Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:6]=[C:5](Cl)[S:4][N:3]=1.C([O-])([O-])=O.[Na+].[Na+].[CH3:14][N:15]1[C:23]2[C:18](=[CH:19][C:20](B(O)O)=[CH:21][CH:22]=2)[CH:17]=[N:16]1>CN(C=O)C.CCOC(C)=O.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>[Cl:1][C:2]1[N:6]=[C:5]([C:20]2[CH:19]=[C:18]3[C:23](=[CH:22][CH:21]=2)[N:15]([CH3:14])[N:16]=[CH:17]3)[S:4][N:3]=1
Reactant: Cn1ncc2cc(B(O)O)ccc21
Reactant: Clc1nsc(Cl)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cn1ncc2cc(-c3nc(Cl)ns3)ccc21
Temperature: 80 °C
Reaction time: 2 h

Procedure:
A solution of 3,5-dichloro-1,2,4-thiadiazole (100 mg, 0.645 mmol), Na2CO3 (0.968 mL, 1.935 mmol) and (1-methyl-1H-indazol-5-yl)boronic acid (114 mg, 0.645 mmol) in DMF (4 mL) was degassed under N2 for 10 min. Pd(Ph3P)4 (149 mg, 0.129 mmol) was added and the mixture was stirred at 80° C. for 2 h. The reaction mixture was cooled to ambient temperature and diluted with EtOAc. The organics were washed with water, brine, dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by preparative TLC (5% MeOH/DCM) to afford the title compound as a solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 4.12 (s, 3H) 7.50 (d, J=8.79 Hz, 1H) 7.94 (d, J=8.79 Hz, 1H) 8.11 (s, 1H) 8.39 (s, 1H). LC/MS (m/z) ES+=251(M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C:22]2[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:23]=2[Cl:29])[C@H:12]([CH3:21])[CH2:13][CH2:14][CH2:15][S:16]([NH:19][CH3:20])(=[O:18])=[O:17])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH2:30](S(Cl)(=O)=O)[CH2:31]CCC.N1CCC1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C:22]2[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:23]=2[Cl:29])[C@H:12]([CH3:21])[CH2:13][CH2:14][CH2:15][S:16]([N:19]2[CH2:31][CH2:30][CH2:20]2)(=[O:17])=[O:18])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CCCCCS(=O)(=O)Cl
Reactant: CNS(=O)(=O)CCC[C@@H](C)N(c1cc(Cl)ccc1Cl)S(=O)(=O)c1ccc(Cl)cc1
Agent: C1CNC1
Product: C[C@H](CCCS(=O)(=O)N1CCC1)N(c1cc(Cl)ccc1Cl)S(=O)(=O)c1ccc(Cl)cc1
Yield: 24 %

Procedure:
4-chloro-N-[2,5-dichlorophenyl]-N-[4-[(1-azetidinyl)sulfonyl]-1(R)-methylbutyl]benzenesulfonamide was prepared analogous to 4-chloro-N-[2,5-dichlorophenyl]-N-[4-[(methylamino)sulfonyl]-1(R)-methylbutyl]benzenesulfonamide by reacting (4R)-4-[2,5-dichlorophenyl][4-chlorophenyl)sulfonyl]-amino]pentylsulfonyl chloride with azetidine. Yield=24%; MS (ESI+), 526 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:6]=[C:7]([S:16][C:17]([S:20][C:21]2[CH:26]=[C:25]([C:27]([CH3:30])([CH3:29])[CH3:28])[C:24]([OH:31])=[C:23]([C:32]([CH3:35])([CH3:34])[CH3:33])[CH:22]=2)([CH3:19])[CH3:18])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])[CH3:3].I[CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39].[F-].[K+]>CN(C)C=O.CCOCC>[CH2:41]([O:40][C:38](=[O:39])[CH2:37][O:11][C:10]1[C:9]([C:12]([CH3:13])([CH3:14])[CH3:15])=[CH:8][C:7]([S:16][C:17]([S:20][C:21]2[CH:22]=[C:23]([C:32]([CH3:35])([CH3:34])[CH3:33])[C:24]([OH:31])=[C:25]([C:27]([CH3:30])([CH3:29])[CH3:28])[CH:26]=2)([CH3:18])[CH3:19])=[CH:6][C:5]=1[C:2]([CH3:1])([CH3:3])[CH3:4])[CH3:42]
Reactant: CCOC(=O)CI
Reactant: CC(C)(Sc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1)Sc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: [F-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCOC(=O)COc1c(C(C)(C)C)cc(SC(C)(C)Sc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)cc1C(C)(C)C
Reaction time: 24 h
Yield: 27.4 %

Procedure:
To a solution of probucol (0.5 g, 0.97 mmol) in dimethylformamide (1.5 mL) were added ethyl iodoacetate (0.31 g, 1.45 mmol) and 40% potassium fluoride on alumina (0.7 g, 4.8 mmol). The mixture was stirred for 24 hours and then diluted with ether (25 mL), filtered and washed with water (2×5 mL). The ether layer was dried over MgSO4, filtered and concentrated. Silica gel chromatography (hexanes/ether 5:95) yielded 160 mg of {2,6-di-tert-butyl-4-[1-(3,5-di-tert-butyl-4-hydroxy-phenylsulfanyl)-1-methyl-ethylsulfanyl]-phenoxy}-acetic acid ethyl ester which was used directly for the next step of reaction.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[NH:7]1[CH:11]=[N:10][CH:9]=[N:8]1.CC1C=CC(S(O[CH2:23][C@@H:24]2[C@@H:29]([OH:30])[C@H:28]([OH:31])[C@@H:27]([OH:32])[C@H:26]([C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]4[S:42][C:43]([C:46]5[O:47][CH:48]=[CH:49][CH:50]=5)=[CH:44][N:45]=4)[CH:34]=3)[O:25]2)(=O)=O)=CC=1.O>CN(C=O)C>[N:7]1([CH2:23][C@@H:24]2[C@@H:29]([OH:30])[C@H:28]([OH:31])[C@H:27]([OH:32])[C@H:26]([C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]4[S:42][C:43]([C:46]5[O:47][CH:48]=[CH:49][CH:50]=5)=[CH:44][N:45]=4)[CH:34]=3)[O:25]2)[CH:11]=[N:10][CH:9]=[N:8]1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2O[C@@H](c3ccc(Cl)c(Cc4ncc(-c5ccco5)s4)c3)[C@H](O)[C@@H](O)[C@@H]2O)cc1
Reactant: c1nc[nH]n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: O[C@H]1[C@H](O)[C@@H](Cn2cncn2)O[C@@H](c2ccc(Cl)c(Cc3ncc(-c4ccco4)s3)c2)[C@H]1O
Temperature: 0 °C
Reaction time: 1 h
Yield: 14 %

Procedure:
Cesium carbonate (660 mg, 2.02 mmol) was added to the solution of 1,2,4-triazole (140 mg, 2.02 mmol) in DMF (2.0 mL) at 0° C. The reaction mixture was stirred at 0° C. for 1 h. The solution of toluenesulfonate 90 (240 mg, 0.41 mmol) in DMF (1.0 mL) was added to the reaction mixture. The reaction mixture was warmed up to room temperature, stirred at room temperature for 3 d. H2O was added to the reaction mixture and then extracted with EtOAc. The organic extract was dried over anhydrous MgSO4, filtered and concentrated in vacuo. Purification by prep HPLC (C18) provided desired triazole 97 (28 mg, 14%) as a solid.
Reaction SMILES: [C:1]1([PH:7](=O)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl-].[In+3].[Cl-].[Cl-]>>[C:8]1([PH:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=[PH](c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [In+3]
Product: c1ccc(Pc2ccccc2)cc1
Temperature: 152 °C
Yield: 44.1 %

Procedure:
172 g (0.852 mol) of diphenylphosphine oxide and 0.8 g of indium chloride are mixed and heated to 152° C., the pressure being reduced simultaneously (8 mbar). Diphenylphosphine distills off through a descending condenser at a transition temperature of 132° C. After a total of 2 hours, the internal temperature has been raised to 195° C. 70 g of diphenylphosphine are obtained. That corresponds to a yield of 88% of theory.
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:19])[NH:5][C:6](=[O:18])[NH:7][C:8]=1[O:9][C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH3:17])[CH:11]=1)[CH3:2].[F:20][C:21]([F:35])([F:34])[C:22]1[CH:23]=[C:24]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[CH2:25]Br>>[F:20][C:21]([F:34])([F:35])[C:22]1[CH:23]=[C:24]([CH:27]=[C:28]([C:30]([F:33])([F:31])[F:32])[CH:29]=1)[CH2:25][N:7]1[C:8]([O:9][C:10]2[CH:11]=[C:12]([CH3:17])[CH:13]=[C:14]([CH3:16])[CH:15]=2)=[C:3]([CH2:1][CH3:2])[C:4](=[O:19])[NH:5][C:6]1=[O:18]
Reactant: CCc1c(Oc2cc(C)cc(C)c2)[nH]c(=O)[nH]c1=O
Reactant: FC(F)(F)c1cc(CBr)cc(C(F)(F)F)c1
Product: CCc1c(Oc2cc(C)cc(C)c2)n(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c(=O)[nH]c1=O
Yield: 49.4 %

Procedure:
5-Ethyl-6-(3,5-dimethylphenoxy)-2,4-pyrimidinedione and 3,5-bis(trifluoromethyl)benzyl bromide were reacted by the same way with the example 1 to obtain the titled compound (240 mg, yield: 49.4%).
Reaction SMILES: C(=O)([O-])O[CH2:3][CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[Cl:14][C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=1>>[C:4]([CH:5]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[NH:19][C:18]1[CH:20]=[CH:21][C:15]([Cl:14])=[CH:16][CH:17]=1)#[CH:3]
Reactant: Nc1ccc(Cl)cc1
Reactant: O=C([O-])OCC=Cc1ccccc1
Product: C#CC(Nc1ccc(Cl)cc1)c1ccccc1
Reaction time: 16 h
Yield: 95.1 %

Procedure:
The general procedure was followed with cinnamyl carbonate (0.188 g, 0.979 mmol) and p-chloroaniline (0.150 g, 11.18 mmol). The reaction was conducted at room temperature for 16 h. 1H NMR analysis of the crude reaction mixture indicated the ratio of regioisomers to be 98/2. The mixture was purified by flash column chromatography on silica gel (2% ethyl acetate in hexanes) to give the title compound (0.225 g, 95%). HPLC analysis indicated the enantiomeric excess of the product was 96% [Diacel CHIRALCEL OD-H (0.46 cm×25 cm); hexane/2-propanol=99.75/0.25; flow rate=0.6 mL/min; detection wavelength=254 nm; TR=29.6 (major), 46.3 (minor) min]: [α]DRT=(c, CHCl3). 1H NMR (400.13 MHz, CDCl3) δ 7.48-7.36 (m, 5H), 7.17 (dt, J=8.8, 2.0 Hz, 2H), 6.59 (dt, J=8.8, 2.4 Hz, 2H), 6.10 (ddd, J=16.8, 10.4, 6.0 Hz, 1H), 5.36 (dt, J=14.8, 1.3 Hz, 1H), 5.33 (dt, J=8.0, 1.2 Hz, 1H), 4.98 (d, J=6.0 Hz, 1H), 4.14 (br s, 1H). 13C NMR (100.59 MHz, CDCl3) δ 145.59, 141.25, 138.51, 128.82, 128.71, 127.52, 127.00, 122.03, 116.20, 114.56, 60.75. Anal. Calcd for C15H14NCl: C, 73.92; H, 5.79; N, 5.75; Cl, 14.55. Found: C, 73.94; H, 5.83; N, 5.83; Cl, 14.67.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:10]([NH2:11])=[C:9]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[N:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[Cl:25])[N:7]=1)=O)C.C(O)(=O)C.[CH:30](N)=[NH:31]>C(OCCO)C>[Cl:18][C:15]1[CH:14]=[CH:13][C:12]([C:9]2[N:8]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[Cl:25])[N:7]=[C:6]3[C:4]([OH:3])=[N:31][CH:30]=[N:11][C:10]=23)=[CH:17][CH:16]=1
Reactant: N=CN
Reactant: CCOC(=O)c1nn(-c2ccccc2Cl)c(-c2ccc(Cl)cc2)c1N
Solvent: CC(=O)O
Solvent: CCOCCO
Product: Oc1ncnc2c(-c3ccc(Cl)cc3)n(-c3ccccc3Cl)nc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 4-amino-1-(2-chlorophenyl)-5-(4-chlorophenyl)-1H-pyrazole-3-carboxylic acid ethyl ester I-2A-1a (19.27 g, 51.2 mmol) and formamidine acetate (15.99g, 153.6 mmol) in 2-ethoxyethanol (100 ml) was refluxed for 3.5 h under nitrogen. The reaction mixture was then cooled to room temperature and poured into ice-cold water. The yellow precipitate that formed was collected by filtration and washed with water. The solid was stirred in 45 ml methyl tert-butyl ether for 30 minutes. Cyclohexane (90 ml) was added, and the stirring was continued for another 45 minutes. The pale yellow solid was collected by filtration and dried to give 3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-ol 1-2A-1 b (17.55 g, 87%): MS: 357.1 (M+1)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([N:11](C(=O)CC1C=CC=CC=1C)[C:12]1[N:17]=[CH:16][C:15]([C:18]([O:20]C)=[O:19])=[CH:14][CH:13]=1)=[O:10].[OH-].[Na+]>O1CCCC1CO>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([NH:11][C:12]1[N:17]=[CH:16][C:15]([C:18]([OH:20])=[O:19])=[CH:14][CH:13]=1)=[O:10]
Reactant: COC(=O)c1ccc(N(C(=O)Cc2ccccc2C)C(=O)Cc2ccccc2C)nc1
Agent: [Na+]
Agent: [OH-]
Solvent: OCC1CCCO1
Product: Cc1ccccc1CC(=O)Nc1ccc(C(=O)O)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a cooled (0° C.) mixture of 5.0 g methyl 6-aminopyridine-3-carboxylate, 12.6 ml of N,N-diisopropylethylamine in 40 ml of dichloromethane is added a solution of 12.2 g of 2-methylbenzeneacetyl chloride in 10 ml of dichloromethane. The mixture is stirred under argon at room temperature overnight. The mixture is diluted with 200 ml of dichloromethane and 50 ml of water and the organic layer separated. The organic layer is washed with 50 ml each of 1M NaHCO3, brine and dried (Na2SO4). The solution is filtered through a thin pad of hydrous magnesium silicate and the filtrate concentrated to dryness. The residue (9.0 g) is chromatographed on a silica gel column with hexane-ethyl acetate (3:1) as eluent to give 8.6 g of solid. This solid, mainly methyl 6-[[bis(2-methylbenzeneacetyl)]-amino]pyridine-3-carboxylate, is dissolved in 60 ml of tetrahydrofuran-methanol (1:1) and 23 ml of 5N NaOH added to the solution. The mixture is stirred at room temperature overnight and the mixture concentrated under vacuum. Water (25 ml) is added and the mixture is stirred and acidified with cold 1N HCl. The mixture is chilled and the solid filtered and washed with water to give 5.9 g of off-white solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][CH:3]=1.C([Li])CCC.[CH3:14][Si:15]([CH3:18])([CH3:17])Cl>CCOCC.CCCCCC>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([Si:15]([CH3:18])([CH3:17])[CH3:14])=[CH:4][CH:3]=1
Reactant: Brc1ccc(Br)cc1
Reactant: C[Si](C)(C)Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: C[Si](C)(C)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Under argon, 94.4 g of p-dibromobenzene is cooled to -20° C. in 400 ml of absolute ether. To the solution is added dropwise 255 ml of 15% butyllithium in hexane so that the temperature does not rise above -10° C. Then the mixture is agitated for one hour at room temperature. After a negative Gilman test (H. Gilman, J. Swiss, J. Amer. Chem. Soc. 62: 1847 [1940]), the mixture is again cooled to -20° C. and 46 ml of trimethylchlorosilane in 200 ml of absolute ether is added dropwise thereto so that the temperature does not exceed -10° C. After the addition step is finished, the mixture is stirred for 16 hours at room temperature and another hour under reflux. The thus-formed precipitate is suctioned off and thoroughly washed with ether. The resultant filtrate is concentrated and then distilled with a water-jet aspirator, thus producing 65.52 g of p-bromotrimethylsilylbenzene, bp (16 torr) 103°-110° C.
Reaction SMILES: S(=O)(=O)(O)[OH:2].[Cl:6][C:7]1[C:8]([CH3:19])=[C:9]([NH:13][C:14](=[O:18])[CH:15]=NO)[CH:10]=[CH:11][CH:12]=1>>[Cl:6][C:7]1[C:8]([CH3:19])=[C:9]2[C:10]([C:15](=[O:2])[C:14](=[O:18])[NH:13]2)=[CH:11][CH:12]=1
Reactant: O=S(=O)(O)O
Reactant: Cc1c(Cl)cccc1NC(=O)C=NO
Product: Cc1c(Cl)ccc2c1NC(=O)C2=O
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 56.5 %

Procedure:
To 2.5 g of concentrated sulfuric acid was added 2.5 g of N-(3-chloro-2-methylphenyl)-2-(hydroxyimino)acetamide at 50° C., and the mixture was stirred at 80° C. for 30 minutes. The reaction mixture was poured into 200 g of ice, and a deposited precipitate was collected by filtration to obtain 1.3 g of 6-chloro-7-methyl-1H-indole-2,3-dione of the formula:
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:14])[CH:7]([CH3:13])[CH:8]([CH3:12])[O:9]2)=[C:4]2[O:15][C:16](=[O:22])[CH:17]=[C:18]([CH2:19][CH2:20][CH3:21])[C:3]=12.[Cl-].[Ce+3].[Cl-].[Cl-].[BH4-].[Na+]>CO>[OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]([OH:14])[CH:7]([CH3:13])[CH:8]([CH3:12])[O:9]2)=[C:4]2[O:15][C:16](=[O:22])[CH:17]=[C:18]([CH2:19][CH2:20][CH3:21])[C:3]=12
Reactant: CCCc1cc(=O)oc2c3c(cc(O)c12)OC(C)C(C)C3=O
Agent: [BH4-]
Agent: [Ce+3]
Agent: [Cl-]
Solvent: CO
Product: CCCc1cc(=O)oc2c3c(cc(O)c12)OC(C)C(C)C3O
Temperature: 0 °C
Reaction time: 2 h
Yield: 98 %

Procedure:
A solution of 5-hydroxy-8,9-dimethyl-4-propyl-8,9-dihydro-pyrano[2,3-f]chromene-2,10-dione (a mixture of cis- and trans-37a) (2 g, 6.61 mmol, 1.00 eq) and cerium(III) chloride septahydrate (2.5 g, 6.71 mol, 1.02 eq) in methanol (300 mL) was cooled to 0° C. Sodium borohydride (0.62 g, 16.39 mmol, 2.48 eq) was added portionwise to the stirred solution within 1 h while the temp was maintained at 0-5° C. The reaction mixture was allowed to warm up to room temperature and stirring continued for 2 h. Solvent was removed under vacuum and the residue partitioned between dichloromethane (200 mL) and ice-cold 1N hydrochloric acid (100 mL). The organic layer was separated, washed successively with saturated solution of sodium bicarbonate (200 mL) and brine (200 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum yielding 1.97 g (98%) of a mixture of cis- and trans-17a. The crude product was used for the next step without further purification.
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][C:7]([OH:9])=O)(=[O:3])[CH3:2].C(N(CC)CC)C.C(Cl)(=O)C(C)(C)C.[CH2:24]([C@@H:31]1[CH2:35][O:34][C:33](=[O:36])[NH:32]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.[Li]CCCC.[Li]>O1CCCC1.C(OCC)(=O)C>[CH2:24]([C@@H:31]1[CH2:35][O:34][C:33](=[O:36])[N:32]1[C:7](=[O:9])[CH2:6][CH2:5][CH2:4][C:1](=[O:3])[CH3:2])[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: CC(=O)CCCC(=O)O
Reactant: O=C1N[C@H](Cc2ccccc2)CO1
Agent: CC(C)(C)C(=O)Cl
Agent: [Li]
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)CCCC(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a stirred solution of 4-acetylbutyric acid (1-7) (25.0 g, 192 mmol), triethylamine (29.5 ml, 211 mmol) in tetrahydrofuran (500 mL) at −78° C. was added pivaloyl chloride (26.0 ml, 211 mmol). After 20 min, the mixture was warmed to 0° C. for 1.0 h and then recooled to −78° C. To a stirred solution of (R)-(−)-4-benzyl-2-oxazolidinone (37.4 g, 211 mmol) in tetrahydrofuran (500 ml) at −78° C. was added nBuLi (84.5 ml, 211 mmol, 2.5M in hexanes) dropwise over 10 minutes. After 20 minutes, the lithium reagent was transferred to the mixed anhydride via cannula. After 10 minutes, the reaction was warmed to 0° C. for 1.0 h. The mixture was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate, saturated aqueous sodium chloride, and dried over anhydrous magnesium sulfate. The reaction mixture was filtered and concentrated at reduced pressure to give 2-1 as a solid which was triturated with ethyl ether and filtered to give a white solid.
Reaction SMILES: [C-:1]#[N:2].[K+].Br[CH2:5][C:6](=[N:11][OH:12])[C:7]([F:10])([F:9])[F:8]>CO>[F:8][C:7]([F:10])([F:9])[C:6]1[CH:5]=[C:1]([NH2:2])[O:12][N:11]=1
Reactant: ON=C(CBr)C(F)(F)F
Reactant: [C-]#N
Agent: [K+]
Solvent: CO
Product: Nc1cc(C(F)(F)F)no1
Temperature: 25 °C
Reaction time: 3 h
Yield: 37.3 %

Procedure:
To a suspension of KCN (1.90 g, 29.1 mmol) in MeOH (35 mL) was added dropwisely 3-bromo-1,1,1-trifluoropropan-2-one oxime (5.00 g, 24.3 mmol) in MeOH (72 mL) at RT. The reaction mixture was stirred at RT for 3 hours. The solution was evaporated and then the residue was dissolved in EtOAc and stirred at RT. The solid was filtered and the filtrate was evaporated to obtain the crude product. The crude product was purified by silica gel column chromatography (Biotage: 25M, 10% to 60% EtOAc/hexane: 550 mL) to obtain 3-(trifluoromethyl)isoxazol-5-amine (1.38 g, 37% yield). MS (ESI) m/z: 153.0 (M+H+).
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9](=[O:25])[NH:10][CH2:11][CH2:12][CH2:13][NH:14][CH2:15][CH2:16][P:17]([O:22][CH2:23][CH3:24])([O:19][CH2:20][CH3:21])=[O:18])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:26]([O:28][C:29]1[C:30](=O)[C:31](=[O:36])[C:32]=1[O:33]CC)[CH3:27]>C(O)C>[C:1]1([CH2:7][O:8][C:9](=[O:25])[NH:10][CH2:11][CH2:12][CH2:13][N:14]([CH2:15][CH2:16][P:17]([O:19][CH2:20][CH3:21])([O:22][CH2:23][CH3:24])=[O:18])[C:30]2[C:31](=[O:36])[C:32](=[O:33])[C:29]=2[O:28][CH2:26][CH3:27])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOP(=O)(CCNCCCNC(=O)OCc1ccccc1)OCC
Reactant: CCOc1c(OCC)c(=O)c1=O
Solvent: CCO
Product: CCOc1c(N(CCCNC(=O)OCc2ccccc2)CCP(=O)(OCC)OCC)c(=O)c1=O
Yield: 88.9 %

Procedure:
A solution of [3-[[2-(diethoxyphosphinyl)ethyl]amino]propyl]carbamic acid phenylmethyl ester (3.17 g, 8.5 mmol) in absolute ethanol (40 mL) was added over 45 minutes to 3,4-diethoxy-3-cyclobutene-1,2-dione (2.3 mL, 16 mmol) dissolved ethanol (55 mL). After leaving overnight, the reaction mixture was preadsorbed onto silica gel and purified by flash chromotography (7 cm diameter, gradient elution was 2.5-10% methanol in dichloromethane) to yield [3-[[2-(diethoxyphosphinyl)ethyl](2-ethoxy-3,4-dioxo-1-cyclobuten-1-yl)amino]propyl]carbamic acid phenylmethyl ester as a viscous oil (3.75 g, 89%); 1H NMR (CDCl3, 400 MHz): δ 7.35 (m, 5H), 5.45 (br m, NH), 5.09 (s, 2H), 4.80-4.71 (m, 2H), 4.16-4.09 (m, 4H), 3.90-3.48 (m, 4H), 3.23-3.20 (m, 2H), 2.16-2.05 (m, 2 H), 1.85-1.79 (m, 2H), 1.47, 1.41 (t, J=7 Hz, 3H), 1.34 (t, J=7 Hz, 6H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6](Cl)[C:5]([Cl:12])=[CH:4][N:3]=1.[Cl:13][C:14]1[CH:26]=[CH:25][C:17]([CH2:18][N:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)=[CH:16][CH:15]=1.C(N(C(C)C)CC)(C)C>C(O)(C)C>[Cl:12][C:5]1[C:6]([N:22]2[CH2:21][CH2:20][N:19]([CH2:18][C:17]3[CH:25]=[CH:26][C:14]([Cl:13])=[CH:15][CH:16]=3)[CH2:24][CH2:23]2)=[C:7]([N+:8]([O-:10])=[O:9])[C:2]([NH2:1])=[N:3][CH:4]=1
Reactant: Nc1ncc(Cl)c(Cl)c1[N+](=O)[O-]
Reactant: Clc1ccc(CN2CCNCC2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: Nc1ncc(Cl)c(N2CCN(Cc3ccc(Cl)cc3)CC2)c1[N+](=O)[O-]
Temperature: 45 °C

Procedure:
To a mixture of 2-amino-4,5-dichloro-3-nitropyridine (0.038 g, 0.18 mmol) and isopropanol (3 ml) was added 1-(4-chlorobenzyl)piperazine (0.042 g, 0.20 mmol) with the aid of isopropanol (0.5 ml) followed by diisopropylethylamine (0.035 ml, 0.20 mmol). The reaction mixture was heated at 45° C. for 18 h, then allowed to cool to room temperature, and diluted with isopropanol (4 ml). The precipitate was collected by filtration, washed with isopropanol and diethyl ether. The title compound was thus obtained as a yellow solid (0.034 g, 50%); 1H-NMR (500 MHz, DMSO-d6) 2.48 (br s, obscured by DMSO peak, 4H, piperazine N(CH2)2), 3.06 (br s, 4H, piperazine N(CH2)2), 3.52 (s, 2H, NCH2), 6.95 (s, 2H, NH2), 7.35 (d, J=8.50 Hz, 2H) and 7.38 (d, J=8.55 Hz, 2H) (3,5-ArH and 2,6-ArH), 8.06 (s, 1H, 6-H);
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([O:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:13]2([C:21]#[N:22])[CH2:18][CH2:17][N:16](C#N)[CH2:15][CH2:14]2)=[CH:4][CH:3]=1.C(O)(=O)C>O.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:13]2([C:21]#[N:22])[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[CH:23][CH:24]=1
Reactant: N#CN1CCC(C#N)(c2ccccc2Oc2ccc(Cl)cc2)CC1
Solvent: CC(=O)O
Solvent: O
Solvent: ClCCl
Product: N#CC1(c2ccccc2Oc2ccc(Cl)cc2)CCNCC1
Temperature: 110 °C
Reaction time: 24 h

Procedure:
A mixture of 1.2 g of 4-[2-(4-chlorophenoxy)phenyl]-1,4-dicyanopiperidine, Example 23, and 15 ml of a glacial acetic acid-3 N hydrochloric acid (1:2) solution is stirred at 110° C. for 24 hours. Thereafter, the solution is diluted with 80 ml of water before being evaporated to dryness. The solid residue is made strongly basic with ammonium hydroxide and the alkaline solution is extracted with ether. The combined ether extracts are successively dried, filtered and concentrated to dryness, leaving a white solid. The solid is dissolved in methylene chloride and this solution is chromatographed (silica gel/methylene chloride column, 10% methyl alcohol in methylene chloride as eluant). The desired fractions are concentrated to dryness leaving an oil which solidifies on standing to a white granular material, mp 128°-130° C. This material, for purposes of obtaining an analytical sample, is recrystallized from cyclohexane to provide white needles of 4-[2-(4-chlorophenoxy)phenyl]-4-cyanopiperidine.