Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][CH3:15])[N:13]=2)[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.Br.BrCC1[CH:51]=[CH:50][N:49]=[CH:48][C:47]=1[Cl:52]>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][C:15]3[CH:51]=[CH:50][N:49]=[CH:48][C:47]=3[Cl:52])[N:13]=2)[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: Clc1cnccc1CBr
Reactant: CCn1nc2nc(C(C)(C)C)nc(N3CCC(F)(F)C3)c2n1
Agent: Br
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn(Cc3ccncc3Cl)nc2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-2-ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 4-(bromomethyl)-3-chloropyridine hydrobromide and isolated as yellow gum. MS (m/e): 408.3 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[C:3]=1[NH:9][C:10](N)=[S:11]>ClC1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[C:3]=1[N:9]=[C:10]=[S:11]
Reactant: NC(=S)Nc1c(Br)cccc1Br
Solvent: Clc1ccccc1
Product: S=C=Nc1c(Br)cccc1Br

Procedure:
A suspension of 101 g. (0.326 mole) of 1-(2,6-dibromophenyl)thiourea in 1 l. of chlorobenzene was stirred and refluxed 20 hours, and the resulting solution was filtered and evaporated. The tan solid obtained was triturated with boiling petroleum ether and filtered. On cooling, the filtrate deposited 63.4 g. of yellow needles of 2,6-dibromophenylisothiocyanate, m.p. 63°-65°. A portion was recrystallized from ether-petroleum ether to give the analytical sample, m.p. 65°-66°.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([Cl:19])=[C:7]([O:9][C:10]2[CH:11]=[C:12]([CH:15]=[C:16]([Cl:18])[CH:17]=2)[C:13]#[N:14])[CH:8]=1.[CH3:20][O:21][C:22]1[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:23]=1[C:24](Cl)=[O:25].CCN(C(C)C)C(C)C>C(#N)C>[Cl:19][C:6]1[CH:5]=[CH:4][C:3]([CH2:2][NH:1][C:24](=[O:25])[C:23]2[CH:27]=[CH:28][C:29]([O:31][CH3:32])=[CH:30][C:22]=2[O:21][CH3:20])=[CH:8][C:7]=1[O:9][C:10]1[CH:11]=[C:12]([C:13]#[N:14])[CH:15]=[C:16]([Cl:18])[CH:17]=1
Reactant: N#Cc1cc(Cl)cc(Oc2cc(CN)ccc2Cl)c1
Reactant: COc1ccc(C(=O)Cl)c(OC)c1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(C(=O)NCc2ccc(Cl)c(Oc3cc(Cl)cc(C#N)c3)c2)c(OC)c1
Reaction time: 8 h
Yield: 57.9 %

Procedure:
3-{[5-(Aminomethyl)-2-chlorophenyl]oxy}-5-chlorobenzonitrile (0.05 g, 0.17 mmol), 2,4-bis(methyloxy)benzoyl chloride (0.046 g, 0.25 mmol) and DIPEA (0.05 mL, 0.25 mmol) were dissolved in acetonitrile (3 mL) and stirred overnight. The solvent was evaporated. Purification was accomplished by Reverse-Phase HPLC (water/acetonitrile with 0.1% TFA). The desired fractions were lyophilized then EtOAc (25 mL) and saturated NaHCO3 (10 mL) were added. The layers were separated and the aqueous layer extracted with EtOAc (2×10 mL). The organic extracts were combined, dried over Na2SO4, filtered and evaporated to afford the title compound (0.045 g, 57%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 8.57 (t, 1H), 7.79 (s, 1H), 7.67-7.77 (m, 1H), 7.58 (d, 1H), 7.44 (s, 1H), 7.36 (s, 1H), 7.22-7.26 (m, 1H), 7.12-7.22 (m, 1H), 6.59 (d, 1H), 6.62 (s, 1H), 4.46 (d, 2H), 3.83 (s, 3H), 3.80 (s, 3H). MS: m/z 457.0 (M+1).
Reaction SMILES: [C:1]([OH:11])(=O)[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[OH-].[Na+].[NH2:14][CH2:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=1>>[C:1]([NH:14][CH2:15][C:16]1[CH:17]=[CH:18][C:19]([C:20]([OH:22])=[O:21])=[CH:23][CH:24]=1)(=[O:11])[CH:2]=[CH:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=C(O)C=Cc1ccccc1
Reactant: NCc1ccc(C(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Product: O=C(C=Cc1ccccc1)NCc1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 90.6 %

Procedure:
To a suspension of 0.33 g (2.01 mmol) of N,N′-carbonyldiimidazole in tetrahydrofunan (10 ml) is added drop-wise a solution of 0.30 g (2.01 mmol) of cinnamic acid at 0° C. Then, the mixture is stirred at room temperature for 3 hours and added drop-wise to a separately prepared 2.0 ml (2.00 mmol) of 1N aqueous sodium hydroxide solution including 0.30 g (2.00 mmol) of 4-aminomethylbenzoic acid, followed by stirring at room temperature for 8 hours. The reaction mixture is evaporated under vacuum. To the residue is added a saturated solution of sodium chloride (2 ml), then the mixture is neutralized with concentrated hydrochloric acid to pH 7. The deposited white solid is collected by filtration, washed with ice-water, and then dried to give the title compound (0.51 g, 91%). HRMS calcd for C17H15NO3: 281.3242. Found: 281.3240. MA calcd for C17H15NO3: C, 72.58%; H, 5.38%; N, 4.98. Found: C, 72.42%; H, 5.37%; N, 4.98%.
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[CH2:6]([O:8][C:9](=[O:17])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:7]>[Cl-].[Na+]>[CH2:6]([O:8][C:9](=[O:17])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([S:2]([Cl:1])(=[O:5])=[O:3])=[CH:13][CH:12]=1)[CH3:7]
Reactant: CCOC(=O)Cc1ccccc1
Reactant: O=S(=O)(O)Cl
Agent: [Cl-]
Agent: [Na+]
Product: CCOC(=O)Cc1ccc(S(=O)(=O)Cl)cc1
Temperature: 70 °C

Procedure:
To a cooled chlorosulfonic acid (83.83 g, 48 mL, 0.71 mol) under nitrogen is added the title A compound, phenylacetic acid ethyl ester (59 g, 0.35 mol) over a period of 1 h. Reaction temperature is brought to RT (28° C.), then heated to 70° C., maintaining it at this temperature for 1 h while stirring. Reaction is cooled to RT and poured over saturated aqueous sodium chloride solution (200 mL) followed by extraction with DCM (2×200 mL). The organic layer is washed with water (5×100 mL), followed by saturated aqueous sodium chloride solution (1×150 mL). The organic layer dried over sodium sulfate, filtered and concentrated in vacuo to give crude (4-chlorosulfonyl-phenyl)acetic acid ethyl ester. Further column chromatography over silica gel (60-120 mesh), using 100% hexane afforded pure (4-chlorosulfonyl-phenyl)-acetic acid ethyl ester as a colorless oil.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11]([CH2:14][S:15]([C:18]([F:21])([F:20])[F:19])(=[O:17])=[O:16])(=[O:13])=[O:12].S([N:32]=[N+:33]=[N-])(C1C=CC(C)=CC=1)(=O)=O.C(N(CC)CC)C.O>C(#N)C.ClCCl>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11]([C:14]([S:15]([C:18]([F:21])([F:19])[F:20])(=[O:16])=[O:17])=[N+:32]=[N-:33])(=[O:13])=[O:12]
Reactant: Cc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Reactant: O=S(=O)(CS(=O)(=O)C(F)(F)F)c1ccc2ccccc2c1
Solvent: ClCCl
Solvent: CC#N
Solvent: O
Product: [N-]=[N+]=C(S(=O)(=O)c1ccc2ccccc2c1)S(=O)(=O)C(F)(F)F
Temperature: 0 °C
Reaction time: 24 h

Procedure:
Crude 2-naphthalenesulfonyl-trifluoromethanesulfonyl-methane (5 g, 0.014 mole) is dissolved in acetonitrile (150 ml) under nitrogen and the solution is cooled to 0° C. using an ice bath. Tosyl azide (8.3 g, 0.042 mole) and then triethylamine (3.9 ml, 0.028 mole) are added in one portion and the reaction mixture is stirred at that temperature for 24 h. After adding water (400 ml) and dichloromethane (200 ml), the phases are separated and the aqueous layer is extracted twice with dichloromethane (150 ml) and the combined organic phases are washed with 1 N HCl, saturated sodium bicarbonate and water. After drying over MgSO4 and removal of the solvent, the crude product is obtained as orange oil.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[CH2:12][C:13]1[N:17]2[N:18]=[C:19]([C:22]3[CH:23]=[N:24][N:25]([CH:27]4[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]4)[CH:26]=3)[CH:20]=[CH:21][C:16]2=[N:15][CH:14]=1.CS(O[CH2:38][C:39]([F:42])([F:41])[F:40])(=O)=O.C([O-])([O-])=O.[Cs+].[Cs+]>C1COCC1.CCOC(C)=O>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[CH2:12][C:13]1[N:17]2[N:18]=[C:19]([C:22]3[CH:23]=[N:24][N:25]([CH:27]4[CH2:32][CH2:31][N:30]([CH2:38][C:39]([F:42])([F:41])[F:40])[CH2:29][CH2:28]4)[CH:26]=3)[CH:20]=[CH:21][C:16]2=[N:15][CH:14]=1
Reactant: Fc1cc2ncccc2cc1Cc1cnc2ccc(-c3cnn(C4CCNCC4)c3)nn12
Reactant: CS(=O)(=O)OCC(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Fc1cc2ncccc2cc1Cc1cnc2ccc(-c3cnn(C4CCN(CC(F)(F)F)CC4)c3)nn12
Temperature: 70 °C
Reaction time: 2 h

Procedure:
A mixture of 7-fluoro-6-[6-(1-piperidin-4-yl-1H-pyrazol-4-yl)-imidazo[1,2-b]pyridazin-3-ylmethyl]-quinoline (Example 180, 50 mg, 0.117 mmol), 2,2,2-trifluoroethyl methanesulfonate (55 μL, 0.468 mmol) and Cs2CO3 (76 mg, 0.234 mmol) in THF (1 mL) was stirred at 70° C. for 2 h. 2,2,2-trifluoroethyl methanesulfonate (69 μL, 0.585 mmol) was then added and the RM was stirred at reflux for 24 h. 2,2,2-trifluoroethyl methanesulfonate (69 μL, 0.585 mmol) was added again and the RM was stirred at reflux for 18 h more. The mixture was diluted with EtOAc and washed with NaHCO3 and brine. The organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography (CombiFlash® Companion System®, with a 4 g RediSep® silica gel column, DCM/(DCM/MeOH 19:1)=100:0→0:100) to afford the title compound (tR 3.74 min (conditions 3), 1H-NMR in DMSO-d6: 8.85 (m, 1H); 8.54 (s, 1H); 8.34 (d, 1H); 8.07 (m, 3H); 7.77 (d, 1H); 7.61 (s, 1H); 7.54 (d, 1H); 7.47 (dd, 1H); 4.55 (s, 2H); 4.39 (m, 1H); 3.67 (m, 2H); 2.94 (m, 4H); 2.16 (m, 2H); 2.00 (m, 2H)).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:22][N:12]3[C:13](=[O:21])[NH:14][C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][C:20]=4[C:11]3=[N:10][CH2:9]2)=[CH:4][CH:3]=1.[C:23]1([CH3:32])[CH:28]=[CH:27][C:26]([N:29]=[C:30]=[O:31])=[CH:25][CH:24]=1>>[CH3:32][C:23]1[CH:28]=[CH:27][C:26]([NH:29][C:30]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([CH:8]3[CH2:22][N:12]4[C:13](=[O:21])[NH:14][C:15]5[CH:16]=[CH:17][CH:18]=[CH:19][C:20]=5[C:11]4=[N:10][CH2:9]3)=[CH:4][CH:3]=2)=[O:31])=[CH:25][CH:24]=1
Reactant: Cc1ccc(N=C=O)cc1
Reactant: Nc1ccc(C2CN=C3c4ccccc4NC(=O)N3C2)cc1
Product: Cc1ccc(NC(=O)Nc2ccc(C3CN=C4c5ccccc5NC(=O)N4C3)cc2)cc1
Yield: 86.9 %

Procedure:
In a manner similar to the procedure described in Example 7, 3-(4-aminophenyl)-2,3,4,7-tetrahydro-6H-pyrimido[1,2-c]quinazolin-6-one (20.2 mg, 0.069 mmol) and para-tolyl isocyanate (0.0096 mL, 0.076 mmol) were reacted to give the title compound as a pale tan solid (25.5 mg, 87%). 1H NMR (DMSO-d6) δ: 10.68 (s, 1H), 8.59 (s, 1H), 8.53 (s, 1H), 7.98 (d, J=7.9 Hz, 1H), 7.40-7.45 (m, 3H), 7.33 (d, J=8.2 Hz, 2H), 7.23 (d, J=8.5 Hz, 2H), 7.05-7.09 (m, 3H), 7.01 (d, J=8.2 Hz, 1H), 4.22 (dt, J=12.6, 3.5 Hz, 1H), 3.72 (dt, J=16.0, 3.4 Hz, 1H), 3.51-3.59 (m, 2H), 2.92-2.99 (m, 1H), 2.24 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[C:3]([O:18][CH3:19])=[C:4]([C:9]([C:11]2(Br)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[O:10])[CH:5]=[C:6]([CH3:8])[CH:7]=1.[Cl-].[Li+]>CN(C)C=O>[CH3:1][C:2]1[C:3]([O:18][CH3:19])=[C:4]([C:9]([C:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]=2)=[O:10])[CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: COc1c(C)cc(C)cc1C(=O)C1(Br)CCCCC1
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: COc1c(C)cc(C)cc1C(=O)C1=CCCCC1
Temperature: 90 °C
Reaction time: 1 h

Procedure:
363.5 Grams of 1-bromocyclohexyl 3,5-dimethyl-2-methoxyphenyl ketone was dissolved in 1 liter of dimethylformamide. To the solution was added 140 g of lithium chloride, followed by stirring at 90° C. for 1 hour. The reaction mixture was poured into 1 liter of ice water with stirring and the organic layer was extracted with 3 liters of methylene chloride. The extract was washed with water and saturated aqueous sodium chloride solution in this order and then dried with anhydrous magnesium sulfate and methylene chloride was distilled off under reduced pressure. The residue was purified by a silica gel column chromatography (eluent: ethyl acetate:n-hexane=96:4) to obtain 197.0 g of 1-cyclohexenyl 3,5-dimethyl-2-methoxyphenyl ketone.
Reaction SMILES: [Cl-].[CH3:2][O:3][C:4](=[O:11])[CH2:5][CH2:6][CH2:7][NH+:8]([CH3:10])[CH3:9].C([O-])([O-])=O.[K+].[K+]>ClCCl>[CH3:9][N:8]([CH3:10])[CH2:7][CH2:6][CH2:5][C:4]([O:3][CH3:2])=[O:11]
Reactant: COC(=O)CCC[NH+](C)C
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: ClCCl
Product: COC(=O)CCCN(C)C
Temperature: 25 °C
Reaction time: 24 h
Yield: 66.1 %

Procedure:
A suspension of 4-methoxy-N,N-dimethyl-4-oxo-1-butanaminium chloride (3) (5.44 g, 0.03 mol) and anh. K2CO3 (5.52 g, 0.04 mol) in dichloromethane (70 ml) was vigorously stirred at ambient temperature for 24 h. The precipitate was filtered, washed with dichloromethane, and the filtrate was evaporated. The residue was distilled at 32-35° C./3-4 mm Hg to give 2.88 g (66%) of methyl 4-(dimethylamino)butanoate.
Reaction SMILES: [C@@H:1]1([N:9]2[CH:16]=[CH:15][C:13](=[O:14])[NH:12][C:10]2=[O:11])[O:8][C@H:5]([CH2:6][OH:7])[C@@H:3]([OH:4])[CH2:2]1.[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1>N1C=CC=CC=1>[S:23]([O:7][CH2:6][C@H:5]1[O:8][C@@H:1]([N:9]2[CH:16]=[CH:15][C:13](=[O:14])[NH:12][C:10]2=[O:11])[CH2:2][C@@H:3]1[OH:4])([C:20]1[CH:21]=[CH:22][C:17]([CH3:27])=[CH:18][CH:19]=1)(=[O:25])=[O:24]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=c1ccn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC[C@H]2O[C@@H](n3ccc(=O)[nH]c3=O)C[C@@H]2O)cc1
Temperature: 0 °C
Reaction time: 24 h
Yield: 66 %

Procedure:
22.8 GM OF DEOXYURIDINE (100 MMOLES) ARE DISSOLVED IN 100 ML OF FRESHLY DISTILLED, DRY PYRIDINE AND KEPT ON ICE AT 4° C. Freshly recrystallized p-toluenesulfonyl chloride (22 gm, 115 mmoles) is dissolved in a separate 100 ml of cold pyridine and then slowly added to the nucleoside solution. The reaction mixture is left standing at 4° C for 24 hours and the solution poured into 400 ml of ice water. This solution is then extracted twice with 500 ml of chloroform, the chloroform extracts combined and back extracted with 250 ml of a saturated solution of sodium bicarbonate and 250 ml of water. The chloroform layer is collected and dried over anhydrous magnesium sulfate. The solvent is removed by rotary evaporation in vacuo to yield 32 gm of a crude, tan-colored product. Recrystallization from 95% ethanol affords 25.3 gm (66% yield) of white crystals, M.P. 162°.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.CON(C)[C:14]([C:16]1[CH:17]=[N:18][C:19]([O:22][CH2:23][C:24]([F:27])([F:26])[F:25])=[CH:20][CH:21]=1)=[O:15].CO.[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+]>C1(C)C=CC=CC=1>[F:27][C:24]([F:25])([F:26])[CH2:23][O:22][C:19]1[N:18]=[CH:17][C:16]([CH:14]=[O:15])=[CH:21][CH:20]=1
Reactant: CON(C)C(=O)c1ccc(OCC(F)(F)F)nc1
Agent: CC(C)C[Al+]CC(C)C
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: CO
Product: O=Cc1ccc(OCC(F)(F)F)nc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Diisobutylaluminum hydride (toluene solution, 1.01 mol/L, 1.95 mL, 1.97 mmol) was added dropwise to a solution of N-methoxy-N-methyl-6-(2,2,2-trifluoroethoxy)pyridine-3-carboxamide obtained (432 mg, 1.64 mmol) in toluene (11 mL) at −78° C. under a nitrogen atmosphere. The mixture was stirred at the same temperature for 1 hr. Methanol (5 mL) was added dropwise to the reaction mixture, the mixture was warmed to room temperature, and 50% aqueous Rochelle salt solution (10 mL) was added thereto, followed by stirring for 1.5 hr. The mixture was extracted with chloroform and the organic layer was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1→7:3) to afford the title compound as a colorless solid (287 mg).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[C:6]([Cl:14])[C:5]=1[N:15]1[C:19]([NH:20][CH2:21][CH2:22][CH2:23][S:24][CH2:25][CH3:26])=[C:18]([S:27]([C:30]([F:33])([F:32])[F:31])(=[O:29])=[O:28])[C:17]([C:34]#[N:35])=[N:16]1.Cl[C:37]([O:39][CH2:40][CH3:41])=[O:38].[Cl-].[NH4+]>O1CCCC1.C(OCC)(=O)C>[Cl:14][C:6]1[CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=[C:4]([Cl:3])[C:5]=1[N:15]1[C:19]([N:20]([C:37]([O:39][CH2:40][CH3:41])=[O:38])[CH2:21][CH2:22][CH2:23][S:24][CH2:25][CH3:26])=[C:18]([S:27]([C:30]([F:33])([F:32])[F:31])(=[O:28])=[O:29])[C:17]([C:34]#[N:35])=[N:16]1
Reactant: CCSCCCNc1c(S(=O)(=O)C(F)(F)F)c(C#N)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Reactant: CCOC(=O)Cl
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)N(CCCSCC)c1c(S(=O)(=O)C(F)(F)F)c(C#N)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Temperature: 20 °C
Reaction time: 1 h
Yield: 81 %

Procedure:
Sodium hydride (0.032 g, 60%, 0.8 mmol) was added to a solution of 1-(2,6-dichloro-4-trifluoromethylphenyl)-3-cyano-5-(3-ethylthiopropylamino)-4-trifluoromethylsulfonylpyrazole (0.3 g, 0.54 mmol) in tetrahydrofuran 20° C. under nitrogen. The mixture was stirred at 20° C. for one hour then ethyl chloroformate (0.121 g, 1.1 mmol) was added. The mixture was stirred at 20° C. for 5 hours, then poured into saturated ammonium chloride and ethyl acetate. The organic layer was washed with water and brine, dried (sodium sulfate), evaporated to provide and purified by chromatography on silica gel eluting with heptane-ethyl acetate (4:1) to give 1-(2,6-dichloro-4-trifluoromethylphenyl)-3-cyano-5-[N-ethoxycarbonyl-N-(3-ethylthiopropyl)amino]-4-trifluoromethylsulfonylpyrazole as an oil (Compound number 3-14, 0.278 g, 81% yield), 19F: −63.9; −77.9.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:10])=[O:9])=[N:6][CH:7]=1.[CH2:11](C([Sn])=C(CCCC)CCCC)[CH2:12]CC>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:11]([C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:10])=[O:9])=[N:6][CH:7]=1)=[CH2:12]
Reactant: CCCCC([Sn])=C(CCCC)CCCC
Reactant: O=C(O)c1ccc(Br)cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1COCCO1
Product: C=Cc1ccc(C(=O)O)nc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 94.8 %

Procedure:
The title compound was prepared by following general procedure 2. To a solution of 5-bromo pyridine-2-carboxylic acid (5 g, 24.75 mmol) in 50 mL of 1,4-dioxan, dichlorobis(triphenylphosphine)palladium(II) (2.08 g, 2.96 mmol) was added at RT and stirred at RT for 5 min. Tributylvinyltin (11.7 g, 36.9 mmol) was added slowly at RT and stirred at 100° C. for 3 h. The reaction mixture was monitored by TLC and LCMS. After completion of the starting material, evaporated the solvent below 40° C. and purified by column chromatography using ethyl acetate to afford the 5-vinylpyridine-2-carboxylic acid (3.5 g, 94.5%).
Reaction SMILES: [CH3:1][C:2]1[S:6][CH:5]=[N:4][C:3]=1[C:7]([OH:9])=O.O1CCCC1.C(Cl)(=O)C(Cl)=O.[NH2:21][C:22]1[CH:23]=[C:24]([CH:41]=[CH:42][C:43]=1[CH3:44])[O:25][C:26]1[CH:27]=[CH:28][C:29]2[N:30]([CH:32]=[C:33]([NH:35][C:36]([CH:38]3[CH2:40][CH2:39]3)=[O:37])[N:34]=2)[N:31]=1>CN(C)C=O.CN(C)C(=O)C>[CH:38]1([C:36]([NH:35][C:33]2[N:34]=[C:29]3[CH:28]=[CH:27][C:26]([O:25][C:24]4[CH:41]=[CH:42][C:43]([CH3:44])=[C:22]([NH:21][C:7]([C:3]5[N:4]=[CH:5][S:6][C:2]=5[CH3:1])=[O:9])[CH:23]=4)=[N:31][N:30]3[CH:32]=2)=[O:37])[CH2:39][CH2:40]1
Reactant: Cc1scnc1C(=O)O
Reactant: Cc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)cc1N
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CC(=O)N(C)C
Product: Cc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)cc1NC(=O)c1ncsc1C
Yield: 61.3 %

Procedure:
In the same manner as in Example 259 and using 5-methyl-1,3-thiazole-4-carboxylic acid (74 mg, 0.52 mmol), tetrahydrofuran (5 mL), N,N-dimethylformamide (1 drop), oxalyl chloride (170 μL, 2.0 mmol), N-[6-(3-amino-4-methylphenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (130 mg, 0.40 mmol) and N,N-dimethylacetamide (7 mL) as starting materials, the title compound (110 mg, 60%) was obtained as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+]([O-])=O)[CH:5]=[CH:4][N+:3]=1[O-:11].[ClH:12]>>[Cl:12][C:6]1[CH:5]=[CH:4][N+:3]([O-:11])=[C:2]([CH3:1])[CH:7]=1
Reactant: Cl
Reactant: Cc1cc([N+](=O)[O-])cc[n+]1[O-]
Product: Cc1cc(Cl)cc[n+]1[O-]
Yield: 75 %

Procedure:
2-methyl-4-nitropyridine 1-oxide (5.0 g, 32 mmol, 1.0 eq) was dissolved in concentrated HCl (80 mL) and refluxed for 3 days. The reaction was cooled and the excess concentrated HCl was removed in vacuo. The viscous oil was neutralized with 10% K2CO3 and extracted with CH2Cl2 (5×). The combined organics were dried (MgSO4), filtered, and concentrated in vacuo. Purification by flash chromatography on silica gel afforded 3.49 g (75%) of the title compound as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 8.23 (d, J=7.0 Hz, 1H), 7.66 (d, J=3.0 Hz, 1H), 7.40 (dd, J=7.0, 3.0 Hz, 1H), 2.32 (s, 3H); ES-MS [M+1]+: 144.2.
Reaction SMILES: [OH:1][C:2]1[C:7](=[O:8])[CH:6]=[CH:5][N:4]([CH3:9])[C:3]=1[CH:10](O)[C:11]([F:14])([F:13])[F:12].[NH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>>[OH:1][C:2]1[C:7](=[O:8])[CH:6]=[CH:5][N:4]([CH3:9])[C:3]=1[CH:10]([N:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)[C:11]([F:14])([F:13])[F:12]
Reactant: C1CCNCC1
Reactant: Cn1ccc(=O)c(O)c1C(O)C(F)(F)F
Product: Cn1ccc(=O)c(O)c1C(N1CCCCC1)C(F)(F)F
Yield: 54 %

Procedure:
In a similar manner, Apo7058 was prepared from 3-hydroxy-1-methyl-2-(2,2,2-trifluoro-1-hydroxyethyl)pyridin-4(1H)-one (1.0 g, 4.5 mmol) and piperidine (0.88 mL, 8.9 mmol). The title compound Apo7058 (700 mg) was obtained as a white solid after purification by flash chromatography (4% MeOH in CH2Cl2 as eluant). Yield=54%; 1H NMR (400 MHz, DMSO-D6, 75° C.) δ (ppm): 7.59 (d, J=6.8 Hz, 1H), 6.19 (d, J=6.8 Hz, 1H), 4.82 (q, J=9.0 Hz, 1H), 3.88 (s, 3H), 2.46-2.84 (m, 4H), 1.29-1.74 (m, 6H) MS m/z 291 [M+1]+, 206 (100%).
Reaction SMILES: Cl.Cl.Cl[CH2:4][C:5]1[N:6]=[C:7]([CH2:10][N:11]([CH3:13])[CH3:12])[S:8][CH:9]=1.[Cl:14][C:15]1[CH:16]=[C:17]([NH:22][C:23]2[C:32]3[C:27](=[CH:28][C:29]([OH:35])=[C:30]([O:33][CH3:34])[CH:31]=3)[N:26]=[CH:25][N:24]=2)[CH:18]=[CH:19][C:20]=1[Cl:21].C(=O)([O-])[O-].[K+].[K+]>>[Cl:14][C:15]1[CH:16]=[C:17]([NH:22][C:23]2[C:32]3[C:27](=[CH:28][C:29]([O:35][CH2:4][C:5]4[N:6]=[C:7]([CH2:10][N:11]([CH3:13])[CH3:12])[S:8][CH:9]=4)=[C:30]([O:33][CH3:34])[CH:31]=3)[N:26]=[CH:25][N:24]=2)[CH:18]=[CH:19][C:20]=1[Cl:21]
Reactant: COc1cc2c(Nc3ccc(Cl)c(Cl)c3)ncnc2cc1O
Reactant: CN(C)Cc1nc(CCl)cs1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1cc2c(Nc3ccc(Cl)c(Cl)c3)ncnc2cc1OCc1csc(CN(C)C)n1
Temperature: 25 °C
Reaction time: 50 h
Yield: 15 %

Procedure:
N-{[4-(Chloromethyl)-1,3-thiazol-2-yl]methyl}-N,N-dimethylamine hydrochloride hydrochloride (0.050 g, 0.220 mmol) and 4-[(3,4-dichlorophenyl)amino]-6-(methoxy)quinazolin-7-ol (0.074 g, 0.220 mmol) were suspended in DMP (4 mL) and potassium carbonate (0.152 g, 1.10 mmol) was added. The mixture was stirred at room temperature for 50 h and then at 70° C. for 3.5 h. An additional portion of N-{[4-(chloromethyl)-1,3-thiazol-2-yl]methyl}-N,N-dimethylamine hydrochloride hydrochloride (0.019 g, 0.084 mmol) was added and the mixture was stirred at 70° C. for a further 25 h. The reaction mixture was concentrated in vacuo. and the residue was partitioned between ethyl acetate and brine. The organic portion was washed with 1 N aqueous sodium hydroxide, brine, dried over sodium sulfate, filtered and concentrated in vacuo. to afford a brown solid. Recrystallization from ethyl acetate/diethyl ether afforded the title compound as a pale brown solid (0.016 g, 0.033 mmol, 15% yield). 1H NMR (400 MHz; CDCl3): 2.37 (s, 6H); 3.79 (s, 2H); 4.00 (s, 3H); 5.34 (s, 2H); 7.00 (s, 1H); 7.15 (br s, 1H); 7.34-7.37 (m, 2H); 7.55 (d, 1H); 7.57 (d, 1H); 7.96 (d, 1H); 8.66 (s, 1H); MS (EI) for C22H21Cl2N5O2S: 490 (MH+).