Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:11])[C@H:5]([CH2:7][CH:8]([CH3:10])[CH3:9])[NH2:6].C(N(CC)C(C)C)(C)C.C([O:23][C:24](=O)[CH:25]=[C:26]([O:29][C:30]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:31]=1[F:37])[CH2:27]Br)C>C(#N)C>[CH3:2][O:3][C:4](=[O:11])[C@@H:5]([N:6]1[CH2:27][C:26]([O:29][C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:31]=2[F:37])=[CH:25][C:24]1=[O:23])[CH2:7][CH:8]([CH3:10])[CH3:9]
Reactant: CCOC(=O)C=C(CBr)Oc1ccc(F)cc1F
Reactant: COC(=O)[C@@H](N)CC(C)C
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@H](CC(C)C)N1CC(Oc2ccc(F)cc2F)=CC1=O
Temperature: 60 °C
Reaction time: 0.75 h
Yield: 34.6 %

Procedure:
A mixture of (L)-leucine methyl ester hydrochloride (0.90 g, 4.96 mmol) in acetonitrile (12.4 mL) was treated with N,N-diisopropylethylamine (0.80 mL, 4.87 mmol). After addition was complete, the mixture was stirred at 60° C. for 45 min. At this time, the reaction was cooled to 25° C., treated with N,N-diisopropylethylamine (0.80 mL, 4.87 mmol) and acetonitrile (12.4 mL) and then heated to 80° C. Upon reaching 80° C., the reaction was treated with a solution of 4-bromo-3-(2,4-difluoro-phenoxy)-but-2-enoic acid ethyl ester (1.45 g, 4.51 mmol) in acetonitrile (11.3 mL). After the addition was complete, the reaction mixture was heated to 80° C. where it stirred overnight. At this time, the reaction mixture was cooled to 25° C. and was concentrated in vacuo. The residue was diluted with dichloromethane (75 mL) and was washed with a 2N aqueous hydrochloric acid solution (1×100 mL), a saturated aqueous sodium bicarbonate solution (1×100 mL), a saturated aqueous sodium chloride solution (1×100 mL), dried over sodium sulfate, filtered and concentrated in vacuo. Purification by Analogix flash chromatography (40 g, 15-50% ethyl acetate/hexanes) afforded (S)-2-[4-(2,4-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid methyl ester (0.53 g, 35%) as a yellow oil: HR-ES-MS m/z calculated for C17H19NO4F2 [M+Na]+ 362.1174, observed 362.1174; 1H NMR (300 MHz, DMSO-d6) δ ppm 0.85 (d, J=6.5 Hz, 3H), 0.91 (d, J=6.5 Hz, 3H), 1.34-1.51 (m, 1H), 1.59 (ddd, J=13.8, 9.4, 4.4 Hz, 1H), 1.71-1.87 (m, 1H), 3.64 (s, 3H), 4.11-4.31 (m, 2H), 4.71 (dd, J=11.3, 4.4 Hz, 1H), 4.94 (s, 1H), 7.07-7.27 (m, 1H), 7.42-7.70 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[CH:4][C:3]=1[C:7]([OH:9])=[O:8].[Br:10][CH:11]([CH:14]=O)[CH:12]=O>Cl>[Br:10][C:11]1[CH:12]=[N:1][C:2]2[N:6]([N:5]=[CH:4][C:3]=2[C:7]([OH:9])=[O:8])[CH:14]=1
Reactant: Nc1[nH]ncc1C(=O)O
Reactant: O=CC(Br)C=O
Agent: Cl
Product: O=C(O)c1cnn2cc(Br)cnc12
Temperature: 95 °C

Procedure:
A suspension of 5-amino-1H-pyrazole-4-carboxylic acid (1 g, 7.8 mmol) and 2-bromomalonaldehyde (1.2 g, 7.8 mmol) in an aqueous solution of hydrochloric acid (6 M, 20 mL) was heated at 95° C. for 15 minutes. The resulting mixture was cooled to room temperature and the solid formed was collected by filtration, rinsed with water and dried in vacuum oven to give 6-bromo-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid.
Reaction SMILES: CON(C)[C:4]([C@@H:6]1[CH2:8][C@H:7]1[C:9]1[C:14]2[CH2:15][CH2:16][O:17][C:13]=2[CH:12]=[CH:11][CH:10]=1)=[O:5].[H-].[H-].[H-].[H-].[Li+].[Al+3].S([O-])(O)(=O)=O.[K+]>C1COCC1.O>[O:17]1[C:13]2[CH:12]=[CH:11][CH:10]=[C:9]([C@@H:7]3[CH2:8][C@H:6]3[CH:4]=[O:5])[C:14]=2[CH2:15][CH2:16]1
Reactant: CON(C)C(=O)[C@@H]1C[C@H]1c1cccc2c1CCO2
Agent: O=S(=O)([O-])O
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: O=C[C@@H]1C[C@H]1c1cccc2c1CCO2
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 92.1 %

Procedure:
A solution of (±)-(trans)-N-methoxy-N-methyl-2-(2,3-dihydrobenzofuran-4-yl)cyclopropanecarboxamide (3.7 g, 15 mmol) in THF (10 mL) was added dropwise to a rapidly stirred suspension of LAH (683 mg, 18 mmol) in THF (50 mL) at -45° C., maintaining the temperature below -40° C. throughout. The cooling bath was removed, the reaction was allowed to warm to 5° C., and then the reaction was immediately recooled to -45° C. Potassium hydrogen sulfate (3.4 g, 25.5 mmol) in H2O (50 mL) was cautiously added dropwise, the temperature maintained below -30° C. throughout. The cooling bath was removed and the suspension was stirred at room temperature for 30 min. The mixture was filtered through Celite and the filter cake was washed with ether. The combined filtrates were then washed with cold 1N HCl, 1N NaOH, and brine. The filtrates were dried over MgSO4, and concentrated in vacuo to give a clear oil (2.6 g, 99%).
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([S:10](Cl)(=[O:12])=[O:11])[CH3:9].[CH2:14]([O:18][C:19]1[CH:20]=[C:21]([CH2:37][CH2:38][C:39]([O:41][CH3:42])=[O:40])[CH:22]=[CH:23][C:24]=1[CH2:25][CH2:26][CH2:27][C:28]1[CH:33]=[CH:32][C:31]([OH:34])=[C:30]([O:35][CH3:36])[CH:29]=1)[CH2:15][CH2:16][CH3:17].[Cl-].[Na+]>ClCCl>[CH2:14]([O:18][C:19]1[CH:20]=[C:21]([CH2:37][CH2:38][C:39]([O:41][CH3:42])=[O:40])[CH:22]=[CH:23][C:24]=1[CH2:25][CH2:26][CH2:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][S:10]([CH2:8][CH3:9])(=[O:12])=[O:11])=[C:30]([O:35][CH3:36])[CH:29]=1)[CH2:15][CH2:16][CH3:17]
Reactant: CCS(=O)(=O)Cl
Reactant: CCCCOc1cc(CCC(=O)OC)ccc1CCCc1ccc(O)c(OC)c1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCOc1cc(CCC(=O)OC)ccc1CCCc1ccc(OS(=O)(=O)CC)c(OC)c1
Temperature: -20 °C
Reaction time: 3 h
Yield: 100.4 %

Procedure:
0.2 ml (1.6 mmol) of triethylamine and then 0.15 ml (1.7 mmol) of ethanesulfonyl chloride are added to a solution of 0.5 g (1.25 mmol) of methyl 3-{3-butoxy-4-[3-(4-hydroxy-3-methoxyphenyl)propyl]phenyl}propanoate (prepared according to Example 1d) in 3 ml of dichloromethane, cooled beforehand to −20° C. The reaction medium is stirred at room temperature for 3 hours and is then treated by addition of saturated aqueous sodium chloride solution and extracted with ethyl acetate. The organic phases are combined, dried over sodium sulfate, filtered and evaporated. The residue is purified by chromatography on a column of silica eluted with a 90/10 heptane/ethyl acetate mixture. 618 mg (99%) of methyl 3-{3-butoxy-4-[3-(4-ethanesulfonyloxy-3-methoxyphenyl)propyl]phenyl}propanoate are obtained in the form of a colorless oil.
Reaction SMILES: Br[CH2:2][CH2:3][CH:4]=[CH2:5].[Mg].O1CCCC1.[NH2:12][C:13]1[N:18]=[C:17]([Cl:19])[C:16]([CH:20]=[O:21])=[C:15]([Cl:22])[N:14]=1>O>[NH2:12][C:13]1[N:14]=[C:15]([Cl:22])[C:16]([CH:20]([OH:21])[CH2:5][CH2:4][CH:3]=[CH2:2])=[C:17]([Cl:19])[N:18]=1
Reactant: C=CCCBr
Reactant: Nc1nc(Cl)c(C=O)c(Cl)n1
Agent: [Mg]
Solvent: C1CCOC1
Solvent: O
Product: C=CCCC(O)c1c(Cl)nc(N)nc1Cl
Temperature: 27.5 °C
Yield: 78 %

Procedure:
4-Bromo-1-butene (14.54 mL) was added to a mixture composed of a magnesium piece (3.17 g) and dehydrated tetrahydrofuran (150 mL) in a nitrogen atmosphere over one hour. After confirming that the internal temperature was increased, the mixture was stirred at an internal temperature of 25 to 30° C. while cooling in an ice bath for one hour to prepare a Grignard reagent. The Grignard reagent was added to a mixture composed of 2-amino-4,6-dichloro-pyrimidine-5-carbaldehyde (5.00 g) and dehydrated tetrahydrofuran (100 mL) under cooling in a dry ice-acetone bath over three hours, followed by stirring for 1.5 hours. Water (100 mL) was added to the reaction mixture, and the dry ice-acetone bath was removed. A saturated ammonium chloride solution (200 mL) was added to the reaction mixture. Then, ethyl acetate (200 mL) was added and the organic layer was separated off. The aqueous layer was extracted with ethyl acetate, and then the combined organic layers were washed with brine. The organic layers were dried over sodium sulfate and filtered. Then, the filtrate was concentrated under reduced pressure and the solvent was evaporated to obtain a crude product of the title compound (5.06 g, 78%) as a solid. The resulting compound was directly used for the next reaction without purification.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([N:13](C(OC(C)(C)C)=O)[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=2[F:22])[CH2:10][CH:9]1[C:30](O)=[O:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:33][C:34]1[CH:35]=[CH:36][C:37]([O:46][CH3:47])=[C:38]([N:40]2[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]2)[CH:39]=1>>[CH2:1]([N:8]1[CH2:12][C@@H:11]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=2[F:22])[CH2:10][C@H:9]1[C:30]([N:43]1[CH2:42][CH2:41][N:40]([C:38]2[CH:39]=[C:34]([Cl:33])[CH:35]=[CH:36][C:37]=2[O:46][CH3:47])[CH2:45][CH2:44]1)=[O:31])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N(Cc1ccc(F)cc1F)C1CC(C(=O)O)N(Cc2ccccc2)C1
Reactant: COc1ccc(Cl)cc1N1CCNCC1
Product: COc1ccc(Cl)cc1N1CCN(C(=O)[C@@H]2C[C@H](NCc3ccc(F)cc3F)CN2Cc2ccccc2)CC1
Yield: 3.5 %

Procedure:
As described for Example 1f, 1-benzyl-4-[tert-butoxycarbonyl-(2,4-difluoro-benzyl)-amino]-pyrrolidine-2-carboxylic acid (60.0 mg, 0.134 mmol) was converted, using 1-(5-chloro-2-methoxy-phenyl)-piperazine instead of 2-piperazin-1-yl-benzonitrile, to the title compound (2.6 mg, 3.5%) as light yellow oil. MS m/e=555.4 [M+H]+.
Reaction SMILES: [OH-].[Na+].[NH2:3][C:4]1[CH:5]=[CH:6][C:7]([OH:17])=[C:8]([CH:16]=1)[C:9]([CH2:11][CH2:12][C:13]([OH:15])=[O:14])=[O:10].[C:18](OC(=O)C)(=[O:20])[CH3:19]>>[C:18]([NH:3][C:4]1[CH:5]=[CH:6][C:7]([OH:17])=[C:8]([CH:16]=1)[C:9]([CH2:11][CH2:12][C:13]([OH:15])=[O:14])=[O:10])(=[O:20])[CH3:19]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc(O)c(C(=O)CCC(=O)O)c1
Agent: [Na+]
Agent: [OH-]
Product: CC(=O)Nc1ccc(O)c(C(=O)CCC(=O)O)c1
Reaction time: 1 h
Yield: 76 %

Procedure:
Sodium hydroxide solution (0.2 N) was added to 3-(5-amino-2-hydroxybenzoyl)propionic acid (2.4g) until all the solid had dissolved. Acetic anhydride (3.0 ml) was quickly added to the solution (pH 10) with vigorous stirring at 10°-15° C, after which the pH reading was in the range 4-5, and stirring was continued for a further 60 minutes. The precipitated solid was collected and washed with water and a second crop was obtained by evaporation of the filtrate and addition of water to the residue. The combined solids were recrystallised from ethanol to give 3-(5-acetamido-2-hydroxybenzoyl)propionic acid (2.2g, 76%), m.p. 205°-206° C.
Reaction SMILES: C(OC([N:8]1[CH2:22][CH2:21][C:12]2=[C:13](Cl)[N:14]3[C:18]([N:19]=[C:11]2[CH2:10][CH2:9]1)=[CH:17][CH:16]=[N:15]3)=O)(C)(C)C.FC(F)(F)C(O)=O.[S:30]1[C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=2[N:32]=[C:31]1[CH:39]1[CH2:42][NH:41][CH2:40]1>>[S:30]1[C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=2[N:32]=[C:31]1[CH:39]1[CH2:40][N:41]([C:13]2[N:14]3[C:18]([N:19]=[C:11]4[CH2:10][CH2:9][NH:8][CH2:22][CH2:21][C:12]=24)=[CH:17][CH:16]=[N:15]3)[CH2:42]1
Reactant: c1ccc2sc(C3CNC3)nc2c1
Reactant: CC(C)(C)OC(=O)N1CCc2nc3ccnn3c(Cl)c2CC1
Solvent: O=C(O)C(F)(F)F
Product: c1ccc2sc(C3CN(c4c5c(nc6ccnn46)CCNCC5)C3)nc2c1

Procedure:
The product was prepared using 10-chloro-5,6,8,9-tetrahydro-1,4,7,10a-tetraaza-cyclohepta[f]indene-7-carboxylic acid tert-butyl ester in route 1 (step e and f), in step e (route 1) 3-benzothiazol-2-yl-azetidine trifluoroacetate was used as the amine.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:8][C@H:9]1[CH2:13][C@@H:12]([N:14]2[CH:22]=[N:21][C:20]3[C:15]2=[N:16][C:17]([Cl:24])=[N:18][C:19]=3[NH2:23])[C@H:11]([OH:25])[C@@H:10]1[OH:26].C(N(C(C)C)CC)(C)C.[C:36](Cl)(=[O:39])[CH2:37][CH3:38]>C1COCC1>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:23][C:19]1[N:18]=[C:17]([Cl:24])[N:16]=[C:15]2[C:20]=1[N:21]=[CH:22][N:14]2[C@@H:12]1[CH2:13][C@H:9]([NH:8][C:36](=[O:39])[CH2:37][CH3:38])[C@@H:10]([OH:26])[C@H:11]1[OH:25]
Reactant: CCC(=O)Cl
Reactant: Nc1nc(Cl)nc2c1ncn2[C@@H]1C[C@H](N)[C@@H](O)[C@H]1O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(N)nc(Cl)nc32)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
(1S,2R,3S,5R)-3-Amino-5-(6-amino-2-chloro-purin-9-yl)-cyclopentane-1,2-diol trifluoroacetate (intermediate for preparing Example 1) (20 mg, 39 μmol) and diisopropylethylamine (25 mg, 190 μmol) are placed in a flask with dry THF (1 ml). Propionyl chloride (3.6 mg, 39 μmol) is added and the reaction mixture is stirred at room temperature. The reaction is shown to be complete by LCMS after 3 hours. The solvent is removed in vacuo and the title compound is obtained, which can be purified by reverse phase column chromatography (Isolute™ C18, 0-100% acetonitrile in water—0.1% TFA). 1H nmr (MeOD, 400 MHz); 8.10(s, 1H), 4.75(m, 1H), 4.60(m, 1H), 4.20(m, 1H), 4.00(m, 1H), 3.75(m, 1H), 3.25(m, 1H), 2.85(m, 1H), 2.40(q, 2H), 2.10(m, 1H), 1.20(t, 3H), MS (ES+) m/e 341 (MH+).
Reaction SMILES: O=[C:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[C:7]([O:9]CC)=O.[NH2:12][C:13]([NH2:15])=[O:14].Cl.[OH-].[Na+]>CCO>[N:12]1[C:2]2[CH2:6][CH2:5][CH2:4][C:3]=2[C:7]([OH:9])=[N:15][C:13]=1[OH:14]
Reactant: NC(N)=O
Reactant: CCOC(=O)C1CCCC1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Oc1nc(O)c2c(n1)CCC2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 52.4 %

Procedure:
To a suspension of ethyl 2-oxocyclopentanecarboxylate (10 mL, 67.2 mmol) and urea (6.07 g, 101 mmol) in EtOH (20 mL), cooled in an ice-bath, was added concentrated HCl (1 mL) dropwise. After completion of addition, the ice bath was removed and the reaction mixture was stirred at RT for 30 min. The reaction mixture was then heated to reflux at 85° C. for 5 h. The reaction mixture was cooled to RT and the EtOH was decanted to give a crystalline solid. The solid was heated to reflux with aqueous 5% NaOH solution (25 mL) for 2 h. The reaction mixture was cooled to RT and the precipitate was collected by filtration. The precipitate was washed with water and dried to afford 6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diol (5.36 g, 52% yield). 1H NMR (400 MHz, DMSO-d6) δ (ppm): 1.81-1.97 (m, 2H), 2.38-2.46 (m, 2H), 2.47-2.60 (m, 2H), 10.70 (s, 1H), 11.05 (s, 1H).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[CH3:6][O-:7].[Na+]>ClC1C=CC=CC=1>[C:6]([N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1)([N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1)=[O:7]
Reactant: c1c[nH]cn1
Reactant: C[O-]
Agent: [Na+]
Solvent: Clc1ccccc1
Product: O=C(n1ccnc1)n1ccnc1
Temperature: 90 °C
Reaction time: 1 h
Yield: 84 %

Procedure:
286.0 g of imidazole were introduced into 1400 g of chlorobenzene in a flask fitted with column and distillation bridge. 720 g of 30% strength methanolic sodium methoxide solution were added dropwise. First methanol was removed by distillation, followed by 300 ml of chlorobenzene. 202 g of phosgene were subsequently passed in at 80-85° C. over the course of one hour. When the addition was complete, the mixture was stirred at 90° C. for a further 1 hour while a vigorous stream of nitrogen was passed through the flask, and the precipitate then present was filtered off at 80° C. and rinsed with 200 g of chlorobenzene at 90° C. The filtrate and the washing liquid were combined and cooled to 0° C. The precipitate which deposited was filtered off, rinsed with 200 g of dry chlorobenzene at 20° C. and dried at 60° C. under reduced pressure (50 mbar). 278.3 g of carbonyldiimidazole were thus obtained in the form of colorless crystals and having a purity of 97.8%. This corresponded to a yield of 84.0% of theory.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH2:8])=[CH:5][CH:4]=1.[Br:11][C:12]1[CH:17]=[C:16](Cl)[C:15]([N+:19]([O-:21])=[O:20])=[CH:14][N:13]=1.C(N(CC)CC)C>C(#N)C.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH:8][C:16]2[C:15]([N+:19]([O-:21])=[O:20])=[CH:14][N:13]=[C:12]([Br:11])[CH:17]=2)=[CH:5][CH:4]=1
Reactant: O=[N+]([O-])c1cnc(Br)cc1Cl
Reactant: COc1ccc(CN)cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COc1ccc(CNc2cc(Br)ncc2[N+](=O)[O-])cc1
Reaction time: 1.5 h
Yield: 77.2 %

Procedure:
A solution of 4-methoxybenzylamine (0.756 g, 5.51 mmol) in acetonitrile (2 mL) was added to a mixture of 2-bromo-4-chloro-5-nitropyridine (1.19 g, 5.01 mmol) and triethylamine (0.768 mL, 5.51 mmol) in acetonitrile (8 mL). After stirring for 1.5 hours, the solution was diluted with ethyl acetate (100 mL) which was then washed successively with water and brine before being concentrated in vacuo to a light brown oil which solidified on standing to give the title compound (1.31 g, 3.87 mmol, 77%). 1H NMR (d6-DMSO, 400 MHz) δ 9.00 (br t, 1H, J=6.3 Hz), 8.80 (s, 1H), 7.35 (d, 2H, J=8.7 Hz), 7.10 (s, 1H), 6.95 (d, 2H, J=8.8 Hz), 4.60 (d, 2H, J=6.0 Hz), 3.70 (s, 3H). LCMS (1) Rt=2.13 min; m/z (ESI−) 336, 338 (M−H).
Reaction SMILES: Br[CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[NH:21][C:20](=[O:22])[N:19]([CH2:23][C:24]([NH:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:36])[F:35])[CH:29]=3)=[O:25])[N:18]=2)=[CH:13][CH:12]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CC(C)=O>[C:6]([O:5][C:3](=[O:4])[CH2:2][N:21]1[C:20](=[O:22])[N:19]([CH2:23][C:24](=[O:25])[NH:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:36])[F:35])[CH:29]=2)[N:18]=[C:17]1[C:14]1[CH:13]=[CH:12][C:11]([Cl:10])=[CH:16][CH:15]=1)([CH3:9])([CH3:8])[CH3:7]
Reactant: O=C(Cn1nc(-c2ccc(Cl)cc2)[nH]c1=O)NCc1cccc(C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)Cn1c(-c2ccc(Cl)cc2)nn(CC(=O)NCc2cccc(C(F)(F)F)c2)c1=O

Procedure:
92.6 mg (0.475 mmol) of tert.-butyl bromoacetate are added to 150.0 mg of (0.365 mmol) 2-[3-(4-chlorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-N-[3-(trifluoromethyl)phenylmethyl]-acetamide from Example 242A and 178.5 mg (0.548 mmol) of caesium carbonate in 5.0 ml of acetone and heated for 5 hrs under reflux. For the workup, the reaction mixture is concentrated after cooling, the residue is partitioned between water and ethyl acetate, the organic phase separated and the aqueous phase extracted several times more with ethyl acetate. The combined organic phases are concentrated and the residue purified by preparative HPLC [Method 12]. 139 mg (73% of theory) of the target compound are thus obtained.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:10]([N:12]([CH3:36])[C@H:13]([C:17]([NH:19][C@H:20]([C:33]([NH2:35])=[O:34])[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[C:24]([C:29]([CH3:32])([CH3:31])[CH3:30])[CH:23]=1)=[O:18])[CH:14]([CH3:16])[CH3:15])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>C(O)(C(F)(F)F)=O>[NH2:1][C@H:2]([C:10]([N:12]([CH3:36])[C@H:13]([C:17]([NH:19][C@H:20]([C:33]([NH2:35])=[O:34])[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[C:24]([C:29]([CH3:30])([CH3:31])[CH3:32])[CH:23]=1)=[O:18])[CH:14]([CH3:15])[CH3:16])=[O:11])[CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CC(C)[C@@H](C(=O)N[C@@H](Cc1ccc(O)c(C(C)(C)C)c1)C(N)=O)N(C)C(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: CC(C)[C@@H](C(=O)N[C@@H](Cc1ccc(O)c(C(C)(C)C)c1)C(N)=O)N(C)C(=O)[C@@H](N)Cc1ccccc1

Procedure:
A solution of 380 mg (0.638 mmol) of Boc-Phe-N-Me-Val-Tyr(3-tBu)-NH2 in 15 ml of TFA was stirred at room temperature for one hour and a half. The reaction solution was concentrated under reduced pressure and the resulting residue was diluted with ethyl acetate and washed first with saturated aqueous NaHCO3, then with saturated brine. The organic layer was dried with anhydrous sodium sulfate and concentrated under reduced pressure; thereafter, the resulting residue was subjected to silica gel column chromatography (eluting solvent consisting of methylene chloride, methanol and aqueous ammonia at a ratio of 100:10:1) to give Phe-N-Me-Val-Tyr(3-tBu)-NH2 in the amount of 240 mg (76%) FAB-MS: 497 (M+H+); NMR(method g,CDCl3): δ 0.74(2H,d,J=6.6 Hz), 0.79(1H,d,J=6.6 Hz), 0.89(1H,d,J=6.6 Hz), 0.92(2H,d,J=6.6 Hz), 1.36(3H,s), 1.38(6H,s), 2.27-2.35(1H,m), 2.71(2H,s), 2.81(1H,s), 2.77-3.19(4H,m), 3.56-3.61(2/3H,m), 3.80-3.90(1/3H,m), 3.95(2/3H,d,J=10.9 Hz), 4.46(1/3H,d,J=11.2 Hz), 4.55-4.65(1/3H,m), 4.70-4.85(2/3H,m), 6.60-7.40(8H,m)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([N:15]1[CH2:20][CH2:19][N:18]([NH:21][CH:22]3[CH2:27][CH2:26][N:25]([C:28]4[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=4)[CH2:24][CH2:23]3)[C:17](=O)[CH2:16]1)(=[O:14])=[O:13])[CH:6]=[CH:5]2.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:36]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([N:15]1[CH2:20][CH2:19][N:18]([NH:21][CH:22]3[CH2:27][CH2:26][N:25]([C:28]4[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=4)[CH2:24][CH2:23]3)[C:17](=[S:36])[CH2:16]1)(=[O:14])=[O:13])[CH:6]=[CH:5]2
Reactant: O=C1CN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CCN1NC1CCN(c2ccncc2)CC1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: c1ccncc1
Product: O=S(=O)(c1ccc2cc(Cl)ccc2c1)N1CCN(NC2CCN(c3ccncc3)CC2)C(=S)C1
Temperature: 100 °C
Reaction time: 5 h
Yield: 37.7 %

Procedure:
A solution of 4-(6-chloronaphthalene-2-sulfonyl)-1-[1-(4-pyridyl)-4-piperidinylamino}-2-piperazinone (200 mg) in pyridine (10 ml) was combined with phosphorus pentasulfide (80 mg) and stirred at 100° C. for 5 hours. The supernatant of the reaction mixture was concentrated and the residue was purified by a column chromatography on a silica gel (dichloromethane: 10% aqueous ammonia-containing methanol=20:1) to obtain the title compound (35 mg) as a colorless solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1)#[N:2].C(=O)([O-])[O-].[K+].[K+].[I-].[K+].Cl[CH2:19][CH:20]1[CH2:22][CH2:21]1>CN(C)C=O.O>[CH:20]1([CH2:19][O:9][C:5]2[CH:4]=[C:3]([CH2:1][NH2:2])[CH:8]=[CH:7][CH:6]=2)[CH2:22][CH2:21]1
Reactant: N#Cc1cccc(O)c1
Reactant: ClCC1CC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: NCc1cccc(OCC2CC2)c1
Temperature: 90 °C
Reaction time: 4 h

Procedure:
3-Cyanophenol (12.4 g) was dissolved in N,N-dimethylformamide (hereinafter, referred to as DMF; 100 mL). To the solution, potassium carbonate (30.5 g), potassium iodide (1.74 g), and (chloromethyl)cyclopropane (10.2 mL) were added, and the mixture was stirred at 90° C. for 4 hours. To the reaction mixture, water (130 mL) was added, and the resultant mixture was then extracted with toluene (130 mL). The organic layer was washed with brine (100 mL), dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran (hereinafter, referred to as THF; 60 mL). To the solution, a solution of lithium aluminum hydride (hereinafter, referred to as LAH) in THF (2.4 M, 68 mL) was gradually added dropwise at 0° C., and the reaction mixture was then stirred at 45° C. for 4 hours. To the reaction mixture, water (10 mL), an aqueous sodium hydroxide solution (1.0 M, 10 mL), and water (5.0 mL) were gradually added at 0° C. The resultant precipitate was removed by filtration and washed with 10% methanol/THF (400 mL). Then, the combined filtrate was concentrated under reduced pressure. To the residue, water (50 mL) was added, and the resultant mixture was then extracted with ethyl acetate (50 mL×3). The organic layer was washed with brine (50 mL), dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to obtain the title compound (18.1 g) as a crude product.