Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH:8](Br)Br)[CH:5]=[CH:4][C:3]=1[C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1.Cl.[NH2:19][OH:20]>>[Cl:1][C:2]1[CH:7]=[C:6]([CH:8]=[N:19][OH:20])[CH:5]=[CH:4][C:3]=1[C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1
Reactant: Oc1ccc(-c2ccc(C(Br)Br)cc2Cl)cc1
Reactant: NO
Agent: Cl
Product: ON=Cc1ccc(-c2ccc(O)cc2)c(Cl)c1

Procedure:
The title compound was prepared by reacting 2′-chloro-4′-(dibromomethyl)-1,1′-biphenyl-4-ol (270 mg, 0.722 mmol) with hydroxylamine hydrochloride (185 mg, 2.66 mmol) according to Method C to yield 160 mg (90%) of white solid: mp 178-179° C.; 1H NMR (DMSO-d6): δ 6.85 (2H, d, J=8.54 Hz), 7.28 (2H, d, J=8.51 Hz), 7.39 (1H, d, J=7.98 Hz), 7.60 (1H, dd, J=7.65 Hz, J=1.42 Hz), 7.72 (1H, d, J=1.34 Hz), 8.18 (1H, s), 9.67 (1H, s), 11.45 (1H, s); MS (ESI) m/z 246/248 (M−H)−.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:12]2[CH2:17][CH2:16][CH:15]([N:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[CH2:14][CH2:13]2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10].[CH3:24][S:25](Cl)(=[O:27])=[O:26].C(N(CC)CC)C>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:12]2[CH2:13][CH2:14][CH:15]([N:18]3[CH2:19][CH2:20][N:21]([S:25]([CH3:24])(=[O:27])=[O:26])[CH2:22][CH2:23]3)[CH2:16][CH2:17]2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10]
Reactant: CS(=O)(=O)Cl
Reactant: COc1cc(N2CCC(N3CCNCC3)CC2)ccc1[N+](=O)[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(N2CCC(N3CCN(S(C)(=O)=O)CC3)CC2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 76.6 %

Procedure:
To a suspension of 1-{1-[3-(methyloxy)-4-nitrophenyl]-4-piperidinyl}piperazine (5.0 g, 11.6 mmol), methane sulfonyl chloride (1.4 mL, 17.5 mmol) and dichloromethane (200 mL) was added triethylamine (8.1 mL, 58.2 mmol). The reaction was stirred at room temperature and monitored by TLC. After complete consumption of the starting material the clear yellow solution was concentrated onto silica gel and purified by chromatography to afford 1-{1-[3-(methyloxy)-4-nitrophenyl]-4-piperidinyl}-4-(methylsulfonyl)piperazine as a yellow solid (3.54 g, 76%). 1H NMR (400 MHz, DMSO-d6) δ 7.85 (d, J=9.5 Hz, 1H), 6.57 (dd, J=9.2, 2.6 Hz, 1H), 6.48 (d, J=2.6 Hz, 1H), 4.09-4.00 (m, 2H), 3.89 (s, 3H), 3.10-3.03 (m, 4H), 2.99-2.90 (m, 2H), 2.84 (s, 3H), 2.61-2.52 (m, 5H), 1.85-1.77 (m, 2H), 1.50-1.37 (m, 2H).
Reaction SMILES: [CH2:1]([C@H:6]1[CH2:11][CH2:10][C@H:9]([CH2:12][CH2:13][CH2:14][O:15][C:16]2[CH:23]=[CH:22][C:19]([CH:20]=[O:21])=[CH:18][CH:17]=2)[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5].[CH2:24]([CH:29]([CH2:32]O)[CH2:30][OH:31])[CH2:25][CH2:26][CH2:27][CH3:28].S(=O)(=O)(O)O.O>C1(C)C=CC=CC=1>[CH2:24]([C@@H:29]1[CH2:30][O:31][C@@H:20]([C:19]2[CH:18]=[CH:17][C:16]([O:15][CH2:14][CH2:13][CH2:12][C@H:9]3[CH2:10][CH2:11][C@H:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[CH2:7][CH2:8]3)=[CH:23][CH:22]=2)[O:21][CH2:32]1)[CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: CCCCC[C@H]1CC[C@H](CCCOc2ccc(C=O)cc2)CC1
Reactant: CCCCCC(CO)CO
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCC[C@H]1CC[C@H](CCCOc2ccc([C@H]3OC[C@H](CCCCC)CO3)cc2)CC1

Procedure:
A solution of 2.1 g of 4-[3-(trans-4-pentylcyclohexyl)-1-propyloxy]benzaldehyde and 1.2 g of 2-pentyl-1,3-propanediol in 50 ml of toluene was treated with 2 drops of 10% (vol., sulfuric acid. The mixture was heated to boiling for 2.5 hours, with the resulting water being distilled off simultaneously. Then, 4 drops of triethylamine were added to the reaction mixture. After cooling the mixture was washed with 20 ml of 1N sodium hydrogen carbonate solution and twice with 20 ml of water each time, dried over sodium sulfate, filtered and concentrated. Chromatography of the residue on silica gel with toluene gave 0.6 g of trans-5-pentyl-2-(4-[3-(trans-4-pentylcyciohexyl)-1-propyloxy]phenyl)-1,3-dioxane. M.p. (C-SB) 65° C. transition SB -N 73° C., cl.p (N-I) 128° C.
Reaction SMILES: [CH3:1][S:2]([NH:5][C@@H:6]([C:10]([CH3:13])([CH3:12])[CH3:11])[C:7](O)=[O:8])(=[O:4])=[O:3].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.[CH2:42]([NH:49][NH2:50])[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1.CCN(CC)CC>>[CH2:42]([NH:49][NH:50][C:7]([C@@H:6]([NH:5][S:2]([CH3:1])(=[O:4])=[O:3])[C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1
Reactant: NNCc1ccccc1
Reactant: CC(C)(C)[C@H](NS(C)(=O)=O)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN1CCOCC1
Product: CC(C)(C)[C@H](NS(C)(=O)=O)C(=O)NNCc1ccccc1
Yield: 58 %

Procedure:
A solution of methanesulfonyl chloride (0.593 mL, 7.62 mmol) in 1M NaOH (7.60 mL, 15.2 mmol) and THF (10 mL) was added drop wise to a stirred mixture of (L)-tert-leucine (1.0 g, 7.6 mmol), dissolved in THF (7.6 mL) and H2O (12 mL) at 0° C. The reaction mixture was stirred at 0° C. for 3 h and then at room temperature overnight. The mixture was acidified with 4M HCl and extracted with EtOAc. The organic phase was separated, dried (Na2SO4), filtered and concentrated under reduced pressure to give (2S)-2-methanesulphonylamino-3,3-dimethyl-butyric acid (0.486 g, 30%), which was analyzed by NMR and then used without further purification. The general procedure for the preparation of hydrazides described above was then followed using the crude (2S)-2-methanesulfonylamino-3,3-dimethyl-butyric acid (0.476 g, 2.27 mmol), EDAC (0.481 g, 2.51 mmol), HOBT (0.338 g, 2.50 mmol), NMM (0.275 mL, 2.50 mmol), benzylhydrazine×2HCl (0.489 g, 2.51 mmol) and Et3N (0.700 mL, 4.98 mmol) which gave the title compound (0.416 g, 58%) as a white solid.
Reaction SMILES: Cl.Cl.[CH3:3][O:4][C:5]1[CH:6]=[C:7](/[CH:17]=[CH:18]/[C:19]([NH:21][NH2:22])=[O:20])[CH:8]=[CH:9][C:10]=1[N:11]1[CH:15]=[C:14]([CH3:16])[N:13]=[CH:12]1.[F:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]=[C:31]=O)=[CH:26][CH:25]=1.O>CN(C=O)C>[F:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][C:31]2[O:20][C:19](/[CH:18]=[CH:17]/[C:7]3[CH:8]=[CH:9][C:10]([N:11]4[CH:15]=[C:14]([CH3:16])[N:13]=[CH:12]4)=[C:5]([O:4][CH3:3])[CH:6]=3)=[N:21][N:22]=2)=[CH:26][CH:25]=1
Reactant: O=C=Nc1ccc(F)cc1
Reactant: COc1cc(/C=C/C(=O)NN)ccc1-n1cnc(C)c1
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(/C=C/c2nnc(Nc3ccc(F)cc3)o2)ccc1-n1cnc(C)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
TEA (1.25 mL) was added to a solution of (E)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylic acid hydrazide dihydrochloride (771 mg) in DMF (15 mL) at room temperature, and the reaction solution was stirred at room temperature for 10 minutes. 4-Fluorophenyl isocyanate (0.26 mL) was added to the reaction solution at room temperature, and the reaction solution was stirred at room temperature for one hour. The reaction solution was added to cold water. The generated solid was separated by filtration, washed with water and diethyl ether and then dried at 60° C. for three hours. Phosphorus oxychloride (15 mL) was added to the resulting solid at room temperature, and the reaction solution was heated under reflux for three hours. The reaction solution was left to cool to room temperature and then concentrated under reduced pressure. A saturated sodium bicarbonate solution was added to the residue. The generated solid was separated by filtration, washed with diethyl ether and then dried at 60° C. for one hour to obtain 820 mg of the title compound. The property value of the compound is as follows.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][C:9](=[O:12])[CH:8]([C:13]([O:15][CH3:16])=[O:14])[S:7][C:6]=2[CH:17]=1.[C:18]1([N:24]2[CH2:29][CH2:28][N:27]([CH2:30][CH2:31][CH2:32]Cl)[CH2:26][CH2:25]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][C:9](=[O:12])[C:8]([CH2:32][CH2:31][CH2:30][N:27]3[CH2:28][CH2:29][N:24]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[CH2:25][CH2:26]3)([C:13]([O:15][CH3:16])=[O:14])[S:7][C:6]=2[CH:17]=1
Reactant: ClCCCN1CCN(c2ccccc2)CC1
Reactant: COC(=O)C1Sc2cc(C)ccc2OCC1=O
Product: COC(=O)C1(CCCN2CCN(c3ccccc3)CC2)Sc2cc(C)ccc2OCC1=O

Procedure:
Methyl 7-methyl-3-oxo-3,4-dihydro-2H-1,5-benzoxathiepin-4-carboxylate (1.7 g) is alkylated with 3-(4-phenylpiperazin-1-yl)propylchloride in the same manner as described in Example 1 to give methyl 7-methyl-3-oxo-4-[3-(4-phenylpiperazin-1-yl)propyl]-3,4-dihydro-2H-1,5-benzoxathiepin-4-carboxylate (0.9 g) as a colorless oil.
Reaction SMILES: CO[C:3](=[O:28])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[C:23]([NH:24][CH:25]([CH3:27])[CH3:26])=[CH:22][CH:21]=[CH:20][N:19]=3)[CH2:14][CH2:13]2)=[O:11])=[CH:6][CH:5]=1.[CH3:29][N:30]([CH3:34])[CH2:31][CH2:32][NH2:33]>>[CH3:29][N:30]([CH3:34])[CH2:31][CH2:32][NH:33][C:3]([C:4]1[CH:5]=[CH:6][C:7]([C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[C:23]([NH:24][CH:25]([CH3:27])[CH3:26])=[CH:22][CH:21]=[CH:20][N:19]=3)[CH2:14][CH2:13]2)=[O:11])=[CH:8][CH:9]=1)=[O:28]
Reactant: CN(C)CCN
Reactant: COC(=O)c1ccc(C(=O)N2CCN(c3ncccc3NC(C)C)CC2)cc1
Product: CC(C)Nc1cccnc1N1CCN(C(=O)c2ccc(C(=O)NCCN(C)C)cc2)CC1
Yield: 79 %

Procedure:
By the same procedure as described in the example 45, synthesis was carried out starting with 4-[1-[3-(isopropylamino)-2-pyridyl]piperazin-4-yl-carbonyl]benzoic acid methyl ester and using N,N-dimethylethylenediamine. Then, the product was recrystallized using ethanol and isopropyl ether to give the desired compound.
Reaction SMILES: CO[C:3]1[CH2:8][CH2:7][CH2:6][C:5](=[O:9])[CH:4]=1.[Li][CH2:11][CH2:12][CH2:13][CH3:14]>C(OCC)(=O)C>[CH2:11]([C:3]1[CH2:8][CH2:7][CH2:6][C:5](=[O:9])[CH:4]=1)[CH2:12][CH2:13][CH3:14]
Reactant: [Li]CCCC
Reactant: COC1=CC(=O)CCC1
Solvent: CCOC(C)=O
Product: CCCCC1=CC(=O)CCC1
Yield: 97.2 %

Procedure:
The general procedure for the preparation of substrates using 3-methoxycyclohexenone (1.26 g, 10 mmol) and n-BuLi (20 mmol, 1.6 M in hexane) gave, after flash chromatography (4:1 hexanes:ethyl acetate) the title compound as a colorless liquid (1.48 g, 97%). Spectroscopic data were consistent with previously reported data for this compound.2
Reaction SMILES: CCN(C(C)C)C(C)C.[F:10][C:11]([F:28])([F:27])[O:12][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[O:21][C:20](=[O:23])[C:19]([C:24]([OH:26])=O)=[CH:18]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:53][O:54][C:55]1[CH:60]=[CH:59][C:58]([O:61][CH3:62])=[CH:57][C:56]=1[C:63]1[CH:68]=[CH:67][CH:66]=[C:65]([NH2:69])[CH:64]=1>CN(C=O)C>[CH3:53][O:54][C:55]1[CH:60]=[CH:59][C:58]([O:61][CH3:62])=[CH:57][C:56]=1[C:63]1[CH:68]=[CH:67][CH:66]=[C:65]([NH:69][C:24]([C:19]2[C:20](=[O:23])[O:21][C:22]3[C:17]([CH:18]=2)=[CH:16][CH:15]=[CH:14][C:13]=3[O:12][C:11]([F:10])([F:28])[F:27])=[O:26])[CH:64]=1
Reactant: COc1ccc(OC)c(-c2cccc(N)c2)c1
Reactant: O=C(O)c1cc2cccc(OC(F)(F)F)c2oc1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc(OC)c(-c2cccc(NC(=O)c3cc4cccc(OC(F)(F)F)c4oc3=O)c2)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 63.4 %

Procedure:
DIEA (0.013 mL, 0.072 mmol) was added to 8-trifluoromethoxy-3-carboxy-coumarin (0.018 g, 0.065 mmol) and HATU (0.027 g, 0.072 mmol) in 0.36 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 2′,5′-dimethoxy-biphenyl-3-ylamine (0.015 g, 0.065 mmol) was added and allowed to react overnight. DMF was removed under vacuum and the reaction was resuspended in DMSO. The crude product was purified on a Parallex Flex parallel preparative reverse phase HPLC instrument (Biotage) using a solvent gradient of 10-95% ACN/H2O with 0.05% TFA at a flow rate of 20 mL/min. UV absorbance was monitored at 254 nm and the fractions corresponding to the product peak were collected and lyophilized for 48 hours to give 0.02 g of product in 64% yield: LCMS (ESI) m/z 486 (MH+).
Reaction SMILES: CS(Cl)(=O)=O.C(N(C(C)C)CC)(C)C.[O:15]1[C:19]2[CH:20]=[CH:21][C:22]([C:24]3[N:28]=[C:27]([CH:29]4[CH2:34][CH2:33][N:32]([S:35]([CH2:38]C5C=CC=CC=5)(=[O:37])=[O:36])[CH2:31][CH2:30]4)[NH:26][C:25]=3[C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][N:46]=3)=[CH:23][C:18]=2[O:17][CH2:16]1>C1COCC1>[O:15]1[C:19]2[CH:20]=[CH:21][C:22]([C:24]3[N:28]=[C:27]([CH:29]4[CH2:34][CH2:33][N:32]([S:35]([CH3:38])(=[O:37])=[O:36])[CH2:31][CH2:30]4)[NH:26][C:25]=3[C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][N:46]=3)=[CH:23][C:18]=2[O:17][CH2:16]1
Reactant: O=S(=O)(Cc1ccccc1)N1CCC(c2nc(-c3ccc4c(c3)OCO4)c(-c3ccccn3)[nH]2)CC1
Agent: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CS(=O)(=O)N1CCC(c2nc(-c3ccc4c(c3)OCO4)c(-c3ccccn3)[nH]2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 28.1 %

Procedure:
Methanesulfonyl chloride (0.009 mL, 0.12 mmol) and diisopropylethylamine (0.026 mL, 0.15 mmol) were added to a solution of 2-(5-benzo[1,3]dioxol-5-yl-2-piperidin-4-yl-3H-imidazol-4-yl)-pyridine (0.035 g, 0.10 mmol; prepared as described in Example 11) in anhydrous THF (3 mL). The reaction mixture was stirred at room temperature for 3 hours. Solvent was removed under reduced pressure, and the residue was dissolved in 1 mL DMSO. The DMSO solution was filtered and injected onto preparative HPLC. HPLC purification eluting with acetonitrile:water gave 0.012 g (28%) of the title compound as a yellow solid. MS (ESP+) m/z 427.1 (M+1). 1H NMR (400 MHz, CDCl3) δ 8.65 (m, 1H), 7.83 (m, 1H), 7.56 (m, 1H), 7.45 (m. 1H), 7.03 (dd, 1H, J=1.8 Hz, 8.1 Hz), 6.97 (d, 1H, J=1.8 Hz), 6.88 (d, 1H, d=8.1 Hz), 6.05 (s, 2H), 3.91 (m, 2H), 3.47 (m, 1H), 2.89 (m, 2H), 2.84 (s, 3H), 2.22 (m, 2H), 2.11 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([CH3:9])=[CH:5][C:6]=1[CH:7]=[O:8].P([O-])(O)(O)=[O:11].[Na+].[OH-].[Na+]>C(#N)C.O.OO>[CH3:1][C:2]1[S:3][C:4]([CH3:9])=[CH:5][C:6]=1[C:7]([OH:11])=[O:8]
Reactant: Cc1cc(C=O)c(C)s1
Reactant: O=P([O-])(O)O
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Product: Cc1cc(C(=O)O)c(C)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 261.8 %

Procedure:
Phosphorus oxychloride (10 ml) was slowly added dropwise to dimethylformamide (30 g) under ice-cooling, and 2,5-dimethylthiophene (11.2 g) was added. The mixture was stirred at 100° C. for 15 hours, poured into water and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 2,5-dimethyl-3-thiophenecarbaldehyde (1.41 g). 2,5-Dimethyl-3-thiophenecarbaldehyde (3.89 g) synthesized in this manner was dissolved in acetonitrile (30 ml), and sodium dihydrogen phosphate (1.2 g) in water (15 ml) and 30% aqueous hydrogen peroxide (3.5 ml) were added dropwise. The mixture was stirred at room temperature for 2 hours, alkalified with 1N aqueous sodium hydroxide and washed with diethyl ether. The aqueous layer was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 2,5-dimethyl-3-thiophenecarboxylic acid (4.09 g) as crystals.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[C:8]([CH2:12][CH2:13][CH2:14][CH2:15][N:16]([CH2:20][CH2:21][CH3:22])[CH2:17][CH2:18][CH3:19])[CH2:9]2)=[CH:5][CH:4]=1.[NH:23]1[CH:27]=[CH:26][N:25]=[C:24]1[CH:28]=O.C(OC)(OC)OC.[BH4-].[Na+]>CO>[NH:23]1[CH:27]=[CH:26][N:25]=[C:24]1[CH2:28][NH:1][CH2:2][C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[C:8]([CH2:12][CH2:13][CH2:14][CH2:15][N:16]([CH2:20][CH2:21][CH3:22])[CH2:17][CH2:18][CH3:19])[CH2:9]2)=[CH:5][CH:4]=1
Reactant: CCCN(CCC)CCCCC1=Cc2ccc(CN)cc2C1
Reactant: O=Cc1ncc[nH]1
Agent: [BH4-]
Agent: [Na+]
Solvent: COC(OC)OC
Solvent: CO
Product: CCCN(CCC)CCCCC1=Cc2ccc(CNCc3ncc[nH]3)cc2C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 53.8 %

Procedure:
The compound (40.1 mg) obtained in Example 11-13 was dissolved in methanol (2.0 ml) and added with 2-imidazole carboxaldehyde (19.2 mg) and trimethyl orthoformate (42.5 mg) and the whole was stirred at room temperature for 30 minutes. Subsequently, the solution was added with sodium borohydride (15.1 mg) under ice-cooling, followed by stirring at room temperature for additional 30 minutes. The reaction solution was concentrated under reduced pressure. The residue was added with water, and extracted with chloroform. The organic layer was washed with a saturated saline solution and dried with anhydrous sodium sulfate, followed by concentration under reduced pressure. The residue was purified through silica gel column chromatography (chloroform/methanol), thereby obtaining the subject compound (27.3 mg) as a yellow oily substance.
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH2:13][NH:14][C:15]([C:17]1[N:18]=[C:19]([C:35]#[N:36])[C:20]2[C:25]([C:26]=1[OH:27])=[CH:24][CH:23]=[C:22]([O:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH:21]=2)=[O:16])[C:10]([OH:12])=[O:11])=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:8][C@@H:9]([CH2:13][NH:14][C:15]([C:17]1[N:18]=[C:19]([C:35]#[N:36])[C:20]2[C:25]([C:26]=1[OH:27])=[CH:24][CH:23]=[C:22]([O:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH:21]=2)=[O:16])[C:10]([OH:12])=[O:11]
Reactant: CC(C)(C)OC(=O)N[C@@H](CNC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O)C(=O)O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1nc(C(=O)NC[C@H](N)C(=O)O)c(O)c2ccc(Oc3ccccc3)cc12
Yield: 83.3 %

Procedure:
To a mixture of 2-(S)-tert-butoxycarbonylamino-3-[(1-cyano-4-hydroxy-7-phenoxy-isoquinoline-3-carbonyl)-amino]-propionic acid (90 mg, 0.18 mmol) in CH2Cl2 (2 mL) was added TFA (0.5 mL). The resultant mixture was stirred at room temperature for 4 h. Reaction mixture was concentrated and residue was treated with water (80 mL). The pH value was adjusted to 9-10 by 1 N NaOH aq. Solution. Then it was acidified by 1 N HCl to pH=4-5. Precipitate was collected, rinsed with water and dried in vacuo to provide the title compound 57 mg (0.15 mmol) in 81% yield. LC-MS ESI−: 391.08 (M−1)−.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)=[C:4](Cl)[N:3]=1.[NH3:18]>CO>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)=[C:4]([NH2:18])[N:3]=1
Reactant: N
Reactant: Clc1nc(Cl)c2ncn(C3CCCCO3)c2n1
Solvent: CO
Product: Nc1nc(Cl)nc2c1ncn2C1CCCCO1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
2,6-Dichloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (55 g) was dissolved in 7N-aqueous ammonia in MeOH (500 ml) and heated at 100° C. in a sealed flask for 6 h. The reaction mixture was cooled to rt and left overnight. Filtration afforded the subtitle compound. Yield 40 g.
Reaction SMILES: C1(C)C=CC(S([N:10]2[CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([Br:19])[CH:16]=3)[CH2:11]2)(=O)=O)=CC=1.C1(O)C=CC=CC=1.C(O)(=O)CC>Br>[BrH:19].[Br:19][C:15]1[CH:16]=[C:17]2[C:12](=[CH:13][CH:14]=1)[CH2:11][NH:10][CH2:18]2
Reactant: Cc1ccc(S(=O)(=O)N2Cc3ccc(Br)cc3C2)cc1
Agent: Br
Solvent: Oc1ccccc1
Solvent: CCC(=O)O
Product: Brc1ccc2c(c1)CNC2
Yield: 176.8 %

Procedure:
In 25 ml of 47% hydrobromic acid was suspended 5.0 g of 2-(p-toluenesulfonyl)-5-bromoisoindoline, and 4.0 g of phenol and 15 ml of propionic acid were added to the suspension, after which the resulting mixture was heated under reflux for four hours. The reaction mixture was concentrated under reduced pressure, and ethanol was added to the residue obtained, after which the resulting crystals were collected by filtration, to obtain 3.5 g of 5-bromoisoindoline hydrobromide. The hydrobromide obtained was suspended in 50 ml of methylene chloride, and 2.8 g of triethylamine was added to the suspension, after which 2.4 g of carbobenzoxy chloride was dropwise added thereto with ice-cooling. Thereafter, the resulting mixture was stirred at room temperature for one hour. The reaction mixture was added 50 ml of water and the pH was adjusted to 1 with 6N hydrochloric acid. Thereafter, the organic layer formed was separated, washed with a saturated saline solution and then dried over anhydrous magnesium chloride. The solvent was then removed by distillation under reduced pressure. To the residue thus obtained was added n-hexane, and the resulting crystals were collected by filtration to obtain 3.8 g of colorless, crystalline 2-benzyloxycarbonyl-5-bromoisoindoline.
Reaction SMILES: [Cl:1][C:2]1[C:21]([C:22]([F:25])([F:24])[F:23])=[CH:20][CH:19]=[CH:18][C:3]=1[CH2:4][NH:5][CH2:6][CH:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:8][CH:9]([CH3:11])[CH3:10].COC1C=CC(C(C)CN([CH2:49][CH2:50][CH2:51][O:52][C:53]2[CH2:54][C:55](=[CH:59][C:60]([O:62][CH3:63])=[O:61])[CH:56]=[CH:57][CH:58]=2)CC2C=CC=C(C(F)(F)F)C=2Cl)=CC=1>>[C:12]1([CH:7]([CH2:8][CH:9]([CH3:11])[CH3:10])[CH2:6][N:5]([CH2:49][CH2:50][CH2:51][O:52][C:53]2[CH2:54][C:55](=[CH:59][C:60]([O:62][CH3:63])=[O:61])[CH:56]=[CH:57][CH:58]=2)[CH2:4][C:3]2[CH:18]=[CH:19][CH:20]=[C:21]([C:22]([F:23])([F:24])[F:25])[C:2]=2[Cl:1])[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CC(C)CC(CNCc1cccc(C(F)(F)F)c1Cl)c1ccccc1
Reactant: COC(=O)C=C1C=CC=C(OCCCN(Cc2cccc(C(F)(F)F)c2Cl)CC(C)c2ccc(OC)cc2)C1
Product: COC(=O)C=C1C=CC=C(OCCCN(Cc2cccc(C(F)(F)F)c2Cl)CC(CC(C)C)c2ccccc2)C1
Yield: 34 %

Procedure:
The titled compound was prepared from N-(2-chloro-3-trifluoromethylbenzyl)-2-phenyl-4-methylpentylamine in 34% yield in the same manner as the preparation of N-(2-[4-methoxyphenyl]-propyl)-N-(2-chloro-3-trifluoromethylbenzyl)-3-(3-carbomethoxymethylenephenoxy)propylamine in Example 188e. MS (ESI) 576 (MH+)
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH:12]1[C:17](=[O:22])[N:18]([O:20][CH3:21])[CH3:19])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C=O.[C:25](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([CH3:25])[CH2:13][CH:12]1[C:17](=[O:22])[N:18]([O:20][CH3:21])[CH3:19])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CON(C)C(=O)C1CNCCN1C(=O)OCc1ccccc1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: ClCCCl
Product: CON(C)C(=O)C1CN(C)CCN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 96 %

Procedure:
To (RS)-2-(methoxy-methyl-carbamoyl)-piperazine-1-carboxylic acid benzyl ester, D52 (3 g, 10 mmol) in 1,2-dichloroethane (50 ml) was added formaldehyde (0.85 ml of 37% w/w solution in water, 11 mmol) and the mixture stirred at ambient temperature for 0.75 h. Sodium triacetoxyborohydride (2.55 g, 12 mmol) was added portionwise over 0.25 h, and the resulting mixture stirred at ambient temperature for 18 h. The reaction was partitioned between dichloromethane (300 ml) and 1M sodium hydroxide (100 ml). The aqueous was re-extracted with dichloromethane (250 ml) and the combined extracts dried (Na2SO4) and the solvent removed in vacuo. The residue was chromatographed on silica gel eluting with ethyl acetate-hexane mixtures to afford the title product (3 g, 96%) as a gum.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5](B2OC(C)(C)C(C)(C)O2)=[C:6]([NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])[CH:7]=1.Br[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1.C([O-])([O-])=O.[K+].[K+].CCCCCC>C(#N)C.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>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=2)=[C:6]([NH:8][C:9](=[O:14])[C:10]([CH3:11])([CH3:12])[CH3:13])[CH:7]=1
Reactant: CC(C)(C)C(=O)Nc1cc(F)ccc1B1OC(C)(C)C(C)(C)O1
Reactant: Brc1ccccn1
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: CC#N
Solvent: CCCCCC
Product: CC(C)(C)C(=O)Nc1cc(F)ccc1-c1ccccn1
Temperature: 80 °C
Yield: 95.6 %

Procedure:
To a solution of N-(5-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pivalamide (23.4 g, 72.97 mmol) in acetonitrile (280 mL) was added 2-bromopyridine (16.14 g, 102.12 mmol) and aqueous solution of K2CO3 (50.40 g, 364.90 mmol). The reaction mixture was degassed by purging N2 for 15 min followed by addition of tetrakis(triphenylphosphine)palladium(0) (8.40 g, 7.30 mmol). The mixture was again degassed for 10-15 min then heated up to 80° C. for 8 h. After completion of reaction (by TLC), the mixture was poured into 100 mL of ice-cold water and extracted with EtOAc (3×250 mL). The combined organics were washed with brine, dried over anhydrous Na2SO4, filtered and evaporated under reduced pressure. The crude residue was purified over 100-200 M silica-gel by using 2.0% EtOAc:hexane to obtain the desired product as a colourless liquid (19.0 g, 96% yield).