Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [BH4-].[Na+].C(O)(=O)C.[C:7]1([N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[N:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH:25]=O)[CH:20]=1>C1COCC1>[C:7]1([N:13]2[CH2:18][CH2:17][N:16]([CH2:25][C:21]3[CH:20]=[N:19][CH:24]=[CH:23][CH:22]=3)[CH2:15][CH2:14]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: O=Cc1cccnc1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: c1ccc(N2CCN(Cc3cccnc3)CC2)cc1
Reaction time: 0.33 h

Procedure:
NaBH4 (1.50 g, 38.88 mmol, 1.2 equiv.) was slowly added over 20 minutes to a solution of acetic acid (glacial, 11.13 mL, 194.41 mmol, 6 equiv.) in anhydrous THF (50 mL) at 20° C. under a nitrogen blanket with stirring at 200 RPM. After aging for another 20 minutes, pre-dried molecular sieves (3A, 45 g) and additional anhydrous THF (20 mL) were added to the reaction mixture and the stirring rate was increased to 350 RPM. Ten minutes after addition of the sieves, 1-phenylpiperazine (4, 5.00 mL, 32.40 mmol, 1 eq.) and 3-pyridinecarboxaldehyde (2, 3.74 mL, 38.88 mmol, 1.2 equiv.) were added, and the mixture aged for another 30 minutes, at which point the reaction was 100% complete, as determined by monitoring the disappearance of 4 with HPLC. The molecular sieves were removed by filtration. The filtrate containing the product was quenched into brine and the pH adjusted to 7.5 to 8. The organic layer containing the product was separated and the aqueous layer discarded. The organic layer was then concentrated to dryness and the solids dissolved in hot hexanes. The desired product was then crystallized by slow cooling to 5–10° C. The resulting crystals were vacuum filtered while cold and washed with cold hexane (50 mL×2). The product was then dried under vacuum at 45° C. and 75 mm Hg pressure. The isolated yield of compound 6 (HPLC area 99.3%, mp 70.5–72.0° C.) was 90.7%.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([C@@H:12]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([OH:26])[CH:19]=1)[CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])[CH2:7]2.[CH:27]1([C:30](Cl)=[O:31])[CH2:29][CH2:28]1>C1COCC1>[OH:26][C:20]1[CH:19]=[C:18]([C@H:12]([N:8]2[C:9](=[O:11])[C:10]3[C:6](=[CH:5][CH:4]=[CH:3][C:2]=3[NH:1][C:30]([CH:27]3[CH2:29][CH2:28]3)=[O:31])[CH2:7]2)[CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])[CH:23]=[CH:22][C:21]=1[O:24][CH3:25]
Reactant: O=C(Cl)C1CC1
Reactant: COc1ccc([C@@H](CS(C)(=O)=O)N2Cc3cccc(N)c3C2=O)cc1O
Solvent: C1CCOC1
Product: COc1ccc([C@@H](CS(C)(=O)=O)N2Cc3cccc(NC(=O)C4CC4)c3C2=O)cc1O
Temperature: 60 °C
Yield: 4.3 %

Procedure:
To a mixture of (S)-7-amino-2-(1-(3-hydroxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)isoindolin-1-one (5.86 g, 15.6 mmol) in THF (60 mL), was added cyclopropanecarbonyl chloride (1.5 mL, 16.1 mmol). The mixture was heated to 60° C. for 1 hour then cooled to room temperature. The solvent was removed and the crude residue purified using column chromatography (MeOH/CH2Cl2: 0-5% over 60 minutes) to give 4.7 g of crude, 68% yield. Further purification was then carried out by prep-HPLC to give (S)—N-(2-(1-(3-hydroxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-3-oxoisoindolin-4-yl)cyclopropanecarboxamide as a white solid (0.3 g, 4.3% yield). HPLC: HPLC: Hypersil DBS C8 column, 250×4.6 mm, 5 μm; 99/1 to 85/15 over 15 minutes Gradient CH3CN/10 mM aq. KH2PO4, 1.0 mL/min, 35° C., run time 20 minutes: tR 11.84 minutes. 1H-NMR (DMSO-d6): 10.50 (1H, s), 9.11 (1H, s), 8.22-825 (1H, d), 7.48-7.53 (1H, t), 7.18-7.2 (1H, d), 6.84-6.95 (3H, m), 5.80-5.85 (1H, m), 4.60-6.66 (1H, d), 3.90-4.30 (3H, m), 3.75 (3H, s), 3.04 (3H, s), 1.79-1.83 (1H, m), 0.88-0.90 (4H, m); LC-MS ES+ (M+1) 445.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([CH2:5][C:6]2[N:7]([CH3:32])[C:8]3[C:13]([N:14]=2)=[C:12]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[N:11]=[C:10]([N:21]2[C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=4[N:23]=[C:22]2[CH2:30][CH3:31])[N:9]=3)[CH2:2]1.[C:33](Cl)(=[O:37])[CH:34]([CH3:36])[CH3:35].CCN(CC)CC>C(Cl)Cl>[CH2:30]([C:22]1[N:21]([C:10]2[N:9]=[C:8]3[C:13]([N:14]=[C:6]([CH2:5][CH:3]4[CH2:2][N:1]([C:33](=[O:37])[CH:34]([CH3:36])[CH3:35])[CH2:4]4)[N:7]3[CH3:32])=[C:12]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)[N:11]=2)[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[N:23]=1)[CH3:31]
Reactant: CC(C)C(=O)Cl
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CC3CNC3)n(C)c2n1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CC3CN(C(=O)C(C)C)C3)n(C)c2n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 8-azetidin-3-ylmethyl-2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purine (121 mg, 0.28 mmol), isobutyryl chloride (30 mg, 0.29 mmol) and NEt3 (50 μL, 0.36 mmol) in DCM (1 mL) was allowed to stir at r.t. for 2 h then concentrated in vacuo. The resulting residue purified by column chromatography (Si-PCC, MeOH:DCM, 0-6%) followed by triturating with Et2O affording 824 as a white solid (86 mg, 61%). LCMS (method I): RT 3.42 min, [M+H]+ 503.2. 1H NMR (CDCl3, 400 MHz): δ 7.99-7.99 (1 H, m), 7.75-7.74 (1 H, m), 7.30-7.22 (2 H, m), 4.50-4.20 (4 H, brd s), 4.41 (1 H, t, J=8.45 Hz), 4.32-4.21 (1 H, m), 3.98 (1 H, dd, J=8.63, 5.41 Hz), 3.90-3.80 (5 H, m), 3.76 (3 H, s), 3.34 (2 H, q, J=7.49 Hz), 3.28-3.25 (1 H, m), 3.16-3.11 (2 H, m), 2.47-2.46 (1 H, m), 1.44 (3 H, t, J=7.48 Hz), 1.12 (6 H, dd, J=6.82, 2.82 Hz)
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][NH:7][C:8]2[CH:16]=[CH:15][C:11]3[N:12]=[CH:13][NH:14][C:10]=3[CH:9]=2)=[CH:4][CH:3]=1.[N:19]1[S:20][N:21]=[C:22]2[CH:27]=[CH:26][C:25]([CH2:28]Br)=[CH:24][C:23]=12.C([O-])([O-])=O.[K+].[K+]>>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][N:7]([CH2:28][C:25]2[CH:26]=[CH:27][C:22]3[C:23]([CH:24]=2)=[N:19][S:20][N:21]=3)[C:8]2[CH:16]=[CH:15][C:11]3[NH:12][CH:13]=[N:14][C:10]=3[CH:9]=2)=[CH:4][CH:3]=1
Reactant: Clc1ccc(CNc2ccc3nc[nH]c3c2)cc1
Reactant: BrCc1ccc2nsnc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Clc1ccc(CN(Cc2ccc3nsnc3c2)c2ccc3[nH]cnc3c2)cc1

Procedure:
The compound was synthesized starting from N-(4-chlorobenzyl)benzimidazol-5-amine (258 mg; 1 mmol; 1 eq.), (benzo-[c][1,2,5]-thiadiazol-6-yl)methylbromide (252 mg; 1.1 mmol; 1.1 eq.) and K2CO3 (152 mg; 1.1 mmol; 1.1 eq.) according to method 6; Yield: 0.151 g (37.2%); MS m/z: 406.4/408.3 [M+H]+; 1H-NMR (500 MHz, DMSO d6): δ 4.77 (s, 2H); 4.88 (s, 2H); 6.73-6.79 (m, 2H); 7.32-7.38 (m, 5H); 7.69 (dd, 1H, 4J=1.5 Hz, 3J=9.2 Hz); 7.86 (s, 1H); 7.92 (s, 1H); 8.05 (d, 1H, 3J=9.2 Hz); 11.87 (br s, 1H); HPLC (METHOD [A]): rt 15.88 min (95.9%)
Reaction SMILES: C(O)(=O)C.[NH2:5][CH2:6][C@H:7]([OH:20])[CH2:8][O:9][C:10]1[C:18]2[NH:17][C:16](=[O:19])[NH:15][C:14]=2[CH:13]=[CH:12][CH:11]=1.O=[C:22]1[CH2:27][CH2:26][N:25]([C:28]2[CH:33]=[CH:32][C:31]([S:34]([N:37]3[CH2:41][C:40](=[O:42])[NH:39][C:38]3=[O:43])(=[O:36])=[O:35])=[CH:30][CH:29]=2)[CH2:24][CH2:23]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CN(C)C=O>[OH:20][C@H:7]([CH2:8][O:9][C:10]1[C:18]2[NH:17][C:16](=[O:19])[NH:15][C:14]=2[CH:13]=[CH:12][CH:11]=1)[CH2:6][NH:5][CH:22]1[CH2:23][CH2:24][N:25]([C:28]2[CH:29]=[CH:30][C:31]([S:34]([N:37]3[CH2:41][C:40](=[O:42])[NH:39][C:38]3=[O:43])(=[O:36])=[O:35])=[CH:32][CH:33]=2)[CH2:26][CH2:27]1
Reactant: NC[C@H](O)COc1cccc2[nH]c(=O)[nH]c12
Reactant: O=C1CCN(c2ccc(S(=O)(=O)N3CC(=O)NC3=O)cc2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: O=C1CN(S(=O)(=O)c2ccc(N3CCC(NC[C@H](O)COc4cccc5[nH]c(=O)[nH]c45)CC3)cc2)C(=O)N1
Reaction time: 0.33 h
Yield: 39.5 %

Procedure:
Acetic acid (0.14 mL, 2.38 mmol) was added dropwise into a mixture of 4-{[(2S)-3-amino-2-hydroxypropyl]oxy}-1,3-dihydro-2H-benzimidazol-2-one (265 mg, 1.19 mmol), 1-[[4-(4-oxo-1-piperidinyl)phenyl]sulfonyl]-2,4-imidazolidinedione (400 mg, 1.19 mmol) and N,N-dimethylformamide (5 mL). The mixture was stirred for 20 minutes and then, sodium triacetoxyborohydride (303 mg, 1.43 mmol) was added, and the new mixture was stirred at room temperature for 24 hours. The volatiles were removed in vacuo and the residue was purified by flash chromatography (dichloromethane/methyl alcohol 3/1) to produce a brown solid (256 mg, 40% yield): mp 230° C. (decomposed); 1H NMR (400 MHz, DMSO-d6): δ 1.52-1.63 (m, 2H), 2.04-2.15 (m, 2H), 2.48 (m, 2H), 2.9-3.0 (m, 2H), 3.13-3.15 (m, 1H), 3.2-3.4 (m, 3H), 4.0-4.1 (m, 5H), 4.42 (s, 2H), 6.6-6.63 (m, 2H), 6.8-6.85 (m, 1H), 7.03-7.05 (m, 2H), 7.78-7.8 (m, 2H), 10.6 (s, 1H), 10.7 (s, 1H); MS m/e 543 (M−H)+;
Reaction SMILES: [CH2:1]([C:4]([C:6]1[S:10][C:9]([NH2:11])=[N:8][C:7]=1[C:12]1[O:13][CH:14]=[CH:15][CH:16]=1)=[O:5])[CH2:2][CH3:3].[CH:17]1([C:20](Cl)=[O:21])[CH2:19][CH2:18]1.C(=O)([O-])O.[Na+]>N1C=CC=CC=1>[C:4]([C:6]1[S:10][C:9]([NH:11][C:20]([CH:17]2[CH2:19][CH2:18]2)=[O:21])=[N:8][C:7]=1[C:12]1[O:13][CH:14]=[CH:15][CH:16]=1)(=[O:5])[CH2:1][CH2:2][CH3:3]
Reactant: O=C(Cl)C1CC1
Reactant: CCCC(=O)c1sc(N)nc1-c1ccco1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: CCCC(=O)c1sc(NC(=O)C2CC2)nc1-c1ccco1
Temperature: 25 °C
Reaction time: 5.5 h
Yield: 55.5 %

Procedure:
Compound 384 (79.8 mg, 0.338 mmol) and N,N-dimethylaminopyridine (2.10 mg, 0.0172 mmol) were dissolved in pyridine (1.5 mL), and cyclopropanecarbonyl chloride (0.0521 mL, 0.570 mmol) was added thereto under ice-cooling, followed by stirring at room temperature for 5.5 hours. Aqueous saturated sodium hydrogencarbonate solution was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and then the solvent was distilled away under reduced pressure. The resulting residue was recrystallized from ethanol to afford the entitled Compound 385 (57.1 mg, 55%) as a white solid.
Reaction SMILES: [O:1]=[C:2]1[C:14]2[C:13]3[CH:12]=[C:11]([CH3:15])[CH:10]=[CH:9][C:8]=3[N:7]=[C:6]([CH3:16])[C:5]=2[C:4](=[O:17])[NH:3]1.Cl[CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1.C([O-])([O-])=O.[K+].[K+].CN(C=O)C>O>[CH3:16][C:6]1[C:5]2[C:4](=[O:17])[N:3]([CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[C:2](=[O:1])[C:14]=2[C:13]2[CH:12]=[C:11]([CH3:15])[CH:10]=[CH:9][C:8]=2[N:7]=1
Reactant: ClCCN1CCOCC1
Reactant: Cc1ccc2nc(C)c3c(c2c1)C(=O)NC3=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc2nc(C)c3c(c2c1)C(=O)N(CCN1CCOCC1)C3=O

Procedure:
A mixture of 5 g (0.022 mole) of 1,3-dioxo-4,8-dimethyl-2H-pyrrolo [3,4-c]quinoline (vii) (also known as 2,6-dimethyl quinoline 3,4-dicarboximide), 4.65 g (0.025 mole) of N-(2-chloroethyl) morpholine, 6.9 g (0.05 mole) K2CO3, and 50 ml of dry DMF was stirred and heated at 50° for 18 hours. The dark mixture was poured into H2O with stirring and the solids filtered; yield, 6 g after drying in vacuo.
Reaction SMILES: [OH:1][C:2]1[C:10]2[CH:9]=[C:8]([C:11]3[O:12][C:13]([CH3:16])=[CH:14][N:15]=3)[S:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.S(C1C=CC([N+]([O-])=O)=CC=1)(O[CH2:21][C@H:22]1[O:24][CH2:23]1)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>>[CH2:21]([O:1][C:2]1[C:10]2[CH:9]=[C:8]([C:11]3[O:12][C:13]([CH3:16])=[CH:14][N:15]=3)[S:7][C:6]=2[CH:5]=[CH:4][CH:3]=1)[C@H:22]1[O:24][CH2:23]1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)OC[C@@H]2CO2)cc1
Reactant: Cc1cnc(-c2cc3c(O)cccc3s2)o1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1cnc(-c2cc3c(OC[C@@H]4CO4)cccc3s2)o1

Procedure:
By the reactions in the same manner as in Starting Material Synthesis Example 1 using 4-hydroxy-2-(5-methyloxazol-2-yl)benzo(b)thiophene (2.20 g), (S)-glycidyl nosylate (2.38 g) and potassium carbonate (3.18 g), a crude product of the title compound was quantitatively obtained as pale-yellow crystals.
Reaction SMILES: [CH2:1]([C:7]1[CH:12]=[CH:11][C:10](C(=O)C)=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[C:16]([OH:19])(=[O:18])[CH3:17].S(=O)(=O)(O)O>O>[CH2:1]([C:7]1[CH:8]=[CH:9][C:10]([CH2:17][C:16]([OH:19])=[O:18])=[CH:11][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCc1ccc(C(C)=O)cc1
Reactant: CC(=O)O
Agent: O=S(=O)(O)O
Solvent: O
Product: CCCCCCc1ccc(CC(=O)O)cc1
Temperature: 150 °C
Yield: 66.3 %

Procedure:
12.0 g (39.3 mmol) of 1-(4-hexylphenyl)ethanone was dissolved in 23.6 g (393 mmol) of glacial acetic acid, mixed with 4.95 g (275 mmol) of water and 5.79 g (58.9 mmol) of sulfuric acid and heated at 150° C. for 6.5 hours under reflux. After completion of the reaction, the reaction solution was diluted with 400 mL of water and extracted with ethyl acetate. The resulting organic layer was dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using ethyl acetate:hexane (1:20 to 1:4) as the eluent to give 5.74 g of the desired product as white crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:5]([NH2:7])=[O:6].C([N:21]=[C:22]=[S:23])(=O)C1C=CC=CC=1.O>CC(C)=O>[CH3:12][O:11][C:10]1[CH:9]=[CH:8][C:4]([C:5]([NH2:7])=[O:6])=[CH:3][C:2]=1[NH:1][C:22]([NH2:21])=[S:23]
Reactant: O=C(N=C=S)c1ccccc1
Reactant: COc1ccc(C(N)=O)cc1N
Solvent: O
Solvent: CC(C)=O
Product: COc1ccc(C(N)=O)cc1NC(N)=S
Temperature: 25 °C

Procedure:
To a solution of 3-amino-4-methoxybenzamide (2.49 g, 15.0 mmol, Alfa) in acetone (30 mL) at reflux was added benzoyl isothiocyanate (2.22 mL, 16.5 mmol) and the mixture was stirred at reflux for 30 min, then was poured into water. The precipitate was collected by vacuum filtration and was treated with 10% aq. NaOH (15 mL). The mixture was heated to reflux for 40 min, cooled to room temperature, and poured into a mixture of ice and 6 N aq. HCl. The mixture was basified to pH 10 with conc. aq. NH4OH and the resulting white solid precipitate was collected by vacuum filtration, affording the crude title compound, which was used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][OH:9])[CH:5]=[N:6][CH:7]=1.C(N(CC)CC)C.[CH3:17][S:18](Cl)(=[O:20])=[O:19]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH2:8][O:9][S:18]([CH3:17])(=[O:20])=[O:19])[CH:5]=[N:6][CH:7]=1
Reactant: OCc1cncc(Br)c1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCc1cncc(Br)c1
Temperature: 0 °C
Yield: 70.5 %

Procedure:
To the stirred solution (5-bromo-pyridin-3-yl)-methanol (3.0 g, 16 mmol) in CH2Cl2 (30 mL) is added triethylamine (2.4 g, 24 mmol). The reaction mixture is cooled to 0° C., methanesulfonyl chloride (2.2 g, 19 mmol) is added slowly at 0° C. Then the reaction mixture is warmed up to room temperature for 3 hrs. Ice cold water is added and the mixture is extracted with CH2Cl2. Organic layers are combined, dried over Na2SO4 and concentrated to give 3.0 g of the crude methanesulfonic acid 5-bromo-pyridin-3-ylmethyl ester which is used without purification.
Reaction SMILES: C[O:2][C:3](=O)[C@H:4]([CH2:34][C:35]1[N:39]=[CH:38][NH:37][CH:36]=1)[NH:5][C:6](=[O:33])[C@H:7]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[NH:8][C:9](=[O:25])[C@H:10]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[NH:11][C:12](=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14].[BH4-].[Na+].Cl>O1CCCC1.CO>[OH:2][CH2:3][CH:4]([NH:5][C:6](=[O:33])[C@H:7]([CH2:26][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[NH:8][C:9](=[O:25])[C@H:10]([CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[NH:11][C:12](=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14])[CH2:34][C:35]1[N:39]=[CH:38][NH:37][CH:36]=1
Reactant: COC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](Cc1ccccc1)NC(=O)C(C)(C)C
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)C(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1ccccc1)C(=O)NC(CO)Cc1c[nH]cn1
Temperature: 25 °C
Reaction time: 4 h
Yield: 68.8 %

Procedure:
N-Pivaloyl-L-phenylalanyl-L phenylalanyl-L-histidine methyl ester (1.90 g) is dissolved in tetrahydrofuran (12 ml), and a solution of sodium borohydride (0.20 g) in methanol (2.5 ml) is added dropwise thereto. The mixture is stirred at room temperature for four hours, and 5% hydrochloric acid (4 ml) is added to the mixture and then the solvent is distilled off. The residue is made alkaline with an aqueous sodium bicarbonate solution and then extracted with ethyl acetate. The extract is washed with an aqueous sodium chloride solution, dried, and concentrated to remove solvent. The residue is triturated with ethyl acetate to give 4-{2-hydroxymethyl-2-[N-(N-pivaloyl-L-phenylalanyl-L-phenylalanyl)amino]ethyl}imidazole (1.24 g) as white powder. Yield: 68.8%
Reaction SMILES: Cl[CH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[N:15][C:16]([Cl:22])=[CH:17][CH:18]=2)[N:13]=1.[CH3:23][N:24]([CH2:28][CH2:29][CH2:30][C:31]([OH:33])=[O:32])[C:25](=[O:27])[CH3:26].N12CCCN=C1CCCCC2>CN(C)C=O>[CH3:23][N:24]([CH2:28][CH2:29][CH2:30][C:31]([O:33][CH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[N:15][C:16]([Cl:22])=[CH:17][CH:18]=2)[N:13]=1)=[O:32])[C:25](=[O:27])[CH3:26]
Reactant: O=C1c2ccccc2C(Cl)N1c1ccc2ccc(Cl)nc2n1
Reactant: CC(=O)N(C)CCCC(=O)O
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: CC(=O)N(C)CCCC(=O)OC1c2ccccc2C(=O)N1c1ccc2ccc(Cl)nc2n1
Yield: 22.8 %

Procedure:
The procedure is as in Example 1, but starting with 3-chloro-2-(7-chloro-1,8-naphthyridin-2-yl)-1-isoindolinone (9.9 g) in anhydrous dimethylformamide (100 cc), 4-(N-methylacetamido)butanoic acid (4.8 g) and 1,8-diazabicyclo[5.4.0]undec-7-ene (4.6 g). The oily residue obtained is purified by chromatography on silica (0.063-0.2 mm; 150 g) contained in a column 3 cm in diameter [eluant: methylene chloride/methanol (99:1 by volume)] and collecting 30-cc fractions. Fractions 76 to 175 are concentrated to dryness under reduced pressure (2.7 kPa) at 60° C. and, after crystallization in ethyl ether, 2-(7-chloro-1,8-naphthyridin-2-yl)-3-oxo-1-isoindolinyl 4-(N-methylacetamido)butyrate (3.1 g), m.p. 170° C., is obtained.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH:8]2[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]2)[CH:5]=[CH:4][CH:3]=1.[NH:15]1[CH2:18][CH:17]([NH:19][C:20]([CH2:22][NH:23][C:24](=[O:36])[C:25]2[CH:30]=[CH:29][C:28]([F:31])=[C:27]([C:32]([F:35])([F:34])[F:33])[CH:26]=2)=[O:21])[CH2:16]1>>[NH2:1][C:2]1[N:7]=[C:6]([CH:8]2[CH2:13][CH2:12][CH:11]([N:15]3[CH2:18][CH:17]([NH:19][C:20]([CH2:22][NH:23][C:24](=[O:36])[C:25]4[CH:30]=[CH:29][C:28]([F:31])=[C:27]([C:32]([F:34])([F:35])[F:33])[CH:26]=4)=[O:21])[CH2:16]3)[CH2:10][CH2:9]2)[CH:5]=[CH:4][CH:3]=1
Reactant: O=C(CNC(=O)c1ccc(F)c(C(F)(F)F)c1)NC1CNC1
Reactant: Nc1cccc(C2CCC(=O)CC2)n1
Product: Nc1cccc(C2CCC(N3CC(NC(=O)CNC(=O)c4ccc(F)c(C(F)(F)F)c4)C3)CC2)n1

Procedure:
The title compounds were prepared as white solids from the reductive amination of 4-(6-amino-pyridin-2-yl)-cyclohexanone (as prepared in the Example 22, Step C) and N-(azetidin-3-ylcarbamoylmethyl)-4-fluoro-3-trifluoromethyl-benzamide (analog synthesis by following the procedure described in Organic Synthesis XII, 40-2, 1932) using the procedure described in Step F of Example 1.
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@@H:18]([C:32](O)=[O:33])[CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[C:23]([NH2:30])=[C:22]([CH3:31])[CH:21]=3)=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:35]=[CH:36][CH:37]=[CH:38][C:4]=2[NH:3]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C.[O:68]1[CH2:73][CH2:72][CH:71]([N:74]2[CH2:79][CH2:78][NH:77][CH2:76][CH2:75]2)[CH2:70][CH2:69]1>CN(C=O)C>[O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@H:18]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:28])([F:27])[F:29])[C:23]([NH2:30])=[C:22]([CH3:31])[CH:21]=3)[C:32](=[O:33])[N:77]3[CH2:76][CH2:75][N:74]([CH:71]4[CH2:72][CH2:73][O:68][CH2:69][CH2:70]4)[CH2:79][CH2:78]3)=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:35]=[CH:36][CH:37]=[CH:38][C:4]=2[NH:3]1
Reactant: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)O)cc(C(F)(F)F)c1N
Reactant: C1CN(C2CCOCC2)CCN1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCN(C3CCOCC3)CC2)cc(C(F)(F)F)c1N
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of 100 mg (0.19 mmol) (R)-2-(4-amino-3-methyl-5-trifluoromethyl-phenyl)-1-carboxy-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate, 67 mg (0.21 mmol) TBTU and 50 μL (0.36 mmol) triethylamine in 1 mL DMF was stirred for 10 min at RT. Then 40 mg (0.24 mmol) 1-(tetrahydropyran-4-yl)-piperazine were added and the reaction mixture was stirred for a further 20 h at RT. The reaction solution was purified by HPLC without any further working up. The fractions containing the product were combined and lyophilised.
Reaction SMILES: O.Cl.[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([S:10][CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[CH:6][CH:5]=1.B(O[O-])=[O:18].[Na+]>Cl>[ClH:3].[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([S:10]([CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[O:18])=[CH:8][CH:9]=1
Reactant: Clc1ccc(SC2CCNCC2)cc1
Reactant: O=BO[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: O=S(c1ccc(Cl)cc1)C1CCNCC1

Procedure:
A solution of 5.78 g (0.020 mole) of 4-[(p-chlorophenyl)thio]piperidine hydrochloride hydrate and 4.61 g (0.030 mole) of sodium perborate in 200 ml of dilute hydrochloride acid was stirred at room temperature overnight. The reaction mixture was quenched in dilute sodium hydroxide and the resulting basic solution was extracted with methylene chloride. The methylene chloride layer was dried over magnesium sulfate and the solvent was removed in vacuo to give a white solid, the free base of the title compound. The free base was reacted with ethereal hydrogen chloride and the salt was recrystallized from methanol-diethyl ether to give the product as a white crystalline solid, m.p. 22°-221° C.
Reaction SMILES: C1(OC)C=CC=CC=1.[Br:9][C:10]1[CH:11]=[CH:12][C:13](/[C:18](/[C:37]2[CH:42]=[CH:41][C:40]([C:43]([CH3:46])([CH3:45])[CH3:44])=[CH:39][CH:38]=2)=[CH:19]/[C@@H:20]2[N:24](CC3C=CC(OC)=CC=3OC)[C:23](=[O:36])[CH2:22][CH2:21]2)=[N:14][C:15]=1[O:16][CH3:17]>FC(F)(F)C(O)=O>[Br:9][C:10]1[CH:11]=[CH:12][C:13](/[C:18](/[C:37]2[CH:38]=[CH:39][C:40]([C:43]([CH3:46])([CH3:45])[CH3:44])=[CH:41][CH:42]=2)=[CH:19]/[C@@H:20]2[NH:24][C:23](=[O:36])[CH2:22][CH2:21]2)=[N:14][C:15]=1[O:16][CH3:17]
Reactant: COc1ccc(CN2C(=O)CC[C@@H]2/C=C(\c2ccc(C(C)(C)C)cc2)c2ccc(Br)c(OC)n2)c(OC)c1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: COc1nc(/C(=C/[C@H]2CCC(=O)N2)c2ccc(C(C)(C)C)cc2)ccc1Br
Temperature: 70 °C
Reaction time: 5 h

Procedure:
Trifluoroacetic acid (10 mL) and anisole (5 mL) were added to (5R)-5-[(E)-2-(5-bromo-6-methoxypyridin-2-yl)-2-(4-tert-butylphenyl)ethenyl]-1-(2,4-dimethoxybenzyl)pyrrolidin-2-one (950 mg), and the mixture was stirred at 70° C. for five hours. The reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1→1:4) to give the title compound as a yellow amorphous (460 mg, 66%).