Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[N:7]2[CH:8]=[CH:9][CH:10]=[C:11]([NH:12][C:13]3[CH:18]=[CH:17][C:16]([S:19](=[O:22])(=[O:21])[NH2:20])=[CH:15][CH:14]=3)[C:6]2=[N:5][CH:4]=1)#[CH:2].I[C:24]1[CH:25]=[C:26]([CH:40]=[CH:41][C:42]=1[CH3:43])[C:27]([NH:29][C:30]1[CH:35]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:33]=[CH:32][N:31]=1)=[O:28]>>[CH3:43][C:42]1[CH:24]=[CH:25][C:26]([C:27]([NH:29][C:30]2[CH:35]=[C:34]([C:36]([F:37])([F:38])[F:39])[CH:33]=[CH:32][N:31]=2)=[O:28])=[CH:40][C:41]=1[C:2]#[C:1][C:3]1[N:7]2[CH:8]=[CH:9][CH:10]=[C:11]([NH:12][C:13]3[CH:14]=[CH:15][C:16]([S:19](=[O:21])(=[O:22])[NH2:20])=[CH:17][CH:18]=3)[C:6]2=[N:5][CH:4]=1
Reactant: C#Cc1cnc2c(Nc3ccc(S(N)(=O)=O)cc3)cccn12
Reactant: Cc1ccc(C(=O)Nc2cc(C(F)(F)F)ccn2)cc1I
Product: Cc1ccc(C(=O)Nc2cc(C(F)(F)F)ccn2)cc1C#Cc1cnc2c(Nc3ccc(S(N)(=O)=O)cc3)cccn12

Procedure:
The title compound was synthesized from 3-ethynyl-N-(4-sulfamoylphenyl)imidazo[1,2-a]pyridin-8-amine and 3-iodo-4-methyl-N-(4-(trifluoromethyl)pyridin-2-yl)benzamide in a manner similar to that described for Example 12. The product was obtained as a solid: 591 m/z (M+H).
Reaction SMILES: [C:1]1(=O)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[BH4-].[Na+].O1CCCC1>CO>[CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: O=C1CCc2ccccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: C1=Cc2ccccc2C1

Procedure:
Alternatively, the keto group in the indanone may simply be reduced under standard conditions (e.g. sodium borohydride in methanol and/or tetrahydrofuran (THF)) followed by dehydration to form the desired indene or indene skeleton-containing compound.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)=[C:5]([CH:13]=[CH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[NH:4][N:3]=1>CO.[Pd]>[CH3:1][C:2]1[C:6]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)=[C:5]([CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[NH:4][N:3]=1
Reactant: Cc1n[nH]c(C=Cc2ccccc2)c1-c1ccncc1
Agent: [Pd]
Solvent: CO
Product: Cc1n[nH]c(CCc2ccccc2)c1-c1ccncc1

Procedure:
4-(3-Methyl-5-(2-phenylethenyl)-1H-pyrazol-4-yl)pyridine (Example 1) (0.177 g, 0.67 mmol) was hydrogenated (5-30 psi) in MeOH in the presence of a catalytic amount of 4% Pd/C at RT for 12 hours. The resulting mixture was filtered and the resulting solution was concentrated to give 4-(3-methyl-5-phenylethyl-1H-pyrazol-4-yl)pyridine quantitatively: MS (M+H+) 264 (100%).
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([C:21]3[NH:25][C:24]([C:26]4[N:31]=[CH:30][C:29]([S:32][CH2:33][C:34]([O:36]CC)=[O:35])=[CH:28][CH:27]=4)=[CH:23][CH:22]=3)[CH2:14][CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.[OH-].[Na+].Cl>CO>[CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([C:21]3[NH:25][C:24]([C:26]4[N:31]=[CH:30][C:29]([S:32][CH2:33][C:34]([OH:36])=[O:35])=[CH:28][CH:27]=4)=[CH:23][CH:22]=3)[CH2:14][CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:9][CH:8]=2)(=[O:5])=[O:6])[CH2:3][CH2:2]1
Reactant: CCOC(=O)CSc1ccc(-c2ccc(C(CC3CCOCC3)c3ccc(S(=O)(=O)C4CC4)cc3)[nH]2)nc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)CSc1ccc(-c2ccc(C(CC3CCOCC3)c3ccc(S(=O)(=O)C4CC4)cc3)[nH]2)nc1
Temperature: 50 °C
Reaction time: 2 h
Yield: 70.2 %

Procedure:
To a solution of ethyl {[6-(5-{1-[4-(cyclopropylsulfonyl)phenyl]-2-(tetrahydro-2H-pyran-4-yl)ethyl}-1H-pyrrol-2-yl)pyridin-3-yl]sulfanyl}acetate (75 mg) in methanol (3 mL) was added 2M aqueous sodium hydroxide solution (170 μL), and the mixture was stirred at 50° C. for 2 hr. After cooling to room temperature, the reaction mixture was neutralized with 1M hydrochloric acid, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated to give the title compound (50 mg, yield 70%) as a pale-yellow amorphous solid. MS: 527 (MH+).
Reaction SMILES: [C:1]([CH2:3][C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][CH:13]=1)[C:7]([O:9][CH3:10])=[O:8])#[N:2].[H-].[Na+].Cl[CH2:17][CH2:18][O:19][CH2:20][CH2:21]Cl.O>CS(C)=O>[C:1]([C:3]1([C:4]2[CH:5]=[C:6]([CH:11]=[CH:12][CH:13]=2)[C:7]([O:9][CH3:10])=[O:8])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1)#[N:2]
Reactant: ClCCOCCCl
Reactant: COC(=O)c1cccc(CC#N)c1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)c1cccc(C2(C#N)CCOCC2)c1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a solution of methyl 3-(cyanomethyl)benzoate 1 (2 g, 11.4 mmol) in DMSO (20 mL) was added NaH (60%, 959 mg, 24.0 mmol) portion wise over 10 min. The reaction mixture was stirred for 40 min at rt and then bis(2-chloroethyl)ether (1.27 mL, 10.9 mmol) was added slowly and stirring continued for 18 hours. The reaction was poured into water and extracted with EtOAc/toluene (2:1). The combined extracts were washed with 2N HCl solution, water, brine, dried and evaporated the crude methyl 3-(4-cyanotetrahydro-2H-pyran-4-yl)benzoate 80 (1.25 g, 44%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[Br:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>C(N(CC)CC)C>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:24]2[CH2:23][CH2:22][N:21]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[Br:14])[CH2:26][CH2:25]2)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Reactant: Brc1ccccc1N1CCNCC1
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccc(S(=O)(=O)N2CCN(c3ccccc3Br)CC2)cc1

Procedure:
In the manner given in Example 1A, p-nitrobenzenesulfonyl chloride, 1-(o-bromophenyl)piperazine and triethylamine are stirred at reflux to give 1-[(p-nitrophenyl)sulfonyl]-4-(o-bromophenyl)piperazine.
Reaction SMILES: [Cl:1][C:2]1[C:16]([Cl:17])=[CH:15][C:5]2[NH:6][C:7]([C:9](=O)[C:10]([F:13])([F:12])[F:11])=[N:8][C:4]=2[CH:3]=1.Cl.[NH2:19][OH:20].O>N1C=CC=CC=1.C(O)C>[Cl:1][C:2]1[C:16]([Cl:17])=[CH:15][C:5]2[NH:6][C:7]([C:9](=[N:19][OH:20])[C:10]([F:13])([F:12])[F:11])=[N:8][C:4]=2[CH:3]=1
Reactant: O=C(c1nc2cc(Cl)c(Cl)cc2[nH]1)C(F)(F)F
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Solvent: O
Product: ON=C(c1nc2cc(Cl)c(Cl)cc2[nH]1)C(F)(F)F
Temperature: 25 °C

Procedure:
1-(5,6-Dichloro-1H-benzoimidazol-2-yl)-2,2,2-trifluoro-ethanone (0.3005 g; 1.062 mmoles) and hydroxylamine hydrochloride (0.2389 g, 3.438 mmoles) were suspended in pyridine (3 mL) and ethanol (3 mL), then heated to 70° C. for 3 hrs. The reaction mixture was cooled to room temperature, water was water (50 mL) and the reaction mixture was then extracted with ethyl acetate (3×40 ml). The extracts were combined then washed with water (20 mL), brine (30 mL) and dried over Na2SO4. The filtrate was concentrated in vacuo and purified by column chromatography (SiO2; 30% ethyl acetate/CH2Cl2) to yield the title compound as an off-white solid, as a mixture of oxime E and Z isomers.
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[CH3:6][O:7][CH2:8][CH2:9][C:10]1[CH:14]=[CH:13][S:12][CH:11]=1>>[CH3:6][O:7][CH2:8][CH2:9][C:10]1[CH:14]=[CH:13][S:12][C:11]=1[S:2]([Cl:1])(=[O:5])=[O:3]
Reactant: COCCc1ccsc1
Reactant: O=S(=O)(O)Cl
Product: COCCc1ccsc1S(=O)(=O)Cl
Temperature: -10 °C
Reaction time: 1 h
Yield: 25 %

Procedure:
To 56 g of chlorosulfonic acid at -15° C. was added with efficient stirring 14.2 g of 3-(2-methoxyethyl)thiophene. The mixture was stirred for one hour at -10° C. and then cautiously added to ice and the resultant mixture extracted with methylene chloride. The methylene chloride extract was washed with cold water, dried over magnesium sulfate, filtered and concentrated to yield 6.0 g of an oil. Infrared absorption spectroscopy showed peaks at 1160, 1180 and 1360 cm-1 consistent for sulfonyl chloride. This product was sufficiently pure for use as an intermediate for the preparation of compounds of this invention.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH2:18][CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])([C:14]([O:16]C)=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O1CCCC1.C([N-]C(C)C)(C)C.[Li+].C(OCC)(=O)C.[Cl-].[NH4+]>O1CCCC1>[CH3:24][O:23][C:21]([CH:20]1[CH2:19][CH2:18][C:11]2([CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])[CH2:9][CH2:10]2)[C:14]1=[O:16])=[O:22]
Reactant: COC(=O)CCCC1(C(=O)OC)CCN(C(=O)OC(C)(C)C)CC1
Agent: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)C1CCC2(CCN(C(=O)OC(C)(C)C)CC2)C1=O
Temperature: -78 °C
Reaction time: 0.42 h
Yield: 110.2 %

Procedure:
To a solution of methyl 4-(1-(tert-butoxycarbonyl)-4-(methoxycarbonyl)piperidin-4-yl)butanoate (20.1 g, 0.058 mol) from Step E in tetrahydrofuran (600 mL) at −78° C. was added lithium diisopropylamide mono(tetrahydrofuran) (47 mL, 0.070 mol, 1.5M solution in cyclohexanes). The reaction mixture was stirred at −78° C. for 25 min. Thin layer chromatography (tlc) analysis (50% ethyl acetate in hexanes) showed that starting material remained. Additional lithium diisopropylamide mono(tetrahydrofuran) (31 mL) was added and the reaction mixture was stirred for 20 min. The reaction mixture was poured into saturated ammonium chloride and extracted three times with diethyl ether. The organic layers were combined, washed with brine, dried over sodium sulfate, and concentrated to afford the title compound (19.9 g) which was taken on to the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[CH:4]=[CH:5][C:6]1[S:7][C:8]([C:11](=[O:33])[NH:12][CH2:13][C@H:14]([NH:22]C(OCC2C=CC=CC=2)=O)[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[CH:9][CH:10]=1.[ClH:35]>CO.[Pd]>[ClH:35].[C:18]([O:17][C:15](=[O:16])[C@@H:14]([NH2:22])[CH2:13][NH:12][C:11]([C:8]1[S:7][C:6]([CH2:5][CH2:4][C:3]([O:2][CH3:1])=[O:34])=[CH:10][CH:9]=1)=[O:33])([CH3:21])([CH3:19])[CH3:20]
Reactant: COC(=O)C=Cc1ccc(C(=O)NC[C@H](NC(=O)OCc2ccccc2)C(=O)OC(C)(C)C)s1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: COC(=O)CCc1ccc(C(=O)NC[C@H](N)C(=O)OC(C)(C)C)s1
Reaction time: 14 h

Procedure:
6.85 g of 3-(5-(((2S)-2-benzyloxycarbonylamino-2-tert-butoxycarbonyl-ethyl)carbamoyl)-2-thienyl)-acrylic acid methyl ester (example 3, step a) were dissolved in 220 ml of methanol. 1.3 g of 10% palladium on charcoal and 2.8 ml of a 5N solution of hydrogen chloride in methanol were added and the hydrogenation was started. After 6 hours the pH was adjusted with 5N solution of hydrogen chloride in methanol to 3.5, and further 0.6 g of the catalyst were added. After 14 hours the hydrogenation was complete. The catalyst was removed by filtration. After standard work-up 4.88 g of the title compound were obtained.
Reaction SMILES: [C@H:1]12[CH2:6][C@H:5]1[CH2:4][C@@H:3]([CH2:7][NH:8][C:9]([C:11]1[C:20]3[O:19][CH2:18][CH2:17][O:16][C:15]=3[CH:14]=[CH:13][CH:12]=1)=[O:10])[NH:2]2.[F:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[S:32][C:31]([CH3:33])=[N:30][C:29]=2[C:34](O)=[O:35])=[CH:24][CH:23]=1>>[F:21][C:22]1[CH:23]=[CH:24][C:25]([C:28]2[S:32][C:31]([CH3:33])=[N:30][C:29]=2[C:34]([N:2]2[C@H:3]([CH2:7][NH:8][C:9]([C:11]3[C:20]4[O:19][CH2:18][CH2:17][O:16][C:15]=4[CH:14]=[CH:13][CH:12]=3)=[O:10])[CH2:4][C@H:5]3[C@@H:1]2[CH2:6]3)=[O:35])=[CH:26][CH:27]=1
Reactant: O=C(NC[C@@H]1C[C@@H]2C[C@@H]2N1)c1cccc2c1OCCO2
Reactant: Cc1nc(C(=O)O)c(-c2ccc(F)cc2)s1
Product: Cc1nc(C(=O)N2[C@H](CNC(=O)c3cccc4c3OCCO4)C[C@@H]3C[C@@H]32)c(-c2ccc(F)cc2)s1

Procedure:
prepared by reaction of 2,3-dihydro-benzo[1,4]dioxine-5-carboxylic acid [(1S,3S,5S)-2-aza-bicyclo[3.1.0]hex-3-ylmethyl]-amide with 5-(4-fluoro-phenyl)-2-methyl-thiazole-4-carboxylic acid. LC-MS (basic): tR=1.35 min; [M+H]+=494.1.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:38])=[C:4]([CH:35]=[CH:36][CH:37]=1)[NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:33][CH3:34])=[C:13]([O:16][C@H:17]3[CH2:21][N:20]([C:22](OC(C)(C)C)=O)[C@H:19]([C:29]([O:31][CH3:32])=[O:30])[CH2:18]3)[CH:14]=2)[N:9]=[CH:8][N:7]=1.C=O>C(O)=O>[Cl:1][C:2]1[C:3]([F:38])=[C:4]([CH:35]=[CH:36][CH:37]=1)[NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:33][CH3:34])=[C:13]([O:16][C@H:17]3[CH2:21][N:20]([CH3:22])[CH:19]([C:29]([O:31][CH3:32])=[O:30])[CH2:18]3)[CH:14]=2)[N:9]=[CH:8][N:7]=1
Reactant: COC(=O)[C@@H]1C[C@@H](Oc2cc3c(Nc4cccc(Cl)c4F)ncnc3cc2OC)CN1C(=O)OC(C)(C)C
Agent: C=O
Solvent: O=CO
Product: COC(=O)C1C[C@@H](Oc2cc3c(Nc4cccc(Cl)c4F)ncnc3cc2OC)CN1C
Temperature: 85 °C
Yield: 65.3 %

Procedure:
A solution of 4-(3-chloro-2-fluoroanilino)-6-[(2S,4R)-1-(tert-butoxycarbonyl)-2-(methoxycarbonyl)pyrrolidin-4-yloxy]-7-methoxyquinazoline (480 mg, 0.88 mmol) in formic acid (50 ml) was reacted with paraformaldehyde (29 mg, 0.97 mmol) and the resulting mixture heated at 85° C. for 6 hours. The reaction mixture was evaporated and the residues partitioned between saturated aqueous NaHCO3 (50 ml) and ethyl acetate (100 ml). The organic layer was dried over MgSO4, filtered and evaporated. The residue was purified by flash chromatography on silica eluting with increasingly polar mixtures of methylene chloride/methanol (100/0 to 90/10). The fractions containing the expected product were combined and evaporated to give 4-(3-chloro-2-fluoroanilino)-6-[(2RS,4R)-1-methyl-2-(methoxycarbonyl)pyrrolidin-4-yloxy]-7-methoxyquinazoline as a white foam (265 mg); Mass Spectrum: (M+H)+ 461.
Reaction SMILES: [CH2:1]([NH:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[C:16]([CH2:17][O:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[CH:20]=3)=[C:15]([C:26](OCC)=[O:27])[N:14]=[N:13]2)=[CH:8][CH:7]=1)=[O:5])[CH3:2].[CH2:31]([CH2:33][NH2:34])[OH:32]>O>[CH2:1]([NH:3][C:4]([C:6]1[CH:7]=[CH:8][C:9]([N:12]2[C:16]([CH2:17][O:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[CH:20]=3)=[C:15]([C:26]([NH:34][CH2:33][CH2:31][OH:32])=[O:27])[N:14]=[N:13]2)=[CH:10][CH:11]=1)=[O:5])[CH3:2]
Reactant: CCNC(=O)c1ccc(-n2nnc(C(=O)OCC)c2COc2cccc(C)c2)cc1
Reactant: NCCO
Solvent: O
Product: CCNC(=O)c1ccc(-n2nnc(C(=O)NCCO)c2COc2cccc(C)c2)cc1
Temperature: 50 °C

Procedure:
A mixture of ethyl 1-{4-[(ethylamino)carbonyl]phenyl}-5-[(3-methylphenoxy)methyl]-1H-1,2,3-triazole-4-carboxylate (720 mg) obtained in Example 515a) and ethanolamine (2.5 ml) was heated at 50° C. for 14 hr. Water was added to the reaction mixture, and the mixture was extracted with chloroform, and washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column (ethyl acetate to ethyl acetate/methanol=95/5) and recrystallized from ethyl acetate to give the title compound as a colorless powder (680 mg).
Reaction SMILES: [NH:1]([C:42]([O:44][CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)=[O:43])[C@H:2]([C:11]([NH:13][C@@H:14]([C:16]([NH:18][CH2:19][C:20]([NH:22][C@H:23]([C:31]([NH:33][NH:34]C(OC(C)(C)C)=O)=[O:32])[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:21])=[O:17])[CH3:15])=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1>FC(F)(F)C(O)=O>[NH:1]([C:42]([O:44][CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)=[O:43])[C@H:2]([C:11]([NH:13][C@@H:14]([C:16]([NH:18][CH2:19][C:20]([NH:22][C@H:23]([C:31]([NH:33][NH2:34])=[O:32])[CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)=[O:21])=[O:17])[CH3:15])=[O:12])[CH2:3][C:4]1[CH:5]=[CH:6][C:7]([OH:10])=[CH:8][CH:9]=1
Reactant: C[C@@H](NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OCc1ccccc1)C(=O)NCC(=O)N[C@@H](Cc1ccccc1)C(=O)NNC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H](NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OCc1ccccc1)C(=O)NCC(=O)N[C@@H](Cc1ccccc1)C(=O)NN
Reaction time: 0.33 h

Procedure:
In 30 ml of trifluoroacetic acid is dissolved 3.5 g of Z-Tyr-(D)-Ala-Gly-Phe-NH-NH-BOC and the solution is allowed to stand at room temperature for 20 minutes. The trifluoroacetic acid is distilled offand the residue is treated with diethyl ether and collected by filtration. The resulting powders are dissolved in 10 ml of DMF and stirred with 1.4 ml of TEA. The DMF is distilled off and the residue is treated with water,collected by filtration and purified by reprecipitation with methanol-diethylether. 2.8 g (96%); m.p. 182°-184° C. (decomp.); [α]D22 -23.0° (c=0.5, DMF); Rf1 =0.17.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:20][C:21]1[O:25][N:24]=[C:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:22]=1[C:32]1[N:36]2[CH2:37][C:38]3[C:43]([C:35]2=[N:34][N:33]=1)=[CH:42][C:41]([OH:44])=[CH:40][CH:39]=3.O[CH:46]1[CH2:51][CH2:50][N:49]([C:52]([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[O:53])[CH2:48][CH2:47]1.N(C(OCC)=O)=NC(OCC)=O>ClCCl.C(O)(C(F)(F)F)=O>[C:55]([O:54][C:52]([N:49]1[CH2:50][CH2:51][CH:46]([O:44][C:41]2[CH:42]=[C:43]3[C:38]([CH2:37][N:36]4[C:32]([C:22]5[C:23]([C:26]6[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=6)=[N:24][O:25][C:21]=5[CH3:20])=[N:33][N:34]=[C:35]43)=[CH:39][CH:40]=2)[CH2:47][CH2:48]1)=[O:53])([CH3:58])([CH3:56])[CH3:57]
Reactant: Cc1onc(-c2ccccc2)c1-c1nnc2n1Cc1ccc(O)cc1-2
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1onc(-c2ccccc2)c1-c1nnc2n1Cc1ccc(OC3CCN(C(=O)OC(C)(C)C)CC3)cc1-2
Temperature: 25 °C
Reaction time: 8 h
Yield: 0.9 %

Procedure:
Under nitrogen atmosphere, triphenylphosphine bound resin (1.22 g, 1.36 mmol, 1.12 mmol/g) was swelled in dichloromethane for 30 minutes. 3-(5-Methyl-3-phenylisoxazol-4-yl)-5H-[1,2,4]triazolo[3,4-a]isoindol-8-ol (0.3 g, 0.91 mmol) (prepared as in Example 3, Step (a)), 4-hydroxy-boc-piperidine (0.27 g, 1.36 mmol, 1.5 eq.) and diethyl azodicarboxylate (0.21 ml, 1.36 mmol, 1.5 eq.) were added and the reaction was stirred at room temperature overnight. The resin was filtered off and washed with dichloromethane, methanol and ether. The combined organics were concentrated in vacuo. The residue was purified by alumina chromatography, eluting with dichloromethane 2% methanol/dichloromethane (0.5% methanol gradient), and was used without further purification in the next step. b) 3-(5-Methyl-3-phenylisoxazol-4-yl)-8-(piperidin-4-yloxy)-5H-[1,2,4]triazolo[3,4-α]isoindole 4-[3-(5-Methyl-3-phenylisoxazol-4-yl)-5H-[1,2,4]triazolo[3,4-α]isoindol-8-yloxy]-piperidine-1-carboxylic acid tert-butyl ester (466 mg, 0.91 mmol) was dissolved in TFA (5 ml) and stirred at room temperature for 1 hour. The reaction was concentrated in vacuo and the residue was partitioned between ethyl acetate and saturated K2CO3 (aq). The organic layer was dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by alumina chromatography, eluting with dichloromethane→5% methanol/dichloromethane (in 1% methanol gradient), to afford the title compound as a white solid (4 mg, 1% over 2 steps). 1H NMR (400 MHz, d4 MeOH) δ 7.53–7.43 (6H, m), 7.32 (1H, d, J=8.5 Hz), 7.08 (1H, dd, J=8.5, 2.4 Hz), 4.63–4.60 (1H, m), 4.24 (2H, s), 3.16–3.11 (2H, m), 2.85–2.79 (2H, m), 2.64 (3H, s), 2.09–2.05 (2H, m), 1.78–1.72 (2H, m). m/z (ES+) 414 (M+H)+.
Reaction SMILES: [CH:1]([C:3]1[CH:25]=[CH:24][C:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]([F:23])([F:22])[CH:19]([F:21])[F:20])=[CH:12][CH:11]=2)=[O:8])=[CH:5][CH:4]=1)=[O:2].[F:26][C:27]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=1[C@:34]([OH:49])([C@H:41]([S:43][CH:44]([CH2:47]O)[CH2:45][OH:46])[CH3:42])[CH2:35][N:36]1[CH:40]=[N:39][CH:38]=[N:37]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>O1CCCC1.ClCCl>[F:26][C:27]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=1[C@@:34]([OH:49])([CH2:35][N:36]1[CH:40]=[N:39][CH:38]=[N:37]1)[C@H:41]([S:43][C@@H:44]1[CH2:45][O:46][C@@H:1]([C:3]2[CH:4]=[CH:5][C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]([F:22])([F:23])[CH:19]([F:20])[F:21])=[CH:12][CH:11]=3)=[O:8])=[CH:24][CH:25]=2)[O:2][CH2:47]1)[CH3:42]
Reactant: C[C@@H](SC(CO)CO)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Reactant: O=Cc1ccc(C(=O)Nc2ccc(OCC(F)(F)C(F)F)cc2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H](S[C@H]1CO[C@H](c2ccc(C(=O)Nc3ccc(OCC(F)(F)C(F)F)cc3)cc2)OC1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Molecular sieve 4A (3 g) was added to a mixture of 4-formyl-4′-(2,2,3,3-tetrafluoropropoxy)benzanilide (300 mg, 0.84 mmol) obtained in example 1 (1), (2R,3R)-2-(2,4-difluorophenyl)-3-[[1-(hydroxymethyl)-2-hydroxyethyl]thio]-1-(1H-1,2,4-triazol-1-yl)-2-butanol (disclosed in Japanese Patent Application Publication No. Hei-8-333350; 253 mg, 0.70 mmol), p-toluenesulfonic acid monohydrate (160 mg, 0.84 mmol) in anhydrous tetrahydrofuran (10 ml) and anhydrous dichloromethane (5 ml). The resulting mixture was stirred at room temperature for two days. Aqueous sodium hydrogencarbonate solution was added to the reaction mixture at 0° C., and the mixture was filtered to remove the molecular sieve. The filtrate was partitioned between ethyl acetate and water. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting oily residue was chromatographed on a silica gel column using ethyl acetate-hexane (2:1) as the eluant to afford the trans isomer of the title compound (87 mg, yield 18%) as a white solid and then using ethyl acetate-hexane (4:1) as the eluant to give the cis isomer (55 mg, yield 11%) as a colorless oil. The trans isomer was recrystallized from ethyl acetate-isopropyl ether to give white powdery crystals.
Reaction SMILES: P(=O)(O)(O)O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[F:20][C:21]1[CH:22]=[C:23]([CH:35]=[CH:36][CH:37]=1)[C:24]([NH:26][CH2:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=O.N>O>[F:20][C:21]1[CH:22]=[C:23]([C:24]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH2:28][CH2:27][N:26]=2)[CH:35]=[CH:36][CH:37]=1
Reactant: O=C(NCCc1ccccc1)c1cccc(F)c1
Agent: N
Agent: O=P(O)(O)O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: O
Product: Fc1cccc(C2=NCCc3ccccc32)c1
Temperature: 150 °C
Reaction time: 0.5 h
Yield: 105.2 %

Procedure:
Phosphoric acid (11.9 mL) was added to diphosphorus pentoxide (20.0 g) over 5 minutes. The mixture was stirred at 150° C. for 0.5 hours. 3-fluoro-N-(2-phenylethyl)benzamide (5.00 g) was added to the mixture, followed by stirring at 160° C. for 2.5 hours. After cooling, water was added to the reaction solution to which 28% aqueous ammonia was then added to be alkaline. The reaction solution was extracted with EtOAc, washed with saturated brine, and dried over magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain 1-(3-fluorophenyl)-3,4-dihydroisoquinoline (4.87 g).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][C:5](=O)[CH:4]([CH2:9][C:10](=O)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:3]1.[NH2:18][C:19]1[CH:20]=[CH:21][C:22]([C:25]([OH:27])=[O:26])=[N:23][CH:24]=1>>[CH3:1][CH:2]1[CH2:7][CH2:6][C:5]2[N:18]([C:19]3[CH:20]=[CH:21][C:22]([C:25]([OH:27])=[O:26])=[N:23][CH:24]=3)[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:9][C:4]=2[CH2:3]1
Reactant: CC1CCC(=O)C(CC(=O)c2ccccc2)C1
Reactant: Nc1ccc(C(=O)O)nc1
Product: CC1CCc2c(cc(-c3ccccc3)n2-c2ccc(C(=O)O)nc2)C1
Yield: 71 %

Procedure:
Following the general methods as outlined under Intermediate 13, starting from 4-methyl-2-(2-oxo-2-phenylethyl)cyclohexanone and 5-aminopyridine-2-carboxylic acid, the title compound was isolated in 71% yield (96% purity by HPLC). MS(ESI+): 334.7; MS(ESI−): 332.4.