Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:15]2[O:19][N:18]=[C:17]([CH2:20][S:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)(=[O:23])=[O:22])[N:16]=2)[CH2:11][C:12](O)=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[NH2:43][OH:44]>O1CCCC1>[NH3:16].[CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:15]2[O:19][N:18]=[C:17]([CH2:20][S:21]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)(=[O:23])=[O:22])[N:16]=2)[CH2:11][C:12]([NH:43][OH:44])=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(O)C[C@@H](CCCC1CCCCC1)c1nc(CS(=O)(=O)c2ccccc2)no1
Reactant: NO
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: N
Product: O=C(C[C@@H](CCCC1CCCCC1)c1nc(CS(=O)(=O)c2ccccc2)no1)NO
Temperature: 25 °C
Reaction time: 2 h
Yield: 49.2 %

Procedure:
A solution of (3R)-6-cyclohexyl-3-{3-[(phenylsulfonyl)methyl]-1,2,4-oxadiazol-5-yl)hexanoic acid (Preparation 55) (60 mg, 0.14 mmol) in anhydrous tetrahydrofuran (4 ml) was treated with 1,1′-carbonyldiimidazole (25 mg, 0.15 mmol) and the mixture stirred at room temperature under a nitrogen atmosphere for 2 hours. Hydroxylamine hydrochloride (10 mg, 0.14 mmol) was then added and the mixture was stirred for 18 hours. The solvent was removed under reduced pressure and the residue was purified by column chromatography on silica gel eluting with dichloromethane:methanol:0.88 ammonia (95:5:0.5) to afford the title compound as an oil (15 mg).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][C:13]([OH:15])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:16](N(CC)CC)[CH3:17].C(OC(ON=C(C#N)C(N)=O)=O)C>C(OCC)(=O)C.O1CCCC1>[CH2:16]([O:14][C:13](=[O:15])[CH2:12][NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])[CH3:17]
Reactant: CCN(CC)CC
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Agent: CCOC(=O)ON=C(C#N)C(N)=O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)CNC(=O)OCc1ccccc1
Reaction time: 2 h

Procedure:
To a solution of N-benzyloxycarbonylglycine (1.05 g) and triethylamine (0.73 ml) in ethyl acetate (10 ml) and tetrahydrofuran (10 ml), 2-ethoxycarbonyloxyimino-2-cyanoacetic acid amide (1.11 g) is added, and the resulting mixture is stirred for 2 hours. The reaction mixture is treated as in Example A to give N-benzyloxycarbonylglycine ethyl ester (1.2 g) as an oil.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[Cl:11][S:12](O)(=[O:14])=[O:13]>>[F:1][C:2]1[CH:10]=[CH:9][C:8]([S:12]([Cl:11])(=[O:14])=[O:13])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=C(O)c1ccccc1F
Reactant: O=S(=O)(O)Cl
Product: O=C(O)c1cc(S(=O)(=O)Cl)ccc1F

Procedure:
o-Fluorobenzoic acid is reacted with chlorosulfonic acid by the method of Example 1 to form 2-fluoro-5-chlorosulfonylbenzoic acid. This is reacted with 3,5-dimethylpiperidine by the method of Example 1 to form 2-fluoro-5-(3,5-dimethylpiperidinosulfonyl)benzoic acid. This product (0.0015 mole) is heated to 60° C. with diethylamine (10 ml.) and ethanol (3.0 ml.) to form a clear solution, and the reaction mixture is then heated at reflux temperature for 24 hours. The resulting brown solid is filtered off, dissolved in 1N NaOH, washed twice with ether, and the product precipitated by the addition of concentrated HCl. Recrystallization from diethyl ether replaced by isopropyl ether yields the product, m.p. 139.5°-140° C.
Reaction SMILES: [C:1]([P:3](=[O:10])([O:7]CC)[O:4][CH2:5][CH3:6])#[N:2].[I-].[CH3:12][S+:13]([CH3:16])([CH3:15])=[O:14].CC(N(C)C)=O.CCOCC>CC(C)=O>[CH2:5]([O:4][P:3]([C:1]#[N:2])(=[O:7])[O-:10])[CH3:6].[CH3:12][S+:13]([CH3:16])([CH3:15])=[O:14]
Reactant: CCOP(=O)(C#N)OCC
Agent: C[S+](C)(C)=O
Agent: [I-]
Solvent: CCOCC
Solvent: CC(=O)N(C)C
Solvent: CC(C)=O
Product: CCOP(=O)([O-])C#N
Temperature: 80 °C
Yield: 67.6 %

Procedure:
Diethyl cyanophosphonate (0.50 g, 3.06 mmol) and trimethylsulfoxonium iodide (0.673 g, 3.06 mmol) were added to dimethylacetamide (1 mL) which was heated to 80° C. for 1 hour. Then ether (9 mL) containing 1 mL of acetone was added to give 0.47 g (78% yield) of a viscous residue which was crystallized within 15 hours. It was washed by CH2Cl2 and dried under vacuum, and analyzed by NMR and mass spectrometry. 31P NMR (D2O) δ (ppm) -19.7 (t, 3JPH =9.15 Hz); 1H NMR (D2O) δ (ppm) 1.22 (t), 3.78 (s), and 4.05 (qnt); 13C NMR (D2O) δ (ppm) 118.1 (d, 1JCP =178.9 Hz), 63.3 (d, 1JCP =6.3 Hz), 39.5, 15.0 (d, 3JCP =6.87 Hz). Mass spectral analysis (FAB+, DTT:DTE, 1:1) detected a peak at m/z 320.1, corresponding to the complex [[+OS(CH3)3 -O(OC2H5)POCN] [OS(CH3)3 ]+ ], the presence of a cation at m/z 93 ([OS(CH3)3 ]+) and an anionic species (FAB-, DTT:DTE, 1:1) at m/z 134 [NCP(O)(OC2H5)O - ].
Reaction SMILES: [CH:1]12[O:7][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6]2.[CH2:8]([NH2:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>O>[CH2:8]([NH:15][C@@H:2]1[CH2:3][CH2:4][CH2:5][CH2:6][C@H:1]1[OH:7])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: C1CCC2OC2C1
Reactant: NCc1ccccc1
Solvent: O
Product: O[C@@H]1CCCC[C@H]1NCc1ccccc1

Procedure:
A mixture of cyclohexene oxide (1) (19 mL, 0.2 mol, Aldrich cat #C10,280-4) and benzylamine (27) (21 mL, 0.2 mol, Aldrich cat #407712) in water (5 mL) was refluxed for 3 hours. The cooled reaction mixture was partitioned between 4M aq NaOH (100 mL) and methyl t-butyl ether (150 mL). The aqueous layer was further extracted with methyl t-butyl ether (2×100 mL), and the combined organic extracts were dried over anhydrous magnesium sulfate and concentrated in vacuo to give trans-2-benzylaminocyclohexan-1-ol (28) as a low melting point solid (39.4 g, 96% yield); 1H-NMR (300 MHz, CDCl3) δ: 7.31-7.22 (m, 5H, Ar), 3.91 (d, J 13 Hz, 1H, CH2aN), 3.65 (d, J 13 Hz, 1H, CH2bN), 3.18 (dt, J 5 Hz, J 10 Hz, CH), 2.28 (dt, J 5 Hz, J 10 Hz, CH), 2.15-2.10 (m, 1H, CH), 2.00-1.94 (m, 1H, CH), 1.70-1.60 (m, 2H, CH2), 1.31-1.12 (m, 3H, CH2 & CH), 1.03-0.90 (m, 1H, CH); 13C-NMR (75 MHz, CDCl3) δ: 140.44 (+), 128.31 (−), 128.00 (−), 126.87 (−), 73.62 (−), 62.97 (−), 50.71 (+), 33.35 (+), 30.36 (+), 24.96 (+), 24.28 (+), 19.32 (+).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][OH:8].[C:9]1([P:15]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[Br-:1].[OH:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][P+:15]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: OCCCCCCBr
Product: OCCCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Product: [Br-]
Temperature: 25 °C
Yield: 93.2 %

Procedure:
Into a 5 L, 3 neck round bottom flask fitted with nitrogen inlet, condenser, thermometer, mechanical stirring and nitrogen outlet is added 6-bromo-1-hexanol (500 g, 2.76 mol), triphenylphosphine (768 g, 2.9 mol) and acetonitrite (1800 ml) under nitrogen. The reaction mixture is heated to reflux for 72 hrs. The reaction mixture is cooled to room temperature and transferred into a 5 L beaker. The product is recrystallized from anhydrous ethyl ether (1.5 L) at 10° C. Vacuum filtration of the mixture followed by washing the white crystals with ethyl ether and drying in a vacuum oven at 50° C. for 2 hrs. gives 1140 g of the desired product.
Reaction SMILES: [CH2:1]([N:4]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1)[C:2]#[CH:3].I[C:11]1[CH:16]=[CH:15][C:14](/[C:17](/[C:37]2[CH:42]=[CH:41][C:40]([C:43]([F:46])([F:45])[F:44])=[CH:39][CH:38]=2)=[CH:18]\[CH2:19][O:20][C:21]2[C:26]3[O:27][CH:28]=[CH:29][C:25]=3[C:24]([O:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:23][CH:22]=2)=[CH:13][CH:12]=1>O1CCCC1.C(N(CC)CC)C.C1C=CC=CC=1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cu]I>[N:4]1([CH2:1][C:2]#[C:3][C:11]2[CH:12]=[CH:13][C:14](/[C:17](/[C:37]3[CH:42]=[CH:41][C:40]([C:43]([F:45])([F:44])[F:46])=[CH:39][CH:38]=3)=[CH:18]\[CH2:19][O:20][C:21]3[C:26]4[O:27][CH:28]=[CH:29][C:25]=4[C:24]([O:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:23][CH:22]=3)=[CH:15][CH:16]=2)[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1
Reactant: C#CCN1CCOCC1
Reactant: CCOC(=O)COc1ccc(OC/C=C(\c2ccc(I)cc2)c2ccc(C(F)(F)F)cc2)c2occc12
Agent: [Cu]I
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)COc1ccc(OC/C=C(\c2ccc(C#CCN3CCOCC3)cc2)c2ccc(C(F)(F)F)cc2)c2occc12
Temperature: 0 °C
Reaction time: 120 h

Procedure:
N-Propargylmorpholine (0.64 g, 5.1 mmol) was added under nitrogen atmosphere to a degassed solution of ethyl (Z)-[7-[3-(4-iodophenyl)-3-(4-trifluoromethylphenyl)allyloxy]-benzo[b]furan-4-yl]oxyacetate (0.68 g, 1.09 mmol) in a mixture of tetrahydrofuran (20 mL) and triethylamine (10 mL) The solution was cooled to 0° C., tetrakis(triphenylphosphine)-palladium (0.17 g, 0.147 mmol) and copper(I) iodide (0.03 g, 0.16 mmol) were added. The reaction mixture was stirred at ambient temperature for 120 h, diluted with benzene (100 mL), decanted and evaporated in vacuo. The residue was purified by column chromatography (silica gel Fluka 60, benzene/ethyl acetate 1:0-0:1) yielding ethyl (E)-[7-[3-[4-[3-(morpholin-4-yl)propynyl]phenyl]-3-(4-trifluoromethylphenyl)allyloxy]benzo[b]furan-4-yl]oxyacetate.
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:21])=CC=1>C1(C)C(C)=CC=CC=1.CCCCCC>[C:1]([O:9][CH2:10][CH3:11])(=[S:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CCOC(=O)c1ccccc1
Solvent: CCCCCC
Solvent: Cc1ccccc1C
Product: CCOC(=S)c1ccccc1
Yield: 175.3 %

Procedure:
70 ml (0.487 mol) of ethyl benzoate were heated to reflux for 12 hours with 100 g (0.247 mol) of Lawesson reagent in 350 ml of xylene. After cooling to 20° the reaction mixture was diluted with 500 ml of hexane and filtered. The filtrate was flash-chromatographed on 1 kg of silica gel. Elution was carried out with hexane. The fractions which were pure according to the thin-layer chromatogram (eluent: toluene) were combined and evaporated under reduced pressure. There were obtained 72 g (89%) of O-ethyl thiobenzoate as a dark yellow evil-smelling oil which was used without further purification.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][C:10]([F:13])([F:12])[F:11])=[CH:5][CH:4]=1.[C-:14]#[N:15].[Na+]>CS(C)=O>[F:11][C:10]([F:13])([F:12])[O:9][C:6]1[CH:7]=[CH:8][C:3]([CH2:2][C:14]#[N:15])=[CH:4][CH:5]=1
Reactant: [C-]#N
Reactant: FC(F)(F)Oc1ccc(CBr)cc1
Agent: [Na+]
Solvent: CS(C)=O
Product: N#CCc1ccc(OC(F)(F)F)cc1
Temperature: 90 °C
Reaction time: 1 h
Yield: 96.4 %

Procedure:
Using analogous conditions and workup as described for the preparation of I-24a above, 1-(bromomethyl)-4-(trifluoromethoxy)benzene (5 g, 19.607 mmol) in DMSO (30 mL) was reacted with NaCN (1.44 g, 35.1864 mmol). The resulting mixture was stirred at 90° C. for 1 hour to afford 3.8 g of the product (95% yield). 1H NMR (300 MHz, CDCl3): 7.45-7.20 (m, 4H), 3.8 (s, 2H)
Reaction SMILES: O1CCCCC1[N:7]1[C:15]2[C:10](=[CH:11][C:12]([C:16]3[N:20]=[CH:19][N:18](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:17]=3)=[CH:13][CH:14]=2)[C:9]([C:40]2[CH:45]=[CH:44][C:43]([NH2:46])=[CH:42][CH:41]=2)=[N:8]1.[C:47](Cl)(=O)[C:48]1C=CC=[CH:50][CH:49]=1.[O:56]1[CH2:60][CH2:59][CH2:58][CH2:57]1>>[NH:18]1[CH:19]=[N:20][C:16]([C:12]2[CH:11]=[C:10]3[C:15](=[CH:14][CH:13]=2)[NH:7][N:8]=[C:9]3[C:40]2[CH:45]=[CH:44][C:43]([NH:46][C:60](=[O:56])[CH2:59][C:58]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:57]=3)=[CH:42][CH:41]=2)=[N:17]1
Reactant: C1CCOC1
Reactant: Nc1ccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)cc1
Reactant: O=C(Cl)c1ccccc1
Product: O=C(Cc1ccccc1)Nc1ccc(-c2n[nH]c3ccc(-c4nc[nH]n4)cc23)cc1
Yield: 5 %

Procedure:
The title compound was prepared as described in Example 376, using 4-{1-perhydro-2H-pyran-2-yl-5-[1-(triphenylmethyl)(1,2,4-triazol-3-yl)]-1H-indazol-3-yl}phenylamine (0.303 g, 0.50 mmol) in tetrahydrofuran (4.5 mL) was added benzoyl chloride (0.10 mL, 0.76 mmol) and triethylamnine (0.35 mL, 2.52 mmol). The final crude product was purified by preparative HPLC (30–80% acetonitrile to H2O, 30 min.) (0.010 g, 5% yield): 1H NMR (DMSO-d6) δ 10.37 (s, 1H), 8.68 (br s, 1H), 8.07 (d, 1H), 7.95 (br s, 2H), 7.80 (d, 2H), 7.69 (br s, 1H), 7.30 (m, 5H), 3.69 (s, 2H); ES-MS (m/z) 395 [M+1]+.
Reaction SMILES: [Na].[C:2]([O:10][CH2:11][CH3:12])(=[O:9])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].Br[CH2:14][CH2:15][CH2:16][CH:17]=[CH2:18]>C(O)C>[CH2:18]([CH:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:2]([O:10][CH2:11][CH3:12])=[O:9])[CH2:17][CH2:16][CH:15]=[CH2:14]
Reactant: C=CCCCBr
Reactant: CCOC(=O)CC(=O)OCC
Agent: [Na]
Solvent: CCO
Product: C=CCCCC(C(=O)OCC)C(=O)OCC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 300 mL of ethanol are added 5 g of sodium spheres and after a clear solution is obtained, 32.1 g of diethyl malonate is added in one portion. After 1 hour at room temperature, 15 g of 5-bromopent-1-ene is added and the reaction mixture is stirred at room temperature for 16 hours. The reaction mixture is evaporated to dryness and the residue is distilled under high vacuum to obtain diethyl pent-4-enylmalonate.
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[N:8][CH:9]=[CH:10][CH:11]=1)=[O:5].[CH3:13]OC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=S)=CC=1>O1CCOCC1>[N:8]1[CH:9]=[CH:10][CH:11]=[C:6]([CH:4]([OH:5])[CH3:13])[N:7]=1
Reactant: CON(C)C(=O)c1cccnn1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1COCCO1
Product: CC(O)c1cccnn1
Temperature: 150 °C
Reaction time: 0.58 h
Yield: 328.8 %

Procedure:
A suspension of compound 2 (20 mg, 0.049 mmol) and Lawesson's Reagent (20 mg, 0.049 mmol) in anhydrous dioxane (1 mL) was stirred at 150° C. for 35 min in a CEM microwave reactor. The mixture was concentrated in vacuo, and the residue was purified by prep-TLC to give compound 3 (20 mg, 96%) as a yellow solid.
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6](=[O:8])[CH:5]=[N:4][N:3]1[C:9]1[CH:10]=[CH:11][C:12]([CH3:27])=[C:13]([CH:26]=1)[C:14]([NH:16][CH2:17][C:18]1([OH:25])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)=[O:15].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:35][C:36]([NH2:38])=[O:37]>CS(C)=O.O>[C:36]([CH2:35][N:7]1[C:6](=[O:8])[CH:5]=[N:4][N:3]([C:9]2[CH:10]=[CH:11][C:12]([CH3:27])=[C:13]([CH:26]=2)[C:14]([NH:16][CH2:17][C:18]2([OH:25])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)=[O:15])[C:2]1=[O:1])(=[O:37])[NH2:38]
Reactant: NC(=O)CBr
Reactant: Cc1ccc(-n2ncc(=O)[nH]c2=O)cc1C(=O)NCC1(O)CCCCCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: Cc1ccc(-n2ncc(=O)n(CC(N)=O)c2=O)cc1C(=O)NCC1(O)CCCCCC1
Temperature: 25 °C
Reaction time: 14 h
Yield: 45.5 %

Procedure:
A slurry of 5-(3,5-Dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl)-N-(1-hydroxy-cycloheptylmethyl)-2-methyl-benzamide (200.0 mg, 0.537 mmol) and Cs2CO3 (290.3 mg, 0.891 mmol) were stirred in DMSO (1.79 mL, 0.3 M) at ambient temperature for 15 minutes. 2-Bromoacetamide (74.1 mg, 0.537 mmol) was added and the reaction stirred at ambient temperature for 14 hours. The reaction was diluted with water (15-fold) and the aqueous extracted with CH2Cl2 (3×). The organics were dried over sodium sulfate, and concentrated in vacuo to a tan oil. The crude was triterated from IPE/Et2O/CH2Cl2 to give the title compound as a tan solid (105 mg). LCMS (m/z) 430.5 M+1.
Reaction SMILES: [Mg:1].[F:2][C:3]1[C:4]([F:12])=[C:5]([F:11])[C:6]([F:10])=[C:7]([F:9])[CH:8]=1.C([Br:16])(C)C>O1CCCC1>[F:2][C:3]1[C:8]([Mg:1][Br:16])=[C:7]([F:9])[C:6]([F:10])=[C:5]([F:11])[C:4]=1[F:12]
Reactant: Fc1cc(F)c(F)c(F)c1F
Reactant: [Mg]
Reactant: CC(C)Br
Solvent: C1CCOC1
Product: Fc1c(F)c(F)c([Mg]Br)c(F)c1F

Procedure:
Air inside a reaction vessel of the same kind as the one used in Example 13 is displaced by a nitrogen gas in a satisfactory manner. Then, 2.025 g (0.083 mole) of magnesium, 13.198 g (0.079 mole) of pentafluorobenzene, and 20 ml of tetrahydrofuran (THF) serving as the solvent (e) (ether solvent (e)) are charged to the reaction vessel. Also, 10.782 g (0.083 mole) of isopropyl bromide is charged to the dropping funnel. Next, isopropyl bromide is dropped to the above contents with stirring under a nitrogen gas flow. After the completion of the dropping, the resulting reaction solution is subject to reaction for 2 hours at 57.0° C. with stirring. Consequently, pentafluorophenyl magnesium bromide is obtained in the form of a THF solution. A reaction yield of pentafluorophenyl magnesium bromide found in the same manner as Example 13 is 82.9 percent by mole.
Reaction SMILES: [Mg:1].[F:2][C:3]1[C:4]([F:12])=[C:5]([F:11])[C:6]([F:10])=[C:7]([F:9])[CH:8]=1.C([Br:16])(C)C>C(OCC)C>[F:2][C:3]1[C:8]([Mg:1][Br:16])=[C:7]([F:9])[C:6]([F:10])=[C:5]([F:11])[C:4]=1[F:12]
Reactant: [Mg]
Reactant: CC(C)Br
Reactant: Fc1cc(F)c(F)c(F)c1F
Solvent: CCOCC
Product: Fc1c(F)c(F)c([Mg]Br)c(F)c1F

Procedure:
Air inside a reaction vessel of the same kind as the one used in Example 13 is displaced by a nitrogen gas in a satisfactory manner. Then, 2.040 g (0.084 mole) of magnesium, 13.577 g (0.081 mole) of pentafluorobenzene, and 20 ml of diethyl ether are charged to the reaction vessel. Also, 10.518 g (0.081 mole) of isopropyl bromide is charged to the dropping funnel. Next, isopropyl bromide is dropped to the above contents with stirring under a nitrogen gas flow. After the completion of the dropping, the resulting reaction solution is subject to reaction for 3 hours at 63.0° C. with stirring. Consequently, pentafluorophenyl magnesium bromide is obtained in the form of a diethyl ether solution. A reaction yield of pentafluorophenyl magnesium bromide found in the same manner as Example 13 is 80.3 percent by mole.
Reaction SMILES: [Mg].[CH2:2](Cl)[C:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([CH3:5])[CH3:4].BrCCBr.Cl.[C:18](=[O:20])=[O:19]>CC(OC)(C)C.O1CCCC1>[CH3:4][C:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([CH3:5])[CH2:2][C:18]([OH:20])=[O:19]
Reactant: CC(C)(CCl)c1ccccc1
Reactant: O=C=O
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Solvent: COC(C)(C)C
Solvent: BrCCBr
Product: CC(C)(CC(=O)O)c1ccccc1

Procedure:
Magnesium (4,86 g, 0.2 mol, 50-150 mesh), neophylchloride (0.2 g) and tetrahydrofurane(10 ml) were placed in a flask under an atmosphere of argon. A Grignard reaction was then started with 1,2-dibromoethane (0.2 ml). Neophylchloride (35,47 g, 0.2 mol) dissolved in MTBE (50 ml) was then added at reflux over a period of 50 minutes. After stirring for 2½ h at the same temperature, the reaction mixture was diluted with MTBE and dried CO2 was introduced above the surface at a temperature of 35° C. (ice cooling). The mixture was then acidified with HCl and extracted with MTBE. GC revealed the presence of 2,5-dimethyl-2,5-diphenyl-hexane and phenylisobutyric in a ratio of 54:46.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH3:12])[CH:8]=2)[N:3]=1.[N+:13]([O-])([OH:15])=[O:14].S(=O)(=O)(O)O>O>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH3:12])[C:8]=2[N+:13]([O-:15])=[O:14])[N:3]=1
Reactant: O=[N+]([O-])O
Reactant: Cc1ccc2nc(Cl)ccc2c1
Agent: O=S(=O)(O)O
Solvent: O
Product: Cc1ccc2nc(Cl)ccc2c1[N+](=O)[O-]
Reaction time: 4 h

Procedure:
4.12 g of 2-chloro-6-methylquinoline (J. Med. Chem. 1992, pp. 2761-2768) is added at 0° C. to a solution that consists of 15 ml of 100% nitric acid and 2 ml of 96% sulfuric acid. After 4 hours at 0° C., it is added to water, and the product is filtered off. 4.66 g of 2-chloro-6-methyl-5-nitroquinoline is obtained as a beige solid. The latter is reacted for 80 hours at 100° C. in 46 ml of glacial acetic acid and 26 ml of water. The thus obtained 6-methyl-5-nitroquinolin-2(1H)-one is filtered off from the reaction solution. The 3.45 g of product that is obtained is reacted with hydrogen under normal pressure in methanol on palladium on activated carbon to form aniline. 2.89 g of the title compound is obtained as a beige solid.
Reaction SMILES: C(#N)C1C=CC=NC=1.[F:9][C:10]1[C:11]([NH:38][C@@H:39]([C:42]([CH3:45])([CH3:44])[CH3:43])[CH2:40][OH:41])=[N:12][C:13]([C:18]2[C:26]3[C:21](=[N:22][CH:23]=[C:24]([F:27])[CH:25]=3)[N:20]([S:28]([C:31]3[CH:37]=[CH:36][C:34]([CH3:35])=[CH:33][CH:32]=3)(=[O:30])=[O:29])[CH:19]=2)=[C:14]([CH:17]=1)[C:15]#[N:16].C(N(CC)CC)C.[CH3:53][S:54](Cl)(=[O:56])=[O:55]>ClCCl>[CH3:53][S:54]([O:41][CH2:40][C@@H:39]([NH:38][C:11]1[C:10]([F:9])=[CH:17][C:14]([C:15]#[N:16])=[C:13]([C:18]2[C:26]3[C:21](=[N:22][CH:23]=[C:24]([F:27])[CH:25]=3)[N:20]([S:28]([C:31]3[CH:37]=[CH:36][C:34]([CH3:35])=[CH:33][CH:32]=3)(=[O:29])=[O:30])[CH:19]=2)[N:12]=1)[C:42]([CH3:45])([CH3:44])[CH3:43])(=[O:56])=[O:55]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3nc(N[C@H](CO)C(C)(C)C)c(F)cc3C#N)c3cc(F)cnc32)cc1
Agent: N#Cc1cccnc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)n2cc(-c3nc(N[C@H](COS(C)(=O)=O)C(C)(C)C)c(F)cc3C#N)c3cc(F)cnc32)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.5 %

Procedure:
To a cold (0° C.) solution of (S)-5-fluoro-2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-6-(1-hydroxy-3,3-dimethylbutan-2-yl)amino)nicotinonitrile, 98a, (3.77 g, 7.17 mmol) and triethylamine (1.25 mL, 8.96 mmol) in dichloromethane (75 mL) was added methanesulfonyl chloride (0.69 mL, 8.96 mmol). The solution was stirred at room temperature for 1 hour. The solvent was removed under reduced pressure and water (100 mL) and EtOAc (200 mL) were added. The organic phase was separated, dried (MgSO4), filtered and concentrated under reduced pressure to afford 4.22 g of the desired product as a yellow foamy solid that was used without further purification: LC/MS (60-90% ACN/water 5 min with 0.9% FA, C4) m/z 604.45 (M+H) retention time=2.03 minutes.
Reaction SMILES: CO[C:3](=[O:37])[N:4]=[C:5](SC)[C:6]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28](=[O:31])[NH:29][CH3:30])=[C:22]([O:32][CH2:33][CH3:34])[CH:21]=1)=[N:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:18]=C(C)O[N:15]=2)=[CH:10][CH:9]=1.[CH3:38][O:39][C:40]1[C:41]([NH:46][NH2:47])=[N:42][CH:43]=[CH:44][CH:45]=1.COC(=O)N=C(SC)C(C1C=C(OC)C2OCOCC=2C=1)=NC1C=CC(C2N=C(C)ON=2)=CC=1.N(C1N=CC=CN=1)N>>[C:33]([OH:39])(=[O:32])[CH3:34].[C:14]([C:11]1[CH:12]=[CH:13][C:8]([NH:7][CH:6]([C:5]2[NH:4][C:3](=[O:37])[N:46]([C:41]3[C:40]([O:39][CH3:38])=[CH:45][CH:44]=[CH:43][N:42]=3)[N:47]=2)[C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]([NH:29][CH3:30])=[O:31])=[C:22]([O:32][CH2:33][CH3:34])[CH:21]=2)=[CH:9][CH:10]=1)(=[NH:18])[NH2:15]
Reactant: COc1cccnc1NN
Reactant: CCOc1cc(C(=Nc2ccc(-c3noc(C)n3)cc2)C(=NC(=O)OC)SC)ccc1OCC(=O)NC
Agent: COC(=O)N=C(SC)C(=Nc1ccc(-c2noc(C)n2)cc1)c1cc2c(c(OC)c1)OCOC2
Agent: NNc1ncccn1
Product: CC(=O)O
Product: CCOc1cc(C(Nc2ccc(C(=N)N)cc2)c2nn(-c3ncccc3OC)c(=O)[nH]2)ccc1OCC(=O)NC

Procedure:
The same procedure was carried out as in Examples (21i)-(21j), except that {2-(3-ethoxy-4-methylcarbamoylmethoxyphenyl)-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylimino]-1-methylsulfanylethylidene}carbamic acid methyl ester and (3-methoxy-pyridin-2-yl)hydrazine were used instead of respectively the {2-(8-methoxy-4H-benzo[1,3]dioxin-6-yl)-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)-phenylimino]-1-methylsulfanylethylidene}carbamic acid methyl ester in Example (21i) and 2-hydrazinopyrimidine in Example (21i), to give the title compound.