Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:34])[CH2:3][CH:4]([OH:33])[CH2:5][N:6]1[C:18]2[C:17]3[N:19]([CH3:26])[C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=4[C:16]=3[C:15]3[C:27](=[O:32])N(C)[C:29](=[O:30])[C:14]=3[C:13]=2[C:12]2[C:7]1=[CH:8][CH:9]=[CH:10][CH:11]=2.[OH-:35].[K+]>>[CH3:34][N:2]([CH3:1])[CH2:3][CH:4]([OH:33])[CH2:5][N:6]1[C:18]2[C:17]3[N:19]([CH3:26])[C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=4[C:16]=3[C:15]3[C:27](=[O:32])[O:30][C:29](=[O:35])[C:14]=3[C:13]=2[C:12]2[C:7]1=[CH:8][CH:9]=[CH:10][CH:11]=2
Reactant: [OH-]
Reactant: CN(C)CC(O)Cn1c2ccccc2c2c3c(c4c5ccccc5n(C)c4c21)C(=O)N(C)C3=O
Agent: [K+]
Product: CN(C)CC(O)Cn1c2ccccc2c2c3c(c4c5ccccc5n(C)c4c21)C(=O)OC3=O

Procedure:
The starting material is prepared in the following manner: 950 mg (2.1 mmol) (±)-12-(3-dimethylamino-2-hydroxy-1-propyl)-6,7,12,13-tetrahydro-6,13-dimethyl-5,7-dioxo-5H-indolo[2,3-a]pyrrolo[3,4-c]carbazole are heated under reflux for 16 hours in 150 ml 15% methanolic potassium hydroxide solution. The solution is evaporated to one half, mixed with 100 ml of water and weakly acidified with semi-concentrated hydrochloric acid. The precipitate obtained is filtered off, stirred with 50 ml 5% sodium hydrogen carbonate solution, again filtered and dried. (±)-12-(3-Dimethylamino-2-hydroxy-1-propyl)-6,7,12,13-tetrahydro-13-methyl-5,7-dioxo-indolo[2,3-a]furano[3,4-c]carbazole is obtained in the form of a yellow amorphous powder.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])[NH2:6].[C:15](Cl)(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O.[OH-].[Na+]>N1C=CC=CC=1>[C:15]([NH:6][C:5]1[CH:7]=[CH:8][C:9]([N+:10]([O-:12])=[O:11])=[C:3]([C:2]([F:13])([F:14])[F:1])[CH:4]=1)(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Nc1ccc([N+](=O)[O-])c(C(F)(F)F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: c1ccncc1
Product: O=C(Nc1ccc([N+](=O)[O-])c(C(F)(F)F)c1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.1 %

Procedure:
A mixture of 3-(trifluoromethyl)-4-nitroaniline (1.00 g, 4.85 mmol) and benzoyl chloride (0.62 ml, 5.34 mmol) were heated in pyridine (20 ml) at reflux for 3 hours under an inert atmosphere. The reaction was allowed to cool to ambient temperature, poured into water (200 ml) and basified by addition of 2.0 N aqueous sodium hydroxide solution. An oily liquid separated out which crystallised on standing at 4° C. overnight. The solid was collected by suction filtration, washed with water (3×20 ml) and then purified by flash chromatography on silica gel, eluting with dichloromethane. This yielded N-benzoyl 3-(trifluoromethyl)-4-nitroaniline (1.01 g, 67% yield) as a white solid:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([C:11]([NH:13][CH:14]3[CH2:21][CH2:20][CH2:19][CH2:18][NH:17][C:15]3=O)=O)=[CH:8][C:7]=2[CH:22]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:24]>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([C:11]3[S:24][C:15]4[NH:17][CH2:18][CH2:19][CH2:20][CH2:21][C:14]=4[N:13]=3)=[CH:8][C:7]=2[CH:22]=1
Reactant: COc1ccc2oc(C(=O)NC3CCCCNC3=O)cc2c1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: c1ccncc1
Product: COc1ccc2oc(-c3nc4c(s3)NCCCC4)cc2c1
Temperature: 0 °C
Yield: 66.6 %

Procedure:
A mixture of DL-α-(5-methoxybenzofuran-2-yl)carbonylamino-ε-caprolactam (0.2 g) and phosphorus pentasulfide (0.2 g) in pyridin (2 ml) was stirred under reflux for 6.5 hours. After being cooled, the resulting mixture was poured into ice-water, and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and concentrated under reduced pressure to give crude crystal, which was collected by filtration and washed with ethanol to give 2-(5-methoxybenzofuran-2-yl)-4,5,6,7-tetrahydro-8H-thiazolo[5,4-b]azepine (0.09 g).
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][C:8]1[CH:9]=[N:10][CH:11]=[C:12](B2OC(C)(C)C(C)(C)O2)[CH:13]=1.Br[C:24]1[CH:25]=[C:26]2[C:30](=[C:31]([C:33]([NH2:35])=[O:34])[CH:32]=1)[NH:29][CH:28]=[C:27]2[CH:36]1[CH2:41][CH2:40][N:39]([S:42]([CH2:45][CH3:46])(=[O:44])=[O:43])[CH2:38][CH2:37]1.C(=O)([O-])[O-].[K+].[K+]>>[CH2:45]([S:42]([N:39]1[CH2:38][CH2:37][CH:36]([C:27]2[C:26]3[C:30](=[C:31]([C:33]([NH2:35])=[O:34])[CH:32]=[C:24]([C:12]4[CH:11]=[N:10][CH:9]=[C:8]([CH2:7][N:3]5[CH2:4][CH2:5][CH2:6][CH:2]5[CH3:1])[CH:13]=4)[CH:25]=3)[NH:29][CH:28]=2)[CH2:41][CH2:40]1)(=[O:44])=[O:43])[CH3:46]
Reactant: CC1CCCN1Cc1cncc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(Br)cc23)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cncc(CN5CCCC5C)c4)cc23)CC1
Yield: 16 %

Procedure:
Following the general procedure of 5-(5-{[(cyclopropylmethyl)amino]methyl}-3-pyridinyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide, 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinecarbaldehyde (30 mg, 0.129 mmol), 2-methylpyrrolidine (0.013 mL, 0.129 mmol), and NaCNBH3 (16 mg, 0.258 mmol) were reacted to give 25 mg of crude 3-[(2-methyl-1-pyrrolidinyl)methyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine. The crude 3-[(2-methyl-1-pyrrolidinyl)methyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine was then reacted with 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide (30 mg, 0.0723 mmol), potassium carbonate (60 mg, 0.434 mmol), and chloro-2-(dimethylaminomethyl)-ferrocen-1-yl-(dinorbornylphosphine)palladium(II) (4.4 mg, 0.00723 mmol) to give 6 mg of the title compound (16%).
Reaction SMILES: [S:1]1[C:5]2=[C:6]3[C:10](=[CH:11][CH:12]=[C:4]2[N:3]=[CH:2]1)[NH:9][C:8](=[O:13])[C:7]3=O.Cl.[CH3:16][O:17][C:18]1[CH:19]=[C:20]([NH:24][NH2:25])[CH:21]=[CH:22][CH:23]=1>>[CH3:16][O:17][C:18]1[CH:19]=[C:20]([NH:24][N:25]=[C:7]2[C:6]3[C:10](=[CH:11][CH:12]=[C:4]4[N:3]=[CH:2][S:1][C:5]4=3)[NH:9][C:8]2=[O:13])[CH:21]=[CH:22][CH:23]=1
Reactant: COc1cccc(NN)c1
Reactant: O=C1Nc2ccc3ncsc3c2C1=O
Agent: Cl
Product: COc1cccc(NN=C2C(=O)Nc3ccc4ncsc4c32)c1
Yield: 44 %

Procedure:
Prepared according to Procedure H using 6H-[1,3]thiazolo[5,4-e]indole-7,8-dione (Procedure A) and 3-methoxyphenylhydrazine hydrochloride in 44% yield. APCI-MS m/z 323 (M−H)−.
Reaction SMILES: Cl.[CH3:2][CH:3]([O:5][C:6]1[CH:13]=[CH:12][C:11]([C:14]2[O:18][N:17]=[C:16]([C:19]3[C:29]4[O:28][CH2:27][CH2:26][NH:25][CH2:24][C:23]=4[CH:22]=[CH:21][CH:20]=3)[N:15]=2)=[CH:10][C:7]=1[C:8]#[N:9])[CH3:4].C(N(CC)C(C)C)(C)C.Br[CH2:40][CH2:41][C:42]([O:44][CH2:45][CH3:46])=[O:43]>C(#N)C>[C:8]([C:7]1[CH:10]=[C:11]([C:14]2[O:18][N:17]=[C:16]([C:19]3[C:29]4[O:28][CH2:27][CH2:26][N:25]([CH2:40][CH2:41][C:42]([O:44][CH2:45][CH3:46])=[O:43])[CH2:24][C:23]=4[CH:22]=[CH:21][CH:20]=3)[N:15]=2)[CH:12]=[CH:13][C:6]=1[O:5][CH:3]([CH3:2])[CH3:4])#[N:9]
Reactant: CCOC(=O)CCBr
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4c3OCCNC4)no2)cc1C#N
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CCN1CCOc2c(cccc2-c2noc(-c3ccc(OC(C)C)c(C#N)c3)n2)C1
Temperature: 80 °C
Yield: 38.5 %

Procedure:
To a solution of 2-[(1-methylethyl)oxy]-5-[3-(2,3,4,5-tetrahydro-1,4-benzoxazepin-9-yl)-1,2,4-oxadiazol-5-yl]benzonitrile hydrochloride (Example 32) (90 mg, 0.218 mmol) in acetonitrile (10 ml) was added N,N-diisopropylethylamine (0.076 ml, 0.436 mmol) followed by ethyl 3-bromopropanoate (0.056 ml, 0.436 mmol). The reaction mixture was heated at 80° C. overnight. A further 1 equivalent of N,N-diisopropylethylamine and ethyl 3-bromopropanoate were added and heating continued overnight. The reaction mixture was cooled and evaporated. Purification of the residue by column chromatography on silica, eluting with 60-70% ethyl acetate in cyclohexane to give the title compound as a brown oil (40 mg).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:14](=[O:16])[CH3:15])[CH:5]=[C:6]([S:8]([F:13])([F:12])([F:11])([F:10])[F:9])[CH:7]=1.Br[CH2:18][CH:19]([O:21][CH3:22])C.[H-].[Na+].[Br-]>CN(C=O)C.CC(=O)OCC>[CH3:22][O:21][CH2:19][CH2:18][O:1][C:2]1[CH:3]=[C:4]([C:14](=[O:16])[CH3:15])[CH:5]=[C:6]([S:8]([F:13])([F:9])([F:10])([F:11])[F:12])[CH:7]=1
Reactant: CC(=O)c1cc(O)cc(S(F)(F)(F)(F)F)c1
Reactant: COC(C)CBr
Agent: [Br-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COCCOc1cc(C(C)=O)cc(S(F)(F)(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.4 %

Procedure:
1-[3-Hydroxy-5-(pentafluorosulfanyl)phenyl]ethanone (O3.050; 700 mg) and 1-bromo-2-methoxypropane (490 mg) were dissolved in DMF (10 ml), and sodium hydride (77 mg) was added. After stirring at RT for 2 h, further bromide (100 μl) was added and the mixture was heated to 50° C. for 6 h. Then the DMF was drawn off and the residue was taken up in EA, washed with water, dried, filtered and concentrated. 670 mg of the title compound were obtained. LC-MS rt: 1.71 min [M+H]+: 335.1 (met. a)
Reaction SMILES: [C:1]([C:6]1[C:7](=[O:22])[CH2:8][CH:9]([C:13]2[C:18]([CH3:19])=[CH:17][C:16]([CH3:20])=[CH:15][C:14]=2[CH3:21])[CH2:10][C:11]=1[OH:12])(=[O:5])[CH2:2][CH2:3][CH3:4].[CH3:23][O:24]C(Cl)Cl>ClC(Cl)C.[Ti](Cl)(Cl)(Cl)Cl>[C:1]([C:6]1[C:11](=[O:12])[CH2:10][CH:9]([C:13]2[C:14]([CH3:21])=[CH:15][C:16]([CH3:20])=[C:17]([CH:23]=[O:24])[C:18]=2[CH3:19])[CH2:8][C:7]=1[OH:22])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: COC(Cl)Cl
Reactant: CCCC(=O)C1=C(O)CC(c2c(C)cc(C)cc2C)CC1=O
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: CC(Cl)Cl
Product: CCCC(=O)C1=C(O)CC(c2c(C)cc(C)c(C=O)c2C)CC1=O
Yield: 26.7 %

Procedure:
To a solution of 2-butyryl-3-hydroxy-5-mesitylcyclohex-2-en-1-one (1.20 g) in dichloroethane (20 ml) at 0° C. was added titanium tetrachloride (3.00 g) over a period of 3 minutes. While the solution was stirred and cooled dichloromethyl methyl ether (0.46 g) in dichloroethane (20 ml) was added dropwise over a 25 minute period. After the addition was complete, the mixture was stirred for 5 minutes at 0° C., for 30 minutes at room temperature and for 2 hours under reflux. The cooled reaction mixture was poured into a separatory funnel containing crushed ice and was shaken thoroughly. The organic layer was separated, and the aqeuous solution was extracted with methylene chloride. The combined organic solution was washed with water, dried over anhydrous sodium sulfate and evaporated to dryness to give a crude brown oil (0.70 g). Purification by column chromatography over silica gel (eluant dichloromethane) gave 2-butyryl-3-hydroxy-5-(3-formyl-2,4,6-trimethylphenyl)cyclohex-2-en-1-one (0.35 g) as a pale yellow oil. Proton nuclear magnetic resonance spectrum (CDCl3 ; δ in ppm): 1.0 (3H, t); 1.68 (2H, m); 2.43 (3H, s); 2.48 (3H, s); 2.61 (3H, s); 2.65-4.20 (7H, m); 6.94 (1H, s); 10.54 (1H, s); 18.33 (1H, s).
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[C@H:4]([CH:5]=[C:6]2[CH2:9][CH2:8][CH2:7]2)[C@H:3]1[C:10](Cl)=[O:11].[CH:14]([OH:17])([CH3:16])[CH3:15]>>[CH3:1][C:2]1([CH3:13])[C@H:4]([CH:5]=[C:6]2[CH2:9][CH2:8][CH2:7]2)[C@H:3]1[C:10]([O:17][CH:14]([CH3:16])[CH3:15])=[O:11]
Reactant: CC(C)O
Reactant: CC1(C)[C@H](C=C2CCC2)[C@H]1C(=O)Cl
Product: CC(C)OC(=O)[C@@H]1[C@@H](C=C2CCC2)C1(C)C
Reaction time: 8 h

Procedure:
A mixture of 12 g of (1R,trans) 2,2-dimethyl-3-cyclobutylidenemethyl-cyclopropane-1-carboxylic acid chloride in 25 ml of isopropanol was stirred for 8 hours and was distilled to dryness at 45° C. under reduced pressure. The residue was taken up in isopropyl ether and the solution was washed with water, dried and evaporated to dryness under reduced pressure at 45° C. The residue was chromatographed over silica gel and was eluted with a 9-1 petroleum ether (b.p.=60°-80° C.)-isopropyl ether mixture to recover the fraction with an Rf=0.35. The solvent was evaporated under reduced pressure to obtain 7.8 g of isopropyl (1R,trans) 2,2-dimethyl-3-cyclobutylidenemethyl-cyclopropane-1-carboxylate with a boiling point of 64°-66° C. at 0.1 mm Hg and a specific rotation of [α]D20 =-24.5° (c=2% in chloroform).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[O:7][C:6](=[O:8])[N:5]([C:9]2[CH:14]=[CH:13][C:12]([S:15]([CH2:17][CH3:18])=[O:16])=[C:11]([F:19])[CH:10]=2)[CH2:4]1.[C:20](SCC)(=[S:22])[CH3:21]>CN(C=O)C>[C:20]([NH:1][CH2:2][C@@H:3]1[O:7][C:6](=[O:8])[N:5]([C:9]2[CH:14]=[CH:13][C:12]([S:15]([CH2:17][CH3:18])=[O:16])=[C:11]([F:19])[CH:10]=2)[CH2:4]1)(=[S:22])[CH3:21]
Reactant: CCS(=O)c1ccc(N2C[C@H](CN)OC2=O)cc1F
Reactant: CCSC(C)=S
Solvent: CN(C)C=O
Product: CCS(=O)c1ccc(N2C[C@H](CNC(C)=S)OC2=O)cc1F

Procedure:
Prepared analogously to the Method A of General Methods of Preparation of 5-(S)-Thioamidomethyloxazolidinones (Example 1) from 5-(S)-aminomethyl-3-[4′-ethylsulfinyl-3′-fluorophenyl]oxazolidine-2-one (0.0885 g, 0.309 mmol) and ethyl dithioacetate. Reaction was performed in DMF overnight. Yield 0.104 g (98%). M.p. 138-9° C. MS (m/z): [M+H]+=345.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:25])[C@@H:13]([NH:17][C:18]([O:20][C:21]([CH3:24])(C)C)=[O:19])[CH2:14][CH:15]=[CH2:16])[CH2:8][CH2:7]1)=[O:5])[CH3:2]>ClCCl.C(O)(C(F)(F)F)=O>[CH2:1]([O:3][C:4]([N:6]1[CH2:7][CH2:8][N:9]([C:12](=[O:25])[C@@H:13]([NH:17][C:18]([O:20][CH2:21][C:24]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:19])[CH2:14][CH:15]=[CH2:16])[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: C=CC[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCN(C(=O)OCC)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C=CC[C@H](NC(=O)OCc1ccccc1)C(=O)N1CCN(C(=O)OCC)CC1

Procedure:
A solution of 767 mg 4-((S)-2-tert-Butoxycarbonylamino-pent-4-enoyl)-piperazine-1-carboxylic acid ethyl ester in 5 ml dichloromethane and 1.6 ml TFA was stirred for 2 h. The reaction mixture was concentrated, the residue dissolved in 4 ml dioxane/water (1:1) and 661 mg NaHCO3 and 688 mg N-(Benzyloxycarbonyloxy)succinimide were added. After 12 h the reaction mixture was diluted with ethyl acetate and washed with water, 0.1 M HCl and half-saturated aqueous NaHCO3 solution. The crude product obtained after evaporation of the solvent was purified by chromatography on silica using ethyl acetate/heptane 1:2 to 2:1 as eluent. Yield: 640 mg.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]1[S:10][C:11]2[CH:17]=[C:16]([O:18][C:19]3[CH:24]=[CH:23][N:22]=[C:21]([C:25](O)=[O:26])[CH:20]=3)[CH:15]=[CH:14][C:12]=2[N:13]=1.CN(C(ON1N=NC2[CH:39]=[CH:40][CH:41]=[N:42]C1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.C1(N)CC1>CN1C(=O)CCC1>[CH:41]1([NH:42][C:25](=[O:26])[C:21]2[CH:20]=[C:19]([O:18][C:16]3[CH:15]=[CH:14][C:12]4[N:13]=[C:9]([NH:8][C@@H:3]5[CH2:4][CH2:5][CH2:6][CH2:7][C@H:2]5[OH:1])[S:10][C:11]=4[CH:17]=3)[CH:24]=[CH:23][N:22]=2)[CH2:39][CH2:40]1
Reactant: O=C(O)c1cc(Oc2ccc3nc(N[C@@H]4CCCC[C@H]4O)sc3c2)ccn1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: NC1CC1
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NC1CC1)c1cc(Oc2ccc3nc(N[C@@H]4CCCC[C@H]4O)sc3c2)ccn1
Temperature: 25 °C
Reaction time: 12 h
Yield: 5.9 %

Procedure:
To the reaction solution of 4-(2-((1R,2R)-2-hydroxycyclohexylamino)benzo[d]thiazol-6-yloxy)picolinic acid (5 mg, 39 μmol), HATU (15 mg, 39 μmol) and DIPEA (14 μL, 78 μmol) in 1 ml of NMP was added cyclopropylamine (7 ul mg, 30 μmol). The reaction solution was stirred at room temperature for 12 hours. The crude reaction solution was purified on prep HPLC and evaporated in vacuo to give N-cyclopropyl-4-(2-((1R,2R)-2-hydroxycyclohexylamino)benzo[d]thiazol-6-yloxy)picolinamide (1 mg, 2.3 μmol) as white powder. ES/MS m/z 425.2 (MH+).
Reaction SMILES: O[C:2]1([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[CH2:7][CH:6]2[CH2:8][CH2:9][CH:3]1[CH2:4][C:5]2=[O:10].CC1C=CC(S(O)(=O)=O)=CC=1>CC(C)=O.CCOC(C)=O>[CH3:18][O:17][C:14]1[CH:13]=[CH:12][C:11]([C:2]2[CH:3]3[CH2:9][CH2:8][CH:6]([CH:7]=2)[C:5](=[O:10])[CH2:4]3)=[CH:16][CH:15]=1
Reactant: COc1ccc(C2(O)CC3CCC2CC3=O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: COc1ccc(C2=CC3CCC2CC3=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84 %

Procedure:
3.03 g of crude 5-hydroxy-5-(4-methoxy-phenyl)-bicyclo[2.2.2]octan-2-one (intermediate K2A.1) was dissolved in 100 mL of acetone, 2.90 g of TsOH were added and the mixture was stirred at rt overnight. Then the reaction mixture was diluted with EtOAc, the organic phase washed with sat. aq. NaHCO3 and evaporated. The crude material was purified by CC with Hep-EtOAc (20:1) to yield 2.36 g of rac-(1R*,4R*)-5-(4-methoxy-phenyl)-bicyclo[2.2.2]oct-5-en-2-one.
Reaction SMILES: [C:1]1(=[N:7][OH:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].[CH:11]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH:20]([CH3:22])[CH3:21])[C:15]=1[N:23]=[C:24]=[N:25][C:26]1[C:31]([CH:32]([CH3:34])[CH3:33])=[CH:30][CH:29]=[CH:28][C:27]=1[CH:35]([CH3:37])[CH3:36])([CH3:13])[CH3:12]>C1COCC1>[CH:35]([C:27]1[CH:28]=[CH:29][CH:30]=[C:31]([CH:32]([CH3:34])[CH3:33])[C:26]=1[NH:25][C:24](=[N:23][C:15]1[C:14]([CH:11]([CH3:13])[CH3:12])=[CH:19][CH:18]=[CH:17][C:16]=1[CH:20]([CH3:22])[CH3:21])[O:8][N:7]=[C:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)([CH3:37])[CH3:36]
Reactant: CC(C)c1cccc(C(C)C)c1N=C=Nc1c(C(C)C)cccc1C(C)C
Reactant: ON=C1CCCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)c1cccc(C(C)C)c1N=C(Nc1c(C(C)C)cccc1C(C)C)ON=C1CCCCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 82 %

Procedure:
To a solution of cyclohexanone oxime (1.13 g, 0.01 mol) in dry THF (25 ml) is added finely powdered NaOH (0.04 g) and bis(2,6-diisopropylphenyl)carbodiimide (3.65 g, 0.01 mol). The mixture is then stirred 4 h at room temperature under argon. The turbid mixture is thereafter filtered and evaporated under reduced pressure. The solid residue is crystallized from dichloro-methane-hexane to afford 3.9 g of the title compound as a colorless solid, mp. 150-152° C.
Reaction SMILES: [CH3:1][CH:2]1[O:7][C:6]2[CH:8]=[CH:9][C:10]([CH2:12][CH:13]3[CH2:18][CH2:17][N:16]([C:19]4[CH:29]=[CH:28][C:22]([C:23](OCC)=[O:24])=[CH:21][CH:20]=4)[CH2:15][CH2:14]3)=[CH:11][C:5]=2[NH:4][C:3]1=[O:30].Cl.[CH2:32]([NH2:34])[CH3:33]>>[CH2:32]([NH:34][C:23](=[O:24])[C:22]1[CH:21]=[CH:20][C:19]([N:16]2[CH2:15][CH2:14][CH:13]([CH2:12][C:10]3[CH:9]=[CH:8][C:6]4[O:7][CH:2]([CH3:1])[C:3](=[O:30])[NH:4][C:5]=4[CH:11]=3)[CH2:18][CH2:17]2)=[CH:29][CH:28]=1)[CH3:33]
Reactant: CCN
Reactant: CCOC(=O)c1ccc(N2CCC(Cc3ccc4c(c3)NC(=O)C(C)O4)CC2)cc1
Agent: Cl
Product: CCNC(=O)c1ccc(N2CCC(Cc3ccc4c(c3)NC(=O)C(C)O4)CC2)cc1

Procedure:
Saponification of 390D was performed using the general procedure for hydrolysis of carboxylic esters. The resulting carboxylic acid and ethylamine hydrochloride were used in the general procedure for coupling an amine to a carboxylic acid to give the title compound as a pinkish, tan solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.09 (t, J=7.20 Hz, 3H) 1.13-1.31 (m, 2H) 1.40 (d, J=6.82 Hz, 3H) 1.56-1.72 (m, 3H) 2.44 (d, J=6.82 Hz, 2H) 2.62-2.78 (m, 2H) 3.17-3.29 (m, 2H) 3.76-3.89 (m, 2 H) 4.61 (q, J=6.82 Hz, 1H) 6.63-6.78 (m, 2H) 6.88 (dd, J=15.41, 8.59 Hz, 3H) 7.68 (d, J=9.09 Hz, 2H) 8.13 (t, J=5.43 Hz, 1H) 10.59 (s, 1H). ESI-MS: m/z 408.4 (M+H)+.
Reaction SMILES: [CH:1]([N:14]1[C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][N:16]=[CH:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:23]1(C)C(S(O)(=O)=O)=CC=C[CH:28]=1>C(O)CC>[CH:1]([N:14]1[C:18]([C:19]([O:21][CH2:22][CH2:23][CH3:28])=[O:20])=[CH:17][N:16]=[CH:15]1)([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: COC(=O)c1cncn1C(c1ccccc1)c1ccccc1
Reactant: Cc1ccccc1S(=O)(=O)O
Solvent: CCCO
Product: CCCOC(=O)c1cncn1C(c1ccccc1)c1ccccc1

Procedure:
The compound was prepared by transesterification of 2.9 g (0.01 mol) of 1-benzhydryl-5-methoxycarbonyl-imidazole of Example 8. To this end it was refluxed for some time in 100 cc of propanol and in the presence of catalytic amounts of toluene sulfonic acid. The colorless crystals obtained had a melting point of 81° C.
Reaction SMILES: [CH2:1]([O:3][NH:4][C:5](=[C:8]1[C:13](=[O:14])[CH2:12][C:11]([CH3:16])([CH3:15])[CH2:10][C:9]1=[O:17])[CH2:6][CH3:7])[CH3:2].[Cl:18][C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[CH:21][CH:20]=1>C(Cl)(Cl)Cl>[Cl:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([O:17][C:9]2[CH2:10][C:11]([CH3:15])([CH3:16])[CH2:12][C:13](=[O:14])[C:8]=2[C:5](=[N:4][O:3][CH2:1][CH3:2])[CH2:6][CH3:7])=[O:24])=[CH:21][CH:20]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: CCONC(CC)=C1C(=O)CC(C)(C)CC1=O
Solvent: ClC(Cl)Cl
Product: CCON=C(CC)C1=C(OC(=O)c2ccc(Cl)cc2)CC(C)(C)CC1=O

Procedure:
The same reaction procedures as Example 1 were carried out by using 2.4 g of 2-[1-(N-ethoxyamino)propylidene]-5,5-dimethylcyclohexane-1,3-dione and 1.75 g of 4-chlorobenzoylchloride, and chloroform was distilled off under reduced pressure and thereby the desired product as a white crystal was obtained after recrystallization the residual material from n-hexane.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)/[CH:5]=[CH:6]/[C:7]1[S:8][C:9]2[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=2[N:11]=1.CCCCCC.C([Li])CCC.[C:30]1(=[O:35])[O:34][CH2:33][CH2:32][CH2:31]1>O1CCCC1>[OH:35][CH2:30][CH2:31][CH2:32][C:33]([NH:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)/[CH:5]=[CH:6]/[C:7]1[S:8][C:9]2[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=2[N:11]=1)=[O:34]
Reactant: Nc1cccc(/C=C/c2nc3ccccc3s2)c1
Reactant: O=C1CCCO1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=C(CCCO)Nc1cccc(/C=C/c2nc3ccccc3s2)c1
Temperature: -78 °C
Reaction time: 0.42 h
Yield: 11.9 %

Procedure:
A solution of 1.0 g of 2-(trans-3-aminostyryl)benzothiazole dissolved in 15 ml of anhydrous tetrahydrofuran was cooled to -78° C. and 2.8 ml of a n-hexane solution (1.55M) of n-butyl lithium was added dropwise in a nitrogen gas atmosphere. After a mixture was stirred at the same temperature for 25 minutes, 375 mg of γ-butyrolactone was injected, followed by stirring for 1 hour. After completion of the reaction, the mixture was extracted with ethyl acetate, dried over magnesium sulfate and the solvent was evaporated under reduced pressure. The crude crystals obtained were washed with ethyl ether and dried to obtain 160 mg (yield 12%) of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:21]([O:23]C)=O)[CH2:10][CH:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[F:20])[C:12]#[N:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H].C(=O)([O-])[O-].[K+].[K+]>C(O)C.[Ni]>[F:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[C@H:11]1[CH2:12][NH:13][C:21](=[O:23])[C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:10]1
Reactant: [H][H]
Reactant: COC(=O)[C@H](CC(C#N)c1ccccc1F)NC(=O)OC(C)(C)C
Agent: [Ni]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CC(C)(C)OC(=O)N[C@H]1C[C@@H](c2ccccc2F)CNC1=O
Temperature: 23 °C
Reaction time: 4 h

Procedure:
To a solution of methyl N-(tert-butoxycarbonyl)-4-(2-fluorophenyl)-5-nitrilonorvalinate (3.88 g, 11.5 mmol) in ethanol (50 mL) was added Raney nickel (slurry in water, ca. 10 g). The mixture was placed under a balloon of hydrogen and the reaction was stirred at 23° C. for 4 h. The mixture was filtered and concentrated to afford a mixture of 4 diastereoisomers. A solution of this residue in ethanol (100 mL) was stirred in the presence of solid potassium carbonate (1.30 g, 9.44 mmol) at 60° C. for 2 h. The bulk of the ethanol was removed under reduced pressure and the remaining slurry was diluted with water to afford a white precipitate. The precipitate was filtered, washed with water and then dried under vacuum at 40° C. for 18 h. The enantiomers were separated using normal-phase HPLC using a ChiralPak® AD column, eluting with 40% hexane in ethanol (0.1% diethylamine used as a modifier) to afford the title compound as the second major enantiomer to elute. MS: m/z=331.1 (M+Na).