Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C:3](=[O:11])O1.[NH2:13][CH2:14][CH2:15][CH2:16][N:17]([CH3:22])[CH2:18][CH2:19][CH2:20][NH2:21]>>[O:12]=[C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C:3](=[O:11])[N:13]1[CH2:14][CH2:15][CH2:16][N:17]([CH3:22])[CH2:18][CH2:19][CH2:20][N:21]1[C:3](=[O:11])[CH2:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:1]1=[O:12]
Reactant: O=C1Cc2ccccc2C(=O)O1
Reactant: CN(CCCN)CCCN
Product: CN(CCCN1C(=O)Cc2ccccc2C1=O)CCCN1C(=O)Cc2ccccc2C1=O

Procedure:
N,N-Bis-[3-(3,4-dihydro-1,3-dioxo-2-(1H)-isoquinolyl)-propyl]-methylamine was prepared analogous to Example 30 from 15 gm of isochroman-1,3-dione and N,N-bis-(3-amino-propyl)-methylamine. The hydrochloride was precipitated from acetone with ethereal hydrochloric acid and recrystallized from ethanol. M.p. of the hydrochloride: 202° -205° C; yield: 13.8 gm (32% of theory).
Reaction SMILES: I[C:2]1[CH:3]=[N:4][N:5]([CH2:7][CH2:8][O:9][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][O:11]2)[CH:6]=1.[C:16]([C:20]1[CH:21]=[C:22]([NH2:25])[NH:23][N:24]=1)([CH3:19])([CH3:18])[CH3:17].C([O-])([O-])=O.[K+].[K+].CN(C)[C@@H]1CCCC[C@H]1N>[Cu]I.O.C1(C)C=CC=CC=1>[C:16]([C:20]1[CH:21]=[C:22]([NH2:25])[N:23]([C:2]2[CH:3]=[N:4][N:5]([CH2:7][CH2:8][O:9][CH:10]3[CH2:15][CH2:14][CH2:13][CH2:12][O:11]3)[CH:6]=2)[N:24]=1)([CH3:19])([CH3:18])[CH3:17]
Reactant: Ic1cnn(CCOC2CCCCO2)c1
Reactant: CC(C)(C)c1cc(N)[nH]n1
Agent: [Cu]I
Agent: CN(C)[C@@H]1CCCC[C@H]1N
Agent: O=C([O-])[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)c1cc(N)n(-c2cnn(CCOC3CCCCO3)c2)n1
Temperature: 150 °C
Yield: 81 %

Procedure:
To a mixture of 4-iodo-1-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-1H-pyrazole (for reference procedure see for example WO 2010/139731, which is incorporated herein by reference; 1.54 g, 4.81 mmol), 5-tert-butyl-2H-pyrazol-3-ylamine (668 mg, 4.81 mmol), copper (I) iodide (45 mg, 0.24 mmol) and K2CO3 (1.39 g, 10.1 mmol) was added a solution of toluene (5 mL), previously degassed by using a stream of argon. (R,R)-(−)—N,N-Dimethyl-1,2-cyclohexanediamine (151 μL, 0.96 mmol) was then added and the reaction mixture was heated at 150° C. for 2.5 h under microwave irradiation. The crude reaction mixture was poured into water and extracted with EtOAc (×3). The combined organic layers were washed with brine, dried (MgSO4) and concentrated in vacuo. The resultant residue was purified by FCC on silica, using a gradient of 0-100% EtOAc in cyclohexane, to give the title compound (1.29 g, 81%). LCMS (Method 1): Rt 2.31 min, m/z 334 [MH+].
Reaction SMILES: [I:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[Br:9][CH2:10][C:11](Br)=[O:12].C(N(CC)CC)C>ClCCl>[Br:9][CH2:10][C:11]([NH:6][C:5]1[CH:7]=[CH:8][C:2]([I:1])=[CH:3][CH:4]=1)=[O:12]
Reactant: Nc1ccc(I)cc1
Reactant: O=C(Br)CBr
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CBr)Nc1ccc(I)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 60 %

Procedure:
To a solution of 4-iodoaniline (14.5 mmol) in anhydrous dichloromethane at 0° C. was added a-bromo-acetylbromide (1.4 mL) and triethylamine (15 mmol). The mixture was warmed to room temperature, stirred for 1 h, the solvent removed, and residue dissolved in 5% hydrochloric acid. The aqueous solution was extracted with ethyl acetate, the organic layer washed with brine, dried (Na2SO4), filtered, and evaporated. The solid residue was purified by recrystallization form ethyl acetate to afford the desired intermediate.
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH:5]([S:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH2:30][C:31]([O:33]CC)=[O:32])=[C:25]([CH3:36])[CH:24]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)[N:7]=1)[CH3:2].[OH-].[Na+].Cl>C1COCC1.CO>[CH2:1]([O:3][CH2:4][CH:5]([S:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH2:30][C:31]([OH:33])=[O:32])=[C:25]([CH3:36])[CH:24]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[CH:13]=[CH:14][C:15]([C:18]([F:21])([F:19])[F:20])=[CH:16][CH:17]=2)[N:7]=1)[CH3:2]
Reactant: CCOCC(Sc1ccc(OCC(=O)OCC)c(C)c1)c1cccc(-c2ccc(C(F)(F)F)cc2)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCOCC(Sc1ccc(OCC(=O)O)c(C)c1)c1cccc(-c2ccc(C(F)(F)F)cc2)n1
Temperature: 25 °C
Reaction time: 15 h
Yield: 61.9 %

Procedure:
A solution of the ethyl ({4-[(2-(ethyloxy)-1-{6-[4-(trifluoromethyl)phenyl]-2-pyridinyl}ethyl)thio]-2-methylphenyl}oxy)acetate (Enantiomer 1) (12 mg, 0.023 mmol) in THF (1 mL) and MeOH (1 mL) was treated with aqueous NaOH (2N, 1 mL) and the resulting mixture agitated at ambient temperature for 15 h. Aqueous HCl (2N, 1 mL) was then added and the organic solvents removed under vacuum using a Genevac. The residue was the then made up to 2 mL by the addition of water and then extracted using DCM (3×3 mL) in an hydrophobic frit. The residue was reduced and then purified further by mass directed autoprep HPLC to afford the title compound as an oil (7 mg).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH:8]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:9]2)=[CH:4][CH:3]=1.[N+]([C:23]1[CH:28]=[CH:27][N:26]=[C:25]([NH:29][C:30]([CH:32]2[CH2:34][CH2:33]2)=[O:31])[CH:24]=1)([O-])=O.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH:32]1([C:30]([NH:29][C:25]2[CH:24]=[C:23]([O:1][C:2]3[CH:11]=[C:10]4[C:5]([CH2:6][CH2:7][CH:8]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:16])([CH3:18])[CH3:17])[CH2:9]4)=[CH:4][CH:3]=3)[CH:28]=[CH:27][N:26]=2)=[O:31])[CH2:33][CH2:34]1
Reactant: O=C(Nc1cc([N+](=O)[O-])ccn1)C1CC1
Reactant: CC(C)(C)OC(=O)NC1CCc2ccc(O)cc2C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1CCc2ccc(Oc3ccnc(NC(=O)C4CC4)c3)cc2C1
Temperature: 65 °C
Reaction time: 8 h

Procedure:
A mixture of tert-butyl (7-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)carbamate (2.07 g, 0.00707 mol), N-(4-nitropyridin-2-yl)cyclopropanecarboxamide (1.46 g, 0.00707 mol) and cesium carbonate (6.92 g, 0.0212 mol) in DMF was heated with stirring at 65° C. overnight. The reaction mixture was extracted with EtOAc. The organic solution was washed with water and brine, dried over MgSO4, filtered, and concentrated. The residue was purified by column chromatography to tert-butyl [7-({2-[(cyclopropylcarbonyl)amino]pyridin-4-yl}oxy)-1,2,3,4-tetrahydronaphthalen-2-yl]carbamate. 1H NMR (CDCl3, 300 MHz) δ: 9.18 (s, 1H); 8.02 (d, 1H); 7.82 (d, 1H); 7.32 (dd, 1H); 7.11 (d, 1H); 6.90 (d, 1H); 6.78 (s, 1H); 6.58 (dd, 1H); 4.60 (s, 1H); 4.1 (m, 1H); 3.96 (s, 1H); 3.10 (d, 1H); 2.86 (m, 2H); 2.61 (dd, 1H); 2.08 (m, 1H); 2.04 (m, 1H); 1.75 (m, 1H); 1.60 (m, 1H); 1.45 (s, 9H); 1.25 (m, 1H); 1.07 (m, 2H); 0.87 (m, 2H). LCMS ES+ 424.4; ES− 422.5.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[O:11]([CH2:18][C:19]1[O:20][C:21]2[CH2:22][NH:23][CH2:24][CH2:25][C:26]=2[N:27]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(Cl)Cl.C([O-])(O)=O.[Na+]>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:23]2[CH2:24][CH2:25][C:26]3[N:27]=[C:19]([CH2:18][O:11][C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)[O:20][C:21]=3[CH2:22]2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: c1ccc(OCc2nc3c(o2)CNCC3)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=C(c1ccc(F)cc1)N1CCc2nc(COc3ccccc3)oc2C1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 66.2 %

Procedure:
4-Fluorobenzoyl chloride (0.25 mL, 2.12 mmol) was added dropwise to a stirred solution of 4,5,6,7-tetrahydro-2-(phenoxymethyl)-oxazolo[5,4-c]pyridine (0.37 g, 1.63 mmol) and TEA (0.34 mL, 2.44 mmol) in DCM (8.15 mL) at 0° C. The reaction mixture was stirred at room temperature for 15 minutes and then diluted with a saturated solution of NaHCO3. The organic layer was separated, dried (Na2SO4), filtered and the solvent evaporated in vacuo. The crude product was purified by flash column chromatography (silica; AcOEt in DCM 0/100 to 30/70). The desired fractions were collected and the solvents evaporated in vacuo. The crude product was triturated with heptane to yield 5-(4-fluorobenzoyl)-4,5,6,7-tetrahydro-2-(phenoxymethyl)-oxazolo[5,4-c]pyridine (0.38 g, 67% yield) as a white solid. C20H17FN2O3. 1H NMR (400 MHz, CDCl3) δ ppm 2.73 (br. s., 2 H), 3.69 (br. s., 1.4 H), 3.99 (br. s., 0.6 H), 4.57 (br. s., 0.6 H), 4.78 (br. s., 1.4 H), 5.12 (br. s., 2 H), 7.02 (d, J=7.4 Hz, 3 H), 7.14 (t, J=8.6 Hz, 2 H), 7.31 (t, J=7.7 Hz, 2 H), 7.43-7.51 (m, 2 H).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19](=[O:26])[NH:20][C:21]1[NH:22][CH:23]=[CH:24][N:25]=1)(C)(C)C.[ClH:28].O1CCOCC1>>[ClH:28].[ClH:28].[NH:22]1[CH:23]=[CH:24][N:25]=[C:21]1[NH:20][C:19](=[O:26])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][NH2:7]
Reactant: CC(C)(C)OC(=O)NCCCCCCCCCCCC(=O)Nc1ncc[nH]1
Agent: Cl
Solvent: C1COCCO1
Product: NCCCCCCCCCCCC(=O)Nc1ncc[nH]1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
[11-(1H-Imidazol-2-ylcarbarmoyl)undecyl]carbamic acid tert-butyl ester (13) (0.060 g, 0.16 mmol) was treated with 4 M HCl in dioxane (2 mL, 8 mmol) and the mixture stirred at room temperature for 14 hours. The reaction mixture was concentrated in vacuo and further dried under high vacuum. The resulting white solid (0.056 g, 99%) was used directly without further purification. m/z (ESI) 281 [C15H28N4O+H]+.
Reaction SMILES: C([O:9][C@H:10]1[C@@H:14]([O:15]C(=O)C2C=CC=CC=2)[C@H:13]([CH2:24][O:25]C(=O)C2C=CC=CC=2)[O:12][C@@H:11]1[N:34]1[CH:42]=[N:41][C:40]2[C:35]1=[N:36][CH:37]=[N:38][C:39]=2Cl)(=O)C1C=CC=CC=1.SC([OH:47])C.C[O-].[Na+].C(O)(=O)C>CO>[C@H:11]1([N:34]2[CH:42]=[N:41][C:40]3[C:39](=[O:47])[NH:38][CH:37]=[N:36][C:35]2=3)[O:12][C@@H:13]([CH2:24][OH:25])[C@H:14]([OH:15])[C@@H:10]1[OH:9]
Reactant: O=C(OC[C@@H]1O[C@H](n2cnc3c(Cl)ncnc32)[C@@H](OC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1)c1ccccc1
Reactant: CC(O)S
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: O=c1[nH]cnc2c1ncn2[C@H]1O[C@@H](CO)[C@H](O)[C@@H]1O
Yield: 1359.3 %

Procedure:
A mixture of 9 (1.05 g, 1.70 mmol), mercaptoethanol (0.48 ml, 6.9 mmol), and NaOMe in MeOH (100 ml) was refluxed for four hours. The reaction mixture was cooled, neutralized with glacial acetic acid and evaporated to dryness. The solid obtained was washed with CHCl3 and the residue was crystallized from EtOH to give pure 11 (6.198 g, 47%) as white crystals: m.p. 212°-213° C. (dec).
Reaction SMILES: C([Li])CCC.CCCCCC.[CH3:12][P:13](=[O:18])([O:16][CH3:17])[O:14][CH3:15].[CH3:19][C:20]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([CH3:25])[C:21](OC)=[O:22]>C1COCC1.O.C(O)(=O)C>[CH3:25][C:20]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([CH3:19])[C:21](=[O:22])[CH2:12][P:13](=[O:18])([O:16][CH3:17])[O:14][CH3:15]
Reactant: COC(=O)C(C)(C)c1ccccc1
Reactant: COP(C)(=O)OC
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: O
Solvent: C1CCOC1
Product: COP(=O)(CC(=O)C(C)(C)c1ccccc1)OC
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A solution of n-butyl lithium in hexane (1.59N, 44.0 ml, 70.0 mmol) was added to a solution of dimethyl methylphosphonate (8.74 g, 70.0 mmol) in anhydrous THF (130 ml) cooled at -78° C. under argon atmosphere, and the mixture was stirred for 30 minutes. To this reaction mixture was added a solution of methyl 2-methyl-2-phenylpropionate (5.00 g, 28.0 mmol) in anhydrous THF (15 ml) at -78° C. The mixture was stirred for 2 hours, allowed to warm to room temperature and neutralized with acetic acid. The reaction mixture was diluted with water (10 ml), and concentrated. The residue was combined with ethyl acetate (100 ml) and water (30 ml). The separated organic layer was washed with water (30 ml) and brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was distilled (b.p. 135°-141° C./0.05 mmHg) to give an oil of dimethyl 3-methyl-2-oxo-3-phenylbuthylphosphonate (5.73 g, 21.2 mmol, 75.7%). This compound was assigned the structure by the following data:
Reaction SMILES: [Cl:1][C:2]1[N:7]2[N:8]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=3)[CH:10]=[C:6]2[N:5]=[C:4]([CH3:18])[C:3]=1[CH:19]([OH:24])[C:20]([O:22][CH3:23])=[O:21].C(O[C:29]([CH3:32])([CH3:31])[CH3:30])(=O)C.Cl(O)(=O)(=O)=O>C(Cl)Cl>[C:29]([O:24][CH:19]([C:3]1[C:4]([CH3:18])=[N:5][C:6]2[N:7]([N:8]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=3)[CH:10]=2)[C:2]=1[Cl:1])[C:20]([O:22][CH3:23])=[O:21])([CH3:32])([CH3:31])[CH3:30]
Reactant: COC(=O)C(O)c1c(C)nc2cc(-c3cccc(Cl)c3)nn2c1Cl
Reactant: CC(=O)OC(C)(C)C
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: ClCCl
Product: COC(=O)C(OC(C)(C)C)c1c(C)nc2cc(-c3cccc(Cl)c3)nn2c1Cl
Temperature: 25 °C
Reaction time: 5 h
Yield: 0.1 %

Procedure:
To a suspension of methyl 2-(7-chloro-2-(3-chlorophenyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-hydroxyacetate (3550 mg, 9.69 mmol) in tert-butyl acetate (50 mL, 9.69 mmol) at room temperature was added CH2Cl2 (30 mL) followed by perchloric acid (1.250 mL, 14.54 mmol). The reaction mixture was stirred for 5 h at room temperature. The reaction mixture was quenched with water and diluted with ethyl acetate. The organic phase was washed with saturated NaHCO3 and dried over sodium sulfate. The solvent was evaporated. Purification by silica gel chromatography provided the title compound (2.7 mg, 66%). 1H NMR (400 MHz, CHLOROFORM-d) δ 8.07-8.00 (m, 1H), 7.89 (dt, J=6.7, 1.9 Hz, 1H), 7.48-7.37 (m, 2H), 6.93 (s, 1H), 5.68 (s, 1H), 3.75 (s, 3H), 2.69 (s, 3H), 1.29 (s, 9H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[NH:10][C:9]([CH3:12])([CH3:11])[O:8][C:7]([CH3:14])([CH3:13])[C:6]=2[CH:15]=1.Br[C:17]1[CH:18]=[C:19]([C:22]#[N:23])[S:20][CH:21]=1>>[CH3:11][C:9]1([CH3:12])[O:8][C:7]([CH3:14])([CH3:13])[C:6]2[CH:15]=[C:2]([C:17]3[CH:18]=[C:19]([C:22]#[N:23])[S:20][CH:21]=3)[CH:3]=[CH:4][C:5]=2[NH:10]1
Reactant: N#Cc1cc(Br)cs1
Reactant: CC1(C)Nc2ccc(Br)cc2C(C)(C)O1
Product: CC1(C)Nc2ccc(-c3csc(C#N)c3)cc2C(C)(C)O1

Procedure:
Prepared using the coupling procedure for Example 13 starting with 6-bromo-2,2,4,4-tetramethyl-1,4-dihydro-2H-3,1-benzoxazine and 4-bromo-2-cyanothiophene. An amorphous orange solid: 1H-NMR (DMSO-d6) δ 8.4 (d, 1H, J=1.69 Hz), 8.14 (d, 1H, J=1.69 Hz), 7.49 (d, 1H, J=2.20 Hz), 7.38 (dd, 1H, J=8.43, 2.02 Hz), 6.61 (d, 1H, J=8.43 Hz), 6.26 (s, 1H), 1.49 (s, 6H), 1.32 (s, 6H); MS (ES) m/z 299 ([M+H]+).
Reaction SMILES: [CH3:1][N:2]([CH3:30])[C:3]([O:5][C:6]1(O)[CH:15]=[CH:14][C:13]2[CH:12]([CH2:16][C:17](OCC)=[O:18])[N:11]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:10][CH2:9][C:8]=2[CH2:7]1)=[O:4].[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1>[CH3:30][N:2]([CH3:1])[C:3]([O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[CH:12]([CH2:16][CH2:17][OH:18])[N:11]([C:22]([O:24][C:25]([CH3:27])([CH3:26])[CH3:28])=[O:23])[CH2:10][CH2:9]2)=[O:4]
Reactant: CCOC(=O)CC1C2=C(CCN1C(=O)OC(C)(C)C)CC(O)(OC(=O)N(C)C)C=C2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CN(C)C(=O)Oc1ccc2c(c1)CCN(C(=O)OC(C)(C)C)C2CCO
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 78.2 %

Procedure:
To a solution of t-butyl 6-dimethylcarbamoyloxy-1-ethoxycarbonylmethyl-6-hydroxy-3,4-dihydro-1H-isoquinoline-2-carboxylate (1.97 g, 4.84 mmol) synthesized in step (e) of Example 187 in tetrahydrofuran (30 ml) was added lithium aluminum hydride (270 mg, 7.2 mmol) at −78° C., and the resulting mixture was stirred for 20 minutes at −78° C. and for 20 minutes at 0° C. successively under a nitrogen atmosphere. After stirring, to the reaction mixture were added water (0.3 ml), 15% aqueous sodium hydroxide solution (0.3 ml) and water (0.9 ml) in this order with stirring, and the resulting mixture was dried over anhydrous sodium sulfate, filtered, and evaporated in vacuo to afford the crude product. The crude product was purified by chromatography on a silica gel column using a mixed solvent of hexane and ethyl acetate (1:1-0:1) as the eluent to afford the title compound (1.38 g, yield: 78%) as a colorless oil.
Reaction SMILES: [C:1]([C:3]([C:11]1[S:12][C:13]([C:16]#[N:17])=[CH:14][CH:15]=1)([CH:8]([CH3:10])[CH3:9])[CH2:4][CH2:5][CH2:6]I)#[N:2].[F:18][C:19]([F:36])([F:35])[C:20]1[CH:21]=[CH:22][C:23]([O:26][CH2:27][CH2:28][N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[N:24][CH:25]=1>>[C:1]([C:3]([C:11]1[S:12][C:13]([C:16]#[N:17])=[CH:14][CH:15]=1)([CH:8]([CH3:10])[CH3:9])[CH2:4][CH2:5][CH2:6][N:32]1[CH2:33][CH2:34][N:29]([CH2:28][CH2:27][O:26][C:23]2[CH:22]=[CH:21][C:20]([C:19]([F:36])([F:18])[F:35])=[CH:25][N:24]=2)[CH2:30][CH2:31]1)#[N:2]
Reactant: CC(C)C(C#N)(CCCI)c1ccc(C#N)s1
Reactant: FC(F)(F)c1ccc(OCCN2CCNCC2)nc1
Product: CC(C)C(C#N)(CCCN1CCN(CCOc2ccc(C(F)(F)F)cn2)CC1)c1ccc(C#N)s1

Procedure:
The title compound was synthesized in accordance with Example 77 from 4-cyano-4-(5-cyano-2-thienyl)-5-methylhexyl iodide and 1-[2-(5-trifluoromethyl-2-pyridyloxy)ethyl]piperazine. The physico-chemical data of the compound was as below.
Reaction SMILES: ClCCl.[CH3:4][C:5]1([CH3:24])[CH2:10][CH:9]([NH:11][CH:12]2[CH2:17][C:16]([CH3:19])([CH3:18])[NH:15][C:14]([CH3:21])([CH3:20])[CH2:13]2)[CH2:8][C:7]([CH3:23])([CH3:22])[NH:6]1.[C:25](Cl)(=[O:28])[CH:26]=[CH2:27].[OH-].[Na+]>CN(C)C1C=CN=CC=1.O>[CH3:22][C:7]1([CH3:23])[CH2:8][CH:9]([N:11]([CH:12]2[CH2:17][C:16]([CH3:19])([CH3:18])[NH:15][C:14]([CH3:21])([CH3:20])[CH2:13]2)[C:25](=[O:28])[CH:26]=[CH2:27])[CH2:10][C:5]([CH3:24])([CH3:4])[NH:6]1
Reactant: CC1(C)CC(NC2CC(C)(C)NC(C)(C)C2)CC(C)(C)N1
Reactant: C=CC(=O)Cl
Agent: CN(C)c1ccncc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: C=CC(=O)N(C1CC(C)(C)NC(C)(C)C1)C1CC(C)(C)NC(C)(C)C1
Yield: 19.3 %

Procedure:
A 2500 ml flask equipped with stirrer, termometer and dropping funnel is charged with 1000 ml of dichloromethane, 147.75 g (500 mmol) N,N-bis-(2,2,6,6-tetramethyl-piperidin-4-yl)-amine (prepared as described in EP 838 455 A1) and 1.6 g 4-dimethylaminopyridine. Then, 47.5 g (525 mmol) of acryloylchloride are added during 4 h while keeping the temperature at 0-2° C. After additional 90 minutes of stirring the solution of 21 g (521 mmol) NaOH in 100 ml water is slowly added. The organic layer is separated, dried over MgSO4 and evaporated. The residue (174.55 g) is recrystallized 3× from acetonitrile to afford 33.78 g of the title compound as white crystals, mp 115-118° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10](I)[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[CH3:13][N:14](C)C=O>C(OCC)(=O)C.[C-]#N.[Zn+2].[C-]#N.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd]>[Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([C:13]#[N:14])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1cc(Br)cc(I)c1
Reactant: CN(C)C=O
Agent: [Pd]
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(Br)cc(C#N)c1
Temperature: 80 °C
Yield: 61 %

Procedure:
A solution of methyl 3-bromo-5-iodobenzoate (4.5 g, 13.2 mmol) in N,N-dimethylformamide (36 mL) was treated with zinc cyanide (1.7 g, 14.5 mmol) and tetrakis(triphenylphosphine)palladium(O) (Pd(PPh3)4, 1.5 g, 1.3 mmol). The reaction mixture was heated, under an argon atmosphere, for 1 hour at 80° C. After cooling the mixture was diluted with ethyl acetate. The resulting organic solution was washed with water (3×), saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Silica gel chromatography using a gradient of hexane to 10% ethyl acetate in hexane afforded 1.9 g (61%) of methyl 3-bromo-5-cyanobenzoate.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[N:6]([CH2:12][CH2:13][CH2:14][CH3:15])[CH2:5]2.[CH:16]([C:18]1[CH:19]=[N:20][CH:21]=[CH:22][C:23]=1[NH:24][C:25](=[O:30])[C:26]([CH3:29])([CH3:28])[CH3:27])=O.C([O-])(O)=O.[Na+].[BH4-].[Na+]>C(O)(=O)C.CO.O>[CH2:12]([N:6]1[CH2:5][C:4]2[C:8](=[CH:9][CH:10]=[C:2]([NH:1][CH2:16][C:18]3[CH:19]=[N:20][CH:21]=[CH:22][C:23]=3[NH:24][C:25](=[O:30])[C:26]([CH3:28])([CH3:27])[CH3:29])[CH:3]=2)[C:7]1=[O:11])[CH2:13][CH2:14][CH3:15]
Reactant: CC(C)(C)C(=O)Nc1ccncc1C=O
Reactant: CCCCN1Cc2cc(N)ccc2C1=O
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: CO
Product: CCCCN1Cc2cc(NCc3cnccc3NC(=O)C(C)(C)C)ccc2C1=O
Reaction time: 120 h

Procedure:
5-Amino-2-butylisoindolin-1-one (49.5 mg, 0.242 mmol) was added to a solution of N-(3-formylpyridin-4-yl)pivalamide (50 mg, 0.242 mmol) in acetic acid (1 mL). After stiffing for 5 days, water and sat aqueous NaHCO3 solution were added. The mixture was extracted with EtOAc, the combined organic layers were washed with water, dried over MgSO4 and the solvent was removed in vacuo. The residue obtained was dissolved in MeOH (3 mL) and NaBH4 (18.3 mg, 0.485 mmol) was added. After stirring overnight, water and sat. aqueous NaHCO3 solution were added. Extraction with EtOAc, washing of the combined organic layers with water and drying over MgSO4 provided the crude product which was purified by HPLC (24 mg, 19%). ESI-MS [M+H]+=395.2.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH:14]([CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)[CH2:15][N:16]([CH2:21][CH:22]([CH3:24])[CH3:23])[S:17]([CH3:20])(=[O:19])=[O:18])[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:31].CCOC(C)=O>>[ClH:31].[ClH:31].[CH:25]1([CH:14]([N:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)[CH2:15][N:16]([CH2:21][CH:22]([CH3:24])[CH3:23])[S:17]([CH3:20])(=[O:18])=[O:19])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]1
Reactant: CC(C)CN(CC(C1CCCCC1)N1CCN(C(=O)OC(C)(C)C)CC1)S(C)(=O)=O
Agent: Cl
Solvent: CCOC(C)=O
Product: CC(C)CN(CC(C1CCCCC1)N1CCNCC1)S(C)(=O)=O

Procedure:
A solution of the product from Step III (446 mg, 1.22 mmol) in 1N HCl/EtOAc (25 mL) was stirred at room temperature overnight. Solvent was removed under reduced pressure and solid washed twice with Et2O to afford the title compound as a white solid. MS m/z 346.3 (M++1).
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:11]1([S:17](Cl)(=[O:19])=[O:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.Cl>N1C=CC=CC=1>[N+:1]([C:4]1[CH:10]=[CH:9][C:7]([NH:8][S:17]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)(=[O:19])=[O:18])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: Nc1ccc([N+](=O)[O-])cc1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: Cl
Solvent: c1ccncc1
Product: O=[N+]([O-])c1ccc(NS(=O)(=O)c2ccccc2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 99.2 %

Procedure:
A solution of p-nitroaniline (1 kg, 7.245 mol) in pyridine (3.6 L) was brought to 45° C. Benzenesulfonyl chloride (1.41 kg, 8 mol) was poured in over 70 minutes, while maintaining the temperature ranging from 45 to 50° C. After 1 hour at 50° C., the reaction medium was poured onto 8 kg of ice and 4.35 L of hydrochloric acid. A yellow precipitate formed and was filtered off by suction and then dissolved in 20 L of 0.5 N sodium hydroxide at 55° C. The insoluble matter was removed by filtration and the filtrate was then neutralized hydrochloric acid while still hot. A yellow precipitate formed and was filtered off by suction, reslurried in water, and then air-dried. 2 kg of product with a melting point of 137° C. were obtained.