Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:4]1([C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH2:25][CH:24]([CH2:26][O:27]C(=O)CCC)[O:23][C:22]3=[O:33])=[CH:17][CH:16]=2)[O:8][C:7]2=[N:9][C:10]([N+:12]([O-:14])=[O:13])=[CH:11][N:6]2[CH2:5]1)[CH:2]=[CH2:3].C([O-])([O-])=O.[K+].[K+]>CO.C(Cl)Cl>[CH2:1]([C:4]1([C:15]2[CH:16]=[CH:17][C:18]([N:21]3[CH2:25][CH:24]([CH2:26][OH:27])[O:23][C:22]3=[O:33])=[CH:19][CH:20]=2)[O:8][C:7]2=[N:9][C:10]([N+:12]([O-:14])=[O:13])=[CH:11][N:6]2[CH2:5]1)[CH:2]=[CH2:3]
Reactant: C=CCC1(c2ccc(N3CC(COC(=O)CCC)OC3=O)cc2)Cn2cc([N+](=O)[O-])nc2O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: ClCCl
Product: C=CCC1(c2ccc(N3CC(CO)OC3=O)cc2)Cn2cc([N+](=O)[O-])nc2O1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 8.1 %

Procedure:
To a solution of Butyric acid 3-[4-(2-allyl-6-nitro-2,3-dihydro-imidazo[2,1-b]oxazol-2-yl)-phenyl]-2-oxo-oxazolidin-5-ylmethyl ester (32 mg, 0.07 mmol) in MeOH/CH2Cl2 (3:1, 2.7 mL total) was added K2CO3 (15 mg, 0.105 mmol) and stirred for 1 h 30 min at rt, quenched with 10% aq. AcOH, diluted with water and EtOAc, concentrated and extracted with EtOAc. The concentrate was applied on prep-TLC to provide 2.2 mg of product.
Reaction SMILES: [CH:1]1([C:4](N)=O)[CH2:3][CH2:2]1.F[B-](F)(F)F.C([O+](CC)CC)C.[NH2:19][C:20]1[C:21]([NH:29][C@@H:30]2[CH2:35][O:34][C@@H:33]([CH2:36][OH:37])[CH2:32][CH2:31]2)=[C:22]2[S:28][CH:27]=[CH:26][C:23]2=[N:24][CH:25]=1>C1COCC1.C(O)C.CO>[CH:1]1([C:4]2[N:29]([C@@H:30]3[CH2:35][O:34][C@@H:33]([CH2:36][OH:37])[CH2:32][CH2:31]3)[C:21]3=[C:22]4[S:28][CH:27]=[CH:26][C:23]4=[N:24][CH:25]=[C:20]3[N:19]=2)[CH2:3][CH2:2]1
Reactant: Nc1cnc2ccsc2c1N[C@H]1CC[C@H](CO)OC1
Reactant: NC(=O)C1CC1
Agent: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Solvent: CCO
Solvent: CO
Solvent: C1CCOC1
Product: OC[C@H]1CC[C@H](n2c(C3CC3)nc3cnc4ccsc4c32)CO1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of cyclopropanecarboxamide (72.6 mg, 0.853 mmol) and triethyloxonium tetrafluoroborate (0.161 g, 0.845 mmol) in THF (2 mL) was stirred at room temperature for 2 h. The solvent was removed and the residue dissolved in ethanol (0.48 mL) and added to a suspension of {(2R,5S)-5-[(6-aminothieno[3,2-b]pyridin-7-yl)amino]tetrahydro-2H-pyran-2-yl}methanol (72.0 mg, 0.258 mmol) in ethanol (1.8 mL). The mixture was stirred at 80° C. for 1 h. The reaction mixture was cooled to room temperature, diluted with methanol, and purified with prep-LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 60 mL/min) to give the desired product. LCMS calculated for C17H20N3O2S (M+H)+: m/z=330.1. Found: 330.0.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]([N:10]=[S:11]([C:14]2[CH:15]=[C:16]([CH:21]=[CH:22][CH:23]=2)[C:17]([O:19][CH3:20])=[O:18])([CH3:13])=[O:12])=[O:9])[CH:5]=[N:6][CH:7]=1.[C:24]([C:26]1[CH:27]=[C:28]([NH:32][C:33]([C:35]2[N:39]([CH3:40])[N:38]=[C:37]([CH3:41])[CH:36]=2)=[O:34])[CH:29]=[CH:30][CH:31]=1)#[CH:25]>>[CH3:40][N:39]1[C:35]([C:33]([NH:32][C:28]2[CH:27]=[C:26]([C:24]#[C:25][C:2]3[CH:3]=[C:4]([C:8]([N:10]=[S:11]([C:14]4[CH:15]=[C:16]([CH:21]=[CH:22][CH:23]=4)[C:17]([O:19][CH3:20])=[O:18])([CH3:13])=[O:12])=[O:9])[CH:5]=[N:6][CH:7]=3)[CH:31]=[CH:30][CH:29]=2)=[O:34])=[CH:36][C:37]([CH3:41])=[N:38]1
Reactant: C#Cc1cccc(NC(=O)c2cc(C)nn2C)c1
Reactant: COC(=O)c1cccc(S(C)(=O)=NC(=O)c2cncc(Br)c2)c1
Product: COC(=O)c1cccc(S(C)(=O)=NC(=O)c2cncc(C#Cc3cccc(NC(=O)c4cc(C)nn4C)c3)c2)c1

Procedure:
In a manner similar to that described in Example 460, methyl 3-{N-[(5-bromopyridin-3-yl)carbonyl]-S-methylsulfonimidoyl}benzoate and N-(3-ethynylphenyl)-1,3-dimethyl-1H-pyrazole-5-carboxamide were reacted to give the title compound.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH:21]=[C:20]([C:22]([NH:24][NH2:25])=[O:23])[N:19]=[C:18]3[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[C:32]([F:35])([F:34])[F:33])=[CH:13][CH:12]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3].[C:36](OC(=O)C)(=O)[CH3:37].C([O-])([O-])=O.[Na+].[Na+].[Na+].[Cl-]>N1C=CC=CC=1>[CH3:36][C:37]1[O:23][C:22]([C:20]2[N:19]=[C:18]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[C:32]([F:35])([F:33])[F:34])[N:17]([C:14]3[CH:15]=[CH:16][C:11]([C:7]4[CH:8]=[CH:9][CH:10]=[C:5]([S:2]([CH3:1])(=[O:3])=[O:4])[CH:6]=4)=[CH:12][CH:13]=3)[CH:21]=2)=[N:24][N:25]=1
Reactant: CC(=O)OC(C)=O
Reactant: CS(=O)(=O)c1cccc(-c2ccc(-n3cc(C(=O)NN)nc3-c3ccccc3C(F)(F)F)cc2)c1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: c1ccncc1
Product: Cc1nnc(-c2cn(-c3ccc(-c4cccc(S(C)(=O)=O)c4)cc3)c(-c3ccccc3C(F)(F)F)n2)o1
Temperature: 120 °C
Reaction time: 1 h
Yield: 12.4 %

Procedure:
To a 0° C. solution of 1-(3′-(methylsulfonyl)biphenyl-4-yl)-2-(2-(trifluoromethyl)-phenyl)-1H-imidazole-4-carbohydrazide (192 mg, 0.383 mmol) in 1 mL pyridine was added acetic anhydride (0.085 mL, 0.767 mmol). The ice bath was removed and the reaction stirred for 1 h. The solvent was removed in vacuo and approximately 3 mL of PPA was added to the flask. The reaction was heated to 120° C. for 2 h. Upon completion of the reaction 10 mL ice water was added to the reaction. The mixture was transferred to a 150 mL Erlenmeyer flask and neutralized with 2M Na2CO3. Solid NaCl was added the solution was extracted with ethyl acetate 3×20 mL. The combined organic layers were dried with MgSO4 and the solvent was removed in vacuo. The residue was absorbed onto silica and purified by column chromatography using hexanes:ethyl acetate as eluents to afford 2-methyl-5-(1-(3′-(methylsulfonyl)biphenyl-4-yl)-2-(2-(trifluoromethyl)phenyl)-1H-imidazol-4-yl)-1,3,4-oxadiazole (25 mgs, 13%) as a white solid. 1H-NMR (DMSO, 400 MHz) δ 8.53 (s, 1H), 8.15-8.14 (m, 1H), 8.05-8.02 (m, 1H), 7.93-7.90 (m, 1H), 7.88-7.83 (m, 3H), 7.75-7.71 (m, 3H), 7.69-7.66 (m, 1H), 7.41 (d, J=8.58 Hz, 2H), 3.28 (s, 3H), 2.58 (s, 3H); MS (ES): 525.0 [M+H]+ and 547.3 [M+Na]+.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:6][CH:7]=1.[CH3:12][C:13]1[CH:14]=[C:15]([N:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[CH:16]=[CH:17][CH:18]=1.C(N(CC)CC)C>C1C=CC=CC=1>[CH3:12][C:13]1[CH:14]=[C:15]([N:19]2[CH2:24][CH2:23][N:22]([C:2]3[N:3]=[N:4][C:5]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:6][CH:7]=3)[CH2:21][CH2:20]2)[CH:16]=[CH:17][CH:18]=1
Reactant: CS(=O)(=O)c1ccc(Cl)nn1
Reactant: Cc1cccc(N2CCNCC2)c1
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: Cc1cccc(N2CCN(c3ccc(S(C)(=O)=O)nn3)CC2)c1
Reaction time: 24 h
Yield: 89 %

Procedure:
A mixture of 3.2 parts of 3-chloro-6-(methylsulfonyl)pyridazine, 3 parts of 1-(3-methylphenyl)piperazine, 2 parts of N,N-diethylethanamine and 180 parts of benzene was stirred for 24 hours at reflux. The reaction mixture was evaporated. Water was added to the residue. The precipitated product was filtered off, washed with water and dissolved in trichloromethane. The solution was dried, filtered and evaporated. The residue was crystallized from methanol. The product was filtered off and dried, yielding 5 parts (89%) of 3-[4-(3-methylphenyl)-1piperazinyl]-6-(methylsulfonyl)pyridazine; mp. 201° C. (compound 209).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH:9]=[C:10]2[CH2:15][CH2:14][N:13]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:12][CH2:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.B.O.S(=O)(=O)(O)[OH:26]>CCOCC.C1COCC1.CCN(CC)CC.CCOC(C)=O>[CH2:16]([N:13]1[CH2:12][CH2:11][CH:10]([C:9](=[O:26])[CH2:8][CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:15][CH2:14]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: C(CCc1ccccc1)=C1CCN(Cc2ccccc2)CC1
Reactant: O=S(=O)(O)O
Agent: B
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(CCc1ccccc1)C1CCN(Cc2ccccc2)CC1
Reaction time: 1.5 h

Procedure:
To a solution of 1.115 g 4-(3-phenylpropylidene)-1-benzylpiperidine from Step B in 40 mL anhydrous ether under nitrogen was added 11.5 mL 1M borane solution in THF with stirring. After stirring for three hours, 2 mL of water was added dropwise, and the mixture was stirred for 30 min. After cooling with ice, a solution prepared from 0.287 g chromic anhydride, 0.624 mL concentrated sulfuric acid and 15 mL water was added dropwise with vigorous magnetic stirring over 5 minutes. After stirring for an additional 5 minutes, the cooling bath was removed. After 1.5 hours more, 100 mL each of 0.5N NaOH & ether was added, and the mixture was stirred to disolve a solid residue. After separating the layers, the aqueous layer was extracted with 2×100 mL ether. The combined ether layer was washed with 100 mL each of EDTA, water, and saturated brine, dried over Na2SO4, and concentrated under reduced pressure to give a colorless gel. The oxidation step were then repeated with half of the reagent used above. Flash chromatography on silica gel with 30˜50% EtOAc in hexanes with 3% (v/v) Et3N gave 0.293 g of the title compound as a colorless gel. RF: 0.41 (30% EtOAc in hexanes having 3% (v/v) Et3N). 1H NMR (500 MHz, CDCl3): δ7.17˜7.33 (m, ˜10H), 3.51 (s, 2H), 2.88˜2.92 (m, 2H), 2.75˜2.80 (m, 2H), 2.26˜2.32 (m, 1H), 1.98˜2.04 (m, 2H), 1.76˜1.82 (m, 2H), 1.63˜1.72 (m, 4H). ESI-MS 308.1 (M+H), HPLC A: 2.45 min.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][C:15]=1[N+:16]([O-:18])=[O:17])[CH:5]=[C:6]1[S:10][C:9](=[O:11])[NH:8][C:7]1=[O:12].[CH2:19]([NH2:21])[CH3:20]>COCCOC>[CH2:19]([NH:21][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][C:15]=1[N+:16]([O-:18])=[O:17])[CH:5]=[C:6]1[S:10][C:9](=[O:11])[NH:8][C:7]1=[O:12])[CH3:20]
Reactant: O=C1NC(=O)C(=Cc2ccc([N+](=O)[O-])c(F)c2)S1
Reactant: CCN
Solvent: COCCOC
Product: CCNc1cc(C=C2SC(=O)NC2=O)ccc1[N+](=O)[O-]
Temperature: 60 °C

Procedure:
5-(3-Fluoro-4-nitro-benzylidene)-thiazolidine-2,4-dione (200 mg, 0.75 mmol, 1 eq.), was dissolved in DME (6 mL) and TEA (208 μL, 1.5 mmol, 2 eq.) and a solution of ethylamine (2 eq.) was added. The reaction mixture was shaken at 60° C. over night. The solvent was removed in vacuo and residue dissolved in ethyl acetate and washed with 10% ammonium chloride aqueous solution. The organic layer was dried on Na2SO4 and the solvent evaporated to give the corresponding aniline derivative as either red oil, which was used for the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[CH:4](/[CH:5]=[CH:6]\[C:7]([O:9][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)=[O:8])[CH:3]1[C:16]([OH:18])=[O:17].[C:20]([C@@H:22](O)[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([O:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:24]=1)#[N:21]>>[CH3:1][C:2]1([CH3:19])[C@@H:4](/[CH:5]=[CH:6]\[C:7]([O:9][CH:10]2[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]2)=[O:8])[C@H:3]1[C:16]([O:18][C@H:22]([C:20]#[N:21])[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([O:29][C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:24]=1)=[O:17]
Reactant: N#C[C@@H](O)c1cccc(Oc2ccccc2)c1
Reactant: CC1(C)C(/C=C\C(=O)OC2CCCCC2)C1C(=O)O
Product: CC1(C)[C@H](C(=O)O[C@H](C#N)c2cccc(Oc3ccccc3)c2)[C@@H]1/C=C\C(=O)OC1CCCCC1
Yield: 42.4 %

Procedure:
Using the procedure of Step D in Example 7, 2.5 g of the product of Step C and 2.2 g of (S)α-cyano-3-phenoxy-benzyl alcohol were reacted and the product was chromatographed over silica gel. Elution with a 9-1 hexane-ether mixture yielded 1.883 g of (S)α-cyano-3-phenoxy-benzyl (1R,cis) 2,2-dimethyl-3-[Z-2-(cyclohexyloxycarbonyl)-ethenyl]-cyclopropane-carboxylate with a specific rotation of [α]D20 =+41°±2.5° (c=0.5% in chloroform).
Reaction SMILES: Br[C:2]1[C:7]([F:8])=[CH:6][C:5]([N:9]2[C:18]3[C:13](=[CH:14][C:15]([S:19]([NH:22][C:23]4[CH:27]=[CH:26][O:25][N:24]=4)(=[O:21])=[O:20])=[CH:16][CH:17]=3)[N:12]=[CH:11][C:10]2=[O:28])=[C:4]([O:29][CH3:30])[CH:3]=1.CN(C=O)C.C(NC(C)C)(C)C.[C:43]([CH:45]1[CH2:49][CH2:48][CH2:47][CH2:46]1)#[CH:44]>CCOC(C)=O.[Cu]I.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>[CH:45]1([C:43]#[C:44][C:2]2[C:7]([F:8])=[CH:6][C:5]([N:9]3[C:18]4[C:13](=[CH:14][C:15]([S:19]([NH:22][C:23]5[CH:27]=[CH:26][O:25][N:24]=5)(=[O:20])=[O:21])=[CH:16][CH:17]=4)[N:12]=[CH:11][C:10]3=[O:28])=[C:4]([O:29][CH3:30])[CH:3]=2)[CH2:49][CH2:48][CH2:47][CH2:46]1
Reactant: COc1cc(Br)c(F)cc1-n1c(=O)cnc2cc(S(=O)(=O)Nc3ccon3)ccc21
Reactant: C#CC1CCCC1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CC(C)NC(C)C
Product: COc1cc(C#CC2CCCC2)c(F)cc1-n1c(=O)cnc2cc(S(=O)(=O)Nc3ccon3)ccc21
Temperature: 60 °C
Yield: 65 %

Procedure:
A vial was charged with 1-(4-bromo-5-fluoro-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoxaline-6-sulfonamide (147.0 mg, 0.297 mmol), copper(i) iodide (8.48 mg, 0.045 mmol), and Pd(PPh3)4 (34.3 mg, 0.030 mmol). The vial was flushed with Ar (g), then DMF (1484 μl), N,N-diisopropylamine (423 μl, 2.97 mmol), and ethynylcyclopentane (140 mg, 1.484 mmol) were added in sequence. The vial was sealed and heated to 60° C. for 1 h. The mixture was cooled, diluted with EtOAc, washed with 2N aq. HCl (2×), dried over sodium sulfate, filtered, and concentrated. The residue was taken up in DMSO-MeOH and filtered through a 0.2 micron filter. The filtrate was purified by reverse-phase HPLC (25-75 CH3CN/H2O with 0.1% TFA). Fractions containing desired product were combined and lyophilized to give 1-(4-(cyclopentylethynyl)-5-fluoro-2-methoxyphenyl)-N-3-isoxazolyl-2-oxo-1,2-dihydro-6-quinoxalinesulfonamide (98.2 mg, 65%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ=11.74 (s, 1H), 8.75 (d, J=2.0 Hz, 1H), 8.47 (s, 1H), 8.30 (d, J=2.3 Hz, 1H), 7.90 (dd, J=2.2, 8.8 Hz, 1H), 7.48 (d, J=9.1 Hz, 1H), 7.38 (d, J=6.3 Hz, 1H), 6.95 (d, J=8.9 Hz, 1H), 6.49 (d, J=2.0 Hz, 1H), 3.67 s, 3H), 2.98 (t, J=7.3 Hz, 1H), 2.09-1.98 (m, 2H), 1.80-1.58 (m, 6H). m/z (ESI) 509.2 (M+H)+.
Reaction SMILES: [CH:1](=[O:5])[CH:2]([CH3:4])[CH3:3].[C:6](#[N:9])[CH:7]=[CH2:8].[OH-].[Na+]>O1CCOCC1.C1(C=CC(O)=CC=1)O>[CH3:3][C:2]([CH3:4])([CH:1]=[O:5])[CH2:8][CH2:7][C:6]#[N:9]
Reactant: C=CC#N
Reactant: CC(C)C=O
Agent: Oc1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(C)(C=O)CCC#N
Temperature: 65 °C
Reaction time: 16 h
Yield: 62.3 %

Procedure:
To a stirred solution of isobutyraldehyde (6.3 mL, 69.3 mmol), hydroquinone (25 mg) and acrylonitrile (5.7 mL, 86.7 mmol) in 1,4-dioxane (25 mL) was added 5% sodium hydroxide (4.6 mL). The reaction was heated at 65° C. for 2.5 hours and then stirred at ambient temperature for 16 hours. The dioxane was removed in vacuo and the residue was taken up in dichloromethane (80 mL). The dichloromethane was washed with water (3×80 mL), dried (magnesium sulfate), concentrated in vacuo and then distilled to afford the title compound (5.4 g, 63%) as a colorless liquid; bp 70° C. (0.8 mm);
Reaction SMILES: [CH2:1]1[O:12][C:4]([CH:6]2[CH2:10][CH2:9][CH2:8][C:7]2=[O:11])(O)[O:3][CH2:2]1.C([N:15](CC)CC)C.ClC(OCC)=O>C(Cl)(Cl)Cl>[CH2:1]1[O:12][C:4]([CH:6]2[CH2:10][CH2:9][CH2:8][C:7]2=[O:11])([NH2:15])[O:3][CH2:2]1
Reactant: CCN(CC)CC
Reactant: O=C1CCCC1C1(O)OCCO1
Agent: CCOC(=O)Cl
Solvent: ClC(Cl)Cl
Product: NC1(C2CCCC2=O)OCCO1
Reaction time: 0.5 h

Procedure:
To a stirred, cold (0° C.) solution of 1.72 g (0.01 mole) of 2-oxocyclopentanecarboxylic acid ethylene ketal in 35 ml of chloroform was added first 1.11 g (0.011 mole) of triethylamine and then 1.085 g (0.01 mole) of ethyl chloroformate, the latter being added in dropwise fashion. After stirring for 30 minutes, dry ammonia gas was bubbled in over about 5 minutes. A white solid separated while the mixture was stirred at about 0° C. for 30 minutes. The solid was separated by filtration and washed with chloroform, and the combined washings and filtrate were evaporated to provide a white solid residue of 2-oxocyclopentanecarboxamide ethylene ketal. Infrared spectral analysis showed the product to be identical to that obtained in Example 1.
Reaction SMILES: [O:1]=[S:2]1(=[O:36])[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]([C:18]3[CH:23]=[CH:22][C:21]([C:24]4[CH:29]=[C:28]([NH2:30])[CH:27]=[CH:26][C:25]=4[O:31][C:32]([F:35])([F:34])[F:33])=[CH:20][CH:19]=3)=[O:17])=[CH:11][CH:10]=2)[CH2:4][CH2:3]1.CN1CCOCC1.[CH:44]1([C:47](Cl)=[O:48])[CH2:46][CH2:45]1>ClCCl>[O:36]=[S:2]1(=[O:1])[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([NH:15][C:16]([C:18]3[CH:23]=[CH:22][C:21]([C:24]4[CH:29]=[C:28]([NH:30][C:47]([CH:44]5[CH2:46][CH2:45]5)=[O:48])[CH:27]=[CH:26][C:25]=4[O:31][C:32]([F:35])([F:33])[F:34])=[CH:20][CH:19]=3)=[O:17])=[CH:13][CH:14]=2)[CH2:4][CH2:3]1
Reactant: Nc1ccc(OC(F)(F)F)c(-c2ccc(C(=O)Nc3ccc(CN4CCS(=O)(=O)CC4)cc3)cc2)c1
Reactant: O=C(Cl)C1CC1
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: O=C(Nc1ccc(CN2CCS(=O)(=O)CC2)cc1)c1ccc(-c2cc(NC(=O)C3CC3)ccc2OC(F)(F)F)cc1
Reaction time: 18 h
Yield: 90.9 %

Procedure:
5′-Amino-2′-trifluoromethoxy-biphenyl-4-carboxylic acid [4-(1,1-dioxo-1lambda*6*-thiomorpholin-4-ylmethyl)-phenyl]-amide (50 mg) in dichloromethane (1 ml) containing N-methylmorpholine (0.03 ml) was treated with cyclopropanecarbonyl chloride (9 mg), the mixture being stirred for 18 h. The solvent was then evaporated and the residue purified on silica gel. Elution with dichloromethane:ethanol:0.880 ammonia; 800:8:1 to 100:8:1 gave a colourless solid (46 mg).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH:15]([OH:32])[CH:16]([N:23]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=[CH:24]2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:33].Cl.N1(C(C2C=CC=CC=2)C(O)CN2CCN(C)CC2)C2C(=CC=CC=2)C=C1.C(OC(N1CCNCC1)=O)(C)(C)C.Cl.O1CCOCC1>C(OCC)C>[ClH:33].[ClH:33].[N:23]1([CH:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:15]([OH:32])[CH2:14][N:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24]1
Reactant: CC(C)(C)OC(=O)N1CCN(CC(O)C(c2ccccc2)n2ccc3ccccc32)CC1
Agent: CC(C)(C)OC(=O)N1CCNCC1
Agent: CN1CCN(CC(O)C(c2ccccc2)n2ccc3ccccc32)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: OC(CN1CCNCC1)C(c1ccccc1)n1ccc2ccccc21
Temperature: 25 °C
Reaction time: 15 h

Procedure:
In an analogous manner to EXAMPLE 1, step 3 (2SR,3RS)-4-(2-hydroxy-3-indol-1-yl-3-phenyl-propyl)-piperazine-1-carboxylic acid tert-butyl ester was prepared from (2RS,3RS)-toluene-4-sulfonic acid 2-hydroxy-3-indol-1-yl-3-phenyl-propyl ester (EXAMPLE 1, step 3, 0.211 g, 0.5 mmol) and tert-butyl-1-piperazine carboxylate (0.19 g, 1.0 mmol). The product was dissolved in diethyl ether (3 mL) and treated with a 4N solution of hydrochloric acid in dioxane (0.75 mL, 3.0 mmol). The reaction mixture was then stirred at room temperature for 15 hours, and the crude solid product was filtered and recrystallized from ethanol with a minimum amount of diethyl ether to give the titled compound, (1RS,2SR)-1-(1H-indol-1-yl)-1-phenyl-3-piperazin-1-ylpropan-2-ol dihydrochloride as a tan solid. MS (ESI) m/z 336 ([M+H]+); HRMS: calcd for C21H25N30+H+, 336.20704; found (ESI, [M+H]+), 336.2085.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1.C(N(CC)CC)C.[C:16]1([CH3:26])[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH3:26][C:16]1[CH:21]=[CH:20][C:19]([S:22]([NH:1][CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=2)(=[O:24])=[O:23])=[CH:18][CH:17]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: NCc1ccccn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)NCc2ccccn2)cc1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 71.2 %

Procedure:
To a 0° C. solution of 15.0 g of 2-(aminomethyl)pyridine, 15.44 g of triethylamine and 150 ml of methylene chloride is added 29.1 g of p-toluenesulfonyl chloride in 100 ml of methylene chloride. The reaction mixture is allowed to warm to room temperature and is stirred for 4.5 hours. The solution is poured into saturated sodium bicarbonate and extracted with methylene chloride. The combined organic layers are washed with saturated sodium chloride, dried and concentrated in vacuo. The residue is purified by column chromatography (silica gel: 50% ethyl acetate/hexane 20% methyl alcohol/ethyl acetate); then recrystallized from ethyl acetate/hexane to give 25.9 g of the desired product as colorless crystals.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[C:10]1([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>C1(C)C=CC=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]>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([N:16]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:3][CH:4]=1)#[N:7]
Reactant: N#Cc1ccc(Br)cc1
Reactant: c1ccc(Nc2ccccc2)cc1
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: N#Cc1ccc(N(c2ccccc2)c2ccccc2)cc1
Reaction time: 1 h
Yield: 97.3 %

Procedure:
The above general procedure was followed using 4-bromobenzonitrile (188 mg, 1.03 mmol) and diphenylamine (169 mg, 1.00 mmol) with 1 mol % Pd(dba)2 and 0.8 mol % tri-t-butylphosphine in 1.5 mL of toluene. After one hour, the reaction mixture was adsorbed onto silica gel and chromatographed with 50% toluene/hexanes to give 263 mg (97%) of N-(4-cyanophenyl)diphenylamine as a white solid. 1H NMR (500 MHz, C6D6) δ 6.97 (t, J=8 Hz, 4H), 6.92 (d, J=8.9 Hz, 2H), 6.86-6.83 (m, 6H), 6.56 (d, J=8.7 Hz, 2H). 13C NMR (125 MHz, C6D6) δ 151.3, 146.6, 133.2, 129.9, 126.1, 124.9, 120.5, 119.4, 104.0.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([C:10]#[C:11]C(O)(C)C)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[H-].[Na+]>C1(C)C=CC=CC=1>[C:10]([C:8]1[CH:7]=[CH:6][C:3]([C:4]#[N:5])=[C:2]([F:1])[CH:9]=1)#[CH:11]
Reactant: CC(C)(O)C#Cc1ccc(C#N)c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: C#Cc1ccc(C#N)c(F)c1
Yield: 66.3 %

Procedure:
To a solution of 2-fluoro-4-(3-hydroxy-3-methyl-but-1-ynyl)-benzonitrile (2.6 g, 13 mmol) in toluene (55 mL) was added NaH (53 mg of a 60% suspension in mineral oil, 1.3 mmol). The reaction mixture was heated to reflux. After refluxing for several hours, heating was discontinued, and the cooled reaction mixture was quenched by the addition of 2M Na2CO3 solution. The layers were separated and the toluene layer was washed with H2O (2×20 mL), brine (25 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to afford the crude product. The crude material was purified by flash chromatography eluting with a gradient from 0% to 10% ethyl acetate/hexane to afford 4-ethynyl-2-fluoro-benzonitrile (1.25 g, 66% yield). 1H-NMR (400 MHz, CDCl3): δ 7.61-7.57 (1H, m), 7.38-7.30 (2H, m), 3.36 (1H, s).
Reaction SMILES: [Na].[C:2]1([SH:8])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(S[C:12]([CH3:22])([CH3:21])[C:13]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[O:14])C>C(O)C>[C:2]1([S:8][C:12]([CH3:21])([CH3:22])[C:13]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[O:14])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)CC(=O)C(C)(C)SCC
Reactant: Sc1ccccc1
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)CC(=O)C(C)(C)Sc1ccccc1
Reaction time: 3 h
Yield: 84.2 %

Procedure:
To a solution of 11.5 g of metallic sodium dissolved in 250 ml of ethanol, 55 g of thiophenol was added, and then ethanol was distilled off. After adding 400 ml of formamide to the residue to form a uniform solution, the solution was immersed in an ice bath, and to the solution 119 g of ethyl (2-ethylthio2-methylpropionyl)acetate was gradually added. After the completion of the addition, the reaction mixture was removed from the ice bath and stirred for three hours. The reaction mixture was poured into one liter of water and extracted twice, each time with 800 ml of diethyl ether. The extract was washed with a saturated aqueous sodium chloride solution and dried with anhydrous sodium carbonate. After distilling off the diethyl ether, the residue was recrystallized from n-hexane to obtain 112 g (yield 84%) of the intended compound having a melting point of 44° to 45° C.