Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)(=O)C.I[CH:6]([CH2:14][C:15]([F:27])([F:26])[C:16]([F:25])([F:24])[C:17]([F:23])([F:22])[C:18]([F:21])([F:20])[F:19])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][OH:13]>C(O)C.[Zn]>[F:22][C:17]([F:23])([C:18]([F:19])([F:20])[F:21])[C:16]([F:24])([F:25])[C:15]([F:27])([F:26])[CH2:14][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][OH:13]
Reactant: OCCCCCCC(I)CC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CCO
Product: OCCCCCCCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 50 °C
Reaction time: 0.25 h

Procedure:
To a slurry of 98.0 g of zinc powder in 600 mL of ethanol was added 3.0 g of acetic acid. A solution of the crude 7-iodo-8-(nonafluorobutyl)-1-octanol prepared above in 100 mL of ethanol was added dropwise with stirring over 15 min, and the reaction mixture was heated at 50° C. for 3 hr. The mixture was filtered, and the filtrate was concentrated to 100.0 g of a viscous, light yellow fluid. A 79.6 g portion of this material was stirred with 300 mL of hexanes, and the supernatant was filtered through diatomaceous earth (marketed under the trade designation “CELITE” by Johns-Manville Corporation, Denver, Colo.) and concentrated to give 44.24 g of 8-(nonafluorobutyl)-1-octanol as a clear, colorless oil, which was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([N:11]=[CH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:7][N:6]=1)=[O:4].[BH4-].[Na+]>CN(C)C=O.CO>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:7][N:6]=1)=[O:4]
Reactant: COC(=O)c1ccc(N=Cc2ccccc2)cn1
Agent: [BH4-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: COC(=O)c1ccc(NCc2ccccc2)cn1
Temperature: -20 °C

Procedure:
The solution of 24.9 g of 5-benzylideneaminopyridine-2-carboxylic acid methyl ester in 70 ml of hot dimethylformamide is added all at once to the solution of 7.0 g of sodium borohydride in 300 ml of methanol while stirring at -20° C. The temperature of the reaction mixture raises spontaneously to 20° and is lowered to 0° by cooling. After 2 hours the mixture is warmed to room temperature for 15 minutes to ensure complete reaction. Approximately 1/2 of the methanol is distilled off, the concentrate is cooled to 0° and 3 ml of acetic acid and the solution of 12 ml of 12 N hydrochloric acid in 100 ml ice water is added. A precipitate begins to separate and 200 ml more ice water are added. After 30 minutes the precipitate is collected and washed well with water and recrystallized from acetonitrile, to yield the 5-benzylaminopyridine-2-carboxylic acid methyl ester, melting at 104°-107°.
Reaction SMILES: [SH:1][CH:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:3].[C:10](Cl)(=[O:14])[CH2:11][CH2:12][CH3:13]>>[C:4]1([CH:2]([S:1][C:10](=[O:14])[CH2:11][CH2:12][CH3:13])[CH3:3])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CCCC(=O)Cl
Reactant: CC(S)c1ccccc1
Product: CCCC(=O)SC(C)c1ccccc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 98 %

Procedure:
At room temperature, 13.8 g of 1-mercapto-1-phenylethane is dissolved in 50 mL of butyryl chloride. The mixture is stirred at room temperature for 6 hours. It is then cooled down to 0° C. and the reaction is quenched by careful addition of 100 ml of dry methanol in small portions. The mixture is then washed with bicarbonate, dried over magnesium sulfate, filtered and concentrated to give the butyrated compound in 98% yield.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([Mg]Br)=[CH:4][CH:3]=1.[CH3:10][CH2:11][O:12][C:13]([C@H:15]1[CH2:19][CH2:18][C:17](=[O:20])[N:16]1[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[O:14].[Cl-].[NH4+]>O1CCCC1>[CH2:11]([O:12][C:13](=[O:14])[C@H:15]([NH:16][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:19][CH2:18][C:17]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)=[O:20])[CH3:10]
Reactant: CCOC(=O)[C@H]1CCC(=O)N1C(=O)OC(C)(C)C
Reactant: Fc1ccc([Mg]Br)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCOC(=O)[C@@H](CCC(=O)c1ccc(F)cc1)NC(=O)OC(C)(C)C

Procedure:
Under a nitrogen atmosphere, 4-fluorophenyl magnesium bromide (25.6 mL, 1 M tetrahydrofuran solution) was added dropwise at −40° C. into a tetrahydrofuran (100 mL) solution containing (R)-5-oxopyrrolidine-1,2-dicarboxylic acid 1-t-butyl ester 2-ethyl ester (6 g). After stirring for 1 hour at the same temperature, saturated ammonium chloride aqueous solution was added, and the resultant was extracted with ethyl acetate. After washing the organic layer with brine, the resultant was dried over anhydrous magnesium sulfate. After removing the solvent under a vacuum, the residue was purified with silica gel column chromatography, and the title compound (6.33 g) was obtained. The physical property values are as follows.
Reaction SMILES: [C:1]1([N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[CH2:16]O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1C(=O)N([Br:44])C(=O)C1>C(Cl)Cl>[Br:44][CH2:16][C:8]1[N:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: OCc1nc2ccccc2n1-c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: BrCc1nc2ccccc2n1-c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 217.1 %

Procedure:
To a stirred solution of (1-phenyl-1H-benzoimidazol-2-yl)methanol (240 mg, 1.02 mmol) and triphenylphospine (295 mg, 1.12 mmol) in DCM (10 mL) was added NBS (200 mg, 1.12 mmol) and the mixture was stirred at RT for 3 h. Volatiles were evaporated under reduced pressure and the residue was purified by column chromatography (Si—PCC, gradient 0-5% MeOH in DCM) affording 2-Bromomethyl-1-phenyl-1H-benzoimidazole as a colourless oil (0.636 g, quantitative yield). LCMS: RT 3.31 min [M+H]+ 386.8/388.8
Reaction SMILES: Cl.Cl.[N:3]1([CH2:9][C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[CH2:16][NH:15][CH2:14][CH2:13]3)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.C(N(CC)CC)C.O=[C:28]1[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>ClCCCl>[N:3]1([CH2:9][C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[CH2:16][N:15]([CH:32]2[CH2:28][CH2:29][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:31]2)[CH2:14][CH2:13]3)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]1
Reactant: c1cc2c(cc1CN1CCCCC1)CCNC2
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(N2CCc3cc(CN4CCCCC4)ccc3C2)C1
Reaction time: 2 h

Procedure:
6-(Piperidin-1-ylmethyl)-1,2,3,4-tetrahydroisoquinoline dihydrochloride (0.5 g, 1.65 mmol), triethylamine (0.57 ml, 4.12 mmol) and tert-butyl 3-oxopyrrolidine-1-carboxylate (305 mg, 1.65 mmol) were dissolved in 1,2-dichloroethane (13 ml), and sodium triacetoxyborohydride (480 mg, 2.309 mmol) was added. The reaction mixture was stirred for 2 h, and then sat. sodium hydrogen carbonate solution was added. After phase separation, the aqueous phase was extracted with dichloromethane (2×). The combined organic phases were washed with sat. sodium chloride solution (1×), dried over magnesium sulfate and concentrated under vacuum. The crude product was purified by column chromatography (silica gel, ethyl acetate/methanol/ammonia (25% aq.) (200:20:1). Yield: 0.55 g (83%)
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[C:12]([NH:14][CH:15]([CH3:19])[CH2:16][O:17][CH3:18])[N:11]=[CH:10][N:9]=2)[CH:5]=[CH:4][N:3]=1.[Cl:20][C:21]1[CH:22]=[C:23]([CH:25]=[CH:26][CH:27]=1)[NH2:24].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>O1CCOCC1>[Cl:20][C:21]1[CH:22]=[C:23]([NH:24][C:2]2[N:7]=[C:6]([C:8]3[CH:13]=[C:12]([NH:14][CH:15]([CH3:19])[CH2:16][O:17][CH3:18])[N:11]=[CH:10][N:9]=3)[CH:5]=[CH:4][N:3]=2)[CH:25]=[CH:26][CH:27]=1
Reactant: Nc1cccc(Cl)c1
Reactant: COCC(C)Nc1cc(-c2ccnc(Cl)n2)ncn1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1COCCO1
Solvent: O
Product: COCC(C)Nc1cc(-c2ccnc(Nc3cccc(Cl)c3)n2)ncn1
Temperature: 100 °C
Reaction time: 18 h

Procedure:
To a solution of 2′-chloro-N-(2-methoxy-1-methylethyl) [4,4′-bipyrimidine]-6-amine (i.e., the product of Step C) (100 mg, 0.357 mmol) and 3-chloroaniline (57 mg, 0.45 mmol) in 1,4-dioxane (3.5 mL) under a nitrogen atmosphere was added p-toluenesulfonic acid monohydrate (57 mg, 0.30 mmol). The resulting mixture was stirred at 100° C. for 18 h. The solution was concentrated under reduced pressure to give a yellow solid residue. The residue was then purified on silica gel eluted with 40% ethyl acetate in hexanes, followed by acetone to give 113 mg of title compound as a solid.
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:10][C:9]2[CH2:11][CH2:12][CH2:13][C:8]=2[CH:7]=1)=[O:5])C.O.[OH-].[Li+]>>[NH:10]1[C:6]([C:4]([OH:5])=[O:3])=[CH:7][C:8]2[CH2:13][CH2:12][CH2:11][C:9]1=2
Reactant: CCOC(=O)c1cc2c([nH]1)CCC2
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1cc2c([nH]1)CCC2
Yield: 72.1 %

Procedure:
The title compound was synthesized from the above ethyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate (100 mg, 0.56 mmol) using lithium hydroxide monohydrate (94 mg, 2.23 mmol) as the base according to General Procedure 7. The crude product was purified by flash chromatography (0-100% EtOAc/heptane) to give 61 mg (73%) of 1,4,5,6-tetrahydro-cyclopenta[b]pyrrole-2-carboxylic acid (1). 1H NMR (400 MHz, METHANOL-d) δ ppm 2.35-2.44 (m, 2H), 2.54-2.61 (m, 2H), 2.64-2.72 (m, 2H), 6.59 (s, 1H); LCMS-MS (ESI+) 151.9 (M+H); HPLC (UV=100%), (ELSD=100%).
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH3:15][C:16]([CH3:20])([CH3:19])[CH2:17][OH:18]>>[CH3:15][C:16]([CH3:20])([CH3:19])[CH2:17][O:18][C:2]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: CC(C)(C)CO
Reactant: CS(=O)(=O)c1ccc(Cl)c(C(=O)O)c1
Product: CC(C)(C)COc1ccc(S(C)(=O)=O)cc1C(=O)O

Procedure:
Prepared in analogy to Example A1 (b) from 2-chloro-5-methanesulfonyl-benzoic acid (Example A1(a)) and 2,2-dimethyl-propan-1-ol. The crude material was purified by preparative HPLC to yield the title compound as a white solid. MS (m/e): 285.1 ([M−H]−, 100%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)=[CH:9][CH2:10][OH:11])=[CH:4][CH:3]=1.C(P(CCCC)CCCC)CCC.[CH2:32]([O:34][C:35](=[O:48])[C@@H:36]([O:45][CH2:46][CH3:47])[CH2:37][C:38]1[CH:43]=[CH:42][C:41](O)=[CH:40][CH:39]=1)[CH3:33]>>[CH2:32]([O:34][C:35](=[O:48])[C@@H:36]([O:45][CH2:46][CH3:47])[CH2:37][C:38]1[CH:43]=[CH:42][C:41]([O:11][CH2:10][CH:9]=[C:8]([C:12]2[CH:13]=[CH:14][C:15]([CH3:18])=[CH:16][CH:17]=2)[C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=2)=[CH:40][CH:39]=1)[CH3:33]
Reactant: CCOC(=O)[C@H](Cc1ccc(O)cc1)OCC
Reactant: Cc1ccc(C(=CCO)c2ccc(C)cc2)cc1
Agent: CCCCP(CCCC)CCCC
Product: CCOC(=O)[C@H](Cc1ccc(OCC=C(c2ccc(C)cc2)c2ccc(C)cc2)cc1)OCC
Yield: 39.5 %

Procedure:
Reaction of 3,3-di-(4-methylphenyl)-prop-2-en-1-ol (1.0 g, 4.20 mmol), tributylphosphine (1.27 g, 6.30 mmol), (2S)-2-ethoxy-3-(4-hydroxy-phenyl)-propionic acid ethyl ester (1.10 g, 4.62 mmol) and azodicarboxylic dipiperidide (1.59 g, 6.30 mmol) in an identical manner to example 3 gave the title compound (0.76 g, 39%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][CH2:12][C@H:11]([NH:15][C@@H:16]3[CH2:21][CH2:20][CH2:19][CH2:18][C@H:17]3[NH:22][C:23](=[O:35])CC3C4C(=CC=CC=4)N(C)C=3)[CH2:10]2)=[CH:5][CH:4]=1)#[N:2].[Cl:36][C:37]1[CH:42]=[CH:41][CH:40]=[C:39]([N:43]=C=O)[CH:38]=1>>[Cl:36][C:37]1[CH:38]=[C:39]([NH:43][C:23]([NH:22][C@@H:17]2[CH2:18][CH2:19][CH2:20][CH2:21][C@H:16]2[NH:15][C@H:11]2[CH2:12][CH2:13][CH2:14][N:9]([C:6]3[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=3)[CH2:10]2)=[O:35])[CH:40]=[CH:41][CH:42]=1
Reactant: O=C=Nc1cccc(Cl)c1
Reactant: Cn1cc(CC(=O)N[C@@H]2CCCC[C@H]2N[C@H]2CCCN(c3ccc(C#N)cc3)C2)c2ccccc21
Product: N#Cc1ccc(N2CCC[C@H](N[C@@H]3CCCC[C@H]3NC(=O)Nc3cccc(Cl)c3)C2)cc1

Procedure:
1-(3-Chlorophenyl)-3-((1R,2R)-2-((S)-1-(4-cyanophenyl)piperidin-3-ylamino)cyclohexyl)urea was synthesized using 4-((S)-3-((1R,2R)-2-aminocyclohexylamino)piperidin-1-yl)benzonitrile (from intermediate D, Example 10) (60 mg, 0.20 mmol) and 1-chloro-3-isocyanatobenzene (30.9 mg, 0.20 mmol) according to General Procedure G to give 20 mg (22%) of a white solid. Anal. Calcd. for C25H30ClN5O m/z 451.2, found: 452.2 (M+H)+; 1H NMR (400 MHz, DMSO-d6) δ ppm 9.00 (s, 1H), 7.66 (s, 1H), 7.43 (d, J=8.9 Hz, 2H), 7.24 (t, J=8.0 Hz, 1H), 7.17 (d, J=8 Hz, 1H), 6.95 (m, 3H), 6.45 (bs, 1H), 3.88 (d, J=11.3 Hz, 1H), 3.72 (d, J=12.6 Hz, 1H), 2.84 (m, 4H), 1.97 (m, 4H), 1.68 (m, 3H), 1.50 (m, 4H), 1.25 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:34]=[CH:33][C:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:16]2[CH:24](OCC)[C:23]3[CH:22]=[C:21]4[CH:28]=[CH:29][CH:30]=[CH:31][C:20]4=[CH:19][C:18]=3[C:17]2=[O:32])=[O:8])=[CH:5][CH:4]=1.[CH2:35]([O:37][C:38]([O:40][Si](C)(C)C)=[CH2:39])[CH3:36].B(F)(F)F.CCOCC>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:16]2[CH:24]([CH2:39][C:38]([O:37][CH2:35][CH3:36])=[O:40])[C:23]3[CH:22]=[C:21]4[CH:28]=[CH:29][CH:30]=[CH:31][C:20]4=[CH:19][C:18]=3[C:17]2=[O:32])=[O:8])=[CH:33][CH:34]=1
Reactant: C=C(OCC)O[Si](C)(C)C
Reactant: CCOC1c2cc3ccccc3cc2C(=O)N1c1ccccc1NC(=O)c1ccc(OC)cc1
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: CCOC(=O)CC1c2cc3ccccc3cc2C(=O)N1c1ccccc1NC(=O)c1ccc(OC)cc1
Yield: 50.9 %

Procedure:
A solution of N-(4-methoxybenzoyl)-2-(1-ethoxy-1,3-dihydro-3-oxo-2H-benz[f]isoindol-2-yl)benzeneamine (0.75 g, 1.7 mmol) and 1-ethoxy-1-trimethylsilyloxyethylene (0.80 g, 5.0 mmol) in methylene chloride at −78° C. was treated dropwise with boron triflouride etherate (0.23 mL, 1.8 mmol). Upon complete addition, the cooling bath was removed and the mixture was allowed to warm for 0.5 h. The mixture was poured into a mixture of ethyl acetate and aqueous saturated sodium bicarbonate solution. The organic layer was washed with water, saturated sodium chloride solution, dried (potassium carbonate), and filtered. Concentration and purification of the residue by radial chromatography (silica gel, hexanes/ethyl acetate) yielded 428 mg (44%) of the title compound. An analytical sample was obtained by recrystallization from ethyl acetate/hexanes.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][C:14]([C:24]([O:26][CH2:27][CH3:28])=[O:25])([CH2:17][CH2:18][CH:19]2OCC[O:20]2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C(=O)([O-])O.[Na+]>O1CCCC1>[CH2:1]([O:8][C:9]([N:11]1[CH2:12][CH2:13][C:14]([C:24]([O:26][CH2:27][CH3:28])=[O:25])([CH2:17][CH2:18][CH:19]=[O:20])[CH2:15][CH2:16]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C1(CCC2OCCO2)CCN(C(=O)OCc2ccccc2)CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C1(CCC=O)CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.5 %

Procedure:
4-Ethoxycarbonyl-4-[2-(1,3-dioxolan-2-yl)ethyl]piperidine-1-carboxylic acid benzyl ester (460 mg) was dissolved in tetrahydrofuran (5 ml) and thereto was dropwise added conc. hydrochloric acid (5 ml) with ice-cooling, and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, the reaction mixture was poured into aqueous sodium hydrogencarbonate solution and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated and the obtained residue was purified by silica gel column chromatography (hexane:acetone=5:1) to give the title compound (300 mg).
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:28])[C:6]1[CH:11]=[CH:10][C:9]([CH2:12][N:13]2[C:21](=[O:22])[C:20]3[C@@H:19]4[C:23]([CH3:25])([CH3:24])[C@@:16]([CH3:26])([CH2:17][CH2:18]4)[C:15]=3[N:14]2[CH3:27])=[CH:8][CH:7]=1>CO.O1CCCC1>[CH3:27][N:14]1[C:15]2[C@@:16]3([CH3:26])[C:23]([CH3:24])([CH3:25])[C@H:19]([CH2:18][CH2:17]3)[C:20]=2[C:21](=[O:22])[N:13]1[CH2:12][C:9]1[CH:8]=[CH:7][C:6]([C:5]([OH:28])=[O:4])=[CH:11][CH:10]=1
Reactant: COC(=O)c1ccc(Cn2c(=O)c3c(n2C)[C@]2(C)CC[C@H]3C2(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cn1c2c(c(=O)n1Cc1ccc(C(=O)O)cc1)[C@H]1CC[C@]2(C)C1(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.6 %

Procedure:
1 M NaOH (1.1 mL, 1.1 mmol) was added to a solution of (4S,7R)-4-(1,7,8,8-tetramethyl-3-oxo-1,3,4,5,6,7-hexahydro-4,7-methano-indazol-2-ylmethyl)-benzoic acid methyl ester (228 mg, 0.644 mmol) in methanol (0.9 mL) and tetrahydrofuran (1.8 mL). The reaction mixture was stirred at room temperature overnight, and it was then partitioned between water (100 mL) and ether (100 mL). The aqueous layer was acidified with 1 M HCl to pH<3 and the resulting mixture was extracted with chloroform (100 mL). The chloroform extract was washed with brine (100 mL), dried (magnesium sulfate), filtered, and evaporated to give (4S,7R)-4-(1,7,8,8-tetramethyl-3-oxo-1,3,4,5,6,7-hexahydro-4,7-methano-indazol-2-ylmethyl)-benzoic acid (168 mg, 77%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]2[N:9]=[C:10]([NH2:12])[N:11]=[C:7]2[C:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:5][CH:4]=1.[F:19][C:20]1[CH:25]=[CH:24][C:23]([C:26](Cl)=[O:27])=[CH:22][CH:21]=1>>[F:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]([NH:12][C:10]2[N:11]=[C:7]3[C:6]([C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=4)=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[N:8]3[N:9]=2)=[O:27])=[CH:22][CH:21]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: COc1ccc(-c2ccccc2)c2nc(N)nn12
Product: COc1ccc(-c2ccccc2)c2nc(NC(=O)c3ccc(F)cc3)nn12

Procedure:
According to example 6, the title compound was synthesized from 5-methoxy-8-phenyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl-amine and 4-fluoro-phenyl carboxylic acid chloride.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C@@H:15]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:16][C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.[I:29]I.CCOC(C)=O.N1C=CC=CC=1>C(Cl)(Cl)Cl.[O-]S(C(F)(F)F)(=O)=O.[Ag+]>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C@@H:15]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH2:16][C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)[C:10]([I:29])=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: II
Reactant: COc1ccc([C@H](Cc2ccncc2)c2ccccc2)cc1OC1CCCC1
Agent: [Ag+]
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: COc1cc(I)c([C@H](Cc2ccncc2)c2ccccc2)cc1OC1CCCC1

Procedure:
From (R)-(+)-4-[2-(3-cyclopentyloxy-4-methoxyphenyl)-2-phenylethyl]pyridine (made as described in International Patent Specification No. WO 94/14742) (1.82 g, 4.88 mmol) in CHCl3 (50 ml)m, silver triflate (1.26 g, 4.88 mmol) and iodine (1.24 g, 4.88 mmol). Chromatography (SiO2;EtOAc) afforded the title comgound (2.2 g) as a colourless gum. (Found C, 59.23; H, 5.32; N, 2.67. C23H26NO2I requires C, 60.13; H, 5.25; N, 2.81) δH (CDCl3) 1.5-1.9 (8H, m,CH2)4), 3.25 (1H, d, J 5 Hz, CH2pyridine), 3.27 (1H, d, J 5 Hz, CH2 pyridine), 3.74 (3H, s, OCH3), 4.6-4.7 (1H, m, OCH), 4.64 (1H, t, J 8 Hz, CH phenyl), 6.74 (1H, s, C6H2), 7.01 (2H, d, J 5 Hz, H3, H5 pyridine), 7.24 (1H, s, C6H2), 7.25-7.4 (5H, m, C6H5), and 8.39 (2H, d. J 5 Hz, H2, H6 pyridine). m/z 500 (M+, 100%), 406 (25) and 212 (14).
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([CH:15]([CH3:17])[CH3:16])[C:12]=1[O:13][CH3:14])[C:7]([OH:9])=O)([CH3:3])[CH3:2].C(Cl)(=O)C(Cl)=O.[Sn](Cl)(Cl)(Cl)Cl.[Br:29][C:30]1[CH:43]=[CH:42][C:33]([CH2:34][C:35]2[O:36][C:37]([CH3:41])=[C:38]([CH3:40])[CH:39]=2)=[CH:32][CH:31]=1>C(Cl)Cl>[Br:29][C:30]1[CH:43]=[CH:42][C:33]([CH2:34][C:35]2[O:36][C:37]([CH3:41])=[C:38]([CH3:40])[C:39]=2[C:7]([C:6]2[CH:10]=[C:11]([CH:15]([CH3:17])[CH3:16])[C:12]([O:13][CH3:14])=[C:4]([CH:1]([CH3:2])[CH3:3])[CH:5]=2)=[O:9])=[CH:32][CH:31]=1
Reactant: COc1c(C(C)C)cc(C(=O)O)cc1C(C)C
Reactant: Cc1cc(Cc2ccc(Br)cc2)oc1C
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: COc1c(C(C)C)cc(C(=O)c2c(Cc3ccc(Br)cc3)oc(C)c2C)cc1C(C)C
Yield: 77.5 %

Procedure:
The title compound was prepared according to the procedure in Example 5, step 2 using 3,5-diisopropyl-p-anisic acid (1.03 g, 4.35 mmol, RN-117439-59-5), oxalyl chloride (0.417 mL, 4.79 mmol), N,N-dimethylformaride (2 drops), tin (IV) chloride (0.560 mL, 4.79 mmol) and 2-(4-bromo-benzyl)-4,5-dimethyl-furan (1.15 g, 4.35 mmol) in CH2Cl2. Purification on Biotage KP-Sil eluting with 3% EtOAc/pet. ether gave 1.63 g (77%) of the title compound as a yellow clear oil. 1H NMR (DMSO-d6) δ 1.16 (d, 12 H), 1.80 (s, 3 H), 2.19 (s, 3 H), 3.28 (septet, 2 H), 3.74 (s, 3 H), 3.83 (s, 2 H), 6.98 (d, 2 H), 7.41 (dd, 2 H), 7.44 (s, 2 H).
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].[CH3:6][O:7][C:8]1[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=1[C:10](Cl)=[O:11]>C1(C)C=CC=CC=1>[CH3:6][O:7][C:8]1[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=1[C:10]([N:3]([CH2:4][CH3:5])[CH2:1][CH3:2])=[O:11]
Reactant: COc1ccccc1C(=O)Cl
Reactant: CCNCC
Solvent: Cc1ccccc1
Product: CCN(CC)C(=O)c1ccccc1OC
Yield: 94 %

Procedure:
A solution of diethylamine (25.8 g, 0.352 mol) in toluene (toluene 30.8 g) was placed in a 200-mL four-neck flask. Under cooling with ice, a solution of 2-methoxybenzoic chloride (20 g, 0.117 mol) in toluene (toluene 10.0 g) was added dropwise gradually in order to prevent sudden surge of heat. After completion of addition of the entire amount of the solution, the formed amine hydrochloride was removed through extraction with water. The thus-obtained toluene layer was dried over MgSO4, and the solvent was vaporized out, to thereby yield 22.8 g of 2-methoxy-N,N-diethylbenzamide (yield: 94%).
Reaction SMILES: Cl.[CH3:2][NH:3][CH2:4][CH2:5][Cl:6].[SH:7][C:8]1[N:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]2=[N:10][N:9]=1.C(N(CC)CC)C.Cl>C(O)C.C(OCC)C.CC(C)=O.C(OCC)C>[ClH:6].[CH3:2][NH:3][CH2:4][CH2:5][S:7][C:8]1[N:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]2=[N:10][N:9]=1
Reactant: Sc1nnc2ccccn12
Reactant: CNCCCl
Agent: Cl
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: CCO
Product: CNCCSc1nnc2ccccn12
Yield: 38.9 %

Procedure:
A solution of 18 g of N-methyl-2-chloroethylamine hydrochloride, 20 g of 3-mercapto-1,2,4-triazolo(4,3-a)pyridine and 40 ml of triethylamine in 150 ml of ethanol is heated under reflux for 2 hours. After evaporation, the residue is taken up in water, 0.1N sodium hydroxide is added and extraction is carried out with chloroform. The chloroform phase is washed with water, dried over sodium sulfate and evaporated to dryness. The residue obtained is dissolved in an ethyl ether/acetone mixture and the solution is acidified by the addition of a solution of ethyl ether saturated with hydrogen chloride gas. The precipitate formed is filtered off, washed with ether and dried to give 12.6 g of 3-[2-(methylamino)ethylmercapto]-1,2,4-triazolo(4,3-a)pyridine hydrochloride in the form of crystals melting at 195°-7° C.
Reaction SMILES: [CH2:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[H][H]>[Pd].C(OCC)(=O)C>[CH2:1]([O:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]2[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=2)=[CH:14][CH:15]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCOc1ccc(-c2ccc([N+](=O)[O-])cc2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCCCCCCOc1ccc(-c2ccc(N)cc2)cc1

Procedure:
4'-n-Octyloxy-4-nitrobiphenyl, a known substance, was reduced with hydrogen in an ethyl acetate solution using a Pd/C catalyst and recrystallized from ethanol to obtain 4'-n-octyloxy-4-aminobiphenyl. 3 g of the obtained product was reacted with 2.2 g S-p-(2-methylbutyloxycarbonyl)benzaldehyde in the same manner as described in Example 19 and recrystallized from ethyl acetate to obtain bright yellow crystals.