Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C:5]1[C:13]2[N:12]=[C:11]([C:14](=[O:25])[NH:15][CH:16]3[CH2:21][CH2:20][N:19]([CH:22]([CH3:24])[CH3:23])[CH2:18][CH2:17]3)[N:10]([CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([O:33][CH3:34])[CH:28]=3)[C:9]=2[CH:8]=[CH:7][CH:6]=1)=[O:4].C[O:36][C:37]([C:39]1[C:47]2[N:46]([CH2:48][C:49]3[CH:54]=[CH:53][CH:52]=[C:51]([O:55][CH3:56])[CH:50]=3)[C:45]([C:57](=[O:68])[NH:58][CH:59]3[CH2:64][CH2:63][N:62]([CH:65]([CH3:67])[CH3:66])[CH2:61][CH2:60]3)=[N:44][C:43]=2[CH:42]=[CH:41][CH:40]=1)=[O:38].[Li+].[OH-].Cl>CO>[CH:22]([N:19]1[CH2:18][CH2:17][CH:16]([NH:15][C:14]([C:11]2[N:10]([CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([O:33][CH3:34])[CH:28]=3)[C:9]3[CH:8]=[CH:7][CH:6]=[C:5]([C:3]([OH:4])=[O:2])[C:13]=3[N:12]=2)=[O:25])[CH2:21][CH2:20]1)([CH3:24])[CH3:23].[CH:65]([N:62]1[CH2:63][CH2:64][CH:59]([NH:58][C:57]([C:45]2[N:46]([CH2:48][C:49]3[CH:54]=[CH:53][CH:52]=[C:51]([O:55][CH3:56])[CH:50]=3)[C:47]3[C:39]([C:37]([OH:38])=[O:36])=[CH:40][CH:41]=[CH:42][C:43]=3[N:44]=2)=[O:68])[CH2:60][CH2:61]1)([CH3:67])[CH3:66]
Reactant: COC(=O)c1cccc2nc(C(=O)NC3CCN(C(C)C)CC3)n(Cc3cccc(OC)c3)c12
Reactant: COC(=O)c1cccc2c1nc(C(=O)NC1CCN(C(C)C)CC1)n2Cc1cccc(OC)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: COc1cccc(Cn2c(C(=O)NC3CCN(C(C)C)CC3)nc3c(C(=O)O)cccc32)c1
Product: COc1cccc(Cn2c(C(=O)NC3CCN(C(C)C)CC3)nc3cccc(C(=O)O)c32)c1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
1.45 g (4.21 mmol) 2-(1-Isopropyl-piperidin-4-ylcarbamoyl)-1H-benzoimidazole-4-carboxylic acid methyl ester were dissolved in 45 mL DMF. Subsequently 698.2 mg (5.05 mmol) K2CO3 and 888.8 mg (4.42 mmol) 1-bromomethyl-3-methoxy-benzene were added and the resulting mixture was stirred for 2 h at 60° C. The solvent was distilled off. The residue was taken up in 300 mL ethyl acetate and washed once with a saturated NaHCO3-solution and with brine. The organic layer was dried over anhydrous MgSO4, concentrated under reduced pressure and purified by flash chromatography on silica gel using an ethyl acetate-methanol mixture as eluent to give 1.19 g of a 4:1-mixture of 2-(1-Isopropyl-piperidin-4-ylcarbamoyl)-1-(3-methoxy-benzyl)-1H-benzoimidazole-4-carboxylic acid methyl ester and 2-(1-Isopropyl-piperidin-4-ylcarbamoyl)-3-(3-methoxy-benzyl)-3H-benzoimidazole-4-carboxylic acid methyl ester. That mixture of isomers was dissolved in 100 mL MeOH. 12.8 mL (12.8 mmol) of a 1 M aqueous LiOH-solution were added and the resulting suspension was stirred for 3 h at 60° C. The mixture was acidified by the addition of a 1M HCl-solution and concentrated under reduced pressure. Final purification by preparative RP-HPLC (CH3CN/H2O gradient+0.05% formic acid) gave both isomers a) 2-(1-Isopropyl-piperidin-4-ylcarbamoyl)-1-(3-methoxy-benyl)-1H-benzoimidazole-4-carboxylic acid and b) 2-(1-Isopropyl-piperidin-4-ylcarbamoyl)-3-(3-methoxy-benzyl)-3H-benzoimidazole-4-carboxylic acid as white amorphous solids. Both isomers were transformed to the corresponding dihydrochlorides.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8]CC)=[O:7])=[CH:4][CH:3]=1.Br[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][O:19][CH:20]=[CH2:21].C(=O)([O-])[O-].[K+].[K+].CN(C)C(=O)C>O>[CH:20]([O:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([OH:8])=[O:7])=[CH:11][CH:12]=1)=[CH2:21]
Reactant: CCOC(=O)c1ccc(O)cc1
Reactant: C=COCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: C=COCCCCCOc1ccc(C(=O)O)cc1
Temperature: 120 °C
Reaction time: 5 h
Yield: 128.6 %

Procedure:
Ethyl p-hydroxybenzoate (33.2 g), 5-bromopentylvinyl ether (58.0 g), potassium carbonate (41.5 g) and N,N-dimethylacetamide (200 mL) were put into a 500-mL three-neck flask, and stirred at 120° C. for 5 hours. After cooled, the reaction mixture was poured into water (200 mL), extracted with ethyl acetate (500 mL), and washed two times with water (100 mL). This was dried with anhydrous magnesium sulfate, and filtered. The solvent was removed through concentration under reduced pressure, the residue was dissolved in methanol (100 mL), and a methanol solution (20 mL) of potassium hydroxide (16.8 g) was dropwise and gradually added thereto, and heated under reflux for 2 hours. After cooled, the formed crystal was collected through filtration and dissolved in water (1 L). Concentrated hydrochloric acid (25.7 mL) was added thereto, and the precipitated crystal was collected through filtration under reduced pressure, and washed with water. This was dried to give 4-(5-vinyloxypentyloxy)benzoic acid (TP-29C) (64.3 g, 90%). Production of 2,3,6,7,10,11-hexa(4-(5-vinyloxypentyloxy)benzoyloxy)triphenylene (TP-29):
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:4]=[CH:5][C:6]([O:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][C:17]([OH:19])=O)=[CH:12][CH:11]=2)=[N:7][CH:8]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:34][C:35]1[CH:40]=[CH:39][N:38]=[C:37]([CH2:41][CH3:42])[C:36]=1[Cl:43]>>[Cl:43][C:36]1[C:37]([CH2:41][CH3:42])=[N:38][CH:39]=[CH:40][C:35]=1[NH:34][C:17](=[O:19])[CH2:16][C:13]1[CH:12]=[CH:11][C:10]([O:9][C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:21])[F:20])=[CH:8][N:7]=2)=[CH:15][CH:14]=1
Reactant: O=C(O)Cc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Reactant: CCc1nccc(N)c1Cl
Agent: O=C(n1ccnc1)n1ccnc1
Product: CCc1nccc(NC(=O)Cc2ccc(Oc3ccc(C(F)(F)F)cn3)cc2)c1Cl
Temperature: 25 °C
Yield: 59.9 %

Procedure:
3.6 g (12.1 mmol) of 4-[(5-trifluoromethylpyridin-2-yl)oxy]phenylacetic acid was dissolved in 20 ml of 4dioxane, and the solution was stirred at room temperature. Then, 2.4 g (14.8 mmol) of 1,1'-carbonyldiimidazole was gradually added thereto, and the mixture was stirred for one hour at room temperature. Then, 1.8 g (11.5 mmol) of 4-amino-3-chloro-2-ethylpyridine was added thereto, and the mixture was refluxed under heating for 30 minutes. The reaction solution was concentrated, and the residue was extracted with ethyl acetate. The organic layer was washed with water and then dried over anhydrous magnesium sulfate. Then, ethyl acetate was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solvent: n-hexane/ethyl acetate) to obtain 3.0 g of the desired product as colorless cotton-like crystals (melting point: 124.5° to 125° C.).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH2:9].CN(C)C=O.[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>O>[CH2:15]([N:9]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[F:1])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Nc1ccc(F)cc1F
Reactant: BrCc1ccccc1
Solvent: O
Solvent: CN(C)C=O
Product: Fc1ccc(N(Cc2ccccc2)Cc2ccccc2)c(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90 %

Procedure:
To 2,4-difluoro-phenylamine (a, 2.0 g, 15.5 mmol) in N,N-dimethylformamide (20 mL) potassium carbonate (6.0 g, 45 mmol) and benzyl bromide (5.49 mL, 35 mmol) were added. The reaction was stirred at room temperature overnight. The reaction was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography eluting with hexane to give dibenzyl-(2,4-difluoro-phenyl)-amine as colourless oil (4.34 g, 90%).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([CH3:3])=[CH2:2].[NH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.Cl>>[OH:10][C:7]1[CH:8]=[CH:9][C:4]([C:1]([C:15]2[CH:16]=[CH:17][C:12]([NH2:11])=[CH:13][CH:14]=2)([CH3:3])[CH3:2])=[CH:5][CH:6]=1
Reactant: C=C(C)c1ccc(O)cc1
Reactant: Nc1ccccc1
Agent: Cl
Product: CC(C)(c1ccc(N)cc1)c1ccc(O)cc1
Temperature: 150 °C
Reaction time: 3 h
Yield: 93.7 %

Procedure:
A mixture of 13.4 g (0.1 mole) of p-isopropenyl phenol monomer and 18.6 g (0.2 mole) of aniline was stirred at 150° C. To the mixture was added 0.50 g of a solution obtained by adding 1.28 g of 35% hydrochloric acid to 93 g of aniline and stirring the mixture well (to be referred to as a catalyst solution) (0.0018 mole of catalyst per mole of p-isopropenyl phenol), and the reaction was carried out for 3 hours. Gas-chromatographic analysis of the reaction mixture showed that 21.3 g (yield 94%) of 2-(4'-hydroxyphenyl)-2-(4'-aminophenyl)-propane of the formula ##STR11## was formed.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][NH2:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:13]([P:15](=[O:22])([O:19][CH2:20][CH3:21])[O:16][CH2:17][CH3:18])=[CH2:14]>CO>[CH2:17]([O:16][P:15]([CH2:13][CH2:14][NH:12][CH2:11][CH2:10][CH2:9][NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])(=[O:22])[O:19][CH2:20][CH3:21])[CH3:18]
Reactant: CC(C)(C)OC(=O)NCCCN
Reactant: C=CP(=O)(OCC)OCC
Solvent: CO
Product: CCOP(=O)(CCNCCCNC(=O)OC(C)(C)C)OCC
Reaction time: 48 h
Yield: 81.3 %

Procedure:
To a solution of 3-(t-butyloxycarbonylamino) propanamine (77 g, 0.44 mole) in methanol (500 mL) was added diethyl vinylphosphonate 97% (75 g, 0.44 mole; Aldrich 11, 613-0) under nitrogen and kept in a water bath at ~20° C. for 48 hr. The reaction mixture was concentrated in vacua and the residue (~160 g) was put on a pad of "Florisil" (3"×6") and eluted with methylene chloride/hexane 1:1, methylene chloride and finally 10% methanol/methylene chloride to give the title compound as a colorless oil (121 g, 80%).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]([OH:19])=[C:9]([CH:18]=1)[C:10]([CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])=[O:11])(=[O:3])[CH3:2].[CH2:20]([CH:22]1[O:24][CH2:23]1)Br>CC(CC)=O>[C:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]([O:19][CH2:20][CH:22]2[O:24][CH2:23]2)=[C:9]([CH:18]=1)[C:10]([CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])=[O:11])(=[O:3])[CH3:2]
Reactant: BrCC1CO1
Reactant: COC(=O)CCC(=O)c1cc(NC(C)=O)ccc1O
Solvent: CCC(C)=O
Product: COC(=O)CCC(=O)c1cc(NC(C)=O)ccc1OCC1CO1
Yield: 57.8 %

Procedure:
Methyl 3-(5-acetamido-2-hydroxybenzoyl)propionate (0.75 g, 0.0028 mole) anhydrous potassium carbonate (0.39 g, 0.0028 mole), epibromohydrin (0.78 g, 0.00565 mole) and dry ethyl methyl ketone (20 ml) were stirred and heated under reflux for 16 hours. The cooled mixture was filtered and evaporated under reduced pressure to an oil which was purified by elution from a silica column with chloroform-methanol to give methyl 3-[5-acetamido-2-(2,3-epoxypropoxy)-benzoyl]propionate (0.52 g, 57%, m.p. 84°-87°). (Found: M+, 321, C16H19NO6 requires M, 321).
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].Br[CH:8](Br)[C:9]([C:11]([F:14])([F:13])[F:12])=O.[NH2:16][CH:17]([C:21]1[CH:26]=[C:25]([O:27][CH3:28])[C:24]([Cl:29])=[CH:23][C:22]=1[F:30])[C:18]([NH2:20])=[O:19].Cl>O>[Cl:29][C:24]1[C:25]([O:27][CH3:28])=[CH:26][C:21]([C:17]2[C:18](=[O:19])[NH:20][C:9]([C:11]([F:14])([F:13])[F:12])=[CH:8][N:16]=2)=[C:22]([F:30])[CH:23]=1
Reactant: O=C(C(Br)Br)C(F)(F)F
Reactant: COc1cc(C(N)C(N)=O)c(F)cc1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: COc1cc(-c2ncc(C(F)(F)F)[nH]c2=O)c(F)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixed solution of 17.2 g of sodium carbonate and 61 ml of water was added dropwise 10.9 g of 1,1-dibromo-3,3,3-trifluoroacetone at such a rate that the temperature of the reaction mixture became not higher than 55° C. After completion of the dropwise addition, the mixture was stirred at room temperature for 30 minutes, followed by adding 84 ml of water and then 7.10 g of 2-amino-2-(4-chloro-2-fluoro-5-methoxyphenyl)acetamide, and the reaction was allowed to proceed at 60° C. for 2 hours. After completion of the reaction, the reaction mixture was cooled to 10° C. or lower, made acidic by adding 9.2 ml of concentrated hydrochloric acid at the same temperature, and extracted with ethyl acetate. The organic layer was washed with water and then saturated sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography (eluent, hexane/ethyl acetate=4:1), which afforded 3.61 g (yield, 37%) of the desired compound, 3-(4-chloro-2-fluoro-5-methoxyphenyl)-6-trifluoromethyl-2-oxo-1,2-dihydropyrazine (compound 1-1008).
Reaction SMILES: Cl[CH2:2][C:3]1[O:7][N:6]=[CH:5][C:4]=1[CH3:8].[CH2:9]([NH2:11])[CH3:10]>C1COCC1>[CH2:9]([NH:11][CH2:2][C:3]1[O:7][N:6]=[CH:5][C:4]=1[CH3:8])[CH3:10]
Reactant: CCN
Reactant: Cc1cnoc1CCl
Solvent: C1CCOC1
Product: CCNCc1oncc1C

Procedure:
prepared by reaction of 5-chloromethyl-4-methyl-isoxazole with 2M ethylamine in THF.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH:13][CH2:14][CH2:15][CH2:16][O:17][C:18]2[N:19](CC3C=CC=CC=3)[N:20]=[C:21]([C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH3:32])[CH:24]=3)[CH:22]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[H][H]>C(O)(=O)C.[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH:13][CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:22]=[C:21]([C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH3:32])[CH:24]=3)[NH:20][N:19]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: [H][H]
Reactant: COc1ccc(CCNCCCOc2cc(-c3ccc(OC)c(OC)c3)nn2Cc2ccccc2)cc1OC
Agent: [Pd]
Solvent: CC(=O)O
Product: COc1ccc(CCNCCCOc2cc(-c3ccc(OC)c(OC)c3)[nH]n2)cc1OC
Yield: 27 %

Procedure:
4.9 g of 3-{3-[N-(2-(3,4-dimethoxyphenyl)-ethyl)-amino]-propyloxy}-2-benzyl-5-(3,4-dimethoxyphenyl)-pyrazole were dissolved in glacial acetic acid, 0.5 g of palladium on charcoal was added, and the reaction mixture was hydrogenated at 80 bar hydrogen pressure and at 80° C. for 24 hours. After removal of the catalyst by filtration, the reaction mixture was concentrated by evaporation and rendered alkaline (pH=10) with sodium hydroxide solution, and the product was extracted with ethyl acetate. The organic phase was separated, concentrated and purified by flash chromatography over silica gel. 1.1 g of 3-{3-[N-(2-(3,4-dimethoxyphenyl)-ethyl)-amino]-propyloxy}-5-(3,4-dimethoxyphenyl)-pyrazole were obtained. The IR spectrum of the base (as film) showed bands at 1511 cm-1, 1465 cm-1, 1262 cm-1.
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9]1.C(N(CC)C(C)C)(C)C.[C:27]1([S:37]([Cl:40])(=[O:39])=[O:38])[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[CH:29][CH:28]=1>C(Cl)Cl>[ClH:40].[CH2:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:16][CH2:17][N:8]1[CH2:7][CH2:6][CH2:5][CH2:4][NH:3][S:37]([C:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[CH:29][CH:28]=1)(=[O:39])=[O:38]
Reactant: O=S(=O)(Cl)c1cccc2ccccc12
Reactant: NCCCCN1CCc2ccccc2C1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=S(=O)(NCCCCN1CCc2ccccc2C1)c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.9 %

Procedure:
A solution of 2-(4-aminobutyl)-1,2,3,4-tetrahydroisoquinoline dihydrochloride (272 mg, 1 mmol), N,N-diisopropylethylamine (517 mg, 4 mmol) in CH2Cl2 (10 mL), was added naphtalene-1-sulfonyl chloride (238 mg, 1.05 mmol) and was stirred overnight at room temperature. The resulting solution was washed with water (3×15 mL) and dried over Na2SO4, and evaporated to dryness. The free base was dissolved in 2-propanol (5 mL). A 2.8 M solution of hydrogen chloride in ethanol (0.40 mL) was then added. The product was crystallized and collected by filtration, and vacuum dried to give a white solid (310 mg, 72%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH:7]1([C:13]([CH:16]2[CH2:21][CH2:20][CH:19]([NH2:22])[CH2:18][CH2:17]2)([CH3:15])[CH3:14])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.Cl[CH2:24][CH:25]([O:27][CH:28]([CH3:31])[CH2:29]Cl)[CH3:26].O>C1(O)CCCCC1>[CH3:24][CH:25]1[O:27][CH:28]([CH3:31])[CH2:29][N:22]([CH:19]2[CH2:18][CH2:17][CH:16]([C:13]([CH:7]3[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]3)([CH3:15])[CH3:14])[CH2:21][CH2:20]2)[CH2:26]1
Reactant: CC(C)(C1CCCCC1)C1CCC(N)CC1
Reactant: CC(CCl)OC(C)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: OC1CCCCC1
Product: CC1CN(C2CCC(C(C)(C)C3CCCCC3)CC2)CC(C)O1

Procedure:
41.4 g (0.3 mole) of potassium carbonate is added to a solution of 23.3 g (0.1 mole) of 4-(2-cyclohexylprop-2-yl)-cyclohexylamine and 17.1 g (0.1 mole) of di-(1-chloro-2-propyl)-ether in 200 ml of cyclohexanol, and the mixture is refluxed for 8 hours while stirring. After cooling, approx. 100 ml of water is added, and the organic phase is separated and dried over a small amount of Na2SO4. The residue remaining after the cyclohexanol has been distilled off is fractionally distilled under reduced pressure. At 160°-164° C./0.2 mm there is obtained 16 g (50% of theory) of the captioned compound as a colorless oil (isomer mixture; compound no. 1).
Reaction SMILES: [C:1](=[O:22])([O:12][N:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[N:15]=[N:14]1)ON1C2C=CC=CC=2N=N1.Cl.[C:24]([N:41](C)[NH2:42])([O:26][CH2:27][CH:28]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[C:34]2[C:29]1=[CH:30][CH:31]=[CH:32][CH:33]=2)=[O:25].[CH2:44](N(CC)CC)C>C(#N)C>[CH:30]1[C:29]2[CH:28]([CH2:27][O:26][C:24]([NH:41][N:42]([CH3:44])[C:1]([O:12][N:13]3[C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=4[N:15]=[N:14]3)=[O:22])=[O:25])[C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[C:34]=2[CH:33]=[CH:32][CH:31]=1
Reactant: CN(N)C(=O)OCC1c2ccccc2-c2ccccc21
Reactant: CCN(CC)CC
Reactant: O=C(On1nnc2ccccc21)On1nnc2ccccc21
Agent: Cl
Solvent: CC#N
Product: CN(NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)On1nnc2ccccc21
Reaction time: 2.5 h

Procedure:
Bis-benzotriazol-1-yl carbonate (4.23 g) was added to a stirred suspension of N1 -Fmoc-N1 -methylhydrazine hydrochloride (3.05 g) and triethylamine (1.4 ml) in acetonitrile (50 ml) whereupon the suspension rapidly cleared. The mixture was stirred for 2.5 hours at laboratory temperature and then filtered. The solid residue was washed with acetonitrile and then diethyl ether, and then dried. There was thus obtained Fmoc-Azala-OBt as an amorphous solid (1.56 g), the structure of which was confirmned by FAB mass spectroscopy (MH+ =430).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1)[CH3:2].[Br:9]N1C(=O)CCC1=O.[Cl:17]C(Cl)(Cl)C>C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[ClH:17].[Br:9][CH:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1)[CH3:2]
Reactant: CCc1ccccn1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(Cl)(Cl)Cl
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Product: CC(Br)c1ccccn1
Product: Cl

Procedure:
A mixture of 2-ethylpyridine (20.0 g, 187 mmol), N-bromosuccinimide (38.0 g, 213 mmol), and benzoyl peroxide (1.0 g, 75% in water) in 1,1,1-trichloroethane (200 ml), was heated under reflux for 3 hours. The cooled mixture was filtered, and the filtrate washed with water (2×100 ml), aqueous sodium thiosulphate solution (100 ml), and brine (100 ml). The solution was dried (MgSO4), filtered through charcoal, and then hydrobromic acid (25 ml, 62%) added. This solution was concentrated under reduced pressure and azeotroped with toluene to give 2-(1-bromoethyl)pyridine hydrochloride as a dark oil (66.0 g).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)[CH:3]=1.[Mg+2].[Cl-].[Cl-].C(N(CC)CC)C.[CH2:31]=[O:32]>CC#N.CCOC(C)=O>[CH:31]([C:7]1[C:2]([OH:1])=[CH:3][C:4]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[N:5][CH:6]=1)=[O:32]
Reactant: C=O
Reactant: CC(C)(C)OC(=O)N1CCN(c2cc(O)ccn2)CC1
Agent: [Cl-]
Agent: [Mg+2]
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(c2cc(O)c(C=O)cn2)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 27.1 %

Procedure:
To a mixture of t-butyl 4-(4-hydroxypyridin-2-yl)piperazine-1-carboxylate (5.03 g, 18.0 mmol) and MgCl2 (3.42 g, 36 mmol) in CH3CN (100 mL) was added triethylamine (15.1 mL, 90 mmol). After the mixture was stirred for 10 minutes at ambient temperature, paraformaldehyde (5.4 g, 180 mmol) was added to the mixture. The mixture was stirred for 18 hours at 60° C., and then cooled to room temperature. The mixture was then diluted with EtOAc (400 mL) and washed with 1 M Rochelle salt solution (200 mL) and saturated NH4Cl solution (200 mL). The organic layer was concentrated under the reduced pressure and purified by column chromatography (30%-80% EtOAc/hexanes) to yield 1.5 g (27%) of t-butyl 4-(5-formyl-4-hydroxypyridin-2-yl)piperazine-1-carboxylate as white solid. MS m/z 308.2 [M+H]+; 1H NMR (500 MHz, CDCl3) δ (ppm) 11.37 (1H, s), 9.64 (1H, s), 8.27 (1H, s), 5.98 (1H, s), 3.71 (4H, m), 3.56 (4H, m), 1.48 (9H, s).
Reaction SMILES: [C:1]1([C:7]2[CH:19]=[CH:18][C:10]3[S:11][C:12]([C:14]([O:16]C)=[O:15])=[CH:13][C:9]=3[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O[Li].O>C1COCC1.O>[C:1]1([C:7]2[CH:19]=[CH:18][C:10]3[S:11][C:12]([C:14]([OH:16])=[O:15])=[CH:13][C:9]=3[CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)c1cc2cc(-c3ccccc3)ccc2s1
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cc2cc(-c3ccccc3)ccc2s1
Yield: 99.1 %

Procedure:
A solution of compound 13b (510 mg, 1.9 mmol) and LiOH.H2O (319 mg, 7.6 mmol) in THF/H2O (10/10 mL) was stirred at room temperature overnight. The resulting mixture was concentrated and diluted with water. The water layer was acidified with 1N aqueous HCl to pH˜4 and extracted with CH2Cl2. The organic solution was dried over Na2SO4 and concentrated to give compound 13c (479 mg), which was used in the next reaction without further purification. MS m/z (M+H+) 255.0.
Reaction SMILES: [H-].[Na+].[C:3]([O:11][CH2:12][CH3:13])(=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].Cl[CH2:15][CH:16]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:17]Br>O1CCOCC1>[C:21]1([CH2:20][O:19][CH:16]2[CH2:17][C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])([C:3]([O:11][CH2:12][CH3:13])=[O:10])[CH2:15]2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: ClCC(CBr)OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCOC(=O)C1(C(=O)OCC)CC(OCc2ccccc2)C1
Temperature: 25 °C
Yield: 44.4 %

Procedure:
To a stirred suspension of oil-free sodium hydride (10.7 g, 0.446 mol) in 270 ml of dry dioxane under nitrogen at room temperature was added over twenty minutes 69.1 g (0.432 mol) of diethyl malonate. After the addition, 1-chloro-2-benzyloxy-3-bromopropane (115 g, 0.437 mol) was added over 20 minutes, and the reaction was refluxed for 44 hours. The reaction was cooled to room temperature, and then a slurry of 10.7 g (0.446 mol) of oil-free sodium hydride in 100 ml of dioxane was cautiously added in portions. The mixture was refluxed for 120 hours and cooled to room temperature. The inorganics were removed by filtration, and the filtrate was concentrated in vacuo to an oil, which was partitioned between ether and water. The ether layer was dried (Na2SO4) and concentrated to an oil, which was distilled to give 58.8 g of desired product having a b.p. 142°-146°/0.3 mm.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].CN(C)C=O.O1CCCC1.[NH2:16][C:17]1[CH:37]=[CH:36][C:20]([O:21][CH2:22][CH2:23][O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[CH:31]([CH3:35])[C:32]([OH:34])=[O:33])=[CH:19][CH:18]=1>N1C=CC=CC=1>[CH3:1][S:2]([NH:16][C:17]1[CH:18]=[CH:19][C:20]([O:21][CH2:22][CH2:23][O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[CH:31]([CH3:35])[C:32]([OH:34])=[O:33])=[CH:36][CH:37]=1)(=[O:4])=[O:3]
Reactant: CC(C(=O)O)c1ccccc1OCCOc1ccc(N)cc1
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CC(C(=O)O)c1ccccc1OCCOc1ccc(NS(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 16 %

Procedure:
38 mg (0.332 mM) of methanesulfonyl chloride are added to a mixture of 0.25 ml of dimethylformamide and 1.5 ml of tetrahydrofuran in a 15 ml reactor. 100 mg (0.332 mM) of 2-{2-(4-aminophenoxy)ethoxy}phenylpropanoic acid are then added, followed by addition of 0.060 ml (0.74 mM) of pyridine. The reaction medium is then stirred for 48 hours at room temperature. After extraction with ethyl acetate, 20 mg of 2-{2-[4-(methylsulfonylamino)phenoxy]ethoxy}phenyl-propanoic acid are obtained (yield: 16%).