Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8]C)=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:3]=1.C([O-])([O-])=O.[K+].[K+]>Br.C(O)(=O)C.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([C:10]([F:11])([F:12])[F:13])[CH:3]=1
Reactant: COc1ccc(Br)cc1C(F)(F)F
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Product: Oc1ccc(Br)cc1C(F)(F)F

Procedure:
A solution of 3.0 g (11.8 mmol) 4-bromo-1-methoxy-2-trifluoromethyl-benzene in 20 mL 1 M HBr in glacial acetic acid is stirred for 60 h at 90° C. The reaction solution is diluted with 300 mL water, adjusted to pH 7 with K2CO3. The aqueous phase is extracted with EtOAc, the combined organic extracts are with washed 40 mL quarter-saturated NaHCO3 solution and dried over MgSO4. The solvent is eliminated i.vac. and the product is further reacted without any more purification.
Reaction SMILES: Br[C:2]1[CH:19]=[CH:18][C:5]([O:6][CH2:7][C@H:8]([OH:17])[CH2:9][CH2:10][C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[CH:4][CH:3]=1.[C:20]1([C:26]#[CH:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.O>C(N(CC)CC)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:20]1([C:26]#[C:27][C:2]2[CH:19]=[CH:18][C:5]([O:6][CH2:7][C@H:8]([OH:17])[CH2:9][CH2:10][C:11]3[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=3)=[CH:4][CH:3]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O[C@H](CCc1cccnc1)COc1ccc(Br)cc1
Reactant: C#Cc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: O
Product: O[C@H](CCc1cccnc1)COc1ccc(C#Cc2ccccc2)cc1
Temperature: 90 °C
Reaction time: 4 h
Yield: 3.6 %

Procedure:
Copper (I) iodide (0.03 g) was added to a mixture of (2R)-1-(4-bromophenoxy)-4-(3-pyridyl)-2-butanol (1.05 g, Example 40a), phenylacetylene (0.33 g) and bis(triphenylphosphine)palladium(II) chloride (0.23 g) in triethylamine (10 ml), and the reaction mixture heated to 90° C. with stirring under nitrogen for 4 hours. The reaction mixture was allowed to cool to room temperature and then poured into water (150 ml). The product was extracted with ethyl acetate which was washed with brine and dried over anhydrous magnesium sulfate. The solution was concentrated under reduced pressure and the residue purified by column chromatography over silica eluting with dichloromethane:methanol (19:1) to give the title compound as a white solid (0.040 g).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[C:6]=2[N:7]=1.[F:19][C:20]([F:28])([F:27])[C:21]1([OH:26])[CH2:25][CH2:24][NH:23][CH2:22]1>>[Cl:1][C:2]1[N:3]=[C:4]([N:23]2[CH2:24][CH2:25][C:21]([C:20]([F:28])([F:27])[F:19])([OH:26])[CH2:22]2)[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[C:6]=2[N:7]=1
Reactant: OC1(C(F)(F)F)CCNC1
Reactant: Fc1ccc(C2CCc3c(Cl)nc(Cl)nc32)cc1
Product: OC1(C(F)(F)F)CCN(c2nc(Cl)nc3c2CCC3c2ccc(F)cc2)C1
Yield: 62 %

Procedure:
2,4-dichloro-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine (Preparation H) (286 mg, 1.010 mmol) and 3-(trifluoromethyl)pyrrolidin-3-ol (157 mg, 1.010 mmol) were combined and purified as per Preparation Hb to give 1-(2-chloro-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-3-(trifluoromethyl)pyrrolidin-3-ol (62% yield). LC-MS (M+H)+=402.0.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].Br[CH2:8][CH2:9][CH2:10][Cl:11].[CH2:12]([NH:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C1CCCCC1>[CH2:20]([N:19]([CH2:8][CH2:9][CH2:10][Cl:11])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: ClCCCBr
Reactant: c1ccc(CNCc2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCCCC1
Product: ClCCCN(Cc1ccccc1)Cc1ccccc1
Reaction time: 20 h
Yield: 52.8 %

Procedure:
To a stirred suspension of K2CO3 (200 g, 1.5 mole) in cyclohexane 200 mL and 1-bromo-3-chloropropane (540 gms, 3.4 mole) is added dropwise over a period of 1 h at 20° C. dibenzyl amine (442 g, 2.24 mole). After complete addition the reaction is allowed to stir for an additional 20 h. The crude reaction mixture is filtered and then washed with saturated NaCl (3×100 mL). The organic phase is extracted with 3N HCl (3×100 mL). The resulting aqueous phase, containing the desired product as the hydrochloric salt, is washed with hexanes (3×100 mL) to remove any residual BCP. The aqueous phase is subsequently basified with 50 wt % NaOH and extracted with cyclohexane (3×100 mL). After solvent removal 324 g (53% yield) of the title compound was isolated as a yellow oil.
Reaction SMILES: [CH2:1]([C:3]([CH2:12][CH3:13])([C:8]([O:10][CH3:11])=[O:9])[C:4]([O:6][CH3:7])=[O:5])[CH3:2].[CH2:14]([N:17]1[C:22]([CH3:24])([CH3:23])[CH2:21]C(O)[CH2:19][C:18]1([CH3:27])[CH3:26])[CH:15]=[CH2:16]>C1(C)C(C)=CC=CC=1>[CH2:12]([C:3]([CH2:1][CH3:2])([C:8]([O:10][CH:11]1[CH2:27][C:18]([CH3:19])([CH3:26])[N:17]([CH2:14][CH:15]=[CH2:16])[C:22]([CH3:21])([CH3:23])[CH2:24]1)=[O:9])[C:4]([O:6][CH:7]1[CH2:24][C:22]([CH3:23])([CH3:21])[N:17]([CH2:14][CH:15]=[CH2:16])[C:18]([CH3:27])([CH3:26])[CH2:19]1)=[O:5])[CH3:13]
Reactant: C=CCN1C(C)(C)CC(O)CC1(C)C
Reactant: CCC(CC)(C(=O)OC)C(=O)OC
Solvent: Cc1ccccc1C
Product: C=CCN1C(C)(C)CC(OC(=O)C(CC)(CC)C(=O)OC2CC(C)(C)N(CC=C)C(C)(C)C2)CC1(C)C
Reaction time: 6 h

Procedure:
After the addition of 1 g of tetrabutyl-orthotitanate, 47 g of dimethyl diethylmalonate and 98.6 g of 1-allyl-2,2,6,6-tetramethyl-4-hydroxypiperidine in 100 ml of xylene are heated under a gentle stream of nitrogen to about 140°. The methanol forming during the reaction is continuously distilled off, and after about 6 hours the reaction is virtually completed. The reaction mixture is diluted with 200 ml of toluene, extracted three times with 100 ml of water each time, dried over sodium sulphate and concentrated by evaporation. Crystallisation of the residue from hexane yields bis-(1-allyl-2,2,6,6-tetramethyl-4-piperidinyl) diethylmalonate (compound 18), m.p. 135°-136°.
Reaction SMILES: [Br:1][C:2]1[N:6]2[N:7]=[C:8](F)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.Cl.[F:13][C:14]([F:20])([F:19])[CH2:15][CH2:16][CH2:17][NH2:18].CCN(C(C)C)C(C)C>CC(O)C>[Br:1][C:2]1[N:6]2[N:7]=[C:8]([NH:18][CH2:17][CH2:16][CH2:15][C:14]([F:20])([F:19])[F:13])[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1
Reactant: NCCCC(F)(F)F
Reactant: Fc1ccc2ncc(Br)n2n1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: FC(F)(F)CCCNc1ccc2ncc(Br)n2n1
Yield: 93.7 %

Procedure:
A stirred solution of 3-bromo-6-fluoro-imidazo[1,2-b]pyridazine (1.7 g, 7.6 mmol), 4,4,4-trifluoro-butylamine hydrochloride [84153-82-2] (1.3 g, 7.6 mmol), and Hunig's base [7087-68-5] (4.0 mL, 23.0 mmol) in 2-propanol (40 mL) was heated to 65° C., under N2 blanket for 3d, cooled, and partitioned between brine (pH adjusted to 10 with 3N aqueous sodium hydroxide) and ethyl acetate. The phase separated extract was dried (MgSO4) and evaporated to provide 2.3 g of yellow solid. LRMS (ESI) m/z 323.1/325.1 [(M+H)]+, calc'd for C10H10BrF3N4: 323.12.
Reaction SMILES: [C:1]1([CH:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:8][CH2:9][O:10][C:11](=[O:17])[CH2:12][C:13]([CH2:15]Cl)=[O:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH:26]1([CH2:32][CH2:33][OH:34])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1>C1COCC1>[C:1]1([CH:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:8][CH2:9][O:10][C:11](=[O:17])[CH2:12][C:13](=[O:14])[CH2:15][O:34][CH2:33][CH2:32][CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(CCl)CC(=O)OCCC(c1ccccc1)c1ccccc1
Reactant: OCCC1CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(COCCC1CCCCC1)CC(=O)OCCC(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
2.5 ml of a solution of 610 mg (1.84 mmol) of (3,3-diphenylpropane-1-yl)4-chloroacetoacetate in THF was added dropwise to a suspension of 158 mg (3.95 mmol) of sodium hydride (60% oily) in 5 ml of THF at 0° C., and they were stirred at room temperature for 20 minutes. An alkoxide solution previously prepared by adding 397 mg (3.09 mmol) of 2-cyclohexylethanol to 5 ml of a solution of 134 mg (3.36 mmol) of sodium hydride (60% oily) in THF was added to the obtained mixture at 0° C., and they were stirred at room temperature for 3 nights. THF was evaporated under reduced pressure. Water was added to the residue. The obtained mixture was washed with ethyl acetate. The aqueous layer was acidified with 2 N hydrochloric acid. After the extraction with ethyl acetate followed by drying over sodium sulfate, ethyl acetate was evaporated under reduced pressure to obtain the title compound.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5](=[O:12])[C:6](=[N:10][OH:11])[C:7]([CH3:9])=[O:8].Cl[CH2:14][O:15][CH3:16].C(OCC)(=O)C>O1CCCC1>[CH3:3][O:4][C:5](=[O:12])[C:6](=[N:10][O:11][CH2:14][O:15][CH3:16])[C:7]([CH3:9])=[O:8]
Reactant: COC(=O)C(=NO)C(C)=O
Reactant: COCCl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COCON=C(C(C)=O)C(=O)OC
Reaction time: 0.5 h

Procedure:
To a suspension of 4.13 g of 80% NaH in 50 ml of dry tetrahydrofuran are added successively at 0° 18.14 g of 2-hydroxyiminoacetoacetic acid methyl ester and 9 g of chloromethylmethylether. After 30 minutes at room temperature, the mixture is divided between 200 ml of ethyl acetate and aqueous buffer (pH 5.5). The contents of the ethyl acetate phase are bulb distilled to obtain the heading compound, m.p. 115°-120°/0.1 Torr.
Reaction SMILES: C(OC([N:11]1[CH2:15][CH:14]([O:16][C:17](=[O:19])[CH3:18])[CH2:13][CH:12]1[CH2:20][C:21]1[C:29]2[C:24](=[CH:25][C:26]([F:30])=[CH:27][CH:28]=2)[NH:23][C:22]=1[C:31]1[NH:32][C:33]2[C:38]([C:39]=1[CH2:40][CH:41]1[CH2:45][CH:44]([O:46][C:47](=[O:49])[CH3:48])[CH2:43][N:42]1C(OCC1C=CC=CC=1)=O)=[CH:37][CH:36]=[C:35]([F:60])[CH:34]=2)=O)C1C=CC=CC=1>[Pd].CCOC(C)=O.CO>[C:17]([O:16][CH:14]1[CH2:15][NH:11][CH:12]([CH2:20][C:21]2[C:29]3[C:24](=[CH:25][C:26]([F:30])=[CH:27][CH:28]=3)[NH:23][C:22]=2[C:31]2[NH:32][C:33]3[C:38]([C:39]=2[CH2:40][CH:41]2[NH:42][CH2:43][CH:44]([O:46][C:47](=[O:49])[CH3:48])[CH2:45]2)=[CH:37][CH:36]=[C:35]([F:60])[CH:34]=3)[CH2:13]1)(=[O:19])[CH3:18]
Reactant: CC(=O)OC1CC(Cc2c(-c3[nH]c4cc(F)ccc4c3CC3CC(OC(C)=O)CN3C(=O)OCc3ccccc3)[nH]c3cc(F)ccc23)N(C(=O)OCc2ccccc2)C1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(=O)OC1CNC(Cc2c(-c3[nH]c4cc(F)ccc4c3CC3CC(OC(C)=O)CN3)[nH]c3cc(F)ccc23)C1
Reaction time: 3 h
Yield: 102.1 %

Procedure:
A suspension containing 9 (35 g, 42.7 mmol) in 1:1 EtOAc/MeOH (400 mL) was distributed into two 500 mL Parr bottles (ca. 200 mL/each), and charged with 10% Pd-on-C (wet, 5000 mg/each, Aldrich®). The reaction mixture was pressurized to 50 PSI H2 and shaken for 3 h. The reaction mixture was filtered through a pad of Celite® and the solids were washed with EtOAc. The clarified filtrate was concentrated in vacuo to afford 24 g of 10 as an off-white solid which was used directly in the next reaction. 1H NMR (300 MHz, CDCl3): 613.10 (br s, 2H) 7.45 (dd, J=5.2, 8.9 Hz, 2H), 7.03 (dd, J=2.3, 9.8 Hz, 2H), 6.85 (m, 2H), 5.35 (m, 2H), 3.71 (m, 2H), 3.18-3.35 (m, 4H), 2.90-3.14 (m, 4H), 2.56 (m, 2H), 2.00-2.10 (m, 2H), 2.04 (s, 6H), 1.80-1.92 (m, 2H) ppm; 13C NMR (75 MHz, CDCl3): δ171.3, 161.7, 158.6, 136.1, 135.9, 130.5, 130.4, 125.4, 119.1, 118.9, 109.6, 108.0, 107.6, 97.6, 97.5, 75.1, 57.7, 51.6, 38.7, 32.8, 21.6 ppm. Mass spectrum (ESI), m/z 550.9 [(M)+; calcd for C30H32F2N4O4: 550.6].
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]#[C:10][C:11]2[CH:12]=[C:13]3[C:19]([NH:20][C:21](=[O:42])[C:22]4[CH:27]=[CH:26][C:25]([N:28]5[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]5)=[CH:24][C:23]=4[NH:35][CH:36]4[CH2:41][CH2:40][O:39][CH2:38][CH2:37]4)=[N:18][NH:17][C:14]3=[N:15][CH:16]=2)[CH:5]=[C:6]([F:8])[CH:7]=1>O1CCCC1.CO.[Pd]>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([F:8])[CH:7]=1)[CH2:9][CH2:10][C:11]1[CH:12]=[C:13]2[C:19]([NH:20][C:21](=[O:42])[C:22]3[CH:27]=[CH:26][C:25]([N:28]4[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]4)=[CH:24][C:23]=3[NH:35][CH:36]3[CH2:37][CH2:38][O:39][CH2:40][CH2:41]3)=[N:18][NH:17][C:14]2=[N:15][CH:16]=1
Reactant: CN1CCN(c2ccc(C(=O)Nc3n[nH]c4ncc(C#Cc5cc(F)cc(F)c5)cc34)c(NC3CCOCC3)c2)CC1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: CN1CCN(c2ccc(C(=O)Nc3n[nH]c4ncc(CCc5cc(F)cc(F)c5)cc34)c(NC3CCOCC3)c2)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 61.5 %

Procedure:
10 mg of 10% Pd/C is added to 100 mg (0.175 mmol) of N-(5-((3,5-difluorophenyl)ethynyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-4-(4-methylpiperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)benzamide in solution in a mixture of 10 ml of tetrahydrofuran and 5 ml of methanol before placing the reaction medium under an atmosphere of hydrogen. The reaction mixture is stirred for 12 hours at room temperature and then filtered on Celite and concentrated. 62 mg (yield=60%) of N-(5-(3,5-difluorophenethyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-4-(4-methylpiperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)benzamide are isolated in the form of a white solid. LCMS (EI, m/z): (M+1) 576.23.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:27]=[CH:26][C:12]([C:13]([NH:15][C:16]3[CH:17]=[CH:18][C:19]([CH3:25])=[C:20]([CH:24]=3)[C:21](O)=[O:22])=[O:14])=[CH:11][CH:10]=2)[CH2:4][CH2:3]1.[NH2:28][C:29]1[CH:30]=[C:31]2[CH:37]=[C:36]([C:38]([O:40][CH3:41])=[O:39])[NH:35][C:32]2=[N:33][CH:34]=1.C(N(CC)CC)C.OC1C2N=NNC=2C=CC=1.C(=O)(O)O.CN(C)CCCN=C=NCC>ClCCl>[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([CH2:8][C:9]2[CH:27]=[CH:26][C:12]([C:13]([NH:15][C:16]3[CH:17]=[CH:18][C:19]([CH3:25])=[C:20]([CH:24]=3)[C:21]([NH:28][C:29]3[CH:30]=[C:31]4[CH:37]=[C:36]([C:38]([O:40][CH3:41])=[O:39])[NH:35][C:32]4=[N:33][CH:34]=3)=[O:22])=[O:14])=[CH:11][CH:10]=2)[CH2:6][CH2:7]1
Reactant: COC(=O)c1cc2cc(N)cnc2[nH]1
Reactant: Cc1ccc(NC(=O)c2ccc(CN3CCN(C)CC3)cc2)cc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: O=C(O)O
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1cc2cc(NC(=O)c3cc(NC(=O)c4ccc(CN5CCN(C)CC5)cc4)ccc3C)cnc2[nH]1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 8.3 %

Procedure:
A reactor is charged successively with 150 mg (0.4 mmol) of the solid obtained in step 3, 15 ml of anhydrous dichloromethane, 90 mg (0.4 mmol) of methyl 5-amino-1H-pyrrolo[2,3-b]pyridine-2-carboxylate, 0.12 g (0.49 mmol) of triethylamine and 93 mg (0.61 mmol) of hydroxybenzotriazole. The mixture is stirred at room temperature for 15 min and then 90 mg (0.49 mmol) of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrogen carbonate (EDCl) is added. The mixture is stirred for 16 hours. The solvent is then evaporated under reduced pressure and the residue is taken off in 100 ml of water. The aqueous phase is extracted by 6*50 ml dichloromethane. The aqueous phases are combined, dried on sodium sulphate and then evaporated under reduced pressure. The raw product obtained is purified by preparative HPLC and 18 mg (8%) of a solid is obtained.
Reaction SMILES: [CH2:1]([C:5]1[NH:9][C:8]([CH:10]=[O:11])=[CH:7][N:6]=1)[CH2:2][CH2:3][CH3:4].CN(C=O)C.C1C(=O)N([Br:24])C(=O)C1>>[Br:24][C:7]1[N:6]=[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])[NH:9][C:8]=1[CH:10]=[O:11]
Reactant: CCCCc1ncc(C=O)[nH]1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Product: CCCCc1nc(Br)c(C=O)[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-Butyl-3H-imidazole-4-carbaldehyde (30.0 g, 197 mmol) was dissolved in DMF (220 mL, 2.8 mol). NBS (36.8 g, 207 mmol) was added and the mixture was stirred at room temperature overnight. The mixture was then concentrated and taken up in EtOAc and water. The aqueous layer was extracted three times with EtOAc, and the combined organic extracts washed with saturated aqueous NaCl, dried over MgSO4, filtered, and concentrated. The mixture was purified by silica gel chromatography (0-50%
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][S:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=[O:21])[CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])=[CH:8][CH:7]=1.[CH3:22][CH2:23][CH2:24][C:25]1[C:30]([OH:31])=[C:29]([C:32]([CH3:34])=[O:33])[CH:28]=[CH:27][C:26]=1[OH:35].C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[C:32]([C:29]1[CH:28]=[CH:27][C:26]([O:35][CH2:2][CH2:3][CH2:4][S:5][C:6]2[CH:11]=[CH:10][C:9]([C:12](=[O:21])[CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])=[CH:8][CH:7]=2)=[C:25]([CH2:24][CH2:23][CH3:22])[C:30]=1[OH:31])(=[O:33])[CH3:34]
Reactant: COC(=O)CCCCC(=O)c1ccc(SCCCBr)cc1
Reactant: CCCc1c(O)ccc(C(C)=O)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCCc1c(OCCCSc2ccc(C(=O)CCCCC(=O)OC)cc2)ccc(C(C)=O)c1O

Procedure:
The compound of Step A above, (2.0 g, 5.36 mmoles), 2,4-dihydroxy-3-propylacetophenone (2.08 g, 10.72 mmole) and potassium carbonate (3.0 g, 21.44 mmole) were stirred in methyl ethyl ketone (100 ml) and heated at reflux for three hours. The reaction mixture was filtered and concentrated in vacuo. The residue was dissolved in ether-methanol and extracted with 1N NaOH (3×50 ml). The organics were dried and concentrated in vacuo. The residue was triturated with methanol, filtered and dried, to yield the title compound. NMR (CDCl3): 0.94 (3H, m), 1.73 (6H, m), 2.28 (6H, m), 2.95 (2H, m), 3.22 (2H, m), 3.66 (3H, s), 4.17 (2H, m), 6.42 (1H, d), 7.40 (2M, d), 7.61 (1H, d), 7.90 (2H, d), 12.73 (1H, s).
Reaction SMILES: NC1C=CC=CC=1.[N:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH:14]=O.[Cl:16][C:17]1[CH:42]=[CH:41][CH:40]=[CH:39][C:18]=1[O:19][C:20]1[CH:21]=[C:22]([NH2:38])[C:23]([NH2:37])=[CH:24][C:25]=1[O:26][C:27]1[CH:28]=[N:29][C:30]([S:33]([CH3:36])(=[O:35])=[O:34])=[CH:31][CH:32]=1>CO>[Cl:16][C:17]1[CH:42]=[CH:41][CH:40]=[CH:39][C:18]=1[O:19][C:20]1[C:25]([O:26][C:27]2[CH:28]=[N:29][C:30]([S:33]([CH3:36])(=[O:34])=[O:35])=[CH:31][CH:32]=2)=[CH:24][C:23]2[NH:37][C:14]([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][N:8]=3)=[N:38][C:22]=2[CH:21]=1
Reactant: O=Cc1ccccn1
Reactant: CS(=O)(=O)c1ccc(Oc2cc(N)c(N)cc2Oc2ccccc2Cl)cn1
Solvent: CO
Solvent: Nc1ccccc1
Product: CS(=O)(=O)c1ccc(Oc2cc3[nH]c(-c4ccccn4)nc3cc2Oc2ccccc2Cl)cn1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
0.26 ml of 1 M methanol solution of aniline and pyridine-2-carboxaldehyde (1/1) was added to a methanol (1 ml) solution of 35 mg of 4-(2-chlorophenoxy)-5-(6-methanesulfonyl-pyridin-3-yloxy)-benzene-1,2-diamine obtained in (step 1), and the reaction liquid was stirred overnight at 60° C. The solvent was evaporated away under reduced pressure, and the resulting residue was purified through reversed-phase middle-pressure liquid chromatography [ODS-AS-360-CC (by YMC), mobile phase: water-acetonitrile-0.1% trifluoroacetic acid]. The solvent of the resulting fraction was diluted with ethyl acetate, washed with aqueous saturated sodium bicarbonate, and then dried with anhydrous sodium sulfate. The solvent was evaporated away under reduced pressure to obtain the entitled compound as a pale yellow solid.
Reaction SMILES: [F:1][C:2]1[C:35]([F:36])=[CH:34][CH:33]=[CH:32][C:3]=1[O:4][C:5]1[C:19]([O:20][C:21]2[CH:22]=[N:23][C:24]([S:27]([CH2:30][CH3:31])(=[O:29])=[O:28])=[CH:25][CH:26]=2)=[CH:18][C:8]2[NH:9][C:10]([C:12]3[CH:17]=[CH:16]C=C[N:13]=3)=[N:11][C:7]=2[CH:6]=1.[CH3:37][N:38]1C=CC(C(O)=O)=N1>>[F:1][C:2]1[C:35]([F:36])=[CH:34][CH:33]=[CH:32][C:3]=1[O:4][C:5]1[C:19]([O:20][C:21]2[CH:22]=[N:23][C:24]([S:27]([CH2:30][CH3:31])(=[O:29])=[O:28])=[CH:25][CH:26]=2)=[CH:18][C:8]2[NH:9][C:10]([C:12]3[CH:17]=[CH:16][N:38]([CH3:37])[N:13]=3)=[N:11][C:7]=2[CH:6]=1
Reactant: Cn1ccc(C(=O)O)n1
Reactant: CCS(=O)(=O)c1ccc(Oc2cc3[nH]c(-c4ccccn4)nc3cc2Oc2cccc(F)c2F)cn1
Product: CCS(=O)(=O)c1ccc(Oc2cc3[nH]c(-c4ccn(C)n4)nc3cc2Oc2cccc(F)c2F)cn1

Procedure:
The entitled compound was obtained as a colorless solid in the same method as in Example 203 or in accordance with the method or by combining it with an ordinary method but using 4-(2,3-difluoro-phenoxy)-5-(6-ethanesulfonyl-pyridin-3-yloxy)-benzene-1,2-diamine obtained in Example 226 and 1-methyl-1H-pyrazole-3-carboxylic acid.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3](=O)/[CH:4]=[C:5](\O)/[C:6]1[S:7][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([S:17]([CH3:20])(=[O:19])=[O:18])[CH:12]=2)=[CH:9][CH:10]=1.Cl.[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=1[NH:34][NH2:35].C(O)(=O)C>CN(C=O)C>[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=1[N:34]1[C:5]([C:6]2[S:7][C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([S:17]([CH3:20])(=[O:19])=[O:18])[CH:12]=3)=[CH:9][CH:10]=2)=[CH:4][C:3]([C:2]([F:24])([F:23])[F:1])=[N:35]1
Reactant: CS(=O)(=O)c1cccc(-c2ccc(/C(O)=C/C(=O)C(F)(F)F)s2)c1
Reactant: NNc1cc(Cl)ccc1Cl
Agent: Cl
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CS(=O)(=O)c1cccc(-c2ccc(-c3cc(C(F)(F)F)nn3-c3cc(Cl)ccc3Cl)s2)c1
Temperature: 102.5 °C
Reaction time: 3 h

Procedure:
Into an 8 mL vial was weighed 202.7 mg (539 μmol) of (Z)-1,1,1-trifluoro-4-hydroxy-4-(5-(3-(methylsulfonyl)phenyl)thiophen-2-yl)but-3-en-2-one, 117.4 mg (550 μmol) of 2,5-dichlorophenylhydrazine hydrochloride, 3 mL of acetic acid, and 1 mL of DMF. The resulting reaction was stirred at 100-105° C. for 3 h then was concentrated to dryness in vacuo. The residue was purified by silica gel flash chromatography (3×23 cm, 1:1 ethyl acetate-hexanes) and was dried affording the product as a faintly yellow solid, yield: 89 mg (55%). 1H NMR (400 MHz, CDCl3): δ 8.08 (s, 1H), 7.87 (d, J=9 Hz, 1H), 7.75 (d, J=9 Hz, 1H), 7.6 (m, 2H), 7.5 (m, 2H), 7.27 (d, J=4 Hz, 1H), 6.90 (s, 1H), 6.87 (d, J=4 Hz, 1H), 3.09 (s, 3H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[N:8][C:7]=12)#[CH:2].Br[C:27]1[CH:28]=[C:29]([OH:33])[CH:30]=[N:31][CH:32]=1>>[F:15][C:12]([F:14])([F:13])[C:11]1[N:6]2[N:5]=[CH:4][C:3]([C:1]#[C:2][C:27]3[CH:28]=[C:29]([OH:33])[CH:30]=[N:31][CH:32]=3)=[C:7]2[N:8]=[C:9]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)[CH:10]=1
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: Oc1cncc(Br)c1
Product: Oc1cncc(C#Cc2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)c1

Procedure:
The title compound was prepared from 3-ethynyl-7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.1) (355 mg, 1.0 mmol) and commercially available 5-bromo-3-pyridinol (156 mg, 1.0 mmol) according to general procedure II. Obtained as a yellow solid (280 mg, 62%). MS (ISP) 449.2[(M+H)+]; mp 258-260° C.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[C:12]([C:14]1[CH:29]=[CH:28][C:17]2[CH2:18][CH2:19][C:20]3[C:21]([C:26](=[O:27])[C:16]=2[CH:15]=1)=[N:22][CH:23]=[CH:24][CH:25]=3)#[N:13]>C(Cl)(Cl)Cl>[C:12]([C:14]1[CH:29]=[CH:28][C:17]2[CH2:18][CH2:19][C:20]3[C:21]([C:26](=[O:27])[C:16]=2[CH:15]=1)=[N+:22]([O-:9])[CH:23]=[CH:24][CH:25]=3)#[N:13]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: N#Cc1ccc2c(c1)C(=O)c1ncccc1CC2
Solvent: ClC(Cl)Cl
Product: N#Cc1ccc2c(c1)C(=O)c1c(ccc[n+]1[O-])CC2

Procedure:
In a manner similar to that described in Example II, 1.19 grams (0.0055 mole) of m-chloroperbenzoic acid is added to a solution of 1.29 grams (0.005 mole) of 9-cyano-5,6-dihydrobenzo[5,6]cyclohepta[1,2-b]pyridin-11-one in 20 milliliters of chloroform and the resulting mixture stirred at ambient temperature for several days with an addition of an about 0.5 gram portion of m-chloroperbenzoic acid after the first 24 hours. At the end of this period the mixture is washed, dried and evaporated to obtain a 9-cyano-5,6-dihydrobenzo[5,6]cyclohepta[1,2-b]-pyridin-11-one N-oxide intermediate as residue.