Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]23[CH2:23][CH:16]([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:22]=42)[C:15]2[C:10]3=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:4][CH2:3]1.Cl[C:25]1[N:30]=[CH:29][C:28]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[CH:27][N:26]=1>>[CH:21]1[C:22]2[C:9]3([CH2:8][N:5]4[CH2:6][CH2:7][CH:2]([NH:1][C:25]5[N:26]=[CH:27][C:28]([C:31]6[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=6)=[CH:29][N:30]=5)[CH2:3][CH2:4]4)[CH2:23][CH:16]([C:15]4[C:10]3=[CH:11][CH:12]=[CH:13][CH:14]=4)[C:17]=2[CH:18]=[CH:19][CH:20]=1
Reactant: Clc1ncc(-c2ccccc2)cn1
Reactant: NC1CCN(CC23CC(c4ccccc42)c2ccccc23)CC1
Product: c1ccc(-c2cnc(NC3CCN(CC45CC(c6ccccc64)c4ccccc45)CC3)nc2)cc1

Procedure:
Using a procedure similar to that described in Example 86 except starting with 4-amino-1-(9,10-dihydro-9,10-methanoanthracene-9-ylmethyl)piperidine (prepared as described in Example 8b) and 2-chloro-5-phenylpyrimidine the hydochloride salt of the title compound was obtained as a white solid (60%), mp 292°-294° C.; MS(CI): 459 (M+H); NMR (300 MHz, DMSO-d6): 9.95(br s, 1H), 8.70-8.66(m, 2H), 7.66-7.62(m, 3H), 7.47-7.33(m, 7H), 7.04-6.96(m, 4H), 4.46(s, 1H), 4.35-4.33(m, 2H), 4.25-4.00(br m, 1H), 3.60-3.35(m, 4H), 2.74(s, 2H), 2.15-1.91(m, 4H).
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([N:11]2[CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3[C:20]([F:23])([F:22])[F:21])[C:12]2=[O:24])[C:8](O)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.[CH3:31][N:32]1[CH:36]=[CH:35][C:34]([NH2:37])=[N:33]1.N1C(C)=CC=CC=1C>C(Cl)Cl.CN(C)C=O>[CH:1]1([CH2:6][C@H:7]([N:11]2[CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3[C:20]([F:22])([F:21])[F:23])[C:12]2=[O:24])[C:8]([NH:37][C:34]2[CH:35]=[CH:36][N:32]([CH3:31])[N:33]=2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)[C@H](CC1CCCC1)N1Cc2c(cccc2C(F)(F)F)C1=O
Reactant: Cn1ccc(N)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: Cc1cccc(C)n1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cn1ccc(NC(=O)[C@H](CC2CCCC2)N2Cc3c(cccc3C(F)(F)F)C2=O)n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 77.1 %

Procedure:
A solution of (S)-3-cyclopentyl-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-propionic acid (100 mg, 0.29 mmol) in methylene chloride (2.9 mL) at 0° C. was treated with oxalyl chloride (0.03 mL, 0.34 mmol) followed by N,N-dimethylformamide (5 drops). The resulting solution was stirred at 0° C. for 30 min. At this time, the solution was warmed to room temperature and stirred for 30 min. The reaction was then concentrated in vacuo. The residue was re-suspended in methylene chloride (2×5 mL) and then concentrated in vacuo. The residue was then dissolved in methylene chloride (1 mL) and was added to a pre-cooled solution of 1-methyl-1H-pyrazol-3-ylamine (Matrix, 30 mg, 1.05 mmol) and 2,6-lutidine (0.05 mL, 0.47 mmol) in methylene chloride (3 mL) at 0° C. The reaction was allowed to gradually warm to room temperature and was stirred at room temperature overnight. After this time, the reaction was diluted with methylene chloride (50 mL) and was washed with a 1N aqueous hydrochloric acid solution (2×100 mL), a saturated aqueous sodium bicarbonate solution (2×100 mL) and water (1×100 mL), dried over sodium sulfate, filtered and concentrated in vacuo. Flash chromatography (50-75% ethyl acetate/hexanes) afforded (S)-3-cyclopentyl-N-(1-methyl-1H-pyrazol-3-yl)-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-propionamide (94 mg, 77%) as a white solid; ES+-HRMS m/e calcd for C21H23N4O2F3 (M+H)+ 421.1846 found 421.1844. 1H-NMR (300 MHz, DMSO-d6) δ ppm 10.87 (s, 1H), 8.01 (t, J=8.6 Hz, 2H), 7.68-7.81 (m, 1H), 7.54 (d, J=1.9 Hz, 1H), 6.39 (d, J=1.9 Hz, 1H), 5.02-5.15 (m, 1H), 5.03 (d, J=18.5 Hz, 1H), 4.71 (d, J=18.5 Hz, 1H), 3.73 (s, 3H), 0.98-2.12 (m, 11H).
Reaction SMILES: Br.[C:2]([C:4]1[CH:20]=[CH:19][C:7]([CH2:8][N:9]2[C:13]([CH2:14][O:15]C(=O)C)=[CH:12][N:11]=[CH:10]2)=[CH:6][CH:5]=1)#[N:3].O.[OH-].[Li+]>C1COCC1.O>[C:2]([C:4]1[CH:20]=[CH:19][C:7]([CH2:8][N:9]2[C:13]([CH2:14][OH:15])=[CH:12][N:11]=[CH:10]2)=[CH:6][CH:5]=1)#[N:3]
Reactant: CC(=O)OCc1cncn1Cc1ccc(C#N)cc1
Agent: Br
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1ccc(Cn2cncc2CO)cc1
Reaction time: 1 h

Procedure:
1-(4-Cyanobenzyl)-5-(acetoxymethyl)-imidazole hydrobromide (50.4 g, 150 mmol) in 3:1 THF/water (1.5 L) at 0° C. was added lithium hydroxide monohydrate (18.9 g, 450 mmol). After 1 hr, the reaction was concentrated in vacuo, diluted with EtOAc (3 L), and washed with water, sat. aq. NaHCO3 and brine. The solution was then dried (Na2SO4), filtered, and concentrated in vacuo to provide the crude product as a pale yellow fluffy solid which was sufficiently pure for use in the next step without further purification.
Reaction SMILES: C[C:2]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:10][C:9]2[C:4](=[C:5]([Cl:16])[C:6]([Cl:15])=[C:7]([OH:14])[C:8]=2[CH2:11][CH:12]=[CH2:13])[C:3]1=[O:17].C([O-])(=[O:26])C.[Na+].C(OO)(=O)C>ClCCl>[Cl:15][C:6]1[C:7]2[O:14][CH:12]([CH2:13][OH:26])[CH2:11][C:8]=2[C:9]2[CH2:10][CH:2]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:3](=[O:17])[C:4]=2[C:5]=1[Cl:16]
Reactant: CC(=O)[O-]
Reactant: C=CCc1c(O)c(Cl)c(Cl)c2c1CC(C)(c1ccccc1)C2=O
Agent: CC(=O)OO
Agent: [Na+]
Solvent: ClCCl
Product: O=C1c2c(Cl)c(Cl)c3c(c2CC1c1ccccc1)CC(CO)O3
Temperature: 120 °C

Procedure:
To a solution of 2-methyl-2-phenyl-4-allyl-5-hydroxy-6,7-dichloro-1-indanone (8.2 g., 0.024 mole) in dichloromethane (80 ml.) is added sodium acetate (150 mg.) and 40% peracetic acid (6 ml.). The reaction is stirred at 25°C. for 12 days during which time two 1 ml. portions of 40% peracetic acid are added at four day intervals. The reaction mixture is washed with water, aqueous sodium bicarbonate and brine. The solvent is distilled at reduced pressure and the residual oil is heated at 120°C. for 20 minutes affording 4,5-dichloro-2-hydroxymethyl-6-oxo-7-phenyl-1,2,7,8-tetrahydro-6H-indeno-[5,4-b]-furan (α-isomer) which is used in the next step without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:18][CH2:17][CH2:16][C@H:12]1[C:13]([OH:15])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.ClC(OCC)=O.[CH2:32]([NH2:36])[CH2:33][CH2:34][CH3:35]>C1COCC1.C(OCC)(=O)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:18][CH2:17][CH2:16][C@H:12]1[C:13]([NH:36][CH2:32][CH2:33][CH2:34][CH3:35])=[O:15])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCN
Reactant: O=C(O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCCNC(=O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Reaction time: 1 h
Yield: 70.7 %

Procedure:
In 50 ml of THF was dissolved 4.99 g of N-benzyloxycarbonyl-L-proline and then 2.23 g of triethylamine was added to the solution. Then, after slowly adding thereto 2.39 g of ethyl chloroformate under ice-cooling, the reaction was maintained for one hour at 0° C. to 5° C. Then, 2.19 g of n-butylamine was slowly added to the reaction mixture under ice-cooling, the reaction was further performed for one hour at 0° C. to 5° C. The solvent was removed from the reaction mixture, the residue thus formed was dissolved in ethyl acetate, and the solution was washed successively with an aqueous solution of 1N hydrochloric acid, a saturated aqueous sodium hydrogencarbonate solution, and a saturated aqueous sodium chloride solution. The organic layer this formed was collected, dried by Glauber's salt, and then concentrated by dryness. The product was recrystallized from water to provide 4.31 g of (S)-1-benzyloxycarbonyl-N-butyl-2-pyrrolidinecarboxamide (30). M.p. 88°-90° C.
Reaction SMILES: [NH2:1][CH:2]([CH:5]1[CH2:10][CH2:9][N:8]([O:11][CH3:12])[CH2:7][CH2:6]1)[C:3]#[N:4].CCN(CC)CC.[CH3:20][C:21]1[CH:26]=[C:25]([CH3:27])[CH:24]=[C:23]([CH3:28])[C:22]=1[CH2:29][C:30](Cl)=[O:31].O>C1COCC1>[C:3]([CH:2]([CH:5]1[CH2:6][CH2:7][N:8]([O:11][CH3:12])[CH2:9][CH2:10]1)[NH:1][C:30](=[O:31])[CH2:29][C:22]1[C:21]([CH3:20])=[CH:26][C:25]([CH3:27])=[CH:24][C:23]=1[CH3:28])#[N:4]
Reactant: CON1CCC(C(N)C#N)CC1
Reactant: Cc1cc(C)c(CC(=O)Cl)c(C)c1
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CON1CCC(C(C#N)NC(=O)Cc2c(C)cc(C)cc2C)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred mixture of amino-(1-methoxy-piperidin-4-yl)-acetonitrile (500 mg, 2.95 mmol) and Et3N (610 mg, 6.02 mmol) in THF (15 ml), was added (2,4,6-trimethyl-phenyl)-acetyl chloride (581 mg, 2.95 mmol). After the addition, the mixture was stirred at room temperature for 0.5 h. Then, the mixture was poured into water (100 ml) and extracted with CH2Cl2 (3×50 ml). The combined organic layers were dried over Na2SO4, filtered and evaporated under vacuum. The residue was purified by chromatography on silica gel. Yield: 700 mg of N-[cyano-(1-methoxy-piperidin-4-yl)-methyl]-2-(2,4,6-trimethyl-phenyl)-acetamide as a solid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:5]=1[S:14](Cl)(=[O:16])=[O:15])([O-:3])=[O:2].[CH3:18][N:19]([CH3:25])[CH2:20][CH2:21][CH2:22][NH:23][CH3:24]>C(Cl)Cl>[CH3:18][N:19]([CH3:25])[CH2:20][CH2:21][CH2:22][N:23]([CH3:24])[S:14]([C:5]1[CH:6]=[CH:7][C:8]([C:10]([F:13])([F:12])[F:11])=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2])(=[O:16])=[O:15]
Reactant: CNCCCN(C)C
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1S(=O)(=O)Cl
Solvent: ClCCl
Product: CN(C)CCCN(C)S(=O)(=O)c1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 2-nitro-4-(trifluoromethyl)benzene-1-sulfonyl chloride (500 mg, 1.73 mmol) in CH2Cl2 (5 ml) was added N1,N1,N3-trimethylpropane-1,3-diamine (0.26 ml, 1.8 mmol). The resulting mixture was allowed to stir at room temperature for 20 min. Diluted with CH2Cl2 (30 ml) and washed the organic layer with 9% aq. Na2CO3 (10 ml) and brine (10 ml). Dried over anhydrous sodium sulfate, filtered and concentrated to a white solid, which was used without further purification. MS m/z=370.1 [M+H]+. Calc'd for C13H18F3N3O4S: 369.4.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:11])[C:5](=[CH:9][CH:10]=1)[C:6]([OH:8])=[O:7].[OH-].[Na+].C([O-])([O-])=O.[Na+].[Na+].Cl[C:21]1[C:26](CC=O)=[C:25]([CH3:30])[CH:24]=[CH:23][C:22]=1[S:31]([O-:34])(=[O:33])=[O:32].C1C[O:38][CH2:37][CH2:36]1>O.C(OCC)C>[OH:11][C:4]1[CH:3]=[C:2]([NH:1][C:37](=[O:38])[CH2:36][O:34][S:31]([C:22]2[CH:21]=[CH:26][C:25]([CH3:30])=[CH:24][CH:23]=2)(=[O:32])=[O:33])[CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7]
Reactant: Nc1ccc(C(=O)O)c(O)c1
Reactant: Cc1ccc(S(=O)(=O)[O-])c(Cl)c1CC=O
Reactant: C1CCOC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Product: Cc1ccc(S(=O)(=O)OCC(=O)Nc2ccc(C(=O)O)c(O)c2)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of p-amino salicylic acid (102 mg, 0.67 mmol) and NaOH (27 mg, 0.67 mmol) in water (6 ml) was stirred at room temperature for 10 min until all of the solid material had dissolved. Na2CO3 (59 mg, 0.5561 mmol) was then added and the mixture cooled to 0° C. A solution of 2-chloro-2-oxoethyl-4-methylbenzenesulfonate (4, 200 mg, 0.8044 mmol) in THF (2 ml) was injected rapidly and the resulting solution allowed to warm to room temperature and stirred for 2 h. Then reaction mixture was poured into a separating funnel containing diethyl ether. The phases were separated and the aqueous phase washed with a further portion of diethyl ether. The aqueous phase was acidified to pH 1 by addition of 1N HCl solution and the product extracted into ethyl acetate. The ethyl acetate was washed twice with 1N HCl solution and the organic phase was dried (Na2SO4), filtered and the solvent removed in vacuo. The resulting pale yellow solid was triturated with chloroform leaving 1 as a white powder (155 mg, 63%). δH (400 MHz, DMSO) 2.37 (3H, s, Me), 4.68 (2H, s, CH2), 6.93 (1H, d, J=7.4 Hz, ArH), 7.17 (1H, s, ArH), 7.46 (2H, d, J=6.8 Hz, ArH), 7.69 (1H, d, J=7.4 Hz, ArH), 7.81 (2H, d, J=6.8 Hz, ArH), 10.32 (1H, s, NH); δc (100.6 MHz, DMSO) 21.8, 68.0, 107.0, 110.7, 128.5, 130.9, 131.7, 132.7, 144.5, 146.0, 162.8, 164.5, 172.2; MS (ES+) 366.0 (100%, [M+H]+), 388.0 (50%, [M+Na]+); (ion not detected in ES−).
Reaction SMILES: [O:1]=[C:2]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:3][NH:4][C:5](=[O:7])[CH3:6].[C:14]([O-])(O)=[O:15].[Na+].C=O.[Na+].[Cl-]>CCO>[OH:15][CH2:14][CH:3]([NH:4][C:5](=[O:7])[CH3:6])[C:2](=[O:1])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC(=O)NCC(=O)c1ccccc1
Reactant: O=C([O-])O
Agent: C=O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Product: CC(=O)NC(CO)C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 144.8 %

Procedure:
N-(1-oxo-1-phenylethan-2-yl)acetamide (10) (1.1 g, 6.0 mmol, 1.0 equiv.) was added to a 100 mL RBF followed by EtOH (25 mL, 200 proof). Next, a 0.5 M solution of NaHCO3 (250 mg, 3.0 mmol, 0.5 equiv.) was added followed by a 37% solution of formaldehyde (730 μL, 9.0 mmol, 1.5 equiv.). The solution was stirred at rt. for 24 h and transferred to a separatory funnel with a 1.0 M solution of NaCl (2.9 g, 50.0 mmol). The solution was extracted with CH2Cl2 (5×60 mL). The organic layer was dried over Na2SO4, concentrated on a rotary evaporator, and dried under vacuum to give a crude off-white solid. The solid was washed with EtOAc (10 mL) to remove all impurities. The remaining solid was dried under vacuum to give 900 mg (72%) of 11 as a white solid. Rf=0.11 (5% MeOH/CH2Cl2); mp=115-117° C.; IR (KBr) 3312, 3262, 2915, 1696, 1639, 1537, 1228, 1101 cm−1; 1H NMR (500 MHz, CDCl3) δ 8.00 (d, J=7.0 Hz, 2H, Ph-H), 7.61 (t, J=7.0 Hz, 1H, Ph-H), 7.48 (t, J=7.0 Hz, 2H, Ph-H), 7.17 (d, J=7.0 Hz, 1H, Ac—NH), 5.63 (m, 1H, Ac—NH—CH), 4.01 (m, 1H, CH—CH2), 3.88 (m, 1H, CH—CH2), 2.06 (s, 3H, NH—COCH3); 13C NMR (125 MHz, CDCl3) δ 197.0, 171.2, 134.3, 129.1, 128.9, 64.4, 57.3, 23.2; LRMS (ESI-MS m/z): Mass calcd for C11H13NNaO3 [M+Na]+, 230.22 Found 208. Anal. calcd for C11H13NO3: C, 63.76; H, 6.32; N, 6.76 Found: C, 63.92; H, 6.34; N, 6.74. Spectroscopic data were consistent with the literature data for this compound.
Reaction SMILES: [CH3:1][C:2]1[C:7]2[N:8]=[C:9]([NH2:11])[S:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.Cl.[NH2:13]N.O.NN.C(O)CO>O>[CH3:1][C:2]1[C:7]2[N:8]=[C:9]([NH:11][NH2:13])[S:10][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: NN
Reactant: Cc1cccc2sc(N)nc12
Agent: Cl
Solvent: O
Solvent: OCCO
Product: Cc1cccc2sc(NN)nc12
Temperature: 140 °C
Reaction time: 15 h
Yield: 89 %

Procedure:
4-Methyl-2-aminobenzothiazole (8.21 g.; 0.05 mole), hydrazine monohydrochloride (1.14 g.; 0.017 mole), 85% hydrazine hydrate (1.96 g.; 0.033 mole), and 41 ml. of ethylene glycol were mixed, and the mixture heated under N2 atmosphere to 140°C. These reaction conditions were continued for 15 hours; the reaction mixture was then permitted to cool slowly to romm temperature and, for convenience only, stored overnight under N2 atmosphere. Water (45 ml.) was added to the reaction mixture in the morning to force crystallization. The reaction mixture was then filtered to separate the desired 4-methyl-2-hydrazinobenzothiazole compound. It was dried in vacuo overnight at 60°C. The yield was 8.00 g., 89% yield, m.p. 143°-51°C. Non-aqueous titration showed the product to be 85.8% pure.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.C(O)C.[CH3:26][C:27]1[CH:28]=[C:29]([C:33]([N:35]=[C:36]=[S:37])=[O:34])[CH:30]=[CH:31][CH:32]=1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:36]([NH:35][C:33](=[O:34])[C:29]2[CH:30]=[CH:31][CH:32]=[C:27]([CH3:26])[CH:28]=2)=[S:37])=[CH:18][CH:17]=1
Reactant: Cc1cccc(C(=O)N=C=S)c1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4cccc(C)c4)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 96 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. Commercially available 3-methyl-1-benzenecarbonyl isothiocyanate (50 μl) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (77 mg, yield 96%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1)[CH2:5]N.C([N:17](C(C)C)CC)(C)C.[CH:23]([C:26]1([C:32](Cl)=[O:33])[CH2:30][CH2:29][C:28](=[O:31])[CH2:27]1)([CH3:25])[CH3:24]>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1)[CH2:5][C:26]([CH:23]([CH3:25])[CH3:24])([C:32]([NH2:17])=[O:33])[CH2:27][C:28](=[O:31])[CH2:29][CH3:30]
Reactant: NCc1cc(F)cc(C(F)(F)F)c1
Reactant: CC(C)C1(C(=O)Cl)CCC(=O)C1
Reactant: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCC(=O)CC(Cc1cc(F)cc(C(F)(F)F)c1)(C(N)=O)C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.2 %

Procedure:
A solution of 3-fluoro-5-trifluoromethylbenzylamine (3.07 g, 15.9 mmol) and diisopropylethylamine (2.77 mL, 15.9 mmol) in dichloromethane (60 mL) was slowly treated with 1-isopropyl-3-oxocyclopentanoyl chloride (3.0 g, 15.9 mmol) and stirred at ambient temperature overnight. The mixture was diluted with dichloromethane washed with a saturated solution of sodium bicarbonate, 2N HCl, water and brine. The organic phase was dried with anhydrous magnesium sulfate and the solvent was evaporated in vacuo to yield 6.0 g of crude product. This was further purified by column chromatography (silica gel, ethyl acetate hexane (40:60%) to yield 4.10 g (85%) of the pure product. 1H NMR (500 MHz, CDCl3): 7.32 (s, 1H), 7.23 (d, J=8.23 Hz, 1H), 7.19 (d, J=8.93 Hz, 1H), 4.52 (m, 2H), 2.79 (d, J=18.53 Hz, 1H), 2.40 to 2.18 (bm, 4H), 2.0 (m, 2H), 0.98 (d, J=6.63 Hz, 3H), 0.96 (d, 6.60 Hz, 3H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH2:14][O:15][C:16](=[O:23])[NH:17][CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)=[CH:4][CH:3]=1.[CH2:24]([O:26][C:27]([C:29]1([C:32]2[CH:37]=[CH:36][C:35](B3OC(C)(C)C(C)(C)O3)=[CH:34][CH:33]=2)[CH2:31][CH2:30]1)=[O:28])[CH3:25]>>[CH2:24]([O:26][C:27]([C:29]1([C:32]2[CH:37]=[CH:36][C:35]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[CH2:14][O:15][C:16](=[O:23])[NH:17][CH:18]4[CH2:22][CH2:21][CH2:20][CH2:19]4)=[CH:4][CH:3]=3)=[CH:34][CH:33]=2)[CH2:30][CH2:31]1)=[O:28])[CH3:25]
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1COC(=O)NC1CCCC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4COC(=O)NC4CCCC4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 3, Step 5, using cyclopentyl-carbamic acid 5-(4-bromo-phenyl)-3-methyl-isoxazol-4-ylmethyl ester and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: CS(Cl)(=O)=O.C(N(CC)CC)C.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([N:23]2[C:27]3[CH2:28][CH:29]4[N:34]([S:35]([C:38]5[CH:43]=[CH:42][C:41]([Cl:44])=[CH:40][CH:39]=5)(=[O:37])=[O:36])[CH:33]([C:26]=3[CH:25]=[N:24]2)[CH2:32][CH:31]([CH:45]=[N:46]O)[CH2:30]4)(=[O:22])=[O:21])=[CH:16][CH:15]=1.[Cl:48][C:49]1[CH:54]=[CH:53][C:52]([S:55]([N:58]2[CH2:62][C:61]3[CH:63]4[N:69]([S:70]([C:73]5[CH:78]=[CH:77][C:76]([Cl:79])=[CH:75][CH:74]=5)(=[O:72])=[O:71])[CH:67]([CH2:68][C:60]=3[NH:59]2)[CH2:66][CH:65]([CH:80]=[N:81]O)[CH2:64]4)(=[O:57])=[O:56])=[CH:51][CH:50]=1>C(Cl)Cl>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([S:20]([N:23]2[C:27]3[CH2:28][CH:29]4[N:34]([S:35]([C:38]5[CH:39]=[CH:40][C:41]([Cl:44])=[CH:42][CH:43]=5)(=[O:37])=[O:36])[CH:33]([C:26]=3[CH:25]=[N:24]2)[CH2:32][CH:31]([C:45]#[N:46])[CH2:30]4)(=[O:22])=[O:21])=[CH:18][CH:19]=1.[Cl:48][C:49]1[CH:50]=[CH:51][C:52]([S:55]([N:58]2[CH:62]=[C:61]3[CH:63]4[N:69]([S:70]([C:73]5[CH:74]=[CH:75][C:76]([Cl:79])=[CH:77][CH:78]=5)(=[O:72])=[O:71])[CH:67]([CH2:68][C:60]3=[N:59]2)[CH2:66][CH:65]([C:80]#[N:81])[CH2:64]4)(=[O:57])=[O:56])=[CH:53][CH:54]=1
Reactant: O=S(=O)(c1ccc(Cl)cc1)N1C2Cc3c(cnn3S(=O)(=O)c3ccc(Cl)cc3)C1CC(C=NO)C2
Reactant: O=S(=O)(c1ccc(Cl)cc1)N1CC2=C(CC3CC(C=NO)CC2N3S(=O)(=O)c2ccc(Cl)cc2)N1
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: N#CC1CC2Cc3c(cnn3S(=O)(=O)c3ccc(Cl)cc3)C(C1)N2S(=O)(=O)c1ccc(Cl)cc1
Product: N#CC1CC2Cc3nn(S(=O)(=O)c4ccc(Cl)cc4)cc3C(C1)N2S(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Methanesulfonyl chloride (30 μL, 0.390 mmol) and triethylamine (162 μL, 1.17 mmol) were added to a solution of 1-{1,10-bis[(4-chlorophenyl)sulfonyl]-4,5,6,7,8,9-hexahydro-1H-4,8-epiminocycloocta[c]pyrazol-6-yl}-N-hydroxymethanimine and 1-{2,10-bis[(4-chlorophenyl)sulfonyl]-4,5,6,7,8,9-hexahydro-1H-4,8-epiminocycloocta[c]pyrazol-6-yl}-N-hydroxymethanimine (60) (73 mg, 0.130 mmol) in CH2Cl2 (1 mL) and the resulting solution was stirred at room temperature for 0.5 h. The reaction mixture was diluted with CH2Cl2 and washed with saturated aqueous NaHCO3. The organic phase was dried (Na2SO4), filtered, and concentrated to give 1,10-bis[(4-chlorophenyl)sulfonyl]-4,5,6,7,8,9-hexahydro-1H-4,8-epiminocycloocta[c]pyrazole-6-carbonitrile and 2,10-bis[(4-chlorophenyl)sulfonyl]-4,5,6,7,8,9-hexahydro-2H-4,8-epiminocycloocta[c]pyrazole-6-carbonitrile (61). MS (ESI) 537.0 (M+H).
Reaction SMILES: C(N(CC)CC)C.Br[C:9]1[N:14]=[C:13]([O:15][CH3:16])[C:12]([N:17]2[CH:21]=[C:20]([CH3:22])[N:19]=[CH:18]2)=[CH:11][CH:10]=1.[C:23]([NH2:27])(=[O:26])[CH:24]=[CH2:25]>CN(C)C=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>[CH3:16][O:15][C:13]1[N:14]=[C:9](/[CH:25]=[CH:24]/[C:23]([NH2:27])=[O:26])[CH:10]=[CH:11][C:12]=1[N:17]1[CH:21]=[C:20]([CH3:22])[N:19]=[CH:18]1
Reactant: COc1nc(Br)ccc1-n1cnc(C)c1
Reactant: C=CC(N)=O
Agent: [Pd]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1nc(/C=C/C(N)=O)ccc1-n1cnc(C)c1
Temperature: 100 °C
Reaction time: 0.83 h
Yield: 89.5 %

Procedure:
Triethylamine (52 ml) was added to a suspension of 6-bromo-2-methoxy-3-(4-methyl-1H-imidazol-1-yl)pyridine (49.8 g), tris(dibenzylideneacetone)dipalladium (0) (5.11 g), tri-o-tolylphosphine (3.41 g) and acrylamide (14.5 g) in N,N-dimethyl formamide (260 ml). The reaction solution was stirred at 100° C. for 50 minutes. The reaction solution was returned to room temperature and then filtered through celite. The filter cake was sequentially washed with N,N-dimethylformamide, methanol, a 50% N,N-dimethylformamide solution and N,N-dimethylformamide. The resulting filtrate was filtered through celite again, and the filtrate was concentrated under reduced pressure. Toluene was added to the residue, and the reaction solution was concentrated again. Toluene and a saturated sodium bicarbonate solution were added to the resulting residue, and the insoluble matter was collected by filtration. The resulting powder was dried under reduced pressure to obtain 42.96 g of the title compound. The property values of the compound are as follows.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)[C:3]=1[CH2:22][C:23]([O:25][CH3:26])=[O:24].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.C1COCC1.Br[CH2:43][CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1>CN(C=O)C>[CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:15]2[CH:16]=[CH:17][C:18]([CH3:21])=[CH:19][CH:20]=2)[C:3]=1[CH:22]([CH2:43][CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[C:23]([O:25][CH3:26])=[O:24]
Reactant: COC(=O)Cc1c(C)nc2sc3c(c2c1-c1ccc(C)cc1)CCCC3
Reactant: BrCCc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COC(=O)C(CCc1ccccc1)c1c(C)nc2sc3c(c2c1-c1ccc(C)cc1)CCCC3
Yield: 54.5 %

Procedure:
This compound was prepared according to the procedure C from methyl [2-methyl-4-(p-tolyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]acetate (0.183 g; 0.5 mmol), LHMDS 1N in THF (0.75 mL; 0.75 mmol), (2-bromoethyl)benzene (0.136 mL; 1 mmol) in DMF (2.5 mL) for 18 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (3-30%) in heptane furnished 0.128 g (55%) of the title compound as a yellow oil.