Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C:9]1[CH:10]=[CH:11][C:12]([C:17]([F:20])([F:19])[F:18])=[C:13]([CH:16]=1)[C:14]#[N:15].[C:21]([O:24][CH2:25][C:26](Cl)=[O:27])(=[O:23])[CH3:22]>C(Cl)Cl>[C:21]([O:24][CH2:25][C:26]([NH:8][C:9]1[CH:10]=[CH:11][C:12]([C:17]([F:18])([F:19])[F:20])=[C:13]([C:14]#[N:15])[CH:16]=1)=[O:27])(=[O:23])[CH3:22]
Reactant: N#Cc1cc(N)ccc1C(F)(F)F
Reactant: CC(=O)OCC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)OCC(=O)Nc1ccc(C(F)(F)F)c(C#N)c1
Reaction time: 0.25 h
Yield: 71.6 %

Procedure:
Triethylamine (1.09 g, 10.8 mmol) was added to a stirred solution of 5-amino-2-(trifluoromethyl)benzonitrile (Intermediate 37, 1.0 g, 5.37 mmol) in DCM (40 mL), at 0° C., and the mixture was stirred for 15 min. Chloro-2-oxoethyl acetate (1.10 g, 8.06 mmol) was added at 0° C. and the mixture was stirred for 4 h at room temperature. The reaction mixture was diluted with DCM and washed with ice water, and saturated brine solution. The organic layer was dried over anhydrous Na2SO4, and concentrated under reduced pressure to afford the crude compound. This was purified by column chromatography (100-200 mesh silica gel), eluting with 20%-40% EtOAc/pet.ether to give the title compound (1.1 g).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][C:8]=1[CH:16]1[C:21]([C:22]([O:24][CH3:25])=[O:23])=[C:20]([CH3:26])[NH:19][C:18]([CH3:27])=[C:17]1[C:28]([O:30][CH3:31])=[O:29].[C:32](OC(=O)C)(=[O:34])[CH3:33]>C(Cl)Cl>[C:32]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][C:8]=1[CH:16]1[C:21]([C:22]([O:24][CH3:25])=[O:23])=[C:20]([CH3:26])[NH:19][C:18]([CH3:27])=[C:17]1[C:28]([O:30][CH3:31])=[O:29])(=[O:34])[CH3:33]
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1c1cc([N+](=O)[O-])ccc1OCCCCN
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1c1cc([N+](=O)[O-])ccc1OCCCCNC(C)=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In 2 ml of methylene chloride was dissolved 0.31 g of dimethyl 4-[2-(4-aminobutoxy)-5-nitrophenyl]-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate. After 2 ml of acetic anhydride was added to the solution under ice cooling, the mixture was stirred for 30 minutes at room temperature. The reaction solution was concentrated under reduced pressure and ether was added to the residue to solidify. The solid was recrystallized from chloroform-n-hexane to give 0.26 g of dimethyl 4-[2-[4-(acetylamino)butoxy]-5-nitrophenyl]-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate. This compound has the following physicochemical properties.
Reaction SMILES: O1CCOCC1.[CH2:7]([S:9]([N:12](S(CC)(=O)=O)[C:13]1[C:14]([Cl:33])=[CH:15][C:16]([Cl:32])=[C:17]([N:19]2[C:24](=[O:25])[CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[N:21]([CH3:30])[C:20]2=[O:31])[CH:18]=1)(=[O:11])=[O:10])[CH3:8].[OH-].[Na+].Cl>O>[Cl:32][C:16]1[CH:15]=[C:14]([Cl:33])[C:13]([NH:12][S:9]([CH2:7][CH3:8])(=[O:10])=[O:11])=[CH:18][C:17]=1[N:19]1[C:24](=[O:25])[CH:23]=[C:22]([C:26]([F:28])([F:27])[F:29])[N:21]([CH3:30])[C:20]1=[O:31]
Reactant: CCS(=O)(=O)N(c1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(Cl)cc1Cl)S(=O)(=O)CC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CCS(=O)(=O)Nc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(Cl)cc1Cl
Reaction time: 4 h
Yield: 69.4 %

Procedure:
To 8 ml of dioxane, 0.80 g of the obtained 3-[5-bis(ethanesulfonyl)amino-2,4-dichlorophenyl]-1-methyl-6-trifluoromethyl-2,4(1H,3H)-pyrimidinedione was dissolved and 0.12 g of sodium hydroxide (93%) and 2 ml of water were added to the obtained solution After the mixed solution was stirred for 4 hours, a dilute hydrochloric acid was added thereto in order to acidify the resultant solution. The reaction mixture was extracted with ethyl acetate. The obtained extract of the ethyl acetate layer was washed with water and a saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate. Then ethyl acetate was distilled off to obtain a crude product. The obtained product was purified by preparative thin-layer chromatography (developing solvent: hexane/ethyl acetate =3/2) to obtain 0.46 g of the objective product as white crystals.
Reaction SMILES: Cl.[CH3:2][N:3]([CH2:5][CH:6]1[CH2:15][CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]1=[O:16])[CH3:4].[NH:17]([C:24]1([C:30]#[N:31])[CH2:29]CNC[CH2:25]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(O)C>[O:16]=[C:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:14][CH2:15][CH:6]1[CH2:5][N:3]1[CH2:2][CH2:25][C:24]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)([C:30]#[N:31])[CH2:29][CH2:4]1
Reactant: N#CC1(Nc2ccccc2)CCNCC1
Reactant: CN(C)CC1CCc2ccccc2C1=O
Agent: Cl
Solvent: CCO
Product: N#CC1(Nc2ccccc2)CCN(CC2CCc3ccccc3C2=O)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2-[(Dimethylamino)methyl]-3,4-dihydro-1(2H)-naphthalenone, hydrochloride (10.0 g) and 4-anilino isonipecotonitrile (10.2 g) are dissolved in absolute ethanol (150 ml) by brief heating. The reaction mixture is stirred at room temperature under nitrogen for 16 hours. The resulting precipitate is collected by filtration, washed with additional absolute ethanol, and dried in vacuo to give the title compound.
Reaction SMILES: [I:1]N1C(=O)CCC1=O.[CH2:9]([O:13][C:14]([N:16]([C:36]1[C:41]([O:42][CH3:43])=[N:40][C:39]([CH3:44])=[CH:38][N:37]=1)[S:17]([C:20]1[C:21]([C:26]2[CH:31]=[CH:30][C:29]([Si](C)(C)C)=[CH:28][CH:27]=2)=[N:22][CH:23]=[CH:24][CH:25]=1)(=[O:19])=[O:18])=[O:15])[CH:10]([CH3:12])[CH3:11]>C(#N)C>[I:1][C:29]1[CH:30]=[CH:31][C:26]([C:21]2[C:20]([S:17]([N:16]([C:14]([O:13][CH2:9][CH:10]([CH3:12])[CH3:11])=[O:15])[C:36]3[C:41]([O:42][CH3:43])=[N:40][C:39]([CH3:44])=[CH:38][N:37]=3)(=[O:19])=[O:18])=[CH:25][CH:24]=[CH:23][N:22]=2)=[CH:27][CH:28]=1
Reactant: COc1nc(C)cnc1N(C(=O)OCC(C)C)S(=O)(=O)c1cccnc1-c1ccc([Si](C)(C)C)cc1
Reactant: O=C1CCC(=O)N1I
Solvent: CC#N
Product: COc1nc(C)cnc1N(C(=O)OCC(C)C)S(=O)(=O)c1cccnc1-c1ccc(I)cc1
Temperature: 65 °C
Reaction time: 24 h

Procedure:
N-Iodosuccinimide (0.84 g) was added to a solution of N-(isobutoxycarbonyl)-N-(3-methoxy-5-methylpyrazin-2-yl)-2-(4-trimethylsilylphenyl)pyridine-3-sulphonamide (1.58 g) in acetonitrile (15 ml) and the reaction mixture was stirred and heated at 65° C. for 17 hours. A further portion of N-iodosuccinimide (50 mg) was added and heating continued for 24 hours, then more N-iodosuccinimide (100 mg) was added and heating continued a further 24 hours. The mixture was cooled and volatile material was removed by evaporation. The residue was purified by chromatography on a silica gel Mega Bond Elut column, eluting with 0-25% ethyl acetate/hexane, followed by trituration with hexane (2×25 ml) to give 2-(4-iodophenyl)-N-isobutoxycarbonyl-N-(3-methoxy-5-methylpyrazin-2-yl)pyridine-3-sulphonamide as a solid, m.p. 156-158° C.; 1H NMR (CDCl3): 0.7 (d, 6H), 1.7 (m, 1H), 2.5 (s, 3H), 3.8 (d, 2H), 4.0 (s, 3H), 7.4 (d, 2H), 7.5 (dd, 1H), 7.7 (d, 2H), 7.9 (s, 1H), 8.8 (dd, 1H), 8.0 (dd, 1H); mass spectrum (+ve ESP): 583 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[S:9]([NH:12][C:13]1[CH:21]=[C:20]([I:22])[CH:19]=[CH:18][C:14]=1[C:15](O)=[O:16])(=[O:11])=[O:10].Cl.[CH3:24][O:25][C:26](=[O:38])[C@@H:27]([NH2:37])[CH2:28][C:29]1[CH:34]=[CH:33][C:32]([F:35])=[C:31]([Br:36])[CH:30]=1>>[CH3:24][O:25][C:26](=[O:38])[C@@H:27]([NH:37][C:15](=[O:16])[C:14]1[CH:18]=[CH:19][C:20]([I:22])=[CH:21][C:13]=1[NH:12][S:9]([C:3]1[C:4]([F:8])=[CH:5][CH:6]=[CH:7][C:2]=1[F:1])(=[O:11])=[O:10])[CH2:28][C:29]1[CH:34]=[CH:33][C:32]([F:35])=[C:31]([Br:36])[CH:30]=1
Reactant: COC(=O)[C@@H](N)Cc1ccc(F)c(Br)c1
Reactant: O=C(O)c1ccc(I)cc1NS(=O)(=O)c1c(F)cccc1F
Agent: Cl
Product: COC(=O)[C@H](Cc1ccc(F)c(Br)c1)NC(=O)c1ccc(I)cc1NS(=O)(=O)c1c(F)cccc1F

Procedure:
2-(2,6-Difluoro-benzenesulfonylamino)-4-iodo-benzoic acid was coupled to (S)-2-amino-3-(3-bromo-4-fluoro-phenyl)-propionic acid methyl ester hydrochloride as in EXAMPLE 1, Part C, to afford the title compound. HPLC: RT=10.54 min. MS (ESI+): mass calcd. for C23H17BrF3IN2O5S, 697.26; m/z found, 697/699 [M+H]+. 1H NMR (500 MHz, CDCl3): 11.37 (s, 1H), 8.11 (d, J=1.4, 1H), 7.55-7.44 (m, 1H), 7.40 (dd, J=8.3, 1.4, 1H), 7.27-7.26 (m, 1H), 7.09-7.04 (m, 2H), 7.02-6.96 (m, 3H), 6.63 (d, J=6.8, 1H), 4.98 (q, J=5.6, 1H), 3.81 (s, 3H), 3.27-3.13 (m, 2H).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[N+:21]([O-:23])=[O:22])[C:5]([N:7]([CH2:13][CH2:14][CH:15]([CH3:17])[CH3:16])[CH2:8][CH2:9][CH:10]([CH3:12])[CH3:11])=[O:6].[N:24]1([CH2:30][CH2:31][CH2:32][NH2:33])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:11][CH:10]([CH3:12])[CH2:9][CH2:8][N:7]([CH2:13][CH2:14][CH:15]([CH3:17])[CH3:16])[C:5](=[O:6])[C:4]1[CH:18]=[CH:19][C:20]([N+:21]([O-:23])=[O:22])=[C:2]([NH:33][CH2:32][CH2:31][CH2:30][N:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)[CH:3]=1
Reactant: NCCCN1CCCCC1
Reactant: CC(C)CCN(CCC(C)C)C(=O)c1ccc([N+](=O)[O-])c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)CCN(CCC(C)C)C(=O)c1ccc([N+](=O)[O-])c(NCCCN2CCCCC2)c1
Yield: 78 %

Procedure:
A mixture of 3-fluoro-N,N-bis(3-methylbutyl)-4-nitrobenzamide (430 mg, 1 eq, prepared according to Example A1), 3-piperidino-propylamine (212 mg, 1.1 eq) and potassium carbonate (365 mg, 2 eq) in acetonitrile (10 ml) is heated under reflux for 3 hours then concentrated under reduced pressure at 40° C. The residue is taken up in dichloromethane (50 ml) and water (20 ml). After decantation and extractions, the combined organic phases are washed with salt water, dried over Na2SO4 then concentrated under reduced pressure at 40° C. Purification of the residue by flash chromatography on silica gel (eluent: ethyl acetate 100%) produces the expected compound in the form of a yellow oil (460 mg; 78% yield).
Reaction SMILES: [ClH:1].[C:2]([N:5]([C:7]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:8]=1[CH2:9][CH2:10][CH:11]([NH:17][CH2:18][CH2:19][CH3:20])[CH2:12]2)C)(=O)C.[OH-].[K+]>C(O)COCCO.O>[ClH:1].[ClH:1].[CH3:2][NH:5][C:7]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:8]=1[CH2:9][CH2:10][CH:11]([NH:17][CH2:18][CH2:19][CH3:20])[CH2:12]2
Reactant: CCCNC1CCc2c(cccc2N(C)C(C)=O)C1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: OCCOCCO
Solvent: O
Product: CCCNC1CCc2c(cccc2NC)C1

Procedure:
0.50 g (1.92 mmol) of 5-(N-acetyl-N-methyl-amino)-2-n-propylamino-tetraline-hydrochloride (Example 4.7.8) are stirred with 12.5 g (0.22 mol) of potassium hydroxide in 40 ml of diethyleneglycol for 24 hours at 150° C. The mixture is then cooled, diluted with 400 ml of water and extracted three times with ethyl acetate (50, 15 and 15 ml). The combined extracts are washed with 20 ml of water, dried with sodium sulphate and, after the drying agent has been filtered off, concentrated by rotary evaporation, finally at 80° C. under a complete water-jet vacuum. The residue is crystallised as the hydrochloride analogously to Example 4.1.1. The title compound is obtained in a yield of 0.39 g (69.7% of theory) and with a melting point of 245° C. which does not change when recrystallised from ethanol/ether.
Reaction SMILES: [CH2:1]([NH2:11])[C:2]1[CH:10]=[CH:9][C:8]2[O:7][CH2:6][O:5][C:4]=2[CH:3]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH:26][C:27]1([CH2:34][CH2:35][C:36]2[C:45]3[C:40](=[CH:41][CH:42]=[C:43]([O:46][CH3:47])[CH:44]=3)[N:39]=[CH:38][N:37]=2)[CH2:32][CH2:31][C:30](=O)[CH2:29][CH2:28]1>ClCCl>[O:7]1[C:8]2[CH:9]=[CH:10][C:2]([CH2:1][NH:11][CH:30]3[CH2:29][CH2:28][C:27]([CH2:34][CH2:35][C:36]4[C:45]5[C:40](=[CH:41][CH:42]=[C:43]([O:46][CH3:47])[CH:44]=5)[N:39]=[CH:38][N:37]=4)([OH:26])[CH2:32][CH2:31]3)=[CH:3][C:4]=2[O:5][CH2:6]1
Reactant: COc1ccc2ncnc(CCC3(O)CCC(=O)CC3)c2c1
Reactant: NCc1ccc2c(c1)OCO2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc2ncnc(CCC3(O)CCC(NCc4ccc5c(c4)OCO5)CC3)c2c1
Reaction time: 8 h

Procedure:
Piperonylamine (0.030 ml, 0.24 mmol) and sodium triacetoxyborohydride (0.08 g, 0.377 mmol) were added to a solution of 4-hydroxy-4-[2-(6-methoxy-quinazolin-4-yl)-ethyl]-cyclohexanone (0.06 g, 0.2 mmol) in dichloromethane (1 ml). The reaction mixture was stirred overnight and then filtered over Hydromatrix (wetted with an NaHCO3 solution, 2 ml) and subsequently washed with dichloromethane. The filtrate was concentrated to dryness by rotary evaporation. The residue was purified by column chromatography on silica gel (dichloromethane:MeOH 9/1 and then dichloromethane:MeOH 9/1 and 2% triethylamine).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=1.[CH2:9]([O:11][C:12](=[O:20])[C:13](=[CH:16]OCC)[C:14]#[N:15])[CH3:10]>C1(C)C=CC=CC=1>[CH2:9]([O:11][C:12](=[O:20])[C:13]([C:14]#[N:15])=[CH:16][NH:1][C:2]1[CH:3]=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=1)[CH3:10]
Reactant: Cc1ccc(N)cn1
Reactant: CCOC=C(C#N)C(=O)OCC
Solvent: Cc1ccccc1
Product: CCOC(=O)C(C#N)=CNc1ccc(C)nc1
Yield: 65.5 %

Procedure:
To a solution of 3-amino-6-picoline (ChemPacific, 15.00 g, 138.70 mmol), in toluene (400 mL) was added ethyl(ethoxymethylene)-cyano-acetate (Aldrich, 98%, 35.88 g, 208.00 mol), and the reaction mixture was refluxed for 4 hrs. The reaction mixture was concentrated and the solid was collected by filtration to give 2-cyano-3-(6-methyl-pyridin-3-ylamino)-acrylic acid ethyl ester (21.0 g). The filtrate was concentrated and the residue was then purified by Biotage column, eluting with a gradient of 30-75% AcOEt in nHex to give 2-cyano-3-(6-methyl-pyridin-3-ylamino)-acrylic acid ethyl ester (7.6 g, total yield: 28.6 g, 89.0%) which was used in the next step without further purification.
Reaction SMILES: [I:1][C:2]1[CH:11]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[C:5]([OH:12])=[CH:4][CH:3]=1.N1C=CN=C1.Cl[Si:19]([CH:26]([CH3:28])[CH3:27])([CH:23]([CH3:25])[CH3:24])[CH:20]([CH3:22])[CH3:21]>CN(C=O)C>[CH3:10][O:9][C:7](=[O:8])[C:6]1[CH:11]=[C:2]([I:1])[CH:3]=[CH:4][C:5]=1[O:12][Si:19]([CH:26]([CH3:28])[CH3:27])([CH:23]([CH3:25])[CH3:24])[CH:20]([CH3:22])[CH3:21]
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: COC(=O)c1cc(I)ccc1O
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: COC(=O)c1cc(I)ccc1O[Si](C(C)C)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 92.1 %

Procedure:
A solution of methyl 5-iodosalicylate (2.00 g, 7.20 mmol) in DMF (20 mL) was treated with imidazole (1.22 g, 18.0 mmol) then chlorotriisopropylsilane (1.85 mL, 8.60 mmol). The mixture was stirred at RT for 18 h. The mixture was evaporated in vacuo and the residue was partitioned between EtOAc and water. The aqueous layer was then extracted with EtOAc (2×). The combined organic layers were washed with a 10% aqueous citric acid solution, 1N aqueous NaOH solution and brine, dried (Na2SO4), filtered and evaporated in vacuo. The residue was purified by FCC, using 0-10% EtOAc in cyclohexane, to give the title compound as a colorless oil (2.88 g, 92%). LCMS (Method 3): Rt 5.72 min, m/z 435 [MH+].
Reaction SMILES: [Na].[F:2][C:3]([F:10])([F:9])[C:4]1O[N:7]=[CH:6][CH:5]=1.[Br-].[Cl:12][C:13]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[C:15]([Cl:23])[C:14]=1[N:24]([C:26](=O)[C:27]([F:30])([F:29])[F:28])[NH2:25]>C(O)C>[C:6]([C:5]1[C:4]([C:3]([F:10])([F:9])[F:2])=[N:25][N:24]([C:14]2[C:13]([Cl:12])=[CH:18][C:17]([C:19]([F:22])([F:21])[F:20])=[CH:16][C:15]=2[Cl:23])[C:26]=1[C:27]([F:30])([F:29])[F:28])#[N:7]
Reactant: NN(C(=O)C(F)(F)F)c1c(Cl)cc(C(F)(F)F)cc1Cl
Reactant: FC(F)(F)c1ccno1
Agent: [Br-]
Agent: [Na]
Solvent: CCO
Product: N#Cc1c(C(F)(F)F)nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 9.3 %

Procedure:
0.92 g (0.04 mol) of sodium is dissolved in 25 ml of ethanol, 5.48 g (0.04 mol) of 5-trifluoromethylisoxazole are added at 0° C. and the mixture is stirred at room temperature for 15 minutes. 16.16 g (0.04 mol) of N-(2,6-dichloro-4-trifluoromethylphenyl)-trifluoroacetohydrazide bromide are added dropwise to this mixture, while cooling, and the mixtureis subsequently stirred at 25° C. for a further 10 hours. After the sodium bromide which has precipitated out is filtered off, the filtrate isconcentrated and the residue is separatad by column chromatography. 1.65 g (9.3% of theory) of 4-cyano-3,5-di(trifluoromethyl)-1-(2,6-dichloro-4-trifluoromethylphenyl)-pyrazole of melting point 88° C.-92° C. are obtained.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:9]2[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:10]=2[O:18][CH3:19])[CH:6]=[CH:7][CH:8]=1)#[N:2].[ClH:20].CO>O1CCCC1>[ClH:20].[NH2:2][CH2:1][C:3]1[CH:4]=[C:5]([C:9]2[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:10]=2[O:18][CH3:19])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1ccc([N+](=O)[O-])cc1-c1cccc(C#N)c1
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc([N+](=O)[O-])cc1-c1cccc(CN)c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 47.9 %

Procedure:
To a stirring solution of 2-(3-cyanophenyl)-4-nitroanisole from Example 111 (4.0 g, 16 mmol) in tetrahydrofuran (100 mL) was added borane-tetrahydrofuran complex dropwise (48 mL of a 1.0 M solution in tetrahydrofuran, 3 equiv, 48 mmol). The solution was heated to reflux for 3 hours. The solution was allowed to cool to room temperature and hydrochloride acid (24 mL of 4.0 M solution in dioxane, 96 mmol) was added slowly. Methanol (100 mL) was added slowly and the solution was evaporated to dryness. The residue was diluted with methanol (100 mL) and evaporated to dryness. The residue was dissolved in dichloromethane (100 mL). A clear solution was achieved, from which a precipitate began to form (<1 min). The solution was stirred at room temperature for 14 hours and the solid was collected on a Büchner funnel, washed with dichloromethane (10 mL), and dried under high vacuum to afford 2-(3-aminomethylphenyl)-4-nitroanisole hydrochloride (2.26 g, 55% yield).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH:10]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1.C([BH3-])#N.[Na+]>C(O)C.O>[CH2:1]([N:8]1[CH2:13][CH2:12][C@H:11]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C@H:10]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1COCCN1
Reactant: O=C1CCN(Cc2ccccc2)CC1c1ccc(Cl)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Clc1ccc([C@@H]2CN(Cc3ccccc3)CC[C@@H]2N2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.5 %

Procedure:
To a mixture of 1-benzyl-3-(4-chloro-phenyl)-piperidin-4-one (1.0 g, 3.34 mmol) and morpholine (1.16 mL, 13.3 mmol) was added tetraisopropyl-orthotitanate (3.95 mL, 13.3 mmol) at room temperature. After stirring at room temperature overnight the reaction mixture was diluted with ethanol (30.0 mL) and sodium cyanoborohydride (930 mg, 13.3 mmol) was added. The reaction mixture was stirred at room temperature for 24 h and was diluted with water (2.0 mL). The inorganic precipitate was filtered off and washed with ethanol. The filtrate was evaporated and purified by flash chromatography on silica gel with hexane/ethyl acetate/triethylamine 40:10:1 to give rac-cis-4-[1-benzyl-3-(4-chloro-phenyl)-piperidin-4-yl]-morpholine (650 mg, 52%) as a yellow solid, MS: m/e=371.3 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[C:5]([CH3:18])[C:4]=1[CH3:19].C([O-])(=O)C.[Na+].[Br:25]Br.O>C(O)(=O)C>[Br:25][C:8]1[C:7]([CH3:9])=[C:6]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:14])([CH3:15])[CH3:16])[C:5]([CH3:18])=[C:4]([CH3:19])[C:3]=1[O:2][CH3:1]
Reactant: BrBr
Reactant: COc1cc(C)c(NC(=O)OC(C)(C)C)c(C)c1C
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COc1c(C)c(C)c(NC(=O)OC(C)(C)C)c(C)c1Br
Reaction time: 1 h
Yield: 91 %

Procedure:
To a solution of tert-butyl 4-methoxy-2,3,6-trimethylphenylcarbamate synthesized in Reference Example 128 (12.7 g, 47.9 mmol) and sodium acetate (4.72 g, 57.5 mmol) in acetic acid (50 mL) was added bromine (8.42 g, 52.7 mmol) at room temperature and the mixture was stirred at the same temperature for 1 hour. Water (80 mL) was poured into the reaction mixture, and the precipitated crystals were collected by filtration and then dissolved in ethyl acetate. The solution was washed with a saturated sodium hydrogen carbonate solution and water, dried over magnesium sulfate, filtered, and then concentrated under reduced pressure. The residue was crystallized from methanol to obtain 15.0 g (yield 91%) of the title compound. Melting point: 159-161° C.
Reaction SMILES: [O-]CC.[Na+].C(O)C.[C:8]1([CH3:28])[CH:13]=[CH:12][C:11]([C:14]([NH:16][CH:17]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[O:15])=[CH:10][CH:9]=1.[Br:29][C:30]1[CH:31]=[C:32]([CH:35]=[CH:36][CH:37]=1)[CH2:33]Br>C(O)C>[Br:29][C:30]1[CH:37]=[CH:36][CH:35]=[C:32]([CH2:33][C:17]([C:23]([O:25][CH2:26][CH3:27])=[O:24])([C:18]([O:20][CH2:21][CH3:22])=[O:19])[NH:16][C:14]([C:11]2[CH:12]=[CH:13][C:8]([CH3:28])=[CH:9][CH:10]=2)=[O:15])[CH:31]=1
Reactant: CCOC(=O)C(NC(=O)c1ccc(C)cc1)C(=O)OCC
Reactant: BrCc1cccc(Br)c1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(Cc1cccc(Br)c1)(NC(=O)c1ccc(C)cc1)C(=O)OCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 107.5 %

Procedure:
To 100 ml of dry ethanol, 21.45 g of 20% sodium ethoxide-ethanol solution and 17.61 g of diethyl p-toluoylaminomalonate were added and stirred for 30 minutes at room temperature under argon atmosphere. After 15.00 g of 3-bromobenzyl bromide was added dropwise, the reaction solution was stirred for 8 hours at 55° C. and then concentrated. To the residue was added water, and extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to provide 29.82 g of the objective compound as yellow oil.
Reaction SMILES: [CH3:1][N:2]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]([SH:11])=[S:10])[CH2:4][CH2:3]1.[OH-:12].[Na+:13]>O>[OH2:12].[CH3:1][N:2]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]([S-:11])=[S:10])[CH2:4][CH2:3]1.[Na+:13]
Reactant: CN1CCCN(C(=S)S)CC1
Reactant: [OH-]
Agent: [Na+]
Solvent: O
Product: CN1CCCN(C(=S)[S-])CC1
Yield: 54.3 %

Procedure:
57.0 g (0.3 moles) of 4-methyl-1-homopiperazinedithiocarboxylic acid (FLA-57) was dissolved in 300 ml of water with 12.0 g (0.3 moles) of NaOH. The solution was evaporated. The residue was recrystallized from ethanol-isopropyl ether, 37.5 g of sodium 4-methyl-1-homopiperazinedithiocarboxylate monohydrate was obtained. Mp 123°-125° C. elemental analysis. C calculated 36.60%, found 36.5%, H calculated 6.56%, found 6.54%, N calculated 12.16%, found 12.1%, S calculated 27.84%, found 27.8%.
Reaction SMILES: [OH:1][C@H:2]([CH2:6][CH:7]([CH3:9])[CH3:8])[C:3]([OH:5])=O.[CH2:10]([N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N(CC)CC)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[CH2:10]([N:17]1[CH2:22][CH2:21][N:20]([C:3](=[O:5])[C@H:2]([OH:1])[CH2:6][CH:7]([CH3:9])[CH3:8])[CH2:19][CH2:18]1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CC(C)C[C@@H](O)C(=O)O
Reactant: c1ccc(CN2CCNCC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)C[C@@H](O)C(=O)N1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a cooled solution (0-5° C.) of (R)-α-hydroxyisocaproic acid (64.5 g, 0.5 mol), 1-benzylpiperazine (88 g, 0.5 mol) and triethylamine (71 ml, 0.5 mol) in CH2Cl2 (850 ml) was added in portions HOBt (68 g, 0.5 mol) and EDCI•HCl (96 g, 0.5 mol). The reaction mixture was stirred at room temperature overnight. The organic layer was washed with water (3×) and once with brine, dried over Na2SO4, and filtered, and the solvent was removed in vacuo. Crude (R)-1-(4-benzyl-piperazin-1-yl)-2-hydroxy-4-methyl-pentan-1-one (132 g, 91%) was used in the next step without further purification.