Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:12]2[O:13][C:14]3[C:20]([F:21])=[C:19]([F:22])[CH:18]=[CH:17][C:15]=3[N:16]=2)[C:5]([NH:8][CH2:9][CH2:10][CH3:11])=[CH:6][CH:7]=1.[CH:23]1[C:28]([C:29]([OH:31])=[O:30])=[CH:27][C:26]2[C:32]([O:34][C:35](=O)[C:25]=2[CH:24]=1)=[O:33]>>[F:22][C:19]1[CH:18]=[CH:17][C:15]2[N:16]=[C:12]([C:4]3[CH:3]=[C:2]([N:1]4[C:32](=[O:33])[C:26]5[C:25](=[CH:24][CH:23]=[C:28]([C:29]([OH:31])=[O:30])[CH:27]=5)[C:35]4=[O:34])[CH:7]=[CH:6][C:5]=3[NH:8][CH2:9][CH2:10][CH3:11])[O:13][C:14]=2[C:20]=1[F:21]
Reactant: O=C(O)c1ccc2c(c1)C(=O)OC2=O
Reactant: CCCNc1ccc(N)cc1-c1nc2ccc(F)c(F)c2o1
Product: CCCNc1ccc(N2C(=O)c3ccc(C(=O)O)cc3C2=O)cc1-c1nc2ccc(F)c(F)c2o1

Procedure:
Prepared by the method of Example 15f), from 2-(3-amino-6-propylaminophenyl)-6,7-difluorobenzoxazole (121 mg, 0.4 mmol) and 1,2,4-benzenetricarboxylic anhydride (96 mg, 0.5 mmol) the title compound was obtained (105 mg, 55%). 1H NMR (DMSO) δ 8.41(dd, 1H), 8.29(s, 1H), 8.25(t, 1H), 8.14(d, 1H), 8.06(d, 1H), 7.67(m, 1H), 7.50(m, 2H), 7.04(d, 1H), 3.34(m, 2H), 1.74(m, 2H), 1.05(t, 3H). MS 475.7 m/z (M−H)−.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[CH:10][C:11]([O:16][CH3:17])=[C:12]([CH:15]=2)[CH:13]=O)[CH:5]=[N:6][CH:7]=1.[C:18]([O:22][C:23](=[O:33])[N:24]([CH:26]1[CH2:31][CH2:30][CH:29]([NH2:32])[CH2:28][CH2:27]1)[CH3:25])([CH3:21])([CH3:20])[CH3:19]>>[C:18]([O:22][C:23](=[O:33])[N:24]([CH:26]1[CH2:27][CH2:28][CH:29]([NH:32][CH2:13][C:12]2[CH:15]=[C:8]([C:4]3[CH:5]=[N:6][CH:7]=[C:2]([F:1])[CH:3]=3)[CH:9]=[CH:10][C:11]=2[O:16][CH3:17])[CH2:30][CH2:31]1)[CH3:25])([CH3:21])([CH3:19])[CH3:20]
Reactant: COc1ccc(-c2cncc(F)c2)cc1C=O
Reactant: CN(C(=O)OC(C)(C)C)C1CCC(N)CC1
Product: COc1ccc(-c2cncc(F)c2)cc1CNC1CCC(N(C)C(=O)OC(C)(C)C)CC1

Procedure:
Following the synthetic protocol described in Method C′; {4-[5-(5-Fluoro-pyridin-3-yl)-2-methoxy-benzylamino]-cyclohexyl}-methyl-carbamic acid tert-butyl ester is prepared starting from 5-(5-Fluoro-pyridin-3-yl)-2-methoxy-benzaldehyde and (4-Amino-cyclohexyl)-methyl-carbamic acid tert-butyl ester. The desired product is isolated in 64%.
Reaction SMILES: C[O:2][C:3]([C:5]1([C:10]([CH:12]2[CH2:14][CH2:13]2)=[O:11])[CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:4].O[Li].O>CCO.O>[CH:12]1([C:10]([C:5]2([C:3]([OH:4])=[O:2])[CH2:6][CH2:7][CH2:8][CH2:9]2)=[O:11])[CH2:14][CH2:13]1
Reactant: COC(=O)C1(C(=O)C2CC2)CCCC1
Agent: [Li]O
Solvent: CCO
Solvent: O
Product: O=C(O)C1(C(=O)C2CC2)CCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.7 %

Procedure:
To a solution of 1-cyclopropanecarbonyl-cyclopentane carboxylic acid methyl ester (0.62 g, 3.1 mmol) in EtOH (10 mL) were added LiOH.H2O (0.53 g, 12.6 mmol) and water (3 mL). The reaction mixture was stirred at room temperature overnight then diluted with water and washed with Et2O. The aqueous layer was acidified with conc. HCl to pH=2 then extracted with Et2O (2×). The combined second organic extracts were dried over Na2SO4 and concentrated to afford 0.36 g (64%) of 1-cyclopropanecarbonyl-cyclopentane carboxylic acid as a pale yellow oil.
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[NH:4][N:3]=1.[F:11][C:12]1[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:13]=1[CH2:14]Br>>[F:11][C:12]1[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:13]=1[CH2:14][N:4]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:10]2[C:2]([I:1])=[N:3]1
Reactant: Fc1cccc(CBr)c1F
Reactant: Ic1n[nH]c2ncccc12
Product: Fc1cccc(Cn2nc(I)c3cccnc32)c1F
Temperature: 0 °C

Procedure:
Analogously to the synthesis of Example 7A, 54.00 g (215.98 mmol) of 3-iodo-1H-pyrazolo[3,4-b]pyridine (synthesis described in WO 2006/130673 Example 4) were reacted with 50.18 g (237.578) of 2,3-difluorobenzyl bromide. Ice-water was added to the crude product, the mixture was filtered off with suction and the precipitate was washed with isopropanol and pentane and then dried under high vacuum. This gave 73.00 g of the title compound (85% of theory).
Reaction SMILES: C([Li])CCC.[Br-].C1([C:13]([PH3+])([C:20]2[CH:25]=[CH:24]C=[CH:22][CH:21]=2)C2C=CC=CC=2)C=CC=CC=1.[C:27]([O:31][C:32]([N:34]1CCC(C=O)C1)=[O:33])([CH3:30])([CH3:29])[CH3:28].[Cl-].[NH4+]>CCCCCC.O1CCCC1.C(OCC)(=O)C>[C:27]([O:31][C:32]([N:34]1[CH2:24][CH2:25][CH:20]([CH:21]=[CH2:22])[CH2:13]1)=[O:33])([CH3:30])([CH3:29])[CH3:28]
Reactant: [PH3+]C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)C1
Agent: [Br-]
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C=CC1CCN(C(=O)OC(C)(C)C)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 89.7 %

Procedure:
n-Butyllithium in hexane (44 cm3 of a 1.6 N solution) was added drop-wise to a suspension of 25.5 g (71 mmol) of triphenylmethylphosphonium bromide in 300 cm3 of tetrahydrofuran, which was under argon and cooled to 0° C. The reaction mixture was stirred at 0° C. for 0.5 h and then admixed with a solution of 7.1 g (35.6 mmol) of racemic 3-formylpyrrolidine-1-carboxylic acid tert-butyl ester in 100 cm3 of tetrahydrofuran. After 2.5 hours of reaction at a temperature in the region of 22° C., the mixture was poured into 600 cm3 of saturated aqueous ammonium chloride solution. Following addition of ethyl acetate the organic phase was taken off by decanting, washed twice with water and with saturated sodium chloride solution and then dried over magnesium sulfate and concentrated to dryness under reduced pressure (2.7 kPa). The resulting oil was purified by chromatography on silica gel [eluent: cyclohexane/ethyl acetate (95/5 then 9/1 by volume)]. Concentration of the fractions under reduced pressure (2.7 kPa) gave 6.3 g of racemic 3-vinylpyrrolidine-1-carboxylic acid tert-butyl ester in the form of a colorless oil. Mass spectrum (ES): m/z 198 (MH+), m/z=142.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[N:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(Cl)(Cl)=O.[CH3:15]O>>[CH3:15][O:5][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][N:9]=[CH:10][C:2]=1[NH2:1]
Reactant: CO
Reactant: Nc1cnccc1C(=O)O
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccncc1N

Procedure:
A mixture of 3-amino-isonicotinic acid (613 mg, 4.44 mmol), methanol (15 mL) and thionyl chloride (0.7 mL, 8.88 mmol) was stirred at reflux for 3 days. The volatiles were removed under reduced pressure and the residue stirred with diethylether (20 mL) and saturated solution of sodium hydrogenocarbonate (40 mL). The phases were separated and the aqueous phase extracted with diethylether (2×20 mL). The combined organic phases were dried over sodium sulfate and evaporated to dryness affording 400 mg of the title compound.
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:43]([CH2:44][O:45][CH2:46][C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[O:42][C@H:8]([O:9][C@H:10]2[C@H:14]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:13][N:12]([C:23]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:24])[C@@H:11]2[CH2:33][O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C@H:7]([O:53][CH2:54][C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)[C@H:6]1[O:61][CH2:62][C:63]1[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=1)(=O)C.C(=O)([O-])[O-].[K+].[K+]>CO.C(OCC)(=O)C>[CH2:54]([O:53][C@@H:7]1[C@@H:6]([O:61][CH2:62][C:63]2[CH:64]=[CH:65][CH:66]=[CH:67][CH:68]=2)[C@H:5]([OH:4])[C@@H:43]([CH2:44][O:45][CH2:46][C:47]2[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=2)[O:42][C@@H:8]1[O:9][C@H:10]1[C@H:14]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:13][N:12]([C:23]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:24])[C@@H:11]1[CH2:33][O:34][CH2:35][C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)[C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1
Reactant: CC(=O)O[C@H]1[C@H](OCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H](O[C@@H]2[C@@H](COCc3ccccc3)N(C(=O)OCc3ccccc3)C[C@H]2OCc2ccccc2)O[C@@H]1COCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CO
Product: O=C(OCc1ccccc1)N1C[C@@H](OCc2ccccc2)[C@H](O[C@H]2O[C@H](COCc3ccccc3)[C@@H](O)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)[C@H]1COCc1ccccc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 94.2 %

Procedure:
The compound (1.57 g, 1.70 mmol) synthesized in Example 19 (19a) was dissolved in methanol (30 mL) and potassium carbonate (235 mg, 1.70 mmol) was added thereto, followed by stirring of the mixture at room temperature for 14 hours. The reaction mixture was diluted with ethyl acetate (10 mL) and the mixture was washed with saturated aqueous sodium hydrogencarbonate (10 mL) and saturated brine (10 mL). After the organic layer was dried with anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was purified using silica gel flash column chromatography (hexane:ethyl acetate, 3:1, V/V) to obtain the desired title compound (1.41 g, 94.0%) as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([CH2:12][CH:13]=[CH2:14])[C:9](O)=[O:10])=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:18])=O>CN(C)C=O.ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([CH2:12][CH:13]=[CH2:14])[C:9]([Cl:18])=[O:10])=[CH:4][CH:3]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: C=CC[C@H](C(=O)O)c1ccc(F)cc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: C=CC[C@H](C(=O)Cl)c1ccc(F)cc1
Reaction time: 2 h

Procedure:
Combine (S)-2-(4-fluorophenyl)pent-4-enoic acid (3.61 g, 18.6 mmol), dichloromethane (20 mL), and dimethylformamide (2 drops). Add oxalyl chloride (1.94 mL, 22.3 mmol). After 2 hours, evaporate in vacuo to give (S)-2-(4-fluorophenyl)pent-4-enoyl chloride. Combine with toluene (10 mL) and slowly add, with vigorous stirring, to a cooled (ice bath) aqueous solution of methylamine (4 mL, 40%). After 1 hour, partition the reaction mixture between water and dichloromethane. Separate the layers, extract the organic layer with a saturated aqueous sodium bicarbonate solution. Dry the organic over MgSO4, filter, and evaporate in vacuo to give a residue. Triturate the residue with hexane to give a solid. Collect the solid by filtration and dry to give (S)-2-(4-fluorophenyl)pent-4-enoic acid, N-methyl amide: mp; 104-105° C. Rf=0.42 (silica gel, 50% ethyl acetate/hexane).
Reaction SMILES: [CH3:1][N:2]([CH:10]1[CH2:15][CH2:14][C:13]([C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([NH:25][C:26]([C:28]4[S:29][CH:30]=[CH:31][CH:32]=4)=[NH:27])[CH:23]=3)[NH:18][CH:17]=2)=[CH:12][CH2:11]1)C(=O)OC(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][NH:2][CH:10]1[CH2:15][CH2:14][C:13]([C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([NH:25][C:26]([C:28]4[S:29][CH:30]=[CH:31][CH:32]=4)=[NH:27])[CH:23]=3)[NH:18][CH:17]=2)=[CH:12][CH2:11]1
Reactant: CN(C(=O)OC(C)(C)C)C1CC=C(c2c[nH]c3ccc(NC(=N)c4cccs4)cc23)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNC1CC=C(c2c[nH]c3ccc(NC(=N)c4cccs4)cc23)CC1
Reaction time: 1 h
Yield: 73.5 %

Procedure:
A solution of compound 99 (0.35 g, 0.776 mmol) was treated with 20% TFA in CH2Cl2 (20 mL) at 0° C. and stirring was continued for 1 h at the same temperature. The solvent was evaporated and crude was diluted with 10% aq. NH3 (15 mL) and product was extracted into CH2Cl2 (3×20 mL). The combined CH2Cl2 layer was washed with brine (10 mL) and dried (Na2SO4). The solvent was evaporated and the crude product was purified by column chromatography (2 M NH3 in methanol: CH2Cl2, 1:9) to obtain compound 100 (0.2 g, 74%) as a solid. mp 167-169° C.; 1H NMR (DMSO-d6) δ: 1.39-1.47 (m, 2H), 1.88-1.96 (m, 3H), 2.33 (s, 3H), 2.40-2.46 (m, 1H), 2.57-2.61 (m, 1H), 6.01 (s, 1H), 6.19 (brs, 2H), 6.65 (dd, 1H, J=1.5, 8.2 Hz), 7.09 (dd, 1H, J=4.2, 4.9 Hz), 7.20 (s, 1H), 7.28-7.31 (m, 2H), 7.59 (d, 1H, J=4.2 Hz), 7.71 (d, 1H, J=3.3 Hz), 10.87 (s, 1H); ESI-MS m/z (%): 351 (MH+, 66), 320 (54), 160 (63), 119 (100); ESI-HRMS calculated for C20H23N4S (MH+), Calculated: 351.1654; Observed: 351.1637.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:3]=1[C:4]([NH:6][C:7]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[O:9][N:8]=1)=[O:5].[CH3:24]I>C[O-].[Na+]>[Cl:1][C:2]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:3]=1[C:4]([N:6]([CH3:24])[C:7]1[CH:11]=[C:10]([C:12]2[CH:13]=[CH:14][C:15]([Cl:18])=[CH:16][CH:17]=2)[O:9][N:8]=1)=[O:5]
Reactant: CI
Reactant: O=C(Nc1cc(-c2ccc(Cl)cc2)on1)c1c(Cl)cccc1Cl
Agent: C[O-]
Agent: [Na+]
Product: CN(C(=O)c1c(Cl)cccc1Cl)c1cc(-c2ccc(Cl)cc2)on1
Reaction time: 0.25 h

Procedure:
2,6-Dichloro-N-(5-(4-chlorophenyl)-3-isoxazolyl)benzamide (1 gram prepared according to the teaching of synthesis route III and Example 15) and sodium methoxide (160 milligrams in 100 ml. methanol) were placed in a reaction vessel and stirred for about 15 minutes. Excess methyl iodide was added and the reaction mixture was then heated to reflux for 4 hours. Upon cooling a solid formed which was filtered and then recrystallized from ethanol. NMR analysis confirmed that the final product was a mixture of exo- and endo-alkylated isoxazole, m.p.=175°-178° C.
Reaction SMILES: [C:1]1([C:7]2[C:12]([NH2:13])=[CH:11][CH:10]=[CH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.C([BH3-])#N.[Na+].[CH3:19][O:20][C:21]1[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=1[CH:23]=O>CO>[CH3:19][O:20][C:21]1[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=1[CH2:23][NH:13][C:12]1[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[N:8][CH:9]=[CH:10][CH:11]=1
Reactant: COc1ccccc1C=O
Reactant: Nc1cccnc1-c1ccccc1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: COc1ccccc1CNc1cccnc1-c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.4 %

Procedure:
Under a nitrogen atmosphere, in a round-bottom flask were placed 500 mg (2.9 mmol) of 2-phenyl-3-aminopyridine, 10 mL of methanol and 1 g of 3A molecular sieves. The pH of the system was adjusted to ca. 4.5, using methanol saturated with HCl , and 190 mg (2.9 mmol) of sodium cyanoborohydride was added to the system. The pH of the system was adjusted to 4.5, 474 mg (3.5 mmol) of 2-methoxybenzaldehyde was added and the mixture was stirred at room temperature overnight. The mixture was filtered through (Celite®) and the filtrate was concentrated. The residue was partitioned between CH2Cl2 and saturated aqueous sodium bicarbonate, the layers were separated and the aqueous phase was extracted with three portions of CH2Cl2. The combined organic fractions were dried (Na2SO4) and concentrated with a rotary evaporator. The crude material was purified by flash column chromatography to obtain 475 mg of 3-(2-methoxybenzylamino)-2-phenylpyridine. Mp. 128°-129° C.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[S:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[C:18]([OH:20])=[O:19].[I:21]N1C(=O)CCC1=O>C1COCC1>[I:21][C:17]1[S:13][C:14]([C:18]([OH:20])=[O:19])=[CH:15][CH:16]=1
Reactant: O=C(O)c1cccs1
Reactant: O=C1CCC(=O)N1I
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: O=C(O)c1ccc(I)s1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 10.9 mL (78.0 mmol) of freshly distilled diisopropylamine in 150 mL of THF under argon at -78° C. was added 48.7 mL (78.0 mmol) of 1.6 M n-BuLi in hexanes to give a pale yellow solution which was allowed to stir at -78° C. for 10 min when 5.0 g (39.0 mmol) of 2-thiophenecarboxylic acid in 31 mL of THF was added dropwise over 10 min to give a grey-white suspension. The metallation was allowed to proceed for 30 min when 8.77 g (39.0 mmol) of N-iodosuccinimide in 25 mL of THF was added very rapidly to give an orange-yellow solution which was allowed to gradually warm to 0° C. After 0.5 h at 0° C., the brown-yellow mixture was quenched with water, diluted with ether and made acidic by the addition of solid citric acid to give a very dark brown-orange solution. The organic layer was separated and washed with water, saturated NaHSO3, brine, dried over MgSO4 and evaporated to provide 9.5 g (96%) of title acid as a brown-yellow solid which was used directly in the following reaction.
Reaction SMILES: [C:1]1(O)([C:9]2([CH:14]3CCCC3)CCCC2)[CH2:5][CH2:4][CH:3](O)[C:2]1([OH:8])[OH:7].[CH:20]1([C:25]2([CH:30]3[CH2:34][CH2:33][CH2:32][CH2:31]3)[CH2:29][CH2:28][CH2:27][CH2:26]2)[CH2:24][CH2:23][CH2:22][CH2:21]1>>[C:2]([OH:7])(=[O:8])[C:3]1[CH:4]=[CH:5][CH:1]=[CH:9][CH:14]=1.[C:2]([OH:7])(=[O:8])[C:3]1[CH:4]=[CH:5][CH:1]=[CH:9][CH:14]=1.[C:2]([OH:7])(=[O:8])[C:3]1[CH:4]=[CH:5][CH:1]=[CH:9][CH:14]=1.[C:2]([OH:7])(=[O:8])[C:3]1[CH:4]=[CH:5][CH:1]=[CH:9][CH:14]=1.[C:2]([OH:7])(=[O:8])[C:3]1[CH:4]=[CH:5][CH:1]=[CH:9][CH:14]=1.[C:2]([OH:7])(=[O:8])[C:3]1[CH:4]=[CH:5][CH:1]=[CH:9][CH:14]=1.[CH:30]1([C:25]2([CH:20]3[CH2:21][CH2:22][CH2:23][CH2:24]3)[CH2:29][CH2:28][CH2:27][CH2:26]2)[CH2:31][CH2:32][CH2:33][CH2:34]1
Reactant: OC1CCC(O)(C2(C3CCCC3)CCCC2)C1(O)O
Agent: C1CCC(C2(C3CCCC3)CCCC2)C1
Product: O=C(O)c1ccccc1

Procedure:
Using the ter-cyclopentane tetra-ol synthesized as described in Example 5, a ter-cyclopentane hexa-benzoate was prepared in order to determine the solution structure (i.e., symmetry) of the ter-cyclopentane structure. The ter-cyclopentane hexa-benzoate was prepared according to the synthesis scheme below.
Reaction SMILES: [C:1]1([CH:11]=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[OH:13][C:14]1[C:15]([C:24]([NH:26][NH2:27])=[O:25])=[CH:16][C:17]2[C:22]([CH:23]=1)=[CH:21][CH:20]=[CH:19][CH:18]=2>>[C:1]1([CH:11]=[N:27][NH:26][C:24]([C:15]2[C:14]([OH:13])=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=2)=[O:25])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=Cc1cccc2ccccc12
Reactant: NNC(=O)c1cc2ccccc2cc1O
Product: O=C(NN=Cc1cccc2ccccc12)c1cc2ccccc2cc1O
Yield: 76 %

Procedure:
Following the general procedure of Example 1, condensation of 1naphthaldehyde and 3-hydroxy-2-naphthoic hydrazide gave a pale yellow solid (76%): mp 214° C.; 1H NMR d 11.73 (br s, 1 H), 11.05 (br s, 1 H), 8.72 (s, 1 H), 8.52 (d, 1 H, J=8.4 Hz), 8.13 (s, 1 H), 7.60-6.80 (m, 11 H); 13C NMR d 164.00, 154.31, 148.56, 135.99, 133.57, 130.80, 130.40. 130.30, 129.48, 128.81, 128.78, 128.29, 128.12, 127.37, 126.85, 126.31. 125.89, 125.54, 124.39, 123.84, 120.13, 110.75; HRMS Calcd for C22H16N2O2 :340.1212, found 340.1208; Anal. (C22H16N2O2) C, H, N.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:10][C:11](=O)[CH:12]([CH3:14])[CH3:13])=[CH:4][CH:3]=1.[NH2:23][CH2:24][CH2:25][C@H:26]1[O:31][C:30]2([CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]2)[O:29][C@@H:28]([CH2:37][C:38]([O:40][C:41]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)([CH3:43])[CH3:42])=[O:39])[CH2:27]1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:23]([CH2:24][CH2:25][C@H:26]3[O:31][C:30]4([CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]4)[O:29][C@@H:28]([CH2:37][C:38]([O:40][C:41]([C:44]4[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=4)([CH3:43])[CH3:42])=[O:39])[CH2:27]3)[C:11]([CH:12]([CH3:14])[CH3:13])=[CH:10][C:9]=2[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:4][CH:3]=1
Reactant: CC(C)C(=O)CC(C(=O)c1ccc(F)cc1)c1ccccc1
Reactant: CC(C)(OC(=O)C[C@H]1C[C@@H](CCN)OC2(CCCCC2)O1)c1ccccc1
Product: CC(C)c1cc(-c2ccccc2)c(-c2ccc(F)cc2)n1CC[C@@H]1C[C@H](CC(=O)OC(C)(C)c2ccccc2)OC2(CCCCC2)O1

Procedure:
According to the same method as in Example 4-1, the title compound was synthesized using 1-(4-fluorophenyl)-5-methyl-2-phenyl-1,4-hexanedione and 2-phenylpropan-2-yl 2-((2R,4R)-4-(2-aminoethyl)-1,5-dioxaspiro[5.5]undecan-2-yl)acetate.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[C:12]2[N:13]([N:17]=[C:18]([NH2:20])[N:19]=2)[CH:14]=[CH:15][CH:16]=1)(=[O:4])=[O:3].Br[C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]2)=[CH:24][CH:23]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[C:12]2[N:13]([N:17]=[C:18]([NH:20][C:22]3[CH:23]=[CH:24][C:25]([N:28]4[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]4)=[CH:26][CH:27]=3)[N:19]=2)[CH:14]=[CH:15][CH:16]=1)(=[O:3])=[O:4]
Reactant: CN1CCN(c2ccc(Br)cc2)CC1
Reactant: CS(=O)(=O)c1ccccc1-c1cccn2nc(N)nc12
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: CN1CCN(c2ccc(Nc3nc4c(-c5ccccc5S(C)(=O)=O)cccn4n3)cc2)CC1

Procedure:
8-(2-Methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine was prepared from 8-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (0.50 g, 2.3 mmol) and 2-(methylsulfonyl)phenylboronic acid (0.56 g, 2.8 mmol) in a manner analogous to Step 2c. The reaction product was isolated as a pale yellow solid (0.249 g, 37%). 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 8.56 (d, J=6.6 Hz, 1H), 8.10 (d, J=7.8 Hz, 1H), 7.79 (t, J=7.6 Hz, 1H), 7.73 (d, J=7.7 Hz, 1H), 7.48 (d, J=7.3 Hz, 1H), 7.36 (d, J=7.1 Hz, 1H), 6.93 (d, J=6.9 Hz, 1H), 5.99 (s, 2H), 3.16 (s, 3H). MS=289 (MH)+. 66b) [8-(2-Methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[4-(4-methyl-piperazin-1-yl)-phenyl]-amine was prepared from 8-(2-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (75.0 mg, 0.260 mmol) and 1-(4-bromo-phenyl)-4-methyl-piperazine (80.0 mg, 0.314 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (30.0 mg, 0.0549 mmol) as the ligand in a manner analogous to Step 2d. The title compound was isolated as a yellow foam (0.067 g, 56%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.47 (d, J=6.6 Hz, 1H), 8.24 (d, J=7.7 Hz, 1H), 7.74 (t, J=7.0 Hz, 1H), 7.67 (t, J=7.4 Hz, 1H), 7.47 (t, J=8.0 Hz, 2H), 7.41 (d, J=7.8 Hz, 2H), 6.99-6.91 (m, 3H), 6.57 (s, 1H), 3.17-3.12 (m, 4H), 2.97 (s, 3H), 2.61-2.56 (m, 4H), 2.36 (s, 3H). MS=463 (MH)+.
Reaction SMILES: CS(Cl)(=O)=O.O[CH2:7][CH2:8][CH2:9][NH:10][C:11]([C:13]1[CH:21]=[C:20]2[C:16]([CH:17]=[CH:18][NH:19]2)=[C:15]([Br:22])[CH:14]=1)=[O:12].C(N(CC)CC)C.[NH:30]1[CH2:34][CH2:33][CH2:32][C@H:31]1[CH2:35][OH:36]>C1COCC1>[OH:36][CH2:35][C@@H:31]1[CH2:32][CH2:33][CH2:34][N:30]1[CH2:7][CH2:8][CH2:9][NH:10][C:11]([C:13]1[CH:21]=[C:20]2[C:16]([CH:17]=[CH:18][NH:19]2)=[C:15]([Br:22])[CH:14]=1)=[O:12]
Reactant: OC[C@@H]1CCCN1
Reactant: O=C(NCCCO)c1cc(Br)c2cc[nH]c2c1
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(NCCCN1CCC[C@H]1CO)c1cc(Br)c2cc[nH]c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.3 %

Procedure:
A solution methanesulfonyl chloride (0.13 mL, 1.68 mmol) in THF (1 mL) was added to a solution of 4-bromo-1H-indole-6-carboxylic acid (3-hydroxy-propyl)-amide (0.50 g, 1.68 mmol) and triethylamine (0.25 mL, 1.84 mmol) in tetrahydrofuran (5 mL) at 0° C. and slowly warmed to room temperature over 30 minutes. (S)-(+)-2-pyrrolidinemethanol (1.0 g, 9.88 mmol) was added and stirred at room temperature overnight. The reaction was concentrated in vacuo and purified by column chromatography (5% methanol in dichloromethane) to yield 0.50 g (78%) of (S)-4-bromo-1H-indole-6-carboxylic acid [3-(2-hydroxymethyl-pyrrolidin-1-yl)-propyl]-amide. Mass spectrum (LCMS, ESI pos.): Calcd for C17H22BrN3O2 379.09. Found 380.0; (M+H).
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[Cl:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[CH:12]=[N:13][OH:14]>CN(C)C=O.C(OC)(C)(C)C>[Cl:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12]([Cl:1])=[N:13][OH:14]
Reactant: O=C1CCC(=O)N1Cl
Reactant: ON=Cc1ccccc1Cl
Solvent: CN(C)C=O
Solvent: COC(C)(C)C
Product: ON=C(Cl)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.6 %

Procedure:
N-Chlorosuccinimide (56.1 g) was added slowly to a 0° C. solution of the compound prepared in Example 4 (65.4 g) in N,N-dimethylformamide (1.2 L). The reaction was stirred at room temperature overnight and then diluted with ice water and methyl tert-butyl ether. The layers were separated and the aqueous phase was extracted once more with methyl tert-butyl ether. The organic phases were combined, washed with brine, dried over anhydrous magnesium sulfate and concentrated to obtain the title compound (79.5 g) having the following physical data.