Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [BH4-].[Na+].[CH3:3][O:4][C:5]1[CH:17]=[CH:16][C:8]([CH:9]=[C:10]2[CH2:15][CH2:14][S:13][CH2:12][CH2:11]2)=[C:7]([N+:18]([O-])=O)[CH:6]=1.Cl>COCCOC.CO>[CH3:3][O:4][C:5]1[CH:17]=[CH:16][C:8]([CH2:9][CH:10]2[CH2:15][CH2:14][S:13][CH2:12][CH2:11]2)=[C:7]([CH:6]=1)[NH2:18]
Reactant: COc1ccc(C=C2CCSCC2)c([N+](=O)[O-])c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CO
Product: COc1ccc(CC2CCSCC2)c(N)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 41.9 %

Procedure:
Sodium borohydride (63.58 mg; 1.68 mmol; 0.07 eq) is suspended in DME (6.5 mL) at room temperature. Borane-methyl sulfide complex (39.61 mL; 2 M; 79.22 mmol; 3.3 eq) is added dropwise. After 30 min stirring at room temperature, a solution of 4-(4-methoxy-2-nitrobenzylidene)tetrahydro-2H-thiopyran (6.37 g; 24.01 mmol; 1 eq) in DME (100 mL) is added dropwise over 30 min and the orange solution is stirred at room temperature for 30 min then heated up to reflux for 3.5 days. The reaction mixture is quenched with MeOH (40 mL) upon which a yellow-brownish solution is obtained. The solution is stirred at room temperature for 1 h prior to evaporation of the solvent. The oily brownish residue obtained is taken up in MeOH (10 mL) and 5 N HCl (10 mL˜2 eq) is added dropwise while cooling the solution to 0° C. with an ice bath. After addition of ⅔ of the HCl, precipitation starts. The suspension is stored at 4° C. for 30 min. The precipitate is filtered off then washed twice with cold EtOAc (10 mL) to afford 2.39 g (36%) of the title compound as a yellow powder. 1H NMR (DMSO-d6) δ 9.61 (br s, 2H), 7.09-7.06 (m, 1H), 9.95-6.87 (m, 1H), 6.83-6.79 (m, 1H), 3.72 (s, 3H), 2.54-2.47 (m, 6H), 1.87-1.81 (m, 2H), 1.68-1.59 (m, 1H), 1.33-1.20 (m, 2H). HPLC (max plot) 95%; Rt 2.57 min. LC/MS: (ES+): 238.1; (ES−): 236.1.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][CH:7]=[C:4]2[CH2:5][CH2:6][C:3]=12.[Mg].C[O:12][B:13](OC)[O:14]C>C1COCC1>[CH:6]1[C:3]2[CH:2]=[CH:9][C:8]([B:13]([OH:14])[OH:12])=[CH:7][C:4]=2[CH:5]=1
Reactant: COB(OC)OC
Reactant: Brc1cccc2c1CC2
Agent: [Mg]
Solvent: C1CCOC1
Product: OB(O)c1ccc2c(c1)C=C2
Temperature: 0 °C
Yield: 97.4 %

Procedure:
The process described in Example 8 was performed with a preformed Grignard reagent from the reaction of 4-bromobenzocyclobutene (18.3 g, 0.1 mol) with magnesium turnings (2.92 g, 0.12 mol) in THF (80 mL) and trimethylborate (12.5 g, 0.12 mol) in THF (80 mL). To recover the product, the reactor was cooled to 0° C. and water (50 mL) was slowly added with vigorous stirring. The reaction was neutralized with aqueous H2SO4, and was extracted with ether (2×300 mL). The ether layer was washed with water (2×150 mL), dried over anhydrous MgSO4, then concentrated on a roto-evaporator to afford an off-white color solid (14.22 g, 96 percent). 1H and 13C NMR spectra were consistent with the following structure. ##STR12##
Reaction SMILES: [C:1]([N:5]1[C:10](=[O:11])[C:9]([Cl:12])=[C:8]([SH:13])[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[F:14][C:15]([F:32])([F:31])[C:16]1[CH:30]=[CH:29][C:19]([O:20][C:21]2[CH:28]=[CH:27][C:24]([CH2:25]Br)=[CH:23][CH:22]=2)=[CH:18][CH:17]=1.C(=O)([O-])[O-].[Na+].[Na+].O>CN(C)C=O>[C:1]([N:5]1[C:10](=[O:11])[C:9]([Cl:12])=[C:8]([S:13][CH2:25][C:24]2[CH:23]=[CH:22][C:21]([O:20][C:19]3[CH:29]=[CH:30][C:16]([C:15]([F:14])([F:31])[F:32])=[CH:17][CH:18]=3)=[CH:28][CH:27]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: FC(F)(F)c1ccc(Oc2ccc(CBr)cc2)cc1
Reactant: CC(C)(C)n1ncc(S)c(Cl)c1=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)n1ncc(SCc2ccc(Oc3ccc(C(F)(F)F)cc3)cc2)c(Cl)c1=O
Yield: 85.5 %

Procedure:
In 30 ml of N,N-dimethylformamide were dissolved 2.2 g (0.01 mol) of 2-tert.-butyl-4-chloro-5-mercapto-3(2H)-pyridazinone and 3.5 g (0.0105 mol) of 4-(4'-trifluoromethylphenoxy) benzyl bromide, and thereto was added 2.1 g (0.02 mol) of anhydrous sodium carbonate to effect reaction at 85° to 90° C. for 4 hours. After the reaction, the reaction liquid was allowed to cool, poured into water and then extracted with benzene. The benzene layer was washed with 5% aqueous solution of sodium hydroxide and then with water, dried over anhydrous sodium sulfate and then freed of benzene by distillation under reduced pressure. The oily residue was incorporated with n-hexane and the precipitated crystals were filtered off to obtain white crystals (yield: 85.5%).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][NH:5][CH:6]=1.Cl[C:8]1[C:13]([O:14][CH3:15])=[CH:12][C:11]([N+:16]([O-:18])=[O:17])=[CH:10][N:9]=1.[OH-].[K+].O>CS(C)=O>[Cl:1][C:2]1[N:3]=[CH:4][N:5]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][C:11]([N+:16]([O-:18])=[O:17])=[CH:10][N:9]=2)[CH:6]=1
Reactant: Clc1c[nH]cn1
Reactant: COc1cc([N+](=O)[O-])cnc1Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: COc1cc([N+](=O)[O-])cnc1-n1cnc(Cl)c1
Temperature: 80 °C
Reaction time: 16 h
Yield: 77.4 %

Procedure:
Step O (1): A mixture of 4-chloro-1H-imidazole (2.72 g, 26.5 mmol), 2-chloro-3-methoxy-5-nitropyridine (5.0 g, 26.5 mmol), and KOH flakes 1.488 g, 26.5 mmol) in anhydrous DMSO (25 mL) was heated at 80° C. for 5 h. The reaction mixture was allowed to cool to rt and was poured into 1.0 L of water with vigorous stirring. The mixture was stirred at rt for 16 h. The precipitate was collected by vacuum filtration using a coarse sintered glass funnel. The solid was dried under high vacuum for 24 h to provide 2-(4-chloro-1H-imidazol-1-yl)-3-methoxy-5-nitropyridine (5.22 g, 20.50 mmol, 77% yield) as a light brown solid. LC-MS (M+H)+=255.0. 1H NMR (500 MHz, DMSO-d6) δ ppm 8.94 (d, J=2.44 Hz, 1 H) 8.51 (d, J=1.83 Hz, 1 H) 8.42 (d, J=2.44 Hz, 1 H) 8.02 (d, J=1.83 Hz, 1 H) 4.12 (s, 3 H).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1([C:12]#[N:13])[CH2:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Ni]>[C:1]([O:5][C:6]([C:8]1([CH2:12][NH2:13])[CH2:9][CH2:10][CH2:11]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)C1(C#N)CCC1
Agent: [Ni]
Solvent: CO
Product: CC(C)(C)OC(=O)C1(CN)CCC1
Reaction time: 8 h

Procedure:
A suspension of Raney Ni (0.6 g, 13.19 mmol) in MeOH (30 ml) in a hydrogenation steel pressure vessel was treated with 1-cyano-cyclobutanecarboxylic acid tert-butyl ester (2.39 g, 13.19 mmol). The reaction mixture was placed under an atmosphere of hydrogen (3 bar) overnight. The mixture was filtered and concentrated in vacuo. The residue was dissolved in MeOH and passed through a 20 g Isolute® SCX-2 cartridge. The cartridge was washed with MeOH followed by product 7M ammonia in MeOH. The ammonia washings were concentrated in vacuo to afford the title product which was used without further purification. 1H NMR (400 MHz, CDCl3) δ 2.45 (2H, m), 2.01-1.67 (6H, m), 0.49 (9H, s).
Reaction SMILES: [O:1]=[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][C:6]([C:12]#[N:13])=[CH:7][CH:8]=2)[N:3]1[CH2:14][CH:15]=C.I([O-])(=O)(=O)=[O:18].[Na+]>O1CCOCC1.O.O=[Os](=O)(=O)=O>[O:1]=[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][C:6]([C:12]#[N:13])=[CH:7][CH:8]=2)[N:3]1[CH2:14][CH:15]=[O:18]
Reactant: C=CCn1c(=O)ccc2ccc(C#N)cc21
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: N#Cc1ccc2ccc(=O)n(CC=O)c2c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 107.2 %

Procedure:
A solution of 2-oxo-1-(2-propen-1-yl)-1,2-dihydro-7-quinolinecarbonitrile (600 mg, 2.9 mmol) in 1,4-dioxane (30 ml) and water (20 ml) was cooled to 0° C. and treated with OsO4 (4% in water, 3 ml) and sodium periodate (1.4 g, 6.67 mmol). The reaction was warmed to rt; 0.6 g and then 3.7 g more of sodium periodate were added. After 4 h in total, the solvent was evaporated and residue partitioned between water and 20% methanol-DCM. The phases were separated and the organic phase was dried and evaporated to afford the desired compound (660 mg, 107%).
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]([F:22])([CH2:7][CH2:8][C:9]([F:21])([F:20])[C:10]([F:19])([F:18])[C:11]([F:17])([F:16])[C:12]([F:15])([F:14])[F:13])[C:4]([O-:6])=[O:5].[Na+].Cl.CCOCC>O>[F:1][C:2]([F:23])([F:24])[C:3]([F:22])([CH2:7][CH2:8][C:9]([F:20])([F:21])[C:10]([F:18])([F:19])[C:11]([F:16])([F:17])[C:12]([F:13])([F:14])[F:15])[C:4]([OH:6])=[O:5]
Reactant: O=C([O-])C(F)(CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)C(F)(F)F
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: O=C(O)C(F)(CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)C(F)(F)F

Procedure:
Sodium 2-trifluoromethyl-2,5,5,6,6,7,7,8,8,8-decafluorooctanoate was dissolved in water with vigorous stirring and 6N aqueous hydrochloric acid was added slowly to adjust the pH of the solution to about 1.0, and then ether was added to extract the product. The organic layer was separated, washed with water, and dried over magnesium sulfate. After removal of the solvent in vacuo, the residue was dried under high vacuum to give quantitative yield of 2-trifluoromethyl-2,5,5,6,6,7,7,8,8,8-decafluorooctanoic acid, formula above, as a white solid having a melting point of 45°-46° C.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1.[OH:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][C:25]=3[O:27][CH2:28][C@H:29]([N:31]([CH3:35])[C:32](=[O:34])[CH3:33])[CH3:30])[N:20]=[CH:19][N:18]=2)=[CH:12][C:11]=1[CH3:36]>>[CH3:35][N:31]([C@H:29]([CH3:30])[CH2:28][O:27][C:25]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:26]=1[C:17]([NH:16][C:13]1[CH:14]=[CH:15][C:10]([O:9][CH2:2][C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=3)=[C:11]([CH3:36])[CH:12]=1)=[N:18][CH:19]=[N:20]2)[C:32](=[O:34])[CH3:33]
Reactant: ClCc1ccccn1
Reactant: CC(=O)N(C)[C@H](C)COc1cccc2ncnc(Nc3ccc(O)c(C)c3)c12
Product: CC(=O)N(C)[C@H](C)COc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(C)c3)c12
Yield: 43 %

Procedure:
The procedure described in Example 3 was repeated using 2-(chloromethyl)pyridine and N-[(1R)-2-({4-[(4-hydroxy-3-methylphenyl)amino]quinazolin-5-yl}oxy)-1-methylethyl]-N-methylacetamide to give the title compound as a light beige solid in 43% yield; NMR spectrum (DMSO-d6 373K) 1.21 (d, 3H), 1.85 (s, 3H), 2.27 (s, 3H), 2.84 (s, 3H), 4.34 (m, 1H), 4.40 (t, 1H), 5.07 (m, 1H), 5.20 (s, 2H), 7.01 (d, 1H), 7.17 (d, 1H), 7.33 (m, 2H), 7.42 (d, 1H), 7.47 (dd, 1H), 7.55 (d, 1H), 7.67 (t, 1H), 7.82 (td, 1H), 8.41 (s, 1H), 8.57 (d, 1H), 9.50 (s, 1H); Mass spectrum MH+ 472.
Reaction SMILES: [Na].[Cl:2][C:3]1[C:8]([CH3:9])=[CH:7][CH:6]=[C:5]([Cl:10])[C:4]=1[NH:11][S:12]([C:15]1[N:25]=[C:18]2[N:19]=[C:20]([CH3:24])[CH:21]=[C:22](Cl)[N:17]2[N:16]=1)(=[O:14])=[O:13].Cl.[CH3:27][OH:28]>>[Cl:2][C:3]1[C:8]([CH3:9])=[CH:7][CH:6]=[C:5]([Cl:10])[C:4]=1[NH:11][S:12]([C:15]1[N:25]=[C:18]2[N:19]=[C:20]([CH3:24])[CH:21]=[C:22]([O:28][CH3:27])[N:17]2[N:16]=1)(=[O:14])=[O:13]
Reactant: CO
Reactant: Cc1cc(Cl)n2nc(S(=O)(=O)Nc3c(Cl)ccc(C)c3Cl)nc2n1
Agent: Cl
Agent: [Na]
Product: COc1cc(C)nc2nc(S(=O)(=O)Nc3c(Cl)ccc(C)c3Cl)nn12
Reaction time: 0.33 h

Procedure:
Sodium (0.6 g, 26 mmol) was added to about 40 ml of methanol and allowed to react. N-(2,6-dichloro-3-methylphenyl)-7-chloro-5-methyl-1,2,4-triazolo[1,5-a]pyrimidine-2-sulfonamide (2.5 g, 6.9 mmol) was added with stirring. After about 20 minutes, thin layer chromatography indicated the starting material had reacted. The solution was then acidified by adding 6N hydrochloric acid dropwise and then concentrated by evaporation under reduced pressure. The residue was triturated with water and the solid that formed was washed with water and dried to obtain 1.35 g of the title compound as a white solid, m.p. 239°-42° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[C:9]([Br:11])[C:8](=[O:12])[N:7]([CH2:13][CH:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[C:6]=1[CH3:19])=[O:4].[Br:20]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[C:9]([Br:11])[C:8](=[O:12])[N:7]([CH2:13][CH:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[C:6]=1[CH2:19][Br:20])=[O:4]
Reactant: COC(=O)c1cc(Br)c(=O)n(CC2CCCC2)c1C
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1cc(Br)c(=O)n(CC2CCCC2)c1CBr
Yield: 45.2 %

Procedure:
A mixture of 5-bromo-1-cyclopentylmethyl-2-methyl-6-oxo-1,6-dihydro-pyridine-3-carboxylic acid methyl ester (4.46 g, 13.6 mmol), N-bromosuccinimide (2.66 g, 15.0 mmol), and benzoyl peroxide (0.33 g, 1.36 mmol) in CCl4 (130 mL) was refluxed for 16 h. The resulting suspension was filtered, and the filtrate was evaporated in vacuo. The residue was purified by silica gel chromatography (0-25% EtOAc/hexanes) to give 2.5 g of the title compound. MS: (+) m/z 408.10 (M+1).
Reaction SMILES: [CH3:1][N:2]([C:12]([NH:14][C@H:15]([C:19]([OH:21])=O)[CH:16]([CH3:18])[CH3:17])=[O:13])[CH2:3][C:4]1[N:5]=[C:6]([CH:9]([CH3:11])[CH3:10])[S:7][CH:8]=1.[NH2:22][C@@H:23]([CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)[CH2:24][C@H:25]([OH:44])[C@@H:26]([NH:34][C:35]([O:37][CH2:38][C:39]1[S:43][CH:42]=[N:41][CH:40]=1)=[O:36])[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.O.ON1C2C=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C>C1COCC1>[CH3:1][N:2]([C:12]([NH:14][C@H:15]([C:19]([NH:22][C@@H:23]([CH2:45][C:46]1[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=1)[CH2:24][C@H:25]([OH:44])[C@@H:26]([NH:34][C:35]([O:37][CH2:38][C:39]1[S:43][CH:42]=[N:41][CH:40]=1)=[O:36])[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:21])[CH:16]([CH3:17])[CH3:18])=[O:13])[CH2:3][C:4]1[N:5]=[C:6]([CH:9]([CH3:10])[CH3:11])[S:7][CH:8]=1
Reactant: N[C@@H](Cc1ccccc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)OCc1cncs1
Reactant: CC(C)c1nc(CN(C)C(=O)N[C@H](C(=O)O)C(C)C)cs1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: C1CCOC1
Product: CC(C)c1nc(CN(C)C(=O)N[C@H](C(=O)N[C@@H](Cc2ccccc2)C[C@H](O)[C@H](Cc2ccccc2)NC(=O)OCc2cncs2)C(C)C)cs1
Yield: 74.6 %

Procedure:
A solution of 70 mg (0.223 mmol) of N-((N-methyl-N-((2-isopropyl-4-thiazolyl)methyl)amino)carbonyl)-L-valine, 79 mg (0.186 mmol) of (2S,3S,5S)-5-amino-2-(N-((5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane, 30 mg (0.223 mmol) of 1-hydroxybenzotriazole hydrate, and 51 mg (0.266 mmol) of N-ethyl-N'-dimethylaminopropyl carbodiimide in 2 ml of THF was stirred at ambient temperature for 16 h. The resulting solution was concentrated in vacuo, and the residue was purified by silica gel chromatography using 97:3 CH2Cl2 :CH3OH to provide 100 mg (74%) of the desired compound (Rf 0.4, 95:5 CH2Cl2 :CH3OH) as a solid. 1H NMR (d6 -DMSO) δ0.73 (d, J=7 Hz, 6H), 1.30 (d, J=7 Hz, 6H), 1.45 (m, 2H), 1.87 (m, 1H), 2,5-2.7 (m, 4H), 2.87 (s, 3H), 3.23 (heptet, J=7 Hz, 1H), 3.57 (m, 1H), 3.81 (m, 1H), 3.93 (m, 1H), 4.15 (m, 1H), 4.44 (AA', 2H), 4.62 (d, J=6 Hz, 1H), 5.13 (AA', 2H), 6.01 (d, J=9 Hz, 1H), 6.89 (d, J=9 Hz, 1H), 7.1-7.2 (m, 11H), 7.68 (d, J=9 Hz, 1H), 7.85 (s, 1H), 9.05 (s, 1H). Mass spectrum: (M+H)+ =721. Anal. Calcd for C37H48N6O5S2.0.5H2O: C, 60.88; H, 6.77; N, 11.51. Found: C, 60.68; H, 6.53; N, 11.36.
Reaction SMILES: [CH2:1]([N:3]([CH2:34][CH3:35])[C:4]([C:6]1[CH:11]=[CH:10][C:9]([CH:12]([N:21]2[CH2:26][CH2:25][N:24]([CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:23][CH2:22]2)[C:13]2[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=2)[C:16]#[N:17])=[CH:8][CH:7]=1)=[O:5])[CH3:2].[OH-:36].[K+]>C(O)(C)(C)C.ClCCl>[CH2:34]([N:3]([CH2:1][CH3:2])[C:4]([C:6]1[CH:7]=[CH:8][C:9]([CH:12]([N:21]2[CH2:22][CH2:23][N:24]([CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:25][CH2:26]2)[C:13]2[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=2)[C:16]([NH2:17])=[O:36])=[CH:10][CH:11]=1)=[O:5])[CH3:35]
Reactant: [OH-]
Reactant: CCN(CC)C(=O)c1ccc(C(c2cccc(C#N)c2)N2CCN(Cc3ccccc3)CC2)cc1
Agent: [K+]
Solvent: ClCCl
Solvent: CC(C)(C)O
Product: CCN(CC)C(=O)c1ccc(C(c2cccc(C(N)=O)c2)N2CCN(Cc3ccccc3)CC2)cc1
Yield: 84.2 %

Procedure:
To a solution of INTERMEDIATE 4a (428 mg) in tert-butanol (10 mL) was added crushed potassium hydroxide (129 mg, 2.5 eq) and the reaction was heated to reflux. After 90 minutes the reaction was cooled and diluted with dichloromethane (40 mL). The reaction was washed with water (30 mL) and the organic layer separated. The aqueous layer was neutralized with 2 N hydrochloric acid and washed with dichloromethane (2×25 mL). The combined organic extracts were dried (MgSO4), filtered and concentrated. The residue was purified by flash chromatography, eluting 3% methanol in dichloromethane to yield COMPOUND 1 as a colorless foam (374.5 mg, 84%). 1H NMR (CD3OD) δ 1.06 (t, J=6.9 Hz, 3H), 1.20 (t, J=6.8 Hz, 3H), 3.15-3.40 (m, 6H), 3.545-3.54 (m, 2H), 3.57-3.67 (m, 4H), 4.44 (s, 2H), 5.39 (br s, 1H), 7.40 (d, J=8.4 Hz, 2H), 7.43-7.59 m, 6H), 7.82 (d, J=7.8 Hz, 3H), 7.93 (d, J=7.0 Hz, 1H), 8.22 (s, 1H).
Reaction SMILES: B(Br)(Br)Br.[Cl:5][C:6]1[CH:7]=[CH:8][C:9]([O:26]C)=[C:10]([CH:12]2[C:20]3[C:15](=[CH:16][C:17]([C:21]([F:24])([F:23])[F:22])=[CH:18][CH:19]=3)[NH:14][C:13]2=[O:25])[CH:11]=1>C(Cl)Cl>[Cl:5][C:6]1[CH:7]=[CH:8][C:9]([OH:26])=[C:10]([CH:12]2[C:20]3[C:15](=[CH:16][C:17]([C:21]([F:23])([F:24])[F:22])=[CH:18][CH:19]=3)[NH:14][C:13]2=[O:25])[CH:11]=1
Reactant: COc1ccc(Cl)cc1C1C(=O)Nc2cc(C(F)(F)F)ccc21
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=C1Nc2cc(C(F)(F)F)ccc2C1c1cc(Cl)ccc1O
Temperature: 25 °C
Yield: 92.3 %

Procedure:
A solution of BBr3 (12 mL, 12 mmol; 1M in CH2Cl2) was added to a stirred cold (-78° C.) solution of (±)-3-(5-chloro-2-methoxyphenyl)-1,3-dihydro -6-(trifluoromethyl)-2H-indol-2-one (1.37 g, 4 mmol) in anhydrous CH2Cl2 (20 mL). The mixture was allowed to warm to ambient temperature and maintained for 2 hours. The reaction was quenched with saturated NaHCO3 and then acidified with 1N HCl. The organic layer was separated, washed with water, brine and then dried (MgSO4). Evaporation of CH2Cl2 gave an off-white solid which was triturated with warm CH2Cl2 to afford the title compound (1.21 g, 93%): mp 266°-268° C.; IR (KBr, cm-1) 3320, 1690, 1310, 1250, 1160, 1125; 1H NMR (300 MHz, DMSO-d6)δ 4.85 (1H, s), 6.75 (1H, d, J=8.6 Hz), 7.04 (1H, s), 7.11, (1H, d, J=7.7 Hz), 7.17 (1H, dd, J=8.6 and 2.6 Hz), 7.22 (1H, d, J=8.0 Hz), 7.26 (1H, d, J=2.4 Hz), =9.82 (1H, s), 10.73 (1H, s); 13C NMR (75 MHz, DMSO-d6)δ 48.47, 104.94, 116.84. 118.16, 122.27, 124.20, 125.61, 126.06, 128.05, 128.41, 130.76, 134.72, 143.69, 154.26, 176.92. MS m/e 328 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7](I)[CH:6]=[CH:5][C:3]=1[NH2:4].[C:10]([Si:12]([CH3:15])([CH3:14])[CH3:13])#[CH:11]>CCOCC.[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>[F:1][C:2]1[CH:8]=[C:7]([C:11]#[C:10][Si:12]([CH3:15])([CH3:14])[CH3:13])[CH:6]=[CH:5][C:3]=1[NH2:4]
Reactant: C#C[Si](C)(C)C
Reactant: Nc1ccc(I)cc1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCOCC
Product: C[Si](C)(C)C#Cc1ccc(N)c(F)c1
Temperature: 25 °C
Yield: 100.6 %

Procedure:
A stirred mixture of 2-fluoro-4-iodoaniline (5.0 g, 21.1 mmol), CuI (90 mg, 0.42 mmol), and PdCl2(PPh3)2 (300 mg, 0.42 mmol) in a pressure tube was flushed with argon. Ethynyltrimethylsilane (2.28 g, 23.2 mmol) in TEA (20 mL) was added and the resulting mixture was stirred at rt over night. The reaction mixture was then diluted with Et2O and filtered through a Celite pad. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel chromatography eluting with 5% EtOAc in hexanes to afford 2-fluoro-4-((trimethylsilyl)ethynyl)aniline (4.4 g, 100%) as a brown solid. LCMS (ESI) m/z 208 (M+H)+.
Reaction SMILES: [CH2:1]([OH:13])[CH2:2][O:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][OH:12].C(N(CC)CC)C.[C:21]1([C:27](Cl)([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>ClCCl>[C:21]1([C:27]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[O:12][CH2:11][CH2:10][O:9][CH2:8][CH2:7][O:6][CH2:5][CH2:4][O:3][CH2:2][CH2:1][OH:13])[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: OCCOCCOCCOCCO
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: OCCOCCOCCOCCOC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 96.7 %

Procedure:
To tetraethylene glycol (213.65 g, 1.1 mol) and triethylamine (20.24 g, 27.8 ml, 200 mmol) in dry dichloromethane (1500 ml) was added dropwise triphenylmethyl chloride (27.88 g, 100 mmol) in dry dichloromethane (500 ml). This solution was left to stir under argon at room temperature for 24 hours. After 24 hours, the reaction was concentrated in vacuo to give a mixture of product and starting material as a yellow oil. This oil was then re-dissolved in dichloromethane (1000 ml), partitioned with sat. aq. NaHCO3 (500 ml), water (3×400 ml) and finally sat. aq. NaCl (500 ml). The organic layer was separated, dried over anhydrous sodium sulphate and concentrated in vacuo to give the title compound as a yellow oil (42.2 g, 95%) which was used without further purification.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH:18]=[C:17]([C:19]3[CH:20]=[N:21][C:22]([NH2:34])=[C:23](B4OC(C)(C)C(C)(C)O4)[CH:24]=3)[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=O)(C)(C)C.[Br:35][C:36]1[C:41]2[N:42]=[C:43](I)[S:44][C:40]=2[CH:39]=[C:38]([O:46][C:47]([F:50])([F:49])[F:48])[CH:37]=1.C(=O)([O-])[O-].[K+].[K+]>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>[Br:35][C:36]1[C:41]2[N:42]=[C:43]([C:23]3[C:22]([NH2:34])=[N:21][CH:20]=[C:19]([C:17]4[CH:16]=[N:15][N:14]([CH:11]5[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]5)[CH:18]=4)[CH:24]=3)[S:44][C:40]=2[CH:39]=[C:38]([O:46][C:47]([F:50])([F:49])[F:48])[CH:37]=1
Reactant: FC(F)(F)Oc1cc(Br)c2nc(I)sc2c1
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(-c3cnc(N)c(B4OC(C)(C)C(C)(C)O4)c3)cn2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: Nc1ncc(-c2cnn(C3CCNCC3)c2)cc1-c1nc2c(Br)cc(OC(F)(F)F)cc2s1
Temperature: 80 °C

Procedure:
A mixture of 4-{4-[6-amino-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-3-yl]-pyrazol-1-yl}-piperidine-1-carboxylic acid tert-butyl ester (BB8) (75 mg, 0.16 mmol), 4-bromo-2-iodo-6-trifluoromethoxy-1,3-benzothiazole (81 mg, 0.19 mmol), potassium carbonate (66 mg, 0.48 mmol), Pd(PPh3)4 (18 mg, 0.016 mmol) in DME (3 mL) and H2O (1 mL) was evacuated and refilled with N2 (3×), then it was heated at 80° C. for 2 h. The mixture was diluted with EtOAc (30 mL), washed with brine (10 mL), and dried over anhydrous sodium sulfate. The residue was purified by silica gel chromatography (Hex.:EtOAc=30:70→15:85) to give the Boc-protected title compound as a yellow solid, MS (ES+): m/z=639/641 (1/1) [MH+]. This material was dissolved in DCM (1 mL) and treated with 1M HCl in diethyl ether (3 mL, 3 mmol). The resulting mixture was stirred at room temperature overnight. The solid that formed was filtered off, washed with DCM, and dried in vacuo to give the title compound as yellow solid. MS (ES+): m/z=538.98/540.96 (1/1) [MH+].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][CH:14]=1)[NH:5][CH:6]([CH3:11])[CH2:7][C:8]([OH:10])=O.[C:15](Cl)([Cl:17])=[O:16].C(Cl)Cl.[Cl-].[Al+3].[Cl-].[Cl-]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:12]([C:8](=[O:10])[CH2:7][CH:6]([CH3:11])[N:5]2[C:15]([Cl:17])=[O:16])=[CH:13][CH:14]=1
Reactant: CC(CC(=O)O)Nc1cccc(Cl)c1
Reactant: O=C(Cl)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC1CC(=O)c2ccc(Cl)cc2N1C(=O)Cl

Procedure:
7-Chloro-1-chloroformyl-2-methyl-1,2,3,4-tetrahydro-4-quinolinone is prepared in a manner similar to that described in Example 5 but starting from 3-(3-chloroanilino)butanoic acid (5.42 g; 25.4 mmol), phosgene (6.7 g; 67.7 mmol), methylene chloride (25 cc), dimethylformamide (0.23 cc) and aluminum chloride (8.15 g; 61.1 mmol).