Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: OO.[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:5]=1[N:11]1[CH2:15][CH2:14][C:13](=[O:16])[NH:12]1.[Se](=O)=O.O>C(O)(=O)C>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:5]=1[N:11]1[CH:15]=[CH:14][C:13](=[O:16])[NH:12]1
Reactant: O=C1CCN(c2cc(Cl)ccc2Cl)N1
Agent: O=[Se]=O
Agent: OO
Solvent: O
Solvent: CC(=O)O
Product: O=c1ccn(-c2cc(Cl)ccc2Cl)[nH]1

Procedure:
Hydrogen peroxide (30% solution in water, 120 ml) is slowly added to a well stirred suspension of 1-(2,5-dichlorophenyl)-3-pyrazolidone (200 g, 0.86 mol) and selenium dioxide (3.0 g) in acetic acid (1000 ml). The temperature is controlled by cooling, not to exceed +50° C. After stirring at this temperature for 1 hour crushed ice and water is added. The product is filtered and dried yielding 1-(2,5-dichlorophenyl)-3-pyrazolone, m.p. 201°-202° C.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][N:5]1[C:9](=[O:10])[C:8]2=[CH:11][CH:12]=[CH:13][CH:14]=[C:7]2[C:6]1=[O:15].[CH3:16][N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1>C1(C)C(C)=CC=CC=1>[CH3:16][N:17]1[CH2:22][CH2:21][N:20]([CH2:2][CH2:3][CH2:4][N:5]2[C:9](=[O:10])[C:8]3=[CH:11][CH:12]=[CH:13][CH:14]=[C:7]3[C:6]2=[O:15])[CH2:19][CH2:18]1
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Reactant: CN1CCNCC1
Solvent: Cc1ccccc1C
Product: CN1CCN(CCCN2C(=O)c3ccccc3C2=O)CC1
Yield: 72 %

Procedure:
A solution of N-(3-bromopropyl)phthalimide (8.04 g, 30 mM) in xylene (60 mL) was added dropwise to a solution of 1-methylpiperazine (6.61 g, 66 mM) in xylene (90 mL) at 70° C. After the addition was complete, the mixture was heated under reflux for 20 hours. A precipitate was removed by filtration and the filtrate was concentrated. The crude product was purified by silica gel chromatography with 9:1 CH2Cl2:MeOH to give the product N-(3-(4-methylpiperazin-1-yl)propyl)phthalimide as an oil in 72% yield.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:24]=[C:23]([O:25][CH2:26][CH2:27][F:28])[CH:22]=[CH:21][C:16]=2[C:17]([O:19]C)=[O:18])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O[Li].O.O>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:24]=[C:23]([O:25][CH2:26][CH2:27][F:28])[CH:22]=[CH:21][C:16]=2[C:17]([OH:19])=[O:18])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)c1ccc(OCCF)cc1OC1CCN(C(=O)OC(C)(C)C)CC1
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2cc(OCCF)ccc2C(=O)O)CC1
Yield: 39.3 %

Procedure:
Using a procedure similar to that of Example 6-E, methyl 2-(1-tert-butoxycarbonylpiperidin-4-yloxy)-4-(2-fluoroethoxy)benzoate (7.28 g) is hydrolyzed using LiOH.H2O (1.78 g, 2.2 equivalents), water (20 mL) and THF (60 mL) at 60-65° C. to afford the acid (2.76 g, 40%).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][Cl:6].C(=O)([O-])[O-].[Cs+].[Cs+].[OH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1/[CH:20]=[CH:21]/[CH:22]([CH2:35][C:36]1[CH:41]=[CH:40][C:39]([C:42]([O:44][CH3:45])=[O:43])=[CH:38][CH:37]=1)[CH2:23][CH2:24][C:25]1[CH:34]=[CH:33][C:28]([C:29]([O:31][CH3:32])=[O:30])=[CH:27][CH:26]=1>C1(C)C=CC=CC=1>[Cl:6][CH2:5][CH2:4][CH2:3][CH2:2][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1/[CH:20]=[CH:21]/[CH:22]([CH2:35][C:36]1[CH:37]=[CH:38][C:39]([C:42]([O:44][CH3:45])=[O:43])=[CH:40][CH:41]=1)[CH2:23][CH2:24][C:25]1[CH:34]=[CH:33][C:28]([C:29]([O:31][CH3:32])=[O:30])=[CH:27][CH:26]=1
Reactant: ClCCCCBr
Reactant: COC(=O)c1ccc(CCC(/C=C/c2ccccc2O)Cc2ccc(C(=O)OC)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(CCC(/C=C/c2ccccc2OCCCCCl)Cc2ccc(C(=O)OC)cc2)cc1
Temperature: 60 °C
Reaction time: 18 h

Procedure:
1.54 g (9.0 mmol) of 1-bromo-4-chlorobutane [CAS Reg. No. 6940-78-9] and 7.33 g (22.5 mmol) of anhydrous cesium carbonate are added to a solution of 1.0 g (2.25 mmol) of methyl 4-{(4E)-5-(2-hydroxyphenyl)-3-[4-(methoxycarbonyl)benzyl]pent-4-en-1-yl}benzoate (racemate; Example 18A) in 15 ml of dry toluene, and the mixture is then stirred at 60° C. for 18 h. The mixture is then filtered, and the filtrate is evaporated to dryness. The crude product obtained is taken up in ethyl acetate and washed twice with saturated sodium bicarbonate solution, and the organic phase dried over sodium sulfate and concentrated. The crude product is then purified by flash chromatography on silica gel (mobile phase: dichloromethane). This gives 0.850 g (1.59 mmol, 70.6% of theory) of a colorless oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[CH2:7][CH2:6][CH:5]([C:8]2[S:9][C:10]3[N:11]=[C:12]([CH3:19])[N:13]=[C:14]([CH2:17][OH:18])[C:15]=3[N:16]=2)[CH2:4][CH2:3]1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[O-]S([O-])(=S)=O.[Na+].[Na+]>C(Cl)Cl>[CH3:1][C:2]1([CH3:20])[CH2:3][CH2:4][CH:5]([C:8]2[S:9][C:10]3[N:11]=[C:12]([CH3:19])[N:13]=[C:14]([CH:17]=[O:18])[C:15]=3[N:16]=2)[CH2:6][CH2:7]1
Reactant: Cc1nc(CO)c2nc(C3CCC(C)(C)CC3)sc2n1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: Cc1nc(C=O)c2nc(C3CCC(C)(C)CC3)sc2n1
Temperature: 0 °C
Reaction time: 3 h
Yield: 99.1 %

Procedure:
To a mixture of [2-(4,4-dimethylcyclohexyl)-5-methyl[1,3]thiazolo[5,4-d]pyrimidin-7-yl]methanol (500 mg) and DCM (10 mL) was added Dess-Martin periodinane (1.46 g) under ice-cooling, followed by stirring at 0° C. for 3 hours. To the reaction mixture was added an aqueous Na2S2O3 solution, followed by extraction with DCM. The organic layer was washed sequentially with saturated aqueous sodium bicarbonate and brine, dried over Na2SO4, and then concentrated under reduced pressure to obtain 2-(4,4-dimethylcyclohexyl)-5-methyl[1,3]thiazolo[5,4-d]pyrimidine-7-carbaldehyde (492 mg). To a mixture of the obtained aldehyde, NaH2PO4 (245 mg), 2-methyl-2-butene (542 μL), water (5 mL), and acetone (10 mL) was added NaClO2 (231 mg) under ice-cooling, followed by stirring at room temperature for 1 hour. To the reaction mixture were added an aqueous Na2S2O3 solution and Na2SO4, followed by extraction with a mixed solution (1:9) of 2-propanol and chloroform. The organic layer was dried over Na2SO4 and then concentrated under reduced pressure to obtain 2-(4,4-dimethylcyclohexyl)-5-methyl[1,3]thiazolo[5,4-d]pyrimidine-7-carboxylic acid (870 mg).
Reaction SMILES: [C:1]1([C:7]2[NH:8][CH:9]=[CH:10][N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:13][C:14]#[N:15]>>[C:1]1([C:7]2[N:11]([CH2:13][C:14]#[N:15])[CH:10]=[CH:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: N#CCBr
Reactant: c1ccc(-c2ncc[nH]2)cc1
Product: N#CCn1ccnc1-c1ccccc1

Procedure:
The title compound is synthesized by coupling of 2-Phenyl-1H-imidazole and bromoacetonitrile analogously to the preparation of Intermediate 269.4 as a colorless oil; ES-MS: M+H=184.1: CtRef=3.48.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([C:18](O)=[O:19])=[C:13]2[N:12]=[CH:11][C:10]=1[C:21]([N:23]1[CH2:28][CH2:27][C:26]2([C:32]3[CH:33]=[CH:34][C:35]([F:37])=[CH:36][C:31]=3[O:30][CH2:29]2)[CH2:25][CH2:24]1)=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:38][S:39]([NH2:42])(=[O:41])=[O:40]>>[CH2:1]([NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([C:18]([NH:42][S:39]([CH3:38])(=[O:41])=[O:40])=[O:19])=[C:13]2[N:12]=[CH:11][C:10]=1[C:21]([N:23]1[CH2:28][CH2:27][C:26]2([C:32]3[CH:33]=[CH:34][C:35]([F:37])=[CH:36][C:31]=3[O:30][CH2:29]2)[CH2:25][CH2:24]1)=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1cnn2c(NCc3ccccc3)c(C(=O)N3CCC4(CC3)COc3cc(F)ccc34)cnc12
Reactant: CS(N)(=O)=O
Product: CS(=O)(=O)NC(=O)c1cnn2c(NCc3ccccc3)c(C(=O)N3CCC4(CC3)COc3cc(F)ccc34)cnc12
Yield: 47.6 %

Procedure:
In the same manner as in Example 1, step 6 and using 7-benzylamino-6-(6-fluoro-2H-spiro[benzofuran-3,4′-piperidine]-1′-ylcarbonyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (0.075 g, 0.149 mmol) obtained in step 2 and methanesulfonamide (0.070 g, 0.745 mmol), the title compound (0.041 g, 47%) was obtained.
Reaction SMILES: [C:1]([C:4]1[CH:31]=[CH:30][C:7]([CH2:8][N:9]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[CH2:13][N:12]([C:20](=[O:28])[C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=3)[CH2:11][C:10]2=[O:29])=[CH:6][CH:5]=1)([OH:3])=O.[NH:32]1[CH2:36][CH:35]=[CH:34][CH2:33]1.C(N(CC)CC)C>ClCCl>[N:32]1([C:1]([C:4]2[CH:5]=[CH:6][C:7]([CH2:8][N:9]3[C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=4[CH2:13][N:12]([C:20](=[O:28])[C:21]4[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=4)[CH2:11][C:10]3=[O:29])=[CH:30][CH:31]=2)=[O:3])[CH2:36][CH:35]=[CH:34][CH2:33]1
Reactant: C1=CCNC1
Reactant: O=C(O)c1ccc(CN2C(=O)CN(C(=O)c3ccc(Cl)cc3)Cc3ccccc32)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(c1ccc(CN2C(=O)CN(C(=O)c3ccc(Cl)cc3)Cc3ccccc32)cc1)N1CC=CC1
Reaction time: 8 h

Procedure:
23 mg (0.053 mmol) of 1-(4-carboxybenzyl)-4-(4-chlorobenzoyl)-1,3,4,5-tetrahydrobenzo[e][1,4]diazepin-2-on was dissolved in 5 ml of dichloromethane. 6 mg (0.079 mmol) of 3-pyrroline, 13 mg (0.079 mmol) of 2-chloro-1,3-dimethylimidazonium chloride and 0.022 ml (0.159 mmol) of triethylamine were added to the obtained solution, and they were stirred overnight. The solvent was evaporated, and the obtained crude product was treated in the same manner as in step 3 in Example 1 to obtain the title compound.
Reaction SMILES: [CH:1]1[N:5]2[C:6]3[C:11]([NH:12][CH2:13][C:4]2=[CH:3][CH:2]=1)=[CH:10][CH:9]=[CH:8][CH:7]=3.C(N(CC)CC)C.[F:21][C:22]1[CH:23]=[CH:24][C:25]([CH3:40])=[C:26]([CH:39]=1)[C:27]([NH:29][C:30]1[N:35]=[CH:34][C:33]([C:36](Cl)=[O:37])=[CH:32][CH:31]=1)=[O:28]>ClCCl.O>[CH:1]1[N:5]2[C:6]3[C:11]([N:12]([C:36]([C:33]4[CH:32]=[CH:31][C:30]([NH:29][C:27](=[O:28])[C:26]5[CH:39]=[C:22]([F:21])[CH:23]=[CH:24][C:25]=5[CH3:40])=[N:35][CH:34]=4)=[O:37])[CH2:13][C:4]2=[CH:3][CH:2]=1)=[CH:10][CH:9]=[CH:8][CH:7]=3
Reactant: Cc1ccc(F)cc1C(=O)Nc1ccc(C(=O)Cl)cn1
Reactant: c1ccc2c(c1)NCc1cccn1-2
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1ccc(F)cc1C(=O)Nc1ccc(C(=O)N2Cc3cccn3-c3ccccc32)cn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 44.5 %

Procedure:
To a chilled (0° C.) solution of 0.341 g of 4,5-dihydropyrrolo [1,2-a]quinoxaline and 1.11 ml of triethylamine in 5 ml of dichloromethane is added 1.17 g of 6-[(5-fluoro-2-methylbenzoyl)amino]pyridine-3-carbonyl chloride. The mixture is stirred under argon at room temperature for 16 hours. The mixture is diluted with 50 ml of dichloromethane and 20 ml of water and the organic layer is separated. The organic layer is washed with 20 ml each of 1M NaHCO3 and brine and dried (Na2SO4). The solution is filtered through a thin pad of hydrous magnesium silicate and the pad washed with dichloromethane. The filtrate is concentrated and the residue purified on silica gel prep-plates with ethyl acetate-hexane (1:1) as solvent to give a solid. The solid is crystallized from ethyl acetate to give 0.38 g of crystals, m.p. 190°-196° C.
Reaction SMILES: [CH2:1]([OH:6])[CH2:2][CH2:3][CH:4]=[CH2:5].[CH2:7]=[CH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]CC>C1COCC1>[CH2:1]([OH:6])[CH2:2][CH2:3]/[CH:4]=[CH:5]\[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: C=CCCCCCCCCCC
Reactant: C=CCCCO
Solvent: C1CCOC1
Product: CCCCCCCCCC/C=C\CCCO
Temperature: 35 °C
Reaction time: 6 h
Yield: 62 %

Procedure:
In a glovebox, a 20 mL vial was charged with 4-pentenol (410 μL, 3.98 mmol), 1-dodecene (4.4 mL), and THF (2.7 mL). A solution of 1 (0.025 g, 1 mol %) in THF (0.5 mL) was added, and the mixture was stirred in an open vial for 6 hours at 35° C. The vial was removed from the glovebox, the reaction was quenched with excess ethyl vinyl ether, and the solvent was removed in vacuo. Flash chromatography of the residue (SiO2, using a gradient of hexanes to 8% EtOAc in hexanes) provided 21 (0.56 g, 62% yield, 84% Z as determined by 13C-NMR) as a colorless oil; 1H NMR (CDCl3): δ 5.38 (2H, m), 3.65 (2H, m), 1.95-2.14 (4H, m), 1.63 (2H, m), 1.52 (1H, s), 1.25 (16H, m), 0.87 (3H, t, J=6.9 Hz); 13C NMR (100 Hz, CDCl3): δ 131.0, 128.9, 62.8, 32.8, 32.1, 29.9, 29.8, 29.7 (2C), 29.5 (2C), 29.3, 23.7, 22.8, 14.2; HRMS (FAB): 227.2372, [C15H30O+H]+ requires 227.2369.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[C:22]([CH2:23][OH:24])=[C:21]([C:25]3[CH:30]=[C:29]([N:31]=C(C4C=CC=CC=4)C4C=CC=CC=4)[C:28](=[O:45])[N:27]([CH3:46])[CH:26]=3)[CH:20]=[CH:19][N:18]=1)[N:9]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2]>Cl.O1CCOCC1>[NH2:31][C:29]1[C:28](=[O:45])[N:27]([CH3:46])[CH:26]=[C:25]([C:21]2[CH:20]=[CH:19][N:18]=[C:17]([N:10]3[N:9]=[CH:8][C:7]4[C:12](=[C:13]([F:15])[CH:14]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH:6]=4)[C:11]3=[O:16])[C:22]=2[CH2:23][OH:24])[CH:30]=1
Reactant: Cn1cc(-c2ccnc(-n3ncc4cc(C(C)(C)C)cc(F)c4c3=O)c2CO)cc(N=C(c2ccccc2)c2ccccc2)c1=O
Agent: Cl
Solvent: C1COCCO1
Product: Cn1cc(-c2ccnc(-n3ncc4cc(C(C)(C)C)cc(F)c4c3=O)c2CO)cc(N)c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 49.6 %

Procedure:
A mixture of 123b (1.6 g, 2.6 mmol) in HCl/dioxane (4M, 10 mL) was stirred at 25° C. for 1 h. The mixture was evaporated in vacuo and the residue was purified by reverse-phase prep-HPLC to afford 123d (580 mg, 50%) as a pale yellow solid. MS-ESI: [M+H]+ 450.1. 1H NMR (500 MHz, DMSO-d6) δ 8.53-8.52 (m, 2H), 7.90 (d, J=1.0 Hz, 1H), 7.79-7.76 (m, 1H), 7.45 (d, J=5.0 Hz, 1H), 7.24 (d, J=2.5 Hz, 1H), 6.65 (d, J=2.0 Hz, 1H), 5.33 (s, 2H), 4.95-4.93 (m, 1H), 4.39 (s, 2H), 3.52 (s, 3H), 1.38 (s, 9H).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[CH2:3][O:4][C:5]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[CH:11][C:6]=1[C:7]([O:9]C)=O.[NH2:23][CH2:24][CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][NH:26]1.O>C1(C)C=CC=CC=1>[CH:13]1[C:12]([O:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[CH:11][C:6]([C:7]([NH:23][CH2:24][CH:25]2[NH:26][CH2:27][CH2:28][CH2:29][CH2:30]2)=[O:9])=[C:5]([O:4][CH2:3][C:2]([F:1])([F:22])[F:21])[CH:14]=1
Reactant: COC(=O)c1cc(OCC(F)(F)F)ccc1OCC(F)(F)F
Reactant: NCC1CCCCN1
Solvent: O
Solvent: Cc1ccccc1
Product: O=C(NCC1CCCCN1)c1cc(OCC(F)(F)F)ccc1OCC(F)(F)F
Temperature: 25 °C
Yield: 87.1 %

Procedure:
A mixture of methyl 2,5-bis(2,2,2-trifluoroethoxy)benzoate (1.5 g), 2-(aminomethyl)piperidine (0.62 g) in toluene (3 ml) was stirred at reflux for 10 hours. After cooling to room temperature, water (10 ml) was added and two layers solution were separated. The aqueous layer was extracted with toluene (2×10 ml) and the combined organic layers were washed with water (3×10 ml). The organic layer was concentrated under reduced pressure to give Flecainide free base as a white solid (1.63 g, 85%).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2([OH:15])[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1.Cl[C:17]1[CH:18]=[CH:19][C:20]2[N:21]([C:23]([C:26]([F:29])([F:28])[F:27])=[N:24][N:25]=2)[N:22]=1>>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2([OH:15])[CH2:14][CH2:13][N:12]([C:17]3[CH:18]=[CH:19][C:20]4[N:21]([C:23]([C:26]([F:27])([F:29])[F:28])=[N:24][N:25]=4)[N:22]=3)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1
Reactant: FC(F)(F)c1nnc2ccc(Cl)nn12
Reactant: COc1ccc(C2(O)CCNCC2)cn1
Product: COc1ccc(C2(O)CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cn1
Yield: 58 %

Procedure:
A mixture of 4-(6-methoxypyridin-3-yl)piperidin-4-ol and 6-chloro-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine was allowed to react by the method of Example 306 to give 4-(6-methoxypyridin-3-yl)-1-[3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-ol in 58% yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=O)[CH2:10][C:11](=O)[C:12]([F:15])([F:14])[F:13])=[CH:5][CH:4]=1.[NH2:18][C:19]1[N:20]=[CH:21][NH:22][C:23]=1[C:24]#[N:25]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]([C:12]([F:15])([F:14])[F:13])[N:20]3[CH:21]=[N:22][C:23]([C:24]#[N:25])=[C:19]3[N:18]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C(=O)CC(=O)C(F)(F)F)cc1
Reactant: N#Cc1[nH]cnc1N
Product: COc1ccc(-c2cc(C(F)(F)F)n3cnc(C#N)c3n2)cc1
Yield: 39.3 %

Procedure:
Reaction of 1-(4-methoxy-phenyl)-4,4,4-trifluoro-butane-1,3-dione (246 mg, 1.0 mmol), prepared from commercially available 4-methoxy-acetophenone according to general procedure A, and 4-amino-5-cyano-1H-imidazole (108 mg, 1.0 mmol) according to general procedure B yielded the title compound as a yellow solid (125 mg, 39%). MS (ISP) 319.1 [(M+H)+]; mp 192° C.
Reaction SMILES: [N+:1]([C:4]1[CH:32]=[CH:31][C:7]([O:8][CH:9]([CH3:30])[C:10]([O:12][CH2:13][CH2:14][O:15][C:16](=[O:29])[CH:17]([O:19][C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-])=O)=[CH:22][CH:21]=2)[CH3:18])=[O:11])=[CH:6][CH:5]=1)([O-])=O>CN(C)C=O.[Pd]>[NH2:26][C:23]1[CH:24]=[CH:25][C:20]([O:19][CH:17]([CH3:18])[C:16]([O:15][CH2:14][CH2:13][O:12][C:10](=[O:11])[CH:9]([O:8][C:7]2[CH:6]=[CH:5][C:4]([NH2:1])=[CH:32][CH:31]=2)[CH3:30])=[O:29])=[CH:21][CH:22]=1
Reactant: CC(Oc1ccc([N+](=O)[O-])cc1)C(=O)OCCOC(=O)C(C)Oc1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CN(C)C=O
Product: CC(Oc1ccc(N)cc1)C(=O)OCCOC(=O)C(C)Oc1ccc(N)cc1
Reaction time: 4 h
Yield: 72.1 %

Procedure:
2-(4—Nitrophenoxy)-propionic acid 2-[2-(4-nitrophenoxy)propionyloxy]-ethyl ester 31 (50 g, 89.3 mmol) was dissolved in dry dimethylformamide (400 ml) in a pressure vessel. Palladium on carbon(5%, 12.5 g) was added, and the mixture stirred under an atmosphere of hydrogen (4 kg) for 4 hours. Catalyst was removed by filtration and ice water (3 L) was added to the filtrate. Crude 32 was extracted into ethyl acetate, dried over Na2SO4, and distilled and purified by column chromatography on silica gel using chloroform as eluant to give pure 32 (25 g, 58%) as a syrup.
Reaction SMILES: N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH2:37][CH2:38][NH:39][C:40](=[O:46])[O:41][C:42]([CH3:45])([CH3:44])[CH3:43].[Si:47]([O:54][C:55]1[NH:59][N:58]=[C:57]([C:60]([O:62][CH2:63][CH3:64])=[O:61])[CH:56]=1)([C:50]([CH3:53])([CH3:52])[CH3:51])([CH3:49])[CH3:48]>C1COCC1>[C:42]([O:41][C:40]([NH:39][CH2:38][CH2:37][N:58]1[C:57]([C:60]([O:62][CH2:63][CH3:64])=[O:61])=[CH:56][C:55]([O:54][Si:47]([C:50]([CH3:51])([CH3:53])[CH3:52])([CH3:49])[CH3:48])=[N:59]1)=[O:46])([CH3:45])([CH3:44])[CH3:43]
Reactant: CCOC(=O)c1cc(O[Si](C)(C)C(C)(C)C)[nH]n1
Reactant: CC(C)(C)OC(=O)NCCO
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)c1cc(O[Si](C)(C)C(C)(C)C)nn1CCNC(=O)OC(C)(C)C
Temperature: 80 °C
Reaction time: 16 h
Yield: 94.3 %

Procedure:
Di-tert-butyl azodicarboxylate (1.07 g, 4.66 mmol) was added to a stirred solution of triphenylphosphine (1.22 g, 4.66 mmol), tert-butyl N-(2-hydroxyethyl)carbamate (0.8 mL, 5.18 mmol) and ethyl 5-{[tert-butyl(dimethyl)silyl]oxy}-1H-pyrazole-3-carboxylate (0.7 g, 2.59 mmol) in THF (22 mL). The mixture was stirred at 80° C. for 16 hours and the solvents were evaporated in vacuo. The crude product was purified by flash column chromatography (silica; AcOEt in heptane 0/100 to 30/70). The desired fractions were collected and the solvents evaporated in vacuo to yield ethyl 1-{2-[(tert-butoxycarbonyl)amino]ethyl}-3-{[tert-butyl(dimethyl)silyl]oxy}-1H-pyrazole-5-carboxylate (1.01 g, 94% yield) as a white solid.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([N:8]([CH3:22])[C:9](=[O:21])[C:10]([C:13]2[CH:18]=[C:17]([Cl:19])[CH:16]=[C:15]([Cl:20])[CH:14]=2)([CH3:12])[CH3:11])=[C:4]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[Cl:29])[CH:3]=1.[CH2:30]([CH2:32][NH2:33])[OH:31]>C([O-])(O)=O.[Na+]>[Cl:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[C:4]1[CH:3]=[C:2]([NH:33][CH2:32][CH2:30][OH:31])[N:7]=[CH:6][C:5]=1[N:8]([CH3:22])[C:9](=[O:21])[C:10]([C:13]1[CH:18]=[C:17]([Cl:19])[CH:16]=[C:15]([Cl:20])[CH:14]=1)([CH3:11])[CH3:12]
Reactant: NCCO
Reactant: CN(C(=O)C(C)(C)c1cc(Cl)cc(Cl)c1)c1cnc(Cl)cc1-c1ccccc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: CN(C(=O)C(C)(C)c1cc(Cl)cc(Cl)c1)c1cnc(NCCO)cc1-c1ccccc1Cl
Temperature: 25 °C
Yield: 54 %

Procedure:
A solution of 0.14 g (0.29 mmol) N-[6-chloro-4-(2-chloro-phenyl)-pyridin-3-yl]-2-(3,5-dichloro-phenyl)-N-methyl-isobutyramide and 4 ml ethanolamine was stirred at 130° for 9 h. After cooling to ambient temperature, the solution was poured into 20 ml 0.5N NaHCO3-solution and extracted three times with 30 ml CH2Cl2. The combined organic layers were dried (Na2SO4), filtered and evaporated. The residue was purified by flash-chromatography (SiO2, CH2Cl2/ethyl acetate 1:3) to give 0.08 g (54%) of the title compound as a white foam.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][N:6]([C:12](=[O:16])[CH2:13][CH2:14][OH:15])[C:5]2=[O:17].[CH3:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[C:20]=1B(O)O.C(=O)([O-])[O-].[K+].[K+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)(O)[O-]>CN(C)C(=O)C.C(O)C.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(Cl)Cl>[CH3:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[C:20]=1[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][N:6]([C:12](=[O:16])[CH2:13][CH2:14][OH:15])[C:5]2=[O:17]
Reactant: O=C(CCO)n1cnc2ccc(Br)cc2c1=O
Reactant: Cc1cccc(C)c1B(O)O
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])O
Solvent: O
Solvent: CCO
Solvent: CC(=O)N(C)C
Product: Cc1cccc(C)c1-c1ccc2ncn(C(=O)CCO)c(=O)c2c1
Yield: 48.9 %

Procedure:
To a solution of 6-Bromo-3-(3-hydroxy-propionyl)-3H-quinazolin-4-one (9.8 mg, 0.033 mmol) dissolved in 1 ml N,N-dimethylacetamide in a 20 ml vial, 2,6-dimethylphenyl boronic acid (9.89 mg, 0.066 mmol) dissolved in 0.5 ml ethanol and potassium carbonate (5 mg, 0.036 mmol) dissolved in 0.5 ml water were added. Triphenylphosphine (0.87 mg, 3.3 umol) and tris(dibenzylideneacetone)dipalladium(0) (0.6 mg, 0.6 umol) were added to the mixture which refluxed overnight. The crude product was poured into 5 ml saturated bicarbonate solution and methylene chloride was used to extract the product. Solvent in the organic phase was removed under vacuum. The resulted residue was purified by preparative HPLC. 5.2 mg product was obtained. Yield: 49%; 1H NMR (500 MHz, DMSO-d6): δ 1.96247(s, 6H), 2.76290–2.79002(t, J=6.805 Hz, 2H), ), 4.15954–4.18664 (t, J=6.785 Hz, 2H), 7.14682–7.7.1621(d, J=7.64 Hz, 1H), 7.19338–7.21062(dd, J1=8.62 Hz, J2=6.41 Hz, 1H), 7.60532–7.62604(dd, J1=8.365 Hz, J2=2.03 Hz, 1H), 7.75204–7.76861 (d, J=8.285 Hz, 1H), 7.84928–7.85312(d, J=1.92 Hz, 1H), 8.41195(s, 1H); ESI-MS: m/z 323 (M++1)
Reaction SMILES: [BH4-].[Na+].[CH3:3][C:4]([CH3:24])([CH3:23])[C:5](=[O:22])[CH:6]([N:17]1[CH:21]=[N:20][CH:19]=[N:18]1)[CH2:7][S:8]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=[O:10])=[O:9].[Cl-].[Ca+2].[Cl-]>O.C(O)(C)C>[CH3:3][C:4]([CH3:24])([CH3:23])[CH:5]([OH:22])[CH:6]([N:17]1[CH:21]=[N:20][CH:19]=[N:18]1)[CH2:7][S:8]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=[O:10])=[O:9]
Reactant: CC(C)(C)C(=O)C(CS(=O)(=O)c1ccccc1)n1cncn1
Agent: [BH4-]
Agent: [Ca+2]
Agent: [Cl-]
Solvent: O
Solvent: CC(C)O
Product: CC(C)(C)C(O)C(CS(=O)(=O)c1ccccc1)n1cncn1
Reaction time: 18 h
Yield: 66 %

Procedure:
A solution of 0.87 g (0.0229 mol) of sodium borohydride in 20 ml of water was added dropwise to a suspension of 10 g (0.0328 mol) of 4,4-dimethyl-1-phenylsulphonyl-2-(1,2,4-triazol-1-yl)-pentan-3-one (obtained as described in Example 4) and 2.42 g (0.0221 mol) of calcium chloride in 150 ml of isopropanol at -10° C. After 18 hours, the reaction mixture was worked up according to Example 3. 7 g (68.6% of theory) of 4,4-dimethyl-1-phenylsulphonyl-2-(1,2,4-triazol-1-yl)-pentan-3-ol of melting point 145° C. were obtained.