Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]2[O:23][C:17]3=[CH:18][N:19]=[C:20](Cl)[CH:21]=[C:16]3[CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:24]([NH:26][C:27]([C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1)=[O:28])[CH3:25]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]2[O:23][C:17]3=[CH:18][N:19]=[C:20]([C:32]4[CH:33]=[CH:34][C:29]([C:27](=[O:28])[NH:26][CH2:24][CH3:25])=[CH:30][CH:31]=4)[CH:21]=[C:16]3[CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(C2Cc3cc(Cl)ncc3O2)CC1
Reactant: CCNC(=O)c1ccc(B(O)O)cc1
Product: CCNC(=O)c1ccc(-c2cc3c(cn2)OC(C2CCN(C(=O)OC(C)(C)C)CC2)C3)cc1

Procedure:
The title compound is prepared from 4-(5-chloro-2,3-dihydro-furo[2,3-c]pyridin-2-yl)-piperidine-1-carboxylic acid tert-butyl ester and 4-(N-ethylaminocarbonyl)phenylboronic acid following a procedure analogous to that described in Example 28. LC (method 10): tR=1.66 min; Mass spectrum (ESI+): m/z=452 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:22])[N:13]([C:15]3[N:20]=[C:19]([OH:21])[CH:18]=[CH:17][CH:16]=3)[CH:14]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:23]I>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:22])[N:13]([C:15]3[N:20]([CH3:23])[C:19](=[O:21])[CH:18]=[CH:17][CH:16]=3)[CH:14]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1nc(C#Cc2cccc(Cl)c2)cn1-c1cccc(O)n1
Reactant: CI
Product: Cc1nc(C#Cc2cccc(Cl)c2)cn1-c1cccc(=O)n1C

Procedure:
The title compound, off-white cristalline solid, MS: m/e=324.2, 326.1 (M+H), was prepared in accordance with the general method of example 3 from 6-[4-(3-chloro-phenylethynyl)-2-methyl-imidazol-1-yl]-pyridin-2-ol and methyl iodide, along with the O-alkylation product from which it was separated by flash chromatography (gradient: EtOAc to EtOAc/MeOH 95:5).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]=[C:16]3[C:22]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[O:29][C:30]([F:33])([F:32])[F:31])=[N:21][N:20](COCC[Si](C)(C)C)[C:17]3=[N:18][CH:19]=2)=[CH:10][C:9]=1[C:42]([N:44]1[CH2:48][CH2:47][CH:46]([N:49]([CH3:51])[CH3:50])[CH2:45]1)=[O:43])(C)(C)C>C(O)(=O)C.SCC(O)=O>[NH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]=[C:16]3[C:22]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[O:29][C:30]([F:33])([F:32])[F:31])=[N:21][NH:20][C:17]3=[N:18][CH:19]=2)=[CH:10][C:9]=1[C:42]([N:44]1[CH2:48][CH2:47][CH:46]([N:49]([CH3:51])[CH3:50])[CH2:45]1)=[O:43]
Reactant: CN(C)C1CCN(C(=O)c2cc(-c3cnc4c(c3)c(-c3ccccc3OC(F)(F)F)nn4COCC[Si](C)(C)C)ccc2NC(=O)OC(C)(C)C)C1
Agent: O=C(O)CS
Solvent: CC(=O)O
Product: CN(C)C1CCN(C(=O)c2cc(-c3cnc4[nH]nc(-c5ccccc5OC(F)(F)F)c4c3)ccc2N)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
{2-(3-Dimethylaminopyrrolidine-1-carbonyl)-4-[3-(2-trifluoromethoxy-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-phenyl}-carbamic acid tert-butyl ester (220 mg, 0.3 mmol) was dissolved in 1 ml of 5% v/v of 70% perchlroric acid in glacial acetic acid containing 0.4 ml of mercaptoacetic acid and the resulting mixture stirred overnight at room temperature. The crude was filtered over a 0.45 μm PTFE syringe filter and directly purified by mass-triggered reverse phase HPLC to afford {2-amino-5[3-(2-trifluoromethoxy-phenyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-phenyl}-(3-dimethylamino-pyrrolidin-1-yl)-methanone. 1H NMR (500 MHz, DMSO-d6) δ 1.65 (m, 1H), 1.92-2.02 (m, 7H), 3.15-3.68 (m, 5H), 5.45 (s, 2H), 6.78 (d, 1H), 7.45 (m, 2H), 7.50-7.58 (m, 3H), 7.88, (d, 1H), 8.18 (s, 1H), 8.66 (s, 1H). MS: m/z 511.2 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[NH:10][C:9]2[C:8](=[O:11])[N:7]([CH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=O)[C:6](=[O:19])[N:5]([CH2:20][CH3:21])[C:4]=2[N:3]=1.[F:22][C:23]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:24]=1[C:25](=[N:27]O)[NH2:26]>CS(C)=O>[Cl:1][C:2]1[NH:10][C:9]2[C:8](=[O:11])[N:7]([CH2:12][CH2:13][CH2:14][CH2:15][C:16]3[O:18][N:26]=[C:25]([C:24]4[CH:29]=[CH:30][C:31]([F:33])=[CH:32][C:23]=4[F:22])[N:27]=3)[C:6](=[O:19])[N:5]([CH2:20][CH3:21])[C:4]=2[N:3]=1
Reactant: NC(=NO)c1ccc(F)cc1F
Reactant: CCn1c(=O)n(CCCCC(=O)O)c(=O)c2[nH]c(Cl)nc21
Solvent: CS(C)=O
Product: CCn1c(=O)n(CCCCc2nc(-c3ccc(F)cc3F)no2)c(=O)c2[nH]c(Cl)nc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 5-(8-chloro-3-ethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)pentanoic acid (0.05 g, 0.16 mmol) in DMSO (1 ml) was treated with CDl (0.029 g, 0.18 mmol) and the mixture stirred at room temperature for 1 h. Subsequently, the mixture was treated with 2,4-difluorobenzamidoxime (0.03 g, 0.18 mmol) and then heated to 120° C. for 30 min. The product was purified from the crude mixture using MDAP. Product-containing fractions were evaporated using a stream of nitrogen and the resulting colourless gum triturated in ether and dried to reveal the title compound as a white solid (50 mg, 70%).
Reaction SMILES: ON1C2C=CC=CC=2N=N1.[NH:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([CH2:20][NH2:21])=[CH:12]1.CN1CCOCC1.Cl.[CH3:30][N:31]([CH3:48])[C:32]1([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH2:37][CH2:36][CH:35]([CH2:38][C:39](O)=[O:40])[CH2:34][CH2:33]1.C1(N=C=NC2CCCCC2)CCCCC1.[OH-].[Na+]>CN(C)C=O.O>[CH3:48][N:31]([CH3:30])[C:32]1([C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=2)[CH2:37][CH2:36][CH:35]([CH2:38][C:39]([NH:21][CH2:20][C:13]2[C:14]3[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=3)[NH:11][CH:12]=2)=[O:40])[CH2:34][CH2:33]1
Reactant: CN(C)C1(c2ccccc2)CCC(CC(=O)O)CC1
Reactant: NCc1c[nH]c2ccccc12
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CN(C)C1(c2ccccc2)CCC(CC(=O)NCc2c[nH]c3ccccc23)CC1
Temperature: 25 °C
Reaction time: 168 h
Yield: 30 %

Procedure:
1-Hydroxybenzotriazole (546 mg, 4.0 mmol), C-(1H-indol-3-yl)methylamine (292 mg, 2.0 mmol) and N-methylmorpholine (0.444 ml, 4.0 mmol) were added to a solution of (4-dimethylamino-4-phenylcyclohexyl)acetic acid hydrochloride (596 mg, 2.0 mmol) in dry dimethylformamide under argon. Dicyclohexylcarbodiimide (834 mg, 4.0 mmol) was added at 0° C. and the mixture was stirred at RT for 7 d. Working up of the mixture was carried out by separating off the urea which had precipitated out and introducing the filtrate into a mixture of saturated NaCl solution (40 ml) and saturated NaHCO3 solution (10 ml). A mixture of urea and product thereby precipitated out (482 mg) and was separated off. The filtrate obtained was diluted with water (300 ml), 5 M sodium hydroxide solution (4 ml, 20 mmol) was added and the mixture was stored at 5° C. for 16 h. A crude product thereby precipitated out as a beige-coloured substance (234 mg), which was separated off by filtration. After purification of the two product fractions by chromatography on silica gel with EA/methanol (4:1) and methanol, the product was isolated as a beige-coloured solid in a yield of 30% (230 mg).
Reaction SMILES: [F:1][C:2]([F:40])([F:39])[C:3]1[CH:4]=[C:5]([C:13]([CH3:38])([CH3:37])[C:14]([N:16]([CH3:36])[C:17]2[CH:18]=[N:19][C:20]([N:30]3[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)=[CH:21][C:22]=2[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[CH3:29])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C(N(CC)CC)C.[CH3:48][S:49](Cl)(=[O:51])=[O:50]>ClCCl>[F:40][C:2]([F:1])([F:39])[C:3]1[CH:4]=[C:5]([C:13]([CH3:38])([CH3:37])[C:14]([N:16]([C:17]2[CH:18]=[N:19][C:20]([N:30]3[CH2:35][CH2:34][N:33]([S:49]([CH3:48])(=[O:51])=[O:50])[CH2:32][CH2:31]3)=[CH:21][C:22]=2[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[CH3:29])[CH3:36])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:10])[F:11])[CH:8]=1
Reactant: CS(=O)(=O)Cl
Reactant: Cc1ccccc1-c1cc(N2CCNCC2)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccccc1-c1cc(N2CCN(S(C)(=O)=O)CC2)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Yield: 75.3 %

Procedure:
To a solution of 0.16 g (0.31 mmol) 2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-N-(6-piperazin-1-yl-4-o-tolyl-pyridin-3-yl)-isobutyramide and 38 mg (0.38 mmol) triethylamine in 4 ml dichloromethane were added 38 mg (0.33 mmol) methanesulfonyl chloride at 0° C. After completed addition the reaction mixture was allowed to warm to room temperature. Conversion was monitored by thin layer chromatography. After complete consumption of the starting material the reaction mixture was diluted with water and extracted with three portions of tert-butyl methyl ether. The combined organic layers were dried over sodium sulfate and concentrated in vacuo. Flash column chromatography gave 0.15 g (75%) of the title compound as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[C:9]1[CH2:13][CH2:12][CH2:11][C:10]=1[C:14]1[CH:15]=[C:16]([NH:23][C:24](=[O:27])[CH2:25][CH3:26])[CH:17]=[C:18]([CH:22]=1)[C:19]([OH:21])=[O:20].[F:28][C:29]1[CH:36]=[CH:35][C:32]([CH2:33]Br)=[CH:31][CH:30]=1>CC(C)=O>[F:28][C:29]1[CH:36]=[CH:35][C:32]([CH2:33][O:20][C:19](=[O:21])[C:18]2[CH:22]=[C:14]([C:10]3[CH2:11][CH2:12][CH2:13][C:9]=3[C:3]3[CH:4]=[C:5]([CH3:8])[CH:6]=[CH:7][C:2]=3[O:1][CH2:33][C:32]3[CH:35]=[CH:36][C:29]([F:28])=[CH:30][CH:31]=3)[CH:15]=[C:16]([NH:23][C:24](=[O:27])[CH2:25][CH3:26])[CH:17]=2)=[CH:31][CH:30]=1
Reactant: CCC(=O)Nc1cc(C(=O)O)cc(C2=C(c3cc(C)ccc3O)CCC2)c1
Reactant: Fc1ccc(CBr)cc1
Solvent: CC(C)=O
Product: CCC(=O)Nc1cc(C(=O)OCc2ccc(F)cc2)cc(C2=C(c3cc(C)ccc3OCc3ccc(F)cc3)CCC2)c1

Procedure:
Prepared by general procedure 5 but using 5-[2-(2-hydroxy-5-methylphenyl)cyclopent-1-enyl]-3-(propionamido)benzoic acid instead of 6-[2-(5-chloro-2-hydroxyphenyl)cyclopent-1-enyl]pyridine-2-carboxylic acid, 4-fluorobenzyl bromide instead of 4-chlorobenzyl bromide and acetone instead of 2-butanone.
Reaction SMILES: [Br:1][CH2:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][CH:7]([CH3:15])[CH:8]2OC.CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Br:1][CH2:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][C:7]([CH3:15])=[CH:8]2
Reactant: COC1c2cccc(CCBr)c2CC1C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC1=Cc2cccc(CCBr)c2C1

Procedure:
To a hot (110° C.) solution of 12.0 g (44.6 mmol) of 4-(2-bromoethyl)-1-methoxy-2-methylindane in 200 ml of toluene 1.0 g of TsOH was added. This mixture was refluxed with Dean-Stark trap for 10 minutes and then passed through 5 cm layer of silica gel 60 (40-63 μm). The silica gel layer was additionally washed by 500 ml of toluene. The combined organic extract was evaporated to dryness. The product was isolated by flash chromatography on silica gel 60 (40-63 μm, eluent: hexanes). Yield 10.2 g (97%) of a ca. 1 to 1.5 mixture of 4- and 7-(2-bromoethyl)-2-methyl-1H-indenes. Anal. calc. for C12H13Br: C, 60.78; H, 5.53. Found: C, 60.66; H, 5.46. 1H NMR (CDCl3): δ 6.92-7.31 (m, 6H, 5,6,7-H and 4,5,6-H of minor and major isomers, respectively), 6.60 (m, 1H, 3-H in indenyl of minor isomer), 6.51 (m, 1H, 3-H in indenyl of major isomer), 3.62 (m, 2H, CH2Br of major isomer), 3.57 (m, 2H, CH2Br of minor isomer), 3.32 (br.s, 2H, 1,1′-H in indenyl of minor isomer), 3.28 (br.s, 2H, 1,1′-H in indenyl of major isomer), 3.27 (m, 2H, CH2CH2Br of minor isomer), 3.23 (m, 2H, CH2CH2Br of major isomer), 2.19 (m, 3H, 2-Me in indenyl of minor isomer), 2.18 (m, 3H, 2-Me in indenyl of major isomer).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.O.[NH2:13][NH2:14]>C(O)C>[NH:13]([C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1)[NH2:14]
Reactant: NN
Reactant: Clc1ccc2ccccc2n1
Solvent: CCO
Solvent: O
Product: NNc1ccc2ccccc2n1
Temperature: 0 °C

Procedure:
21.0 g (128.4 mmol) of 2-chloroquinoline are initially charged in 210 ml of ethanol. 64.3 g (1.3 mol) of hydrazine hydrate are added, and the mixture is stirred under reflux for 16 h. The mixture is then cooled to 0° C., and the solid formed is filtered off and washed with a little ethanol. The product is initially air-dried and then dried under high vacuum.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8]C)=[CH:4][C:3]=1[CH:10]([CH3:29])[C:11]([C:17]1[CH:18]=[CH:19][C:20]2[O:25][CH2:24][C:23](=[O:26])[N:22]([CH3:27])[C:21]=2[CH:28]=1)([OH:16])[C:12]([F:15])([F:14])[F:13].B(Br)(Br)Br.C([O-])(O)=O.[Na+]>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[CH:10]([CH3:29])[C:11]([C:17]1[CH:18]=[CH:19][C:20]2[O:25][CH2:24][C:23](=[O:26])[N:22]([CH3:27])[C:21]=2[CH:28]=1)([OH:16])[C:12]([F:13])([F:14])[F:15]
Reactant: COc1ccc(Cl)c(C(C)C(O)(c2ccc3c(c2)N(C)C(=O)CO3)C(F)(F)F)c1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(c1cc(O)ccc1Cl)C(O)(c1ccc2c(c1)N(C)C(=O)CO2)C(F)(F)F
Temperature: 0 °C
Reaction time: 1 h
Yield: 101.3 %

Procedure:
A solution of 6-[2-(2-chloro-5-methoxy-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-4-methyl-4H-benzo[1,4]oxazin-3-one (553 mg) in dichloromethane (13 ml) was cooled to −70° C. A 1 M solution of boron tribromide in dichloromethane (5.14 ml) was added and the mixture was stirred at −70° C. for 1.5 h and at 0° C. for 1 h. A mixture of ice water and saturated aqueous NaHCO3 solution was added and the mixture was extracted with dichloromethane. The organic phase was washed with water and dried (MgSO4). The product was purified by chromatography (SiO2, cyclohexane/EtOAc 9:1=>2:3) to give the title compound (542 mg) as off-white foam. MS (m/e, ISP neg. ion)=414.0 [M−H+].
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[CH:13]=[CH:14][C:15]([CH3:17])=[CH:16][C:11]=2[N:10]=[C:9]1[CH:18]([NH:22][CH2:23][CH2:24][CH2:25][N:26]1[C:34](=[O:35])[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27]1=[O:36])[CH:19]([CH3:21])[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:44]1([CH3:53])[CH:49]=[CH:48][C:47]([C:50](Cl)=[O:51])=[CH:46][CH:45]=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(OCC)(=O)C>[CH2:1]([N:8]1[C:12]2[CH:13]=[CH:14][C:15]([CH3:17])=[CH:16][C:11]=2[N:10]=[C:9]1[CH:18]([N:22]([CH2:23][CH2:24][CH2:25][N:26]1[C:27](=[O:36])[C:28]2[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:34]1=[O:35])[C:50](=[O:51])[C:47]1[CH:48]=[CH:49][C:44]([CH3:53])=[CH:45][CH:46]=1)[CH:19]([CH3:21])[CH3:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc2c(c1)nc(C(NCCCN1C(=O)c3ccccc3C1=O)C(C)C)n2Cc1ccccc1
Reactant: Cc1ccc(C(=O)Cl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Cc1ccc(C(=O)N(CCCN2C(=O)c3ccccc3C2=O)C(c2nc3cc(C)ccc3n2Cc2ccccc2)C(C)C)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 54 %

Procedure:
To a solution of 2-{3-[1-(1-benzyl-5-methyl-1H-benzimidazol-2-yl)-2-methyl-propylamino]-propyl}-isoindole-1,3-dione (0.56 mmol) and triethylamine (0.58 mL, 3.36 mmol) in DCM (3 mL) at 0° C., was added p-toluoyl chloride (0.38 mL, 2.8 mmol). The reaction mixture was stirred at 0° C. for 30 min. Ethyl acetate and saturated sodium bicarbonate were added. The mixture was extracted with ethyl acetate. The organic layers was combined, dried over MgSO4, filtered, and the filtrate was concentrated in vacuo. The crude material was purified by flash chromatography to give N-[1-(1-benzyl-5-methyl-1H-benzimidazol-2-yl)-2-methyl-propyl]-N-[3-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-propyl]-4-methyl-benzamide (181 mg).
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[CH2:9][CH:8]([C:10]2[C:18]3[C:13](=[CH:14][C:15]([F:19])=[CH:16][CH:17]=3)[NH:12][CH:11]=2)[CH:7]2[N:20]([C:23](=[O:39])[CH:24]([NH:31]C(OC(C)(C)C)=O)[CH:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)[CH2:21][CH2:22][CH:6]12)=[O:4].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][O:2][C:3]([N:5]1[CH2:9][CH:8]([C:10]2[C:18]3[C:13](=[CH:14][C:15]([F:19])=[CH:16][CH:17]=3)[NH:12][CH:11]=2)[CH:7]2[N:20]([C:23](=[O:39])[CH:24]([NH2:31])[CH:25]3[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]3)[CH2:21][CH2:22][CH:6]12)=[O:4]
Reactant: COC(=O)N1CC(c2c[nH]c3cc(F)ccc23)C2C1CCN2C(=O)C(NC(=O)OC(C)(C)C)C1CCCCC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)N1CC(c2c[nH]c3cc(F)ccc23)C2C1CCN2C(=O)C(N)C1CCCCC1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 92.5 %

Procedure:
A solution containing 50 (226 mg, 0.42 mmol) in DCM (5 mL) was cooled to 0° C. TFA (2 mL) was added and the reaction mixture was warmed to ambient temperature. After 90 min, the reaction mixture was concentrated in vacuo. The residue was dissolved in EtOAc and the resultant organic solution was washed successively with saturated aqueous NaHCO3 and brine, dried over anhydrous Na2SO4, filtered, and concentrated to afford 172 mg of 51 as an off-white-colored foam which was used without further purification. Mass spectrum, m/z [443.3] (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH2:7][CH:6]([C:8]2[CH:13]=[C:12]([CH3:14])[CH:11]=[CH:10][C:9]=2[Cl:15])[CH2:5][C:4](=[O:16])[CH:3]=1.[OH-].[K+]>C(O)C.C1(C)C=CC=CC=1>[Cl:15][C:9]1[CH:10]=[CH:11][C:12]([CH3:14])=[CH:13][C:8]=1[CH:6]1[CH2:7][C:2]2[N:1]=[CH:7][CH:2]=[C:3]([CH3:4])[C:3]=2[C:4](=[O:16])[CH2:5]1
Reactant: Cc1ccc(Cl)c(C2CC(=O)C=C(N)C2)c1
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CCO
Product: Cc1ccc(Cl)c(C2CC(=O)c3c(C)ccnc3C2)c1
Yield: 130.8 %

Procedure:
In ethanol (70 ml) and toluene (120 ml) was dissolved 1-amino-5-(2-chloro-5-methylphenyl)cyclohexen-3-one (2.9 g), and to the solution were added 3-oxobutylaldehydedimethylacetal (4.1 g) and powdery potassium hydroxide (0.5 g). The mixture was refluxed, and to the mixture was added powdery potassium hydroxide (0.14 g), 30 minutes later; were added powdery potassium hydroxide (0.14 g) and 3-oxobutylaldehydedimethylacetal (0.33 g), 1 hour later; and was added powdery potassium hydroxide (0.14 g), 1.5 hours later. The mixture was refluxed at the same temperature 2 hours and cooled. Under reduced pressure, the solvent was evaporated, and to the residue was added ethyl acetate. The organic layer was washed with water and saturated brine, and dried with magnesium sulfate. Under reduced pressure, ethyl acetate was evaporated, and the residue was purified with silica gel column (ethyl acetate-hexane). The resulting crystals were recrystallized from ethyl acetate-hexane to give 7-(2-chloro-5-methylphenyl)-4-methyl-5,6,7,8-tetrahydroquinolin-5-one (2.3 g).
Reaction SMILES: [CH:1]([C:3]1[CH:14]=[CH:13][C:6]([CH2:7][CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:5][CH:4]=1)=O.C(O)(=O)[CH2:16][C:17]([OH:19])=[O:18].N1CCCCC1.Cl>N1C=CC=CC=1>[CH3:12][O:11][C:9]([CH2:8][CH2:7][C:6]1[CH:13]=[CH:14][C:3]([CH:1]=[CH:16][C:17]([OH:19])=[O:18])=[CH:4][CH:5]=1)=[O:10]
Reactant: COC(=O)CCc1ccc(C=O)cc1
Reactant: O=C(O)CC(=O)O
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: COC(=O)CCc1ccc(C=CC(=O)O)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 84.9 %

Procedure:
A solution of methyl 4-formylhydrocinnamate (2.30 g), malonic acid (2.50 g) and piperidine (0.1 ml) in 12 ml pyridine was stirred at 100° C. for 2 hours, and subsequently at 140° C. for 2 hours. After addition of 100 ml ice-cold water, 210 ml of 0.5 mol/l hydrochloric acid was added dropwise to the reaction mixture to precipitate a solid, which was then filtered, washed with water, and dried by heating under reduced pressure to give 4-[2-(methoxycarbonyl)ethyl]cinnamic acid (2.38 g, 84%) as a colorless solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([N:8]=[C:9]=[O:10])[CH:5]=[CH:6][CH:7]=1.[NH2:11][CH2:12][C:13]1[N:17]([C:18]2[S:19][C:20]([CH2:32][C:33]([O:35][CH3:36])=[O:34])=[CH:21][C:22]=2[C:23](=[O:31])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[Cl:30])[C:16]([CH3:37])=[N:15][N:14]=1>>[Cl:30][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[C:23]([C:22]1[CH:21]=[C:20]([CH2:32][C:33]([O:35][CH3:36])=[O:34])[S:19][C:18]=1[N:17]1[C:16]([CH3:37])=[N:15][N:14]=[C:13]1[CH2:12][NH:11][C:9]([NH:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[CH:3]=1)=[O:10])=[O:31]
Reactant: Cc1cccc(N=C=O)c1
Reactant: COC(=O)Cc1cc(C(=O)c2ccccc2Cl)c(-n2c(C)nnc2CN)s1
Product: COC(=O)Cc1cc(C(=O)c2ccccc2Cl)c(-n2c(C)nnc2CNC(=O)Nc2cccc(C)c2)s1

Procedure:
3-Methylphenyl isocyanate and methyl (2-(3-aminomethyl-5-methyl[1,2,4]triazol-4-yl)-3-(2-chlorobenzoyl)thiophen-5-yl)acetate are reacted to give methyl (3-(2-chlorobenzoyl)-2-(3-(3-(3-methylphenyl)ureidomethyl)-5-methyl[1,2,4]triazol-4-yl)thiophen-5-yl)acetate.
Reaction SMILES: [CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[C:6](=[CH:16][C:17]3[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][CH:18]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH2:24]([S:27](Cl)(=[O:29])=[O:28])[CH2:25][CH3:26]>>[CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[C:6](=[CH:16][C:17]3[CH:22]=[CH:21][C:20]([NH:23][S:27]([CH2:24][CH2:25][CH3:26])(=[O:29])=[O:28])=[CH:19][CH:18]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: CCCS(=O)(=O)Cl
Reactant: Nc1ccc(C=C2c3ccccc3CCc3ccccc32)cc1
Product: CCCS(=O)(=O)Nc1ccc(C=C2c3ccccc3CCc3ccccc32)cc1
Yield: 50.9 %

Procedure:
Following procedures essentially as described in Example 90, 4-(10,11-dihydro-dibenzo[a,d]cyclohepten-5-ylidenemethyl)-phenylamine (100 mg, 0.336 mmol) and 1-propanesulfonyl chloride (144 mg, 1.01 mmol) affords 69 mg (51%) of the title compound as a colorless oil. MS (ES) 426 (M+Na), 402 (M−H); HPLC shows 99% purity.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([C:36]#[N:37])[CH:31]=2)[N:9]2[CH2:12][CH:11]([CH:13]([C:18]3[CH:19]=[C:20]([CH:26]=[C:27]([F:29])[CH:28]=3)[C:21]([O:23]CC)=[O:22])[C:14]([F:17])([CH3:16])[CH3:15])[CH2:10]2)=[CH:4][CH:3]=1.[Li+].[OH-].Cl>CCO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([C:36]#[N:37])[CH:31]=2)[N:9]2[CH2:12][CH:11]([CH:13]([C:18]3[CH:19]=[C:20]([CH:26]=[C:27]([F:29])[CH:28]=3)[C:21]([OH:23])=[O:22])[C:14]([F:17])([CH3:16])[CH3:15])[CH2:10]2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cc(F)cc(C(C2CN(C(c3ccc(Cl)cc3)c3cccc(C#N)c3)C2)C(C)(C)F)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(F)C(c1cc(F)cc(C(=O)O)c1)C1CN(C(c2ccc(Cl)cc2)c2cccc(C#N)c2)C1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A mixture of 112 mg (0.214 mmol) of ethyl 3-(1-{1-[(4-chlorophenyl)(3-cyanophenyl)methyl]azetidin-3-yl}-2-fluoro-2-methylpropyl)-5-fluorobenzoate and 1.2 mL of 1M LiOH in 5 mL of EtOH was stirred for 2.5 h at rt. The solution was adjusted to pH=5-6 with 6N HCl and concentrated to remove solvents. The residue was dissolve in 10 mL of CH2Cl2 and solids were removed by filtration. The solution was concentrated to afford the title compound as a white solid; Mass Spectrum: m/e=495 (M+1, 35Cl), 497 (M+1, 37Cl).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]=[C:7]([CH3:21])[CH2:8][CH2:9][CH:10]=[C:11]([CH3:20])[CH2:12][CH2:13][CH:14]=[C:15]([CH3:19])[C:16]([OH:18])=O)=[O:5])[CH3:2].[NH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1>>[CH2:1]([O:3][C:4]([CH:6]=[C:7]([CH3:21])[CH2:8][CH2:9][CH:10]=[C:11]([CH3:20])[CH2:12][CH2:13][CH:14]=[C:15]([CH3:19])[C:16]([N:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1)=[O:18])=[O:5])[CH3:2]
Reactant: CCOC(=O)C=C(C)CCC=C(C)CCC=C(C)C(=O)O
Reactant: C1CCNC1
Product: CCOC(=O)C=C(C)CCC=C(C)CCC=C(C)C(=O)N1CCCC1

Procedure:
Starting materials: 11-ethoxycarbonyl-2,6,10-trimethyl-2,6,10-undecatrienoic acid and pyrrolidine.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[SH:11])[C:6]#[N:7])#[N:2].[Hg](C#N)C#N.[C:17]([O:20][C@@H:21]1[C@@H:26]([O:27][C:28](=[O:30])[CH3:29])[C@H:25]([O:31][C:32](=[O:34])[CH3:33])[CH2:24][S:23][C@@H:22]1Br)(=[O:19])[CH3:18]>>[C:17]([O:20][C@@H:21]1[C@@H:26]([O:27][C:28](=[O:30])[CH3:29])[C@H:25]([O:31][C:32](=[O:34])[CH3:33])[CH2:24][S:23][C@H:22]1[S:11][C:10]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[C:1]#[N:2])(=[O:19])[CH3:18]
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@@H](Br)SC[C@H]1OC(C)=O
Reactant: N#Cc1ccc(S)c(C#N)c1
Agent: N#C[Hg]C#N
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](Sc2ccc(C#N)cc2C#N)SC[C@H]1OC(C)=O
Yield: 40.5 %

Procedure:
If the procedure described in Preparation I is followed starting from 1.5 g (9.10-3 mol) of 3-cyano-4-mercaptobenzonitrile, 2.78 g (11.10-3 mol) of mercuric cyanide, Hg(CN)2, and 3.66 g (11.10-3 mol) of 2,3,4-tri-O-acetyl-5-thio-α-D-xylopyranosyl bromide, 1.65 g (yield: 40.5%) of the expected product are obtained.