Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:10](B3OC(C)(C)C(C)(C)O3)=[CH:9][N:8]([S:20]([C:23]3[CH:29]=[CH:28][C:26]([CH3:27])=[CH:25][CH:24]=3)(=[O:22])=[O:21])[C:5]2=[N:6][CH:7]=1.Cl[C:31]1[C:36]([C:37]#[N:38])=[CH:35][N:34]=[C:33]([S:39][CH3:40])[N:32]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[CH3:1][C:2]1[CH:3]=[C:4]2[C:10]([C:31]3[C:36]([C:37]#[N:38])=[CH:35][N:34]=[C:33]([S:39][CH3:40])[N:32]=3)=[CH:9][N:8]([S:20]([C:23]3[CH:29]=[CH:28][C:26]([CH3:27])=[CH:25][CH:24]=3)(=[O:22])=[O:21])[C:5]2=[N:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(B3OC(C)(C)C(C)(C)O3)c3cc(C)cnc32)cc1
Reactant: CSc1ncc(C#N)c(Cl)n1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CSc1ncc(C#N)c(-c2cn(S(=O)(=O)c3ccc(C)cc3)c3ncc(C)cc23)n1
Reaction time: 0.17 h
Yield: 87.5 %

Procedure:
A mixture of 5-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (306 mg, 0.74 mmol) and 4-chloro-2-(methylthio)pyrimidine-5-carbonitrile (207 mg, 1.12 mmol) in dioxane (9 mL) was degassed and stirred under nitrogen for 10 minutes. The reaction mixture was treated with potassium carbonate (336 mg, 2.23 mmol) and bis(tri-t-butylphosphine)palladium(0) (38 mg, 0.074 mmol) and degassed again. The reaction mixture and stirred under nitrogen for 10 minutes. Water (1.35 mL) was added and the reaction mixture was degassed and stirred under nitrogen for 2 hours. A suspension was observed. The resulting mixture was filtered and the solid was washed with dioxane and water. The solid was dried in a vacuum oven to afford the title compound as a white solid (282 mg, 87% yield).
Reaction SMILES: N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F.[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2[N:39]([C:40]3[CH:45]=[CH:44][C:43]([Cl:46])=[CH:42][C:41]=3[Cl:47])[N:38]=[C:37]([C:48]([OH:50])=O)[C:36]=2[CH3:51])=[CH:31][CH:30]=1.[NH2:52][CH:53]1[CH2:58][CH2:57][N:56]([C:59]([O:61][C:62]([CH3:65])([CH3:64])[CH3:63])=[O:60])[CH2:55][CH2:54]1.C(N(CC)CC)C>O1CCCC1>[Cl:28][C:29]1[CH:30]=[CH:31][C:32]([C:35]2[N:39]([C:40]3[CH:45]=[CH:44][C:43]([Cl:46])=[CH:42][C:41]=3[Cl:47])[N:38]=[C:37]([C:48]([NH:52][CH:53]3[CH2:54][CH2:55][N:56]([C:59]([O:61][C:62]([CH3:65])([CH3:64])[CH3:63])=[O:60])[CH2:57][CH2:58]3)=[O:50])[C:36]=2[CH3:51])=[CH:33][CH:34]=1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: Cc1c(C(=O)O)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1c(C(=O)NC2CCN(C(=O)OC(C)(C)C)CC2)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Reaction time: 16 h
Yield: 87.5 %

Procedure:
Benzotriazole-1-yl-oxytris(dimethylamino)phosphonium-hexafluorophosphate (BOP) (1 eq, 490 mg, 1.11 mmol) was added to a solution of 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxylic acid (1 eq, 422 mg, 1.11 mmol), tert-butyl 4-amino-1-piperidinecarboxylate (1 eq, 222 mg, 1.11 mmol), and triethylamine (3 eq., 0.46 mL, 3.32 mmol) in tetrahydrofuran (5 mL). The reaction mixture was stirred for 16 h. The reaction was concentrated in vacuo. The crude reaction material was then purified by silica gel column chromatography using 0-100% ethyl acetate/hexane to yield pure tert-butyl 4-[5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-amido]piperidine-1-carboxylate (548 mg, 88%). 1H NMR (300 MHz, CHLOROFORM-d) d ppm 1.33-1.51 (m, 9H) 1.93-2.10 (m, 2H) 2.37 (s, 3H) 2.91 (t, J=11.82 Hz, 2H) 3.89-4.23 (m, 2H) 6.84 (d, J=8.19 Hz, 1H) 7.00-7.12 (m, 2H) 7.19-7.36 (m, 4H) 7.43 (d, J=1.32 Hz, 1H).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5](Cl)(=[O:8])[CH2:6][CH3:7].[CH3:10][CH:11]1[S:15][C:14]2[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=2[CH2:12]1.Cl>ClC=CCl>[C:5]([C:18]1[CH:17]=[CH:16][C:14]2[S:15][CH:11]([CH3:10])[CH2:12][C:13]=2[CH:19]=1)(=[O:8])[CH2:6][CH3:7]
Reactant: CCC(=O)Cl
Reactant: CC1Cc2ccccc2S1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClC=CCl
Product: CCC(=O)c1ccc2c(c1)CC(C)S2
Temperature: 10 °C
Reaction time: 3 h

Procedure:
To 0.15M of aluminum chloride, 0.11M of propionyl chloride and 150 ml of 1,2-dichloroethylene, 0.1M of 2-methyl2,3-dihydrobenzo[b]-thiophene (prepared according to method of Petropoulos, J. Am. Chem. Soc., 75, 1130, 1953) are added slowly, temperature being maintained at ±10° C. After addition, the mixture is still stirred for 3 hours at room temperature, then a mixture of ice and HCl is added. The mixture is extracted with 1,2-dichloroethylene, dried on MgSO4 and solvent is evaporated. The oily residue as stripped in vacuum. 14 gr. of 5-propionyl-2-methyl-2,3-dihydrobenzo[b]thiophene are so obtained.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[CH:5][C:6]2[CH:12]=[CH:11][C:10]3[CH:13]=[CH:14][CH:15]=[CH:16][C:9]=3[CH:8](O)[C:7]=2[CH:18]=1.[ClH:19]>O1CCOCC1>[Cl:19][CH:8]1[C:7]2[CH:18]=[C:3]([S:2][CH3:1])[CH:4]=[CH:5][C:6]=2[CH:12]=[CH:11][C:10]2[CH:13]=[CH:14][CH:15]=[CH:16][C:9]1=2
Reactant: CSc1ccc2c(c1)C(O)c1ccccc1C=C2
Reactant: Cl
Solvent: C1COCCO1
Product: CSc1ccc2c(c1)C(Cl)c1ccccc1C=C2

Procedure:
A solution of 18 g. (0.071 mole) of 3-methylmercapto-5H-dibenzo[a,d]cyclohepten-5-ol in 90 ml. of dry dioxane is cooled in an ice-bath and saturated with dry hydrogen chloride. A solid separates and when precipitation appears to be complete, the mixture is stirred with 150 ml. of petroleum ether and the product collected, washed with petroleum ether, and dried in a vacuum desiccator over potassium hydroxide. The yield of 5-chloro-3-methylmercapto-5H-dibenzo[a,d]cycloheptene is 16 g. (84%), m.p. 135°-138° C. The melting point is unchanged by recrystallization from cyclohexane.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([CH:10]=[O:11])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[H-].[Na+].[C:14]1([CH3:24])[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1.O>CN(C)C=O>[CH3:24][C:14]1[CH:19]=[CH:18][C:17]([S:20]([N:1]2[C:9]3[C:4](=[CH:5][C:6]([CH:10]=[O:11])=[CH:7][CH:8]=3)[CH:3]=[CH:2]2)(=[O:22])=[O:21])=[CH:16][CH:15]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=Cc1ccc2[nH]ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2ccc3cc(C=O)ccc32)cc1
Temperature: 25 °C
Reaction time: 13 h
Yield: 69.2 %

Procedure:
To a solution of indole-5-carboxaldehyde (2.00 g, 13.8 mmol) in dimethylformamide (50 mL) were added sodium hydride (60% oil dispersion; 828 mg, 20.7 mmol) and p-toluenesulfonyl chloride (3.16 g, 16.6 mmol) at 0° C. under nitrogen atmosphere, and the mixture was stirred for 13 h at room temperature. Water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried on anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (5:1 hexane/ethyl acetate) to afford 1-(4-methylphenyl)sulfonylindole-5-carboxaldehyde (2.86 g, 69%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:62])[CH2:7][N:8]([C:17]1[CH:22]=[CH:21][C:20]([C:23]2([OH:53])[C:36]3[CH:35]=[C:34]([F:37])[C:33]([O:38][CH2:39][O:40][CH2:41][CH2:42][O:43][CH3:44])=[CH:32][C:31]=3[O:30][C:29]3[C:24]2=[CH:25][C:26]([F:52])=[C:27]([O:45][CH2:46][O:47][CH2:48][CH2:49][O:50][CH3:51])[CH:28]=3)=[CH:19][C:18]=1[O:54]CC1C=CC=CC=1)[CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])([CH3:4])([CH3:3])[CH3:2]>C(O)C.CCOC(C)=O.[Pd]>[C:13]([O:12][C:10](=[O:11])[CH2:9][N:8]([CH2:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:62])[C:17]1[CH:22]=[CH:21][C:20]([C:23]2([OH:53])[C:36]3[CH:35]=[C:34]([F:37])[C:33]([O:38][CH2:39][O:40][CH2:41][CH2:42][O:43][CH3:44])=[CH:32][C:31]=3[O:30][C:29]3[C:24]2=[CH:25][C:26]([F:52])=[C:27]([O:45][CH2:46][O:47][CH2:48][CH2:49][O:50][CH3:51])[CH:28]=3)=[CH:19][C:18]=1[OH:54])([CH3:16])([CH3:15])[CH3:14]
Reactant: COCCOCOc1cc2c(cc1F)C(O)(c1ccc(N(CC(=O)OC(C)(C)C)CC(=O)OC(C)(C)C)c(OCc3ccccc3)c1)c1cc(F)c(OCOCCOC)cc1O2
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: COCCOCOc1cc2c(cc1F)C(O)(c1ccc(N(CC(=O)OC(C)(C)C)CC(=O)OC(C)(C)C)c(O)c1)c1cc(F)c(OCOCCOC)cc1O2
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.4 %

Procedure:
To a solution of 14 (956 mg, 1.1 mmol) in 95% ethanol (25 mL) and EtOAc (25 mL) was added 10% Pd/C (130 mg). The resulting mixture was stirred at room temperature overnight under H2 (1 atm). The catalyst was then removed by filtration and, after evaporation to dryness, the crude product was purified by flash column chromatography, eluting with 40% EtOAc in hexane (with 0.1% Et3N) to yield 671 mg (78%) of 15 as a light yellow oil. Rf=0.3 (in 40% EtOAc/hexane); 1H NMR (300 MHz, CDCl3) δ 8.1 (s, 1H), 7.18 (d, 1H, J=8.0 Hz), 6.95 (d, 2H, J=7.2 Hz), 6.69 (m, 3H), 6.57 (m, 1H), 5.28 (s, 4H), 4.94 (s, 1H), 3.85 (m, 4H), 3.69 (s, 4H), 3.57 (m, 4H), 3.38 (s, 6H), 1.41 (s, 18H); 13C NMR (75 MHz, CDCl3) δ 171.2, 153.8, 150.6, 147.4, 146.5, 144.8, 144.4, 144.2, 136.3, 126.3, 119.6, 116.7, 116.6, 116.1, 115.8, 115.5, 105.9, 94.6, 81.9, 71.4, 68.0, 59.0, 56.9, 43.1, 27.9; 19F NMR (282 MHz, CDCl3) δ −140.4 (dd, 2 F); mass spectrum, calculated for C46H55F2NO13 (M−17) 761.3, Found 761.7.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:12])=[C:6]([S:8](Cl)(=[O:10])=[O:9])[CH:7]=1.[NH4+:13].[OH-]>CC(C)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:12])=[C:6]([S:8]([NH2:13])(=[O:10])=[O:9])[CH:7]=1
Reactant: Cc1ccc(F)cc1S(=O)(=O)Cl
Reactant: [NH4+]
Agent: [OH-]
Solvent: CC(C)=O
Product: Cc1ccc(F)cc1S(N)(=O)=O
Yield: 98 %

Procedure:
To a solution of 5-fluoro-2-methyl-benzenesulfonyl chloride (4.18 g, 20 mmol) in acetone (20 mL) was added, dropwise, concentrated NH4OH (3 mL) and the resulting mixture stirred for 5 min. Acetone was removed in vacuo and the precipitates were filtered, washed thoroughly with water and dried in vacuo to provide 3.7 g (Yield 98%) of the title compound as a white solid; 1H NMR (500 MHz, DMSO-D6) δ ppm: 2.55 (3H, s) 7.33-7.40 (1H, m) 7.40-7.46 (1H, m) 7.54 (2H, s) 7.59 (1H, dd, J=9.2, 2.7 Hz); LC/MS m/z 190 (M+H).
Reaction SMILES: [CH3:1][C:2]([C:20]1[CH:29]=[CH:28][C:23]([C:24]([O:26][CH3:27])=O)=[CH:22][CH:21]=1)([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)=[CH:8][N:7]=1)[CH:3]([CH3:5])[CH3:4].[C:30]1(C)C=CC=CC=1>C1COCC1.[CH3-].C[Al+]C.[CH-]1C=CC=C1.[CH-]1C=CC=C1.[Cl-].[Ti+3]>[CH3:27][O:26][C:24]([C:23]1[CH:28]=[CH:29][C:20]([C:2]([C:6]2[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)=[CH:8][N:7]=2)([CH3:1])[CH:3]([CH3:5])[CH3:4])=[CH:21][CH:22]=1)=[CH2:30]
Reactant: COC(=O)c1ccc(C(C)(c2ccc(OCc3ccccn3)cn2)C(C)C)cc1
Reactant: Cc1ccccc1
Agent: [Ti+3]
Agent: C[Al+]C
Agent: [CH3-]
Solvent: C1CCOC1
Product: C=C(OC)c1ccc(C(C)(c2ccc(OCc3ccccn3)cn2)C(C)C)cc1
Reaction time: 16 h

Procedure:
Tebbe reagent (15.2 mL of a 0.5 M solution in toluene, 7.60 mmol) was added to a stirred solution of 1a (2.70 g, 6.91 mmol) in THF (100 mL) at rt and the resulting mixture aged for approximately 16 h. The reaction was quenched by the addition of basic alumina, and the resulting suspension was filtered through a short column of basic alumina eluting with EtOAc. The filtrate was concentrated in vacuo and the crude residue containing 1b was used without further purification in the subsequent reaction.
Reaction SMILES: [BH4-].[Na+].[CH3:3][O:4][C:5]1[CH:14]=[CH:13][C:8]([C:9](OC)=[O:10])=[CH:7][N:6]=1>C(O)C>[CH3:3][O:4][C:5]1[N:6]=[CH:7][C:8]([CH2:9][OH:10])=[CH:13][CH:14]=1
Reactant: COC(=O)c1ccc(OC)nc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: COc1ccc(CO)cn1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Sodium borohydride (11.30 g, 299 mmol) was added to a solution of the methyl 6-methoxynicotinate (5.00 g, 29.9 mmol) in ethanol (100 mL) at 0° C. The reaction was allowed to warm to room temperature and stirred for 3 days. The reaction was cooled to 0° C. and quenched by slow addition of 1 N HCl until pH 4.0. The reaction mixture was concentrated to remove ethanol. The remaining aqueous solution was washed with ethyl acetate (2×), then neutralized with saturated aqueous sodium bicarbonate, then extracted with ethyl acetate (3×). The organic layers were combined, washed with brine, dried (Na2SO4), filtered and concentrated. The crude material was purified by silica chromatography (hexanes/ethyl acetate 1:1, 3:7) to give a clear oil. Mass/Yield-3.9 g/94% TLC (hexanes/ethyl acetate=1:1) Rf=0.22, UV active. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 3.91 (s, 3 H) 4.61 (s, 2 H) 6.68-6.77 (m, 1 H) 7.49-7.68 (m, 1 H) 8.09 (s, 1 H).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[C:11]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=3)=[CH:10][C:9]([CH:22]([CH2:28][CH:29]([CH3:31])[CH3:30])[C:23]([O:25]CC)=[O:24])=[CH:8][C:7]=2[N+:32]([O-:34])=[O:33])[CH2:3][CH2:2]1.C1COCC1.O.[Li+].[OH-]>CO>[CH:1]1([CH2:4][O:5][C:6]2[C:11]([C:12]3[CH:13]=[CH:14][C:15]([C:18]([F:19])([F:21])[F:20])=[CH:16][CH:17]=3)=[CH:10][C:9]([CH:22]([CH2:28][CH:29]([CH3:30])[CH3:31])[C:23]([OH:25])=[O:24])=[CH:8][C:7]=2[N+:32]([O-:34])=[O:33])[CH2:2][CH2:3]1
Reactant: CCOC(=O)C(CC(C)C)c1cc(-c2ccc(C(F)(F)F)cc2)c(OCC2CC2)c([N+](=O)[O-])c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)CC(C(=O)O)c1cc(-c2ccc(C(F)(F)F)cc2)c(OCC2CC2)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 74.5 %

Procedure:
Ethyl 2-(6-(cyclopropylmethoxy)-5-nitro-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoate (100 mg, 0.208 mmol) was taken in a mixture of MeOH; THF:Water (30 ml, 10:10:2) and to it added LiOH (30 mg, 0.7 mmol). The reaction mixture was stirred at room temperature for 3 h. After completion of the reaction, it was poured into water (50 ml) and extracted with ethyl acetate (100 ml×2). The ethyl acetate layer was washed with 1N HCl, water and finally brine solution. The organic layer was then distilled off and the crude residue was purified by column chromatography using Ethyl acetate:hexane (1:1) as eluent provided 70 mg of 2-(6-(cyclopropylmethoxy)-5-nitro-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoic acid. 1H NMR (CDCl3): δ 8.20 (s 1H), 7.40-7.20 (m, 5H), 3.60 (t, 1H), 3.45 (d, 2H), 1.95-2.00 (m, 1H), 1.75-1.80 (m, 1H), 1.45-1.50 (m, 1H), 1.00 (m, 6H), 0.35-0.25 (m, 5H). Mass: (452, M+1, 100%).
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:4]=[C:5]([C:9]2[C:17]3[C:12](=[CH:13][C:14]([C:18]([O:20][CH3:21])=[O:19])=[CH:15][CH:16]=3)[NH:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1.[H-].[Na+].[CH3:26]I>CN(C=O)C.CCOC(C)=O.O>[F:23][C:2]([F:22])([F:1])[C:3]1[CH:4]=[C:5]([C:9]2[C:17]3[C:12](=[CH:13][C:14]([C:18]([O:20][CH3:21])=[O:19])=[CH:15][CH:16]=3)[N:11]([CH3:26])[CH:10]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: CI
Reactant: COC(=O)c1ccc2c(-c3cccc(C(F)(F)F)c3)c[nH]c2c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc2c(-c3cccc(C(F)(F)F)c3)cn(C)c2c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 101.9 %

Procedure:
To a solution of compound 15d (300 mg, 0.78 mmol) in DMF (3 mL) was added NaH (60% in mineral oil, 68.9 mg, 1.72 mmol) at 0° C. The mixture was stirred at 0° C. for 30 min, then CH3I (0.053 mL, 0.86 mmol) was added and stirring continued at 0° C. for another 1 h. The resulting mixture was diluted with EtOAc and water. The organic layer was washed with brine and concentrated. The residue was recrystallized from heptane, filtered and the solid dried to give compound 15f (265 mg) as a light yellow solid. MS m/z (M+H+) 284.1.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([CH2:10][O:11][C:12]3[CH:13]=[C:14]([CH:19]=[CH:20][CH:21]=3)[C:15]([O:17][CH3:18])=[O:16])[N:7]([CH3:22])[C:6]=2[CH:23]=1.[Br:24][C:25]1[C:26]([Cl:32])=[N:27][C:28](F)=[CH:29][CH:30]=1.N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>[Cu](I)I.CN(C=O)C>[Br:24][C:25]1[CH:30]=[CH:29][C:28]([O:1][C:2]2[CH:3]=[CH:4][C:5]3[N:9]=[C:8]([CH2:10][O:11][C:12]4[CH:13]=[C:14]([CH:19]=[CH:20][CH:21]=4)[C:15]([O:17][CH3:18])=[O:16])[N:7]([CH3:22])[C:6]=3[CH:23]=2)=[N:27][C:26]=1[Cl:32]
Reactant: Fc1ccc(Br)c(Cl)n1
Reactant: COC(=O)c1cccc(OCc2nc3ccc(O)cc3n2C)c1
Agent: I[Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(OCc2nc3ccc(Oc4ccc(Br)c(Cl)n4)cc3n2C)c1
Yield: 67.6 %

Procedure:
The reaction and post-treatment were carried out according to Example (1f) using methyl 3-[(6-hydroxy-1-methyl-1H-benzimidazol-2-yl)methoxy]benzoate produced in Example (1e) (1.56 g, 5.0 mmol), 3-bromo-2-chloro-6-fluoropyridine (1.16 g, 5.50 mmol), copper iodide (0.10 g, 0.50 mmol), 1,10-phenanthroline (0.09 g, 0.50 mmol), cesium carbonate (4.89 g, 15 mmol) and DMF (30 mL) to obtain the title compound (1.70 g, 68%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5](/[CH:9]=[N:10]/[S@@:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[O:12])=[CH:4][C:3]=1[CH3:17].[CH2:18]1COC[CH2:19]1>>[Cl:1][C:2]1[C:3]([CH3:17])=[CH:4][C:5]([C@H:9]([NH:10][S@@:11]([C:13]([CH3:14])([CH3:16])[CH3:15])=[O:12])[CH2:18][CH3:19])=[CH:6][C:7]=1[CH3:8]
Reactant: C1CCOC1
Reactant: Cc1cc(/C=N/[S@](=O)C(C)(C)C)cc(C)c1Cl
Product: CC[C@@H](N[S@](=O)C(C)(C)C)c1cc(C)c(Cl)c(C)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
In a separate flask a solution of INT 36 (3.5 g, 12.88 mmol) in THF (100 mL) was cooled in a dry ice bath under argon to −78° C. At this temperature the organozincate solution from above was added dropwise over a period of about 30 minutes. Stirring was continued for another 90 minutes before the resulting mixture was first quenched carefully with 10% ammonium chloride solution (40 mL), then water (50 mL). The reaction mixture was allowed to warm up to room temperature and was then extracted with Et2O (200 mL). The organic layer was washed with water and brine, dried over sodium sulfate, filtered and concentrated. The crude was purified by chromatography on silica gel (cyclohexane/EtOAc).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:10]([OH:12])=O)[CH:3]=[CH:2]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)C(C)C)(C)C.[C:44]([C:48]1[CH:65]=[CH:64][C:51]([CH2:52][NH:53][CH2:54][CH2:55][C:56]2[CH:61]=[CH:60][C:59]([F:62])=[C:58]([Cl:63])[CH:57]=2)=[CH:50][CH:49]=1)([CH3:47])([CH3:46])[CH3:45]>CN(C=O)C.O>[C:44]([C:48]1[CH:65]=[CH:64][C:51]([CH2:52][N:53]([CH2:54][CH2:55][C:56]2[CH:61]=[CH:60][C:59]([F:62])=[C:58]([Cl:63])[CH:57]=2)[C:10]([C:8]2[CH:7]=[CH:6][CH:5]=[C:4]3[C:9]=2[NH:1][CH:2]=[CH:3]3)=[O:12])=[CH:50][CH:49]=1)([CH3:47])([CH3:45])[CH3:46]
Reactant: CC(C)(C)c1ccc(CNCCc2ccc(F)c(Cl)c2)cc1
Reactant: O=C(O)c1cccc2cc[nH]c12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)c1ccc(CN(CCc2ccc(F)c(Cl)c2)C(=O)c2cccc3cc[nH]c23)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 101.5 %

Procedure:
To a solution of 48 mg (0.3 mmol) 1H-indole-7-carboxylic acid and 96 mg of TBTU (0.3 mmol) in 3 ml DMF, were added 0.26 ml (1.5 mmol) of N,N-diisopropylethyl amine. After stirring for 5 min at rt, 96 mg (0.3 mmol) of (4-tert-butyl-benzyl)-[2-(3-chloro-4-fluoro-phenyl)-ethyl]-amine in 2 ml DMF were added. After stirring for 3 h at rt, the reaction mixture was diluted with 50 ml water and extracted with 2×50 ml EtOAc. The combined organic phases were washed with water and brine, dried with magnesium sulfate, filtered and concentrated in vacuo to give 141 mg white solid (99%). MS (ISP) 463.4 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH2:12][C:13]3[CH:14]=[C:15]([CH:18]=[CH:19][C:20]=3[F:21])[C:16]#[N:17])[CH2:7][CH:6]3[CH2:22][O:23][CH2:24][CH2:25][N:5]3[C:4]=2[N:3]=1.[NH:26]1[C:34]2[C:29](=[C:30](B(O)O)[CH:31]=[CH:32][CH:33]=2)[CH:28]=[CH:27]1>O1CCOCC1.C([O-])(O)=O.[Na+].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[NH:26]1[C:34]2[C:29](=[C:30]([C:2]3[N:11]=[CH:10][C:9]4[N:8]([CH2:12][C:13]5[CH:14]=[C:15]([CH:18]=[CH:19][C:20]=5[F:21])[C:16]#[N:17])[CH2:7][CH:6]5[CH2:22][O:23][CH2:24][CH2:25][N:5]5[C:4]=4[N:3]=3)[CH:31]=[CH:32][CH:33]=2)[CH:28]=[CH:27]1
Reactant: OB(O)c1cccc2[nH]ccc12
Reactant: N#Cc1ccc(F)c(CN2CC3COCCN3c3nc(Cl)ncc32)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])O
Solvent: C1COCCO1
Product: N#Cc1ccc(F)c(CN2CC3COCCN3c3nc(-c4cccc5[nH]ccc45)ncc32)c1

Procedure:
The title compound was prepared in a manner similar to EXAMPLE 3 using 3-((2-chloro-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-5(6H)-yl)methyl)-4-fluorobenzonitrile (PREPARATION x15, 73 mg, 0.203 mmol), PdCl2(dppf) (7.42 mg, 10.14 μmol) and 1H-indol-4-ylboronic acid (65.3 mg, 0.406 mmol) in dioxane (2 mL) and aqueous saturated NaHCO3 (0.4 mL). 1H NMR (400 MHz, DMSO-d6) δ 3.18-3.30 (m, 3 H), 3.46-3.53 (m, 1 H), 3.56-3.67 (m, 1 H), 3.92-4.05 (m, 2 H), 4.07-4.17 (m, 1 H), 4.58-4.78 (m, 3 H), 6.98-7.08 (m, 1 H), 7.22-7.32 (m, 1 H), 7.48-7.60 (m, 3 H), 7.60-7.70 (m, 2 H), 7.89-8.03 (m, 2 H), 11.47-11.58 (m, 1 H). ESI-MS m/z [M+H]+ calc'd for C25H21FN6O, 441.18; found 441.3.
Reaction SMILES: Cl.[CH2:2]([O:4][NH2:5])[CH3:3].C([O:8][C:9]([C:11]1[C:16]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([S:24][CH3:25])=[CH:20][C:19]=2[F:26])=[C:15]([CH3:27])[N:14]2[N:28]=[CH:29][CH:30]=[C:13]2[N:12]=1)=O)C.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1>[CH2:2]([O:4][NH:5][C:9]([C:11]1[C:16]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([S:24][CH3:25])=[CH:20][C:19]=2[F:26])=[C:15]([CH3:27])[N:14]2[N:28]=[CH:29][CH:30]=[C:13]2[N:12]=1)=[O:8])[CH3:3]
Reactant: CCON
Reactant: CCOC(=O)c1nc2ccnn2c(C)c1Nc1ccc(SC)cc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: CCONC(=O)c1nc2ccnn2c(C)c1Nc1ccc(SC)cc1F
Temperature: 0 °C
Reaction time: 1 h

Procedure:
O-Ethyl-hydroxylamine HCl salt (2.50 equivalents) is added to a solution of 6-(2-fluoro-4-methylsulfanyl-phenylamino)-7-methylpyrazolo[1,5-a]pyrimidine-5-carboxylic acid ethyl ester (1.00 equivalent) in THF. The solution is cooled to 0° C. and lithium bis(trimethylsilyl)amide (6.00 equivalents, 1.0 M solution in hexanes) is added dropwise. The reaction mixture is warmed to room temperature. After stirring for 1 hour, the reaction is quenched by addition of a saturated aqueous solution of NaHCO3 and partitioned between EtOAc and brine. The aqueous layer is re-extracted with EtOAc. The combined organic extracts is dried (MgSO4) and concentrated. The product is purified by flash chromatography as necessary.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][CH:3]=1.C1OCCOCCOCCOCCOCCOC1.[H-].[Na+].[Cl:31][C:32]1[CH:47]=[CH:46][C:35]([N:36]=[CH:37][C:38]2[C:43]([F:44])=[CH:42][CH:41]=[CH:40][C:39]=2[F:45])=[CH:34][CH:33]=1>CN(C=O)C>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:8][CH:37]([NH:36][C:35]2[CH:46]=[CH:47][C:32]([Cl:31])=[CH:33][CH:34]=2)[C:38]2[C:43]([F:44])=[CH:42][CH:41]=[CH:40][C:39]=2[F:45])=[O:7])=[CH:4][CH:3]=1
Reactant: Fc1cccc(F)c1C=Nc1ccc(Cl)cc1
Reactant: NC(=O)c1ccc(Br)cc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(NC(Nc1ccc(Cl)cc1)c1c(F)cccc1F)c1ccc(Br)cc1
Temperature: 50 °C
Yield: 17.4 %

Procedure:
4-Bromobenzamide 117 (0.94 g, 4.56 mmol) and 18-crown-6 (1.2 g, 4.54 mmol) in DMF (6 mL) was treated with sodium hydride (0.37 g, 9.25 mmol) for 5 minutes at room temperature. 4-Chloro-N-(2,6-difluorobenzylidene)aniline 116 (0.936 g, 3.72 mmol) in DMF (4 mL) was added and the mixture was heated to 50° C. for 5 minutes. The reaction mixture was quenched with crushed ice and the product was isolated by a typical aqueous workup and extraction with ethyl acetate. Chromatographic purification (9:1 hexanes:ethyl acetate) followed by trituration (ethanol) of the material gave 4-bromo-N-((4-chlorophenylamino)(2,6-difluorophenyl)methyl)benzamide (Compound-6) as a white solid (292 mg, 17%). 1H NMR (300 MHz, CDCl3): δ=7.62-7.52 (series m, 4H), 7.38-7.28 (m, 1H), 7.19-7.15 (m, 2H), 7.14-7.08 (m, 1H), 7.02-6.96 (m, 2H), 6.88-6.85 (m, 1H), 6.76-6.72 (m, 2H).