Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:16]([N:18]([CH2:21][CH3:22])[CH2:19]C)C.C[NH:24][C:25]1C(N)=C[CH:28]=[CH:29][CH:30]=1.CCN=C=NCCCN(C)C>C(Cl)Cl.C(OCC)(=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([NH:15][C:19]2[N:18]([CH3:16])[C:21]3[CH:22]=[CH:28][CH:29]=[CH:30][C:25]=3[N:24]=2)=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccc(OCc2ccccc2)cc1
Reactant: CNc1ccccc1N
Reactant: CCN(CC)CC
Agent: CCN=C=NCCCN(C)C
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cn1c(Nc2ccc(OCc3ccccc3)cc2)nc2ccccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-benzyloxy-phenylamine (2 g, 8.4 mmol) in 30 mL of DCM was added triethylamine (1 mL) and di-2-pyridylthionocarbonate (2.5 g, 8.4 mmol). The resulting mixture was stirred at RT for 2 h. The reaction mixture was diluted with DCM and washed with water and brine. The organic layer was then dried over Na2SO4, filtered and concentrated. The residue was dissolved in 30 mL DMF, N-methyl-benzene-1,2-diamine (1.5 g, 12.7 mmol) and EDCI (2 g, 10.5 mmol). The resulting mixture was heated at 70° C. for 4 h. The reaction was cooled to RT, diluted with ethyl acetate and washed with water and brine. Purification by silica gel chromatography (98:2 chlorforma/MeOH) afforded the desired product (4-benzyloxy-phenyl)-(1-methyl-1H-benzoimidazol-2-yl)-amine. [M+1]=330.1
Reaction SMILES: [OH:1][N:2]=[C:3]([C:9](=[O:12])[CH2:10][Cl:11])[C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH2:13](O)[CH2:14][OH:15]>C1(C)C=CC(S(O)(=O)=O)=CC=1.C1C=CC=CC=1>[OH:1][N:2]=[C:3]([C:9]1([O:15][CH2:14][CH2:13][O:12]1)[CH2:10][Cl:11])[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)C(=NO)C(=O)CCl
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: CCOC(=O)C(=NO)C1(CCl)OCCO1
Temperature: 25 °C
Yield: 58.9 %

Procedure:
A mixture of ethyl 2-hydroxyimino-3-oxo-4-chlorobutyrate (syn isomer, 10 g), ethylene glycol (16 g), p-toluenesulfonic acid (0.3 g) and dried benzene (100 ml) was heated for 19 hours under reflux while removing water azeotropically. After the reaction mixture was cooled to ambient temperature, water (30 ml) and benzene (20 ml) were added thereto. The mixture was saturated with sodium chloride and the benzene layer was separated, and the remaining aqueous layer was further extracted with benzene (20 ml). The benzene layer and extract were combined together, washed with a saturated aqueous solution of sodium chloride (30 ml×2), dried over magnesium sulfate and then filtered. The filtrate was evaporated to give an oil of ethyl 2-hydroxyimino-3,3-ethylenedioxy-4-chlorobutyrate (syn isomer, 7.23 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12](I)=[C:13]([F:17])[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1>>[C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[C:13]([F:17])[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1Cc2cc(F)c(I)cc2C1
Reactant: C1COCCN1
Product: CC(C)(C)OC(=O)N1Cc2cc(F)c(N3CCOCC3)cc2C1

Procedure:
Prepared in analogy to Example A3 (d) from 5-fluoro-6-iodo-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester and morpholine. Yellow solid. MS (m/e): 323.4 ([M+H]+, 100%).
Reaction SMILES: CC([NH:9][S:10](/[CH:13]=[CH:14]/[C:15]1[S:16][CH:17]=[CH:18][CH:19]=1)(=[O:12])=[O:11])(C)CC(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[S:16]1[CH:17]=[CH:18][CH:19]=[C:15]1/[CH:14]=[CH:13]/[S:10]([NH2:9])(=[O:11])=[O:12]
Reactant: CC(C)(C)CC(C)(C)NS(=O)(=O)/C=C/c1cccs1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NS(=O)(=O)/C=C/c1cccs1
Yield: 88.8 %

Procedure:
(E)-2-Thiophen-2-yl-ethenesulfonic acid (1,1,3,3-tetramethyl-butyl)-amide (5.17 g, 17.2 mmol) was stirred for 15 minutes in a 1:1 mixture of trifluoroacetic acid and dichloromethane (40 mL). The mixture was concentrated in vacuo to afford a solid that was washed with dichloromethane (10 mL) in heptane (100 mL). The resultant solid was collected by suction filtration and dried under vacuum at ambient temperature to afford (E)-2-thiophen-2-yl-ethenesulfonic acid amide (2.89 g, 89%).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:6][CH:7]1[CH2:11][CH2:10][CH2:9][C:8]1=O)[C:3]([OH:5])=[O:4].O=C1CCCC1CC(NC(N)=O)C(O)=O.N.[H][H]>O.[Pd]>[NH:1]1[C@H:2]([C:3]([OH:5])=[O:4])[CH2:6][C@@H:7]2[CH2:11][CH2:10][CH2:9][C@H:8]12
Reactant: [H][H]
Reactant: N[C@@H](CC1CCCC1=O)C(=O)O
Agent: [Pd]
Agent: N
Agent: NC(=O)NC(CC1CCCC1=O)C(=O)O
Solvent: O
Product: O=C(O)[C@@H]1C[C@@H]2CCC[C@@H]2N1
Yield: 100 %

Procedure:
(S)-2-amino-3-(2-oxocyclopentyl)propanoic acid as obtained in Example 3 (130 mg, 0.76 mmol) was dissolved in water (2 mL) and the pH was adjusted to 9 with 25% aqueous NH3 solution. Then, 10% Pd/C (5 mg) was added and hydrogenation was performed under 5 bar of hydrogen gas for 16 h. At the end of the reaction, the catalyst was filtered off on a pad of celite under suction and the product (2S,3aS,6aS)-octahydrocyclopenta[b]pyrrole-2-carboxylic acid was isolated after evaporation of the water layer in vacuo at 80° C. Weight 118 mg. 100% yield. Diastereomeric excess >95% (determined by chiral HPLC). 1H NMR: (DMSO-d6, 300 MHz): δ 10.54 (br s, 1H), 8.71 (br s, 1H), 4.22 (dd, 1H), 3.98 (t, 1H), 2.86-2.76 (m, 1H), 2.49-2.42 (m, 1H), 2.00-1.96 (m, 1H), 1.80-1.40 (m, 6H).
Reaction SMILES: Cl[CH:2]1[C:7](=[O:8])[CH2:6][C:5]([CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([Cl:24])[CH:17]=2)([CH:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[O:4][C:3]1=[O:25].[SH:26][C:27]1[S:28][CH:29]=[C:30]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[N:31]=1>>[Cl:24][C:18]1[CH:17]=[C:16]([CH2:15][CH2:14][C:5]2([CH:9]3[CH2:13][CH2:12][CH2:11][CH2:10]3)[O:4][C:3](=[O:25])[C:2]([S:26][C:27]3[S:28][CH:29]=[C:30]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[N:31]=3)=[C:7]([OH:8])[CH2:6]2)[CH:21]=[CH:20][C:19]=1[O:22][CH3:23]
Reactant: COc1ccc(CCC2(C3CCCC3)CC(=O)C(Cl)C(=O)O2)cc1Cl
Reactant: Sc1nc(-c2ccccc2)cs1
Product: COc1ccc(CCC2(C3CCCC3)CC(O)=C(Sc3nc(-c4ccccc4)cs3)C(=O)O2)cc1Cl

Procedure:
The title compound was prepared as described in Example C(70), where 3-chloro-6-[2-(3-chloro-4-methoxyphenyl)ethyl]-6-cyclopentyldihydro-2H-pyran-2,4(3H)-dione was used in place of 3-chloro-6-[2-(5-chloro-2,4-dimethoxyphenyl)ethyl]6-cyclopentyldihydro-2H-pyran-2,4(3H)-dione and 2-mercapto-4-phenylthiazole was used in place of 6-hydroxy-8-mercaptopurine monohydrate.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[C:8]([C:11]3[CH:12]=[C:13]([CH:15]=[CH:16][CH:17]=3)[NH2:14])[CH:9]=[CH:10][C:5]=2[N:4]=[CH:3]1.[O:18]1[CH2:20][CH:19]1[CH2:21][N:22]1[CH2:31][CH2:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:23]1>CCO>[CH2:23]1[C:24]2[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:30][CH2:31][N:22]1[CH2:21][CH:19]([OH:18])[CH2:20][NH:14][C:13]1[CH:15]=[CH:16][CH:17]=[C:11]([C:8]2[CH:9]=[CH:10][C:5]3[N:4]=[CH:3][N:2]([CH3:1])[C:6]=3[CH:7]=2)[CH:12]=1
Reactant: c1ccc2c(c1)CCN(CC1CO1)C2
Reactant: Cn1cnc2ccc(-c3cccc(N)c3)cc21
Solvent: CCO
Product: Cn1cnc2ccc(-c3cccc(NCC(O)CN4CCc5ccccc5C4)c3)cc21
Temperature: 120 °C
Yield: 29.4 %

Procedure:
To a solution of 3-(1-methyl-1H-benzo[d]imidazol-6-yl)aniline (300 mg, 1.34 mmol) in EtOH (3 mL) were added 2-(oxiran-2-ylmethyl)-1,2,3,4-tetrahydroisoquinoline (250 mg, 1.32 mmol). The reaction mixture was heated at 120° C. under microwave conditions for 30 min. After cooling, the resulting solution was concentrated in vacuo and purified via column chromatography to yield the title compound (160 mg, 28.9%) LCMS (m/z): 413.2 [M+H]+
Reaction SMILES: [OH:1]OS([O-])=O.[K+].[Br:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([C:15]2[CH:16]=[C:17]([C:27]([NH2:29])=[O:28])[N:18]3[C:23]([S:24][CH3:25])=[CH:22][C:21]([CH3:26])=[N:20][C:19]=23)=[C:10]([CH3:30])[CH:9]=1>O.C(O)C>[Br:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([C:15]2[CH:16]=[C:17]([C:27]([NH2:29])=[O:28])[N:18]3[C:23]([S:24]([CH3:25])=[O:1])=[CH:22][C:21]([CH3:26])=[N:20][C:19]=23)=[C:10]([CH3:30])[CH:9]=1
Reactant: CSc1cc(C)nc2c(-c3c(C)cc(Br)cc3C)cc(C(N)=O)n12
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: CCO
Solvent: O
Product: Cc1cc(S(C)=O)n2c(C(N)=O)cc(-c3c(C)cc(Br)cc3C)c2n1
Temperature: 0 °C
Yield: 2180.4 %

Procedure:
To a solution of Oxone (9.12 g) in water (50 mL) was added a solution of 8-(4-bromo-2,6-dimethyl-phenyl)-2-methyl-4-methylsulfanyl-pyrrolo[1,2-a]pyrimidine-6-carboxylic acid amide (3.00 g) in ethanol (50 mL) in an ice-cooling bath. The reaction mixture was stirred under ice-cooling for 30 minutes, poured into water and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium hydrogencarbonate and brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by a silica gel column chromatography (silica gel: Wako Gel (C200), eluent: ethyl acetate) to give 8-(4-bromo-2,6-dimethyl-phenyl)-4-methanesulfinyl-2-methyl-pyrrolo[1,2-a]pyrimidine-6-carboxylic acid amide (1:68 g).
Reaction SMILES: [CH3:1][NH:2][S:3]([CH:6]=[CH2:7])(=[O:5])=[O:4].Br[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[CH:12]2.C(N(CC)CC)C>C(O)(C)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>[CH3:1][NH:2][S:3](/[CH:6]=[CH:7]/[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[CH:12]2)(=[O:5])=[O:4]
Reactant: Brc1ccc2[nH]ccc2c1
Reactant: C=CS(=O)(=O)NC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: CNS(=O)(=O)/C=C/c1ccc2[nH]ccc2c1
Temperature: 25 °C
Yield: 221.2 %

Procedure:
A mixture of N-methylethenesulphonamide (45 g), 5-bromoindole (60 g), palladium acetate (0.9 g), tri-o-tolylphosphine (18.6 g) and triethylamine (90 mL) in isopropanol (300 mL) was heated at 85° under nitrogen for 18 h. The reaction mixture was cooled to ambient temperature, filtered and the filter-cake washed with isopropanol (30 mL). The combined washings and filtrate were concentrated in vacuo to give a yellow-brown solid (160 g). This material was purified by column chromatography on silica gel. Eluting initially with ethyl acetate/cyclohexane (1:1) followed by ethyl acetate provided the product (26.4 g, 36% of theory) as a yellow powder.
Reaction SMILES: [Na].C(OC(=O)C)(=O)C.C([O-])(=O)C.[K+].[F:14][C:15]([F:47])([F:46])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][NH:31][C:32]1[CH:37]=[CH:36][C:35]([CH:38](O)[CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41])=[CH:34][CH:33]=1>C(OCC)(=O)C>[F:14][C:15]([F:46])([F:47])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][NH:31][C:32]1[CH:37]=[CH:36][C:35]([CH:38]=[CH:39][C:40]([O:42][CH2:43][CH3:44])=[O:41])=[CH:34][CH:33]=1
Reactant: CCOC(=O)CC(O)c1ccc(NCCCCCCCCCCCCCCCC(F)(F)F)cc1
Agent: CC(=O)[O-]
Agent: [K+]
Agent: [Na]
Solvent: CCOC(C)=O
Solvent: CC(=O)OC(C)=O
Product: CCOC(=O)C=Cc1ccc(NCCCCCCCCCCCCCCCC(F)(F)F)cc1

Procedure:
The [4-(polyfluoroalkylamino)phenyl]alkenoic acids may be prepared by condensation of the appropriate aldehydes or by dehydration of the corresponding substituted-phenyl-hydroxyalkanoic acids. For example, ethyl 5-{4-[15-(trifluoromethyl)pentadecylamino]phenyl}-2,4-pentadienoate is obtained by the Wittig reaction of 4-[15-(trifluoromethyl)-pentadecylamino]benzaldehyde with the Wittig reagent, triethyl 4-phosphonocrotonate. Alternatively, these alkenoic acids are obtained by heating 4-[N-polyfluoroalkyl-N-(methyl or acetyl)amino]benzaldehydes with the sodium salt of the carbanion of ethyl acetate or with a mixture of ethyl acetate, acetic anhydride and potassium acetate. The second method is illustrated by dehydration of ethyl 3-{4-[15-(trifluoromethyl)pentadecylamino]phenyl}-3-hydroxypropionate to yield ethyl 4-[15-(trifluoromethyl)pentadecylamino]cinnamate.
Reaction SMILES: C(OC([NH:8][CH2:9][CH:10]1[CH:15]2[CH:11]1[CH2:12][N:13]([C:16]1[N:21]=[CH:20][C:19]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:18][N:17]=1)[CH2:14]2)=O)(C)(C)C.Cl.O1CCOCC1>C(Cl)Cl>[NH2:8][CH2:9][CH:10]1[CH:15]2[CH:11]1[CH2:12][N:13]([C:16]1[N:17]=[CH:18][C:19]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:20][N:21]=1)[CH2:14]2
Reactant: CCOC(=O)c1cnc(N2CC3C(CNC(=O)OC(C)(C)C)C3C2)nc1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CCOC(=O)c1cnc(N2CC3C(CN)C3C2)nc1
Reaction time: 0.5 h
Yield: 97.3 %

Procedure:
Ethyl 2-(6-{[(tert-butoxycarbonyl)amino]methyl}-3-azabicyclo[3.1.0]hex-3-yl)pyrimidine-5-carboxylate (1.7 g, 4.7 mmol) was stirred in DCM (20 ml) at r.t. under N2. 4M HCl in dioxane (2.35 ml, 9.4 mmol) was added, immediately causing a solid to precipitate. The reaction was left to stir for 30 min and then the solvent was removed in vacuo. The residue was dissolved in DCM (100 ml) and washed with sat. aq. NaHCO3 (100 ml). The organic layer was then dried (Na2SO4) and the solvent removed in vacuo to give the title compound as an orange solid (1.2 g, 97%). LCMS purity 97%, m/z 263 [M+H]+, 1H NMR (300 MHz, d6-DMSO) δ: 0.64 (1H, m), 1.29 (3H, t, J=7.2 Hz), 1.58 (2H, m), 3.33 (4H, m), 3.55 (2H, d, J=11.7 Hz), 3.82 (2H, d, J=11.7 Hz), 4.26 (2H, q, J=7.2 Hz), 8.76 (2H, s).
Reaction SMILES: C1(N[N:8]=[C:9]2[C:14](=O)[CH2:13][CH2:12][CH2:11][CH2:10]2)C=CC=CC=1.[CH2:16](O)[CH2:17][O:18][CH2:19][CH2:20][OH:21].O.[C:24]1(C)[CH:29]=CC(S(O)(=O)=O)=[CH:26][CH:25]=1>C1(C)C=CC=CC=1>[O:21]1[CH2:20][CH2:19][O:18][C:17]21[CH2:16][CH2:26][C:25]1[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[NH:8][C:24]=1[CH2:29]2
Reactant: O=C1CCCCC1=NNc1ccccc1
Reactant: OCCOCCO
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: c1ccc2c3c([nH]c2c1)CC1(CC3)OCCO1

Procedure:
The title compound was prepared essentially according to published procedures (R. F. Borch et al., J. Org. Chem. 38 (15), 2729 (1973); Nader G. et al., French Patent 2729141 (1996)). A mixture of cyclohexane-2,3-dione monophenylhydrazone (10.1 g, 0.05 mol), diethylene glycol (25 mL) and para-toluene sulfonic acid monohydrate (11.4 g, 0.06 mol) in toluene (500 mL) was heated under nitrogen in an oil bath kept at 135° C. with water removal (Dean-Stark). After heating for 15 hours the mixture was cooled, the toluene was decanted and the tarry residue extracted three times with small portions of toluene. The combined organic phase was washed three times with saturated aqueous sodium bicarbonate, and dried over anhydrous magnesium sulfate. Removal of the solvent provided the crude title compound as a brown oil that partially solidified in vacuo (9.2 g). It was used as such in the next step. MS (ES): [M+H]+ @m/z 230.1
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:35])=[C:7]2[C:12](=[C:13]([C:15]3[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=3)[N:14]=1)[N:11]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:10](=[O:28])[C:9]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[CH:8]2)=[O:4].[NH2:36][CH2:37][CH2:38][C:39]([OH:41])=[O:40].C[O-].[Na+]>C([O-])(O)=O.[Na+]>[CH2:21]([N:11]1[C:12]2[C:7](=[C:6]([OH:35])[C:5]([C:3]([NH:36][CH2:37][CH2:38][C:39]([OH:41])=[O:40])=[O:4])=[N:14][C:13]=2[C:15]2[CH:16]=[CH:17][N:18]=[CH:19][CH:20]=2)[CH:8]=[C:9]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:10]1=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: NCCC(=O)O
Reactant: COC(=O)c1nc(-c2ccncc2)c2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Agent: C[O-]
Agent: O=C([O-])O
Agent: [Na+]
Product: O=C(O)CCNC(=O)c1nc(-c2ccncc2)c2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Temperature: 25 °C
Yield: 34.5 %

Procedure:
A mixture of 1-benzyl-5-hydroxy-2-oxo-3-phenyl-8-pyridin-4-yl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (36 mg, 0.078 mmol), β-alanine (693 mg, 7.8 mmol) and NaOMe solution (11.7 mL, 5.8 mmol, 0.5 M in MeOH) was refluxed for 16 h. After the mixture was cooled to r.t., the solvent was evaporated in vacuo. The residue was partitioned between EtOAc and water. 1 M HCl was added with vigorous stirring until pH was about 3-4. The aqueous layer was extracted with additional EtOAc, and the organic layers were combined, dried over MgSO4 and concentrated. The crude product was purified by silica gel chromatography (20-100% EtOAc/hexanes+1% AcOH). The product isolated was dissolved in saturated NaHCO3 and washed several times with ether. The aqueous layer was acidified to pH about 3-4, and the resulting precipitate was isolated by filtration to give 14 mg of the title compound as a light yellow solid. MS: (+) m/z 521.34 (M+1).
Reaction SMILES: C1CCCCC1.N[C:8]1([O:17]O)[CH2:13][CH:12]([CH3:14])[CH2:11][C:10]([CH3:16])([CH3:15])[CH2:9]1.S([O-])([O-])(=O)=O.[Mg+2]>S(=O)(=O)(O)O.C(O)C>[C:8]1(=[O:17])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.[CH3:14][CH:12]1[CH2:11][C:10]([CH3:16])([CH3:15])[CH2:9][C:8](=[O:17])[CH2:13]1
Reactant: CC1CC(C)(C)CC(N)(OO)C1
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CCO
Solvent: C1CCCCC1
Product: CC1CC(=O)CC(C)(C)C1
Product: O=C1CCCCC1
Reaction time: 0.17 h

Procedure:
To a stirred mixture of cyclohexane (19.6 g.) and ethanol (50 c.c.), kept at or below 0°C, was added 1-amino-3,3,5-trimethylcyclohexyl hydroperoxide (17.3 g., 78% pure); solution was complete in ca. 10 min. To the solution was added conc. sulphuric acid (3 drops) and magnesium sulphate and the mixture was stored at 0°C for 3 days. The solid was filtered off, the filtrate washed with water, dried and distilled, to give cyclohexanone, dihydroisophorone and a fraction (11.5 g.), b.p. 90° - 100°C at 0.02 mm. Hg., peroxide equivalent 179. By mass spectroscopy the product was shown to contain the unsymmetrical peroxide 1,1'-amino-3,3,5-trimethylcyclohexylamine. ##SPC65##
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]([N:10]=[S:11]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:12])=[O:9])[CH:5]=[N:6][CH:7]=1.[OH:25][C:26]1[CH:27]=[C:28]([C:32]#[CH:33])[CH:29]=[CH:30][CH:31]=1.C(N(CC)CC)C>CN(C=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[OH:25][C:26]1[CH:27]=[C:28]([C:32]#[C:33][C:2]2[CH:3]=[C:4]([C:8]([N:10]=[S@:11]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[O:12])=[O:9])[CH:5]=[N:6][CH:7]=2)[CH:29]=[CH:30][CH:31]=1
Reactant: CCOC(=O)CS(=O)(=NC(=O)c1cncc(Br)c1)c1ccccc1
Reactant: C#Cc1cccc(O)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)C[S@@](=O)(=NC(=O)c1cncc(C#Cc2cccc(O)c2)c1)c1ccccc1
Temperature: 60 °C
Yield: 94.3 %

Procedure:
A solution ethyl {N-[(5-bromopyridin-3-yl)carbonyl]-S-phenylsulfonimidoyl}acetate (216 mg, 0.52 mmol) and 3-hydroxyphenylacetylene (0.052 mL, 0.79 mmol) in anhydrous DMF (3 mL) was treated with triethylamine (0.22 mL, 1.58 mmol). The reaction mixture was degassed (alternating vacuum and argon) and PdCl2(Ph3P)2 (36.9 mg, 0.052 mmol) and triphenylphosphine (3.4 mg, 0.013 mmol) were added. The reaction mixture was degassed (alternating vacuum and argon) and placed under an atmosphere of 1:3 Argon/hydrogen atmosphere. Copper(1+) iodide was added and the reaction mixture was heated at 60° C. for 50 min. The brown reaction mixture was partitioned between saturated aqueous NaHCO3 and EtOAc. The organic layer was collected and washed further with saturated aqueous NaHCO3 (1×), brine (1×), and dried over anhydrous Na2SO4. The residue was purified by chromatography (silica gel, 50:1 CHCl3:MeOH). The product containing fractions were concentrated to give the title compound as a light yellow solid (220 mg, 94%).
Reaction SMILES: [N+:1]([N:4]=[C:5]1[NH:9][CH2:8][CH2:7][S:6]1)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23]Cl)=[CH:19][N:18]=1>C(#N)C>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][N:9]2[CH2:8][CH2:7][S:6][C:5]2=[N:4][N+:1]([O-:3])=[O:2])=[CH:19][N:18]=1
Reactant: ClCc1ccc(Cl)nc1
Reactant: O=[N+]([O-])N=C1NCCS1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=[N+]([O-])N=C1SCCN1Cc1ccc(Cl)nc1

Procedure:
A mixture of 2.9 g of 2-nitroiminothiazolidine, 2.9 g of anhydrous potassium carbonate, 3.2 g of 2-chloro-5-pyridylmethylchloride and 50 ml of acetonitrile was refluxed for 5 hours with vigorously stirring. After the reaction, most of the acetonitrile was removed by distillation and water was added to the residue. As the solid product was separated, it was collected by filtration. The crude material was recrystallized from ethanol to give desired 3-(2-chloro-5-pyridylmethyl)-2-(nitroimino)thiazolidine.
Reaction SMILES: [CH:1]1([Mg]Br)[CH2:3][CH2:2]1.Cl[C:7]1[CH:12]=[C:11]([C:13]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([N+:22]([O-:24])=[O:23])[CH:20]=3)[N:15]([C:25]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[N:14]=2)[CH:10]=[CH:9][N:8]=1>[Cl-].[Cl-].[Zn+2].CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C.CN1C(=O)CCC1>[CH:1]1([C:9]2[CH:10]=[C:11]([C:13]3[C:21]4[C:16](=[CH:17][CH:18]=[C:19]([N+:22]([O-:24])=[O:23])[CH:20]=4)[N:15]([C:25]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)([C:38]4[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=4)[C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[N:14]=3)[CH:12]=[CH:7][N:8]=2)[CH2:3][CH2:2]1
Reactant: Br[Mg]C1CC1
Reactant: O=[N+]([O-])c1ccc2c(c1)c(-c1ccnc(Cl)c1)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CN1CCCC1=O
Product: O=[N+]([O-])c1ccc2c(c1)c(-c1ccnc(C3CC3)c1)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 0.08 h
Yield: 37.9 %

Procedure:
To a tube under nitrogen was added 36.2 ml ZnCl2 (0.5 M in THF, 18.02 mmol) followed by cyclopropylmagnesium bromide (34 ml of 0.5 M in THF soln., 16 mmol). The resultant mixture was stirred for 20 min at r.t. NMP (23 ml) was added, stirred for 5 min followed by 3-(2-Chloro-pyridin-4-yl)-5-nitro-1-trityl-1H-indazole (5.5 gm, 10.6 mmol) and Pd[P(tBu)3]2 (0.108 gm, 0.22 mmol). The tube was sealed under nitrogen and stirred at 100 C for 18 hrs. The reaction mixture was then cooled and evaporated to dryness. Silica gel chromatography using 5-20% ethylacetate/hexanes gave 2.1 g of title product.
Reaction SMILES: [NH2:1][CH2:2][C:3]([N:5]([CH2:12][C:13]([N:15]1[CH2:20][CH2:19][C:18]([CH3:22])([CH3:21])[CH2:17][CH2:16]1)=[O:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:4].[CH3:23][C:24]1[CH:25]=[C:26]([N:30]=[C:31]=[O:32])[CH:27]=[CH:28][CH:29]=1>>[CH3:21][C:18]1([CH3:22])[CH2:19][CH2:20][N:15]([C:13](=[O:14])[CH2:12][N:5]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:3](=[O:4])[CH2:2][NH:1][C:31]([NH:30][C:26]2[CH:27]=[CH:28][CH:29]=[C:24]([CH3:23])[CH:25]=2)=[O:32])[CH2:16][CH2:17]1
Reactant: CC1(C)CCN(C(=O)CN(C(=O)CN)c2ccccc2)CC1
Reactant: Cc1cccc(N=C=O)c1
Product: Cc1cccc(NC(=O)NCC(=O)N(CC(=O)N2CCC(C)(C)CC2)c2ccccc2)c1
Yield: 48.6 %

Procedure:
The procedure is analogous to that described in Example 1, but 1.0 g of 2-amino-N-[2-(4,4-dimethylpiperidino)-2-oxoethyl]-N-phenylacetamide and 0.44 g of 3-methylphenyl isocyanate are used as the starting material. After recrystallization from an ethyl acetate/acetonitrile mixture (50-50 by volume), 0.7 g of N-[2-(4,4-dimethylpiperidino)-2-oxoethyl]-2-[3-(3-methylphenyl)ureido]-N-phenylacetamide melting at 205° C is obtained.