Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:13]=[C:14]4[C:20]([C:21]([OH:23])=O)=[CH:19][N:18]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:15]4=[N:16][CH:17]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.[O:32]1[CH2:35][CH:34]([C@H:36]([NH2:38])[CH3:37])[CH2:33]1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[O:32]1[CH2:35][CH:34]([C@H:36]([NH:38][C:21]([C:20]2[C:14]3[C:15](=[N:16][CH:17]=[C:12]([C:6]4[C:5]5[C:9](=[CH:10][C:2]([F:1])=[CH:3][CH:4]=5)[N:8]([CH3:11])[N:7]=4)[N:13]=3)[N:18]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:30])([CH3:29])[CH3:31])[CH:19]=2)=[O:23])[CH3:37])[CH2:33]1
Reactant: C[C@@H](N)C1COC1
Reactant: Cn1nc(-c2cnc3c(n2)c(C(=O)O)cn3COCC[Si](C)(C)C)c2ccc(F)cc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(F)ccc34)nc12)C1COC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 25.7 %

Procedure:
A round-bottomed flask was charged with 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (100 mg, 0.23 mmol) and (R)-1-oxetan-3-yl-ethylamine (120 mg, 0.59 mmol). DMF (1 ml) was added followed by N,N-diisopropylethylamine (0.16 ml, 0.92 mmol) and HATU (95 mg, 0.25 mmol). The yellow reaction mixture was stirred at room temperature overnight then quenched with water and extracted with diethyl ether (2×). The combined organic layers were washed twice with water and once with brine then dried over sodium sulfate, filtered and concentrated. The residue was chromatographed over silica gel with EtOAc/hexanes (gradient: 0-60% EtOAc) to afford 31 mg (26%) of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((R)-1-oxetan-3-yl-ethyl)-amide as an off-white solid.
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([O:23][C:24]([CH3:29])([CH3:28])[C:25]([OH:27])=O)[N:20]=[CH:19][C:16]=43)[CH:10]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].C[N:31](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl-].[NH4+].C(N(CC)CC)C>CN(C=O)C>[CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[C:16]4[CH:19]=[N:20][C:21]([O:23][C:24]([CH3:28])([CH3:29])[C:25]([NH2:31])=[O:27])=[CH:22][C:15]=4[O:14][CH2:13][CH2:12][N:11]3[CH:10]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1cnc(OC(C)(C)C(=O)O)cc1OCC2
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1cnc(OC(C)(C)C(N)=O)cc1OCC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 39.8 %

Procedure:
To a solution of 2-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulen-8-yloxy]-2-methyl-propionic acid (96 mg, 0.24 mmol) in DMF (3 mL) was added HATU (184 mg, 0.48 mmol), ammonium chloride (39 mg, 0.72 mmol) and triethyl amine (100 μL, 0.72 mmol) and the reaction mixture stirred at RT for 2 h. The reaction mixture was concentrated in vacuo, the residue dissolved in ethyl acetate (10 mL) and the mixture washed with water, extracting with ethyl acetate (3×10 mL). The combined organic extracts were washed with brine, dried (MgSO4) and concentrated in vacuo. The residue was subjected to reverse phase preparative HPLC (C-18, 10-90% MeCN in water 0.1% formic acid, 25 min gradient) to yield 429 as a white solid (38 mg, 38%). LCMS: RT=7.36 min, [M+H]+=398; 1H NMR (400 MHz, d6-DMSO) 8.99 (1H, s), 8.11 (1H, s), 7.87 (1H, s), 7.86 (1H, s), 7.16 (1H, s), 6.89 (1H, s), 6.37 (1H, s), 5.89 (1H, sept, J=6.6 Hz), 4.59-4.42 (4H, m), 1.54 (6H, s), 1.44 (6H, d, J=6.6 Hz)
Reaction SMILES: [CH2:1]([C:8]1[C:13]([Br:14])=[CH:12][CH:11]=[C:10]([SH:15])[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:16][O:17][CH2:18][CH2:19][CH2:20]CS([O-])(=O)=O.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:1]([C:8]1[C:13]([Br:14])=[CH:12][CH:11]=[C:10]([S:15][CH2:20][CH2:19][CH2:18][O:17][CH3:16])[N:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Sc1ccc(Br)c(Cc2ccccc2)n1
Reactant: COCCCCS(=O)(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCCCSc1ccc(Br)c(Cc2ccccc2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.6 %

Procedure:
A mixture of 500 mg of 2-benzyl-3-bromo-6-mercaptopyridine, 360 mg of 3-methoxypropylmethane sulfonate, 370 mg of anhydrous potassium carbonate and 10 ml of N,N-dimethylformamide was stirred at room temperature for one hour in a nitrogen atmosphere. The reaction solution was partitioned between ethyl acetate-water, and the organic phase was washed with water and brine, dried over anhydrous magnesium sulfate and then concentrated. The residue was subjected to silica gel column chromatography using 1-2% ethyl acetate/hexane, to give 425 mg of the target compound.
Reaction SMILES: [CH2:1]([C:8]1[C:9]([O:23][CH3:24])=[N:10][CH:11]=[C:12]([N:14](C(OC(C)(C)C)=O)[CH3:15])[CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C(OCC)(=O)C>C(OCC)(=O)C>[CH2:1]([C:8]1[C:9]([O:23][CH3:24])=[N:10][CH:11]=[C:12]([NH:14][CH3:15])[CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ncc(N(C)C(=O)OC(C)(C)C)cc1Cc1ccccc1
Agent: Cl
Solvent: CCOC(C)=O
Product: CNc1cnc(OC)c(Cc2ccccc2)c1
Yield: 42.2 %

Procedure:
920 mg of 3-benzyl-5-(N-methyl-tert-butoxycarbonylamino)-2-methoxypyridine was dissolved in 5 ml of ethyl acetate, followed by adding 10 ml of 4N hydrochloric acid/ethyl acetate thereto. The resulting solid (640 mg) was collected by filtration. To the solid (230 mg) were added 10 ml of ethyl acetate, 150 mg of benzoyl chloride and 0.5 ml of pyridine in an ice bath, followed by stirring. After adding water thereto, the mixture was extracted with ethyl acetate. The extract was washed with 1N hydrochloric acid, aqueous saturated sodium hydrogencarbonate and brine, dried over anhydrous magnesium sulfate and then evaporated, to give 270 mg of the target compound.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[C:9]2[N:12]2[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]2)=[CH:4][CH:3]=1.[C:19](Cl)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(Cl)Cl.C(=O)(O)[O-].[Na+].C(OCC)(=O)C>[C:19]([O:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[C:9]2[N:12]2[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]2)=[CH:4][CH:3]=1)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CN1CCN(c2cccc3ccc(O)cc23)CC1
Reactant: O=C(Cl)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CN1CCN(c2cccc3ccc(OC(=O)c4ccccc4)cc23)CC1
Temperature: 25 °C

Procedure:
A mixture of 7-hydroxy-1-(4-methyl-1-piperazinyl)-naphthalene (0.065 g, 0.268 mmol) and benzoyl chloride (0.035 mL, 0.302 mmol) in methylene chloride (1 mL) and saturated sodium bicarbonate (1 mL) was stirred at room temperature. After several hours, a second equivalent of benzoyl chloride was added with continued stirring overnight. The reaction was diluted with ethyl acetate and the phases were separated. The organic layer was washed with 1N sodium hydroxide, water and brine; then it was dried over magnesium sulfate and concentrated to an oil which solidified (0.065 g, 69%). A sample recrystallized from ether/hexane as a light pink solid was submitted for analysis: mp 82°-82.5° C. Analysis calculated for C22H22N2O2 ·0.25 H2O: C, 75.30; H, 6.46; N, 7.98. Found: C, 75.51; H, 6.29; N, 7.97.
Reaction SMILES: [CH:1]([C@H:4]1[CH2:8][O:7][C:6](=[O:9])[N:5]1[C:10](=[O:15])/[C:11](/[CH3:14])=[CH:12]/[CH3:13])([CH3:3])[CH3:2].[O:16]1[CH2:20]CN[C:17]1=O.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].COCCl.[Cl-].[NH4+]>C1(C)C=CC=CC=1>[CH:1]([C@H:4]1[CH2:8][O:7][C:6](=[O:9])[N:5]1[C:10](=[O:15])[C@@:11]([CH2:17][O:16][CH3:20])([CH3:14])[CH:12]=[CH2:13])([CH3:3])[CH3:2]
Reactant: C/C=C(\C)C(=O)N1C(=O)OC[C@@H]1C(C)C
Reactant: O=C1NCCO1
Agent: COCCl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: C=C[C@@](C)(COC)C(=O)N1C(=O)OC[C@@H]1C(C)C
Temperature: -78 °C
Reaction time: 1 h
Yield: 48 %

Procedure:
To a solution of (S)-4-isopropyl-3-((E)-2-methyl-but-2-enoyl)-oxazolidin-2-one (prepared according to the method reported in Example 29c but using the opposite enantiomer of the oxazolidinone), (4.44 g, 21 mmol), in anhydrous toluene (40 mL) under nitrogen at −78° C. was added dropwise a solution of Sodium bis(trimethylsily)amide in toluene (0.6 M, 54 mL, 32 mmol). When addition was completed, the reaction mixture was left to stir at −78° C. for another minutes. Chloromethyl methyl ether (3.38 g, 42 mmol) was slowly added. Stirring was maintained at −60° C. for 30 minutes and then for 1 h as the temperature was allowed to rise to 0° C. Saturated ammonium chloride solution (230 mL) was added and the mixture was left to stir at room temperature for 10 minutes. The aqueous layer was extracted with ethyl acetate (2×) and the combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated. The crude residue was purified by silica gel chromatography using a Biotage KP-Sil 100 g cartridge eluting with a gradient of iso-hexanes/ethyl acetate 1:0 to 9:1 to give the title product (2.55 g, 48%) as a colorless oil. 1H NMR (300 MHz, CDCl3) δ 0.80-1.00 (m, 6H), 1.50 (s, 3H), 2.25-2.45 (m, 1H), 3.35 (s, 3H), 3.46 (d, J=8.7 Hz, 1H), 4.16-4.23 (m, 2H), 4.28 (app t, J=8.2 Hz, 1H), 4.45-4.60 (m, 1H), 5.01 (d, J=17.6 Hz, 1H), 5.12 (d, J=10.7 Hz, 1H), 6.19 (dd, J=17.6, 10.7 Hz, 1H). LCMS (m/z) 255.3 [M+H], Tr=2.58 min.
Reaction SMILES: C([O-])(=O)C.[Na+].[CH3:6][O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1.[Br:14]Br.[OH-].[Na+].S([O-])([O-])=O.[Na+].[Na+]>O.C(OCC)(=O)C>[Br:14][C:11]1[CH:12]=[CH:13][C:8]([O:7][CH3:6])=[N:9][CH:10]=1
Reactant: COc1ccccn1
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccc(Br)cn1
Temperature: 20 °C
Reaction time: 5 h
Yield: 85.9 %

Procedure:
Ethyl acetate (325 kg), sodium acetate (58 kg, 707 mol) and 2-methoxypyridine (68.7 kg, 630 mol) were mixed in a reactor vessel (inner volume 1000 L). To this solution was added dropwise bromine (122.3 kg, 765 mol) over 6.5 hr while keeping the inside temperature from exceeding 10° C. After the dropwise addition, the inside temperature was raised to 20° C. and the mixture was stirred for 5 hr. The ratio of reaction progress at this time point was 73%. Thereafter, the inside temperature was raised to 50° C. and the reaction was continued more for 5 hr. The ratio of reaction progress at this time point was 98%. The reaction mixture was cooled and water (70 kg) was added to the reaction mixture. While keeping the inside temperature from exceeding 5° C., the solution obtained by dissolving sodium hydroxide (46.1 kg) and sodium sulfite (17 kg) in water (200 kg) was added dropwise. The reaction mixture was stood still to allow partitioning. After confirming that the pH of the aqueous layer was not less than 8 and peroxide was absent, the organic layer was separated. The aqueous layer was extracted with ethyl acetate (40 kg), and the extract and the above-mentioned organic layers were combined. The mixture was concentrated under reduced pressure to give crude 5-bromo-2-methoxypyridine (gross: 121.8 kg, net: 110.7 kg, yield 93%). The crude product was purified by distillation under reduced pressure to give 5-bromo-2-methoxypyridine (101.8 kg, yield 86%) having the following analytical data at a purity of not less than 99%.
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[C:7]([CH:17]=[CH:18][CH:19]=1)[C:8]([O:10][CH2:11][CH2:12][Si:13]([CH3:16])([CH3:15])[CH3:14])=[O:9])(=[O:4])=[O:3].[CH3:20][NH:21][C:22]1[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][CH:23]=1>N1C=CC=CC=1>[CH3:29][O:28][C:26]([C:25]1[CH:30]=[CH:31][C:22]([N:21]([CH3:20])[S:2]([C:5]2[CH:6]=[C:7]([CH:17]=[CH:18][CH:19]=2)[C:8]([O:10][CH2:11][CH2:12][Si:13]([CH3:16])([CH3:15])[CH3:14])=[O:9])(=[O:4])=[O:3])=[CH:23][CH:24]=1)=[O:27]
Reactant: CNc1ccc(C(=O)OC)cc1
Reactant: C[Si](C)(C)CCOC(=O)c1cccc(S(=O)(=O)Cl)c1
Solvent: c1ccncc1
Product: COC(=O)c1ccc(N(C)S(=O)(=O)c2cccc(C(=O)OCC[Si](C)(C)C)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.3 %

Procedure:
A mixture of 1.50 g of 2-(trimethylsilyl)ethyl 3-(chlorosulfonyl)benzoate, 772 mg of methyl 4-(methylamino)benzoate, and 15 mL of pyridine was stirred at room temperature overnight, and then the reaction mixture was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain 1.54 g of 2-(trimethylsilyl)ethyl 3-{[4-(methoxycarbonyl)phenyl](methyl)sulfamoyl}benzoate as a colorless oily substance. ESI+: 450
Reaction SMILES: C(OC1C=C([N+]([O-])=O)C=CC=1OC)C.[CH2:15]([O:17][C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-])=O)=[CH:20][C:19]=1[O:27][CH2:28][CH3:29])[CH3:16]>>[CH2:28]([O:27][C:19]1[CH:20]=[C:21]([CH:22]=[CH:23][C:18]=1[O:17][CH2:15][CH3:16])[NH2:24])[CH3:29]
Reactant: CCOc1ccc([N+](=O)[O-])cc1OCC
Agent: CCOc1cc([N+](=O)[O-])ccc1OC
Product: CCOc1ccc(N)cc1OCC
Yield: 80 %

Procedure:
By replacing 2-ethoxy-1-methoxy-4-nitrobenzene (XIXaa) in example XXaa by 1,2-diethoxy-4-nitrobenzene (XIXab) and proceeding in the same manner, the abovenamed product is obtained. Yield: 80%. 1H-NMR (CDCl3, 300 MHz): d 1.36–1.46 (m, 6H, 2 times —CH3), 3.44 (s, 2H exchangeable, —NH2), 3.97–4.07 (m, 4H, 2×OCH2), 6.19 (dd, 1H Ar), 6.23 (d, 1H Ar), 6.73 (d, 1H Ar).
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1([CH2:14][OH:15])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH3:17]N(C)C1C2C(=CC=CC=2N(C)C)C=CC=1.F[B-](F)(F)F.C[O+](C)C>C(Cl)Cl>[C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1([CH2:14][O:15][CH3:17])[CH2:9][CH2:10][O:11][CH2:12][CH2:13]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1(CO)CCOCC1
Reactant: CN(C)c1cccc2cccc(N(C)C)c12
Agent: C[O+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: COCC1(NC(=O)OC(C)(C)C)CCOCC1
Reaction time: 5 h

Procedure:
To a solution of tert-butyl[4-(hydroxymethyl)tetrahydro-2H-pyran-4-yl]carbamate (0.89 g, 3.8 mmol) in methylene chloride (19.2 mL) was added sequentially powdered MS 4A, N,N,N′,N′-tetramethyl-1,8-naphthalenediamine (2.0 g, 9.6 mmol), and trimethyloxonium tetrafluoroborate (1.1 g, 7.7 mmol) at RT. The mixture was stirred for 5 h., filtered through a pad of Celite, and washed with EtOAc. The filtrate was washed with aqueous CuSO4, water, brine, dried over MgSO4, filtered, and concentrated. The residue was purified by chromatography on silica gel with EtOAc in hexanes (0-30%) to afford the desired product. LCMS: (M+Na)=268.0
Reaction SMILES: Br[CH:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:3].[OH:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][C:18]=1[O:19][CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH:14]=[O:15].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.C(OCC)(=O)C>[C:4]1([CH:2]([O:10][C:11]2[CH:12]=[C:13]([CH:16]=[CH:17][C:18]=2[O:19][CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:14]=[O:15])[CH3:3])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(Br)c1ccccc1
Reactant: O=Cc1ccc(OCCc2ccccc2)c(O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(Oc1cc(C=O)ccc1OCCc1ccccc1)c1ccccc1
Reaction time: 8 h
Yield: 95.3 %

Procedure:
(1-Bromoethyl)benzene (0.56 mL, 4.13 mmol, 2 eq) was added to a stirred solution of 3-hydroxy-4-(2-phenylethoxy)-benzaldehyde (500 mg, 2.06 mmol, 1 eq) and cesium carbonate (672 mg, 2.06 mmol, 1 eq) in N,N-dimethylformamide (8 mL). The solution was stirred overnight and then diluted with ethyl acetate (50 mL). The organic solution was washed with 1M HCl (2×100 mL), and brine (100 mL), dried over sodium sulfate and evaporated. The residue was purified by chromatography on silica gel and elution with petroleum ether:ethyl acetate (6:1) gave the product as a colourless oil (680 mg, 95%). RF (petroleum ether:ethyl actetate, 4:1) 0.51. 1H NMR (CDCl3) δ 9.72 (s, 1H, O═C—H), 6.93 (d, 1H, J 7.9 Hz, ArH), 5.38 (q, 1H, J 6.4 Hz, CHCH3Ph), 4.33 (m, 2H, CH2CH2Ph), 3.21 (t, 2H, J 6.8 Hz, CH2CH2Ph), 1.67 (d, 3H, J 6.4 Hz, CHCH3Ph).
Reaction SMILES: CCN(C(C)C)C(C)C.[F:10][C:11]1[CH:17]=[CH:16][C:14]([NH2:15])=[CH:13][CH:12]=1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2([NH:28][C:29]3[N:34]=[C:33]([O:35][CH2:36][C:37]([F:40])([F:39])[F:38])[N:32]=[C:31]([NH:41][C:42]4[CH:64]=[CH:63][C:45]([C:46]([NH:48][CH2:49][CH:50]5[CH2:54][CH2:53][CH2:52][CH:51]5[NH:55][C:56](=[O:62])[C:57](OCC)=[O:58])=[O:47])=[CH:44][CH:43]=4)[N:30]=3)[CH2:27][CH2:26]2)=[CH:21][CH:20]=1>CCO>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2([NH:28][C:29]3[N:34]=[C:33]([O:35][CH2:36][C:37]([F:38])([F:39])[F:40])[N:32]=[C:31]([NH:41][C:42]4[CH:43]=[CH:44][C:45]([C:46]([NH:48][CH2:49][CH:50]5[CH2:54][CH2:53][CH2:52][CH:51]5[NH:55][C:56](=[O:62])[C:57]([NH:15][C:14]5[CH:16]=[CH:17][C:11]([F:10])=[CH:12][CH:13]=5)=[O:58])=[O:47])=[CH:63][CH:64]=4)[N:30]=3)[CH2:27][CH2:26]2)=[CH:21][CH:20]=1
Reactant: Nc1ccc(F)cc1
Reactant: CCOC(=O)C(=O)NC1CCCC1CNC(=O)c1ccc(Nc2nc(NC3(c4ccc(Cl)cc4)CC3)nc(OCC(F)(F)F)n2)cc1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(F)cc1)C(=O)NC1CCCC1CNC(=O)c1ccc(Nc2nc(NC3(c4ccc(Cl)cc4)CC3)nc(OCC(F)(F)F)n2)cc1
Temperature: 155 °C
Reaction time: 72 h

Procedure:
iPr2NEt (0.2 mL) and 4-fluoroaniline (39.2 mg) added into the solution of ethyl 2-((2-((4-((4-((1-(4-chlorophenyl)cyclopropyl)amino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-yl)amino)benzamido)methyl)cyclopentyl)amino)-2-oxoacetate (40 mg) in EtOH (2 mL) and the reaction was stirred at 155° C. for 3 days. The product was isolated by preparative HPLC system.
Reaction SMILES: [C:1]([Si:5]([CH3:31])([CH3:30])[O:6][CH2:7][C@@H:8]([C@@H:17]1[C@@H:21]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=2)[CH2:20][NH:19][CH2:18]1)[O:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][N:11]=1)([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:65][C:66]1[N:71]=[N:70][CH:69]=[C:68]([C:72](O)=[O:73])[CH:67]=1>CN(C=O)C.C(OCC)(=O)C>[C:1]([Si:5]([CH3:31])([CH3:30])[O:6][CH2:7][C@@H:8]([C@@H:17]1[C@@H:21]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=2)[CH2:20][N:19]([C:72]([C:68]2[CH:67]=[C:66]([CH3:65])[N:71]=[N:70][CH:69]=2)=[O:73])[CH2:18]1)[O:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][N:11]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(C(=O)O)cnn1
Reactant: CC(C)(C)[Si](C)(C)OC[C@H](Oc1ccc(Cl)cn1)[C@H]1CNC[C@@H]1c1ccc(Cl)c(Cl)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)N2C[C@H]([C@H](CO[Si](C)(C)C(C)(C)C)Oc3ccc(Cl)cn3)[C@@H](c3ccc(Cl)c(Cl)c3)C2)cnn1
Yield: 27.1 %

Procedure:
To a solution of 2-{(R)-2-(tert-butyl-dimethyl-silanyloxy)-1-[(3R,4S)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-ethoxy}-5-chloro-pyridine (220 mg) in DMF (12 mL)at −20° C. were added Hunig base (0.132 mL, 0.78 mmol) and then HATU (202 mg) and then 6-methyl-pyridazine-4-carboxylic acid (0.78 mmol, described herein above). The mixture was diluted with ethyl acetate and washed with aq.ammonium chloride solution three times and aq. sodium bicarbonate solution. The separated organic phase was dried over sodium sulfate and concentrated in vaccuo after filtration. The residue was purified by TLC (SiO2, MeOH/DCM, 1:10) yielded 74 mg (27%) of the title compound as a light yellow oil. ES-MS m/e: 623.3 (M+H+).
Reaction SMILES: [O:1]=[C:2]1[CH:7]=[CH:6][CH2:5][CH2:4][CH:3]1[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10].[F:14][C:15]1[CH:20]=[CH:19][C:18]([Mg]Br)=[CH:17][CH:16]=1>CSC.O1CCCC1>[F:14][C:15]1[CH:20]=[CH:19][C:18]([CH:6]2[CH2:5][CH2:4][CH:3]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:2](=[O:1])[CH2:7]2)=[CH:17][CH:16]=1
Reactant: CCOC(=O)CC1CCC=CC1=O
Reactant: Fc1ccc([Mg]Br)cc1
Solvent: C1CCOC1
Solvent: CSC
Product: CCOC(=O)CC1CCC(c2ccc(F)cc2)CC1=O
Reaction time: 0.33 h

Procedure:
This ester (4 g, 0.022 mmol), copper (I) bromide-dimethyl sulfide complex (4.88 g, 0.023 mmol) in dimethyl sulfide (20 ml) and tetrahydrofuran (120 ml) was cooled to −40° C. under nitrogen and treated dropwise with 4-fluorophenylmagnesium bromide (1M solution in THF, 43.9 ml) so that the temperature did not rise above −40° C. Reaction was stirred for 20 minutes before quenching with 1N HCl (300 ml) and extracting the products with ether (3×300 ml). Combined organic phase washed with saturated sodium chloride, dried over magnesium sulfate and evaporated to dryness. The crude oil was purified by silica chromatography eluting with hexane-ethyl acetate mixtures (10-20%), to give ethyl [4-(4-fluorophenyl)-2-oxo-cyclohexyl]acetate as a colourless oil, 2.8 g. 1H NMR δ (ppm) (CDCl3): 7.26-7.11 (2H, m), 7.04-6.94 (2H, m), 4.18-4.11 (2H, m), 3.55-3.44 (1H, m), 3.00-2.90 (1H, m), 2.80-2.73 (2H, m), 2.69-2.55 (1H, m), 2.28-2.17 (2H, m), 2.10-1.88 (2H, m), 1.61-1.42 (1H, m) and 1.31-1.25 (3H, m).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].Cl[C:8]1[CH:9]=[N+:10]([O-:17])[CH:11]=[CH:12][C:13]=1[N+:14]([O-:16])=[O:15].[CH2:18]([NH:20]CC)[CH3:19]>C1COCC1>[CH2:18]([NH:20][C:8]1[CH:9]=[N+:10]([O-:17])[CH:11]=[CH:12][C:13]=1[N+:14]([O-:16])=[O:15])[CH3:19]
Reactant: CCNCC
Reactant: O=[N+]([O-])c1cc[n+]([O-])cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCNc1c[n+]([O-])ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Anhydrous K2CO3 (19 g, 144.5 mmol) is suspended in a solution of 3-Chloro-4-nitro-pyridine-1-oxide (10 g, 57.8 mmol) in anhydrous acetonitrle (100 mL). Excess diethyl amine (2.0 M) in THF is added to the above suspension under cold conditions (ice-bath). After complete addition of diethyl amine, the reaction mixture is allowed to warm to room temperature and left stirring overnight. The reaction mixture is filtered to remove K2CO3 and the filtrate evaporated under reduced pressure to remove volatile solvents. The organic residue is subjected to chromatography, eluting with 30% EtOAc-hexanes to afford 3-Ethylamino-4-nitro-pyridine-1-oxide as an orange solid. 1H NMR (300 MHz, CDCl3) δ 8.0 1 (d, J=7.5 Hz, 1H), 7.91(s, 1H), 7.8 (brs, NH), 7.44 (d, J=7.2 Hz, 1H), 3.30 (t, J=7.2 Hz, 2H), 1.39 (t, J=7.2 Hz, 3H), m/z 184 [M+1]
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[C:10]([CH3:12])([CH3:11])[S:9][CH2:8][CH2:7][N:6]1[S:13]([C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1)(=[O:15])=[O:14])=[O:4].[O:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH:24]1[O:29][CH2:30][CH2:31][CH2:32][C:33]#[C:34][CH2:35]O>>[CH3:1][O:2][C:3]([CH:5]1[C:10]([CH3:12])([CH3:11])[S:9][CH2:8][CH2:7][N:6]1[S:13]([C:16]1[CH:17]=[CH:18][C:19]([O:22][CH2:35][C:34]#[C:33][CH2:32][CH2:31][CH2:30][O:29][CH:24]2[CH2:25][CH2:26][CH2:27][CH2:28][O:23]2)=[CH:20][CH:21]=1)(=[O:15])=[O:14])=[O:4]
Reactant: COC(=O)C1N(S(=O)(=O)c2ccc(O)cc2)CCSC1(C)C
Reactant: OCC#CCCCOC1CCCCO1
Product: COC(=O)C1N(S(=O)(=O)c2ccc(OCC#CCCCOC3CCCCO3)cc2)CCSC1(C)C
Yield: 64.4 %

Procedure:
According to the procedure of Step 4 of Example 243, Mitsunobu coupling of 3.4 g (9.842 mmol) of 4-(4-hydroxy-benzenesulfonyl)-2,2-dimethyl-thiomorpholine-3-carboxylic acid methyl ester and 2.34 g (11.81 mmol) of 6-(tetrahydro-2H-pyran-2-yloxy)-2-hexyn-1-ol provided 3.33 g (64%) of methyl-2,2-dimethyl-4-[(4-{[6-(tetrahydro-2H-pyran-2-yloxy)-2-hexynyl]oxy}phenyl)sulfonyl]-3-thiomorpholine carboxylate as a colorless oil. Electrospray Mass Spec: 526.3 (M+H)+.