F:16])=[C:14]([I:17])[CH:13]=[CH:12][N:11]=1
Reactant: II
Reactant: Fc1cccnc1Cl
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Fc1c(I)ccnc1Cl
Temperature: -78 °C
Reaction time: 2 h
Yield: 105.3 %

Procedure:
In an oven-dried flask, to a solution of 2.0 M of lithium diisopropylamide in tetrahydrofuran (6.0 mL) in tetrahydrofuran (30 mL, 400 mmol) at −78° C. was added 2-chloro-3-fluoropyridine (1.000 mL, 10.06 mmol). The resulting mixture was stirred at −78° C. for 2 hours. Iodine (3.899 g, 15.36 mmol) was then added as a solution in 5 mL tetrahydrofuran and the reaction was maintained −78° C. for an additional 2.5 hours. The reaction was then quenched with saturated aqueous NH4Cl and warmed to room temp. The reaction mixture was poured into ethyl acetate and washed sequentially with 10% aqueous Na2S2O3 and brine, dried over MgSO4, filtered, and evaporated in vacuo to yield 2.7279 g (100%) of 2-chloro-3-fluoro-4-iodopyridine. LCMS (ESI): M+H=258.0; 1H NMR (500 MHz, CDCl3) δ 7.87 (d, J=4.9 Hz, 1H), 7.71-7.59 (m, 1H).
Reaction SMILES: C[O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][N:9]=[CH:10]2)=[CH:5][CH:4]=1.Cl.N1C=CC=CC=1>C(OCC)(=O)C>[OH:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][N:9]=[CH:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2ccncc2c1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: Oc1ccc2ccncc2c1
Reaction time: 6 h
Yield: 65.6 %

Procedure:
A mixture of 7.4 g of 7-methoxyisoquinoline and 30 g of pyridine hydrochloride was heated with stirring at 180° for 6 hours. The reaction mixture was allowed to cool, dissolved in ethyl acetate, and washed with a saturated aqueous sodium chloride solution. The solution was dried with anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure to give 4.43 g of 7-hydroxyisoquinoline. The compound thus obtained was dissolved in 100 ml of methylene chloride, 5.5 ml of pyridine was added and then 6.6 ml of trifluoromethanesulfonic anhydride was dropwise added. The mixture was stirred for an hour with ice cooling. After reaction, a saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture and extracted with chloroform. The chloroform layer was dried with anhydrous magnesium sulfate and the solution was concentrated under reduced pressure. The crude product thus obtained was purified by silica gel column chromatography using a mixture, ethyl acetate:n-hexane=1:3, as a developer to give 9.18 g of trifluoromethanesulfonic acid-7-isoquinolinyl.
Reaction SMILES: [Br:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][CH2:7][C:8]2[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=2[CH2:10]O)=[CH:4][CH:3]=1.[BrH:18]>>[Br:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][CH2:7][C:8]2[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=2[CH2:10][Br:18])=[CH:4][CH:3]=1
Reactant: Br
Reactant: OCc1ccccc1CCc1ccc(Br)cc1
Product: BrCc1ccccc1CCc1ccc(Br)cc1

Procedure:
A suspension of 28.5 g. (0.098 mole) of 2-(4-bromophenethyl)-benzyl alcohol in 150 ml. of 48% hydrobromic acid is stirred at reflux for 3 hours. The cooled two-phase mixture is extracted with benzene. Evaporation of the washed and dried benzene extract under reduced pressure leaves the product as the residual solid, m.p. 63°-75° C. Recrystallization from hexane affords purified material, m.p. 76°-77.5° C. A sample for analysis melts at 76.5°-78° C. after further recrystallization from hexane.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]([CH2:11][C:12]([OH:14])=O)[N:3]1[C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][N:16]=1.C(N(CC)CC)C.C(OC(Cl)=O)C.[NH:35]1[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1>O1CCCC1>[N:35]1([C:12]([CH2:11][CH:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[C:2](=[O:1])[N:3]2[C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][N:16]=2)=[O:14])[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1
Reactant: C1CCNCC1
Reactant: O=C(O)CC1c2ccccc2C(=O)N1c1ccc(Cl)cn1
Agent: CCOC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(CC1c2ccccc2C(=O)N1c1ccc(Cl)cn1)N1CCCCC1
Temperature: 0 °C
Yield: 26.2 %

Procedure:
3-Oxo-2-(5-chloro-2-pyridyl)isoindoline-1-acetic acid (1 g) and triethylamine (0.8 g) were dissolved in 20 ml of dry tetrahydrofuran and, under ice-cooling with stirring, 0.39 g of ethoxycarbonyl chloride was added portionwise. The mixture was stirred for 3 minutes, 0.56 g of piperidine was added, and the whole mixture was stirred for an additional 30 minutes. The reaction mixture was poured into 500 ml of ice water, followed by extraction with ethyl acetate. The extract was washed with water and dried. The ethyl acetate was then distilled off and the residue was treated with ether. The resulting crystals thus obtained were collected by filtration and recrystallized from ethyl acetate to give 0.32 g of colorless crystals, melted at 165°-166° C.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[O:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[CH:25]=O>>[O:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[CH2:25][N:4]1[CH2:3][CH2:2][N:1]([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:17])([F:18])[F:19])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5]1
Reactant: O=Cc1ccco1
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Product: FC(F)(F)c1nnc2ccc(N3CCN(Cc4ccco4)CC3)nn12

Procedure:
Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with furan-2-carbaldehyde was carried out according to General Synthetic Method 5. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column (5μ silica, 19 mm diameter, 100 mm length) eluted with decreasingly polar mixtures of water (containing 1% aqueous ammonia) and acetonitrile as eluents to give 6-[4-(furan-2-ylmethyl)piperazin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](F)=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[NH2:12][C:13]1[CH:14]=[C:15]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH:16]=[CH:17][CH:18]=1>CN1CCCC1=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:12][C:13]2[CH:14]=[C:15]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:24])([CH3:23])[CH3:25])[CH:16]=[CH:17][CH:18]=2)=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1
Reactant: CC(C)(C)OC(=O)Nc1cccc(N)c1
Reactant: O=[N+]([O-])c1cc(Br)ccc1F
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)Nc1cccc(Nc2ccc(Br)cc2[N+](=O)[O-])c1
Temperature: 25 °C
Yield: 91 %

Procedure:
A mixture of 4-bromo-1-fluoro-2-nitrobenzene (6.0 g, 27 mmol, Aldrich, Cat. No. 539112) and tert-butyl (3-aminophenyl)carbamate (6.7 g, 32 mmol, Aldrich, Cat. No. 53175) in N-methylpyrrolidinone (30 mL) was heated at 150° C. overnight. The solution was cooled to room temperature (r.t.) and quenched with NaHCO3 aqueous solution, then extracted with ethyl acetate twice. The combined organic phases were washed with brine, and dried over MgSO4. After filtration, the filtrate was concentrated under reduced pressure to afford the desired compound (10.1 g, 91%). LCMS (M+H)+: m/z=408.0.
Reaction SMILES: [CH2:1]1[C:5]2([CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)[CH2:4][CH2:3][N:2]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].Br[C:19]1[CH:24]=[CH:23][N:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2]>[F:26][C:25]([F:28])([F:27])[C:21]1[CH:20]=[C:19]([N:8]2[CH2:7][CH2:6][C:5]3([CH2:1][N:2]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:3][CH2:4]3)[CH2:10][CH2:9]2)[CH:24]=[CH:23][N:22]=1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCNCC2)C1
Reactant: FC(F)(F)c1cc(Br)ccn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC2(CCN(c3ccnc(C(F)(F)F)c3)CC2)C1
Temperature: 120 °C
Yield: 62 %

Procedure:
Sodium t-Butylate (6.24 mmol, 3.0 eq.) was added to a stirred solution of tert-butyl 2,8-diazaspiro[4.5]decane-2-carboxylate (2.08 mmol, 1.0 eq.) and 4-bromo-2-(trifluoromethyl)pyridine (2.08 mmol, 1.0 eq.) in toluene (15 ml) and the reaction mixture was then degassed with N2. BINAP (0.12 mmol, 0.06 eq.) and Pd(OAc)2 (0.04 mmol, 0.02 eq.) were added and the reaction mixture obtained was heated at 120° C. for 12 h. The reaction mixture was filtered over Celite and the filtrate was concentrated in vacuo in order to obtain the crude product, which was purified by column chromatography (silica gel, 2% methanol in methylene chloride), in order to obtain the desired product. Yield: 62%
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[O:26]=[C:27]1[CH2:31][CH2:30][CH2:29][N:28]1[CH2:32][C:33](Cl)=[O:34].C(N(CC)CC)C>ClCCl>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][N:20]([C:33](=[O:34])[CH2:32][N:28]4[CH2:29][CH2:30][CH2:31][C:27]4=[O:26])[CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: O=C(Cl)CN1CCCC1=O
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)cc1OC
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(C2=NN(C3CCN(C(=O)CN4CCCC4=O)CC3)C(=O)C2(C)C)cc1OC
Reaction time: 0.5 h

Procedure:
A mixture of 0.5 g of 5-(3,4-di methoxyphenyl)-4,4-dimethyl-2-piperidin-4-yl-2,4-dihydro-3H-pyrazol-3-one hydrochloride (compound B1), 0.24 g of (2-oxo-pyrrolidin-1-yl)acetyl chloride and 0.5 ml of triethyl amine in 50 ml of dichloromethane is stirred for 30 min and washed subsequently with aqueous sodium carbonate. After drying over magnesium sulphate the solvent is evaporated and the residue purified by column chromatography [silica, ethyl acetate/methanol:6:1 (Vol/Vol)]. Crystallized from diethyl ether.
Reaction SMILES: [H-].[Na+].[C:3]([O:14]C)(=O)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([CH3:12])([CH3:11])[CH3:10].[C:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)(=[O:18])[CH3:17]>C1COCC1>[C:19]1([C:16](=[O:18])[CH2:17][C:3]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([CH3:10])([CH3:11])[CH3:12])=[O:14])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC(=O)c1ccccc1
Reactant: COC(=O)CCCCCC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)CCCCCC(=O)CC(=O)c1ccccc1
Temperature: 25 °C
Yield: 25.8 %

Procedure:
A round bottom flask equipped with mechanical stirring, a nitrogen inlet, a thermometer, and an addition funnel was charged with 60% sodium hydride in mineral oil (50 g, 1.24 mol), THF (500 mL), and methyl neodecanoate (229 g, 1.23 mol), and the mixture was stirred at room temperature. Acetophenone (74 g, 0.62 mol) was added over 45 min. The temperature was slowly raised to 60° C. and maintained at that temperature for 24 hr. A sample was withdrawn, and analysis indicated the reaction was perhaps 1/4 complete. The reaction mixture was stirred at 60° C. for a total of eight days, continuously and slowly evolving hydrogen gas. Methanol was added to quench excess sodium hydride, followed by dilute sulfuric acid. The separated organic phase was washed with water, and volatiles were removed under vacuum. The residue was diluted with heptane and washed with 10% potassium hydroxide, then with water, and the volatiles removed under vacuum to leave 267 g. This was distilled, giving a heart cut at about 130° C. at a pressure of 0.1 mm Hg. Thin layer chromatography indicated the presence of some acetophenone plus two major components of similar size. The heart cut was purified by flash chromatography. Heptane elution provided 48 g of the less polar component, which was distilled at 165° C. at 1 mm Hg to give 44 g (0.16 mol, 26% yield) of 1-phenyl-3-neononyl-1,3-propanedione. Toluene elution provided 21 g of the more polar component, which was shown to be dypnone.