Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][CH2:11][NH:10]2)=[CH:5][CH:4]=1.CCN(C(C)C)C(C)C.Cl[C:31]([O:33][C:34]1[CH:39]=[CH:38][C:37]([N+:40]([O-:42])=[O:41])=[CH:36][CH:35]=1)=[O:32].O>C(Cl)Cl>[F:20][C:2]([F:1])([F:19])[C:3]1[CH:4]=[CH:5][C:6]([C@@H:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][CH2:11][N:10]2[C:31]([O:33][C:34]2[CH:35]=[CH:36][C:37]([N+:40]([O-:42])=[O:41])=[CH:38][CH:39]=2)=[O:32])=[CH:7][CH:8]=1
Reactant: FC(F)(F)c1ccc([C@H]2NCCc3ccccc32)cc1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=C(Oc1ccc([N+](=O)[O-])cc1)N1CCc2ccccc2[C@H]1c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (R)-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline (1550 mg, 5590 μmol) and diea (1071 μL, 6149 μmol) in DCM (36 mL) at 0° C. was added 4-nitrophenyl chloroformate (1465 mg, 7267 μmol, Aldrich). After addition, the reaction mixture was stirred at RT for overnight. Then, H2O (60 mL) was added and the mixture was stirred at RT for 15 min. The organic layer was collected and the aqueous was extracted with DCM (1×50 mL). The combined organic extracts were dried over MgSO4 and concentrated. The residue was then mixed with silica gel (4:1, residue: silica gel) and the solid mixture was purified by silica gel flash column chromatography using ISCO instrument (solid loading, 0%-100% EtOAc/hexane) to give the compound as an off-white solid. MS (ESI, positive ion) m/z: 443 (M+H).
Reaction SMILES: C([O:3][C:4](=[O:34])[CH:5]([O:31][CH2:32][CH3:33])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]2[N:16]=[C:17]([C:20]3[CH:25]=[CH:24][C:23]([C:26]([CH3:29])([CH3:28])[CH3:27])=[CH:22][CH:21]=3)[S:18][CH:19]=2)=[C:9]([CH3:30])[CH:8]=1)C.[OH-].[Li+].Cl.S([O-])(O)(=O)=O.[K+]>CO>[C:26]([C:23]1[CH:22]=[CH:21][C:20]([C:17]2[S:18][CH:19]=[C:15]([CH2:14][O:13][C:10]3[CH:11]=[CH:12][C:7]([CH2:6][CH:5]([O:31][CH2:32][CH3:33])[C:4]([OH:34])=[O:3])=[CH:8][C:9]=3[CH3:30])[N:16]=2)=[CH:25][CH:24]=1)([CH3:29])([CH3:28])[CH3:27]
Reactant: CCOC(=O)C(Cc1ccc(OCc2csc(-c3ccc(C(C)(C)C)cc3)n2)c(C)c1)OCC
Agent: Cl
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: CO
Product: CCOC(Cc1ccc(OCc2csc(-c3ccc(C(C)(C)C)cc3)n2)c(C)c1)C(=O)O
Temperature: 55 °C
Reaction time: 1 h
Yield: 98.8 %

Procedure:
140 mg of [rac]-3-{4-[2-(4-tert-butyl-phenyl)-thiazol-4-ylmethoxy]-3-methyl-phenyl}-2-ethoxy-propionic acid ethyl ester (0.29 mmol) were dissolved in 5 ml of methanol; 1 ml of a 2N aqueous lithium hydroxide solution was added and the reaction mixture was stirred at 55° C. for 1 h. After cooling to room temperature, 1 ml of a 2N aqueous hydrochloric acid solution and 0.5 ml of a saturated solution of potassium hydrogen sulfate were added. The reaction mixture was then extracted with two 10 ml portions of dichloromethane. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate and evaporated, leaving 130 mg (98.6% of theory) of [rac]-3-{4-[2-(4-tert-butyl-phenyl)-thiazol-4-ylmethoxy]-3-methyl-phenyl}-2-ethoxy-propionic acid as a colorless solid.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[C:5]([C:8](O)=[O:9])[N:4]=[CH:3]1.[OH-].[K+].C=O>>[CH3:1][N:2]1[C:6]([CH3:7])=[C:5]([CH2:8][OH:9])[N:4]=[CH:3]1
Reactant: Cc1c(C(=O)O)ncn1C
Agent: C=O
Agent: [K+]
Agent: [OH-]
Product: Cc1c(CO)ncn1C
Yield: 69.8 %

Procedure:
A mixture of 1,5-dimethylimidazole-4-carboxylic acid (1.4 g, 0.01 mol), potassium hydroxide (1.12 g, 0.02 mol) and ~37% aqueous formaldehyde solution (3 ml) was heated at 80°-90° C. for 3 hours. After completion of the reaction, the solvent was stripped off in vacuo, and the residue was extracted with isopropanol (40 ml). The isopropanol extract was concentrated to give a crude product. The crude solid was recrystallized from acetone and filtered to afford 0.88 g of 1,5-dimethyl-4-hydroxymethylimidazole as a white crystal, m.p. 161°-163° C. Yield 70%.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@@H:19]([CH:23]([CH3:25])[CH3:24])[C:20]([OH:22])=O)=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)C(Cl)=O.[NH2:32][C:33]1[CH:40]=[CH:39][C:36]([C:37]#[N:38])=[CH:35][C:34]=1[F:41].N1C=CC=CC=1>CN(C)C=O.ClCCl.CN(C)C1C=CN=CC=1>[CH:10]1[C:11]2[CH:12]([CH2:14][O:15][C:16](=[O:17])[NH:18][C@H:19]([C:20](=[O:22])[NH:32][C:33]3[CH:40]=[CH:39][C:36]([C:37]#[N:38])=[CH:35][C:34]=3[F:41])[CH:23]([CH3:24])[CH3:25])[C:13]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[C:6]=2[CH:7]=[CH:8][CH:9]=1
Reactant: N#Cc1ccc(N)c(F)c1
Reactant: CC(C)[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Agent: CN(C)c1ccncc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CC(C)[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)Nc1ccc(C#N)cc1F
Temperature: 0 °C
Reaction time: 2 h
Yield: 0.1 %

Procedure:
To a solution of (S)-2-(9H-fluoren-9-ylmethoxycarbonylamino)-3-methyl-butyric acid (2.5 g, 7.37 mmol) and a few drops of N,N-dimethylformamide in dichloromethane (20 mL) was slowly added oxalyl chloride (1.3 mL, 14.74 mmol) at 0° C. under an atmosphere of dry nitrogen. The mixture was stirred for 15 minutes at 0° C. and 2 hours at room temperature. After removal of the solvent, the residue was dissolved in dichloromethane (20 mL) and to the resulting solution was added 4-amino-3-fluoro-benzonitrile (840 mg, 6.14 mmol), 4-dimethylaminopyridine (150 mg, 1.2 mmol) and pyridine (0.78 mL, 9.21 mmol) at 0° C. The mixture was stirred for 2 hrs at 0° C. and overnight at room temperature. The reaction was quenched with 1 M aqueous citric acid solution and then extracted with dichloromethane (three times). The combined organic extracts were washed with 1 M aqueous citric acid solution, brine, saturated aqueous sodium carbonate, brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by chromatography over silica gel gradient eluted from 100% dichloromethane up to 10% methanol/90% dichloromethane over 30 minutes. Concentration of the product containing fractions gave [(S)-1-(4-cyano-2-fluoro-phenylcarbamoyl)-2-methyl-propyl]-carbamic acid 9H-fluoren-9-ylmethyl ester as a white solid (2.15 mg, 77%).
Reaction SMILES: [CH:1]([O:3][CH2:4][CH2:5][CH2:6][CH3:7])=[CH2:2].[Cl:8][C:9]1[N:14]=[C:13](Cl)[C:12]([CH3:16])=[CH:11][N:10]=1.C(N(CC)CC)C>C(O[Pd]OC(=O)C)(=O)C>[CH2:4]([O:3]/[CH:1]=[CH:2]/[C:13]1[C:12]([CH3:16])=[CH:11][N:10]=[C:9]([Cl:8])[N:14]=1)[CH2:5][CH2:6][CH3:7]
Reactant: Cc1cnc(Cl)nc1Cl
Reactant: C=COCCCC
Agent: CC(=O)O[Pd]OC(C)=O
Solvent: CCN(CC)CC
Product: CCCCO/C=C/c1nc(Cl)ncc1C
Temperature: 80 °C
Reaction time: 18 h
Yield: 124 %

Procedure:
Diacetoxypalladium (0.482 g, 2.15 mmol) was added in one portion to a mixture of 1-(vinyloxy)butane (11.91 mL, 92.02 mmol), 2,4-dichloro-5-methylpyrimidine (5 g, 30.67 mmol) and triethylamine (4.51 mL, 32.21 mmol) in degassed polyethylene glycol 200 (25 mL) under N2. The resulting mixture was stirred at 80° C. for 18 h. The mixture was then cooled and extracted with diethyl ether (3×75 mL). The combined organic solutions were dried (MgSO4), diluted with heptane (115 mL) and filtered through a 75 g silica plug, eluting with 2:1 diethyl ether/heptanes, to give the title compound (8.62 g, 124%) as a yellow oil which was used without further purification; 1H NMR: 0.92 (3H, t), 1.35-1.43 (2H, m), 1.60-1.71 (2H, m), 2.17 (3H, d), 4.06 (2H, t), 5.93 (1H, d), 7.90 (1H, d), 8.33 (1H, d); m/z: ES+ MH+ 226.
Reaction SMILES: C(OC([C@@H]1C[C@H]1CNC(OC(C)(C)C)=O)=O)C.[CH3:18][O:19][C:20]([C@@H:22]1[CH2:25][CH2:24][C@H:23]1[CH:26]([NH:37][C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])S(C1C=CC(C)=CC=1)(=O)=O)=[O:21].[BH4-].[Na+]>>[CH3:18][O:19][C:20]([C@@H:22]1[CH2:25][CH2:24][C@H:23]1[CH2:26][NH:37][C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])=[O:21]
Reactant: COC(=O)[C@@H]1CC[C@H]1C(NC(=O)OC(C)(C)C)S(=O)(=O)c1ccc(C)cc1
Agent: CCOC(=O)[C@@H]1C[C@H]1CNC(=O)OC(C)(C)C
Agent: [BH4-]
Agent: [Na+]
Product: COC(=O)[C@@H]1CC[C@H]1CNC(=O)OC(C)(C)C
Yield: 73.4 %

Procedure:
According to the synthesis of Trans-2-(tert-Butoxycarbonylamino-methyl)-cyclopropanecarboxylic acid ethyl ester (intermediate L, example 43), the title compound was prepared from Trans-2-[tert-Butoxycarbonylamino-(toluene-4-sulfonyl)-methyl]-cyclobutanecarboxylic acid methyl ester (17.7 g, 44.53 mmol), sodium borohydride (3.3 g, 83.74 mmol) and 8.2 g, (33.7 mmol, 73.4% yield) was obtained. MS (m/e): 244.0 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1Br)([CH3:4])([CH3:3])[CH3:2].[CH2:18]([S:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1)[CH3:19].[F-].[Cs+]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:17])=[C:10]([C:24]2[CH:25]=[CH:26][C:21]([S:20][CH2:18][CH3:19])=[CH:22][CH:23]=2)[CH:11]=1
Reactant: CC(C)(C)OC(=O)COc1ccc(Cl)cc1Br
Reactant: CCSc1ccc(B(O)O)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CCSc1ccc(-c2cc(Cl)ccc2OCC(=O)OC(C)(C)C)cc1

Procedure:
A mixture of the product from step (i) (2 g), 4-(ethylthio)phenylboronic acid (1.5 g), cesium fluoride (2 g) and Pd(dppf)Cl2 (0.2 g) in dioxane (40 ml) was heated under reflux for 3 h. After cooling the mixture was partitioned between diethylether and water. The organics were separated, dried and evaporated under reduced pressure. The residue was purified by chromatography on silica eluting with 5% EtOAc/iso-hexane. Yield 0.92 g
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([N:28]1[C:33](=[O:34])[CH:32]=[CH:31][NH:30][C:29]1=[O:35])(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[C:36]([O:55][CH2:56][CH:57]=[CH:58][CH2:59]O)([C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1.CCCCCC.CCOC(C)=O>[C:20]([N:28]1[C:33](=[O:34])[CH:32]=[CH:31][N:30]([CH2:59]/[CH:58]=[CH:57]\[CH2:56][O:55][C:36]([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[C:29]1=[O:35])(=[O:27])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: OCC=CCOC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C(c1ccccc1)n1c(=O)cc[nH]c1=O
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: O=C(c1ccccc1)n1c(=O)ccn(C/C=C\COC(c2ccccc2)(c2ccccc2)c2ccccc2)c1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 28.6 %

Procedure:
Polymer bound triphenylphosphine (0.75 g; 2.25 mmol) was shaken in THF (5 ml) for 15 minutes, then 3-benzoyluracil (290 mg, 1.35 mmol) and tritylated alcohol (1) (300 mg; 0.90 mmol) were added to the suspension of the resin. A solution of DIAD (0.354 ml, 1.80 mmol) in THF (2 ml) was added to the mixture. The reaction was shaken 24 hours at room temperature and monitored by TLC (Hexane/EtOAc 50:50). The resin was filtered and washed twice with THF (5 ml). The filtrate was concentrated under reduced pressure and taken in EtOAc (5 ml), a white solid precipitated. The precipitate was filtered, the filtrate was concentrated again and purified by flash chromatography using Hexane/EtOAc as eluent which gave the title compound as a colourless oil (136 mg, 29%).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]2[S:12][C:11]([NH:13][C:14](=[O:23])[C:15]3[C:20]([F:21])=[CH:19][CH:18]=[CH:17][C:16]=3[F:22])=[N:10][C:9]=2[CH3:24])[CH:5]=[CH:4][N:3]=1.[CH3:25][N:26](C=O)C>[C-]#N.[C-]#N.[Zn+2].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:25]([C:2]1[CH:7]=[C:6]([C:8]2[S:12][C:11]([NH:13][C:14](=[O:23])[C:15]3[C:20]([F:21])=[CH:19][CH:18]=[CH:17][C:16]=3[F:22])=[N:10][C:9]=2[CH3:24])[CH:5]=[CH:4][N:3]=1)#[N:26]
Reactant: Cc1nc(NC(=O)c2c(F)cccc2F)sc1-c1ccnc(Br)c1
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: Cc1nc(NC(=O)c2c(F)cccc2F)sc1-c1ccnc(C#N)c1
Temperature: 110 °C

Procedure:
A solution of N-[5-(2-Bromo-pyridin-4-yl)-4-methyl-thiazol-2-yl]-2,6-difluoro-benzamide (100 mg, 0.24 mmol), Zn(CN)2 (43.0 mg, 0.36 mmol), and Pd(PPh3)4 (20.0 mg, 0.02 mmol) in DMF (4.0 mL) was degassed by purging with a stream of nitrogen for 10 minutes. The mixture was heated to 110° C. overnight, cooled to room temperature, diluted with CH2Cl2, washed with water, dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified on silica gel to give the title compound (45 mg).
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH3:11])=[C:6]([N+:12]([O-])=O)[CH:5]=1>[Pd]>[NH2:12][C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][C:7]=1[NH:10][CH3:11])[C:3]([NH:2][CH3:1])=[O:15]
Reactant: CNC(=O)c1ccc(NC)c([N+](=O)[O-])c1
Agent: [Pd]
Product: CNC(=O)c1ccc(NC)c(N)c1
Yield: 100.4 %

Procedure:
3-Amino-N-methyl-4-methylamino-benzamide (460 mg) was prepared by following General Procedure B starting from N-methyl-4-methylamino-3-nitro-benzamide (535 mg) and Pd/C (10% by weight, 54 mg). The crude product was used in the next step without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([OH:15])[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]2)=[N:6][CH:7]=1.[NH:16]1[CH2:19][CH:18]([NH:20][C:21]([CH2:23][NH:24][C:25](=[O:36])[C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=2)=[O:22])[CH2:17]1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([OH:15])[CH2:13][CH2:12][CH:11]([N:16]3[CH2:19][CH:18]([NH:20][C:21]([CH2:23][NH:24][C:25](=[O:36])[C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:33])[F:34])[CH:27]=4)=[O:22])[CH2:17]3)[CH2:10][CH2:9]2)=[N:6][CH:7]=1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Reactant: O=C1CCC(O)(c2ccc(Br)cn2)CC1
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CN(C2CCC(O)(c3ccc(Br)cn3)CC2)C1

Procedure:
The title compounds were prepared as white solids from reductive amination of 4-(5-bromo-pyridin-2-yl)-4-hydroxy-cyclohexanone, as prepared in the previous step, and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide using the procedure described in Step E of Example 1.
Reaction SMILES: FC(F)(F)S(O[CH2:7][CH2:8][CH2:9][C:10]([F:16])([F:15])[C:11]([F:14])([F:13])[F:12])(=O)=O.[F:19][C:20]([F:29])([F:28])[CH2:21][CH2:22][CH:23]([C:26]#[N:27])[C:24]#[N:25].C(=O)([O-])[O-].[K+].[K+].Cl>COCCOC>[F:16][C:10]([F:15])([C:11]([F:12])([F:13])[F:14])[CH2:9][CH2:8][CH2:7][C:23]([CH2:22][CH2:21][C:20]([F:19])([F:28])[F:29])([C:24]#[N:25])[C:26]#[N:27]
Reactant: O=S(=O)(OCCCC(F)(F)C(F)(F)F)C(F)(F)F
Reactant: N#CC(C#N)CCC(F)(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: N#CC(C#N)(CCCC(F)(F)C(F)(F)F)CCC(F)(F)F
Temperature: 25 °C
Reaction time: 5 h
Yield: 20.4 %

Procedure:
To 10 ml of ethylene glycol dimethyl ether, 6.2 g of 4,4,5,5,5-pentafluoropentyl trifluoromethanesulfonate, 1.6 g of 2-(3,3,3-trifluoropropyl)malononitrile and 1.4 g of potassium carbonate were added and the mixture was stirred at room temperature for 5 hours. Thereafter, dilute hydrochloric acid was added to the reaction mixture and the mixture was extracted with t-butyl methyl ether. The organic layer was washed successively with water, aqueous saturated sodium hydrogen carbonate and aqueous saturated sodium chloride, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.65 g of 2-(4,4,5,5,5-pentafluoropentyl)-2-(3,3,3-trifluoropropyl)malononitrile (hereinafter, referred to as the present compound (89)).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([Cl:9])[CH:3]=1.ClCCl.[CH3:13][N:14](C)C=O>C(OCC)(=O)C.[C-]#N.[Zn+2].[C-]#N.Cl[Pd]Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[Cl:9][C:4]1[CH:3]=[C:2]([CH:7]=[C:6]([F:8])[CH:5]=1)[C:13]#[N:14]
Reactant: CN(C)C=O
Reactant: Fc1cc(Cl)cc(Br)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [C-]#N
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: N#Cc1cc(F)cc(Cl)c1
Yield: 85 %

Procedure:
A mixture of 1-bromo-3-chloro-5-fluorobenzene (25.0 g, 120 mmol), zinc cyanide (8.45 g, 72 mmol) zinc (dust, 235 mg, 3.6 mmol), [1,1′Bis(diphenylphosphino)ferrocene] dichloropalladium(II), complex with dichloromethane (1:1) (1.5 g, 1.8 mmol) in N,N-dimethylformamide (70 ml) was heated at reflux for 1 hour. After cooling the reaction was diluted with ethyl acetate and extracted with water and brine. Silica gel chromatography afforded 15.9g (85%) 3-chloro-5-fluorobenzonitrile.
Reaction SMILES: FC(F)(F)C1ON=C(C2SC(C(O)=O)=CC=2)C=1C.CN(C[C@H]1CCCNC1)C(=O)OC(C)(C)C.[ClH:35].[CH3:36][NH:37][C@@H:38]1[CH2:43][CH2:42][CH2:41][N:40]([C:44]([C:46]2[S:47][C:48]([C:51]3[C:55]([CH3:56])=[C:54]([C:57]([F:60])([F:59])[F:58])[O:53][N:52]=3)=[CH:49][CH:50]=2)=[O:45])[CH2:39]1>>[ClH:35].[CH3:36][NH:37][C@H:38]1[CH2:43][CH2:42][CH2:41][N:40]([C:44]([C:46]2[S:47][C:48]([C:51]3[C:55]([CH3:56])=[C:54]([C:57]([F:60])([F:59])[F:58])[O:53][N:52]=3)=[CH:49][CH:50]=2)=[O:45])[CH2:39]1
Reactant: CN[C@@H]1CCCN(C(=O)c2ccc(-c3noc(C(F)(F)F)c3C)s2)C1
Agent: CN(C[C@H]1CCCNC1)C(=O)OC(C)(C)C
Agent: Cc1c(-c2ccc(C(=O)O)s2)noc1C(F)(F)F
Agent: Cl
Product: CN[C@H]1CCCN(C(=O)c2ccc(-c3noc(C(F)(F)F)c3C)s2)C1

Procedure:
Prepared from 5-(5-Trifluoromethyl-4-methyl-isoxazol-3-yl)-thiophene-2-carboxylic acid and tert-butyl methyl[(3S)-piperidin-3-ylmethyl]carbamate (Preparative Example 36, presumed quantitative yield, 4.48 mmol) in the same manner as the 3R isomer (Example 93) to afford Boc-protected intermediate as a colorless oil (1.51 g, 71%). LC/MS 7.32 min, [M+1]+ 474. The product was obtained as a colorless free-flowing powder (1.06 g, 81%, some loss of material had occurred on rotary evaporation). LC/MS 4.55 min, [M+1]+ 374.
Reaction SMILES: Cl[CH2:2][C:3]1[S:4][C:5]2[CH:11]=[C:10]([O:12][CH3:13])[C:9]([O:14][CH3:15])=[C:8]([O:16][CH3:17])[C:6]=2[CH:7]=1.[NH:18]1[CH2:24][CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1>>[CH3:17][O:16][C:8]1[C:6]2[CH:7]=[C:3]([CH2:2][N:18]3[CH2:24][CH2:23][CH2:22][N:21]([CH2:2][C:3]4[S:4][C:5]5[CH:11]=[C:10]([O:12][CH3:13])[C:9]([O:14][CH3:15])=[C:8]([O:16][CH3:17])[C:6]=5[CH:7]=4)[CH2:20][CH2:19]3)[S:4][C:5]=2[CH:11]=[C:10]([O:12][CH3:13])[C:9]=1[O:14][CH3:15]
Reactant: C1CNCCNC1
Reactant: COc1cc2sc(CCl)cc2c(OC)c1OC
Product: COc1cc2sc(CN3CCCN(Cc4cc5c(OC)c(OC)c(OC)cc5s4)CC3)cc2c(OC)c1OC

Procedure:
2-Hydroxymethyl-4,5,6-trimethoxbenzothiophene (1.15 g) was treated in the same manner as in Preparation Example 4, and 2-chloromethyl-4,5,6-trimethoxy-benzothiophene thus obtained was immediately reacted with homopiperazine (226 mg) in the same manner as in Example 1 without isolating it to obtain the title compound as a free base.
Reaction SMILES: [N+:1]([C:4]1[N:5]=[C:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[NH:7][CH:8]=1)([O-:3])=[O:2].[C:14](=O)([O-])[O-].[K+].[K+].IC.C1CCCCC1.C(OCC)(=O)C>CC(C)=O>[CH3:14][N:7]1[CH:8]=[C:4]([N+:1]([O-:3])=[O:2])[N:5]=[C:6]1[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CCOC(=O)c1nc([N+](=O)[O-])c[nH]1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1nc([N+](=O)[O-])cn1C
Temperature: 60 °C
Reaction time: 4 h

Procedure:
6.80 g (36.7 mmol) of ethyl 4-nitro-1H-imidazole-2-carboxylate are dissolved in 140 ml of acetone, and 11.2 g (80.8 mmol) of potassium carbonate and 4.57 ml (73.5 mmol) of iodomethane are added. The mixture is then stirred at 60° C. for 4 h. According to TLC (cyclohexane/ethyl acetate 2:1), the starting material has been converted completely. After cooling, the mixture is filtered, the residue is washed with dichloromethane and the filtrate is freed from the solvent. The solid obtained is dried in vacuo.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:13]=[CH:14][C:15]=1[CH3:16])[C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].[Br:17]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:17][CH2:16][C:15]1[CH:14]=[CH:13][C:5]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1cc(C(=O)OC(C)(C)C)ccc1C
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COc1cc(C(=O)OC(C)(C)C)ccc1CBr
Temperature: 25 °C
Yield: 95.3 %

Procedure:
A suspension of t-butyl 3-methoxy-4-methylbenzoate (8.92 g), N-bromosuccinimide (8.57 g), and benzoyl peroxide (0.1 g) in carbon tetrachloride (150 ml) was heated to reflux and irradiated with a sun lamp for 1 hour. After cooling to room temperature, the suspension was filtered; and the filtrate was evaporated. The residue was purified by flash chromatography, eluting with 5:95 ethyl acetate: hexane, to give t-butyl 4-bromomethyl-3-methoxybenzoate (11.52 g, 95%) as a pale yellow oil; NMR (80 MHz, CDCl3): 1.5[s, 9H, C(CH3)3 ], 3.9(s, 3H, OCH3), 4.5(s, 2H, CH2Br), 7.15(d, 1H), 7.4(m, 2H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:13]2[CH2:18][CH2:17][N:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)[CH2:15][CH2:14]2)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-])=O.[H][H]>[Pd].C(O)C>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:13]2[CH2:18][CH2:17][N:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)[CH2:15][CH2:14]2)(=[O:12])=[O:11])=[CH:6][CH:5]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)N2CCN(c3ccccn3)CC2)cc1
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(S(=O)(=O)N2CCN(c3ccccn3)CC2)cc1
Yield: 81.3 %

Procedure:
A mixture of 10.62 g (0.0305 m) of 1-[(p-nitrophenyl)sulfonyl]-4-(2-pyridinyl)piperazine, 1.5 g of 5% palladium on charcoal, and 150 ml of absolute ethanol is shaken under hydrogen on a Parr hydrogenator. After the theoretical amount of hydrogen has been taken up, the catalyst is filtered off and the filtrate is taken to dryness. The product, 1-[(p-aminophenyl)sulfonyl]-4-(2-pyridinyl)piperazine, is crystallized from methanol/methylene chloride to give 7.89 g (81%) of 1-[(p-aminophenyl)sulfonyl]-4-(2-pyridinyl)piperazine of melting point 208°-210° C.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[C:9]([O:13][C:14]([N:16]1[C@@H:20]([C:21]2[CH:26]=[CH:25][C:24]([C:27]#[N:28])=[CH:23][CH:22]=2)[CH2:19][C@H:18]([CH2:29][CH:30]=[CH2:31])[C:17]1=[O:32])=[O:15])([CH3:12])([CH3:11])[CH3:10]>C1COCC1>[C:9]([O:13][C:14]([N:16]1[C@H:20]([C:21]2[CH:22]=[CH:23][C:24]([C:27]#[N:28])=[CH:25][CH:26]=2)[CH2:19][C@H:18]([CH2:29][CH:30]=[CH2:31])[C:17]1=[O:32])=[O:15])([CH3:12])([CH3:11])[CH3:10]
Reactant: C=CC[C@H]1C[C@H](c2ccc(C#N)cc2)N(C(=O)OC(C)(C)C)C1=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C=CC[C@H]1C[C@@H](c2ccc(C#N)cc2)N(C(=O)OC(C)(C)C)C1=O
Temperature: -78 °C
Reaction time: 1 h
Yield: 46.4 %

Procedure:
A solution of freshly prepared lithium diisopropylamide (0.75 mmol) in 5 mL of THF was added dropwise into a solution of trans N-tert-butyloxycarbonyl-5-(4-cyanophenyl)-3-(2-propenyl)-2-pyrrolidinone (223 mg, 0.68 mmol) in 5 mL of THF at −78° C. After stirring at −78° C. for 1 hr, the reaction was quenched by adding 5.0 mL of sat'd NH4Cl solution. The mixture was allowed to warm up to rt, and poured into a mixture of brine (20 mL) and CH2Cl2 (20 mL). The aqueous layer was separated and extracted with CH2Cl2 (3×20 mL). Organic layers were combined, dried over Na2SO4 and concentrated. Chromatography on a Biotage 40+S cartridge using 1:3 v/v EtOAc/hexanes as the eluant gave 103 mg (46%) of the title compound and 120 mg (54%) of starting material: 1H NMR δ 1.24 (s, 9H), 1.50-1.57 (m, 1H), 2.22-2.28 (m, 1H), 2.56-2.77 (m, 3H), 4.94-5.07 (m, 3H), 5.71-5.78 (m, 1H), 7.36 (d, J=8.2, 2H), 7.66 (d, J=8.2, 2H).