Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:7]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([O:18][C:19]([F:22])([F:21])[F:20])=[CH:14][CH:13]=3)[N:9]([CH2:23][C:24]3[CH:32]=[CH:31][C:27]([C:28](O)=[O:29])=[CH:26][CH:25]=3)[N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.Cl.[CH2:53]([O:55][C:56](=[O:61])[C@H:57]([CH2:59][NH2:60])N)[CH3:54]>CN(C=O)C.C(Cl)CCl>[CH:1]1([C:7]2[CH:11]=[C:10]([C:12]3[CH:13]=[CH:14][C:15]([O:18][C:19]([F:21])([F:20])[F:22])=[CH:16][CH:17]=3)[N:9]([CH2:23][C:24]3[CH:32]=[CH:31][C:27]([C:28]([NH:60][CH2:59][CH2:57][C:56]([O:55][CH2:53][CH3:54])=[O:61])=[O:29])=[CH:26][CH:25]=3)[N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)c1ccc(Cn2nc(C3CCCCC3)cc2-c2ccc(OC(F)(F)F)cc2)cc1
Reactant: CCOC(=O)[C@@H](N)CN
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CCNC(=O)c1ccc(Cn2nc(C3CCCCC3)cc2-c2ccc(OC(F)(F)F)cc2)cc1
Reaction time: 16 h

Procedure:
A solution of 66.7 mg product from Step A Example 6, 34.5 mg EDC, 24.3 mg HOBt in 0.5 mL DMF was stirred at room temperature for 30 minutes. DIEA (31 μL) and β-amino-alanine ethyl ester hydrochloride (27.6 mg) were added and the mixture stirred for additional 16 hours. The solvent was removed under reduced pressure. The title compound was isolated as a white solid by preparative HPLC using 60˜80% MeCN gradient over 10 minutes at 8.0 mL per minute with 0.1% TFA on a 9.4×250 mm SB-C18 Zorbax column followed by lyophilization. 1H NMR (CD3OD, 600 MHz) δ 7.68 (d, J=8.4 Hz, 2H), 7.39˜7.42 (m, 2H), 7.28 (d, J=8.1 Hz, 2H), 6.99 (d, J=8.3 Hz, 2H), 6.31 (s, 1H), 5.37 (s, 2H), 4.11 (q, J=7.1 Hz, 2H), 3.59 (t, J=6.8 Hz, 2H), 2.66 (tt, J=11.6 & 3.5 Hz, 1H), 2.61 (t, J=6.8 Hz, 2H), 1.96˜2.00 (m, 2H), 1.80˜1.84 (m, 2H), 1.71˜1.75 (m, 1H), 1.45˜1.52 (m, 2H), 1.37˜1.45 (m, 2H), 1.25˜1.33 (m, 1H), 1.21 (t, J=7.1 Hz, 3H). LC-MS: 2.44 min. (M+H=544.4).
Reaction SMILES: C[O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][C:4]=1[C:12]([F:15])([F:14])[F:13].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>>[OH:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][C:4]=1[C:12]([F:13])([F:14])[F:15]
Reactant: COc1ccc(C(=O)O)cc1C(F)(F)F
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Product: O=C(O)c1ccc(O)c(C(F)(F)F)c1
Temperature: 180 °C

Procedure:
10.0 g (45.4 mmol) 4-methoxy-3-trifluoromethyl-benzoic acid and 75 g pyridinium-hydrochloride were mixed well and then heated to 180° C. under a nitrogen atmosphere for 5 h. The reaction mixture was poured onto 1 L 10% citric acid solution and extracted with 50 mL EtOAc. The organic phase was washed with 1 L water and dried over Na2SO4. After the desiccant and solvent had been eliminated the product was further reacted without purification.
Reaction SMILES: [CH2:1]([N:6]1[C:14]2[N:13]=[CH:12][NH:11][C:10]=2[C:9](=[O:15])[N:8]2[N:16]=[N:17][N:18]=[C:7]12)[CH2:2][CH2:3][CH2:4][CH3:5].C1C(=O)N([Br:26])C(=O)C1>C1COCC1>[Br:26][C:12]1[NH:11][C:10]2[C:9](=[O:15])[N:8]3[N:16]=[N:17][N:18]=[C:7]3[N:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[C:14]=2[N:13]=1
Reactant: CCCCCn1c2nc[nH]c2c(=O)n2nnnc12
Reactant: O=C1CCC(=O)N1Br
Solvent: C1CCOC1
Product: CCCCCn1c2nc(Br)[nH]c2c(=O)n2nnnc12
Temperature: 70 °C
Reaction time: 1 h
Yield: 13.8 %

Procedure:
The mixture of 4-pentyl-4,7-dihydro-8H-tetrazolo[1,5-a]purin-8-one (94.6 mg, 0.38 mmol) and NBS (75 mg, 0.42 mmol) in THF (20 ml) was stirred at 70° C. for 1 hour. After evaporation of solvent, the residue was purified by preparative LC-MS to yield the desired product (17.1 mg, 13.7%). LCMS calculated for C10H13BrN7O (M+H): 326.0. found: 326.0.
Reaction SMILES: [OH:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[O:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH2:29][CH2:30][N:31]([CH2:33][CH2:34][CH2:35]Cl)[CH3:32])[CH:24]=[CH:25][C:26]=1[O:27][CH3:28]>CN(C)C=O>[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH2:29][CH2:30][N:31]([CH2:33][CH2:34][CH2:35][O:1][C:2]2[CH:6]=[C:5]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)[O:4][N:3]=2)[CH3:32])[CH:24]=[CH:25][C:26]=1[O:27][CH3:28]
Reactant: COc1ccc(CCN(C)CCCCl)cc1OC
Reactant: Oc1cc(-c2ccccc2)on1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(CCN(C)CCCOc2cc(-c3ccccc3)on2)cc1OC
Temperature: 100 °C
Reaction time: 4 h
Yield: 56.1 %

Procedure:
3.5 g of 3-hydroxy-5-phenyl-isoxazole were dissolved in 100 ml of dimethylformamide. The solution was reacted with 3 g of finely powdered potassium carbonate and the reaction mixture was heated for 15 minutes at 100° C. in a nitrogen atmosphere. Then 5.8 g of 3-[N-(2-(3,4-dimethoxyphenyl)-ethyl)-N-methylamino]-propyl chloride were added batchwise. The reaction mixture was stirred for 4 hours at 100° C., after which the salts that formed were filtered off, the filtrate was concentrated to dryness, and the residue dissolved in methyl-tert-butyl ether. The solution was then washed with aqueous sodium carbonate solution, dried with magnesium sulfate, and concentrated to dryness. The remaining crude oily title compound that was left as a residue was purified by flash chromatography using ethyl acetate as the eluent. 4.75 g of the title compound were obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]=[C:16]3[S:20][C:19](=[O:21])[NH:18][C:17]3=[O:22])[CH:10]=2)=[O:7])=[CH:4][CH:3]=1.[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1.CCCCCC>N1C=CC=CC=1.CCOC(C)=O>[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([S:32]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:6]([NH:8][C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]=[C:16]4[S:20][C:19](=[O:21])[NH:18][C:17]4=[O:22])[CH:10]=3)=[O:7])=[CH:23][CH:24]=2)(=[O:34])=[O:33])=[CH:28][CH:27]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: Nc1ccc(C(=O)Nc2cccc(C=C3SC(=O)NC3=O)c2)cc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: c1ccncc1
Product: O=C1NC(=O)C(=Cc2cccc(NC(=O)c3ccc(NS(=O)(=O)c4ccc(Cl)cc4)cc3)c2)S1

Procedure:
4-Amino-N-[3-(2,4-dioxo-thiazolidin-5-ylidenemethyl)-phenyl]-benzamide was dissolved in pyridine and treated with 4-chloro-benzenesulfonyl chloride in pyridine at 60° C. for 12 h. The solution-was cooled and diluted with EtOAc then washed with 10% aq. NaHSO4 followed by saturated aq. NaCl. The organic phase was separated, dried over Na2SO4 and concentrated under reduced pressure to give an oil. Trituration with hexane gave pure product.
Reaction SMILES: [OH-].[Na+].[C:3]([OH:8])(=[O:7])[C:4]([OH:6])=[O:5].[F:9][C:10]1[CH:11]=[C:12]([CH:48]=[CH:49][CH:50]=1)[CH2:13][O:14][C:15]1[CH:47]=[CH:46][C:18]([O:19][CH:20]2[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]3[CH:30]=[N:31][CH:32]=[C:33]([N:35]4[CH2:40][CH2:39][CH:38]([C:41]([O:43]CC)=[O:42])[CH2:37][CH2:36]4)[CH:34]=3)=[O:27])[CH2:22][CH2:21]2)=[CH:17][CH:16]=1.Cl>C1COCC1>[C:3]([OH:8])(=[O:7])[C:4]([OH:6])=[O:5].[F:9][C:10]1[CH:11]=[C:12]([CH:48]=[CH:49][CH:50]=1)[CH2:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([O:19][CH:20]2[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]3[CH:34]=[C:33]([N:35]4[CH2:40][CH2:39][CH:38]([C:41]([OH:43])=[O:42])[CH2:37][CH2:36]4)[CH:32]=[N:31][CH:30]=3)=[O:27])[CH2:22][CH2:21]2)=[CH:46][CH:47]=1
Reactant: CCOC(=O)C1CCN(c2cncc(OC(=O)N3CCC(Oc4ccc(OCc5cccc(F)c5)cc4)CC3)c2)CC1
Agent: Cl
Agent: O=C(O)C(=O)O
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(O)C1CCN(c2cncc(OC(=O)N3CCC(Oc4ccc(OCc5cccc(F)c5)cc4)CC3)c2)CC1
Temperature: 60 °C
Reaction time: 5 h
Yield: 40.4 %

Procedure:
An aqueous 1 M sodium hydroxide solution (3.24 ml) was added to a THF (10 ml) solution containing 5-[4-(ethoxycarbonyl)piperidin-1-yl]pyridin-3-yl 4-{4-[(3-fluorobenzyl)oxy]phenoxy}piperidine-1-carboxylate oxalate (240 mg), followed by stirring at 60° C. for 5 hours. 1 M hydrochloric acid (3.24 ml) was added to the reaction solution and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform:methanol=10:1 (v/v)). The resulting oil was dissolved in ethanol/water, then oxalic acid (24 mg) was added thereto for crystallization to obtain 1-(5-{[(4-{4-[(3-fluorobenzyl)oxy]phenoxy}piperidin-1-yl)carbonyl]oxy}pyridin-3-yl)piperidine-4-carboxylic acid oxalate (93 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:11])=[CH:4][CH:3]=1.[NH2:12][C:13]1[S:14][CH:15]=[C:16]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)[N:17]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([NH:12][C:13]1[S:14][CH:15]=[C:16]([C:18]2[CH:19]=[CH:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=2)[N:17]=1)=[O:9]
Reactant: COc1ccc(-c2csc(N)n2)cc1
Reactant: O=C(O)c1cc(Cl)ccc1O
Product: COc1ccc(-c2csc(NC(=O)c3cc(Cl)ccc3O)n2)cc1
Yield: 16.4 %

Procedure:
Using 5-chlorosalicylic acid and 2-amino-4-(4-methoxyphenyl)thiazole as the raw materials, the same operation as the Example 16 gave the title compound.
Reaction SMILES: [Br:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][N:5]=[C:4]([CH3:10])[CH:3]=1.C1C(=O)N([Br:18])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl.CCOC(C)=O>[Br:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][N:5]=[C:4]([CH2:10][Br:18])[CH:3]=1
Reactant: COc1cnc(C)cc1Br
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: ClC(Cl)(Cl)Cl
Product: COc1cnc(CBr)cc1Br

Procedure:
A solution of 4-bromo-5-methoxy-2-methyl-pyridine (Step AL3) (1.9 g, 9.4 mmol), NBS (1.8 g, 9.9 mmol), AIBN (15 mg, 0.094 mmol) and benzoyl peroxide (23 mg, 0.094 mmol) in CCl4 (2 mL) was stirred at rt for 18 h. The reaction mixture was dissolved in EtOAc and extracted with a saturated aqueous solution of NaHCO3, washed with brine, dried (Na2SO4), filtered and concentrated. The crude product was purified by silica gel column chromatography (hexane/EtOAc, 100:0→70:30). ESI-MS: tR=0.90 min, [M+H]+ 281.9 (LC-MS 1).
Reaction SMILES: Cl.[Cl:2][C:3]1[C:8]([N:9]2[C:13]([CH3:14])=[C:12]([N:15]3[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24](C)([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]3)[N:11]=[N:10]2)=[CH:7][CH:6]=[CH:5][N:4]=1>O1CCOCC1>[Cl:2][C:3]1[C:8]([N:9]2[C:13]([CH3:14])=[C:12]([N:15]3[CH2:20][CH2:19][N:18]([C:21]([O:23][CH:24]([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]3)[N:11]=[N:10]2)=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: Cc1c(N2CCN(C(=O)OC(C)(C)C)CC2)nnn1-c1cccnc1Cl
Agent: Cl
Solvent: C1COCCO1
Product: Cc1c(N2CCN(C(=O)OC(C)C)CC2)nnn1-c1cccnc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 69.2 %

Procedure:
4N Hydrochloric acid solution in dioxane (10 ml) was added to 3 mg of tert-Butyl 4-[1-(2-chloropyridin-3-yl)-5-methyl-1H-[1,2,3]triazol-4-yl)-piperazine-1-carboxylate prepared in Example 34, the mixture was stirred at room temperature for 3 hours, the solvent was evaporated in vacuo, the residue was dissolved in 1 ml of chloroform and, in a nitrogen atmosphere, 0.03 ml of isopropyl chloroformate and 0.06 ml of triethylamine were added thereto and the mixture was stirred at room temperature for 2 hours. After the solvent was evaporated in vacuo, the resulting residue was purified by a preparative thin-layer silica gel chromatography (chloroform:methanol=9:1) to give 2 mg of the title compound as a white solid.
Reaction SMILES: [N:1]1([C:5]([C:7]2[CH:40]=[CH:39][C:10]([O:11][C:12]3[CH:13]=[C:14]([CH:24]=[C:25]([O:27][C@@H:28]([CH3:38])[CH2:29][O:30][Si](C(C)(C)C)(C)C)[CH:26]=3)[C:15]([NH:17][C:18]3[CH:23]=[N:22][CH:21]=[CH:20][N:19]=3)=[O:16])=[C:9]([Cl:41])[CH:8]=2)=[O:6])[CH2:4][CH2:3][CH2:2]1.C(=O)(O)[O-].[Na+]>CO.Cl>[N:1]1([C:5]([C:7]2[CH:40]=[CH:39][C:10]([O:11][C:12]3[CH:13]=[C:14]([CH:24]=[C:25]([O:27][C@@H:28]([CH3:38])[CH2:29][OH:30])[CH:26]=3)[C:15]([NH:17][C:18]3[CH:23]=[N:22][CH:21]=[CH:20][N:19]=3)=[O:16])=[C:9]([Cl:41])[CH:8]=2)=[O:6])[CH2:4][CH2:3][CH2:2]1
Reactant: C[C@@H](CO[Si](C)(C)C(C)(C)C)Oc1cc(Oc2ccc(C(=O)N3CCC3)cc2Cl)cc(C(=O)Nc2cnccn2)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: C[C@@H](CO)Oc1cc(Oc2ccc(C(=O)N3CCC3)cc2Cl)cc(C(=O)Nc2cnccn2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70.1 %

Procedure:
A mixture of 3-[4-(azetidin-1-ylcarbonyl)-2-chlorophenoxy]-5-((1S)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-methylethoxy)-N-pyrazin-2-ylbenzamide (37 mg, 0.062 mmol) in methanol (0.5 mL) and 3.5M hydrochloric acid (0.018 mL) was stirred for 30 mins at RT. The solution was taken to pH 6 with saturated aqueous sodium bicarbonate solution and the volatiles were removed in vacuo. The residue was taken into ethyl acetate (10 mL) and washed with water (2 mL), brine (2 mL), dried (MgSO4), filtered and the solvents removed in vacuo to give the crude product which was chromatographed on silica, eluting with 0-10% methanol in ethyl acetate, to give the desired compound as a white foam (21 mg).
Reaction SMILES: [C:1]([N:8]1[CH:12]=[CH:11][N:10]=[CH:9]1)([N:3]1[CH:7]=[CH:6]N=[CH:4]1)=[O:2].N1C2[C:17](=[CH:18][CH:19]=CC=2)[CH2:16][CH2:15][CH2:14]1>O1CCCC1>[N:8]1([C:1]([N:3]2[C:4]3[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:19][CH2:6][CH2:7]2)=[O:2])[CH:12]=[CH:11][N:10]=[CH:9]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: c1ccc2c(c1)CCCN2
Solvent: C1CCOC1
Product: O=C(N1CCCc2ccccc21)n1ccnc1

Procedure:
15.4 g of 1,1′-carbonyldimidazole, 125 ml of tetrahydrofuran and 9.43 ml of 1,2,3,4-tetrahydroquinoline are introduced into a 500 ml round-bottomed flask. The reaction medium is brought to reflux for 20 hours. The solvent is evaporated under reduced pressure and the residue is taken up in ethyl acetate and then washed with water. The organic phase is dried over sodium sulfate and the solvent is evaporated under reduced pressure to result in 16.04 g of 1-(1H-imidazol-1-ylcarbonyl)-1,2,3,4-tetrahydroquinoline.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][N:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[C:10](=[O:23])[C@@H:9]1[CH3:24])=O)(C)(C)C.Cl>O1CCOCC1>[CH3:24][C@@H:9]1[NH:8][CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][N:17]2[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]2)[C:10]1=[O:23]
Reactant: C[C@H]1C(=O)N(CCCN2CCCCC2)CCN1C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: C[C@@H]1NCCN(CCCN2CCCCC2)C1=O
Yield: 92.4 %

Procedure:
A solution of (S)-2-methyl-3-oxo-4-(3-piperidin-1-yl-propyl)-piperazine-1-carboxylic acid tert-butyl ester (1.07 g, 3.15 mmol) in 1,4-dioxane (10 ml) was treated at room temperature with hydrogen chloride solution (4 M in 1,4-dioxane, 2.4 ml, 9.6 mmol), then after 4 h the reaction mixture was partitioned between 2 M aq. sodium carbonate solution and dichloromethane. The organic layer was washed with brine, dried (MgSO4), filtered, and evaporated to afford the title compound (697 mg, 92%). Colorless gum, MS (ISP)=240.3 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[CH2:7][CH2:6]1.[C:19]1([N:25]=[C:26]=[O:27])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(O)C>O1CCCC1>[Cl:18][C:15]1[CH:14]=[CH:13][C:12]([CH2:11][N:8]2[CH2:9][CH2:10][N:5]([CH2:4][CH2:3][CH2:2][NH:1][C:26]([NH:25][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[O:27])[CH2:6][CH2:7]2)=[CH:17][CH:16]=1
Reactant: O=C=Nc1ccccc1
Reactant: NCCCN1CCN(Cc2ccc(Cl)cc2)CC1
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(NCCCN1CCN(Cc2ccc(Cl)cc2)CC1)Nc1ccccc1
Reaction time: 3 h
Yield: 21.4 %

Procedure:
A solution of 1-(3-aminopropyl)-4-(4-chlorobenzyl)-piperazine (2.0 g; 7.5 mmole) and phenyl isocyanate (1.6 g; 13.4 mmole) in tetrahydrofuran (5 ml) was stirred at room temperature for 30 minutes. Ethanol (5 ml) was added, and the reaction mixture was stirred for 3 hours and then concentrated under reduced pressure. The residue was crystallized from aqueous ethanol to provide crude product (2.7 g). Recrystallization from the same solvent yielded the title compound as colorless crystals (0.62 g; 21% yield), m.p. 135°-137° C.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH3:11][O:12][CH:13]1[CH2:18][CH2:17][CH:16]([CH:19]2[CH2:24][CH2:23][CH:22]([OH:25])[CH2:21][CH2:20]2)[CH2:15][CH2:14]1.[Cl-].[NH4+]>ClCCl.C(OCC)(=O)C.C(N(CC)CC)C>[CH3:11][O:12][CH:13]1[CH2:14][CH2:15][CH:16]([CH:19]2[CH2:24][CH2:23][C:22](=[O:25])[CH2:21][CH2:20]2)[CH2:17][CH2:18]1
Reactant: COC1CCC(C2CCC(O)CC2)CC1
Agent: O=C(Cl)C(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COC1CCC(C2CCC(=O)CC2)CC1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 62.9 %

Procedure:
A solution of oxalyl chloride (2.14 ml) in dichloromethane (80 ml) was cooled to −78° C. in nitrogen atmosphere, and a solution of dimethylsulfoxide (6 ml) in dichloromethane (6 ml) was added slowly and stirred for 10 minutes at −78° C. To the reaction mixture was added a solution of 4′-methoxy-1,1′-bi(cyclohexyl)-4-ol (2.6 g) in dichloromethane (26 ml) slowly to maintain the reaction temperature and stirred for 2.5 hours at −40° C. To the reaction mixture was added triethylamine (12.4 ml) slowly. Then the reaction mixture allowed to warm to room temperature. To the reaction mixture was added ammonium chloride solution and ethyl acetate. The organic layer was taken and dried over magnesium sulfate. The magnesium sulfate was filtered off, and the filtrate was concentrated under reduced pressure to give 4′-methoxy-1,1′-bi(cyclohexyl)-4-one (1.62 g).
Reaction SMILES: [N:1]#CBr.[F:4][C:5]1[CH:13]=[C:12]2[C:8]([C:9]([CH:14]3[CH2:20][CH:19]4[N:21]([CH3:22])[CH:16]([CH2:17][CH2:18]4)[CH2:15]3)=[N:10][NH:11]2)=[CH:7][CH:6]=1.C(=O)([O-])[O-].[K+].[K+]>C1COCC1.O>[C:22]([N:21]1[CH:19]2[CH2:18][CH2:17][CH:16]1[CH2:15][CH:14]([C:9]1[C:8]3[C:12](=[CH:13][C:5]([F:4])=[CH:6][CH:7]=3)[NH:11][N:10]=1)[CH2:20]2)#[N:1]
Reactant: CN1C2CCC1CC(c1n[nH]c3cc(F)ccc13)C2
Reactant: N#CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: N#CN1C2CCC1CC(c1n[nH]c3cc(F)ccc13)C2
Reaction time: 2 h
Yield: 22.5 %

Procedure:
Cyanogen bromide (2.75 g) was added in one portion to a suspension of 3-(6-fluoro-1H-indazol-3-yl)-8-methyl-8-azabicyclo[3.2.1]octane (4.90 g) and potassium carbonate (2.75 g) in 70 ml of THF at room temperature. The mixture was stirred for 2 hours, then diluted with water and the product was extracted into ethyl acetate. The organic solution was washed with brine, dried over MgSO4, filtered and concentrated to leave 3.4 g of crude solids. The solids were purified by flash chromatography over silica gel and recrystallized from ethanol to yield 1.15 g of the desired product, m.p. 182°-184° C.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([OH:12])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.C1(=O)O[CH2:16][CH2:15][O:14]1.O(C(C)(C)C)[K]>CN(C=O)C.[Cl-].[Na+].O>[NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([O:12][CH2:16][CH2:15][OH:14])[CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: O=C1OCCO1
Reactant: Nc1ccc2cccc(O)c2n1
Agent: CC(C)(C)O[K]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ccc2cccc(OCCO)c2n1
Temperature: 90 °C
Reaction time: 15 h
Yield: 27.7 %

Procedure:
A mixture of 2-amino-8-quinolinol (3.20 g, 20.0 mmol), ethylene carbonate (1.76 g, 20.0 mmol) and KO-t-Bu (2.24 g, 20.0 mmol) in DMF (20 mL) was stirred at 90° C. for 15 h. The mixture was poured into brine, extracted with EtOAc, dried (MgSO4), and concentrated under reduced pressure. The residue was purified by chromatography on silica gel using toluene/EtOAc/MeOH (50:50:2) as eluent to give 1.13 g (28%) of the title product as a solid. HRMS m/z calcd for C11H12N2O2 (M)+ 204.0899, found 204.0906.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]#[C:10][C:11]2[C:12]3[N:13]([CH:23]=[C:24]([CH3:26])[N:25]=3)[CH:14]=[CH:15][C:16]=2[NH:17]C(=O)OCC)=[CH:5][CH:4]=1.[K+].[Br-]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:17]=[C:16]3[C:11](=[C:12]4[N:25]=[C:24]([CH3:26])[CH2:23][N:13]4[CH:14]=[CH:15]3)[CH:10]=2)=[CH:5][CH:4]=1
Reactant: CCOC(=O)Nc1ccn2cc(C)nc2c1C#Cc1ccc(OC)cc1
Agent: [Br-]
Agent: [K+]
Product: COc1ccc(-c2cc3c4n(ccc-3n2)CC(C)=N4)cc1

Procedure:
From 25a (yield: 35%); mp 168° C.; IR (KBr) 3422, 3053, 2917, 2827, 1637, 1521, 1490, 1307, 1027 cm−1; 1H NMR (400 MHz, DMSO-d6) δ 2.30 (s, 3H), 3.80 (s, 3H), 6.93 (d, 1H, J=7.6 Hz), 7.01 (d, 1H, J=2.0 Hz), 7.03 (m, 2H), 7.49 (s, 1H), 7.77 (m, 2H), 8.02 (d, 1H, J=7.2 Hz), 11.83 (s, 1H); 13C NMR (100 MHz, DMSO-d6) δ 14.2, 55.2, 96.8, 100.5, 109.2, 114.2, 114.4, 120.3, 124.6, 126.0, 131.0, 135.8, 139.0, 140.8, 158.5. Anal. Calcd for C17H15N3O: C, 73.63; H, 5.45; N, 15.15. Found: C, 73.89; H, 5.65; N, 15.13.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:37])[CH2:4][N:5]([C:11]1[CH:16]=[C:15]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH:14]=[C:13]([OH:36])[CH:12]=1)[CH2:6][C:7]([O:9][CH3:10])=[O:8].Cl[CH2:39][CH2:40][CH2:41][CH2:42][C:43]1[CH:52]=[CH:51][C:50]2[C:45](=[CH:46][C:47]([O:61][CH2:62][C:63]3[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=3)=[C:48]([O:53][CH2:54][C:55]3[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=3)[CH:49]=2)[CH:44]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>CC(C)=O.CN(C=O)C>[CH3:1][O:2][C:3](=[O:37])[CH2:4][N:5]([CH2:6][C:7]([O:9][CH3:10])=[O:8])[C:11]1[CH:12]=[C:13]([O:36][CH2:39][CH2:40][CH2:41][CH2:42][C:43]2[CH:44]=[C:45]3[C:50](=[CH:51][CH:52]=2)[CH:49]=[C:48]([O:53][CH2:54][C:55]2[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=2)[C:47]([O:61][CH2:62][C:63]2[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=2)=[CH:46]3)[CH:14]=[C:15]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH:16]=1
Reactant: CCCCCCCCCCCCCCCCCCOc1cc(O)cc(N(CC(=O)OC)CC(=O)OC)c1
Reactant: ClCCCCc1ccc2cc(OCc3ccccc3)c(OCc3ccccc3)cc2c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: CCCCCCCCCCCCCCCCCCOc1cc(OCCCCc2ccc3cc(OCc4ccccc4)c(OCc4ccccc4)cc3c2)cc(N(CC(=O)OC)CC(=O)OC)c1
Yield: 49.3 %

Procedure:
A mixture of 1.5 g (2.88 mmol) of N-[3-hydroxy-5-(octadecyloxy)phenyl]-N-(2-methoxy-2-oxoethyl)glycine methyl ester, 1.24 g (2.88 mmol) of 2-(4-chlorobutyl)-6,7-bis(phenylmethoxy) naphthalene, 0.8 g (5.75 mmol) of potassium carbonate and 0.43 g (2.88 mmol) of sodium iodide in 50 ml of acetone and 10 ml of DMF was stirred at reflux under argon for 40 hours. The acetone was removed by distillation and 50 ml of DMF, 1.24 g of 2-(4-chlorobutyl)-6,7-bis(phenylmethoxy)naphthalene, 0.8 g of potassium carbonate and 0.43 g of sodium iodide was added and the mixture was stirred and heated at 85° for 4 days. The DMF was removed using an oil pump at 55°. The residue was extracted with methylene chloride, the extract was concentrated and the product was purified by HPLC using 20% ethyl acetate-hexane to give 1.3 g (49% yield) of N-(2 -methoxy-2-oxoethyl)-N-[3-(octadecyloxy)-5-[4-[2,3-bis(phenylmethoxy)-6-naphthalenyl]butoxy]phenyl]glycine methyl ester as a semisolid. The nmr and mass spectra were consistent with the structure.