Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[Br:2][C:3]1[CH:4]=[N:5][N:6]([CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:7]=1.CCN(C(C)C)C(C)C.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>CC#N>[Br:2][C:3]1[CH:4]=[N:5][N:6]([CH:8]2[CH2:13][CH2:12][N:11]([S:24]([CH3:23])(=[O:26])=[O:25])[CH2:10][CH2:9]2)[CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: Brc1cnn(C2CCNCC2)c1
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)N1CCC(n2cc(Br)cn2)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 86.2 %

Procedure:
To a solution of 4-(4-bromopyrazol-1-yl)piperidine hydrochloride (380 mg, 1.43 mmol) in CH3CN (10 ml) at 0° C. was added DIPEA (0.75 mlml, 4.3 mmol) followed by methanesulphonyl chloride (0.11 ml, 1.43 mmol), stirred at 0° C. for 1 hour then allowed to warm up to RT over 1 hour. The reaction then partitioned between water and EtOAc. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure to give the product (380 mg), which was used without further purification 1H NMR (400 MHz, Me-d3-OD): 7.84 (1H, s), 7.50 (1H, s), 4.40-4.27 (1H, m), 3.86 (2H, d), 3.05-2.93 (2H, m), 2.90 (3H, s), 2.25-2.01 (4H, m).
Reaction SMILES: C1([CH2:4][CH2:5][NH:6][CH2:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]3[CH:26]=[CH:25][C:19]([C:20]([O:22]CC)=[O:21])=[CH:18][CH:17]=3)=[CH:10][C:9]=2[CH:27]([CH3:29])[CH3:28])CC1.[OH-].[Na+].O1[CH2:36][CH2:35][CH2:34]C1>C(O)C>[CH:34]1([N:6]([CH2:7][C:8]2[C:9](=[C:27]([CH3:29])[CH3:28])[CH2:10][C:11]([C:14]#[C:15][C:16]3[CH:17]=[CH:18][C:19]([C:20]([OH:22])=[O:21])=[CH:25][CH:26]=3)=[CH:12][CH:13]=2)[CH2:5][CH3:4])[CH2:35][CH2:36]1
Reactant: C1CCOC1
Reactant: CCOC(=O)c1ccc(C#Cc2ccc(CNCCC3CC3)c(C(C)C)c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCN(CC1=CC=C(C#Cc2ccc(C(=O)O)cc2)CC1=C(C)C)C1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72 %

Procedure:
Using General Procedure I; a solution of ethyl 4-{4-[(cyclopropylethyl-amino)-methyl]-3-isopropyl-phenylethynyl}-benzoate (Compound 133, 68.0 mg, 0.17 mmol) in ethanol (3 mL) and tetrahydrofuran (3 mL) was treated with NaOH (600.0 mg, 15.0 mmols, 3.0 mL of a 5N aqueous solution) and stirred overnight at room temperature and then at 55° C. for 9 hours. Work-up followed by crystallization of the solid residue from hot CH3CN afforded 45.0 mg (72%) of the title compound as a pale-yellow solid.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1>ClCCl>[I:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Nc1ccccn1
Reactant: O=S(=O)(Cl)c1ccc(I)cc1
Solvent: ClCCl
Product: O=S(=O)(Nc1ccccn1)c1ccc(I)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
4-Iodo-benzenesulfonyl chloride, (52.3 g, 0.17 mol) was dissolved in dichloromethane (300 ml) and 2-aminopyridine (65 g, 0.69 mol) was added. The solution was stirred at room temperature for 3 days, washed with 2M sulfuric acid (2×200 ml) and water (100 ml), dried with Na2SO4 and evaporated to dryness. Yield 46.9 g (76%).
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[CH2:3][NH2:4].[NH2:7][C:8]1[N:13]=[C:12]([N:14]([CH3:21])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:11]=[C:10]([C:22]2[N:26]=[C:25]([C:27]3[CH:28]=[CH:29][C:30]([C:33](OC)=[O:34])=[N:31][CH:32]=3)[O:24][N:23]=2)[N:9]=1>C1(C)C=CC=CC=1>[NH2:7][C:8]1[N:13]=[C:12]([N:14]([CH3:21])[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:11]=[C:10]([C:22]2[N:26]=[C:25]([C:27]3[CH:28]=[CH:29][C:30]([C:33]([NH:4][CH2:3][C:2]([F:6])([F:5])[F:1])=[O:34])=[N:31][CH:32]=3)[O:24][N:23]=2)[N:9]=1
Reactant: COC(=O)c1ccc(-c2nc(-c3nc(N)nc(N(C)c4ccccc4)n3)no2)cn1
Reactant: NCC(F)(F)F
Solvent: Cc1ccccc1
Product: CN(c1ccccc1)c1nc(N)nc(-c2noc(-c3ccc(C(=O)NCC(F)(F)F)nc3)n2)n1
Reaction time: 1 h
Yield: 43 %

Procedure:
To a suspension of 2,2,2-trifluoro-ethylamine (39 mg, 395 μmol) in anhydrous toluene (3 mL) was added bis(trimethylaluminum)-1,4-diazabicyclo[2.2.2]-octane (DABAL-Me3) (101 mg, 395 μmol). The resulting solution was stirred at 40 C for 1 h. Methyl 5-(3-{4-amino-6-[methyl(phenyl)amino]-1,3,5-triazin-2-yl}-1,2,4-oxadiazol-5-yl)pyridine-2-carboxylate (prepared in an analogous manner to Example 279, 80 mg, 197 μmol) was then added to the solution and the reaction mixture was stirred for a further 16 h at 80 C. The reaction mixture was quenched with 1M HCl (1 mL), evaporated to dryness and re-dissolved in DCM. The organic solution was washed with water (3×25 mL), dried over magnesium sulfate, evaporated and purified by silica chromatography (50:50 EtOAc:heptane) to afford the title compound as a white solid (40 mg, 43%).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[CH:3]1.[Li]CCCC.Cl[Si](CC)(CC)CC.[Cl:20][C:21]1[N:30]=[C:29]([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([Cl:37])[CH:32]=2)[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([C:38]([C:40]3[CH:45]=[CH:44][C:43]([CH3:46])=[CH:42][CH:41]=3)=[O:39])[CH:27]=2)[N:22]=1>C1COCC1.O>[Cl:20][C:21]1[N:30]=[C:29]([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([Cl:37])[CH:32]=2)[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([C:38]([C:6]3[N:2]([CH3:1])[CH:3]=[N:4][CH:5]=3)([C:40]3[CH:41]=[CH:42][C:43]([CH3:46])=[CH:44][CH:45]=3)[OH:39])[CH:27]=2)[N:22]=1
Reactant: Cc1ccc(C(=O)c2ccc3nc(Cl)nc(-c4cccc(Cl)c4)c3c2)cc1
Reactant: Cn1ccnc1
Agent: CC[Si](Cl)(CC)CC
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(C(O)(c2ccc3nc(Cl)nc(-c4cccc(Cl)c4)c3c2)c2cncn2C)cc1
Temperature: -70 °C
Reaction time: 0.25 h

Procedure:
1-Methyl-1H-imidazole (0.0507 mol) was added at −70° C. to THF (90 ml) under N2 flow. nBuLi (31.5 ml) was added dropwise. The mixture was stirred at −70° C. for 15 minutes. Chlorotriethyl-silane (0.0522 mol) was added dropwise. The mixture was stirred at −70° C. for 15 minutes. nBuLi (28ml) was added. The mixture was stirred at −70° C. for 15 minutes. A mixture of intermediate 23 (0.029 mol) in THF (115 ml) was added dropwise. The mixture was stirred at −70° C. for 1 hour, poured out into water and extracted with DCM. The organic layer was separated, washed with water, dried (MgSO4), filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (15-35 μm) (eluent: DCM/MeOH/NH4OH; 96/4/0.1). The pure fractions were collected and the solvent was evaporated, yielding 9 g (65%). A sample (0.3 g) was crystallized from 2-propanone, The precipitate was filtered off and dried, yielding 2-chloro-4-(3-chlorophenyl)-α-(1-methyl-1H-imidazol-5-yl)-α-(4-methylphenyl)-6-quinazolinemethanol (intermediate 24), mp. 220° C.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:20])=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:12](I)=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:19]=1.[CH3:21][C:22]([OH:39])([CH3:38])[CH2:23][N:24]1[CH:28]=[C:27](B2OC(C)(C)C(C)(C)O2)[CH:26]=[N:25]1>>[Br:1][C:2]1[C:3]([F:20])=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:12]([C:27]4[CH:26]=[N:25][N:24]([CH2:23][C:22]([OH:39])([CH3:38])[CH3:21])[CH:28]=4)=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:19]=1
Reactant: CC(C)(O)Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: NC(=O)c1nc2n(c1I)CCOc1cc(F)c(Br)cc1-2
Product: CC(C)(O)Cn1cc(-c2c(C(N)=O)nc3n2CCOc2cc(F)c(Br)cc2-3)cn1

Procedure:
10-Bromo-9-fluoro-3-iodo-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2-carboxamide (0.1 g) was reacted with 2-methyl-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl]propan-2-ol similar to as described in Example 5 and triturated from water followed by methanol to give 100 mg of 10-bromo-9-fluoro-3-[1-(2-hydroxy-2-methyl-propyl)pyrazol-4-yl]-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2-carboxamide. This intermediate was reacted with 2-Methyl-3-butyne-ol via similar to as described in Procedure E to afford 18.1 mg of 9-fluoro-10-(3-hydroxy-3-methyl-but-1-ynyl)-3-[1-(2-hydroxy-2-methyl-propyl)pyrazol-4-yl]-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2-carboxamide following reverse phase hplc purification. MS (Q1) 468 (M)+. 1H NMR (400 MHz, DMSO) δ 8.62 (d, J=8.5 Hz, 1H), 8.08 (s, 1H), 7.75 (s, 1H), 7.57 (s, 1H), 7.08-6.91 (m, 2H), 5.50 (s, 1H), 4.68 (s, 1H), 4.54-4.45 (m, 2H), 4.41-4.29 (m, 2H), 4.07 (s, 2H), 1.50 (s, 6H), 1.10 (s, 6H).
Reaction SMILES: [C:1]([C:9]1[C:10](=[O:24])[NH:11][C:12]2[CH:13]=[CH:14][CH:15]=[C:16]([C:20]([O:22]C)=[O:21])[C:17]=2[C:18]=1[OH:19])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].O>CS(C)=O>[C:1]([C:9]1[C:10](=[O:24])[NH:11][C:12]2[CH:13]=[CH:14][CH:15]=[C:16]([C:20]([OH:22])=[O:21])[C:17]=2[C:18]=1[OH:19])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1cccc2[nH]c(=O)c(C(=O)c3ccccc3)c(O)c12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: O=C(c1ccccc1)c1c(O)c2c(C(=O)O)cccc2[nH]c1=O
Yield: 94.1 %

Procedure:
To 0.6 grams of methyl 3-benzoyl-4-hydroxy-2-quinolone-5-carboxylate are added 1.5 grams of sodium hydroxide, 30 ml of water and 30 ml of dimethyl sulfoxide, the mixture is heated at 100° to 120° C. for three hours with stirring, cooled, acidified and diluted hydrochloric acid, and crystals separated out therefrom are collected by filtration to give 0.54 grams of 3-benzoyl-4-hydroxy-2-quinolone-5-carboxylic acid, colorless powder, melting at above 300° C.
Reaction SMILES: S(C1C=CC(C)=CC=1)([O-])(=O)=O.[CH3:12][C:13]1[S:14][C:15]2[CH:22]=[C:21](S(O)(=O)=O)[CH:20]=[CH:19][C:16]=2[N+:17]=1[CH3:18].Cl[C:28](=[O:36])[CH2:29][CH2:30][CH2:31][C:32]([O:34][CH3:35])=[O:33]>N1C=CC=CC=1>[CH3:35][O:34][C:32]([CH2:31][CH2:30][CH2:29][C:28](=[O:36])[CH:12]=[C:13]1[N:17]([CH3:18])[C:16]2[CH:19]=[CH:20][CH:21]=[CH:22][C:15]=2[S:14]1)=[O:33]
Reactant: COC(=O)CCCC(=O)Cl
Reactant: Cc1sc2cc(S(=O)(=O)O)ccc2[n+]1C
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Solvent: c1ccncc1
Product: COC(=O)CCCC(=O)C=C1Sc2ccccc2N1C
Temperature: 55 °C

Procedure:
To 1.7 g of 2,3-dimethyl-6-sulfobenzothiazolium tosylate in 20 mL of pyridine at room temperature is added 1.03 mL of methyl 5-chloro-5-oxovalerate. The mixture is heated at 50-60° C. for 3 hours. The pyridine solvent is removed under reduced pressure, and the reaction is worked up with chloroform and brine, and purified by silica gel column to yield 0.92 g of 2-(5-methoxycarbonyl-2-oxopentylidene)-3-methyl-3H-benzothiazole. A mixture of 0.45 g of this benzothiazole and 0.45 g of phosphorous oxychloride in 5 mL of dichloroethane is heated at reflux for 2 hours to generate 2-(2-chloro-2-methoxycarbonylpropylvinyl)-3-methylbenzothiazolium chloride. The volatile components are evaporated and the crude chloride is used without further purification. The crude chloride and 0.45 g of 2,3,3,7-tetramethyl-3H-pyrrolo[2,3-b]pyridinium tosylate is stirred in 5 mL of dichloroethane in the presence of 0.45 mL of triethylamine for 2 hours. The volatile components are removed under reduced pressure, and the residue is dissolved in 5 mL of methanol and added dropwise to a solution of 4.5 g of sodium iodide in 30 mL water. The sticky solid is purified on a silica gel column to yield Compound 79.
Reaction SMILES: [NH3:1].[N+:2]([C:5]1[C:14]2[O:13][C:12]([C:15](OCC)=[O:16])=[CH:11][C:10](=[O:20])[C:9]=2[CH:8]=[CH:7][CH:6]=1)([O-:4])=[O:3]>C(O)C.O1CCCC1>[N+:2]([C:5]1[C:14]2[O:13][C:12]([C:15]([NH2:1])=[O:16])=[CH:11][C:10](=[O:20])[C:9]=2[CH:8]=[CH:7][CH:6]=1)([O-:4])=[O:3]
Reactant: N
Reactant: CCOC(=O)c1cc(=O)c2cccc([N+](=O)[O-])c2o1
Solvent: C1CCOC1
Solvent: CCO
Product: NC(=O)c1cc(=O)c2cccc([N+](=O)[O-])c2o1
Temperature: 25 °C
Reaction time: 4 h
Yield: 81 %

Procedure:
Gas ammonia was bubbled for 30 minutes in a solution of ethyl 8-nitro-4-oxo-4H-benzopyran-2-carboxylate (2.109 g, 8.02 mmol) in anhydrous ethanol (50 ml) and anhydrous tetrahydrofuran (50 ml). After that the mixture was evaporated to dryness and the resulting solid residue was suspended in concentrated hydrochloric acid (20 ml) stirring at room temperature for 4 h. Then the mixture was diluted with water, the solid was recovered by filtration, washed repeatedly with water and dried under vacuum on phosphorous pentoxyde, to obtain 1.515 g of the title product (81% yield).
Reaction SMILES: O[CH2:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.[CH:13]1[C:18](C(O)=O)=[CH:17][C:16]2[C:22]([O:24][C:25](=O)[C:15]=2[CH:14]=1)=[O:23].[N+](C1C=CC=CC=1)([O-])=O>>[CH:8]1[CH:9]=[C:10]2[CH:11]=[CH:12][C:3]([CH:2]3[C:25](=[O:24])[C:15]4[C:16](=[CH:17][CH:18]=[CH:13][CH:14]=4)[C:22]3=[O:23])=[N:4][C:5]2=[CH:6][CH:7]=1
Reactant: OCc1ccc2ccccc2n1
Reactant: O=C(O)c1ccc2c(c1)C(=O)OC2=O
Solvent: O=[N+]([O-])c1ccccc1
Product: O=C1c2ccccc2C(=O)C1c1ccc2ccccc2n1

Procedure:
As shown by this reaction scheme (5), a hydroxyquinaldine derivative and a trimellitic acid anhydride derivative are added to nitrobenzene, and the mixture is heated and stirred at a refluxing temperature for several hours. Subsequently, the product is collected by filtration and washed with methanol, then dried, to yield the quinophthalone compound of the present invention. Here, a process of removing impurity substances such as inorganic salts can be included. The quinophthalone compound and mixed colorant in the present invention preferably have decreased contents of impurity substances such as inorganic salts, whereby the mechanical properties of the thermoplastic resin can be well maintained, and the anti-migration property and anti-sublimation property can be improved. The content of these impurity substances is desirably not more than 2%.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[Cl:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][C:20]=1[F:21])[CH:16]=O.N1CCCCC1>CO>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5](/[C:6](=[CH:16]/[C:15]3[CH:18]=[CH:19][C:20]([F:21])=[C:13]([Cl:12])[CH:14]=3)/[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: O=C1Cc2ccc(Cl)cc2N1
Reactant: O=Cc1ccc(F)c(Cl)c1
Solvent: C1CCNCC1
Solvent: CO
Product: O=C1Nc2cc(Cl)ccc2/C1=C/c1ccc(F)c(Cl)c1
Temperature: 50 °C
Yield: 81.1 %

Procedure:
To the mixture of 6-chloro-2-oxindole (5.3 g, 32 mmol) (Crescent) and 3-chloro-4-fluorobenzaldehyde (5 g, 32 mmol) (Aldrich) in methanol (200 mL) was added piperidine (2.7 g, 32 mmol) (Aldrich) dropwise. The mixture was then heated at 50° C. for 3 h. After cooled to 4° C., the mixture was filtered and resulting precipitate was collected, dried to give E/Z-6-chloro-3-(3-chloro-4-fluoro-benzylidene)-1,3-dihydro-indol-2-one as a yellow solid (Yield 8 g, 82%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N:3]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].[CH3:17][O:18][C:19](=[O:38])[C:20]1[CH:25]=[C:24](B2OC(C)(C)C(C)(C)O2)[CH:23]=[C:22]([N+:35]([O-:37])=[O:36])[CH:21]=1>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:17][O:18][C:19](=[O:38])[C:20]1[CH:21]=[C:22]([N+:35]([O-:37])=[O:36])[CH:23]=[C:24]([C:2]2[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N:3]=2)[CH:25]=1
Reactant: Cc1ccc(Br)nc1
Reactant: COC(=O)c1cc(B2OC(C)(C)C(C)(C)O2)cc([N+](=O)[O-])c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: COC(=O)c1cc(-c2ccc(C)cn2)cc([N+](=O)[O-])c1
Yield: 39.6 %

Procedure:
To a solution of 2-bromo-5-methylpyridine (1.24 g, 7 mmol), Pd(PPh3)4(226 mg, 0.2 mmol) and K3PO4(2.76 g, 13 mmol) in DME/H2O (5 ml/ml) was added 3-nitro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoic acid methyl ester (2.00 g, 6.5 mmol) under N2 atmosphere. The mixture was subjected to microwave radiation at 130° C. for 0.5 hours. The reaction mixture was cooled and solvent was evaporated under reduced pressure. The residue was purified by flash-chromatography (CH2Cl2/MeOH) to give 3-(5-methyl-pyridin-2-yl)-5-nitro-benzoic acid methyl ester as a white solid (700 mg, 40%).
Reaction SMILES: [CH2:1]([N:5]([CH2:23][CH2:24][CH2:25][CH3:26])[C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[CH:13][C:14]2[S:18][C:17]([CH:19]=O)=[CH:16][CH:15]=2)=[C:8]([O:21][CH3:22])[CH:7]=1)[CH2:2][CH2:3][CH3:4].[C:27]([C:29]1[C:30](=[C:40]([C:43]#[N:44])[C:41]#[N:42])[O:31][C:32]([CH3:39])([C:35]([F:38])([F:37])[F:36])[C:33]=1[CH3:34])#[N:28]>C(O)C.O1CCCC1>[CH2:23]([N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[CH:13][C:14]2[S:18][C:17]([CH:19]=[CH:34][C:33]3[C:32]([CH3:39])([C:35]([F:38])([F:36])[F:37])[O:31][C:30](=[C:40]([C:41]#[N:42])[C:43]#[N:44])[C:29]=3[C:27]#[N:28])=[CH:16][CH:15]=2)=[C:8]([O:21][CH3:22])[CH:7]=1)[CH2:24][CH2:25][CH3:26]
Reactant: CC1=C(C#N)C(=C(C#N)C#N)OC1(C)C(F)(F)F
Reactant: CCCCN(CCCC)c1ccc(C=Cc2ccc(C=O)s2)c(OC)c1
Solvent: C1CCOC1
Solvent: CCO
Product: CCCCN(CCCC)c1ccc(C=Cc2ccc(C=CC3=C(C#N)C(=C(C#N)C#N)OC3(C)C(F)(F)F)s2)c(OC)c1
Temperature: 50 °C
Reaction time: 2 h
Yield: 73.3 %

Procedure:
In 4 ml of ethanol and 1.5 ml of tetrahydrofuran were dissolved 100 mg (0.27 mmol) of 5-[2-(4-dibutylamino-2-methoxyphenyl)vinyl]thiophene-2-carboaldehyde and 75 mg (0.3 mmol) of 2-(3-cyano-4,5-dimethyl-5-trifluoromethyl-2(5H)-furanylidene)propanedinitrile. After the mixture was stirred at 50° C. for 2 hours, the solvent was evaporated off. The residue was washed with ethanol to give 120 mg of a brown powdered crystal (yield: 73.5%; mp: 191-193° C.)
Reaction SMILES: [I:1][C@@H:2]1[C@@H:15]([O:16]C(=O)C)[C@H:14]([O:20]C(=O)C)[C@@H:13]([CH2:24][O:25]C(=O)C)[O:12][C@H:3]1[O:4][Si:5]([CH2:10][CH3:11])([CH2:8][CH3:9])[CH2:6][CH3:7].C(=O)([O-])[O-].[K+].[K+]>C(Cl)(Cl)Cl.CO>[I:1][C@@H:2]1[C@@H:15]([OH:16])[C@H:14]([OH:20])[C@@H:13]([CH2:24][OH:25])[O:12][C@H:3]1[O:4][Si:5]([CH2:10][CH3:11])([CH2:6][CH3:7])[CH2:8][CH3:9]
Reactant: CC[Si](CC)(CC)O[C@@H]1O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]1I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CC[Si](CC)(CC)O[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1I
Temperature: 25 °C
Yield: 18.7 %

Procedure:
Subsequently, the 2-deoxy-2-iodo-3,4,6-tri-O-acetyl-1-O-triethylsilyl-β-D-glucopyranose (III) (0.7 g) was dissolved in the mixture of chloroform:methanol (7:3 v/v) (15 mL). Potassium carbonate (4 g) was added, and reaction mixture was stirred at room temperature until substrate deacetylation has been completed. Inorganic salts were filtered off and solvents were evaporated. Such obtained product was purified by column chromatography (SilicaGel 60, Merck) using chloroform and chloroform:methanol 99:1 as eluents, to give (0.1 g) of 2-deoxy-2-iodo-1-O-triethylsilyl-β-D-glucopyranose (VI) (yield 20%).
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[F:15][C:16]([F:30])([F:29])[C:17]1[CH:18]=[C:19]([CH:22]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:24]=1)[CH:20]=O.C(O)(=O)C.[CH:35]([O:38][C:39]([N:41]1[C:50]2[C:45](=[N:46][C:47]([O:51][CH3:52])=[CH:48][CH:49]=2)[C@H:44]([NH2:53])[CH2:43][C@@H:42]1[CH3:54])=[O:40])([CH3:37])[CH3:36].C(=O)(O)[O-].[Na+]>ClC(Cl)C>[CH:35]([O:38][C:39]([N:41]1[C:50]2[C:45](=[N:46][C:47]([O:51][CH3:52])=[CH:48][CH:49]=2)[C@H:44]([NH:53][CH2:20][C:19]2[CH:18]=[C:17]([C:16]([F:30])([F:29])[F:15])[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=2)[CH2:43][C@@H:42]1[CH3:54])=[O:40])([CH3:37])[CH3:36]
Reactant: O=Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: COc1ccc2c(n1)[C@H](N)C[C@H](C)N2C(=O)OC(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: COc1ccc2c(n1)[C@H](NCc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C[C@H](C)N2C(=O)OC(C)C
Temperature: 25 °C
Reaction time: 14 h
Yield: 81.6 %

Procedure:
Add sodium triacetoxyborohydride (1.160 g, 5.50 mmol) to a mixture of 3,5-bis(trifluoromethyl)benzaldehyde (0.217 mL, 1.32 mmol), acetic acid (0.010 mL, 1.65 mmol), and (+/−)-cis-4-amino-6-methoxy-2-methyl-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid isopropyl ester (0.318 mg, 1.12 mmol) in dichloroethane (10 mL). Stir thie mixture at room temperature under an atmosphere of nitrogen for 14 h. Add a saturated solution of sodium bicarbonate, separate the layers, and extract the aqueous layer with dichioromethane. Dry the combined organic layers over anhydrous sodium sulfate, filter, and remove the solvent under reduced pressure. Purify the residue by flash chromatography, eluting with hexanes/ethyl acetate (gradient eluent, 0-60% ethyl acetate in hexane), to afford the title compound (0.462 g, 83%). MS (ES+): 506 (M+H).
Reaction SMILES: O[C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[CH:4][C:3]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12].[Cl:16][C:17]1[C:23]([Cl:24])=[CH:22][CH:21]=[CH:20][C:18]=1[NH2:19]>>[Cl:16][C:17]1[C:23]([Cl:24])=[CH:22][CH:21]=[CH:20][C:18]=1[NH:19][C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[CH:4][C:3]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: Nc1cccc(Cl)c1Cl
Reactant: CCOC(=O)c1cnc2ccnn2c1O
Product: CCOC(=O)c1cnc2ccnn2c1Nc1cccc(Cl)c1Cl
Yield: 79.1 %

Procedure:
Using ethyl 7-hydroxypyrazolo[1,5-a]pyrimidine-6-carboxylate (5.0 g, 24.1 mmol) and 2,3-dichloroaniline (3.13 g, 19.3 mmol) instead of 4-fluoro-2-methylaniline, and in the same manner as in Example 1 step 1, the title compound (5.36 g, 63%) was obtained.
Reaction SMILES: [C:1]([O:22][CH:23]1[CH2:28][C:27]([CH3:30])([CH3:29])[NH:26][C:25]([CH3:32])([CH3:31])[CH2:24]1)(=[O:21])[C:2]1[C:3](=[CH:17][CH:18]=[CH:19][CH:20]=1)[C:4]([O:6][CH:7]1[CH2:12][C:11]([CH3:14])([CH3:13])[NH:10][C:9]([CH3:16])([CH3:15])[CH2:8]1)=[O:5].[C:33]([O:37]O)([CH3:36])([CH3:35])C>[Mo](=O)(=O)=O.C1CCCCC1>[C:4]([O:6][CH:7]1[CH2:8][C:9]([CH3:16])([CH3:15])[N:10]([O:37][CH:33]2[CH2:36][CH2:17][CH2:3][CH2:4][CH2:35]2)[C:11]([CH3:13])([CH3:14])[CH2:12]1)(=[O:5])[C:3]1[C:2](=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:1]([O:22][CH:23]1[CH2:24][C:25]([CH3:32])([CH3:31])[N:26]([O:37][CH:33]2[CH2:36][CH2:20][CH2:2][CH2:1][CH2:35]2)[C:27]([CH3:30])([CH3:29])[CH2:28]1)=[O:21]
Reactant: CC1(C)CC(OC(=O)c2ccccc2C(=O)OC2CC(C)(C)NC(C)(C)C2)CC(C)(C)N1
Reactant: CC(C)(C)OO
Agent: O=[Mo](=O)=O
Solvent: C1CCCCC1
Product: CC1(C)CC(OC(=O)c2ccccc2C(=O)OC2CC(C)(C)N(OC3CCCCC3)C(C)(C)C2)CC(C)(C)N1OC1CCCCC1
Temperature: 81 °C
Reaction time: 1.25 h
Yield: 143.3 %

Procedure:
A mixture of 30.0 grams (67.5 mmol) of di-(2,2,6,6-tetramethylpiperidin-4-yl) phthalate, 27.5 grams (214 mmol) of 70% aqueous tert-butyl hydroperoxide, 2.0 grams of molybdenum trioxide and 200 ml of cyclohexane is heated to reflux at 81° C. Water is collected in a Dean-Stark trap. After 75 minutes, the reaction mixture is red. Another portion of tert-butyl hydroperoxide (42.5 grams of 70% aqueous solution, 330 mmol) is added over 30 minutes. After additional water is collected in the trap, the reaction mixture is transferred to a Fischer-Porter bottle and heated at 140° C. for 4.5 hours. The nearly colorless reaction mixture is treated with 6.9 grams (69 mmol) of 90% aqueous tert-butyl hydroperoxide and heated at 140° C. for 90 minutes to remove the last traces of pink color. The reaction mixture is cooled, filtered and stirred with a solution of 43 grams of sodium sulfite in 530 ml of water for 2 hours. Methylene chloride (600 ml) is added and the organic layer is separated, dried over anhydrous magnesium sulfate and concentrated to a crude solid. Purification (Waters Prep. 500A HPLC, 25:1 heptane:ethyl acetate) affords 31.0 grams (72% yield) of the title compound as a white solid, melting at 149°-151° C.