Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:19]2[CH:20]=[CH:21][C:22]([C:25]#[N:26])=[N:23][CH:24]=2)[CH:5]=[C:6]([NH:8][C:9]2[N:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][N:10]=2)[CH:7]=1.[OH:27]O.[OH-].[Na+]>CS(C)=O>[CH3:1][C:2]1[CH:3]=[C:4]([C:19]2[CH:20]=[CH:21][C:22]([C:25]([NH2:26])=[O:27])=[N:23][CH:24]=2)[CH:5]=[C:6]([NH:8][C:9]2[N:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][N:10]=2)[CH:7]=1
Reactant: OO
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2ccc(C#N)nc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2ccc(C(N)=O)nc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of with 5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyridine-2-carbonitrile (50.0 mg, 0.141 mmol) in DMSO (281 μL) was slowly added to a solution of hydrogen peroxide (10.0 μL, 0.326 mmol) and sodium hydroxide (5 M, 56.3 μL, 0.281 mmol). The reaction was stirred at room temperature overnight. The reaction mixture was filtered, diluted with DMF, and directly purified by reverse phase HPLC (5-95% acetonitrile in water+0.5% TFA) to yield 5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyridine-2-carboxamide. MS APCI calc'd for C18H15F3N5O [M+H]+ 374. found 374. 1H NMR (500 MHz, CDCl3) δ 8.85 (s, 1H), 8.65 (d, J=5.6 Hz, 1H), 8.27 (d, J=8.6 Hz, 1H), 8.09 (d, J=8.5, 1H), 7.98 (s, 1H), 7.39 (s, 1H), 7.19 (s, 1H), 7.09 (d, J=5.5 Hz, 1H), 2.47 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.CN(C=O)C.[CH3:22][C:23]([CH3:26])([O-])[CH3:24].[K+]>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[C:6]([C:8]([O:10][C:23]([CH3:26])([CH3:24])[CH3:22])=[O:9])[CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1cccc(Cl)n1
Reactant: CC(C)(C)[O-]
Agent: O=C(Cl)C(=O)Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)c1cccc(Cl)n1
Reaction time: 3 h
Yield: 45.9 %

Procedure:
6-Chloropyridine-2-carboxylic acid (5.00 g, 31.7 mmol) was dissolved in DCM (150 mL) and oxalyl chloride (5.45 mL, 63.5 mmol) and DMF (1 mL) were added. The reaction mixture was stirred for 3 h, concentrated in vacuo and azeotroped with DCM. The residue was dissolved in THF (150 mL) and potassium tert-butoxide (3.39 mg, 47.6 mmol) was added. The reaction mixture was stirred for 18 h, quenched with water (250 mL) and extracted with DCM (3×150 mL). The combined organic fractions were washed with sat aq NaHCO3 (150 mL), dried (MgSO4) and concentrated in vacuo. The residue was purified by column chromatography to give the title compound (3.11 g, 46%) as a white solid. LCMS (ES+): 236.1 [MNa]+.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[C:13]([F:16])([F:15])[F:14])[C:9](=[O:17])[CH:8]=[CH:7][C:6]2=[O:18].Br[CH:22]1[C:25]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:24]2[CH:23]1Br.BrC1C2=CC=CC=C2C1I.C1(C)C(C)=CC=CC=1>O>[F:1][C:2]([F:19])([F:20])[C:3]1[C:12]([C:13]([F:16])([F:15])[F:14])=[CH:11][C:10]2[C:9](=[O:17])[C:8]3[C:7](=[CH:23][C:24]4[C:25]([CH:22]=3)=[CH:26][CH:27]=[CH:28][CH:29]=4)[C:6](=[O:18])[C:5]=2[CH:4]=1
Reactant: BrC1c2ccccc2C1Br
Reactant: O=C1C=CC(=O)c2cc(C(F)(F)F)c(C(F)(F)F)cc21
Agent: BrC1c2ccccc2C1I
Solvent: Cc1ccccc1C
Solvent: O
Product: O=C1c2cc(C(F)(F)F)c(C(F)(F)F)cc2C(=O)c2cc3ccccc3cc21

Procedure:
25 mmol of 6,7-bis-trifluoromethyl-1,4-naphthquinone, approx. 37 mmol of 1,2-dibromobenzocyclobutene [see J. Am. Chem. Soc. 79, pages 1701 et seq. (1957)] containing a little 1-bromo-2-iodobenzocyclobutene and 100 ml of xylene are kept under reflux for 16 hours in a water separator. The reaction mixture is cooled and the precipitate is filtered off and washed with xylene. The crystalline 2,3-di-(trifluoromethyl)-naphthacene-5,12-dione is obtained in a yield of 5.82 g (71%), melting point>280° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]([OH:15])=O)=[CH:11][C:10]([C:16]([O:18]C)=[O:17])=[N:9]1.[CH3:20][S:21]([C:24]1[CH:25]=[C:26]([CH:31]=[CH:32][CH:33]=1)[C:27]([NH:29][NH2:30])=O)(=[O:23])=[O:22].[Cl-].[NH2+]1CCN=[CH:36]1.C(N(CC)CC)C>ClCCl.O>[CH3:36][C:11]1[C:10]([C:16]([OH:18])=[O:17])=[N:9][N:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[C:12]=1[C:13]1[O:15][C:27]([C:26]2[CH:31]=[CH:32][CH:33]=[C:24]([S:21]([CH3:20])(=[O:23])=[O:22])[CH:25]=2)=[N:29][N:30]=1
Reactant: CS(=O)(=O)c1cccc(C(=O)NN)c1
Reactant: C1=NCC[NH2+]1
Reactant: COC(=O)c1cc(C(=O)O)n(-c2ccccc2Cl)n1
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: Cc1c(C(=O)O)nn(-c2ccccc2Cl)c1-c1nnc(-c2cccc(S(C)(=O)=O)c2)o1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 28.6 %

Procedure:
To an ice cooled stirred solution of compound 7 from Example 2 (750 mg, 2.67 mmol) and 3-(methylsulfonyl)benzohydrazide 3 from Example 1 (575 mg, 2.67 mmol) in dichloromethane (25 mL) was added imidazolinium chloride (902 mg, 5.34 mmol) and stirred for 30 min. Triethyl amine (1.5 mL, 10.68 mmol) was added to the reaction mixture slowly over a period of 30 min, allowed to attain room temperature and stirring continued for over night. Water (50 mL) added to the reaction mixture and extracted with 10% methanol in dichloromethane (50 mL×3). The combined organic layer was washed saturated sodium bicarbonate solution, brine, dried over sodium sulphate and concentrated. The crude reaction mixture on column chromatographic purification using 2% methanol in dichoromethane afforded the title compound 11 (350 mg, 50%). LCMS: 459.25 (M+1)+; HPLC: 93.72% (@210 nm-370 nm) (Rf; 6.704; Method: Column: YMC ODS-A 150 mm×4.6 mm×5μ; Mobile Phase: A; 0.05% TFA in water/B; 0.05% TFA in acetonitrile; Inj. Vol: 10 μL, Col. Temp.: 30° C.; Flow rate: 1.4 m/min.; Gradient: 5% B to 95% B in 8 min, Hold for 1.5 min, 9.51-12 min 5% B); 1H NMR (CDCl3, 400 MHz) δ 8.28 (s, 1H), 8.26 (d, 1H), 8.11 (d, 1H, J=7.6 Hz), 7.75-7.71 (m, 2H), 7.62-7.50 (m, 4H), 4.02 (s, 3H), 3.09 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]([CH3:11])([CH3:10])[CH3:9])=[CH:6][C:5]([C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:4][C:3]=1[N:16]1[N+:20]([O-])=[C:19]2[CH:22]=[CH:23][C:24]([Cl:26])=[CH:25][C:18]2=[N:17]1.C1(C)C=CC=CC=1.CNC.[H][H]>[C].[Pd].O.CC(O)CC>[OH:1][C:2]1[C:7]([C:8]([CH3:10])([CH3:11])[CH3:9])=[CH:6][C:5]([C:12]([CH3:13])([CH3:14])[CH3:15])=[CH:4][C:3]=1[N:16]1[N:20]=[C:19]2[CH:22]=[CH:23][C:24]([Cl:26])=[CH:25][C:18]2=[N:17]1
Reactant: CC(C)(C)c1cc(-n2nc3cc(Cl)ccc3[n+]2[O-])c(O)c(C(C)(C)C)c1
Reactant: [H][H]
Agent: [Pd]
Agent: CNC
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCC(C)O
Product: CC(C)(C)c1cc(-n2nc3ccc(Cl)cc3n2)c(O)c(C(C)(C)C)c1
Yield: 84.9 %

Procedure:
37.4 g (0.1 mol) of 2-(2'-hydroxy-3',5'-di-t-butylphenyl)-5-chlorobenzotriazole-N-oxide, 0.125 g of palladium carbon, 300 ml of a solvent mixture comprising toluene, 2-butanol and water (ratio by volume of 10:7:10) and 5 g of 50% dimethylamine were charged into a 500- ml stainless autoclave equipped with an agitator. After the air in the autoclave had been replaced by hydrogen, the pressure of hydrogen was set to 10 kg/cm2. The temperature of the resultant mixture was increased to 60° C. under agitation, and reaction was been effected while agitation being continued until no more hydrogen was absorbed by the mixture. After the reaction had been completed, the autoclave was cooled, and the catalyst was filtered off. After most part of the solvent had been distilled off from the filtrate, the residual solid was washed with ethanol and dried to obtain 30.4 g of 2-(2'-hydroxy-3',5'-di-t-butylphenyl)-5-chlorobenzotriazole as a target substance (yield, 85.0%; melting point, 153° to 155° C.).
Reaction SMILES: [NH:1]1[C:5]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[C:12]2[CH:17]=[CH:16][C:15]([CH2:18][OH:19])=[CH:14][CH:13]=2)=[N:4][N:3]=[N:2]1.C(N(CC)CC)C.Cl>CS(C)=O.C(OCC)(=O)C>[NH:4]1[C:5]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[C:12]2[CH:17]=[CH:16][C:15]([CH:18]=[O:19])=[CH:14][CH:13]=2)=[N:1][N:2]=[N:3]1
Reactant: OCc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: O=Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Temperature: 12 °C
Reaction time: 1 h

Procedure:
A mixture of [2′-(1H-tetrazol-5-yl)-biphenyl-4-yl]-methanol (1.03 g; 4.0 mmol), triethylamine (2.80 mL; 20 mmol) and dimethylsulfoxide (2 mL) is cooled to 12° C., and a solution of sulfur trioxide pyridine complex (1.27 g; 8.0 mmol) in dimethylsulfoxide (6.4 mL) is added over 10 minutes. The resulting clear solution is stirred at room temperature for almost 48 hours during which time more triethylamine (0.28 mL; 2.0 mmol) is added. The mixture is diluted with ethyl acetate (10 mL), cooled to 0 to 5° C. and slowly treated with a 2 M aqueous hydrochloric acid solution (15 mL). The aqueous layer is separated and extracted with ethyl acetate (10 mL). The combined organic layers are diluted with ethyl acetate (10 mL), washed with a 2 M aqueous hydrochloric acid solution (15 mL), twice with a 1 M aqueous hydrochloric acid solution (10 mL) and with a 10% aqueous solution of sodium chloride (10 mL). The organic extract is concentrated at 45° C. under reduced pressure to a volume of about 4 to 5 mL. The resulting suspension is stirred at room temperature for 45 minutes and at 0 to 5° C. for one hour before it is filtered. The solids are washed with cold ethyl acetate (2 mL) and dried at 45° C. under reduced pressure to give 2′-(1H-tetrazol-5-yl)-biphenyl-4-carbaldehyde as white, crystalline solid. A second crop can be obtained by concentrating the mother liquor to a volume of about 1 mL and filtering the solid formed.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[NH:13][C:12]2[C:14]([OH:21])=[CH:15][CH:16]=[C:17]([C:18]([OH:20])=[O:19])[C:11]=2[N:10]=1.OS(O)(=O)=O.[CH3:27]O>>[CH3:27][O:19][C:18]([C:17]1[C:11]2[N:10]=[C:9]([C:3]3[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=3[Cl:1])[NH:13][C:12]=2[C:14]([OH:21])=[CH:15][CH:16]=1)=[O:20]
Reactant: CO
Reactant: O=C(O)c1ccc(O)c2[nH]c(-c3ccc(Cl)cc3Cl)nc12
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(O)c2[nH]c(-c3ccc(Cl)cc3Cl)nc12
Temperature: 25 °C
Yield: 86 %

Procedure:
2-(2,4-dichloro-phenyl)-7-hydroxy-1H-benzoimidazole-4-carboxylic acid (1.63 g, 5.03 mmol) obtained in step 3 was dissolved in 30 ml of methanol, and H2SO4 (1.08 ml, 20.12 mmol) was added dropwise thereto and refluxed for 15 hours. The resulting solution was cooled to room temperature, concentrated under a reduced pressure to remove methanol, and the residue was neutralized with NaHCO3. Then, the neutralized residue was extracted with ethyl acetate and concentrated under a reduced pressure to obtain a residue which was purified by recrystallization from ethyl acetate/hexane to obtain the title compound (1.5 g, 3.62 mmol) in a yield of 86%.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=[O:20])=[CH:17][N:16]=1.O1CCCC1.C(O)C.[BH4-].[Na+]>O>[CH3:1][C:2]1[S:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[N:16]=[CH:17][C:18]([CH2:19][OH:20])=[CH:21][CH:22]=1
Reactant: Cc1sc(-c2ccccc2)nc1COc1ccc(C=O)cn1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: Cc1sc(-c2ccccc2)nc1COc1ccc(CO)cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97 %

Procedure:
To a mixture of 6-[(5-methyl-2-phenyl-4-thiazolyl)methoxy]nicotinaldehyde (4.20 g), tetrahydrofuran (50 ml) and ethanol (50 mL) was added sodium borohydride (0.51 g) at room temperature and the mixture was stirred at room temperature for 30 min. To the reaction mixture was added water and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give crystals (4.10 g, 97%) of [6-[(5-methyl-2-phenyl-4-thiazolyl)methoxy]-3-pyridyl]methanol. Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 70-71° C.
Reaction SMILES: [CH3:1][C:2]([CH3:10])([CH3:9])[CH2:3][CH:4]([C:7]#[N:8])[C:5]#[N:6].[H-].[Na+].[H][H].Br[CH2:16][CH2:17][C:18]([F:21])([F:20])[F:19]>CN(C)C=O.C(OCC)(=O)C>[CH3:1][C:2]([CH3:10])([CH3:9])[CH2:3][C:4]([CH2:16][CH2:17][C:18]([F:21])([F:20])[F:19])([C:7]#[N:8])[C:5]#[N:6]
Reactant: FC(F)(F)CCBr
Reactant: CC(C)(C)CC(C#N)C#N
Reactant: [H][H]
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)CC(C#N)(C#N)CCC(F)(F)F
Temperature: 25 °C
Reaction time: 12 h
Yield: 64.1 %

Procedure:
400 mg of 2-(2,2-dimethylpropyl)malononitrile was dissolved in 5 ml of N,N-dimethylformamide and then cooled in an ice bath. To this was added 120 mg of sodium hydride (60% oil). After generation of hydrogen gas ceased, 750 mg of 1-bromo-3,3,3-trifluoropropane was added dropwise and the mixture was stirred at room temperature for 12 hours. Thereafter, ice water and ethyl acetate were added to the reaction mixture. The mixture was stirred and then separated into layers. The aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed successively with water and aqueous saturated sodium chloride, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 437 mg of 2-(2,2-dimethylpropyl)-2-(3,3,3-trifluoropropyl)malononitrile (hereinafter, referred to as the present compound (43)).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:6]([CH:9]=1)[C:7]#[N:8].Br[CH2:17][C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=1)=[O:19]>>[NH2:8][C:7]1[C:6]2[C:5](=[CH:4][CH:3]=[C:2]([Cl:1])[CH:9]=2)[N:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:17]=1[C:18](=[O:19])[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=1
Reactant: CCOC(=O)Nc1ccc(Cl)cc1C#N
Reactant: O=C(CBr)c1cccc(Cl)c1
Product: CCOC(=O)n1c(C(=O)c2cccc(Cl)c2)c(N)c2cc(Cl)ccc21

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 1 from 5-chloro-2-[(ethoxycarbonyl)amino]benzonitrile (K. O. Geolotte et al, J. Heterocyclic Chem., 1990, 27, 1549) and 2-bromo-3′-chloroacetophenone (M. Kihara et al., Tetrahedron, 1992, 48, 67-78).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:21]([C:22]3[CH:27]=[CH:26][N:25]=[C:24]([NH:28][CH2:29][CH2:30][CH2:31][CH3:32])[N:23]=3)=[C:11]3[CH:12]=[CH:13][CH:14]=[C:15]([NH:16][CH2:17][CH2:18][CH2:19][CH3:20])[N:10]3[N:9]=2)=[CH:4][CH:3]=1.[C:33]1(B(O)O)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCCC1.CCOCC.O>[C:2]1([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:7]=[CH:6][C:5]([C:8]2[C:21]([C:22]3[CH:27]=[CH:26][N:25]=[C:24]([NH:28][CH2:29][CH2:30][CH2:31][CH3:32])[N:23]=3)=[C:11]3[CH:12]=[CH:13][CH:14]=[C:15]([NH:16][CH2:17][CH2:18][CH2:19][CH3:20])[N:10]3[N:9]=2)=[CH:4][CH:3]=1
Reactant: CCCCNc1nccc(-c2c(-c3ccc(Br)cc3)nn3c(NCCCC)cccc23)n1
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: O
Product: CCCCNc1nccc(-c2c(-c3ccc(-c4ccccc4)cc3)nn3c(NCCCC)cccc23)n1
Yield: 68.6 %

Procedure:
To a solution of 2-(4-Bromophenyl)-N-butyl-3-[2-(butylamino)-4-pyrimidinyl]pyrazolo-[1,5-a]pyridin-7-amine (52 mg, 0.11 mmol) in tetrahydrofuran was added phenylboronic acid (26 mg, 0.21 mmol), sodium carbonate (0.21 mL, 2 M aqueous, 0.42 mmol), and dichlorobistriphenylphosphine palladium (II) (7.5 mg, 0.01 mmol). The mixture was heated at reflux for 3.5 hours. The resultant solution was cooled to room temperature and diluted with ether and water was added. The organic layer was washed with brine. The aqueous layer was extracted with ether and the combined organics dried over magnesium sulfate. Filtration and concentration followed by flash chromatography provided 2-[1,1′-biphenyl]-4-yl-N-butyl-3-[2-(butylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-7-amine (37 mg, 73%) as a yellow solid. 1H NMR (CDCl3): δ 8.05 (d, 1 H), 7.83–7.69 (m, 7 H), 7.51 (m, 2 H), 7.43–7.33 (m, 2 H), 6.44 (d, 1 H), 6.12 (t, 1 H), 6.05 (d, 1 H), 5.16 (broad, 1 H), 3.52 (m, 2 H), 3.42 (m, 2 H), 1.84–1.43 (m, 8 H), 1.05–0.99 (m, 6 H); MS m/z 491 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:30])[N:19]([CH2:23][C@@H:24]5[CH2:28][C@@H:27]([OH:29])[CH2:26][NH:25]5)[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:33]([F:36])([F:35])[F:34])[CH:3]=1.[CH2:37]=O>>[Cl:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:30])[N:19]([CH2:23][C@@H:24]5[CH2:28][C@@H:27]([OH:29])[CH2:26][N:25]5[CH3:37])[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:33]([F:36])([F:35])[F:34])[CH:3]=1
Reactant: C=O
Reactant: O=C1S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C(=O)N1C[C@@H]1C[C@@H](O)CN1
Product: CN1C[C@H](O)C[C@H]1CN1C(=O)S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C1=O

Procedure:
(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-{[(2S,4R)-4-hydroxy-1-methylpyrrolidin-2-yl]methyl}-1,3-thiazolidine-2,4-dione was prepared from (5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-{[(2S,4R)-4-hydroxypyrrolidin-2-yl]methyl}-1,3-thiazolidine-2,4-dione and formaldehyde following General Procedure R.
Reaction SMILES: [C:1]([OH:5])(=[O:4])[C:2]#[CH:3].[CH2:6](O)[CH:7]=[CH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C1(N=C=NC2CCCCC2)CCCCC1>CCOCC.CN(C)C1C=CN=CC=1>[C:1]([O:5][CH2:6][CH:7]=[CH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:4])[C:2]#[CH:3]
Reactant: OCC=Cc1ccccc1
Reactant: C#CC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CCOCC
Product: C#CC(=O)OCC=Cc1ccccc1
Temperature: -20 °C
Reaction time: 8 h

Procedure:
2.71 mg (44 mmol) of propiolic acid and 5.14 ml (40 mmol) of cinnamyl alcohol were dissolved in 20 ml of dry ether. The obtained solution was cooled to −20° C. 100 ml of a solution of 9.27 g (45 mmol) of dicyclohexylcarbodiimide and 0.36 g (30 mmol) of 4-dimethylaminopyridine in dry ether was dropped into the solution. The temperature of the obtained mixture was elevated to room temperature. After stirring overnight, the insoluble matter was filtered out. The filtrate was washed with 2 N hydrochloric acid and saturated aqueous salt solution, and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by the silica gel chromatography (hexane/ethyl acetate=10/1) to obtain the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]([C:11]([OH:13])=O)=[N:9][CH:10]=1)=[O:4].C(N(CC)CC)C.C(Cl)(=O)C(C)(C)C.[N+:28]([C:31]1[C:32]([N:37]2[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]2)=[N:33][CH:34]=[CH:35][CH:36]=1)([O-:30])=[O:29]>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:4])[C:5]1[CH:6]=[CH:7][C:8]([C:11]([N:40]2[CH2:41][CH2:42][N:37]([C:32]3[C:31]([N+:28]([O-:30])=[O:29])=[CH:36][CH:35]=[CH:34][N:33]=3)[CH2:38][CH2:39]2)=[O:13])=[N:9][CH:10]=1
Reactant: COC(=O)c1ccc(C(=O)O)nc1
Reactant: O=[N+]([O-])c1cccnc1N1CCNCC1
Agent: CC(C)(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1ccc(C(=O)N2CCN(c3ncccc3[N+](=O)[O-])CC2)nc1
Temperature: 5 °C
Reaction time: 2 h
Yield: 86 %

Procedure:
5-(Methoxycarbonyl)-2-pyridinecarboxylic acid (20 g) was added in methylene chloride (200 ml), and then, dissolved with the addition of triethylamine (17 ml). The mixture was cooled, pivaloyl chloride (14.5 ml) was added at 0° C.˜5° C. and stirred at 5° C. for 2 hours. 1-(3-Nitro-2-pyridyl)piperazine (23 g) and triethylamine (18 ml) were added to the solution in order and the mixture was reacted at 5° C.˜10° C. for 2 hours. The reaction mixture was washed with aqueous sodium bicarbonate and water each twice and then, the separated organic layer was concentrated under reduced pressure. The concentrated residue was treated with ethanol for crystallization and water was added, then the precipitate was filtered. The crude product was recrystallized with ethanol and ether, filtered and dried to give a desired compound of 35.3 g (yield: 86%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5]Cl.[NH2:11][CH:12]([CH3:15])[CH2:13][OH:14]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5][NH:11][CH:12]([CH3:15])[CH2:13][OH:14]
Reactant: CC(N)CO
Reactant: ClCc1ccc(Cl)c(Cl)c1
Product: CC(CO)NCc1ccc(Cl)c(Cl)c1
Temperature: 50 °C
Reaction time: 2 h
Yield: 79 %

Procedure:
3,4-Dichlorobenzyl chloride (0.988 g) was added to 2-amino-1-propanol (4.10 g) and the mixture was stirred at 50° C. under nitrogen for 2 h. The mixture was partitioned between saturated aqueous sodium bicarbonate (100 ml) and ethyl acetate (100 ml) and the phases were separated. The organic layer was washed with water (4×100 ml) and brine, dried (Na2SO4) then concentrated under vacuum to give the title compound as a white solid (0.935 g).
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]([CH2:9]P(=O)(OCC)OCC)#[N:8].O=[C:19]1[CH2:22][N:21]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:20]1>O1CCCC1>[C:7]([CH:9]=[C:19]1[CH2:22][N:21]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:20]1)#[N:8]
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Reactant: CCOP(=O)(CC#N)OCC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC(=CC#N)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.9 %

Procedure:
To a solution of 1.0 M potassium tert-butoxide in tetrahydrofuran (30.7 mL, 0.0307 mol) at 0° C. was added dropwise a solution of diethyl cyanomethylphosphonate (5.20 mL, 0.0322 mol) in tetrahydrofuran (39.12 mL). The reaction was warmed to room temperature and then cooled at 0° C. again. To the reaction mixture was added a solution of tert-butyl 3-oxoazetidine-1-carboxylate (5.0 g, 0.029 mol, Aldrich: Cat. #696315) in tetrahydrofuran (7.82 mL). The reaction was allowed to warm to room temperature and stirred overnight. After quenched with water, the mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over MgSO4 and evaporated under reduced pressure. The crude mixture was purified by flash chromatography on a silica gel column with ethyl acetate in hexanes (0-70%) to give the desired product (5.40 g, 95%). LCMS (M+Na)+: m/z=217.1.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][C:9]([C:11]([OH:13])=[O:12])=[CH:8][C:7](=O)[C:6]=2[CH:15]=1.[H][H].[CH3:18]S(O)(=O)=O>C1COCC1.[Pd]>[CH3:18][O:13][C:11]([CH:9]1[CH:8]=[CH:7][C:6]2[CH:15]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=2[O:10]1)=[O:12]
Reactant: O=C(O)c1cc(=O)c2cc(F)ccc2o1
Reactant: CS(=O)(=O)O
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: COC(=O)C1C=Cc2cc(F)ccc2O1
Temperature: 22.5 °C
Yield: 480.3 %

Procedure:
20 g of 6-fluoro-4-oxo-4H-1-benzopyran-2-carboxylic acid (96 mmol) were hydrogenated under 4 bars of hydrogen in 200 ml THF with 2 g of methanesulfonic acid (20 mmol) and 2 g of 5% Pd on charcoal (Type Escat 112, Engelhard) at 45-55° C. until consumption of hydrogen was no longer observed. The reaction progress was monitored by TLC. The catalyst was then removed by filtration and the reaction mixture concentrated to 40 ml under reduced pressure. 100 ml of methanol were then added and the mixture (solution) was stirred at 20-25° C. until less than 1% of 6-fluoro-3,4-dihydro-2H-chromen-2-carboxylic acid was detected (TLC). The solution was then concentrated under reduced pressure and the residue was dissolved in 60 ml of THF then concentrated under reduced pressure to remove water by azeotropic distillation to give 20 g of the title compound (yield: 100%).