Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[NH:8][N:7]=[C:6]([O:9][S:10]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)(=[O:12])=[O:11])[C:5]=1[CH:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1)(=O)[CH3:2].[F:25][C:26]1[CH:35]=[CH:34][CH:33]=[CH:32][C:27]=1[C:28]([NH:30][NH2:31])=O.C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1>C1(C)C(C)=CC=CC=1>[CH:20]1([C:5]2[C:6]([O:9][S:10]([C:13]3[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=3)(=[O:12])=[O:11])=[N:7][N:8]3[C:4]=2[C:1]([CH3:2])=[N:31][N:30]=[C:28]3[C:27]2[CH:32]=[CH:33][CH:34]=[CH:35][C:26]=2[F:25])[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: NNC(=O)c1ccccc1F
Reactant: CC(=O)c1[nH]nc(OS(=O)(=O)c2ccc(C)cc2)c1C1CCCC1
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: c1ccc(-c2ccccc2)cc1
Solvent: Cc1ccccc1C
Product: Cc1ccc(S(=O)(=O)Oc2nn3c(-c4ccccc4F)nnc(C)c3c2C2CCCC2)cc1
Temperature: 180 °C

Procedure:
Toluene-4-sulfonic acid 5-acetyl-4-cyclopentyl-1H-pyrazol-3-yl ester (0.65 g, 1.87 mmol) and 2-fluorobenzhydrazide (0.317 g, 1.1 molar eq) were stirred together in xylene (20 ml) at reflux for 2 h. The solvent was reduced to ˜5 ml and Dowtherm A (20 ml) was added and the reaction mixture was heated at 180° C. for 3 h. The mixture was cooled and poured directly onto a column of silica gel, and the Dowtherm was eluted off with dichloromethane before eluting the product off with 3-5% ethyl acetate in dichloromethane (UV detection). Toluene-4-sulfonic acid 3-cyclopentyl-7-(2-fluorophenyl)-4-methylpyrazolo[1,5-d][1,2,4]triazin-2-yl ester was obtained as a light brown solid (0.5 g). 1H NMR (360 MHz, CDCl3) δ 1.72-2.06 (8H, m), 2.42 (8H, s), 2.91 (3H, 8), 3.46 (1H, m), 7.16-7.33 (4H, m), 7.58-7.65 (2H, m), 7.84 (2H, d, J=8.7 Hz); MS (ES+) m/e 467 [MH]+.
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]([N:5]1[CH:10]2[CH2:11][CH2:12][CH:6]1[CH2:7][C:8](=[C:13]1[C:26]3[CH:25]=[CH:24][C:23]([C:27]#[N:28])=[CH:22][C:21]=3O[C:19]3[C:14]1=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:9]2)=[O:4].[NH2:31][OH:32].Cl.C([O-])([O-])=O.[K+].[K+].[OH2:40]>CCO>[OH:32][NH:31][C:27]([C:23]1[CH:22]=[CH:21][C:26]2[C:13](=[C:8]3[CH2:9][CH:10]4[N:5]([C:3](=[O:4])[C:2]([F:30])([F:29])[F:1])[CH:6]([CH2:12][CH2:11]4)[CH2:7]3)[C:14]3[C:15]([O:40][C:25]=2[CH:24]=1)=[CH:16][CH:17]=[CH:18][CH:19]=3)=[NH:28]
Reactant: NO
Reactant: N#Cc1ccc2c(c1)Oc1ccccc1C2=C1CC2CCC(C1)N2C(=O)C(F)(F)F
Reactant: O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: N=C(NO)c1ccc2c(c1)Oc1ccccc1C2=C1CC2CCC(C1)N2C(=O)C(F)(F)F
Temperature: 25 °C

Procedure:
To a suspension of compound 5e (0.44 g, 1.07 mmol) in EtOH (5 mL) were added NH2OH.HCl (0.223 g, 3.19 mmol) and K2CO3 (0.3 g, 2.17 mmol). The reaction mixture was refluxed for 4 h. Upon cooling to room temperature, H2O (1 mL) was added to the mixture. The mixture was extracted with CH2Cl2 (2×5mL), dried (MgSO4), and concentrated to yield compound 6a. The product 6a was used in the next reaction without further purification. MS m/z (MH+) 443.9.
Reaction SMILES: [Cl:1]Cl.[Cl:3][CH:4]([Cl:13])[C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:6].C([O-])(=O)C.[Na+]>>[Cl:3][C:4]([Cl:1])([Cl:13])[C:5]([C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)=[O:6]
Reactant: ClCl
Reactant: O=C(c1ccccc1)C(Cl)Cl
Agent: CC(=O)[O-]
Agent: [Na+]
Product: O=C(c1ccccc1)C(Cl)(Cl)Cl

Procedure:
The synthetic method described in U.S. Pat. No. 4,642,384 involves the preparation of 2,5-bis(2,2,2-trifluoroethoxy)-α,α-dichloroacetophenone as an intermediate by chlorinating the α-unsubstituted 2,5-bis(2,2,2-trifluoroethoxy)acetophenone with chlorine gas at a moderate temperature, such as 50-60° C. The α,α-dichloroacetophenone intermediate is further chlorinated in the presence of a buffering base, such as sodium acetate, at a slightly higher temperature, such as 80-100° C. to yield the α,α,α-trichloroacetophenone. The (α,α,α-trichloroacetophenone is reacted with 2-aminomethylpyridine to yield a benzamide, and the pyridine ring is reduced to yield 2,5-bis(2,2,2-trifluoroethoxy)-N-(2-piperidylmethyl)-benzamide.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:18]([O:19][CH3:20])=[CH:17][C:6]2[CH2:7][C:8](=[O:16])[N:9]([CH2:12][CH2:13][CH2:14]Cl)[CH2:10][CH2:11][C:5]=2[CH:4]=1.[C:21]1([O:27][CH2:28][CH2:29][NH:30][CH3:31])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(N(CC)CC)C.Cl>O.C(Cl)Cl>[CH3:1][O:2][C:3]1[C:18]([O:19][CH3:20])=[CH:17][C:6]2[CH2:7][C:8](=[O:16])[N:9]([CH2:12][CH2:13][CH2:14][N:30]([CH3:31])[CH2:29][CH2:28][O:27][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:10][CH2:11][C:5]=2[CH:4]=1
Reactant: CNCCOc1ccccc1
Reactant: COc1cc2c(cc1OC)CC(=O)N(CCCCl)CC2
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc2c(cc1OC)CC(=O)N(CCCN(C)CCOc1ccccc1)CC2

Procedure:
Here, 3-(7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl)-1-chloropropane (18.5 g, 0.0623 mol) is heated to 110° C. for 2 hours in an autoclave with N-(2-phenyloxyethyl)-methylamine (10.3 g, 0.0623 mol) and triethylamine (8.7 ml, 0.062 mol). After cooling, the reaction mixture is distributed between methylene chloride and water, the organic phase is separated off, dried over sodium sulfate and concentrated by evaporation. The residue is purified by chromatography on silica gel (eluant: methylene chloride/methanol=9/1). The base thus obtained is converted into the hydrochloride in the usual way.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([CH2:14][OH:15])=[CH:12][N:11]=[CH:10][N:9]=2)=[CH:4][CH:3]=1>[O-2].[O-2].[Mn+4].O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:13]([CH:14]=[O:15])=[CH:12][N:11]=[CH:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: OCc1cncnc1-c1ccc(F)cc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: C1CCOC1
Product: O=Cc1cncnc1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.7 %

Procedure:
A mixture of [4-(4-fluorophenyl)pyrimidin-5-yl]methanol (4.8 g), manganese dioxide (28 g) and tetrahydrofuran (300 mL) was stirred overnight at room temperature. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give the title compound (3.6 g).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH3:14])[C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][N:6]=1.[H-].[Na+].Br[CH2:18][CH:19]1[CH2:21][CH2:20]1>C1COCC1.CN(C=O)C.CCOC(C)=O>[CH:19]1([CH2:18][O:1][CH2:2][CH2:3][N:4]([CH3:14])[C:5]2[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][N:6]=2)[CH2:21][CH2:20]1
Reactant: BrCC1CC1
Reactant: CN(CCO)c1ccc([N+](=O)[O-])cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CN(CCOCC1CC1)c1ccc([N+](=O)[O-])cn1
Reaction time: 8 h

Procedure:
(2-Hydroxy-ethyl)-methyl-(5-nitro-pyridin-2-yl)-amine (98.5 mg, 0.5 mmol) in THF (10 mL) and DMF (2 mL) was stirred with 60% NaH in oil (32 mg, 0.8 mmol) for 1 hr. The mixture was cooled and to this was added bromomethylcyclopropane (0.685 mg, 5 mmol). The reaction mixture was allowed to stir overnight. The mixture was diluted with EtOAc, extracted with H2O and dried over MgSO4. The EtOAc was filtered, evaporated to dryness and used without further purification. Yield: 82 mg. ES-MS calcd for C12H17N3O3 (m/e) 251.29, obsd 252.1 (M+H).
Reaction SMILES: [NH2:1][C:2]1[C:11]([C:12]([O:14][CH3:15])=[O:13])=[C:10]2[C:5]([CH:6]3[CH2:16][CH:7]3[CH2:8][O:9]2)=[CH:4][CH:3]=1.[CH2:17]([N:19]1[CH2:23][CH2:22][C@@H:21]([CH2:24][C:25]2[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=2[S:32](Cl)(=[O:34])=[O:33])[CH2:20]1)[CH3:18]>C(Cl)Cl.N1C=CC=CC=1>[CH2:17]([N:19]1[CH2:23][CH2:22][C@@H:21]([CH2:24][C:25]2[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=2[S:32]([NH:1][C:2]2[C:11]([C:12]([O:14][CH3:15])=[O:13])=[C:10]3[C:5]([C@@H:6]4[CH2:16][C@@H:7]4[CH2:8][O:9]3)=[CH:4][CH:3]=2)(=[O:33])=[O:34])[CH2:20]1)[CH3:18]
Reactant: CCN1CC[C@@H](Cc2cc(F)ccc2S(=O)(=O)Cl)C1
Reactant: COC(=O)c1c(N)ccc2c1OCC1CC21
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCN1CC[C@@H](Cc2cc(F)ccc2S(=O)(=O)Nc2ccc3c(c2C(=O)OC)OC[C@H]2C[C@@H]32)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 22.7 %

Procedure:
A solution of methyl (1aRS,7bSR)-5-amino-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate (Intermediate 42, 0.257 g) in DCM (10 mL) and pyridine (5 mL) was treated with a solution of 2-((R)-1-ethylpyrrolidin-3-ylmethyl)-4-fluorobenzenesulfonyl chloride (Intermediate 96, 0.36 g) in DCM (10 mL) and the mixture was stirred at room temperature overnight. The resultant mixture was evaporated to dryness and the residue was re-dissolved in DCM, washed with water, dried (MgSO4) and filtered. The filtrate was evaporated to dryness and the residue was purified by chromatography on silica, eluting with a mixture of methanol and DCM with a gradient of 0-10%, then flushed with 100% methanol to give methyl (1aS,7bR)-5-[2-((R)-1-ethylpyrrolidin-3-ylmethyl)-4-fluorobenzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate (0.13 g) as a gum.
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10]([F:13])[C:9]([CH3:14])=[C:8]2[C:3]=1[C:4](=[O:23])[C:5]([C:18]([O:20]CC)=[O:19])=[CH:6][N:7]2[CH:15]1[CH2:17][CH2:16]1.Cl>C(O)(=O)C>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([F:13])[C:9]([CH3:14])=[C:8]2[C:3]=1[C:4](=[O:23])[C:5]([C:18]([OH:20])=[O:19])=[CH:6][N:7]2[CH:15]1[CH2:17][CH2:16]1
Reactant: CCOC(=O)c1cn(C2CC2)c2c(C)c(F)c(F)c(N)c2c1=O
Agent: Cl
Solvent: CC(=O)O
Product: Cc1c(F)c(F)c(N)c2c(=O)c(C(=O)O)cn(C3CC3)c12
Yield: 87.3 %

Procedure:
A mixture of 14.8 g of ethyl 5-amino-1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylate, 37.2 ml of hydrochloric acid and 150 ml of 90% acetic acid was heated at reflux for 2 hours. After cooling, the deposited crystals were collected by filtration and washed with water to give 11.8 g of the desired compound as yellow crystals. The crystals were subsequently recrystallized from N,N-dimethylformamide to give yellow crystals, m.p. 290.5° C. (decomp.).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([CH3:13])[CH:10](O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:15]([N:17](CC)CC)C.CS(Cl)(=O)=O.O>ClCCl>[CH2:1]([N:8]1[CH2:12][C@H:11]([CH3:13])[C@H:10]([C:15]#[N:17])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1CN(Cc2ccccc2)CC1O
Reactant: CCN(CC)CC
Agent: CS(=O)(=O)Cl
Solvent: O
Solvent: ClCCl
Product: C[C@H]1CN(Cc2ccccc2)C[C@H]1C#N
Reaction time: 1 h

Procedure:
c is-1-Benzyl-3-hydroxy-4-methylpyrrolidine (6.81 g) was dissolved in dichloromethane (70 mL). While this solution was cooled on a dry ice/acetone bath, triethylamine (5.21 mL) was added. Methanesulfonyl chloride (2.89 mL) was then added dropwise and the mixture was further stirred for 1 hour. Following addition of water (50 mL), the temperature of the mixture was allowed to rise to room temperature and the dichloromethane layer was separated. The aqueous layer was extracted with dichloromethane (50 mL) and the extract was combined with the dichloromethane layer. The combined dichloromethane layer was then washed with water, followed by drying over anhydrous sodium sulfate and concentration under reduced pressure. The resulting residue was dissolved in acetonitrile (180 mL). To this solution, tetrabutylammonium cyanide (23.9 g) was added and the mixture was refluxed for 7 hours while heated. Subsequently, the reaction mixture was concentrated under reduced pressure and the resulting residue was dissolved in ethyl acetate (300 mL). The solution was washed with water, was dried over anhydrous sodium sulfate, and was concentrated under reduced pressure. The resulting residue was purified on a silica gel column (hexane:ethyl acetate=1:1) to give 4.61 g of cis-1-benzyl-4-methyl-3-pyrrolidinecarbonitrile as a brown oil.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[CH2:4][CH2:3]1.[C:18](N1C=CN=C1)(N1C=CN=C1)=[S:19].Cl>ClCCl>[N:1]([C@H:2]1[CH2:3][CH2:4][C@H:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH:12]2[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]2)[CH2:6][CH2:7]1)=[C:18]=[S:19]
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: N[C@H]1CC[C@H](CCCCC2CCCCC2)CC1
Agent: Cl
Solvent: ClCCl
Product: S=C=N[C@H]1CC[C@H](CCCCC2CCCCC2)CC1
Reaction time: 8 h

Procedure:
A solution of 12.2 g of trans-4-(4-aminocyclohexyl)-butylcyclohexane in 135 ml of dichloromethane is added dropwise at 0° under nitrogen to a solution of 15.2 g of 1,1'-thiocarbonyldiimidazole in 90 ml of dichloromethane in the course of 1.5 hours. After standing overnight, about 140 ml of 3% hydrochloric acid are added at 0°-4° until pH 2 is obtained. The organic phase separated off is washed with water until pH 6, is dried over sodium sulfate and evaporated. Purification of the crude product (15.6 g) by column chromatography leaves 13.1 g of trans-4-(4-isothiocyanatocyclohexyl)-butylcyclohexane. Melting point (m.p.) +23°; clear point (c.p.) +72.9°.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[C:10]1([C:16]2[O:17][C:18]([C:21]3[CH:22]=[C:23]([CH:25]=[CH:26][CH:27]=3)[NH2:24])=[N:19][N:20]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[Cl:1][C:2]1[N:7]=[C:6]([NH:24][C:23]2[CH:25]=[CH:26][CH:27]=[C:21]([C:18]3[O:17][C:16]([C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=4)=[N:20][N:19]=3)[CH:22]=2)[C:5]([F:9])=[CH:4][N:3]=1
Reactant: Nc1cccc(-c2nnc(-c3ccccc3)o2)c1
Reactant: Fc1cnc(Cl)nc1Cl
Product: Fc1cnc(Cl)nc1Nc1cccc(-c2nnc(-c3ccccc3)o2)c1

Procedure:
In like manner to the preparation of 2-chloro-5-fluoro-N4-[3-(1H-tetrazol-5-yl)phenyl]-4-pyrimidineamine the reaction of 2,4-dichloro-5-fluoropyrimidine with 3-(2-phenyl-1,3,4-oxadiazol-5-yl)aniline gave 2-chloro-5-fluoro-N4-[3-(2-phenyl-1,3,4-oxadiazol-5-yl)phenyl)-4-pyrimidineamine. 1H NMR (DMSO-d6): δ 10.28 (s, 1H), 8.62 (s, 1H), 8.39 (d, 1H, J=3.3 Hz), 8.11 (m, 2H), 7.98 (bd, 1H, J=6.9 Hz), 7.88 (bd, 1H, J=8.4 Hz), 7.65 (m, 4H); LCMS: purity: 76%; MS (m/e): 76%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)=[C:12]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[N:11]=[C:10]3[NH:27][N:28]=[CH:29][C:9]=23)=[CH:4][CH:3]=1.[OH-].[K+].Br[CH2:33][CH:34]([O:38][CH2:39][CH3:40])[O:35][CH2:36][CH3:37].COCCOCCOC>O.CCOC(C)=O>[CH2:36]([O:35][CH:34]([O:38][CH2:39][CH3:40])[CH2:33][N:28]1[CH:29]=[C:9]2[C:10]([N:11]=[C:12]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[C:13]([C:14]3[CH:15]=[CH:16][N:17]=[CH:18][CH:19]=3)=[C:8]2[C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[N:27]1)[CH3:37].[CH2:36]([O:35][CH:34]([O:38][CH2:39][CH3:40])[CH2:33][N:27]1[C:10]2=[N:11][C:12]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)=[C:13]([C:14]3[CH:15]=[CH:16][N:17]=[CH:18][CH:19]=3)[C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)=[C:9]2[CH:29]=[N:28]1)[CH3:37]
Reactant: Fc1ccc(-c2nc3[nH]ncc3c(-c3ccc(F)cc3)c2-c2ccncc2)cc1
Reactant: CCOC(CBr)OCC
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: COCCOCCOC
Product: CCOC(Cn1cc2c(-c3ccc(F)cc3)c(-c3ccncc3)c(-c3ccc(F)cc3)nc2n1)OCC
Product: CCOC(Cn1ncc2c(-c3ccc(F)cc3)c(-c3ccncc3)c(-c3ccc(F)cc3)nc21)OCC
Temperature: 100 °C
Reaction time: 8 h
Yield: 53 %
Yield: 24 %

Procedure:
In a volumetric flask 4,6-bis(4-fluorophenyl)-5-(4-pyridyl)-1H-pyrazolo[3,4-b]pyridine (0.20 g, 0.5 mmol, obtained in example 1), KOH (0.03 g, 0.5 mmol), 2-bromo-1,1-diethoxyethane (0.10 g, 0.5 mmol) and 1-methoxy-2-(2-methoxyethoxy)ethane (2 mL) were introduced under argon atmosphere. The mixture was heated to 100° C. and stirred at this temperature overnight. It was allowed to cool and a mixture of H2O-EtOAc was added. The phases were separated and the aqueous phase was extracted with EtOAc. The combined organic phases were dried over Na2SO4 and concentrated to dryness. The crude product obtained was purified by chromatography on silica gel using hexane-EtOAc mixtures of increasing polarity as eluent, to afford 139 mg of 2-(2,2-diethoxyethyl)-4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridine (yield: 53%) and 60 mg of 1-(2,2-diethoxyethyl)-4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridine (yield: 24%).
Reaction SMILES: [C:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](F)=[CH:5][CH:4]=1)#[N:2].[NH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH:15]1[CH2:20][OH:21]>N1C=CC=CC=1.C(OCC)(=O)C>[OH:21][CH2:20][CH:15]1[CH2:16][CH2:17][CH2:18][CH2:19][N:14]1[C:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]([C:1]#[N:2])=[CH:4][CH:5]=1
Reactant: OCC1CCCCN1
Reactant: N#Cc1ccc(F)c2ccccc12
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: N#Cc1ccc(N2CCCCC2CO)c2ccccc12

Procedure:
A solution of 1-cyano-4-fluoronaphthalene (200 mg, 1.168 mmol) in pyridine (0.5 mL) was transferred to a Pyrex tube and 2-piperidinemethanol (538 mg, 4.67 mmol) was added. The tube was capped and exposed to microwave irradiation (200° C., 60 min). The reaction mixture was diluted with ethyl acetate, washed with 0.4 N HCl and saturated aqueous NaHCO3. The organic phase was dried and evaporated to give a crude product which was purified by preparative TLC (65:35 n-heptane/ethyl acetate), followed by further purification by preparative HPLC to give 173FBA70e (15 mg, 5%).
Reaction SMILES: C(OC(=O)NC(=N)C1C=CC(CNC([C@H]2N3C(=O)C(NS(C)(=O)=O)=CN=C3CC2)=O)=CC=1)(C)(C)C.C(OC(=O)NC(C1C=CC(CNC([C@H]2N3C(=O)C(N(CC)CC)=CN=C3CC2)=O)=CC=1)=N)(C)(C)C.C(OC(=O)NC(=N)C1C=CC(CNC([C@H]2N3C(=O)C([NH:98][S:99]([C:102]4[C:111]5[C:106](=[CH:107][CH:108]=[CH:109][CH:110]=5)[CH:105]=[CH:104][CH:103]=4)(=[O:101])=[O:100])=CN=C3CC2)=O)=CC=1)(C)(C)C>>[C:102]1([S:99]([NH2:98])(=[O:100])=[O:101])[C:111]2[C:106](=[CH:107][CH:108]=[CH:109][CH:110]=2)[CH:105]=[CH:104][CH:103]=1
Reactant: CC(C)(C)OC(=O)NC(=N)c1ccc(CNC(=O)[C@@H]2CCc3ncc(NS(=O)(=O)c4cccc5ccccc45)c(=O)n32)cc1
Agent: CC(C)(C)OC(=O)NC(=N)c1ccc(CNC(=O)[C@@H]2CCc3ncc(NS(C)(=O)=O)c(=O)n32)cc1
Agent: CCN(CC)c1cnc2n(c1=O)[C@H](C(=O)NCc1ccc(C(=N)NC(=O)OC(C)(C)C)cc1)CC2
Product: NS(=O)(=O)c1cccc2ccccc12
Yield: 30 %

Procedure:
Following a procedure similar to that for the preparation of 16a, intermediate 3a (50 mg, 0.117 mmol) and 1-napthylene sulfonyl chloride (39.8 mg, 0.176 mmol) yielded 21.7 mg (30.0%) of 1-napthalene sulfonamide intermediate 30a. MS (ESI) 617.0 (M+H+).
Reaction SMILES: C([O:3][C:4](=O)[CH:5]=[C:6]([NH2:10])OCC)C.[Br:12][C:13]1[CH:21]=[CH:20][C:16]([CH2:17][NH:18][NH2:19])=[CH:15][CH:14]=1>>[NH2:10][C:6]1[NH:19][N:18]([CH2:17][C:16]2[CH:20]=[CH:21][C:13]([Br:12])=[CH:14][CH:15]=2)[C:4](=[O:3])[CH:5]=1
Reactant: CCOC(=O)C=C(N)OCC
Reactant: NNCc1ccc(Br)cc1
Product: Nc1cc(=O)n(Cc2ccc(Br)cc2)[nH]1

Procedure:
17.5 g of β-amino-β-ethoxyacrylic acid ethyl ester and 20 g of 4-bromobenzylhydrazine, on stirring for 5 hours in alcohol at 50° and working up as described in Example 1, yield 15.6 g of the compound identified above, corresponding to 58% of theory, as colorless crystals of melting point 139°.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9](Cl)=[O:10])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([SH:22])=[CH:18][CH:17]=1.N1C=CC=CC=1>C(#N)C>[C:1]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([S:22][C:19]2[CH:20]=[CH:21][C:16]([O:15][CH3:14])=[CH:17][CH:18]=2)=[O:10])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: COc1ccc(S)cc1
Reactant: CC(=O)Oc1ccc(C(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: CC#N
Product: COc1ccc(SC(=O)c2ccc(OC(C)=O)cc2)cc1
Reaction time: 2 h
Yield: 82.2 %

Procedure:
A solution of 4-acetoxybenzoyl chloride (7.06 g) in dry acetonitrile (15 ml) was added to a solution of 4-methoxythiophenol (5.00 g) in dry acetonitrile (60 ml), and the mixture cooled (ice-bath) and stirred whilst pyridine (2.83 ml) was added dropwise over 10 minutes. The solution was allowed to reach room temperature, stirred for a further 2 hours and the volatile solvents evaporated in vacuo. The residue was partitioned between ethyl acetate and water and the separated organic layer was washed successively with water and brine, dried over magnesium sulphate, and evaporated. Column chromatography of the crude material (silica; ethyl acetate/hexane mixtures as eluant) gave the pure thioester as a pale yellow foam (8.84 g).
Reaction SMILES: C([O:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[N:12][C:13]([O:19][CH2:20][CH2:21][N:22]3[CH2:27][CH2:26][N:25]([C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[C:29]=4[Cl:35])[CH2:24][CH2:23]3)=[CH:14][CH:15]=2)[N:10]=1)C1C=CC=CC=1>CO.[Pd]>[Cl:35][C:29]1[C:30]([Cl:34])=[CH:31][CH:32]=[CH:33][C:28]=1[N:25]1[CH2:24][CH2:23][N:22]([CH2:21][CH2:20][O:19][C:13]2[N:12]=[C:11]3[C:16]([CH:17]=[CH:18][C:9](=[O:8])[NH:10]3)=[CH:15][CH:14]=2)[CH2:27][CH2:26]1
Reactant: Clc1cccc(N2CCN(CCOc3ccc4ccc(OCc5ccccc5)nc4n3)CC2)c1Cl
Agent: [Pd]
Solvent: CO
Product: O=c1ccc2ccc(OCCN3CCN(c4cccc(Cl)c4Cl)CC3)nc2[nH]1
Yield: 56.1 %

Procedure:
2-Benzyloxy-7-{2-[4-(2,3-dichloro-phenyl)-piperazin-1-yl]-ethoxy}-[1,8]naphthyridine (1.30 g, 2.55 mmol) was hydrogenated using 5% Pd/C (0.4 g) in MeOH (100 mL) for 40 min. The reaction was filtered and concentrated. Purification by liquid chromatography (2–3% MeOH/EtOAc with 1% NH4OH) gave the title compound as a white foam (600 mg, 1.43 mmol, 56%). The HCl salt was prepared using 1 N HCl in Et2O to give a white solid. MS: APCI: M+1: 419.1 (Exact Mass: 418.10).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.[Br:9][CH2:10][CH2:11][C:12](Cl)=[O:13].Cl.[F:16][C:17]1[CH:18]=[C:19]([Mg]Br)[CH:20]=[CH:21][C:22]=1[F:23]>O1CCCC1>[Br:9][CH2:10][CH2:11][C:12]([N:6]1[CH:7]=[CH:8][C:3](=[O:2])[CH2:4][CH:5]1[C:20]1[CH:19]=[CH:18][C:17]([F:16])=[C:22]([F:23])[CH:21]=1)=[O:13]
Reactant: COc1ccncc1
Reactant: O=C(Cl)CCBr
Reactant: Fc1ccc([Mg]Br)cc1F
Agent: Cl
Solvent: C1CCOC1
Product: O=C1C=CN(C(=O)CCBr)C(c2ccc(F)c(F)c2)C1
Temperature: -20 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-methoxypyridine (2.7 g) in tetrahydrofuran (50 mL), 3,4-difluorophenylmagnesium bromide (0.5 M solution in tetrahydrofuran; 50 mL) was added dropwise at −40° C. to −20° C. over 10 minutes. To this solution, 3-bromopropionyl chloride (2.49 mL) was added dropwise at −40° C. to −20° C., and the reaction solution was stirred at −20° C. for 30 minutes. The reaction solution was poured into a 10% hydrochloric acid solution, and the mixture was stirred for 20 minutes, followed by extraction with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane-ethyl acetate system) to obtain 3.4 g of 1-(3-bromopropionyl)-2-(3,4-difluorophenyl)-2,3-dihydro-1H-pyridin-4-one. A solution of tributyltin hydride (5.75 mL) and 2,2′-azobis(isobutyronitrile) (0.657 g) in benzene (50 mL) was added dropwise to a solution of 1-(3-bromopropionyl)-2-(3,4-difluorophenyl)-2,3-dihydro-1H-pyridin-4-one obtained above (3.4 g) in benzene (50 mL) at 90° C. over four hours. The reaction solution was stirred at the same temperature for three hours. The reaction solution was returned to room temperature and poured into water, followed by extraction with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane-ethyl acetate system) to obtain 1.4 g of the title compound. The property value of the compound is as follows.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([NH2:8])=[N:6][CH:7]=1.[C:10]1([N:16]2[CH:20]=[C:19]([CH:21]=O)[N:18]=[N:17]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[Br:1][C:2]1[CH:3]=[C:4]2[N:9]=[C:21]([C:19]3[N:18]=[N:17][N:16]([C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=4)[CH:20]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: O=Cc1cn(-c2ccccc2)nn1
Reactant: Nc1cc(Br)cnc1N
Product: Brc1cnc2[nH]c(-c3cn(-c4ccccc4)nn3)nc2c1

Procedure:
The title compound was prepared from 5-bromo-2,3-diaminopyridine and 1-phenyl-1H-1,2,3-triazole-4-carboxaldehyde.