Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(N[C:7]2[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]=[C:9]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[N:8]=2)CCCC1.[F:23][C:24]([F:34])([F:33])[O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[NH2:32]>>[CH3:13][C:12]1[C:7]([NH:32][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[O:25][C:24]([F:33])([F:34])[F:23])=[N:8][C:9]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)=[N:10][C:11]=1[CH3:14]
Reactant: Nc1ccccc1OC(F)(F)F
Reactant: Cc1nc(NCc2ccccn2)nc(NC2CCCC2)c1C
Product: Cc1nc(NCc2ccccn2)nc(Nc2ccccc2OC(F)(F)F)c1C

Procedure:
The titled compound was synthesized according to the procedure described for preparation of N4-cyclopentyl-5,6-dimethyl-N2-(pyridin-2-ylmethyl)pyrimidine-2,4-diamine (Example 29) using [2-(trifluoromethoxy)phenyl]amine instead of cyclopentanamine. The crude material was purified by column chromatography eluting with mixture of chloroform/ethanol/20% water solution of ammonia (200:10:1), and then the final product was washed with diethyl ether to afford the titled compound as a light-yellow solid. 1H NMR (300 MHz, CDCl3) δ ppm 1.09 (s, 3H), 2.35 (s, 3H), 4.74 (d, J=5.5 Hz, 2H), 6.81 (s, 1H), 6.98 (t, J=7.8 Hz, 1H), 7.16 (t, J=7.0 Hz, 2H), 7.23 (d, J=7.3 Hz, 1H), 7.36 (d, J=7.8 Hz, 1H), 7.62 (t, J=7.3 Hz, 1H), 8.43 (d, J=7.5 Hz, 1H), 8.59 (d, J=3.8 Hz, 1H); MS (ESI) m/z 390.5 (M+1)+.
Reaction SMILES: [S:1]1[CH2:4][S:3][C:2]1=[C:5]([C:11]([O:13]N1C2C=CC=CC=2N=N1)=O)[C:6]([O:8][CH2:9][CH3:10])=[O:7].[NH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1>>[S:3]1[CH2:4][S:1][C:2]1=[C:5]([C:11](=[O:13])[NH:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCOC(=O)C(C(=O)On1nnc2ccccc21)=C1SCS1
Reactant: Nc1ccccn1
Product: CCOC(=O)C(C(=O)Nc1ccccn1)=C1SCS1
Yield: 51 %

Procedure:
Following the procedure of Example 27, the titled compound (51%) was prepared from ethyl 2-(1,3-dithietan-2-ylidene)-2-[(1-benzotriazolyl)oxycarbonyl]acetate and 2-aminopyridine.
Reaction SMILES: C[Mg]Br.[OH:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12](=[O:14])[CH3:13])=[CH:7][CH:6]=1.[C:15](OCC)(=O)C.Cl>O1CCCC1.O>[OH:14][C:12]([CH3:15])([CH3:13])[CH2:11][C:8]1[CH:7]=[CH:6][C:5]([OH:4])=[CH:10][CH:9]=1
Reactant: CC(=O)Cc1ccc(O)cc1
Reactant: CCOC(C)=O
Agent: C[Mg]Br
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(O)Cc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 77 %

Procedure:
To a solution of methyl magnesium bromide (3 M, 14 mL, 39.94 mmol) cooled to 0° C. was added tetrahydrofuran (10 mL) and as solution of 1-(4-hydroxy-phenyl)-propan-2-one (1 g, 6.66 mmol) in tetrahydrofuran (30 mL). The resulting mixture was then warmed to room temperature and then stirred for 2 h. At this time, the reaction was partioned between ethyl acetate and water. The water layer was made acidic with 1N aqueous hydrochloric acid (pH=1). The organic phase was separated and concentrated in vacuo. The residue was dissolved in a small volume of tetrahydrofuran and the mixture was treated with an excess of hexanes. This resulted in the precipitation of the product 4-(2-hydroxy-2-methyl-propyl)-phenol (0.85 g, 77%) as a white solid.
Reaction SMILES: [CH3:1][N:2]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:4]([CH2:5][C@@H:6]([C:8]([OH:10])=[O:9])[NH2:7])=[CH:3]1.[C:17](=[O:20])([O-])O.[Na+].O>O1CCOCC1>[CH3:1][N:2]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:4]([CH2:5][C@@H:6]([C:8]([OH:10])=[O:9])[NH:7][C:17](=[O:20])[CH:3]=[CH:4][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:3]1
Reactant: O=C([O-])O
Reactant: Cn1cc(C[C@H](N)C(=O)O)c2ccccc21
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Cn1cc(C[C@H](NC(=O)C=Cc2ccccc2)C(=O)O)c2ccccc21
Yield: 68.9 %

Procedure:
The same procedures as in Example 121 were carried out from 1-methyl-L-tryptophan (2.0 g), sodium hydrogencarbonate (0.8 g), 2,5-dioxopyrrolidin-1-yl 3-phenyl acrylate (2.3 g), water (60 mL), and dioxane (140 mL), to give the captioned compound (1.1 g, 33%) as crystals.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH3:13])=[C:11]([C:14]([O:16]CC)=[O:15])[C:10]([CH3:19])=[N:9]2)=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([CH3:13])=[C:11]([C:14]([OH:16])=[O:15])[C:10]([CH3:19])=[N:9]2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1c(C)nn(-c2ccc(F)cc2)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1nn(-c2ccc(F)cc2)c(C)c1C(=O)O
Reaction time: 0.5 h
Yield: 83.1 %

Procedure:
Then, ethyl 1-(4-fluorophenyl)-3,5-dimethylpyrazole-4-carboxylate (15.5 g) was dissolved in a mixed solvent of ethanol (30 ml) and water (30 ml). Sodium hydroxide (2.75 g) was added and the mixture was stirred at a refluxing temperature for 30 min. After evaporation of ethanol, dilute hydrochloric acid was added to the residue. The obtained solid was recrystallized from aqueous methanol solution to give the title compound (11.5 g), melting point: 219–220° C.
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[N:8]=[N:9][N:10]([C:15]3[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:32])[CH2:23][NH:24]C(=O)OC(C)(C)C)=[CH:17][CH:16]=3)[C:11]=2[CH2:12][CH2:13][CH3:14])=[O:6])[CH2:3][CH2:2]1.Cl>C(O)C.C(O)(C)C>[CH:1]1([NH:4][C:5]([C:7]2[N:8]=[N:9][N:10]([C:15]3[CH:16]=[CH:17][C:18]([NH:21][C:22](=[O:32])[CH2:23][NH2:24])=[CH:19][CH:20]=3)[C:11]=2[CH2:12][CH2:13][CH3:14])=[O:6])[CH2:2][CH2:3]1
Reactant: CCCc1c(C(=O)NC2CC2)nnn1-c1ccc(NC(=O)CNC(=O)OC(C)(C)C)cc1
Agent: Cl
Solvent: CC(C)O
Solvent: CCO
Product: CCCc1c(C(=O)NC2CC2)nnn1-c1ccc(NC(=O)CN)cc1
Reaction time: 2 h
Yield: 108.8 %

Procedure:
To a suspension of tert-butyl {2-[(4-{4-[(cyclopropylamino)carbonyl]-5-propyl-1H-1,2,3-triazol-1-yl}phenyl)amino]-2-oxoethyl}carbamate (0.76 g) obtained in Example 22 in ethanol (5 ml) was added 6N hydrochloric acid in isopropyl alcohol solution (6 ml) at room temperature, and the mixture was stirred for 2 hr. The solvent was evaporated under reduced pressure to give the title compound as a white powder (0.64 g, 100%).
Reaction SMILES: [C:1]([C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:17]=1[NH:16]C=[C:14]2[CH2:18][CH2:19][C:20]([OH:22])=[O:21])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([OH:25])C.O=[O+][O-].[I-].[K+]>C(OCC)(=O)C.C(O)(=O)C.O>[NH2:16][C:17]1[C:9]([C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:10][CH:11]=[CH:12][C:13]=1[C:14](=[O:25])[CH2:18][CH2:19][C:20]([OH:22])=[O:21]
Reactant: CCO
Reactant: O=C(O)CCc1c[nH]c2c(C(=O)c3ccccc3)cccc12
Agent: O=[O+][O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: Nc1c(C(=O)CCC(=O)O)cccc1C(=O)c1ccccc1
Reaction time: 1 h
Yield: 67 %

Procedure:
A solution of 8.7 g (0.03 mole) of 7-benzoyl-1H-indole-3-propanoic acid in 300 ml of ethyl acetate and 100 ml of abs. ethanol was ozonized until ozone was present above the solution. The yellow solution was then treated with 16.6 g (0.1 mole) of potassium iodide in 30 ml of acetic acid and 30 ml of water. After stirring 1 hr, the liberated iodine was removed by washing with a 15% sodium thiosulfate solution and the yellow organic layer was concentrated. The residue was dissolved in 100 ml of ethanol and 20 ml of 6N hydrochloric acid and heated at reflux for 16 hr. The dark red solution was concentrated and the residue was partitioned between dil. sodium hydroxide and methylene chloride. The basic aqueous layer was made acidic and the pH was adjusted to 2-3 by the addition of dil. sodium hydroxide. The solid was collected and dried, then recrystallized from benzene isopropyl ether to give 5.9 g (67 %) of yellow powder, m.p. 161.0°-2.5° C.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([S:16](Cl)(=[O:18])=[O:17])=[CH:12][CH:11]=1.[CH2:20]([N:27]1[C:31]2([CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[NH:30][CH:29]([CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:28]1=[O:44])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl>[CH2:20]([N:27]1[C:31]2([CH2:32][CH2:33][N:34]([S:16]([C:13]3[CH:14]=[CH:15][C:10]([O:9][CH3:8])=[CH:11][CH:12]=3)(=[O:18])=[O:17])[CH2:35][CH2:36]2)[NH:30][CH:29]([CH2:37][C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)[C:28]1=[O:44])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=C1C(Cc2ccccc2)NC2(CCNCC2)N1Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(S(=O)(=O)N2CCC3(CC2)NC(Cc2ccccc2)C(=O)N3Cc2ccccc2)cc1
Temperature: 25 °C

Procedure:
Triethylamine (0.12 ml, 0.89 mmol) and subsequently 4-methoxybenzenesulfonyl chloride (308 mg, 1.49 mmol) were added to a solution of 1,3-dibenzyl-1,4,8-triaza-spiro[4,5]decan-2-one (249 mg, 0.75 mmol) in CH2Cl2 (6.7 ml) with stirring under a blanket of nitrogen at RT. The reaction mixture was stirred overnight. The organic phase was rendered alkaline using saturated aqueous sodium carbonate solution (20 ml), and the aqueous phase was extracted with CH2Cl2 (15 ml). The combined organic phases were dried over Na2SO4. After filtration, removal of the solvent, and column chromatography, the desired product 1,3-dibenzyl-8-(4-methoxy-benzenesulfonyl)-1,4,8-triazaspiro[4,5]decan-2-one was obtained in a yield of 301 mg (79% of theory).
Reaction SMILES: Br[C:2]1[CH:20]=[N:19][C:5]2[N:6]([CH2:15][CH:16]([CH3:18])[CH3:17])[CH2:7][CH2:8][C:9]([C:11]([O:13][CH3:14])=[O:12])=[CH:10][C:4]=2[CH:3]=1.[CH2:21]([O:25][CH2:26][CH2:27][O:28][C:29]1[CH:34]=[CH:33][C:32](OB(O)O)=[CH:31][CH:30]=1)[CH2:22][CH2:23][CH3:24].C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C(O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:21]([O:25][CH2:26][CH2:27][O:28][C:29]1[CH:30]=[CH:31][C:32]([C:2]2[CH:20]=[N:19][C:5]3[N:6]([CH2:15][CH:16]([CH3:18])[CH3:17])[CH2:7][CH2:8][C:9]([C:11]([O:13][CH3:14])=[O:12])=[CH:10][C:4]=3[CH:3]=2)=[CH:33][CH:34]=1)[CH2:22][CH2:23][CH3:24]
Reactant: COC(=O)C1=Cc2cc(Br)cnc2N(CC(C)C)CC1
Reactant: CCCCOCCOc1ccc(OB(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: CCCCOCCOc1ccc(-c2cnc3c(c2)C=C(C(=O)OC)CCN3CC(C)C)cc1
Temperature: 115 °C
Reaction time: 0.5 h
Yield: 86.7 %

Procedure:
A suspension of methyl 3-bromo-9-isobutyl-8,9-dihydro-7H-pyrido[2,3-b]azepine-6-carboxylate (640 mg), 4-(2-butoxyethoxy)phenylboric acid (583 mg) and potassium carbonate (678 mg) in toluene (15 ml), ethanol (1.5 ml) and water (1.5 ml) was stirred for 30 minutes under an argon atmosphere. Tetrakis(triphenylphosphine)palladium (110 mg) was added thereto, and the mixture was heated at 115° C. for 6 hours under an argon atmosphere, which was allowed to cool. Water was added thereto and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=19:1→hexane:ethyl acetate=4:1) to give methyl 3-[4-(2-butoxyethoxy)phenyl]-9-isobutyl-8,9-dihydro-7H-pyrido[2,3-b]azepine-6-carboxylate (740 mg) as a yellow oily material.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1.Cl[CH2:16][CH2:17][CH:18]([OH:27])[CH2:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)CCC>[O:20]([CH2:19][CH:18]([OH:27])[CH2:17][CH2:16][N:12]1[CH2:13][CH2:14][N:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)[CH2:10][CH2:11]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COc1cccc(N2CCNCC2)c1
Reactant: OC(CCCl)COc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCCCO
Product: COc1cccc(N2CCN(CCC(O)COc3ccccc3)CC2)c1
Yield: 46.3 %

Procedure:
This compound was prepared according to the procedure of Example 78. A mixture of 3.8 g (0.02 mole) of 1-(3-methoxyphenyl)piperazine, 4.0 g (0.02 mole) of 4-chloro-1-phenoxy-2-butanol and 8.0 g (0.075 mole) of anhydrous sodium carbonate in 150 ml of 1-butanol gave 3.3 g (45%) of off-white powder, m.p. 58°-60° C. Recrystallizing solvent used was diethyl ether-petroleum ether.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:7]([SH:10])[CH2:8][CH3:9].CN(C=O)C.[Cl:16][C:17]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=1[S:24]([NH:27][C:28]1[N:33]=[C:32](Cl)[C:31]([S:35][C:36]2[CH:41]=[CH:40][C:39]([S:42]([N:45]3[CH2:50][CH2:49][CH2:48][CH2:47][CH2:46]3)(=[O:44])=[O:43])=[CH:38][CH:37]=2)=[CH:30][N:29]=1)(=[O:26])=[O:25]>CC(C)=O>[Cl:16][C:17]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=1[S:24]([NH:27][C:28]1[N:33]=[C:32]([S:10][CH2:7][CH2:8][CH3:9])[C:31]([S:35][C:36]2[CH:37]=[CH:38][C:39]([S:42]([N:45]3[CH2:50][CH2:49][CH2:48][CH2:47][CH2:46]3)(=[O:44])=[O:43])=[CH:40][CH:41]=2)=[CH:30][N:29]=1)(=[O:26])=[O:25]
Reactant: O=S(=O)(Nc1ncc(Sc2ccc(S(=O)(=O)N3CCCCC3)cc2)c(Cl)n1)c1ccc(Cl)cc1Cl
Reactant: CCCS
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: CCCSc1nc(NS(=O)(=O)c2ccc(Cl)cc2Cl)ncc1Sc1ccc(S(=O)(=O)N2CCCCC2)cc1
Temperature: 50 °C
Yield: 39.5 %

Procedure:
Cesium carbonate (65 mg, 0.2 mmol) was added to a solution of propanethiol (8 μl, 0.09 mmol) in acetone (0.5 mL). The reaction mixture was heated to 50° C. for 45 minutes then cooled to r.t. DMF (2 mL) and 2,4-Dichloro-N-{4-chloro-5-[4-(piperidine-1-sulfonyl)-phenylsulfanyl]-pyrimidin-2-yl}-benzenesulfonamide 11 (50 mg, 0.08 mmol) were added and the resultant mixture heated to 50° C. for 2 hours. The reaction was allowed to cool, filtered through celite and the solvent evaporated in vacuo. The crude product was purified by flash column chromatography (2% MeOH in DCM) to afford 2,4-Dichloro-N-{5-[4-(piperidine-1-sulfonyl)-phenylsulfanyl]-4-propylsulfanyl-pyrimidin-2-yl}-benzenesulfonamide 32 (20 mg). 1H NMR (CDCl3): δ 1.00 (m, 3H), 1.27 (m, 2H), 1.66 (m, 6H), 2.88 (m, 2H), 2.99 (m, 4H), 7.26 (m, 2H), 7.45 (d, 1H), 7.55 (s, 1H), 7.66 (d, 2H), 8.27 (d, 1H), 8.5149 (s, 1H), 12.61 (br s, 1H) ppm. Mass Spectrum m/e=632.8 (M+1).
Reaction SMILES: [H-].[Na+].[CH3:3][CH:4]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:5]([O:7][CH2:8][CH3:9])=[O:6].[Cl:15][C:16]1[N:17]=[N:18][C:19](Cl)=[CH:20][CH:21]=1>O1CCOCC1>[Cl:15][C:16]1[N:17]=[N:18][C:19]([C:4]([CH3:3])([C:5]([O:7][CH2:8][CH3:9])=[O:6])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:20][CH:21]=1
Reactant: Clc1ccc(Cl)nn1
Reactant: CCOC(=O)C(C)C(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCOC(=O)C(C)(C(=O)OCC)c1ccc(Cl)nn1
Temperature: 0 °C
Reaction time: 1 h
Yield: 24.9 %

Procedure:
To a mixture of NaH (13.42 g, 336 mmol) in dioxane (800 mL) was added diethyl 2-methylmalonate (42.9 ml, 252 mmol) drop-wise at 0° C. The reaction was stirred at 0° C. for 1 hr and allowed to warm to ambient temperature. 3,6-dichloropyridazine (25 g, 168 mmol) was then added portion-wise at 25° C. The reaction was then stirred at reflux for 1 hr. Solvent was removed via rotary evaporation and the resulting residue was dissolved in EtOAc. The organic solution was washed with saturated NaHCO3 (100 mL) followed by 5% citric acid. The organic layer was then dried with MgSO4, filtered, and concentrated to dryness. The resulting residue was purified via MPLC (Hex:EtOAc, 3:1) to provide the title compound, diethyl 2-(6-chloropyridazin-3-yl)-2-methylmalonate 48A (12 g, 25% yield) as a yellow oil. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.18 (s, 6 H) 1.81 (s, 3H) 4.21 (dd, J=7.07, 2.27 Hz, 4 H) 8.00 (s, 2 H). ESI-MS:m/z 287.1 (M+H)+.
Reaction SMILES: C([O:3][C:4]([C:6]([F:28])([F:27])[CH:7]([O:14][C:15]([C:17]12[CH2:26][CH:21]3[CH2:22][CH:23]([CH2:25][CH:19]([CH2:20]3)[CH2:18]1)[CH2:24]2)=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5])C.O1CCOCC1.[OH-].[Na+].[Cl-].[C:38]1([S+:44]([C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>C(Cl)Cl.O>[C:17]12([C:15]([O:14][CH:7]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:6]([F:27])([F:28])[C:4]([O-:5])=[O:3])=[O:16])[CH2:24][CH:23]3[CH2:25][CH:19]([CH2:20][CH:21]([CH2:22]3)[CH2:26]1)[CH2:18]2.[C:51]1([S+:44]([C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)[C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=1
Reactant: CCOC(=O)C(F)(F)C(OC(=O)C12CC3CC(CC(C3)C1)C2)c1ccccc1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Solvent: ClCCl
Product: O=C(OC(c1ccccc1)C(F)(F)C(=O)[O-])C12CC3CC(CC(C3)C1)C2
Reaction time: 0.5 h
Yield: 52.2 %

Procedure:
After stirring a mixed solution of 1-adamantane carboxylic acid 2-ethoxycarbonyl-2,2-difluoro-1-phenyl-ethyl ester (6.6 g) prepared in Synthesis Example 1-5, 1,4-dioxane (20 g) and 25% by mass of caustic soda (2.5 g) for 2 hours, water (30 g) was added to the reaction solution and washed with n-hexane to prepare an aqueous solution of sodium 3-(adamantane-1-carbonyloxy)-2,2-difluoro-3-phenyl propionate. An aqueous solution of triphenylsulfonium chloride (32 g) and methylene chloride (100 g) were added to the product, stirred for 30 minutes, and then an organic layer was isolated and washed with water, and thereafter was concentrated under reduced pressure. Methylisobutyl ketone was added to the concentrated solution, and concentrated again. Diisopropyl ether was added to the concentrated solution for crystallization, and a solid obtained was dried under reduced pressure to obtain a target compound, or triphenylsulfonium 3-(adamantane-1-carbonyloxy)-2,2-difluoro-3-phenyl propionate (5.5 g) as a white crystal (yield: 58%).
Reaction SMILES: CO[C:3]([C:5]1([C:9]#[N:10])[CH2:8][CH2:7][CH2:6]1)=[O:4].[CH2:11]([NH2:14])[CH2:12][NH2:13].Cl>CO.O>[NH2:13][CH2:12][CH2:11][NH:14][C:3]([C:5]1([C:9]#[N:10])[CH2:8][CH2:7][CH2:6]1)=[O:4]
Reactant: NCCN
Reactant: COC(=O)C1(C#N)CCC1
Agent: Cl
Solvent: CO
Solvent: O
Product: N#CC1(C(=O)NCCN)CCC1
Reaction time: 15 h

Procedure:
A solution of compound 1 (8.74 g, 0.063 mol) in CH3OH (50 mL) was added to ethylenediamine (3.77 g, 4.25 mL, 0.63 mol) at room temperature. After 15 h at room temperature, the mixture was evaporated. The yellow oil was obtained and dissolved in 20 mL of distilled water, acidulated with HCl to pH 2 and the solution applied to an AG 50W×8 column cation exchange column (200-400 mesh, H+ form, 100 mL of resin, 3.0 cm column diameter). The column was eluted first with H2O to remove excess ethylenediamine and then with a gradient HCl. The 0.5-1 N HCl solution containing the product was evaporated to dryness, yielding 6.37 g (60.47%). MS (ESI): m/z: 168.08 [M+H]+. Anal. Calcd (Found) for C8H13N3O: C, 57.46 (57.02); H, 7.84 (7.49); N, 25.13 (24.88). 1H NMR (D2O, 400 MHz), δ (ppm): 3.46 (t, J=6.0 Hz, 2H, —NHCH2CH2NH2), 3.07 (t, J=6.0 Hz, 2H, —NHCH2CH2NH2), 2.60-2.50 (m, 4H, —CCH2CH2CH2—), 1.94-2.14 (m, 2H, —CCH2CH2CH2—). 13C NMR (D2O, 400 MHz), δ (ppm): 168.99, 119.95, 41.39, 40.59, 39.38, 31.13, 17.09.
Reaction SMILES: C([O:5][C:6]([CH2:8][CH2:9][C:10]([NH:12][C@H:13]([C:22]([NH:24][C@H:25]([C:35]([NH:37][C@H:38]([C:47]([NH:49][C@H:50]([C:55]([NH:57][C@H:58]([C:63]([NH:65][C@H:66]([CH:70](OC)[O:71]C)[CH2:67][C:68]#[CH:69])=[O:64])[CH2:59][CH:60]([CH3:62])[CH3:61])=[O:56])[C:51]([CH3:54])([CH3:53])[CH3:52])=[O:48])[CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1[CH3:46])=[O:36])[CH2:26][CH2:27][C:28](=[O:34])[O:29]C(C)(C)C)=[O:23])[CH2:14][C:15](=[O:21])[O:16]C(C)(C)C)=[O:11])=[O:7])(C)(C)C.ClCCl.O>FC(F)(F)C(O)=O>[C:6]([CH2:8][CH2:9][C:10]([NH:12][C@H:13]([C:22]([NH:24][C@H:25]([C:35]([NH:37][C@H:38]([C:47]([NH:49][C@H:50]([C:55]([NH:57][C@H:58]([C:63]([NH:65][CH:66]([CH2:67][C:68]#[CH:69])[CH:70]=[O:71])=[O:64])[CH2:59][CH:60]([CH3:62])[CH3:61])=[O:56])[C:51]([CH3:52])([CH3:53])[CH3:54])=[O:48])[CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1[CH3:46])=[O:36])[CH2:26][CH2:27][C:28](=[O:29])[OH:34])=[O:23])[CH2:14][C:15](=[O:16])[OH:21])=[O:11])([OH:7])=[O:5]
Reactant: C#CC[C@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](NC(=O)[C@H](Cc1ccccc1C)NC(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)[C@H](CC(=O)OC(C)(C)C)NC(=O)CCC(=O)OC(C)(C)C)C(C)(C)C)C(OC)OC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: C#CCC(C=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](NC(=O)[C@H](Cc1ccccc1C)NC(=O)[C@H](CCC(=O)O)NC(=O)[C@H](CC(=O)O)NC(=O)CCC(=O)O)C(C)(C)C
Yield: 64.8 %

Procedure:
70 mg (0.067 mmol) of N2-[N-[N-[N-[N-[3-(tert-butoxycarbonyl)propionyl]-O-tert-butyl-L-α-aspartyl]-O-tert-butyl-L-α-glutamyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-N1-[1(S)-(dimethoxymethyl)-3-butynyl]-L-leucinamide were stirred in a mixture of 4 ml of trifluoroacetic acid, 4 ml of dichloromethane and 30 mg of water at room temperature for 30 minutes. The solution was evaporated to dryness in a vacuum and the residue was chromatographed on silica gel using dichloromethane/methanol/acetic acid/water (60:13:2:2) for the elution. There were obtained 36 mg of 2(RS)-[[N-[N-[N-[N-[N-[(3-carboxypropionyl)-L-α-aspartyl]-L-α-glutamyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-L-leucyl]amino]-4-pentynal (9:1 mixture of diastereoisomers) as a white solid. MS: m/e 829.6 [M+H]+.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[NH:20][C:19](=[O:21])[C:18]2[C:13](=[C:14](I)[CH:15]=[CH:16][CH:17]=2)[N:12]=1)[CH2:2][CH3:3].C(N(CCCC)CCCC)CCC.[CH2:36]=[CH:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(OCC)(=O)C>[CH2:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[NH:20][C:19](=[O:21])[C:18]2[C:13](=[C:14]([CH:36]=[CH:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[CH:15]=[CH:16][CH:17]=2)[N:12]=1)[CH2:2][CH3:3]
Reactant: CCCOc1ccccc1-c1nc2c(I)cccc2c(=O)[nH]1
Reactant: C=CCCCCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCOC(C)=O
Solvent: CCCCN(CCCC)CCCC
Solvent: CN(C)C=O
Product: CCCCCC=Cc1cccc2c(=O)[nH]c(-c3ccccc3OCCC)nc12
Temperature: 25 °C

Procedure:
5 g (12.31 mmoles) of the compound from Example III, 3.7 ml (15.4 mmoles) of tributylamine, 6.6 ml (46.2 mmoles) of 1-heptene, 375 mg of tri-o-tolylphosphine (1.23 mmoles), and 138 mg of palladium(II) acetate (0.6 mmole) are stirred in 50 ml of dry DMF for 2.5 h at 100° C. The mixture is cooled to room temperature, 50 ml of ethyl acetate is added, and the mixture is washed 3 times with 50-ml portions of H2O. After drying over MgSO4, the organic phase is evaporated under vacuum, and the residue is chromatographed on silica gel with toluene/ethyl acetate 95:5 as eluant. The fractions containing the product are combined and the solvent is evaporated under vacuum. The initially oily residue is crystallized by stirring with 35 ml petroleum ether.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]#[CH:16])[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>>[CH2:14]([N:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1)[C:15]#[CH:16]
Reactant: C#CCN1CCN(C(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Product: C#CCN1CCNCC1
Temperature: 25 °C

Procedure:
To a flame-dried 25 mL round bottom flask under nitrogen was added 2.1 g of 4-Prop-2-ynyl-piperazine-1-carboxylic acid tert-butyl ester. To this solid was added 5 mL of 98% TFA in 1 mL portions. The solution turned wine red, bubbled and smoked. The additional portions of TFA were added when this activity subsided. After the third portion of TFA had been added only minimal bubbling occurred. The solution was allowed to stir under nitrogen at room temperature for an additional hour and evaporated under reduced pressure to yield the product as a thick red syrup. Assumed quantitative yield of 1.16 g. The residue was suspended in 20 mL dichloromethane and used immediately without further purification for the preparation of compounds JR4031, JR4033, and JR4035.