Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([O:13][CH2:14]/[CH:15]=[CH:16]\[CH2:17][NH2:18])[CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:19]1[CH:23]=[CH:22][CH:21]=[C:20]1[C:24](O)=[O:25]>>[N:1]1([CH2:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([O:13][CH2:14]/[CH:15]=[CH:16]\[CH2:17][NH:18][C:24]([C:20]3[NH:19][CH:23]=[CH:22][CH:21]=3)=[O:25])[CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)c1ccc[nH]1
Reactant: NC/C=C\COc1cc(CN2CCCC2)ccn1
Product: O=C(NC/C=C\COc1cc(CN2CCCC2)ccn1)c1ccc[nH]1
Yield: 64 %

Procedure:
Following a procedure similar to that described in Example 13, but using 4-[4-(1-pyrrolidinylmethyl)-2-pyridyloxy]-cis-2-butenylamine and 2-pyrrolecarboxylic acid as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained as a white powder, melting at 124°-127° C., in a 64% yield.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([C:8]2(O)[CH2:12][CH2:11][O:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.C([SiH](CC)CC)C.C(O)(C(F)(F)F)=O.C([O-])([O-])=O.[K+].[K+]>ClCCl>[I:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH2:12][CH2:11][O:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: OC1(c2cccc(I)c2)CCOC1
Agent: CC[SiH](CC)CC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Ic1cccc(C2CCOC2)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 85.7 %

Procedure:
A solution of the product of step A (2.0 g, 3.79 mmol) in dichloromethane (15 mL) was cooled to 0° C. under a nitrogen atmosphere before addition of triethylsilane (5.0 mL, 31.38 mmol), TFA (4.4 mL, 55.74 mmol) and borontrifluoride-diethyletherate complex (7.0 mL, 55.74 mmol). The reaction mixture was stirred for 48 h at ambient temperature, then poured into K2CO3 (aq.) solution and extracted with dichloromethane. The combined organic layer was dried over Na2SO4, concentrated and the residue purified by flash column chromatography (SiO2, 98:2 hexanes/ethyl acetate) to give 3-(3-iodophenyl)tetrahydrofuran (0.89 g, 86%) as a colorless liquid: 1H NMR (CDCl3, 300 MHz) δ 7.60 (t, J=1.8 Hz, 1H), 7.56 (td, J=7.8 Hz, 1H), 7.22 (d, J=7.8 Hz, 1H), 7.04 (t, J=7.8 Hz, 1H), 4.15-4.00 (m, 2H), 3.96-3.84 (m, 1H), 3.76-3.66 (m, 1H), 3.33 (p, J=7.8 Hz, 1H), 2.43-2.29 (m, 1H), 2.04-1.89 (m, 1H). Step C: The product of step B was coupled with lithium 2-(tert-butoxycarbonyl)-6-chloro-1,2,3,4-tetrahydrobenzofuro[3,2-c]pyridine-8-sulfinate following the procedure of Example 50, step A. The crude product was purified by flash column chromatography (SiO2, 4:1 hexanes/ethyl acetate) to give tert-butyl 6-chloro-8-(3-(tetrahydrofuran-3-yl)phenylsulfonyl)-3,4-dihydrobenzofuro[3,2-c]pyridine-2(1H)-carboxylate (55 mg, 8%) as an off-white solid: 1H NMR (CDCl3, 300 MHz) δ 8.02-7.91 (m, 1H), 7.87-7.76 (m, 3H), 7.51-7.44 (m, 2H), 4.57 (s, 2H), 4.18-4.02 (m, 2H), 3.97-3.78 (m, 3H), 3.77-3.67 (m, 1H), 3.46 (p, J=7.5 Hz, 1H), 2.98-2.84 (m, 2H), 2.49-2.34 (m, 1H), 2.06-1.89 (m, 1H), 1.50 (s, 9H); APCI MS m/z 418 [(M+H)—C5H9O2]+.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[CH:6][N:5]=1)[CH3:2].Cl>C1COCC1>[NH2:9][CH2:8][C:7]1[CH:10]=[CH:11][C:4]([O:3][CH2:1][CH3:2])=[N:5][CH:6]=1
Reactant: CCOc1ccc(C#N)cn1
Agent: Cl
Solvent: C1CCOC1
Product: CCOc1ccc(CN)cn1
Reaction time: 8 h
Yield: 37.2 %

Procedure:
Add a solution of 1M BH3-THF complex in THF (7 mL, 7 mmol) to a solution of 6-(ethoxy)nicotinonitrile (911 mg, 4.41 mmol) in anhydrous THF (7 mL) and stir the mixture overnight at reflux. Add a second aliquot of 1M BH3-THF complex in THF (7 mL, 7 mmol) and stir the mixture overnight at reflux. Add 5N aqueous HCl (10 mL) cautiously and stir the mixture overnight at room temperature. Concentrate in vacuo then dissolve the crude mixture in methanol and filter through an SCX column eluting with methanol followed by 3M ammonia in methanol to obtain the title compound (250 mg, 40%). MS (ES+) m/z: 153 (M+H)+.
Reaction SMILES: [OH-].[K+].[NH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:5]=1[N+:11]([O-:13])=[O:12].Br[CH2:15][C:16]1[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:17]=1[Cl:23].O>CN(C)C=O>[Cl:22][C:21]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:23])[C:16]=1[CH2:15][O:10][C:7]1[CH:8]=[CH:9][C:4]([NH2:3])=[C:5]([N+:11]([O-:13])=[O:12])[CH:6]=1
Reactant: Nc1ccc(O)cc1[N+](=O)[O-]
Reactant: Clc1cccc(Cl)c1CBr
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1ccc(OCc2c(Cl)cccc2Cl)cc1[N+](=O)[O-]
Temperature: 20 °C
Yield: 76.7 %

Procedure:
add 561 mg of anhydrous potassium hydroxide to a solution of 1.54 g of 4-amino-3-nitrophenol in 6 cm3 of N,N-dimethylformamide. Add dropwise, to the purple solution obtained, 2.4 g of 2-(bromomethyl)-1,3-dichlorobenzene in solution in 2 cm3 of N,N-dimethylformamide, without exceeding 20° C. After stirring the reaction mixture for about twenty hours at a temperature around 20° C., the reaction mixture is poured into 200 cm3 of water. The mixture obtained is extracted three times with 100 cm3 of ethyl acetate. The combined organic phases are washed five times with 50 cm3 of water, dried over magnesium sulphate, filtered and concentrated under reduced pressure (0.2 kPa). The residue is taken up successively in a 50/50 mixture of diethyl oxide and diisopropyl oxide, and finally drained, washed three times with 2 cm3 of diisopropyl oxide, then dried under reduced pressure in the presence of potassium hydroxide. We obtain 2.4 g of 4-[(2,6-dichlorobenzyl)oxy]-2-nitroaniline in the form of a white powder, which has the following characteristics:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][CH:9](C(OCC)=O)[C:10]([O:12][CH2:13]C)=[O:11])=[CH:3][CH:2]=1>Cl>[N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:3][CH:2]=1
Reactant: CCOC(=O)C(CCc1ccncc1)C(=O)OCC
Agent: Cl
Product: COC(=O)CCCc1ccncc1
Temperature: 100 °C

Procedure:
A mixture of diethyl 2-(pyridin-4-yl)ethylmalonate (2.4 g, 0.009 mol) and 30 ml of conc. hydrochloric acid was heated at 100° C. for 15 hours and an excess amount of hydrochloric acid was then evaporated under reduced pressure. A mixture of the resultant residue and 10% hydrochloric acid-methanol solution was heated under reflux, evaporated, neutralized with saturated aqueous sodium hydrogen carbonate, and extracted with ethyl acetate. The extract was treated according to conventional techniques. Evaporation of solvent yielded the title compound, methyl 4-(pyridin-4-yl)butanoate, as an oil (0.62 g, 39%).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([NH2:11])[CH:9]=2)[NH:4][N:3]=1.N1C=CC=CC=1.[F:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[C:20]=1[S:26](Cl)(=[O:28])=[O:27]>O1CCCC1>[NH2:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([NH:11][S:26]([C:20]3[C:21]([F:25])=[CH:22][CH:23]=[CH:24][C:19]=3[F:18])(=[O:28])=[O:27])[CH:9]=2)[NH:4][N:3]=1
Reactant: Nc1ccc2[nH]nc(N)c2c1
Reactant: O=S(=O)(Cl)c1c(F)cccc1F
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: Nc1n[nH]c2ccc(NS(=O)(=O)c3c(F)cccc3F)cc12
Yield: 8.4 %

Procedure:
N-(3-Amino-1H-indazol-5-yl)-2,6-difluorobenzenesulfonamide can be obtained as described in Example 39 from 1 g of 3,5-diamino-1H-indazole, 10 ml of pyridine, 10 ml of tetrahydrofuran and 1.4 g of 2,6-difluorobenzenesulfonyl chloride. 179 mg of N-(3-amino-1H-indazol-5-yl)-2,6-difluorobenzenesulfonamide are thus obtained in the form of a gray solid melting at 241° C. (analysis C13H10F2N4O2S % calculated C, 48.15; H, 3.11; F, 11.72; N, 17.28; O, 9.87; S, 9.89. % found C, 47.81; H, 3.18; F, 11.64; N, 17.00; S, 9.67).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[CH2:3]OS(C(F)(F)F)(=O)=O.[CH2:14]([NH2:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1(C)C(C)=CC=CC=1>[CH2:14]([NH:21][CH2:3][C:2]([F:13])([F:12])[F:1])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: NCc1ccccc1
Solvent: Cc1ccccc1C
Product: FC(F)(F)CNCc1ccccc1

Procedure:
2.17 g (9.4 mmol) 2,2,2-trifluoroethyltrifluoromethanesulphonate were added to 2.00 g (18.7 mmol) benzylamine in 50 mL xylene and the reaction mixture was refluxed overnight. After cooling the reaction mixture was suction filtered, washed with DIPE and the filtrate was evaporated down using the rotary evaporator. The residue was purified by flash chromatography. The product fractions were combined and evaporated down using the rotary evaporator.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22]O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Br)(Br)(Br)[Br:25].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Br:25][CH2:22][CH2:21][O:20][CH2:19][CH2:18][O:17][CH2:16][CH2:15][O:14][CH2:13][CH2:12][O:11][CH2:10][CH2:9][O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCCOCCOCCOCCOCCOCc1ccccc1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: BrCCOCCOCCOCCOCCOCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.1 %

Procedure:
To a solution of Compound 19 (2.04 g, 6.21 mmol) in methylene chloride (20 ml), a solution of carbon tetrabromide (4.12 g, 12.4 mmol) in methylene chloride (10 ml) was added at room temperature; after cooling with ice, triphenylphosphine (2.51 g, 12.4 mmol) was added. The water bath was removed, and this was followed by stirring at room temperature for 1 hour. After concentration under reduced pressure, the residue obtained was purified by silica gel column chromatography (Yamazen YFLC Gel, eluent (n-hexane:ethyl acetate 2:1-1:1)) to yield Compound 20 (light-yellow oil 2.14 g, 88%).
Reaction SMILES: [F:1][C:2]([F:23])([S:19](F)(=[O:21])=[O:20])[C:3]([F:18])([F:17])[C:4]([F:16])([F:15])[C:5]([F:14])([F:13])[C:6]([F:12])([F:11])[C:7]([F:10])([F:9])[F:8].C[Si](C)(C)[O-:26].[K+:29]>C1(C)C=CC=CC=1>[F:1][C:2]([F:23])([S:19]([O-:26])(=[O:21])=[O:20])[C:3]([F:18])([F:17])[C:4]([F:16])([F:15])[C:5]([F:14])([F:13])[C:6]([F:12])([F:11])[C:7]([F:10])([F:9])[F:8].[K+:29]
Reactant: O=S(=O)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: C[Si](C)(C)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: O=S(=O)([O-])C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Yield: 65.4 %

Procedure:
The procedure of Example 1 was followed using perfluorohexanesulfonyl fluoride (7.90 g, 19.6 mmol), potassium trimethylsilanolate (2.20 g, 17.1 mmol), and dry toluene (50 mL), while heating at 40° for 3.5 h. Potassium perfluorohexanesulfonate (4.9 g, 65% yield) was isolated as a white solid: 19F NMR (methanol) data were closely similar to those reported in Example 23.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([CH2:7][OH:8])=[N:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH:38]1([CH:41]([C:47]2[CH:52]=[CH:51][CH:50]=[C:49](O)[CH:48]=2)[CH2:42][C:43]([O:45][CH3:46])=[O:44])[CH2:40][CH2:39]1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1.C1(C)C=CC=CC=1>[Br:1][C:2]1[S:6][C:5]([CH2:7][O:8][C:51]2[CH:52]=[C:47]([CH:41]([CH:38]3[CH2:39][CH2:40]3)[CH2:42][C:43]([O:45][CH3:46])=[O:44])[CH:48]=[CH:49][CH:50]=2)=[N:4][C:3]=1[C:9]1[CH:10]=[CH:11][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:13][CH:14]=1
Reactant: COC(=O)CC(c1cccc(O)c1)C1CC1
Reactant: OCc1nc(-c2ccc(C(F)(F)F)cc2)c(Br)s1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COC(=O)CC(c1cccc(OCc2nc(-c3ccc(C(F)(F)F)cc3)c(Br)s2)c1)C1CC1
Yield: 22.9 %

Procedure:
To a solution of (5-bromo-4-(4-(trifluoromethyl)phenyl)thiazol-2-yl)methanol (300 mg) in THF (15 ml) were added triphenylphosphine (349 mg), methyl 3-cyclopropyl-3-(3-hydroxyphenyl)propanoate (293 mg), and a 40% solution of diethyl azodicarboxylate in toluene (520 μL), and the mixture was stirred at room temperature for 30 min. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (110 mg) as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1(C(OCC)=O)[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[Cl:15])[C:6]2[CH:16]=[C:17]([CH2:19][CH3:20])[S:18][C:5]=2[N:4]2[C:21]([CH:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)=[N:22][N:23]=[C:3]12.[OH-].[Ba+2].[OH-]>C(O)C.O>[NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[Cl:15])[C:6]2[CH:16]=[C:17]([CH2:19][CH3:20])[S:18][C:5]=2[N:4]2[C:21]([CH:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)=[N:22][N:23]=[C:3]12
Reactant: CCOC(=O)C1(N)N=C(c2ccccc2Cl)c2cc(CC)sc2-n2c(C3CCCCC3)nnc21
Agent: [Ba+2]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCc1cc2c(s1)-n1c(C3CCCCC3)nnc1C(N)N=C2c1ccccc1Cl
Temperature: 25 °C
Reaction time: 24 h
Yield: 65 %

Procedure:
4-(2-Chlorophenyl)-9-cyclohexyl-2-ethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine (3.4 g) and sodium hydride (0.56 g) were added to diethyl carbonate (50 ml) and the mixture was heated. After refluxing for 1 hour, the reaction mixture was cooled to 20° C., and O-(2,4-dinitrophenyl)-hydroxylamine (2.1 g) was added thereto. The mixture was stirred for 2 hours. After the reaction, the reaction mixture was poured into ice water, and the diethyl carbonate layer was separated. The diethyl carbonate layer was washed twice with water, and dried over anhydrous magnesium sulfate. Diisopropyl ether was added to the residue obtained by distilling away diethyl carbonate under reduced pressure. The precipitated crystals were collected by filtration and recrystallized from ethyl acetate to give 2.1 g of ethyl (6-amino-4-(2-chlorophenyl)-9-cyclohexyl-2-ethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)carboxylate having a melting point of 140°-145° C. Ethyl (6-amino-4-(2-chlorophenyl)-9-cyclohexyl-2-ethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)carboxylate (1.8 g) was dissolved in a mixture of ethanol (60 ml) and water (20 ml) and barium hydroxide 8 hydrate (1.14 g) was added thereto. The mixture was stirred at room temperature for 24 hours. The solvent was distilled away under reduced pressure and water (50 ml) was added thereto. The mixture was adjusted to pH 2 with 1N hydrochloric acid and stirred for 1 hour. The reaction mixture was neutralized with aqueous sodium hydrogencarbonate and extracted twice with chloroform. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled away under reduced pressure. The residue was purified by silica gel column chromatography. The solvent was distilled away and the crystals obtained were recrystallized from diisopropyl ether to give 1.0 g of 6-amino-4-(2-chlorophenyl)-9-cyclohexyl-2-ethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine having a melting point of 175°-176° C.
Reaction SMILES: S(Cl)(Cl)=O.[CH:5]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[C:7]([OH:14])[CH:6]=1.[CH:15]1[N:19]=[CH:18][NH:17][C:16]=1/[CH:20]=[CH:21]/[C:22](O)=[O:23].[Cl-].[Cl-].[Ca+2]>>[NH:19]1[CH:15]=[C:16](/[CH:20]=[CH:21]/[C:22]([O:14][C:7]2[CH:8]=[CH:9][C:10]([N+:11]([O-:13])=[O:12])=[CH:5][CH:6]=2)=[O:23])[N:17]=[CH:18]1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: O=C(O)/C=C/c1cnc[nH]1
Agent: [Ca+2]
Agent: [Cl-]
Solvent: O=S(Cl)Cl
Product: O=C(/C=C/c1c[nH]cn1)Oc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
2 ml (27.5 mmol) of freshly distilled thionyl chloride are added to a finely ground mixture of 1.51 g (10.8 mmol) of p-nitrophenol and 1.5 g (10.8 mmol) of trans-urocanic acid in a round-bottomed flask equipped with a drying tube containing CaCl2. The mixture is progressively brought to 140° C. After 4 h, the mixture is slowly cooled to room temperature. A brown powder is extracted with CHCl3 / MeOH (150 ml, 2:1) while heating. The undissolved material is separated by filtration and the filtrate is treated with active charcoal. Concentration is carried out under vacuum and diethyl ether is added so as to induce precipitation of a solid (1.96 g; overall crude yield: 61%). The latter is recrystallized from MeOH and the product is washed with diethyl ether in order to remove any trace of p-nitrophenol, giving a crystalline white solid, M.p. 220°-222° C.
Reaction SMILES: [C:1]([O:18][CH:19]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[CH2:20][C:21]([OH:23])=O)(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[NH2:39][CH2:40][CH2:41][C:42]([OH:44])=[O:43]>>[C:1]([O:18][CH:19]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[CH2:20][C:21]([NH:39][CH2:40][CH2:41][C:42]([OH:44])=[O:43])=[O:23])(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCC(=O)OC(CCCCCCCCCCCCCCC)CC(=O)O
Reactant: NCCC(=O)O
Product: CCCCCCCCCCCCCCCC(=O)OC(CCCCCCCCCCCCCCC)CC(=O)NCCC(=O)O
Yield: 76.3 %

Procedure:
Starting from 3-hexadecanoyloxyoctadecanoic acid (10.8 g) prepared by the method described in Preparation A-2 (5) and β-alanine (5.36 g), N-[3-hexadecanoyloxyoctadecanoyl]-β-alanine (9.33 g) was obtained as crystals according to a similar manner to that of Preparation B-1.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=3[F:18])[C:6]=2[N:7]=1.C(N(C(C)C)CC)(C)C.[CH3:29][C:30]1[N:34]=[CH:33][N:32]([C:35]2[CH:45]=[CH:44][C:43]([N+:46]([O-:48])=[O:47])=[CH:42][C:36]=2[O:37][CH2:38][CH2:39][CH2:40][NH2:41])[N:31]=1>C(#N)C>[Cl:1][C:2]1[N:3]=[C:4]([NH:41][CH2:40][CH2:39][CH2:38][O:37][C:36]2[CH:42]=[C:43]([N+:46]([O-:48])=[O:47])[CH:44]=[CH:45][C:35]=2[N:32]2[CH:33]=[N:34][C:30]([CH3:29])=[N:31]2)[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=3[F:18])[C:6]=2[N:7]=1
Reactant: Cc1ncn(-c2ccc([N+](=O)[O-])cc2OCCCN)n1
Reactant: Fc1ccc(C2CCc3c(Cl)nc(Cl)nc32)c(F)c1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ncn(-c2ccc([N+](=O)[O-])cc2OCCCNc2nc(Cl)nc3c2CCC3c2ccc(F)cc2F)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 55.4 %

Procedure:
To a solution of 2,4-dichloro-7-(2,4-difluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine (Preparation T, 0.717 g, 2.38 mmol) in acetonitrile (40 mL) was added diisopropylethylamine (0.420 g, 3.25 mmol) followed by 3-(2-(3-methyl-1H-1,2,4-triazol-1-yl)-5-nitrophenoxy)propan-1-amine (Preparation K, 0.60 g, 2.164 mmol) at room temperature. The reaction mixture was stirred at room temperature for 18 h. The solvent was removed under reduced pressure and the residue was taken in dichloromethane (10 mL) and silica (2 g). The resultant slurry of the compound on silica was subjected to flash chromatography using a Teledyne Isco instrument (12 g RediSep silica column, 50% ethyl acetate in pet-ether) to get 2-chloro-7-(2,4-difluorophenyl)-N-(3-(2-(3-methyl-1H-1,2,4-triazol-1-yl)-5-nitrophenoxy)propyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine (0.65 g, 55.4%) as a light yellow solid. LC-MS (M+H)+=542.0. 1H NMR (400 MHz, CDCl3) δ ppm 8.95 (1H, s), 8.05-7.93 (3H, m), 6.95-6.77 (3H, m), 4.86 (1H, br s), 4.86-4.85 (1H, m), 4.37-4.34 (2H, m), 3.75-3.75 (2H, s), 2.69-2.50 (3H, m), 2.50 (3H, s), 2.29-2.26 (2H, m), 2.01-1.98 (1H, m).
Reaction SMILES: [C:1]1([C:7]2[S:8][CH:9]=[C:10]([CH2:12][O:13][C:14]3[CH:42]=[CH:41][C:17]([CH2:18][N:19]4[CH:23]=[C:22]([CH2:24][CH:25](C(OCC)=O)[C:26]([O:28]CC)=[O:27])[C:21]([C:36]5[S:37][CH:38]=[CH:39][CH:40]=5)=[N:20]4)=[CH:16][CH:15]=3)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].O1CCCC1.Cl>C(O)C>[C:1]1([C:7]2[S:8][CH:9]=[C:10]([CH2:12][O:13][C:14]3[CH:42]=[CH:41][C:17]([CH2:18][N:19]4[CH:23]=[C:22]([CH2:24][CH2:25][C:26]([OH:28])=[O:27])[C:21]([C:36]5[S:37][CH:38]=[CH:39][CH:40]=5)=[N:20]4)=[CH:16][CH:15]=3)[N:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)C(Cc1cn(Cc2ccc(OCc3csc(-c4ccccc4)n3)cc2)nc1-c1cccs1)C(=O)OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(O)CCc1cn(Cc2ccc(OCc3csc(-c4ccccc4)n3)cc2)nc1-c1cccs1
Temperature: 110 °C
Reaction time: 2 h
Yield: 95.3 %

Procedure:
A mixture of diethyl [1-[4-(2-phenyl-4-thiazolylmethoxy)benzyl]-3-(2-thienyl)-1H-pyrazol-4-yl]methylmalonate (4.09 g), 1N aqueous sodium hydroxide solution (30 ml), tetrahydrofuran (30 ml), and ethanol (30 ml) was refluxed for 1 hour. After cooling, 1N hydrochloric acid (30 ml) was added to the mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The resulting colorless oily substance was dissolved in pyridine (50 ml), and the mixture was stirred at 110° C. for 2 hours. After removing pyridine under reduced pressure, ethyl acetate was added to the residue. The resulting solution was washed successively with dilute hydrochloric acid and saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The resulting colorless crystals were collected by filtration to obtain 3-[1-[4-(2-phenyl-4-thiazolylmethoxy)benzyl]-3-(2-thienyl)-1H-pyrazol-4-yl]propionic acid (3.25 g, yield: 95%). This was recrystallized from ethyl acetate-hexane. Melting point: 133˜134° C.
Reaction SMILES: [C:1]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][C@@H:16]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:32]=[C:31]([CH2:33][NH:34][CH2:35]C(OC(C)(C)C)=O)[S:30][CH:29]=2)=[CH:24][CH:23]=1)[C:17]([O:19][CH3:20])=[O:18])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[C:1]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][C@@H:16]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:32]=[C:31]([CH2:33][NH:34][CH3:35])[S:30][CH:29]=2)=[CH:24][CH:23]=1)[C:17]([O:19][CH3:20])=[O:18])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)[C@H](Cc1ccc(-c2csc(CNCC(=O)OC(C)(C)C)c2)cc1)Nc1ccccc1C(=O)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNCc1cc(-c2ccc(C[C@H](Nc3ccccc3C(=O)c3ccccc3)C(=O)OC)cc2)cs1
Temperature: 25 °C
Reaction time: 18 h
Yield: 99 %

Procedure:
2.9 g (5 mmol) of methyl 2(S)-(2-benzoylphenylamino)-3-(4-{5-[(tert-butoxycarbonylmethylamino)methyl]thiophen-3-yl}phenyl)propanoate are placed in 30 ml of dichloromethane and 2.5 ml (32 mmol) of trifluoroacetic acid. After stirring at room temperature for 18 hours, the reaction medium is evaporated to dryness. 2.4 g (100%) of methyl 2(S)-(2-benzoylphenylamino)-3-[4-(5-methylaminomethylthiophen-3-yl)phenyl]propanoate are obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([NH:10][C:11](=[O:14])[CH2:12][CH3:13])[CH:7]=[CH:6][C:5]=1[O:15][CH3:16])([O-])=O.C(O)CC.N.[H][H]>[Pd].O>[CH3:16][O:15][C:5]1[CH:6]=[CH:7][C:8]([NH:10][C:11](=[O:14])[CH2:12][CH3:13])=[CH:9][C:4]=1[NH2:1]
Reactant: [H][H]
Reactant: CCC(=O)Nc1ccc(OC)c([N+](=O)[O-])c1
Agent: [Pd]
Agent: N
Solvent: O
Solvent: CCCO
Product: CCC(=O)Nc1ccc(OC)c(N)c1
Reaction time: 1 h

Procedure:
114 parts of 2-nitro-4-propionamidoanisole, 160 parts of propanol, 3.4 parts of a 30% aqueous solution of ammonia and 2 parts of a 50% suspension of palladium on activated charcoal, moist with water, in 3 parts of water are charged to an autoclave equipped with an aerating stirrer. The autoclave is pressurised with hydrogen and, at a pressure of 25 bar and a temperature of 120° C., hydrogenation is carried out for 1 hour. 2-Methoxy-5-propionamidoaniline is obtained in quantitative yield in a purity of >97% (analysis by liquid chromatography).