Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[C:11]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=3)=[N:10][CH2:9][C:8]3[O:19][N:20]=[C:21]([CH3:22])[C:7]=3[C:6]=2[N:23]=1.[OH-].[NH4+:25].[Cl-].[NH4+]>CCO>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([C:11]2[C:5]3[CH:4]=[CH:3][C:2]([NH2:25])=[N:23][C:6]=3[C:7]3[C:21]([CH3:22])=[N:20][O:19][C:8]=3[CH2:9][N:10]=2)=[CH:13][CH:14]=1
Reactant: Cc1noc2c1-c1nc(Cl)ccc1C(c1ccc(Cl)cc1)=NC2
Reactant: [NH4+]
Agent: [Cl-]
Agent: [OH-]
Solvent: CCO
Product: Cc1noc2c1-c1nc(N)ccc1C(c1ccc(Cl)cc1)=NC2

Procedure:
To a solution of 2-chloro-5-(4-chlorophenyl)-10-methyl-7H-isoxazolo[5,4-c]pyrido[2,3-e]azepine (0.050 g, 0.145 mmol) in EtOH (1 mL) was added concentrated ammonium hydroxide (4.00 mL) and ammonium chloride (just enough to saturate the reaction) at room temperature. The reaction was heated to 100° C. overnight before the desired product was extracted using CH2Cl2 (repeated 4 times). The organic layers were combined, dried over Na2SO4 and concentrated to dryness. The residue was purified by flash chromatography (hexane/EtOAc 6:4 to 0:10) to give the title compound as a tan solid (0.008 g). LC/MS m/z 325 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ 7.43 (td, J=2.10, 8.70 Hz, 2H), 7.37 (td, J=2.10, 8.70 Hz, 2H), 7.24 (d, J=8.72 Hz, 1H), 6.77 (br. s, 2H), 6.38 (d, J=8.72 Hz, 1H), 4.61 (s, 2H), 2.56 (s, 3H).
Reaction SMILES: C[O:2][C:3]1[C:4](=O)[CH:5]([C:11](=O)[C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:6]([CH3:10])([CH3:9])[CH2:7][CH:8]=1.[CH3:19][NH:20][NH2:21]>C(O)(=O)C.O>[CH3:19][N:20]1[C:4]2[C:3](=[O:2])[CH2:8][CH2:7][C:6]([CH3:10])([CH3:9])[C:5]=2[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[N:21]1
Reactant: CCOC(=O)C(=O)C1C(=O)C(OC)=CCC1(C)C
Reactant: CNN
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)c1nn(C)c2c1C(C)(C)CCC2=O
Reaction time: 8 h
Yield: 47.7 %

Procedure:
A solution of ethyl (3-methoxy-6,6-dimethyl-2-oxocyclohex-3-en-1-yl)(oxo)acetate from the previous step (40.2 mmol theoretically) in acetic acid (65 mL) was treated dropwise with a solution of methyl hydrazine (2.14 mL, 40.2 mmol) in acetic acid (20 mL) and allowed to stand at room temperature overnight. The mixture was then diluted with water (800 mL) and extracted with ethyl acetate (500 mL×2). The organic extracts were washed with brine, dried on Na2SO4 and evaporated to dryness. The crude material was chromatographed on silica gel eluted with dichloromethane/ethyl acetate 100:5 to obtain the pure title compound (4.8 g, 47.7% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][N:8]([S:12]([CH2:15][CH:16]([C@H:18]3[CH2:22][CH2:21][CH2:20][O:19]3)O)(=[O:14])=[O:13])[CH2:9]2)=[CH:4][CH:3]=1.CCN(CC)CC.CS(Cl)(=O)=O.Cl>C(Cl)Cl>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][N:8]([S:12]([CH:15]=[CH:16][C@H:18]3[CH2:22][CH2:21][CH2:20][O:19]3)(=[O:14])=[O:13])[CH2:9]2)=[CH:4][CH:3]=1
Reactant: O=S(=O)(CC(O)[C@H]1CCCO1)N1CCc2ccc(Cl)cc2C1
Agent: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=S(=O)(C=C[C@H]1CCCO1)N1CCc2ccc(Cl)cc2C1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 100.8 %

Procedure:
A solution of 2-[(7-chloro-3,4-dihydroisoquinolin-2(1H)-yl)sulfonyl]-1-[(2R)-tetrahydrofuran-2-yl]ethanol (420 mg, 1.21 mmol) and Et3N (370 mg, 3.63 mmol) in anhydrous DCM (5 ml) was cooled at 0° C., then methanesulfonyl chloride (0.14 ml, 1.82 mmol) was added dropwise. The resulting mixture was stirred at 0° C. for 5 min., then at RT for 15 hours. The reaction mixture was poured into a 1N aqueous solution of HCl and extracted with EtOAc (2×). The organic layers were combined, dried (MgSO4) and the solvents were removed under reduced pressure to give the title compound as an orange solid (400 mg, quantitative). HPLC, Rt: 3.7 min (purity: 94.2%). LC/MS, M+(ESI): 328.2.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]2([CH2:13][CH3:14])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[O:4][N:3]=1.[CH3:15][O:16][C:17]1[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH3:27])[C:18]=1[C:19](Cl)=[O:20]>C1(C)C=CC=CC=1.ClCCl>[CH2:13]([C:7]1([C:5]2[O:4][N:3]=[C:2]([NH:1][C:19](=[O:20])[C:18]3[C:22]([O:26][CH3:27])=[CH:23][CH:24]=[CH:25][C:17]=3[O:16][CH3:15])[CH:6]=2)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)[CH3:14]
Reactant: COc1cccc(OC)c1C(=O)Cl
Reactant: CCC1(c2cc(N)no2)CCCCC1
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CCC1(c2cc(NC(=O)c3c(OC)cccc3OC)no2)CCCCC1
Temperature: 25 °C
Yield: 60.2 %

Procedure:
A solution of 14 g of 3-amino-5-(1-ethylcyclohexyl)isoxazole and 14.4 g of 2,6-dimethoxybenzoyl chloride in 100 ml of toluene was heated to reflux and stirred for eighteen hours. The reaction mixture then was cooled to room temperature and the solvent was removed by evaporation under reduced pressure to provide a solid. The solid was dissolved in 200 ml of dichloromethane, washed with dilute sodium hydroxide and with brine, dried, and the solvent was removed by evaporation. The product was crystallized from dichloromethane and diethyl ether to provide 15.5 g of N-[5-(1-ethylcyclohexyl)-3-isoxazolyl]-2,6-dimethoxybenzamide. M.P. 179°-181° C. Yield 60%.
Reaction SMILES: [CH:1]1[C:13]2[C:12](=O)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[C:4](C(Cl)=O)=[CH:3][CH:2]=1.C(O)C[O:20]CCO.C(N(CC)CC)C>O1CCCC1>[C:1]1(=[O:20])[C:13]2[C:5]([C:6]3[C:11]([CH:12]=2)=[CH:10][CH:9]=[CH:8][CH:7]=3)=[CH:4][CH:3]=[CH:2]1
Reactant: O=C(Cl)c1cccc2c1-c1ccccc1C2=O
Reactant: OCCOCCO
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C1C=CC=C2C1=Cc1ccccc12
Reaction time: 0.5 h

Procedure:
A 10.0 g quantity of 9-fluorenone-4-carbonyl chloride (0.04 mole, obtained from Aldrich Chemicals Co, Milwaukee, Wis. 53201, USA) and 100 ml of tetrahydrofuran (obtained from Aldrich) were added to a 250 ml, 3-neck round bottom flask equipped with a reflux condenser and a mechanical stirrer. The solution was stirred for about ½ hour, and then 2.186 g of diethylene glycol (0.02 mole, obtained from Aldrich) in 50 ml of tetrahydrofuran were added, followed by the addition of 4.17 g of triethylamine (0.04 mole, obtained from Aldrich). The solution was refluxed for 6 hours, filtered hot to remove triethylamine hydrochloride salt byproduct, and the filtrate was evaporated to dryness to obtain the crude product. The crude product was recrystallized from ethyl acetate with activated charcoal. The product was dried at 60° C. in a vacuum oven for 6 hours to yield a third dimeric fluorenone derivative, which was a yellow solid (5.0 g, 47% yield). The product had a melting point of 137° C. A 1H-NMR (300 MHz) spectrum in CDCl3 yielded chemical shifts (ppm) of: 3.88–4.00 (t, 4H); 4.56–4.65 (t, 4H); 7.15–7.34 (m, 4H); 7.40–7.49 (td, 2H); 7.61–7.68 (d, 2H); 7.71–7.77 (dd, 2H); 7.85–7.92 (dd, 2H); 8.20–8.27 (d, 2H).
Reaction SMILES: [N+](C1C=CC=CC=1S([N:13]([CH2:20][CH2:21][CH:22]1[CH2:24][O:23]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=O)=O)([O-])=O.BrC1C=CC2N(CCCNC3C=CC=CC=3)C3C(C=2C=1)=CC(Br)=CC=3>>[O:23]1[CH2:24][CH:22]1[CH2:21][CH2:20][NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)N(CCC1CO1)c1ccccc1
Agent: Brc1ccc2c(c1)c1cc(Br)ccc1n2CCCNc1ccccc1
Product: c1ccc(NCCC2CO2)cc1

Procedure:
Prepared from 2-nitro-N-(2-(oxiran-2-yl)ethyl)-N-phenylbenzenesulfonamide using an analogous procedure as used to prepare the compound of Example 20.
Reaction SMILES: [C:1]([C:5]([CH2:7][N:8]1[C:14]2[CH:15]=[C:16]([CH3:19])[CH:17]=[CH:18][C:13]=2[N:12]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:11][CH:10]([NH2:26])[C:9]1=[O:27])=[O:6])([CH3:4])([CH3:3])[CH3:2].[C:28]([O:32][C:33]([NH:35][C@H:36]([C:44](O)=[O:45])[CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:34])([CH3:31])([CH3:30])[CH3:29].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O.C(N(CC)CC)C>[C:1]([C:5]([CH2:7][N:8]1[C:14]2[CH:15]=[C:16]([CH3:19])[CH:17]=[CH:18][C:13]=2[N:12]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:11][CH:10]([NH:26][C:44](=[O:45])[C@@H:36]([NH:35][C:33]([O:32][C:28]([CH3:30])([CH3:29])[CH3:31])=[O:34])[CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:9]1=[O:27])=[O:6])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ccc2c(c1)N(CC(=O)C(C)(C)C)C(=O)C(N)CN2c1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)N(CC(=O)C(C)(C)C)C(=O)C(NC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C)CN2c1ccccc1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 101.2 %

Procedure:
Under argon atmosphere, 1-tert-butylcarbonylmethyl-2-oxo-3-amino-5-phenyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine (4.75 g) obtained from Step 2 of Example 95 was dissolved in anhydrous N,N-dimethylformamide (40 ml), N-tert-butoxycarbonyl-L-phenylalanine (3.80 g), 1-hydroxybenzotriazole (1.93 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (2.74 g) and triethylamine (3.65 ml) were added under ice-cooling, the mixture was stirred for 5 minutes at same temperature, and subsequently the resultant mixture was allowed to come to room temperature, stirred for 2 hours. Ice-water was added to the reaction mixture, extracted with ethyl acetate, the organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, the residue was purified by silica gel column chromatography(n-hexane:ethyl acetate=2:1), to thereby obtain 8.06 g of the titled compound (Yield: 100%).
Reaction SMILES: CN1CCN(C2C=CC(C=O)=CC=2)CC1.[CH2:16]([N:18]([CH2:44][C:45]1[CH:50]=[CH:49][C:48]([N:51]2[CH2:56][CH2:55][N:54]([CH3:57])[CH2:53][CH2:52]2)=[CH:47][CH:46]=1)[C:19]1[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[CH:21][C:20]=1[CH:27]1[CH2:36][CH2:35][C:34]2[CH:33]=[C:32]([O:37]C(=O)C(C)(C)C)[CH:31]=[CH:30][C:29]=2[CH2:28]1)[CH3:17]>>[CH2:16]([N:18]([CH2:44][C:45]1[CH:46]=[CH:47][C:48]([N:51]2[CH2:56][CH2:55][N:54]([CH3:57])[CH2:53][CH2:52]2)=[CH:49][CH:50]=1)[C:19]1[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[CH:21][C:20]=1[CH:27]1[CH2:36][CH2:35][C:34]2[CH:33]=[C:32]([OH:37])[CH:31]=[CH:30][C:29]=2[CH2:28]1)[CH3:17]
Reactant: CCN(Cc1ccc(N2CCN(C)CC2)cc1)c1cc(OC)ccc1C1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Agent: CN1CCN(c2ccc(C=O)cc2)CC1
Product: CCN(Cc1ccc(N2CCN(C)CC2)cc1)c1cc(OC)ccc1C1CCc2cc(O)ccc2C1
Yield: 82.6 %

Procedure:
Synthesized from 6-(2-ethylamino-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-yl ester and 4-(4-methylpiperazin-1-yl)benzaldehyde according to an analogous synthetic method to Example 212, pivalic acid 6-{2-{ethyl[4-(4-methylpiperazin-1-yl)benzyl]amino}-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (71 mg) was used according to an analogous synthetic method to Example 213 to provide the title compound (50 mg).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:11]=[C:10]([O:12][C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[N:18]([C:22](=[O:34])[NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=2)[CH2:17][CH2:16]3)[N:9]=[CH:8][N:7]=1)=[O:5])C.[H-].C([Al+]CC(C)C)C(C)C>C1COCC1.CCOC(C)=O.O>[F:32][C:30]([F:31])([F:33])[C:26]1[CH:25]=[C:24]([NH:23][C:22]([N:18]2[C:19]3[C:15](=[CH:14][C:13]([O:12][C:10]4[CH:11]=[C:6]([CH:4]([OH:5])[OH:3])[N:7]=[CH:8][N:9]=4)=[CH:21][CH:20]=3)[CH2:16][CH2:17]2)=[O:34])[CH:29]=[CH:28][CH:27]=1
Reactant: CCOC(=O)c1cc(Oc2ccc3c(c2)CCN3C(=O)Nc2cccc(C(F)(F)F)c2)ncn1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: O=C(Nc1cccc(C(F)(F)F)c1)N1CCc2cc(Oc3cc(C(O)O)ncn3)ccc21
Temperature: 0 °C
Reaction time: 20 h

Procedure:
To solution of 100 mg (0.21 mMol) 6-[1-(3-trifluoromethyl-phenylcarbamoyl)-2,3-dihydro-1H-indol-5-yloxy]-pyrimidine-4-carboxylic acid ethyl ester (Expl. 72) in 3 ml THF at −78° C. are added 1.39 ml of a 1 M solution of diisobutylaluminium hydride in THF. After 20 h at −78° C., the mixture is slowly warmed up to 0° C. and stirred at this temperature for 2 h. Then the mixture is diluted with EtOAc and water, the aqueous layer separeted off and extracted twice with EtOAc. The organic phases are washed with water and brine, dried (Na2SO4) and after addition of 0.25 g of SiO2 concentrated. The resulting powder is put on top of a chromatography column (SiO2; EtOAc/hexane 1:4) and the title compound eluated with EtOAc/hexane 1:1: MS: [M+1]+=446; HPLC: AtRet=13.0.
Reaction SMILES: [ClH:1].[CH2:2]([O:9][C:10](=[O:59])[NH:11][CH2:12][CH2:13][NH:14][C:15](=[O:58])[CH2:16][C@@H:17]([NH:47][C:48]([O:50][CH2:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)=[O:49])[CH2:18][CH2:19][CH2:20][NH:21][C:22](=[O:46])[C@H:23]([CH2:32][CH2:33][CH2:34][NH:35][C:36]([O:38]CC1C=CC=CC=1)=[O:37])[NH:24]C(OC(C)(C)C)=O)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>O1CCOCC1>[ClH:1].[CH2:2]([N:35]([CH2:34][CH2:33][CH2:32][C@H:23]([NH2:24])[C:22](=[O:46])[NH:21][CH2:20][CH2:19][CH2:18][C@H:17]([NH:47][C:48]([O:50][CH2:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)=[O:49])[CH2:16][C:15](=[O:58])[NH:14][CH2:13][CH2:12][NH:11][C:10](=[O:59])[O:9][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)[C:36](=[O:37])[OH:38])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCNC(=O)OCc1ccccc1)C(=O)NCCC[C@@H](CC(=O)NCCNC(=O)OCc1ccccc1)NC(=O)OCc1ccccc1
Agent: Cl
Solvent: C1COCCO1
Product: N[C@@H](CCCN(Cc1ccccc1)C(=O)O)C(=O)NCCC[C@@H](CC(=O)NCCNC(=O)OCc1ccccc1)NC(=O)OCc1ccccc1
Reaction time: 4 h

Procedure:
2.5 ml of a 4M solution of hydrogen chloride in dioxane are added to a solution of 48 mg (0.060 mmol) of benzyl{2-[((3S)-3-{[(benzyloxy)carbonyl]amino}-6-{[N5-[(benzyloxy)carbonyl]-N2-(tert-butoxycarbonyl)-L-ornithyl]amino}hexanoyl)amino]ethyl}carbamate (Example 106A) in 1 ml of dioxane at RT. After 4 h at RT, the reaction solution is concentrated in vacuo, coevaporated with dichloromethane several times and dried under high vacuum. The crude product is reacted without further purification.
Reaction SMILES: [CH3:1][N:2](C)[CH2:3][CH2:4][CH:5]=[C:6]1[C:12]2[CH:13]=[C:14]([S:17]([CH3:20])(=[O:19])=[O:18])[CH:15]=[CH:16][C:11]=2[CH:10]=[CH:9][C:8]2[CH:21]=[CH:22][CH:23]=[CH:24][C:7]1=2.CN(C)CCC=C1C2C=CC=CC=2C=CC2C=CC=CC1=2>>[CH3:1][NH:2][CH2:3][CH2:4][CH:5]=[C:6]1[C:12]2[CH:13]=[C:14]([S:17]([CH3:20])(=[O:18])=[O:19])[CH:15]=[CH:16][C:11]=2[CH:10]=[CH:9][C:8]2[CH:21]=[CH:22][CH:23]=[CH:24][C:7]1=2
Reactant: CN(C)CCC=C1c2ccccc2C=Cc2ccc(S(C)(=O)=O)cc21
Agent: CN(C)CCC=C1c2ccccc2C=Cc2ccccc21
Product: CNCCC=C1c2ccccc2C=Cc2ccc(S(C)(=O)=O)cc21

Procedure:
By substituting 5-(3-dimethylaminopropylidene)-3-methylsulfonyl-5H-dibenzo[a,d]cycloheptene (β-isomer), (Product of Example 23, Step G.), for the 5-(3-dimethylaminopropylidene)-5H-dibenzo[a,d]cycloheptene of Example B 6, and following substantially the procedure of Example 6, Steps A. and B., 5-(3-methylaminopropylidene)-3-methylsulfonyl-5H-dibenzo[a,d]cycloheptene (β-isomer) is obtained in the form of a yellow oil. The product is converted to the hydrogen maleate that melts at 175°-176° C.
Reaction SMILES: Cl[C:2]1(C#N)[CH2:7][CH:6]2[CH2:8][CH2:9][CH:3]1[CH:4]=[CH:5]2.[OH-:12].[K+]>CS(C)=O.O>[CH:3]12[CH2:9][CH2:8][CH:6]([CH:5]=[CH:4]1)[CH2:7][C:2]2=[O:12]
Reactant: [OH-]
Reactant: N#CC1(Cl)CC2C=CC1CC2
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: O=C1CC2C=CC1CC2
Temperature: 25 °C
Reaction time: 15 h
Yield: 50 %

Procedure:
To a stirred solution of 5-chloro-5-cyanobicyclo[2,2,2]oct-2-ene (65 g, 0.39 mol) (representing several runs of the foregoing procedure) in dimethyl sulfoxide (500 mL) was added potassium hydroxide (87.4 g, 1.56 mol) and water (30 mL). The resulting mixture was stirred at room temperature for 15 h, diluted with water (1000 mL) and extracted with ether (4×500 mL). The combined ether extracts were washed with brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by chromatography on silica gel, eluting with mixtures of diethyl ether (1% to 5%) in petroleum ether, to give bicyclo[2,2,2]oct-5-en-2-one (23.8 g. 50% yield) as a white solid, 1H NMR (300 MHz, CDCl3) δ 1.53˜1.84 (m, 4H), 2.01˜2.02 (m, 2H), 2.96˜2.99 (m, 1H), 3.11˜3.13 (m, 1H), 6.15˜6.21 (m, 1H), 6.43˜6.48 (m, 1H); GCMS (m/z): 122.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[C:13](OCC)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:5]1=[O:23])(=O)C.[NH2:24][C:25]1[CH:35]=[CH:34][C:28]2[N:29]([CH3:33])[C:30](=[O:32])[NH:31][C:27]=2[CH:26]=1.[OH-].[Na+]>CN(C=O)C.CO>[CH3:33][N:29]1[C:28]2[CH:34]=[CH:35][C:25]([NH:24]/[C:13](=[C:6]3\[C:5](=[O:23])[NH:4][C:12]4[C:7]\3=[CH:8][CH:9]=[CH:10][CH:11]=4)/[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)=[CH:26][C:27]=2[NH:31][C:30]1=[O:32]
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2ccccc21)c1ccccc1
Reactant: Cn1c(=O)[nH]c2cc(N)ccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CO
Product: Cn1c(=O)[nH]c2cc(N/C(=C3\C(=O)Nc4ccccc43)c3ccccc3)ccc21

Procedure:
Prepared from 1-acetyl-3-{1-ethoxy-1-phenylmethylidene}-2-indolinone and 3 equivalents of crude 5-amino-1-methyl-2-oxo-2,3-dihydro-1H-benzimidazole in DMF followed by treatment with 1N sodium hydroxide solution in MeOH.
Reaction SMILES: C(OC(=O)[N:7]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:43])[C:23]2[CH:28]=[CH:27][C:26]([CH2:29][N:30]([CH2:37][C:38]3[NH:39][CH:40]=[CH:41][N:42]=3)[CH2:31][C:32]3[NH:33][CH:34]=[CH:35][N:36]=3)=[CH:25][CH:24]=2)=[CH:17][CH:16]=1)[CH2:8][C:9]1[NH:10][CH:11]=[CH:12][N:13]=1)(C)(C)C.Cl>CO>[NH:33]1[CH:34]=[CH:35][N:36]=[C:32]1[CH2:31][N:30]([CH2:29][C:26]1[CH:25]=[CH:24][C:23]([C:22]([NH:21][C:18]2[CH:19]=[CH:20][C:15]([CH2:14][NH:7][CH2:8][C:9]3[NH:10][CH:11]=[CH:12][N:13]=3)=[CH:16][CH:17]=2)=[O:43])=[CH:28][CH:27]=1)[CH2:37][C:38]1[NH:42][CH:41]=[CH:40][N:39]=1
Reactant: CC(C)(C)OC(=O)N(Cc1ccc(NC(=O)c2ccc(CN(Cc3ncc[nH]3)Cc3ncc[nH]3)cc2)cc1)Cc1ncc[nH]1
Agent: Cl
Solvent: CO
Product: O=C(Nc1ccc(CNCc2ncc[nH]2)cc1)c1ccc(CN(Cc2ncc[nH]2)Cc2ncc[nH]2)cc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
The compound (105 mg) obtained in Example 34-4 was dissolved in methanol (10 ml) and then added with 1 mol/l hydrochloric acid (2.0 ml), followed by stirring at room temperature for 5 minutes. The solution was concentrated and dried, and then purified through column chromatography (chloroform/methanol), thereby obtaining hydrochloride (64 mg) of the subject compound as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](/[CH:8]=[CH:9]/[C:10]2[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=2)[CH:5]=[CH:6][CH:7]=1.[C:17]([OH:25])(=[O:24])[C:18]([CH2:20][C:21](O)=[O:22])=[CH2:19]>>[F:1][C:2]1[CH:3]=[C:4](/[CH:8]=[CH:9]/[C:10]2[CH:11]=[CH:12][C:13]([N:16]3[C:21](=[O:22])[CH2:20][CH:18]([C:17]([OH:25])=[O:24])[CH2:19]3)=[CH:14][CH:15]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccc(/C=C/c2cccc(F)c2)cc1
Reactant: C=C(CC(=O)O)C(=O)O
Product: O=C(O)C1CC(=O)N(c2ccc(/C=C/c3cccc(F)c3)cc2)C1
Temperature: 130 °C
Reaction time: 1 h
Yield: 62.4 %

Procedure:
A mixture of 600 mg (2.8 mmol) of (E)-4-[2-(3-fluoro-phenyl)-vinyl]-phenylamine and 366 mg (2.8 mmol) of itaconic acid is heated to 130° C. After 1 hour, the molten material is cooled to RT and, thereafter, the resulting solid is triturated with ethyl acetate to yield 568 mg (62% of theory) of (RS)-(E)-1-{4-[2-(3-fluoro-phenyl)-vinyl]-phenyl}-5-oxo-pyrrolidine-3-carboxylic acid as a fine yellow powder; MS: m/e=324 (M−H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:25]=[C:26]([O:30][CH3:31])[C:27]=1[O:28][CH3:29])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([CH2:13][CH2:14]S(C)(=O)=O)[CH2:9]1)=[O:7].[F:32][C:33]1[CH:56]=[CH:55][C:36]([CH2:37][N:38]2[C:42]3[CH:43]=[CH:44][CH:45]=[CH:46][C:41]=3[N:40]=[C:39]2[C:47]([CH:49]2[CH2:54][CH2:53][NH:52][CH2:51][CH2:50]2)=[O:48])=[CH:35][CH:34]=1.C(N(C(C)C)CC)(C)C.C(OCC)(=O)C.CO>ClC1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:25]=[C:26]([O:30][CH3:31])[C:27]=1[O:28][CH3:29])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:13][CH2:14][N:52]2[CH2:53][CH2:54][CH:49]([C:47]([C:39]3[N:38]([CH2:37][C:36]4[CH:35]=[CH:34][C:33]([F:32])=[CH:56][CH:55]=4)[C:42]4[CH:43]=[CH:44][CH:45]=[CH:46][C:41]=4[N:40]=3)=[O:48])[CH2:50][CH2:51]2)([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:9]1)=[O:7]
Reactant: O=C(c1nc2ccccc2n1Cc1ccc(F)cc1)C1CCNCC1
Reactant: COc1cc(C(=O)N2CCC(CCS(C)(=O)=O)(c3ccccc3)C2)cc(OC)c1OC
Solvent: CCOC(C)=O
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C(=O)N2CCC(CCN3CCC(C(=O)c4nc5ccccc5n4Cc4ccc(F)cc4)CC3)(c3ccccc3)C2)cc(OC)c1OC
Reaction time: 18 h

Procedure:
Combine 1-(3,4,5-trimethoxy-benzoyl)-3-phenyl-3-(2-methanesulfonyl-ethyl)-pyrrolidine (0.60 g, 1.30 mmol) and 4-[1-(4-fluoro-benzyl)-1 H-benzoimidazole-2-carbonyl]-piperidine (0.66 g, 1.95 mmol), and diisopropylethylamine (0.453 mL, 2.60 mmol) in chlorobenzene (8 mL). Heat to reflux. After 18 hours, partition the residue between ethyl acetate and water. Extract the organic layer 3 times with water and 1 time with saturated sodium chloride solution. Dry the organic layer over Na2So4, filter, and concentrate in vacuo to obtain a residue. Chromatograph the residue on silica gel eluting with 10/1/0.1 ethyl acetate/methanol/concentrated aqueous ammonium hydroxide to give the title compound: Rf=0.15 (silica gel, 10/1/0.1 ethyl acetate/methanol/concentrated aqueous ammonium hydroxide).
Reaction SMILES: C(O[C:6](=O)[N:7]([CH:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH3:16])[CH2:11][CH2:10]1)C)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[CH2:15]([N:12]1[CH2:13][CH2:14][CH:9]([NH:7][CH3:6])[CH2:10][CH2:11]1)[CH3:16]
Reactant: CCN1CCC(N(C)C(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCN1CCC(NC)CC1
Yield: 93 %

Procedure:
To a solution of (1-ethylpiperidin-4-yl)-methylcarbamic acid tert-butyl ester (1.65 g, 6.8 mmol) in dichloromethane (15 mL) was added TFA (5 mL). After 1 hour at ambient temperature the reaction mixture was concentrated in-vacuo and the residue loaded onto a 70 g SCX-2 cartridge which was washed with methanol, then 2N ammonia in methanol. Concentration of the combined basic fractions in-vacuo afforded the title compound as an orange oil (900 mg, 94%). 1H NMR (300 MHz, CD3OD): 2.95 (d, J=11.6 Hz, 2H), 2.48-2.36 (m, 3H), 2.35 (s, 3H), 1.96-1.95 (m, 4H), 1.40-1.38 (m, 2H), 1.09 (t, J=7.2 Hz, 3H).
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19](SCC)=[N:18][C:17]3=[O:24])=[CH:12][CH:13]=2)[CH:8]=[N:7]1.[CH3:35][N:36]([CH3:44])[CH2:37][CH:38]1[O:43][CH2:42][CH2:41][NH:40][CH2:39]1>>[F:34][C:2]([F:1])([F:33])[C:3]1[CH:28]=[C:27]([C:29]([F:30])([F:32])[F:31])[CH:26]=[CH:25][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19]([N:40]4[CH2:41][CH2:42][O:43][CH:38]([CH2:37][N:36]([CH3:44])[CH3:35])[CH2:39]4)=[N:18][C:17]3=[O:24])=[CH:12][CH:13]=2)[CH:8]=[N:7]1
Reactant: CN(C)CC1CNCCO1
Reactant: CCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(C(F)(F)F)cc3C(F)(F)F)c2)S1
Product: CN(C)CC1CN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(C(F)(F)F)cc4C(F)(F)F)c3)S2)CCO1

Procedure:
5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(2-dimethylaminomethyl-morpholin-4-yl)-thiazol-4-one was prepared from 5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-one and Dimethyl-morpholin-2-ylmethyl-amine following General Procedure B.