Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br-:1].[Li+].C1COCC1.Cl[CH2:9][C:10]1[CH:27]=[CH:26][C:13]2[N:14]([CH2:24][CH3:25])[C:15](=[O:23])[C:16]([CH3:22])([CH3:21])[C:17](=[O:20])[N:18]([CH3:19])[C:12]=2[CH:11]=1>O>[Br:1][CH2:9][C:10]1[CH:27]=[CH:26][C:13]2[N:14]([CH2:24][CH3:25])[C:15](=[O:23])[C:16]([CH3:22])([CH3:21])[C:17](=[O:20])[N:18]([CH3:19])[C:12]=2[CH:11]=1
Reactant: [Br-]
Reactant: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(CCl)ccc21
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(CBr)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.7 %

Procedure:
Lithium bromide (0.678 g) was added to an THF solution (2.3 ml) of 7-chloromethyl-1-ethyl-3,3,5-trimethyl-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione (0.23 g), and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, followed by extraction using ethyl acetate. The organic layer was dried with magnesium sulfate, and was condensed under reduced pressure to give the title compound (0.24 g) as a white solid.
Reaction SMILES: S(Cl)([Cl:3])=O.[Cl:5][C:6]1[CH:7]=[C:8]([N:13]2[CH:17]=[C:16]([CH2:18]O)[N:15]=[CH:14]2)[CH:9]=[CH:10][C:11]=1[Cl:12].[OH-].[Na+]>>[Cl:3][CH2:18][C:16]1[N:15]=[CH:14][N:13]([C:8]2[CH:9]=[CH:10][C:11]([Cl:12])=[C:6]([Cl:5])[CH:7]=2)[CH:17]=1
Reactant: OCc1cn(-c2ccc(Cl)c(Cl)c2)cn1
Reactant: O=S(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Product: ClCc1cn(-c2ccc(Cl)c(Cl)c2)cn1
Reaction time: 24 h
Yield: 95 %

Procedure:
In an ice-bath thionyl chloride (39.5 ml, excess) was slowly added to [1-(3,4-dichloro-phenyl)-1H-imidazol-4-yl]-methanol (9.6 g, 39.5 mmol). The resulting mixture was stirred for 24 h. After evaporation, the oily residue was triturated with ether and 10.12 g (86%) of the hydrochloride salt of the title compound was obtained as an off-white solid. To obtain the free base, the salt was carefully neutralized with aqueous NaOH (2N) and extracted with AcOEt. The organic phase was dried (Na2SO4) and concentrated to obtain 8.43 g (95%) of the title compound as an off-white solid. Mp. 146-147° C. dec. (AcOEt/hexane), MS: m/e=260 (M+)
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][N:9]2[N:12]=[CH:13][C:14](Br)=[C:8]2[N:7]=1)=[O:5])[CH3:2].[Cl:16][C:17]1[CH:18]=[C:19](OB(O)O)[CH:20]=[CH:21][CH:22]=1.P([O-])([O-])([O-])=O.[Ca+2].P([O-])([O-])([O-])=O.[Ca+2].[Ca+2].O1CCOCC1>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>[CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][N:9]2[N:12]=[CH:13][C:14]([C:21]3[CH:20]=[CH:19][CH:18]=[C:17]([Cl:16])[CH:22]=3)=[C:8]2[N:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccn2ncc(Br)c2n1
Reactant: OB(O)Oc1cccc(Cl)c1
Agent: [Pd]
Agent: O=P([O-])([O-])[O-]
Agent: [Ca+2]
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)c1ccn2ncc(-c3cccc(Cl)c3)c2n1
Temperature: 25 °C
Yield: 89.8 %

Procedure:
A mixture of 3-bromo-pyrazolo-[1,5-a]-pyrimidine-5-carboxylic acid ethyl ester (18.00 g), 3-chlorophenyl boric acid (12.50 g), calcium phosphate (31.12 g), and 200 ml of dioxane was stirred under a nitrogen atmosphere, added with tetrakis(triphenylphosphine) palladium (0) (1.50 g), and heated at reflux over 3 hours. The reactant was cooled to room temperature, and thereafter poured into 150 ml of water, and extracted with 300 ml of toluene. The extract was washed with saturated saline solution, dried with magnesium sulfate, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (ethyl acetate:toluene=8:2) to yield 3-(3-chlorophenyl)-pyrazolo-[1,5-a]-pyrimidine-5-carboxylic acid ethyl ester (18.05 g, 89%) as a brown columnar crystal. mp: 126-129° C.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([N:26]3[CH2:31][CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28][CH2:27]3)=[C:6]3[C:12]([C:13]([F:16])([F:15])[F:14])=[N:11][N:10]([CH2:17][C:18]4[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=4)[C:7]3=[N:8][CH:9]=2)[CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:1]1([C:4]2[C:5]([N:26]3[CH2:27][CH2:28][NH:29][CH2:30][CH2:31]3)=[C:6]3[C:12]([C:13]([F:14])([F:16])[F:15])=[N:11][N:10]([CH2:17][C:18]4[CH:19]=[CH:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=4)[C:7]3=[N:8][CH:9]=2)[CH2:3][CH2:2]1
Reactant: COc1ccc(Cn2nc(C(F)(F)F)c3c(N4CCN(C(=O)OC(C)(C)C)CC4)c(C4CC4)cnc32)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(Cn2nc(C(F)(F)F)c3c(N4CCNCC4)c(C4CC4)cnc32)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.7 %

Procedure:
tert-Butyl 4-(5-cyclopropyl-1-(4-methoxybenzyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-4-yl)piperazine-1-carboxylate (270 mg, 0.5 mmol) was placed in DCM (8 mL) at room temperature. TFA (1.5 mL) was then added, and the reaction was stirred at room temperature for 1 hour and concentrated to dryness. The crude product was then azeotroped with toluene (3×) and then dried on a vac line for 1 hour to give the crude product 5-cyclopropyl-1-(4-methoxybenzyl)-4-(piperazin-1-yl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridine (0.2 g, 91% yield), which was used without further purification.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[F:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[C:9]=1[C:15]1[O:16][CH2:17][CH:18]([C:20](OC)=[O:21])[N:19]=1.O.[OH-].[K+]>O1CCCC1>[F:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[C:9]=1[C:15]1[O:16][CH2:17][CH:18]([CH2:20][OH:21])[N:19]=1
Reactant: COC(=O)C1COC(c2c(F)cccc2F)=N1
Agent: [Al+3]
Agent: [H-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: OCC1COC(c2c(F)cccc2F)=N1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 74.9 %

Procedure:
A mixture of 0.58 g (15.3 mmol.) of lithium aluminum hydride and 50 ml of anhydrous tetrahydrofuran was refluxed by heating with stirring for 10 minutes. Then the mixture was cooled to a temperature of 0° C. To the mixture, there was added dropwise a solution of 4.54 g (18.8 mmol.) of 2-(2,6-difluorophenyl)-4-methoxycarbonyl-2-oxazoline obtained in Production Example 21 in 13 ml of anhydrous tetrahydrofuran with stirring at a temperature of 0° C. for 20 minutes. Then the reaction mixture was further stirred at the same temperature for 10 minutes. To the resultant mixture, there was added 0.58 ml of water with stirring at the same temperature for 5 minutes. Then the mixture was further stirred at the same temperature for 5 minutes. To the resultant mixture, there was added 0.58 ml of a 30% aqueous solution of potassium hydroxide and further 1.74 ml of water with stirring at the same temperature. After adding, the above mixture was vigorously stirred overnight at room temperature. Then, the mixture was filtrated with a filter glass to remove the resultant precipitate and concentrated under reduced pressure. The residue was subjected to silica gel chromatography to give 3.0 g of 2-(2,6-difluorophenyl)-4-hydroxymethyl-2-oxazoline as a white solid (m.p. 90.4° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[C:12]3[C:19]([CH3:22])=[N:20][O:21][C:11]=3[CH:10]([C:23]#[N:24])[N:9]=2)=[CH:4][CH:3]=1.Cl.C(O)(C(F)(F)F)=[O:27]>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[C:12]3[C:19]([CH3:22])=[N:20][O:21][C:11]=3[CH:10]([C:23]([NH2:24])=[O:27])[N:9]=2)=[CH:4][CH:3]=1
Reactant: O=C(O)C(F)(F)F
Reactant: Cc1noc2c1-c1ccccc1C(c1ccc(Cl)cc1)=NC2C#N
Agent: Cl
Solvent: O
Product: Cc1noc2c1-c1ccccc1C(c1ccc(Cl)cc1)=NC2C(N)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 47.9 %

Procedure:
To a round bottomed flask was added 6-(4-chlorophenyl)-1-methyl-4H-benzo[c]isoxazolo[4,5-e]azepine-4-carbonitrile (32 mg, 0.096 mmol) and conc. HCl (1 mL, 32.9 mmol). The reaction was stirred at room temperature for 1 h and during this time a precipitate formed. This solution was diluted with water and the precipitate was collected via filtration. Upon washing with water the precipitate dissolved. The layers were separated and the aqueous was extracted with ether (3×). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. This crude mixture was taken up in DCE (1 mL) and TFA (1 mL, 12.98 mmol). The vial was sealed and the reaction heated to 80° C. for 1 h before cooling to room temperature and stirring for an additional 2 h. The solution was concentrated and the crude residue was purified via Biotage (EtOAc/hex) to afford the titled compound (16.2 mg, 0.046 mmol) as a white solid. LC/MS m/z 352 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ 8.07-7.86 (m, 2H), 7.82 (d, J=7.8 Hz, 1H), 7.71 (t, J=7.2 Hz, 1H), 7.52-7.47 (m, 2H), 7.46-7.36 (m, 4H), 4.73-4.42 (m, 1H), 2.50 (s, 3H)
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:23])[C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)=[N:13][CH:12]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].[C@H:24]1([C:33](O)=[O:34])[CH2:29][CH2:28][C@H:27]([C:30]([OH:32])=[O:31])[CH2:26][CH2:25]1.CCN=C=NCCCN(C)C>CN(C=O)C>[I:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:18][CH2:19][N:20]([C:33]([CH:24]4[CH2:25][CH2:26][CH:27]([C:30]([OH:32])=[O:31])[CH2:28][CH2:29]4)=[O:34])[CH2:21][CH2:22]3)=[N:13][CH:12]=2)=[O:23])[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1ccc(NC(=O)c2ccc(N3CCNCC3)nc2)cc1I
Reactant: O=C(O)[C@H]1CC[C@H](C(=O)O)CC1
Agent: CCN=C=NCCCN(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(NC(=O)c2ccc(N3CCN(C(=O)C4CCC(C(=O)O)CC4)CC3)nc2)cc1I
Reaction time: 8 h
Yield: 12.4 %

Procedure:
A mixture of N-(3-iodo-4-methyl-phenyl)-6-piperazin-1-yl-nicotinamide (60 mg, 0.14 mmol), trans-1,4-cyclohexane dicarboxylic acid (122 mg, 0.71 mmol) in DMF (10 mL) was treated with EDCI (130 mg, 0.71 mmol). After stirring overnight the reaction mixture was partitioned between EtOAc and water. The water layer was made basic to pH 13 with solid NaOH. The EtOAc layer was removed and then the water layer was acidified to pH 5 with aq conc. HCl and extracted again with EtOAc. The EtOAc layer obtained after the latter extraction was dried over Na2SO4, filtered and concentrated to the product (10 mg, Yield: 12%). HRMS m/z calcd for C25H29N4O4I [M+H]+: 577.1306. Found: 577.1306.
Reaction SMILES: [N:1]([C:4]12[CH2:13][CH:8]3[CH2:9][CH:10]([CH2:12][CH:6]([CH2:7]3)[CH2:5]1)[CH2:11]2)=[C:2]=[O:3].Cl.[CH3:15][N:16]1[CH2:21][CH2:20][N:19]([C:22]2[CH:27]=[C:26]([C:28]3[CH:37]=[C:36]4[C:31]([CH2:32][CH2:33][NH:34][CH2:35]4)=[CH:30][CH:29]=3)[N:25]=[C:24]([NH2:38])[N:23]=2)[CH2:18][CH2:17]1>>[C:4]12([NH:1][C:2]([N:34]3[CH2:33][CH2:32][C:31]4[C:36](=[CH:37][C:28]([C:26]5[CH:27]=[C:22]([N:19]6[CH2:18][CH2:17][N:16]([CH3:15])[CH2:21][CH2:20]6)[N:23]=[C:24]([NH2:38])[N:25]=5)=[CH:29][CH:30]=4)[CH2:35]3)=[O:3])[CH2:13][CH:8]3[CH2:7][CH:6]([CH2:12][CH:10]([CH2:9]3)[CH2:11]1)[CH2:5]2
Reactant: CN1CCN(c2cc(-c3ccc4c(c3)CNCC4)nc(N)n2)CC1
Reactant: O=C=NC12CC3CC(CC(C3)C1)C2
Agent: Cl
Product: CN1CCN(c2cc(-c3ccc4c(c3)CN(C(=O)NC35CC6CC(CC(C6)C3)C5)CC4)nc(N)n2)CC1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 5 starting from 1-isocyanatoadamantane (Aldrich, Cat. #375073) and 4-(4-methylpiperazin-1-yl)-6-(1,2,3,4-tetrahydroisoquinolin-7-yl)pyrimidin-2-amine HCl salt. Analytic LCMS (M+H)+: m/z=502.3.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]([C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=1)[C:18](O)=[O:19])[C:9]([CH3:25])([CH3:24])[CH2:8]2)=[O:4].C(N1C=CN=C1)(N1C=CN=C1)=O.[CH:38]1([S:41]([NH2:44])(=[O:43])=[O:42])[CH2:40][CH2:39]1.N12CCCN=C1CCCCC2>O1CCCC1.C(OCC)(=O)C>[CH:38]1([S:41]([NH:44][C:18]([C:17]2[CH:16]=[C:15]([CH:10]3[C:9]([CH3:25])([CH3:24])[CH2:8][C:7]4[C:12](=[CH:13][CH:14]=[C:5]([C:3]([O:2][CH3:1])=[O:4])[CH:6]=4)[NH:11]3)[CH:23]=[CH:22][CH:21]=2)=[O:19])(=[O:43])=[O:42])[CH2:40][CH2:39]1
Reactant: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(C(=O)O)c1)N2
Reactant: NS(=O)(=O)C1CC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCOC(C)=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(C(=O)NS(=O)(=O)C3CC3)c1)N2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 110.9 %

Procedure:
A solution of 3-(6-(methoxycarbonyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinolin-2-yl)benzoic acid (150 mg, 0.44 mmol) and 1,1′-carbonyldiimidazole (214 mg, 1.32 mmol) in tetrahydrofuran (3 mL) was heated to 60° C. for 1.5 h, then was cooled to room temperature and treated with cyclopropanesulfonamide (69.1 mg, 0.57 mmol). After stirring for 10 min, the reaction mixture was treated with dropwise addition of a solution of 1,8-diazabicyclo[5.4.0]undec-7-ene (221 mg, 1.45 mmol) in tetrahydrofuran (1 mL). Upon completion of addition, the resultant mixture was stirred for an additional 3 h, Thin layer chromatography (petroleum ether:ethyl acetate=1:1) showed the reaction was complete. The reaction mixture was quenched with brine and acidified with 1N hydrochloric acid solution to pH=6, extracted with ethyl acetate (twice). The combined organic layers were washed with brine for 3 times, dried over anhydrous magnesium sulfate. Removal of the solvent in vacuo gave 216 mg of methyl 2-(3-(cyclopropylsulfonylcarbamoyl)phenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate as a white solid, which was pure enough for next step without further purification. MS (ESI+APCI) M+1=443.2.
Reaction SMILES: [CH2:1]([OH:23])[C@H:2]1[O:7][C@H:6]([O:8][C@H:9]2[C@H:14]([OH:15])[C@@H:13]([OH:16])[C@H:12]([OH:17])[O:11][C@@H:10]2[CH2:18][OH:19])[C@H:5]([OH:20])[C@@H:4]([OH:21])[C@@H:3]1[OH:22].C(O)[C@H]1O[C@H](O[C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)[C@H](O)[C@@H](O)[C@@H]1O>>[CH2:1]([OH:23])[C@H:2]1[O:7][C@H:6]([O:8][C@@H:9]([C@H:14]([OH:15])[C@@H:13]([OH:16])[CH2:12][OH:17])[C@H:10]([OH:11])[CH2:18][OH:19])[C@H:5]([OH:20])[C@@H:4]([OH:21])[C@@H:3]1[OH:22]
Reactant: OC[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@@H]1O
Agent: OC[C@H]1O[C@H](O[C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)[C@H](O)[C@@H](O)[C@@H]1O
Product: OC[C@@H](O)[C@@H](O[C@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O)[C@H](O)[C@@H](O)CO

Procedure:
The maltitol-rich fraction obtained in the above was treated in accordance with the above method for treating the trehalose-rich fraction to obtain a crystalline powder with a maltitol purity of about 93%, except that the maltitol-rich fraction was previously concentrated to give a concentration of about 80%. The yield of solid contents in the step was about 85%, d.s.b. Since the product shows substantially no reducibility, a sharpened sweetness, and a relatively-low-dental-caries-inducibility, it can be arbitrarily used in food products, cosmetics, and pharmaceuticals.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1)[C:6](Cl)=[O:7].[Cl:18][C:19]1[CH:37]=[CH:36][C:22]([CH2:23][N:24]2[CH2:29][CH2:28][CH:27]([CH2:30][NH:31][C:32](=[O:35])[CH2:33][NH2:34])[CH2:26][CH2:25]2)=[CH:21][CH:20]=1.CO>ClCCl.C(Cl)(Cl)Cl>[Cl:18][C:19]1[CH:37]=[CH:36][C:22]([CH2:23][N:24]2[CH2:25][CH2:26][CH:27]([CH2:30][NH:31][C:32](=[O:35])[CH2:33][NH:34][C:6](=[O:7])[C:5]3[CH:4]=[C:3]([C:2]([F:17])([F:16])[F:1])[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=3)[CH2:28][CH2:29]2)=[CH:21][CH:20]=1
Reactant: NCC(=O)NCC1CCN(Cc2ccc(Cl)cc2)CC1
Reactant: O=C(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: ClCCl
Solvent: CO
Solvent: ClC(Cl)Cl
Product: O=C(CNC(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)NCC1CCN(Cc2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 3,5-bis(trifluoromethyl)benzoyl chloride (0.058 mmol) in dichloromethane (1 mL) was added to a mixture of 1-(4-chlorobenzyl)-4-{(glycylamino)methyl}piperidine (0.050 mmol) and piperidinomethylpolystyrene (58 mg) in chloroform (0.2 mL) and dichloromethane (0.75 mL). After the reaction mixture was stirred at room temperature for 2 h, methanol (1.0 mL) was added and the mixture was stirred at room temperature for 30 min. The reaction mixture was loaded onto Varian™ SCX column, and washed with CH3OH (16 mL). Product was eluted off using 2 N NH3 in CH3OH (6 mL) and concentrated to afford 1-(4-chlorobenzyl)-4-[{N-(3,5-bis(trifluoromethyl)benzoyl)glycyl}aminomethyl]piperidine (Compound No. 1213) (24.0 mg, 90%): The purity was determined by RPLC/MS (100%); ESI/MS m/e 536.2 (M++H, C24H24ClF6N3O2).
Reaction SMILES: CN(C)C1C=CC([N+]([O-])=[CH:10][C:11]2[N:15]([C:16]3[C:21]([Cl:22])=[CH:20][C:19]([C:23]([F:26])([F:25])[F:24])=[CH:18][N:17]=3)[N:14]=[CH:13][C:12]=2[C:27]#[N:28])=CC=1.Cl.C(OCC)(=[O:34])C>>[C:27]([C:12]1[CH:13]=[N:14][N:15]([C:16]2[C:21]([Cl:22])=[CH:20][C:19]([C:23]([F:26])([F:25])[F:24])=[CH:18][N:17]=2)[C:11]=1[CH:10]=[O:34])#[N:28]
Reactant: CN(C)c1ccc([N+]([O-])=Cc2c(C#N)cnn2-c2ncc(C(F)(F)F)cc2Cl)cc1
Reactant: CCOC(C)=O
Agent: Cl
Product: N#Cc1cnn(-c2ncc(C(F)(F)F)cc2Cl)c1C=O

Procedure:
To a stirred suspension of 7.6 grams (0.02 mole) of N-[4-(dimethylamino)phenyl]-a-[4-cyano-1-(3-chloro-5-trifluoromethylpyridin-2-yl)-1H-pyrazol-5-yl]nitrone in 300 mL of ethyl acetate was added 400 mL of aqueous 6N hydrochloric acid, at which time all of the solid material dissolved. The aqueous layer was separated and extracted with one portion of ethyl acetate. An aqueous solution saturated with sodium chloride was added to the aqueous layer, and the mixture was extracted several more times with ethyl acetate. The ethyl acetate extracts were combined with the organic layer, and the combination was washed with water. The organic layer was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residual oil. The oil was cooled and triturated with heptane, yielding 2.5 grams of 4-cyano-5-formyl-1-(3-chloro-5-trifluoromethylpyridin-2-yl)-1H-pyrazole. The nmr spectrum was consistent with the proposed structure. (The compounds of Steps E, F, and G were prepared by the method of E. C. Taylor et al., J. Org. Chem., 43, 4, 736 (1978).)
Reaction SMILES: [CH3:1][N:2](OCC1C=CC=CC=1)[C:3]1([CH3:21])[CH2:12][CH2:11][CH2:10][C:9]2[N:8]=[C:7]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:6]=[CH:5][C:4]1=2.B.O1CCCC1.O>O1CCCC1>[CH3:1][NH:2][C:3]1([CH3:21])[CH2:12][CH2:11][CH2:10][C:9]2[N:8]=[C:7]([O:13][CH2:14][C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:6]=[CH:5][C:4]1=2
Reactant: CN(OCc1ccccc1)C1(C)CCCc2nc(OCc3ccccc3)ccc21
Agent: B
Solvent: O
Solvent: C1CCOC1
Product: CNC1(C)CCCc2nc(OCc3ccccc3)ccc21
Temperature: 0 °C
Yield: 70.5 %

Procedure:
5,6,7,8-Tetrahydro-N,5-dimethyl-N,2-bis(phenylmethoxy)-5-quinolinamine (12.3 g) in tetrahydrofuran (160 ml) at 0° C. was treated dropwise with borane-tetrahydrofuran complex (1M in tetrahydrofuran, 63.4 ml). The solution was heated under reflux for 3 hrs, cooled to 0° C., and water (30 ml) was added. The reaction mixture was concentrated in vacuo, 20% potassium hydroxide solution (60 ml) was added, and the mixture was heated at reflux for 2 hrs. The mixture was cooled, acidified with conc hydrochloric acid, and washed with diethyl ether. The aqueous phase was basified with 20% potassium hydroxide solution and extracted with dichloromethane. The combined organic layers were washed with brine, dried over potassium carbonate, filtered, and the filtrate was concentrated to afford 6.3 g (92%) of product.
Reaction SMILES: C[O:2][C:3](=[O:27])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[C:23]([NH:24][CH2:25][CH3:26])=[CH:22][CH:21]=[CH:20][N:19]=3)[CH2:14][CH2:13]2)=[O:11])=[N:6][CH:5]=1.Cl.C(O)(C)C.O>CO.[OH-].[Na+]>[CH2:25]([NH:24][C:23]1[C:18]([N:15]2[CH2:14][CH2:13][N:12]([C:10]([C:7]3[CH:8]=[CH:9][C:4]([C:3]([OH:27])=[O:2])=[CH:5][N:6]=3)=[O:11])[CH2:17][CH2:16]2)=[N:19][CH:20]=[CH:21][CH:22]=1)[CH3:26]
Reactant: CCNc1cccnc1N1CCN(C(=O)c2ccc(C(=O)OC)cn2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: CC(C)O
Product: CCNc1cccnc1N1CCN(C(=O)c2ccc(C(=O)O)cn2)CC1
Temperature: 20 °C
Reaction time: 2 h
Yield: 86 %

Procedure:
6-[1-[3-(Ethylamino)-2-pyridyl]piperazin-4-yl-carbonyl]nicotinic acid methyl ester (3 g) was dissolved in methanol (18 ml) and with the addition of aqueous 1N-sodium hydroxide (18 ml), the mixture was hydrolyzed at 30° C. for 2 hours. 3N-hydrochloric acid was slowly added to the mixture for neutralization (pH=5˜6), followed by the addition of isopropanol (25 ml) and the slow addition of excess of water to precipitate. After 2-hours stirring at 20° C., the precipitate was filtered, washed with water and dried to give a desired compound of 2.48 g (yield: 86%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]([C:24]2[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=2[F:31])[C:12]2[N:17]=[CH:16][C:15](/[CH:18]=[CH:19]/[C:20]([O:22]C)=[O:21])=[CH:14][CH:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[OH-].[Na+].Cl>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]([C:24]2[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=2[F:31])[C:12]2[N:17]=[CH:16][C:15](/[CH:18]=[CH:19]/[C:20]([OH:22])=[O:21])=[CH:14][CH:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: COC(=O)/C=C/c1ccc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(Cl)cc2)nc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)/C=C/c1ccc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(Cl)cc2)nc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 6.6 %

Procedure:
A tetrahydrofuran solution (5 ml) of the methyl(E)-3-[6-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-3-yl]acrylate (460 mg, 0.991 mmol) obtained in Example 44 was added a 1N sodium hydroxide solution (3.0 ml). The resulting mixture was stirred at room temperature for 4 hours. The reaction mixture was acidified with 1N hydrochloric acid, followed by extraction with ethyl acetate. The extract was washed with water and brine, dried over magnesium sulfate and concentrated. The crude title compound was obtained at a stoichiometric ratio. A portion of the resulting solid was recrystallized from ethyl acetate-hexane to give the title compound (29.4 mg, 0.0653 mmol) as a colorless solid.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[N:6][C:7]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([NH:20][C:21]4[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][C:22]=4[F:31])=[O:19])=[CH:13][CH:12]=3)=[CH:8][CH:9]=2)[NH:4][N:3]=1.[S:32]1[CH:36]=[CH:35][C:34]([C:37](Cl)=[O:38])=[CH:33]1.O>N1C=CC=CC=1>[F:31][C:22]1[CH:23]=[CH:24][C:25]([C:27]([F:28])([F:30])[F:29])=[CH:26][C:21]=1[NH:20][C:18](=[O:19])[NH:17][C:14]1[CH:15]=[CH:16][C:11]([C:7]2[N:6]=[C:5]3[NH:4][N:3]=[C:2]([NH:1][C:37]([C:34]4[CH:35]=[CH:36][S:32][CH:33]=4)=[O:38])[C:10]3=[CH:9][CH:8]=2)=[CH:12][CH:13]=1
Reactant: Nc1n[nH]c2nc(-c3ccc(NC(=O)Nc4cc(C(F)(F)F)ccc4F)cc3)ccc12
Reactant: O=C(Cl)c1ccsc1
Solvent: O
Solvent: c1ccncc1
Product: O=C(Nc1ccc(-c2ccc3c(NC(=O)c4ccsc4)n[nH]c3n2)cc1)Nc1cc(C(F)(F)F)ccc1F
Temperature: 25 °C
Reaction time: 5.5 h

Procedure:
A solution of 1-[4-(3-amino-1H-pyrazolo[3,4-b]pyridin-6-yl)phenyl]-3-(2-fluoro-5-trifluoromethylphenyl)urea (80.0 mg, 0.186 mmol) in pyridine (2 ml) is cooled to 5° C. under argon and thiophene-3-carboxylic acid chloride (27 mg, 0.186 mmol, 1.0 eq.) is added. The mixture is stirred at ambient temperature for 5.5 h. Another equivalent of thiophene-3-carboxylic acid chloride (27 mg, 0.186 mmol) is added and the mixture is stirred at ambient temperature overnight. The reaction is taken up with water, and then extracted with ethyl acetate. The organic phase is washed twice with a salt solution, dried with magnesium sulphate, and concentrated. An orange yellow solid is then obtained. The crude is purified on a silica column, with an eluent gradient of 0% to 5% of methanol in dichloromethane. A beige solid is obtained: