Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[C:13]([N+:18]([O-])=O)[CH:12]=2)=[O:10])[CH2:5][CH2:4]1)[CH3:2]>CO.[C].[Pd]>[CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[C:13]([NH2:18])[CH:12]=2)=[O:10])[CH2:5][CH2:4]1)[CH3:2]
Reactant: CCN1CCN(C(=O)c2ccc(C)c([N+](=O)[O-])c2)CC1
Agent: [Pd]
Solvent: CO
Product: CCN1CCN(C(=O)c2ccc(C)c(N)c2)CC1
Yield: 105.8 %

Procedure:
(4-Ethyl-piperazin-1-yl)-(4-methyl-3-nitro-phenyl)-methanone (1.06 g, 3.82 mmol) obtained in Step A was stirred for 16 hours in methanol (20 ml) under a hydrogen atmosphere in the presence of 10% palladium carbon. After the reaction mixture was filtered, the filtrate was concentrated under reduced pressure, to obtain (4-ethyl-piperazin-1-yl)-(3-amino-4-methyl-phenyl)-methanone (1.0 g, quant.).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([NH:7][C:8]([CH3:12])([CH3:11])[CH2:9][OH:10])=[N:4][C:3]=1[C:13]1[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=1.C(N(CC)CC)C.Cl[C:29](Cl)([O:31]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl>[Cl:1][C:2]1[S:6][C:5]([N:7]2[C:8]([CH3:12])([CH3:11])[CH2:9][O:10][C:29]2=[O:31])=[N:4][C:3]=1[C:13]1[CH:14]=[CH:15][C:16]([C:17]#[N:18])=[CH:19][CH:20]=1
Reactant: CC(C)(CO)Nc1nc(-c2ccc(C#N)cc2)c(Cl)s1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(C)COC(=O)N1c1nc(-c2ccc(C#N)cc2)c(Cl)s1
Temperature: 0 °C
Reaction time: 2 h
Yield: 22 %

Procedure:
4-{5-Chloro-2-[(2-hydroxy-1,1-dimethylethyl)amino]-1,3-thiazol-4-yl}benzonitrile (0.93 g, 3.0 mmol), prepared in the previous step, was dissolved in methylene chloride (25 mL), triethylamine (4.15 mL, 30 mmol) was added and the mixture was cooled to 0° C. Triphosgene (1.79 g, 6.0 mmol) was added and the mixture was stirred for 2 h. The mixture was then diluted with methylene chloride, washed with 2N HCl, saturated NaHCO3, brine, dried over anhydrous MgSO4, filtered and concentrated. Flash chromatography (10% acetone/hexane) afforded the title compound (220 mg, 22%) as a pale yellow solid. HRMS: calcd for C15H12ClN3O2S+H+, 334.04115; found (ESI, [M+H]+), 334.04; HPLC purity 100% at 210-370 nm, 10.6 min; 100% at 244 nm, 10.6 min; the Xterra® RP18 column, 3.5μ, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. pH=3.5/ACN+MeOH) for 10 min, hold 4 mm.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].Br[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10].[CH:14]1([SH:19])[CH2:18][CH2:17][CH2:16][CH2:15]1>CN(C=O)C.O>[CH:14]1([S:19][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: SC1CCCC1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CSC1CCCC1
Temperature: 65 °C

Procedure:
Solid K2CO3 (9.01 g, 65.2 mmol) was added to a stirring solution of ethyl bromoacetate (5.16 mL, 46.6 mmol) and cyclopentanethiol (4.97 mL, 46.6 mmol) in DMF (25 mL). The resulting suspension was warmed at 65° C. for 4 hours. The reaction mixture was cooled to room temperature, diluted with water (100 mL) and extracted with hexanes (3×50 mL). The combined extract was washed with saturated brine (30 mL) and concentrated under vacuum to provide the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 1.29 (t, J=7.1 Hz, 3H), 1.43-1.65 (m, 4H), 1.66-1.81 (m, 2H), 1.93-2.10 (m, 2H), 3.13-3.30 (m, 1H), 3.25 (s, 2H), 4.19 (q, J=7.1 Hz, 2H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:32])[N:7]([C:17]1[N:22]2[N:23]=[CH:24][CH:25]=[C:21]2[N:20]=[C:19]([Cl:26])[C:18]=1[CH2:27][CH:28]([OH:31])[CH2:29][OH:30])[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH3:16])=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:40]([Si:44](Cl)([CH3:46])[CH3:45])([CH3:43])([CH3:42])[CH3:41].Cl>C(Cl)Cl>[Si:44]([O:30][CH2:29][CH:28]([OH:31])[CH2:27][C:18]1[C:19]([Cl:26])=[N:20][C:21]2[N:22]([N:23]=[CH:24][CH:25]=2)[C:17]=1[N:7]([C:8]1[CH:9]=[CH:10][C:11]([O:14][CH2:15][CH3:16])=[CH:12][CH:13]=1)[C:6](=[O:32])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])([C:40]([CH3:43])([CH3:42])[CH3:41])([CH3:46])[CH3:45]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CCOc1ccc(N(C(=O)OC(C)(C)C)c2c(CC(O)CO)c(Cl)nc3ccnn23)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOc1ccc(N(C(=O)OC(C)(C)C)c2c(CC(O)CO[Si](C)(C)C(C)(C)C)c(Cl)nc3ccnn23)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 80.7 %

Procedure:
To a methylene chloride (3.6 mL) solution containing tert-butyl[5-chloro-6-(2,3-dihydroxypropyl)pyrazolo[1,5-a]pyrimidin-7-yl](4-ethoxyphenyl)carbamate (500 mg, 1.08 mmol), triethylamine (300 μL, 2.16 mmol), tert-butylchlorodimethylsilane (195 mg, 1.30 mmol) and N,N-dimethylpyridine (13 mg, 0.108 mmol) were added. After the reaction mixture was stirred at room temperature for 5 hr, 1 mol/L hydrochloric acid was added here, and the mixture was extracted with ethyl acetate. The combined ethyl acetate layer was washed with aqueous sodium hydrogen carbonate and then brine and dried over sodium sulfate. After the sodium sulfate was filtered off, the solvent was distilled off and the residue was purified with column chromatography to obtain the title compound (503 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[C:19]3[C:20](=[CH:24][N:25]([CH2:27][CH2:28][CH2:29]O)[N:26]=3)[N:21]=[CH:22][N:23]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1.[CH3:31][S:32]([CH2:35][CH2:36][NH:37][S:38]([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=1[N+:47]([O-:49])=[O:48])(=[O:40])=[O:39])(=[O:34])=[O:33].N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P(CCCC)CCCC)CCC>O1CCCC1.C(OCC)(=O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[C:19]3[C:20](=[CH:24][N:25]([CH2:27][CH2:28][CH2:29][N:37]([CH2:36][CH2:35][S:32]([CH3:31])(=[O:33])=[O:34])[S:38]([C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=4[N+:47]([O-:49])=[O:48])(=[O:39])=[O:40])[N:26]=3)[N:21]=[CH:22][N:23]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1
Reactant: CS(=O)(=O)CCNS(=O)(=O)c1ccccc1[N+](=O)[O-]
Reactant: OCCCn1cc2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c2n1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CS(=O)(=O)CCN(CCCn1cc2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c2n1)S(=O)(=O)c1ccccc1[N+](=O)[O-]

Procedure:
A solution of 3-[7-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-2H-pyrazolo[4,3-d]pyrimidin-2-yl]propanol (50 mg), N-[2-(methylsulfonyl)ethyl]-2-nitrobenzenesulfonamide (47 mg), 1,1′-(azodicarbonyl)dipiperidine (59 mg) and tributylphosphine (47 mg) in tetrahydrofuran (2 mL) was stirred at room temperature for 4 hrs. After the completion of the reaction, water was added to the reaction mixture and the mixture was diluted with ethyl acetate and washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/methanol=4/1→1/4) to give N-{3-[7-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-2H-pyrazolo[4,3-d]pyrimidin-2-yl]propyl}-N-[2-(methylsulfonyl)ethyl]-2-nitrobenzenesulfonamide. To a solution of this compound in tetrahydrofuran (2 mL) were added 2-mercaptoethanol (12 mg) and 1,8-diazabicyclo[5.4.0]undec-7-ene (23 mg), and the mixture was stirred at room temperature for 3 hrs. After the completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/methanol=10/1) to give the title compound (34 mg) as a white solid.
Reaction SMILES: [CH2:1]1[CH:10]2[N:5]([CH2:6][CH2:7][CH2:8][CH2:9]2)[CH2:4][CH2:3][CH:2]1[CH2:11][O:12][C:13]([C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[NH:17][CH:16]=1)=[O:14].Br[CH2:25][CH:26]([CH3:28])[CH3:27]>>[CH2:1]1[CH:10]2[N:5]([CH2:6][CH2:7][CH2:8][CH2:9]2)[CH2:4][CH2:3][CH:2]1[CH2:11][O:12][C:13]([C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH:16]=1)=[O:14]
Reactant: CC(C)CBr
Reactant: O=C(OCC1CCN2CCCCC2C1)c1c[nH]c2ccccc12
Product: CC(C)Cn1cc(C(=O)OCC2CCN3CCCCC3C2)c2ccccc21

Procedure:
eq-Quinolizidin-2-ylmethylindole-3-carboxylate (E9b) was alkylated with 1-bromo-2-methylpropane using the method in Example 18. The product was chromatographed on silica gel eluting initially with ether, then with ethyl acetate, to afford the title compound (E20) as a colourless oil. This was converted to its hydrochloride salt mp 174°-175° C. (acetone/ether).
Reaction SMILES: [CH3:1][C:2]1[CH:17]=[CH:16][C:5]2[N:6]([CH2:9][C:10]3[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=3)[CH:7]=[N:8][C:4]=2[C:3]=1[N+:18]([O-])=O.C(O)(=O)C>C(Cl)Cl.CO.[Fe]>[CH3:1][C:2]1[CH:17]=[CH:16][C:5]2[N:6]([CH2:9][C:10]3[CH:11]=[CH:12][N:13]=[CH:14][CH:15]=3)[CH:7]=[N:8][C:4]=2[C:3]=1[NH2:18]
Reactant: Cc1ccc2c(ncn2Cc2ccncc2)c1[N+](=O)[O-]
Agent: [Fe]
Solvent: CO
Solvent: ClCCl
Solvent: CC(=O)O
Product: Cc1ccc2c(ncn2Cc2ccncc2)c1N
Temperature: 50 °C
Reaction time: 0.25 h

Procedure:
A 200-mL round-bottomed flask equipped with mechanical stirrer was charged with 5-Methyl-4-nitro-1-(pyridin-4-yl)methyl-1H-benzimidazole (881 mg, 3.46 mmol), iron powder (˜325 mesh, 3.87 g, 6.92 mmol) and acetic acid (50 mL), and the resulting mixture stirred at 50° C. for 15 min. After this time the reaction was cooled to room temperature, diluted with 1:1 methylene chloride/methanol (1 L) and filtered through a pad of Celite 521. After washing the filter cake with 1:1 methylene chloride/methanol (2×50 mL), the filtrate was concentrated in vacuo. The resulting residue was dissolved in methylene chloride (50 mL) and vigorously stirred with 1M aqueous sodium hydroxide (50 mL). The resulting emulsion was filtered through a pad of Celite 521, the pad washed with methylene chloride (2×25 mL) and the organic layer of the filtrate separated and dried over sodium sulfate. Removal of the drying agent by filtration, followed by evaporation of the filtrate in vacuo gave a residue which was purified by flash chromatography. This purified material was dissolved in warm methylene chloride (15 mL) and the solution diluted with hexanes (35 mL). The resulting precipitate was filtered, washed with hexanes (3×100 mL) and dried under reduced pressure for 1.5 h to afford compound 2d as an off-white solid.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[CH:3][C:2]=1[OH:11].[O:12]1[C:16]2[CH:17]=[CH:18]C=CC=2N=C1>>[O:12]1[CH2:16][CH:17]1[CH2:18][O:11][C:2]1[CH:3]=[N:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:1]=1
Reactant: c1ccc2ocnc2c1
Reactant: Oc1cnc2ccccc2n1
Product: c1ccc2nc(OCC3CO3)cnc2c1

Procedure:
Compound 71 was prepared in the manner of compound 6 substituting quinoxaline-2-ol for compound 8 in part C-5 of Example 1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:10]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[N:11]=[C:12]3[C:17]=2[CH:16]=[CH:15][CH:14]=[CH:13]3)[CH:5]=[CH:6][CH:7]=1.[CH:25]1([N:31]=[C:32]=[O:33])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]([C:9]2[N:10]([C:18]3[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=3)[N:11]=[C:12]3[C:17]=2[CH:16]=[CH:15][CH:14]=[CH:13]3)[C:32]([NH:31][CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)=[O:33])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C=NC1CCCCC1
Reactant: Clc1ccc(-n2nc3ccccc3c2Nc2cccc(Cl)c2)cc1
Solvent: Cc1ccccc1
Product: O=C(NC1CCCCC1)N(c1cccc(Cl)c1)c1c2ccccc2nn1-c1ccc(Cl)cc1

Procedure:
In analogy to the procedure described in example 1.2, (3-chloro-phenyl)-[2-(4-chloro-phenyl)-2H-indazol-3-yl]-amine was reacted with cyclohexylisocyanate ([3173-53-3]) in toluene for 3 d under reflux conditions to give the title compound as yellow foam. MS: m/e=479.3 [M+H+].
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1[CH3:11].[OH-].[Na+].[CH3:14][C:15]1[O:19][N:18]=[C:17]([CH:20]=O)[CH:16]=1.Cl>CCO.O>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])/[CH:9]=[CH:20]/[C:17]2[CH:16]=[C:15]([CH3:14])[O:19][N:18]=2)=[CH:4][C:3]=1[CH3:11]
Reactant: CC(=O)c1ccc(O)c(C)c1
Reactant: Cc1cc(C=O)no1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1cc(/C=C/C(=O)c2ccc(O)c(C)c2)no1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a mixture of commercially available 4′-hydroxy-3′-methylacetophenone (700 mg, 4.66 mmol) and NaOH (365 mg, 9.1 mmol) in 10 mL of absolute EtOH was added commercially available 5-methylisoxazole-3-carbaldehyde (518 mg, 4.66 mmol). The reaction mixture was stirred at room temperature for 18 hr. 5 mL of water was added and the reaction mixture was acidified with concentrated HCl to pH 5-6. The precipitate was filtered, washed with water and dried to give (E)-1-(4-hydroxy-3-methylphenyl)-3-(5-methylisoxazol-3-yl)prop-2-en-1-one. MS (EI) for C14H13NO3: 244 (MH+).
Reaction SMILES: ClCCl.[F:4][C:5]1[CH:6]=[C:7]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][C:16]=2[O:22]C)[CH:8]=[CH:9][C:10]=1[C:11]([O:13][CH3:14])=[O:12].B(Br)(Br)Br>O>[F:4][C:5]1[CH:6]=[C:7]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][C:16]=2[OH:22])[CH:8]=[CH:9][C:10]=1[C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)c1ccc(-c2ccc(C)cc2OC)cc1F
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: COC(=O)c1ccc(-c2ccc(C)cc2O)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 15.9 %

Procedure:
Under ice cooling, to a dichloromethane solution (10.0 ml) of methyl 3-fluoro-2′-methoxy-4′-methylbiphenyl-4-carboxylate (910 mg) was added a dichloromethane solution (1 M, 9.95 ml) of boron tribromide, followed by stirring at room temperature overnight. The reaction solution was poured into water, and extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. To the resulting residue were added methanol (30.0 ml) and ethyl acetate (3.0 ml). Under ice cooling, a hexane solution (2 M, 8.30 ml) of trimethylsilyldiazomethane was added dropwise, and stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography to afford methyl 3-fluoro-2′-hydroxy-4′-methylbiphenyl-4-carboxylate (137 mg).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]([O:13]CC)=[O:12])=[N:9][CH:10]=1.[OH-].[Na+]>CO>[F:17][C:2]([F:1])([F:16])[CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]([OH:13])=[O:12])=[N:9][CH:10]=1
Reactant: CCOC(=O)c1ccc(OCC(F)(F)F)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccc(OCC(F)(F)F)cn1
Temperature: 25 °C
Reaction time: 4 h
Yield: 53.4 %

Procedure:
A mixture of ethyl 5-(2,2,2-trifluoroethoxy)picolinate (253 mg, 1.0 mmol) and 2 mol/L aqueous sodium hydroxide solution (1.0 mL, 2.0 mmol) in methanol (5 mL) was stirred at room temperature for 4 h. Then, methanol was removed in vacuo. To the residue were added water (2 mL) and 2 mol/L hydrochloric acid (pH˜4). The formed precipitate was collected by filtration to give 118 mg (52% yield) of the title compound as a gray solid:
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([N:9]2[C:13](=[O:14])[N:12]([CH:15]([F:17])[F:16])[C:11]([CH3:18])=[N:10]2)=[C:4]([F:19])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:26][C:27]1([CH3:45])[CH2:31][C:30]2[CH:32]=[C:33]([S:36]([NH:39][C:40](=[O:44])[CH:41](Br)[CH3:42])(=[O:38])=[O:37])[CH:34]=[CH:35][C:29]=2[O:28]1>CC(C)=O>[CH3:45][C:27]1([CH3:26])[CH2:31][C:30]2[CH:32]=[C:33]([S:36]([NH:39][C:40](=[O:44])[CH:41]([O:8][C:7]3[CH:6]=[C:5]([N:9]4[C:13](=[O:14])[N:12]([CH:15]([F:16])[F:17])[C:11]([CH3:18])=[N:10]4)[C:4]([F:19])=[CH:3][C:2]=3[Cl:1])[CH3:42])(=[O:38])=[O:37])[CH:34]=[CH:35][C:29]=2[O:28]1
Reactant: Cc1nn(-c2cc(O)c(Cl)cc2F)c(=O)n1C(F)F
Reactant: CC(Br)C(=O)NS(=O)(=O)c1ccc2c(c1)CC(C)(C)O2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1nn(-c2cc(OC(C)C(=O)NS(=O)(=O)c3ccc4c(c3)CC(C)(C)O4)c(Cl)cc2F)c(=O)n1C(F)F
Yield: 91.1 %

Procedure:
In a manner similar to Step D of Example 9, the reaction of 0.5 g (0.0017 mole) of 1-(4-chloro-2-fluoro-5-hydroxyphenyl)-4-difluoromethyl-4,5-dihydro-3-methyl-1,2,4-triazol-5(1H)-one with 0.7 g (0.0051 mole) of potassium carbonate and 0.62 g (0.0017 mole) of N-(2,3-dihydro-2,2-dimethylbenzofuran-5-yl)sulfonyl-2-bromopropionamide in 35 mL of acetone produced 0.89 g of N-(2,3-dihydro-2,2-dimethylbenzofuran-5-yl)sulfonyl-2-[2-chloro-4-fluoro-5-(4-difluoromethyl-4,5-dihydro-3-methyl-5-oxo-1H-1,2,4-triazol-1-yl)phenoxy]propionamide as a solid.
Reaction SMILES: [C:1](/[C:3](=[C:8]1/[C:9](=[O:19])[NH:10][C:11]2[C:16]/1=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)/[C:4]([O:6][CH3:7])=[O:5])#[N:2].[C-:20]#[N:21].[K+]>>[C:1]([CH:3]([C:8]1([C:20]#[N:21])[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH3:18])[CH:15]=2)[NH:10][C:9]1=[O:19])[C:4]([O:6][CH3:7])=[O:5])#[N:2]
Reactant: [C-]#N
Reactant: COC(=O)/C(C#N)=C1\C(=O)Nc2ccc(OC)cc21
Agent: [K+]
Product: COC(=O)C(C#N)C1(C#N)C(=O)Nc2ccc(OC)cc21
Yield: 90 %

Procedure:
Following the general method as outlined for Intermediate 5, starting from methyl (2Z)-cyano(5-methoxy-2-oxo-1,2-dihydro-3H-indol-3-ylidene)acetate (intermediate 2) and potassium cyanide, the title compound was isolated, after evaporation, as a pale brown solid in 90% yield. This was a mixture of diastereomers.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[C:9](Cl)[N:8]=2)[N:5]=[CH:4][C:3]=1[C:19]#[N:20].[CH2:21]([NH2:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>O1CCCC1.C(Cl)Cl>[NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[C:9]([NH:28][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:8]=2)[N:5]=[CH:4][C:3]=1[C:19]#[N:20]
Reactant: NCc1ccccc1
Reactant: N#Cc1cnn(-c2nc(Cl)c(C(F)(F)F)cc2Cl)c1N
Solvent: ClCCl
Solvent: C1CCOC1
Product: N#Cc1cnn(-c2nc(NCc3ccccc3)c(C(F)(F)F)cc2Cl)c1N
Temperature: 25 °C
Yield: 40.2 %

Procedure:
A stirred solution of 6.0 grams (0.019 mole) of 5 -amino-1-(3,6-dichloro-5-trifluoromethylpyridin-2-yl)-4-cyanopyrazole and 15.4 grams (0.144 mole) of benzylamine in 100 mL of tetrahydrofuran was heated at reflux for 3.5 hours. The reaction mixture was cooled and filtered. The filtrate was evaporated under reduced pressure, leaving a residue. This residue was dissolved in methylene chloride, and the organic solution was washed in succession with water, dilute hydrochloric acid, and water. The washed organic phase was dried over anhydrous magnesium sulfate and filtered. The filtrate was evaporated under reduced pressure, leaving a pale yellow solid residue. This residue, in 200 mL of petroleum ether, was heated to reflux and then allowed to cool to room temperature. The mixture was filtered, and the filter cake was dried to yield 3.0 grams of 5-amino-1-(3-chloro-5-trifluoromethyl-6-phenylmethylaminopyridin -2-yl)-4-cyanopyrazole. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1.[OH:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=[O:20])=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[N:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH:12]=[CH:13][C:4]=1[CH2:3][O:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=[O:20])=[CH:17][CH:16]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: ClCc1ccc2ccccc2n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1ccc(OCc2ccc3ccccc3n2)cc1
Temperature: 90 °C
Reaction time: 8 h
Yield: 91 %

Procedure:
2-Chloromethylquinoline hydrochloride (6.42 g, 30 mmol), 4-hydroxybenzaldehyde (3.66 g, 30 mmol) and potassium carbonate (9.12 g, 66 mmol) were combined, to which 50 ml of DMF were added. The resulting mixture was stirred overnight at 90° C. The solvent was driven off under reduced pressure, the residue was extracted with ethyl acetate. The organic layer was washed with 1 N aqueous solution of sodium hydroxide and a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure, whereby 7.19 g of the title compound were obtained (yield: 91%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][CH2:13]Cl.[C:15]1(=[O:25])[NH:19][C:18](=[O:20])[C:17]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:16]12.[K].[I-].[K+]>CN(C)C=O.O>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][CH2:13][N:19]1[C:15](=[O:25])[C:16]2[C:17](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:18]1=[O:20]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: ClCCCc1c[nH]c2ccc(Br)cc12
Agent: [I-]
Agent: [K+]
Agent: [K]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1c2ccccc2C(=O)N1CCCc1c[nH]c2ccc(Br)cc12
Temperature: 105 °C
Reaction time: 3 h
Yield: 58 %

Procedure:
A mixture of 5-bromo-3-(3-chloropropyl)-1H-indole (1.35 g), potassium phthalimide (0.93 g) and potassium iodide (1.3 g) in dry dimethylformamide (20 ml) was warmed with stirring at 105° C. for 3 hours. The mixture was cooled and diluted with water (30 ml). An oil precipitated which crystallised over the next 5 min. The resulting solid was collected and washed thoroughly with water. The product was recrystallised from 2-propanol (50 ml) to afford the title compound as a pale yellow crystalline solid (1.1 g) m.p. 168.5°-170° C.
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[C:19]([O:20][CH3:21])=[C:18](Cl)[N:17]=[CH:16][N:15]=2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].[CH3:23][C:24]1[C:29]([NH2:30])=[CH:28][CH:27]=[C:26]([CH3:31])[N:25]=1.CC([O-])(C)C.[Na+]>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[C:19]([O:20][CH3:21])=[C:18]([NH:30][C:29]3[C:24]([CH3:23])=[N:25][C:26]([CH3:31])=[CH:27][CH:28]=3)[N:17]=[CH:16][N:15]=2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2]
Reactant: Cc1ccc(N)c(C)n1
Reactant: COc1c(Cl)ncnc1OC1CCN(C(=O)OC(C)C)CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: C1COCCO1
Product: COc1c(Nc2ccc(C)nc2C)ncnc1OC1CCN(C(=O)OC(C)C)CC1

Procedure:
A mixture of 4-(6-chloro-5-methoxy-pyrimidin-4-yloxy)-piperidine-1-carboxylic acid isopropyl ester (1.52 g, 4.60 mmol), 2,6-dimethylpyridin-3-amine (0.562 g, 4.60 mmol), palladium acetate (0.0584 g, 0.260 mmol), and sodium 2-methylpropan-2-olate (0.663 g, 6.90 mmol) in 50 mL dioxane was stirred under reflux for 18 h. Mixture was concentrated and extracted with brine and CH2Cl2. Organic phases were dried over MgSO4, filtered, and concentrated. Residue was purified by column chromatography (AcOEt/hexane 5:1→AcOEt→AcOEt/MeOH 10:1). Fractions containing pure product were concentrated, residue was treated with 4M HCl in dioxane, and concentrated to give 4-[6-(2,6-dimethyl-pyridin-3-ylamino)-5-methoxy-pyrimidin-4-yloxy]-piperidine-1-carboxylic acid isopropyl ester as a white (0.285 g, 15%). Fractions containing product contaminated with 2,6-dimethylpyridin-3-amine was concentrated to give 0.30 g of ca 80% pure product. 1HNMR (CDCl3, 400 MHz) δ 1.24-1.25 (d, J=6.2 Hz, 6H), 1.78-1.84 (m, 2H), 2.00-2.05 (m, 2H), 2.52 (2s, 6H), 3.37-3.44 (m, 2H), 3.76-3.81 (m, 2H), 4.03 (s, 3H), 4.91-4.97 (m, 1H), 5.33-5.38 (m, 1H), 6.81 (s, 1H), 7.04-7.06 (d, J=8.2 Hz, 1H), 8.09 (s, 1H), 8.11-8.13 (d, J=8.2 Hz, 1H). Exact mass calculated for C21H29N5O4 415.22. found 416.5 (MH+).
Reaction SMILES: Br[CH2:2][C:3](=O)/[C:4](=[N:10]/[O:11][CH2:12][C:13]1[C:18]([Cl:19])=[CH:17][CH:16]=[CH:15][C:14]=1[Cl:20])/[C:5]([O:7][CH2:8][CH3:9])=[O:6].CN(C)C1C=CC=CC=1.[NH2:31][C:32]([NH2:34])=[S:33]>C(O)C>[NH2:34][C:32]1[S:33][CH:2]=[C:3](/[C:4](=[N:10]/[O:11][CH2:12][C:13]2[C:18]([Cl:19])=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:20])/[C:5]([O:7][CH2:8][CH3:9])=[O:6])[N:31]=1
Reactant: CCOC(=O)/C(=N\OCc1c(Cl)cccc1Cl)C(=O)CBr
Reactant: NC(N)=S
Solvent: CCO
Solvent: CN(C)c1ccccc1
Product: CCOC(=O)/C(=N\OCc1c(Cl)cccc1Cl)c1csc(N)n1

Procedure:
Ethyl 4-bromo-(Z)-2-(2,6-dichlorobenzyloxyimino)-3-oxobutyrate (7.2 g) was dissolved in ethanol (20 ml) and N,N-dimethylaniline (2.33 ml) and thiourea (1.4 g) added with stirring. After 18 h the title compound was filtered off, washed with ethanol and dried (4.9 g), m.p. 171°-2° C., νmax (KBr) 3423, 1722, 1619, 1529, 1284, 1188, 1021, and 995 cm-1, δH [(CD3)2SO]1.22 (3H, t), 4.33 (2H, q), 5.51 (2H, s), 6.96 (1H, s), 7.24 (2H, br s), and 7.54 (3H, m), [Mass spectrum: M+ (373/375)].