Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[CH:15]=[CH:14][C:13]([C:16](=[O:22])[CH2:17][CH2:18][C:19]([OH:21])=[O:20])=[CH:12][CH:11]=1)([O-:3])=[O:2].C1(N)CCCCC1>>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[CH:15]=[CH:14][C:13]([CH:16]([OH:22])[CH2:17][CH2:18][C:19]([OH:21])=[O:20])=[CH:12][CH:11]=1)([O-:3])=[O:2]
Reactant: O=C(O)CCC(=O)c1ccc(-c2ccccc2[N+](=O)[O-])cc1
Solvent: NC1CCCCC1
Product: O=C(O)CCC(O)c1ccc(-c2ccccc2[N+](=O)[O-])cc1
Yield: 62.5 %

Procedure:
Prepared analogous to Example 25 from 4-(2'-nitro-4-biphenylyl)-4-oxo-butyric acid. Yield: 62.5% of theory; m.p. 114°-115° C.; melting point of the cyclohexylamine salt; 170° C. (decomp.).
Reaction SMILES: [O:1]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH:14]([C:16]1[O:17][C:18]([CH3:21])=[N:19][N:20]=1)[OH:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:22]([O:29]C1C=CC(OCCCCCCC=O)=CC=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[Cl-].[Ce+3].[Cl-].[Cl-].CN1NC=CO1>>[CH2:22]([O:29][C:5]1[CH:4]=[CH:3][C:2]([O:1][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH:14]([C:16]2[O:17][C:18]([CH3:21])=[N:19][N:20]=2)[OH:15])=[CH:7][CH:6]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: Cc1nnc(C(O)CCCCCCOc2ccccc2)o1
Reactant: O=CCCCCCCOc1ccc(OCc2ccccc2)cc1
Agent: CN1NC=CO1
Agent: [Ce+3]
Agent: [Cl-]
Product: Cc1nnc(C(O)CCCCCCOc2ccc(OCc3ccccc3)cc2)o1
Yield: 55 %

Procedure:
The synthesis was carried out analogous to the preparation of 64.1 using 62.2 (0.1 g, 0.32 mmol), cerium chloride (0.44 g, 1.6 mmol) and 63 (0.42 g, 1.6 mmol). Purification by flash column chromatography on silica gel gave pure 64.2 (0.077 mg, 55% yield) as a white solid (m p 98-100° C.).
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][CH2:5][C:6]1[N:7]2[CH:13]=[N:12][CH:11]=[C:8]2[S:9][CH:10]=1.C(N(CC)CC)C.[S:21](Cl)(=[O:24])(=[O:23])[NH2:22]>CN(C=O)C>[NH2:22][S:21]([N:4]([CH2:5][C:6]1[N:7]2[CH:13]=[N:12][CH:11]=[C:8]2[S:9][CH:10]=1)[CH2:3][CH2:2][OH:1])(=[O:24])=[O:23]
Reactant: OCCNCc1csc2cncn12
Reactant: NS(=O)(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: NS(=O)(=O)N(CCO)Cc1csc2cncn12
Temperature: -25 °C
Reaction time: 4 h

Procedure:
A 410 mg potion of 3-[N-(2-hydroxyethyl)amino]methyl imidazo[5,1-b]thiazole was dissolved in 6 ml of DMF, and 1.40 ml of triethylamine and 491 mg of sulfamoyl chloride were added thereto at -30° C., followed by stirring at -30 to -20° C. for 4 hours. The reaction solution was concentrated under reduced pressure, dissolved in water, adjusted to pH 7.5 with an aqueous sodium hydrogencarbonate solution, and then purified by Diaion HP-20 Resin and Cephadex LH-20, whereby 59 mg of 3-[N-aminosulfonyl-N-(2-hydroxyethyl)amino]methylimidazo[5,1-b]thiazole was obtained from the first half of the fraction of Cephadex LH-20.
Reaction SMILES: [NH2:1][C@@H:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]#[N:13])[CH:10]=2)[CH2:5][C:4]([CH3:15])([CH3:14])[C@H:3]1[OH:16].C(N(CC)CC)C.Cl[CH2:25][CH2:26][CH2:27][C:28](Cl)=[O:29].Cl>ClCCl>[O:29]=[C:28]1[CH2:27][CH2:26][CH2:25][N:1]1[C@@H:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]#[N:13])[CH:10]=2)[CH2:5][C:4]([CH3:14])([CH3:15])[C@H:3]1[OH:16]
Reactant: O=C(Cl)CCCCl
Reactant: CC1(C)Cc2ccc(C#N)cc2[C@@H](N)[C@@H]1O
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(C)Cc2ccc(C#N)cc2[C@@H](N2CCCC2=O)[C@@H]1O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of trans-1-amino-3,3-dimethyl-7-cyano-1,2,3,4-tetrahydro-2-napthol (0.5 g), triethylamine (0.5 ml) and 4-chlorobutyrylchloride (0.33 g) in dichloromethane (35 ml) was stirred at room temperature for 1 h. The solution was poured into dilute hydrochloric acid, and the organic layer separated and washed with sodium carbonate solution and dried over magnesium sulphate. Removal of drying agent and solvent gave the crude amide (0.8 g), which was not purified further, but dissolved in dry tetrahydrofuran (60 ml) and sodium hydride (75 mg of 80% dispersion in oil) added portionwise, under nitrogen. The mixture was then stirred at room temperature for 1.5 h, then poured into water and extracted into ethyl acetate. The organic extracts were washed with brine and dried over magnesium sulphate. Removal of drying agent and solvent, followed by crystallisation of the residue from ethyl acetate: 60°-80° petrol (1:1) gave the title compound as colourless microcrystals (0.35 g) having m.p. 203°-4° C.
Reaction SMILES: O.P([O-])([O-])(O)=O.[K+:7].[K+].C(O)C.[CH3:12][C:13]([C@@H:29]1[C:35](=[O:36])[N:34]2[C@@H:30]1[CH2:31][C:32]([S:50][CH2:51][CH2:52][NH:53]C(OCC1C=CC([N+]([O-])=O)=CC=1)=O)=[C:33]2[C:37]([O:39]CC1C=CC([N+]([O-])=O)=CC=1)=[O:38])([O:15]C(OCC1C=CC([N+]([O-])=O)=CC=1)=O)[CH3:14]>O1CCOCC1.[Pt]=O>[NH2:53][CH2:52][CH2:51][S:50][C:32]1[CH2:31][C@H:30]2[N:34]([C:35](=[O:36])[C@H:29]2[C:13]([OH:15])([CH3:14])[CH3:12])[C:33]=1[C:37]([O-:39])=[O:38].[K+:7]
Reactant: CC(C)(OC(=O)OCc1ccc([N+](=O)[O-])cc1)[C@@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(SCCNC(=O)OCc3ccc([N+](=O)[O-])cc3)C[C@H]12
Agent: O=[Pt]
Agent: O=P([O-])([O-])O
Agent: [K+]
Solvent: O
Solvent: CCO
Solvent: C1COCCO1
Product: CC(C)(O)[C@@H]1C(=O)N2C(C(=O)[O-])=C(SCCN)C[C@H]12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of platinum oxide (60.0 mg), water (4.2 ml), aqueous dipotassium hydrogen phosphate (1.0M, 0.385 ml) and ethanol (0.6 ml) was shaken for 30 minutes under a hydrogen atmosphere (50 psi) at ambient temperature. The mixture was added to a solution of 4-nitrobenzyl (5R,6R)-6-[1-methyl-1-(4-nitrobenzyloxycarbonyloxy)ethyl]-3-[2-(4-nitrobenzyloxycarbonylamino)-ethylthio]-7-oxo-1-azabicyclo-[3.2.0]hept-2-ene-2-carboxylate (60.0 mg) in dioxane (7.2 ml) and shaken for 2 hours under a hydrogen atmosphere (50 psi) at ambient temperature. The reaction mixture was filtered using diatomaceous earth and the filter-cake was washed with water (20 ml). The combined filtrates (32 ml) were lyophilized over a period of 4 hours. The residue was chromatographed on non-ionic adsorption resin, Diaion HP-20-AG (trade mark, made by Mitsubishi Chemical Industries) (13×230 mm) eluting with water (120 ml) and then a mixture of water and isopropanol (19:1, 60 ml). The fractions showing UV maxima at 296 nm were collected, concentrated and lyophilized to give potassium (5R,6R)-3-(2-aminoethylthio)-6-(1-hydroxy-1-methylethyl)-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (10.4 mg) as pale yellow powder.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[CH:7][C:8]2[CH2:9][C:10]3[C:15]([C:16]=2[CH:17]=1)=[CH:14][C:13]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:12][CH:11]=3)([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.CCCCCC.[C:33]([C:37]1[CH:38]=[C:39]([CH3:55])[C:40](=[C:42]([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[CH:41]=1)([CH3:36])([CH3:35])[CH3:34].O>C(OCC)C>[C:33]([C:37]1[CH:38]=[C:39]([CH3:55])[CH:40]([C:42]([C:11]2[C:10]3[CH2:9][C:8]4[C:16](=[CH:17][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:6][CH:7]=4)[C:15]=3[CH:14]=[C:13]([C:18]([CH3:21])([CH3:20])[CH3:19])[CH:12]=2)([C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=2)[C:49]2[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=2)[CH:41]=1)([CH3:34])([CH3:35])[CH3:36]
Reactant: CC1=CC(C(C)(C)C)=CC1=C(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)c1ccc2c(c1)-c1cc(C(C)(C)C)ccc1C2
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Solvent: O
Product: CC1=CC(C(C)(C)C)=CC1C(c1ccccc1)(c1ccccc1)c1cc(C(C)(C)C)cc2c1Cc1ccc(C(C)(C)C)cc1-2
Temperature: 25 °C

Procedure:
In a 200 ml three-necked flask equipped with a magnetic stirrer chip and three-way cock thoroughly purged with nitrogen, 3.01 g of 3,6-di-tert-butyl-fluorene (10.8 mmol) was dissolved in 80 ml of dehydrated diethyl ether in a nitrogen atmosphere. To the solution, 7.6 ml of a n-butyl lithium/hexane solution (1.56M: 11.9 mmol) was gradually added dropwise in an ice bath and stirred at room temperature over night. To the reaction solution, 50 ml of a solution prepared by dissolving 4.86 g of 3-tert-butyl-1-methyl-6,6-diphenyl fulvene (16.2 mmol) in 50 ml of dehydrated diethyl ether was added and stirred with refluxing for 13 days. To the reaction mixture, 30 ml of distilled water was gradually added dropwise in an ice bath, and thereafter diethyl ether was added to separate an organic phase. The organic phase was washed with distilled water and saturated brine. The organic phase was dried with anhydrous magnesium sulfate, thereafter the drying agent was filtered off and the solvent was distilled off from the filtrate under reduced pressure to give red solid. The red solid was re-crystallized using ethanol and dried under reduced pressure, and thereby the aimed compound was obtained in an amount of 4.42 g (7.63 mmol) as a pale yellow solid (yield: 71%).
Reaction SMILES: C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2N(C)C)CCCCC1.[CH:29]([N:32]1[CH2:37][CH2:36][N:35]([C:38]([CH:40]2[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]2)=[O:39])[CH2:34][C@@H:33]1[CH3:46])([CH3:31])[CH3:30].Br[C:48]1[CH:49]=[N:50][C:51]([C:54]([F:57])([F:56])[F:55])=[N:52][CH:53]=1.CC(C)([O-])C.[Na+].[ClH:64]>O1CCOCC1.CO.C(Cl)Cl.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[ClH:64].[CH:29]([N:32]1[CH2:37][CH2:36][N:35]([C:38]([CH:40]2[CH2:41][CH2:42][N:43]([C:48]3[CH:49]=[N:50][C:51]([C:54]([F:57])([F:56])[F:55])=[N:52][CH:53]=3)[CH2:44][CH2:45]2)=[O:39])[CH2:34][C@@H:33]1[CH3:46])([CH3:31])[CH3:30]
Reactant: CC(C)N1CCN(C(=O)C2CCNCC2)C[C@@H]1C
Reactant: FC(F)(F)c1ncc(Br)cn1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: CO
Product: CC(C)N1CCN(C(=O)C2CCN(c3cnc(C(F)(F)F)nc3)CC2)C[C@@H]1C
Reaction time: 0.08 h

Procedure:
Tris(dibenzylideneacetone)dipalladium(0)(30 mg) and 2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl (60 mg) were added to a solution of (S)-1-isopropyl4-(piperidine-4-carbonyl]-2-methyl piperazine (free base compound from D29)(0.134 g) and 5-bromo-2-trifluromethylpyrimidine (D30)(0.12 g) in degassed dioxane (3 ml). This was followed by the addition of sodium-t-butoxide (0.1 g). The reaction was carried out in a Personal Chemistry microwave reactor at 120° C. for 5 min. After cooling the reaction mixture was diluted with methanol (10 ml), the solids were filtered off and the filtrate was applied to an SCX resin column. Initial elution with methanol was followed by elubon with methanolic ammonia (2M). The ammoniacal eluates were concentrated to a gum and further purified by silica gel chromatography, eluting with 0-10% methanolic ammonia (2M) in DCM. Evaporation of the appropriate fractions gave the free base which was dissolved in DCM (3 ml) and treated with ethereal 1M HCl (2 ml) to give the title compound (E89) as a light yellow solid (56 mg). MS electrospray (+ve) 400 (MH+). 1H NMR δ [MeOH-d4]: 1.28-1.29 (3H, m), 1.4-1.5 (8H, m), 1.8-1.9 (4H, m), 2.98-3.2 (3H, m), 3.45-3.57 (3H, m), 4.0-4.08 (3H, m), 4.35-4.45 (1H, m), 4.6-4.78 (1H, s), 8.5 (2H, s).
Reaction SMILES: ClC1C=C(Cl)C=CC=1C(Cl)=O.[Cl:12][C:13]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=1[C:20]([N:22]=[C:23]=[S:24])=[O:21].[CH3:25][O:26][C:27]1[CH:28]=[C:29]2[C:34](=[CH:35][C:36]=1[O:37][CH3:38])[N:33]=[CH:32][CH:31]=[C:30]2[O:39][C:40]1[CH:46]=[CH:45][C:43]([NH2:44])=[CH:42][CH:41]=1.C1(C)C=CC=CC=1>C(O)C>[Cl:12][C:13]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=1[C:20]([N:22]=[C:23]=[S:24])=[O:21].[Cl:12][C:13]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=1[C:20]([NH:22][C:23]([NH:44][C:43]1[CH:45]=[CH:46][C:40]([O:39][C:30]2[C:29]3[C:34](=[CH:35][C:36]([O:37][CH3:38])=[C:27]([O:26][CH3:25])[CH:28]=3)[N:33]=[CH:32][CH:31]=2)=[CH:41][CH:42]=1)=[S:24])=[O:21]
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Agent: O=C(Cl)c1ccc(Cl)cc1Cl
Agent: O=C(N=C=S)c1ccc(Cl)cc1Cl
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4ccc(Cl)cc4Cl)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 78 %

Procedure:
2,4-Dichloro-1-benzenecarbonyl isothiocyanate was prepared using commercially available 2,4-dichloro-1-benzenecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 2,4-Dichloro-1-benzenecarbonyl isothiocyanate was dissolved in ethanol (1 ml) to prepare a solution. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (50 mg), toluene (5 ml), and ethanol (1 ml) were added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (70 mg, yield 78%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=O)[CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:5][CH:4]=1.Cl.[NH2:19][OH:20].C([O-])(=O)C.[Na+]>C(O)C.O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[N:19][OH:20])[CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:5][CH:4]=1
Reactant: NO
Reactant: COc1ccc(C(=O)Cc2ccccc2)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COc1ccc(C(Cc2ccccc2)=NO)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution consisting of 1-(4-methoxy-phenyl)-2-phenyl-ethanone (commercially available, 1011 g, 4468 mmoles) in absolute ethanol (2 gallons) is added hydroxylamine hydrochloride (373 g, 5362 mmoles) and sodium acetate (440 g, 5362 mmoles.) The reaction mixture is stirred at room temperature for two days. The mixture is diluted with water (8 L) and the resultant mixture is stirred at room temperature for one hour. The mixture is subsequently filtered to give a solid, which is rinsed with water (3×4 L.) The product is dried to afford the synthetic intermediate 1-(4-methoxy-phenyl)-2-phenyl-ethanone oxime (948 g.)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH3:9])=[C:4](I)[CH:3]=1.C([Mg]Cl)(C)C.C[O:17][B:18](OC)[O:19]C.Cl>O1CCCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH3:9])=[C:4]([B:18]([OH:19])[OH:17])[CH:3]=1
Reactant: CCc1ccc(Br)cc1I
Reactant: COB(OC)OC
Agent: CC(C)[Mg]Cl
Agent: Cl
Solvent: C1CCOC1
Product: CCc1ccc(Br)cc1B(O)O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 87.7 %

Procedure:
To a solution of 4-bromo-1-ethyl-2-iodobenzene (10.00 g, 32.20 mmol) in anhydrous tetrahydrofuran (60 ml) at −78° C. is added a solution of isopropylmagnesium chloride (16.90 ml, 33.80 mmol, 2M solution in tetrahydrofuran) dropwise, maintaining a temperature below −60° C. After stirring for 20 minutes the reaction mixture is allowed to slowly warm to room temperature followed by an additional hour of stirring. The solution is re-cooled to −78° C. and trimethylborate (7.18 ml, 64.32 mmol) is added dropwise, after which the mixture is again allowed to warm to room temperature with further stirring for 2 hours. Dilute aqueous hydrochloric acid (30 ml) is added, and the crude product is extracted into ethyl acetate (100 ml). The aqueous phase is washed with ethyl acetate (2×100 ml), and all organics are combined, dried over anhydrous magnesium sulfate then concentrated in vacuo to give a light brown solid which is triturated with hexanes to afford 5-bromo-2-ethylphenylboronic acid (6.46 g) as a cream powder.
Reaction SMILES: CN(C)C(=O)C.[NH2:7][C:8]1[CH:9]=[C:10]([CH:19]=[CH:20][C:21]=1[NH2:22])[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:12].S([O-])(O)=O.[Na+].[CH:28]([C:30]1[NH:31][CH:32]=[CH:33][CH:34]=1)=O>O>[C:11]([C:10]1[CH:19]=[CH:20][C:21]2[N:22]=[C:28]([C:30]3[NH:31][CH:32]=[CH:33][CH:34]=3)[NH:7][C:8]=2[CH:9]=1)(=[O:12])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=Cc1ccc[nH]1
Reactant: Nc1ccc(C(=O)c2ccccc2)cc1N
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: O=C(c1ccccc1)c1ccc2nc(-c3ccc[nH]3)[nH]c2c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 0.1 %

Procedure:
N,N-Dimethylacetamide (5 ml) was heated to 130° C., and 3,4-diaminobenzophenone (150 mg, 0.71 mol) and sodium hydrogensulfite (89 mg, 0.85 mol) were added and stirred for 5 minutes. 2-Formyl-pyrrole (81 mg, 0.85 mol) was added and stirred at 130° C. for 1.5 hours. The reaction mixture was allowed to cool to room temperature with stirring, and after addition of water to reaction mixture, precipitate was collected by filtration to afford 5-benzoyl-2-(pyrrol-2-yl)-benzimidazole (129 mg, 63%) as a pale yellow solid.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][C@H:7]([N:10]2[CH2:14][CH2:13][C@H:12]([NH:15]C(=O)OCC3C=CC=CC=3)[C:11]2=[O:26])[C@H:6]([CH2:27][CH2:28][CH3:29])[CH2:5]1)([CH3:3])[CH3:2].[H][H]>CO.[Pd]>[NH2:15][C@H:12]1[CH2:13][CH2:14][N:10]([C@H:7]2[CH2:8][CH2:9][N:4]([CH:1]([CH3:2])[CH3:3])[CH2:5][C@H:6]2[CH2:27][CH2:28][CH3:29])[C:11]1=[O:26]
Reactant: CCC[C@@H]1CN(C(C)C)CC[C@@H]1N1CC[C@H](NC(=O)OCc2ccccc2)C1=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CCC[C@@H]1CN(C(C)C)CC[C@@H]1N1CC[C@H](N)C1=O
Reaction time: 8 h
Yield: 95 %

Procedure:
A mixture of benzyl (S)-1-((3R,4S)-1-isopropyl-3-propylpiperidin-4-yl)-2-oxopyrrolidin-3-ylcarbamate (faster) (0.262 g) and Pd/C (0.056 g) in MeOH were stirred at rt under 50 psi hydrogen. After overnight stirring, the reaction was filtered through Celite. Concentrated and dried in vacuo to get the desired product, (3S)-3-amino-1-((3R,4S)-1-isopropyl-3-propylpiperidin-4-yl)pyrrolidin-2-one (faster) (0.166 g, yield=95%) as a clear oil.
Reaction SMILES: [S:1]1CC(O)S[CH2:3][CH:2]1O.[C:9]([CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])#[N:10].C(N(CC)CC)C.O>O1CCCC1.C(O)(=O)C>[C:15]([O:14][C:12]([C:11]1[CH:3]=[CH:2][S:1][C:9]=1[NH2:10])=[O:13])([CH3:18])([CH3:17])[CH3:16]
Reactant: OC1CSC(O)CS1
Reactant: CC(C)(C)OC(=O)CC#N
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1ccsc1N
Temperature: 50 °C
Reaction time: 1.25 h

Procedure:
A solution of 1,4 dithiane-2,5-diol (1.1 g) and t-butyl cyanoacetate (2.2 ml) in dry tetrahydrofuran (20 ml) was warmed to ˜45° C. then treated slowly with triethylamine (2ml). The temperature rose to ˜54° C. and a yellow colouration developed. The mixture was stirred at ˜50° C. for a further 75 mins during which time the colour gradually darkened and became brownish. Water (200 ml) was added, then the mixture was acidified with acetic acid and extracted with ether. The ether extracts were washed with water, dried on magnesium sulfate, filtered and concentrated in vacuo. Residual acetic acid was removed by azeotropic distillation with toluene. The resulting brown liquid was identified as the desired product by NMR. The sample was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH:4]([C:11]1[CH:16]=[CH:15][C:14](I)=[CH:13][CH:12]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.[CH3:19][N:20]([CH3:24])[CH2:21][C:22]#[CH:23]>CN(C)C=O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.C(N(CC)CC)C.[I-]>[CH3:1][O:2][C:3](=[O:18])[CH:4]([C:11]1[CH:16]=[CH:15][C:14]([C:23]#[C:22][CH2:21][N:20]([CH3:24])[CH3:19])=[CH:13][CH:12]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: COC(=O)C(CC1CCCC1)c1ccc(I)cc1
Reactant: C#CCN(C)C
Agent: Cl[Pd]Cl
Agent: [I-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)C(CC1CCCC1)c1ccc(C#CCN(C)C)cc1
Temperature: 70 °C
Yield: 91.2 %

Procedure:
A solution of 3-cyclopentyl-2-(4-iodo-phenyl)-propionic acid methyl ester (716 mg, 2.0 mmol) and triethylamine (2 mL, 0.01 mmol) in N,N-dimethylformamide (2 mL) was treated with 1-dimethylamino-2-propyne (0.54 mL, 5.0 mmol). The resulting reaction mixture was degassed with argon and then treated with cooper iodide (10 mg, 0.05 mmol) and bis(triphenylphosphine)palladium (II) chloride (15 mg, 0.02 mmol). The reaction was then heated at 70° C. for 24 h. At this time, the reaction was cooled to 25° C. and concentrated in vacuo. The residue was diluted with ethyl acetate (40 mL) and washed with a half-saturated aqueous sodium chloride solution (1×20 mL). The resulting aqueous layer was back extracted with ethyl acetate (1×120 mL). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 95/5 chloroform/methanol) afforded 3-cyclopentyl-2-[4-(3-dimethylamino-prop-1-ynyl)-phenyl]-propionic acid methyl ester (572 mg, 91%) as an amber oil: EI-HRMS m/e calcd for C20H27NO3 (M+) 313.2051, found 312.1850.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][CH2:8][CH2:9][CH2:10][CH:11]1[C:16](=[O:17])[N:15]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:14]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:12]1=[O:13].[C:30]([O:36][CH2:37]Cl)(=[O:35])[C:31]([CH3:34])([CH3:33])[CH3:32]>CC(C)=O>[C:24]1([N:14]2[C:12](=[O:13])[C:11]([CH2:10][CH2:9][CH2:8][CH3:7])([CH2:37][O:36][C:30](=[O:35])[C:31]([CH3:34])([CH3:33])[CH3:32])[C:16](=[O:17])[N:15]2[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CC(C)(C)C(=O)OCCl
Reactant: CCCCC1C(=O)N(c2ccccc2)N(c2ccccc2)C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCCC1(COC(=O)C(C)(C)C)C(=O)N(c2ccccc2)N(c2ccccc2)C1=O
Yield: 5 %

Procedure:
Potassium carbonate (2.26 g, 0.016 mole) was suspended in an acetone (125 ml) solution of phenylbutazone and the suspension was refluxed overnight. The next day pivalyloxymethyl chloride (4.99 g, 0.033 mole) was added to the resulting solution and the solution was refluxed overnight. The suspension was cooled and filtered; the residue (2.00 g, 83%) was potassium chloride. The filtrate was concentrated in vacuo and the residue was suspended in ether, then filtered. The residue was washed with ether until the washings did not contain any product by TLC. The residue from the ether suspension was the potassium salt of phenylbutazone (2.25 g, 20%). The ether was then concentrated in vacuo and the residue was absorbed on silica gel and chromatographed on neutral silica gel (CC-7, Mallinckrodt) using petroleum ether bp 30°-60° C. -- ether (1:1) as the eluent to give two fractions. The first fraction (Rf 0.46, silica gel, heptane-ether, 1:1 was crystallized from heptane-petroleum ether bp 30-60° C., 1:1 to give 0.63 g (mp 116°-117° C., 5% yield) of 1,2-diphenyl-4-butyl-4-pivalyloxymethyl-3,5-pyrazolidinedione. nmr (CDCl3) δ 4.40 (S, 2, ##STR10##
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:23])[NH:19][C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:26]([F:29])([F:28])[F:27])[CH:3]=1.[S:30]1[C:34]([CH2:35]O)=[CH:33][N:32]=[CH:31]1>>[Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:23])[N:19]([CH2:35][C:34]5[S:30][CH:31]=[N:32][CH:33]=5)[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:26]([F:27])([F:29])[F:28])[CH:3]=1
Reactant: OCc1cncs1
Reactant: O=C1NC(=O)/C(=C/c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Product: O=C1S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C(=O)N1Cc1cncs1

Procedure:
(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-(1,3-thiazol-5-ylmethyl)-1,3-thiazolidine-2,4-dione was prepared from [(5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidine (from Example 1) and thiazol-5-ylmethanol following General Procedure J.