Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([NH:13][C:14](=[O:22])[NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:8]=2)[CH2:5][CH:4]([C:23]([NH:25][CH:26]([C:33]2[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=2)[CH2:27][C:28]([O:30]CC)=[O:29])=[O:24])[CH2:3]1.[OH-].[Na+:40]>C1COCC1>[O:1]=[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([NH:13][C:14](=[O:22])[NH:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:8]=2)[CH2:5][CH:4]([C:23]([NH:25][CH:26]([C:33]2[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=2)[CH2:27][C:28]([O-:30])=[O:29])=[O:24])[CH2:3]1.[Na+:40]
Reactant: CCOC(=O)CC(NC(=O)C1CC(=O)N(c2cccc(NC(=O)Nc3ccccc3)c2)C1)c1cccnc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C([O-])CC(NC(=O)C1CC(=O)N(c2cccc(NC(=O)Nc3ccccc3)c2)C1)c1cccnc1

Procedure:
A solution of ethyl 3-((5-oxo-1-{3-((N-phenylcarbamoyl)amino)phenyl}pyrrolidin-3-yl)carbonylamino)-3-(3-pyridyl)propanoate (75 mg, 0.14 mmol, 1.0 eq), THF (1.0 mL), and 1.0 N NaOH (0.15 mL, 1.1 eq) was stirred at room temperature overnight. The solvent was removed on rotary evaporator. The title compound was obtained as an off-white solid. 1H NMR (MeOH-d4, 400 MHz): δ 2.77 (m, 4), 3.30 (m, 1, overlap with solvent), 4.08 (m, 2), 5.35 (m, 1), 7.01(m, 2), 7.28 (m, 4), 7.41(m, 3), 7.66 (m, 1), 7.86 (m, 1), 8.39 (m, 1), 8.57 (m, 1). MS (ES+): 488 (M+H)+; (ES−): 486 (M−H)−.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11]([NH:13]/[N:14]=[CH:15]/[C:16]1[CH:21]=[CH:20][C:19]([C:22]2[N:26]=[CH:25][N:24]([C:27]3[CH:32]=[CH:31][C:30]([O:33][C:34]([F:37])([F:36])[F:35])=[CH:29][CH:28]=3)[N:23]=2)=[CH:18][CH:17]=1)=[S:12])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:45][CH:46](Br)[CH3:47]>CC(=O)CC.C(Cl)Cl>[CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[CH:46]([CH3:47])[CH2:45][S:12]/[C:11]/1=[N:13]/[N:14]=[CH:15]\[C:16]1[CH:17]=[CH:18][C:19]([C:22]2[N:26]=[CH:25][N:24]([C:27]3[CH:28]=[CH:29][C:30]([O:33][C:34]([F:37])([F:35])[F:36])=[CH:31][CH:32]=3)[N:23]=2)=[CH:20][CH:21]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1ccccc1NC(=S)N/N=C/c1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Reactant: CC(Br)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCC(C)=O
Product: CC(C)c1ccccc1N1/C(=N\N=C/c2ccc(-c3ncn(-c4ccc(OC(F)(F)F)cc4)n3)cc2)SCC1C
Temperature: 85 °C

Procedure:
To (E)-N-(2-isopropylphenyl)-2-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)benzylidene)hydrazinecarbothioamide (300 mg, 0.572 mmol) and potassium carbonate (316 mg, 2.29 mmol) in butanone (4 ml) was added 1,2-dibromopropane (0.072 ml, 0.686 mmol). The reaction was heated to 85° C. overnight. The reaction was determined to be complete by LCMS. The reaction mixture was diluted with DCM and washed with water. The aqueous layer was extracted with DCM. The organic layers were poured through a phase separator and concentrated. Purification by flash column chromatography provided a yellow solid. The solid was recrystallized from MeOH. The solid was filtered, washed with MeOH, and dried to provide the title compound as a yellow solid which was dissolved in acetone and concentrated (3×). The light yellow solid was collected and dried under to provide the title compound as a 1:1 mixture of rotational diastereoisomers (75.1 mg, 0.133 mmol, 23%): mp 201-204° C.; 1H NMR of mixture (400 MHz, CDCl3) δ 8.56 (s, 2H), 8.18 (dd, J=10.8, 7.4 Hz, 6H), 7.84-7.73 (m, 8H), 7.45-7.30 (m, 8H), 7.30-7.23 (m, 2H), 7.20 (d, J=6.7 Hz, 1H), 7.12 (dd, J=7.8, 1.2 Hz, 1H), 4.43-4.33 (m, 1H), 4.16 (dd, J=12.6, 6.3 Hz, 1H), 3.48 (dt, J=13.3, 6.7 Hz, 1H), 3.37 (dd, J=10.8, 6.2 Hz, 1H), 3.24 (dt, J=13.7, 6.9 Hz, 1H), 3.08-2.92 (m, 3H), 1.33-1.16 (m, 18H); ESIMS m/z 566 (M+H).
Reaction SMILES: [F:1][C:2](=[C:8]([C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][C:20]=1[O:21][CH3:22])[O:17][C:16]([CH3:24])([CH3:23])[CH:15]=[C:14]2C(C)C)[CH2:9][CH3:10])[C:3]([O:5]CC)=O.F/[C:29](=[C:35](/C1C=C2C(=CC=1OC)OC(C)(C)C=C2C(C)C)\CC)/[C:30](OCC)=O.[H-].C([Al+]CC(C)C)C(C)C>>[F:1]/[C:2](=[C:8](/[C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][C:20]=1[O:21][CH3:22])[O:17][C:16]([CH3:24])([CH3:23])[C:15]([CH:29]([CH3:35])[CH3:30])=[CH:14]2)\[CH2:9][CH3:10])/[CH2:3][OH:5]
Reactant: CCOC(=O)/C(F)=C(/CC)c1cc2c(cc1OC)OC(C)(C)C=C2C(C)C
Reactant: CCOC(=O)C(F)=C(CC)c1cc2c(cc1OC)OC(C)(C)C=C2C(C)C
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Product: CC/C(=C(\F)CO)c1cc2c(cc1OC)OC(C)(C)C(C(C)C)=C2

Procedure:
Following General Procedure L, ethyl 2-fluoro-3-(4-isopropyl-7-methoxy-2,2-dimethyl-2H-chromen-6-yl)-pent-2-enoate (Compound 78, 128 mg, 0.34 mmol) and a diisobutylaluminum hydride (1 M in dichloromethane, 1.0 mL, 1.0 mmol) were reacted to give the title compound as yellow solid after purification by flash chromatography (silica gel, 1:4 ethyl acetate/hexane).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[CH3:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([NH2:20])[CH:15]=1>ClCCl>[CH3:12][O:13][C:14]1[CH:15]=[C:16]([NH:20][C:2]2[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=2[N+:8]([O-:10])=[O:9])[CH:17]=[CH:18][CH:19]=1
Reactant: COc1cccc(N)c1
Reactant: O=[N+]([O-])c1ccc(O)cc1F
Solvent: ClCCl
Product: COc1cccc(Nc2cc(O)ccc2[N+](=O)[O-])c1
Temperature: 150 °C
Reaction time: 2.5 h

Procedure:
4 g of 3-fluoro-4-nitrophenol and 9.4 g of m-anisidine were mixed and stirred for 2.5 hours at 150° C. After cooling, it was dissolved in dichloromethane and extracted three times with 1N aqueous hydrochloric acid. The organic phase was dried on sodium sulfate, concentrated by evaporation in a vacuum, and the residue was chromatographed on silica gel.
Reaction SMILES: N#N.[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:14][CH:13]=[N:12][C:11]=2[C:15]([OH:17])=O)=[CH:6][CH:5]=1.CN(C=O)C.C(Cl)(=O)C([Cl:26])=O>C1(C)C=CC=CC=1>[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:14][CH:13]=[N:12][C:11]=2[C:15]([Cl:26])=[O:17])=[CH:6][CH:5]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1ncoc1-c1ccc(F)cc1
Agent: N#N
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: O=C(Cl)c1ncoc1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a suspension of 5-(4-fluoro-phenyl)-oxazole-4-carboxylic acid (51 mg, 0.25 mmol) in toluene (1.0 mL) was treated with a drop of DMF followed by oxalyl chloride (0.08 mL, 0.86 mmol) and the resulting yellow solution was stirred at rt for 30 min. The solvent was then removed under reduced pressure (coevaporation with toluene) to give 5-(4-fluoro-phenyl)-oxazole-4-carbonyl chloride.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[CH2:4][C:5]1[CH:6]=[C:7]([C:12]2[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:13]=2[CH2:20][NH:21][CH2:22][CH3:23])[CH:8]=[C:9]([Cl:11])[CH:10]=1.[CH2:25]([N:32]=[C:33]=[O:34])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[CH3:1][O:2][C:3](=[O:24])[CH2:4][C:5]1[CH:6]=[C:7]([C:12]2[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:13]=2[CH2:20][N:21]([CH2:22][CH3:23])[C:33]([NH:32][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:34])[CH:8]=[C:9]([Cl:11])[CH:10]=1
Reactant: O=C=NCc1ccccc1
Reactant: CCNCc1ccc(OC)cc1-c1cc(Cl)cc(CC(=O)OC)c1
Product: CCN(Cc1ccc(OC)cc1-c1cc(Cl)cc(CC(=O)OC)c1)C(=O)NCc1ccccc1

Procedure:
Prepared according to the procedure described in Example 95, Step 1, using the following starting materials: (5-chloro-2′-ethylaminomethyl-5′-methoxy-biphenyl-3-yl)-acetic acid methyl ester and benzyl isocyanate.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([C:6]([NH:8][NH:9][C:10]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])=O)=[CH:4][CH:3]=1.[OH-].[Na+].Cl>>[CH2:13]([N:12]1[C:6]([C:5]2[CH:20]=[CH:21][C:2]([Cl:1])=[CH:3][CH:4]=2)=[N:8][NH:9][C:10]1=[O:11])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(NCc1ccccc1)NNC(=O)c1ccc(Cl)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=c1[nH]nc(-c2ccc(Cl)cc2)n1Cc1ccccc1
Temperature: 25 °C

Procedure:
A stirred mixture of 1-(4-chlorobenzoyl)-4-benzylsemicarbazide (16.15 g, 5.317×10-2 mole) and 1 molar aqueous NaOH (64 ml, 6.4×10-2 mole) was heated to reflux. After refluxing ca. 22 hrs., the reaction was allowed to cool slightly before being neutralized by the addition of concentrated aqueous HCl (5.5 ml, 6.6×10-2 mole). A colorless solid formed and after the mixture had cooled to room temperature this was collected by filtration. Crystallization from isopropanol afforded colorless needles: 12.76 g (84%), mp. 208°-210° C.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9]2[N:19]3[C:20]4[C:15]([C:16](=[O:21])[CH2:17][CH2:18]3)=[CH:14][CH:13]=[CH:12][C:11]=4[N:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>O1CCCC1>[C:1]1([CH2:7][CH2:8][C:9]2[N:19]3[C:20]4[C:15]([CH:16]([OH:21])[CH2:17][CH2:18]3)=[CH:14][CH:13]=[CH:12][C:11]=4[N:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1CCn2c(CCc3ccccc3)nc3cccc1c32
Solvent: C1CCOC1
Product: OC1CCn2c(CCc3ccccc3)nc3cccc1c32
Reaction time: 3 h
Yield: 79.4 %

Procedure:
(-)-Diisopinocanphenylchloroborane (87.2 g) was dissolved in dry tetrahydrofuran (170 mL) under an argon atmosphere. Fifty grams of 4,5-dihydro-2-(2-phenylethyl)-6H-imidazo[4,5,1-ij]quinolin-6-one obtained in Example 1 was dissolved in 340 mL of dry tetrahydrofuran and the solution was added slowly at -20° C. to -25° C. After stirring for 3 hrs at the same temperature, the solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate (700 mL) and, following the addition of diethanolamine (52.2 mL), the mixture was stirred at room temperature for 2 hrs. The precipitate was separated by filtration and washed with ethyl acetate; thereafter, the filtrate was concentrated. The residue was purified by silica gel column chromatography to yield 40 g of the titled compound with an optical purity of 71.8% ee. The compound was recrystallized from a solvent system consisting of a mixture of ethanol (100 mL) and hexane (400 mL) to yield the titled compound with an optical purity of 99.6% ee or more as colorless crystals (19.9 g).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[CH:4]=O.[CH3:13][NH:14][CH3:15].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].O>C1COCC1>[Cl:1][C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[CH2:4][N:14]([CH3:15])[CH3:13]
Reactant: CNC
Reactant: O=Cc1cc([N+](=O)[O-])ccc1Cl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CN(C)Cc1cc([N+](=O)[O-])ccc1Cl
Temperature: 0 °C
Yield: 81.2 %

Procedure:
2-chloro-5-nitrobenzaldehyde (1 g, 5.39 mmol) was dissolved in THF (10 mL), and added with dimethylamine (2 M THF solution, 2.7 mL, 5.39 mmol). The reaction solution was cooled to 0° C., and NaBH(OAc)3 (1.6 g, 7.55 mmol) was slowly added thereto, followed by stirring for 12 hours or more at room temperature. The reaction mixture was added with water, and subjected to extraction with ethyl acetate. The separated organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the title compound (940 mg, 81%).
Reaction SMILES: [C:1]([O:4][CH2:5][C@@H:6]([OH:23])[C@@H:7]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:3])[CH3:2].[CH3:24][S:25](Cl)(=[O:27])=[O:26].N1C=CC=CC=1>C(OCC)(=O)C>[C:1]([O:4][CH2:5][C@@H:6]([O:23][S:25]([CH3:24])(=[O:27])=[O:26])[C@@H:7]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@@H](O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Reactant: CS(=O)(=O)Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC(=O)OC[C@@H](OS(C)(=O)=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Reaction time: 48 h
Yield: 98.4 %

Procedure:
A mixture composed of 12.4 mmol (4.00 g) of (2S, 3S)-1-acetoxy-3-(t-butoxycarbonylamino)-2-hydroxy-4-phenylbutane, 24.8 mmol (2.48 g) of methanesulfonyl chloride and 20 ml of pyridine was allowed to stand at 4° C. for 48 hours. Thereafter, 30 ml of ethyl acetate was added, the organic layer was washed with three 30-ml portions of 10% hydrochloric acid and finally with 30 ml of water. The organic layer was separated, dried over sodium sulfate, filtered and concentrated under reduced pressure. Hexane (30 ml) was added to the residue, and the mixture was allowed to stand. The resulting white solid precipitate was collected by filtration. Thus was obtained 4.90 g (98%) of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C:10]([NH:18][C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:20])([C:13]([F:17])([F:16])[CH2:14][OH:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:36][S:37](Cl)(=[O:39])=[O:38].S(=O)(=O)(O)[O-].[K+]>C(Cl)(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C:10]([NH:18][C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:20])([C:13]([F:17])([F:16])[CH2:14][O:15][S:37]([CH3:36])(=[O:39])=[O:38])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)OCc2ccccc2)(C(F)(F)CO)C1
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N1CCC(NC(=O)OCc2ccccc2)(C(F)(F)COS(C)(=O)=O)C1
Reaction time: 0.83 h

Procedure:
To a solution of an optically-active compound of 3-benzyloxycarbonylamino-3-(1,1-difluoro-2-hydroxyethyl)pyrrolidine-1-carboxylic acid tert-butyl ester (471 mg) and triethylamine (328 μl) in chloroform (4.7 ml) cooled to 0° C. was added methanesulfonyl chloride (118 μl), and the mixture was stirred for 50 minutes. To the mixture was added 5% aqueous potassium bisulfate solution, and the mixture was extracted with ethyl acetate. The organic layer was sequentially washed with 1M aqueous sodium hydroxide solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the titled compound (565 mg).
Reaction SMILES: [I-].[CH:2]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([CH3:4])[CH3:3].CC(C)([O-])C.[K+].[Br:30][C:31]1[CH:38]=[CH:37][C:34]([CH:35]=O)=[C:33]([CH3:39])[CH:32]=1>>[Br:30][C:31]1[CH:38]=[CH:37][C:34]([CH:35]=[C:2]([CH3:4])[CH3:3])=[C:33]([CH3:39])[CH:32]=1
Reactant: CC(C)[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cc1cc(Br)ccc1C=O
Agent: CC(C)(C)[O-]
Agent: [I-]
Agent: [K+]
Product: CC(C)=Cc1ccc(Br)cc1C

Procedure:
The crude product of the title compound was synthesized by conducting the similar reaction to that mentioned in Example 23 (23d) using isopropyltriphenylphosphonium iodide (7.2 g, 17 mmol), potassium t-butoxide (2.0 g, 18 mmol), and 4-bromo-2-methylbenzaldehyde (2.4 g, 12 mmol) that was obtained in Example 27 (27b). Subsequently, the crude product of the title compound thus obtained was purified by chromatography on a silica gel column using a mixed solvent of ethyl acetate and hexane (0:10 to 6:94) as the eluent to afford the title compound (2.2 g) in a yield of 84% as a colourless oily product.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][C:7](=[O:12])[CH2:6][CH2:5]2.Cl[C:14]1[CH:22]=[CH:21][C:17]([C:18]([NH2:20])=[O:19])=[CH:16][N:15]=1.C([O-])([O-])=O.[K+].[K+]>>[O:1]=[C:2]1[CH2:11][CH2:10][C:9]2[CH:8]=[C:7]([O:12][C:14]3[CH:22]=[CH:21][C:17]([C:18]([NH2:20])=[O:19])=[CH:16][N:15]=3)[CH:6]=[CH:5][C:4]=2[CH2:3]1
Reactant: O=C1CCc2cc(O)ccc2C1
Reactant: NC(=O)c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: NC(=O)c1ccc(Oc2ccc3c(c2)CCC(=O)C3)nc1
Yield: 49 %

Procedure:
Using a method similar to Intermediate 1, using 6-hydroxy-2-tetralone (Journal of Organic Chemistry (1999), 64(26), 9719-9721) (1.55 g, 9.55 mmol), 6-chloronicotinamide (1.49 g, 9.55 mmol) and K2CO3 (1.98 g, 14.3 mmol) gives the title compound (1.32 g), after purification on silica gel (50% THF/DCM), as an amber foam. Mass spectrum (ion spray): m/z=283 (M+1); 1HNMR (DMSO-d6): 8.59 (s, 1H), 8.23 (d, 1H), 8.01 (s, 1H), 7.47 (s, 1H), 7.19 (d, 2H), 7.07 (m, 2H), 6.97 (d, 1H), 3.59 (s, 2H), 3.01 (t, 2H), 2.43 (t, 2H).
Reaction SMILES: [C:1]([O:12][CH3:13])(=[O:11])[C:2]1[CH:10]=[CH:9][C:5]([C:6]([O-:8])=O)=[CH:4][CH:3]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[F:28][C:29]1[CH:35]=[CH:34][C:32]([NH2:33])=[CH:31][CH:30]=1>CN(C=O)C.O>[F:28][C:29]1[CH:35]=[CH:34][C:32]([NH:33][C:6]([C:5]2[CH:4]=[CH:3][C:2]([C:1]([O:12][CH3:13])=[O:11])=[CH:10][CH:9]=2)=[O:8])=[CH:31][CH:30]=1
Reactant: Nc1ccc(F)cc1
Reactant: COC(=O)c1ccc(C(=O)[O-])cc1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: O
Product: COC(=O)c1ccc(C(=O)Nc2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 98.9 %

Procedure:
To a suspension of mono-methyl terephthalate (2.0 g, 11.1 mmol) in DMF (10 mL) was added EDC (2.48 g, 13.3 mmol), HOBt (1.80 g, 13.3 mmol), and 4-fluoroaniline (1.48 g, 13.3 mmol). The reaction was stirred at room temperature for 72 h. The reaction was diluted with water (80 mL) and isolated methyl 4-(4-fluorophenylcarbamoyl)benzoate (3.00 g, 98%) as a white precipitate by vacuum filtration. 1H-nmr (400 MHz, CDCl3) δ 8.18 (d, J=8 Hz, 2H), 7.95 (d, J=8 Hz, 2H), 7.82 (br s, 1H), 7.66-7.59 (m, 2H), 7.15-7.07 (m, 2H), 3.99 (s, 3H); MS (ESI) m/z 273.9.
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]([CH2:11][CH3:12])([CH3:10])[CH3:9])=[CH:6][C:5]([C:13]([CH2:16][CH3:17])([CH3:15])[CH3:14])=[CH:4][C:3]=1[N:18]1[N+:22]([O-])=[C:21]2[CH:24]=[CH:25][CH:26]=[CH:27][C:20]2=[N:19]1.CNC.[H][H]>C1(C)C=CC=CC=1.[C].[Pd]>[OH:1][C:2]1[C:7]([C:8]([CH2:11][CH3:12])([CH3:10])[CH3:9])=[CH:6][C:5]([C:13]([CH2:16][CH3:17])([CH3:15])[CH3:14])=[CH:4][C:3]=1[N:18]1[N:22]=[C:21]2[CH:24]=[CH:25][CH:26]=[CH:27][C:20]2=[N:19]1
Reactant: [H][H]
Reactant: CCC(C)(C)c1cc(-n2nc3ccccc3[n+]2[O-])c(O)c(C(C)(C)CC)c1
Agent: [Pd]
Agent: CNC
Solvent: Cc1ccccc1
Product: CCC(C)(C)c1cc(-n2nc3ccccc3n2)c(O)c(C(C)(C)CC)c1
Yield: 93 %

Procedure:
36.7 g (0.1 mol) of 2-(2'-hydroxy-3',5'-di-t-amylphenyl)benzotriazole-N-oxide, 0.125 g of 5% palladium carbon, 150 ml of a toluene solvent and 7 g of 50% dimethylamine were charged into a 500-ml four neck flask. After the air in the flask had been replaced by nitrogen, the resultant mixture was agitated at room temperature. Hydrogen was then supplemented to allow for the amount of hydrogen absorbed by the mixture, which was then subjected to reaction until no more hydrogen was absorbed by it. After the reaction had been completed, the catalyst was filtered off, and part of the filtrate was subjected to quantitative analysis using gas chromatography (GC). The results revealed a yield of 93% of 2-(2'-hydroxy-3',5'-di-t-amylphenyl)benzotriazole. The solvent was then distilled off from the filtrate, and the residual solid was crystallized using ethanol and then washed with ethanol to obtain 28.1 g of 2-(2'-hydroxy-3',5'-di-t-amylphenyl)benzotriazole (yield, 80%; melting point, 79° to 81° C.).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([C:7]([OH:9])=O)[CH2:3][CH2:2]1.C(Cl)CCl.C1C=CC2N(O)N=[N:20]C=2C=1.[OH-].[NH4+].[Na+].[Cl-]>CC#N.O>[O:1]1[CH2:6][CH2:5][CH:4]([C:7]([NH2:20])=[O:9])[CH2:3][CH2:2]1
Reactant: On1nnc2ccccc21
Reactant: O=C(O)C1CCOCC1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC#N
Solvent: O
Product: NC(=O)C1CCOCC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 46.4 %

Procedure:
A 0° C. solution of tetrahydro-2H-pyran-4-carboxylic acid (0.5 g, 3.84 mmol) in MeCN (15 mL) was treated with EDC (0.884 g, 4.61 mmol) and HOBT (0.706 g, 4.61 mmol) under an argon atmosphere and stirred at 0° C. for 1 h. Ammonium hydroxide (˜15M, 0.512 mL, 7.68 mmol) was added slowly and the mixture was warmed to RT and stirred overnight. The mixture was treated with water, saturated with solid NaCl and the aqueous layer was extracted with THF (2×). The combined organics were washed with brine, dried over Na2SO4 and concentrated to afford tetrahydro-2H-pyran-4-carboxamide (0.23 g, 46%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 7.20 (s, 1H), 6.73 (s, 1H), 3.82-3.81 (m, 2H), 3.30-3.21 (m, 2H), 2.30-2.27 (m, 1H), 1.60-1.46 (m, 4H).
Reaction SMILES: C(C[NH:5][CH:6]([CH2:12][F:13])[CH2:7][CH2:8][C:9]([OH:11])=[O:10])(O)=O>Cl>[NH2:5][CH:6]([CH2:12][F:13])[CH2:7][CH2:8][C:9]([OH:11])=[O:10]
Reactant: O=C(O)CCC(CF)NCC(=O)O
Agent: Cl
Product: NC(CF)CCC(=O)O

Procedure:
A mixture of 0.65 g (3.4 mmol) of 4-carboxymethylamino-5-fluoropentanoic acid and 10 ml of concentrated hydrochloric acid was prepared in a 50 ml flask and heated at reflux overnight. The volatiles were then removed by evaporation under reduced pressure and the gummy residue was dissolved in water and purified by ion exchange chromatography using DOWEX® 50 X-8 resin. The solution was loaded onto the rinsed column, washed with water, and eluted with 6 percent aqueous hydrochloric acid. Evaporation of the product-containing fractions gave 0.42 g (71 percent of theory) of the title compound as an oily crystalline material which tenaciously retained water. This was recrystallized from ethyl acetate/acetic acid to obtain the desired product as white crystals melting at 129° -134° C. and having the expected proton and carbon nmr spectra.
Reaction SMILES: Br[C:2]1[N:3]([C:13]2[N:14]=[CH:15][N:16]=[C:17]([NH2:20])[C:18]=2[N:19]=1)[C@@H:4]1[O:12][C@H:9]([CH2:10][OH:11])[C@@H:7]([OH:8])[C@H:5]1[OH:6].Cl.[Br:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27][NH2:28])=[CH:25][CH:24]=1.C(N(CC)CC)C>C(O)C>[Br:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27][NH:28][C:2]2[N:3]([C:13]3[N:14]=[CH:15][N:16]=[C:17]([NH2:20])[C:18]=3[N:19]=2)[C@@H:4]2[O:12][C@H:9]([CH2:10][OH:11])[C@@H:7]([OH:8])[C@H:5]2[OH:6])=[CH:25][CH:24]=1
Reactant: NCc1ccc(Br)cc1
Reactant: Nc1ncnc2c1nc(Br)n2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: Nc1ncnc2c1nc(NCc1ccc(Br)cc1)n2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Temperature: 25 °C
Yield: 90.5 %

Procedure:
A mixture of 8-bromoadenosine (0.100 g), 4-bromobenzylamine hydrochloride (0.193 g) and triethylamine (0.201 mL) in ethanol (2.9 mL) was stirred under reflux for 96 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by column chromatography on aminopropylated silica gel (eluent: dichloromethane/methanol=10/1) to give the title compound (0.118 g).
Reaction SMILES: [CH:1]([C:3]1[S:7][C:6]([C:8]2[CH:9]=[C:10]3[C:14](=[C:15]([C:17]([NH2:19])=[O:18])[CH:16]=2)[NH:13][CH:12]=[C:11]3[CH:20]2[CH2:25][CH2:24][N:23]([S:26]([CH2:29][CH2:30][CH2:31][N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)(=[O:28])=[O:27])[CH2:22][CH2:21]2)=[CH:5][CH:4]=1)=O.[CH2:38]([NH2:40])[CH3:39].[BH4-].[Na+]>CO.C(Cl)Cl>[CH2:38]([NH:40][CH2:1][C:3]1[S:7][C:6]([C:8]2[CH:9]=[C:10]3[C:14](=[C:15]([C:17]([NH2:19])=[O:18])[CH:16]=2)[NH:13][CH:12]=[C:11]3[CH:20]2[CH2:21][CH2:22][N:23]([S:26]([CH2:29][CH2:30][CH2:31][N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)(=[O:28])=[O:27])[CH2:24][CH2:25]2)=[CH:5][CH:4]=1)[CH3:39]
Reactant: NC(=O)c1cc(-c2ccc(C=O)s2)cc2c(C3CCN(S(=O)(=O)CCCN4CCOCC4)CC3)c[nH]c12
Reactant: CCN
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CCNCc1ccc(-c2cc(C(N)=O)c3[nH]cc(C4CCN(S(=O)(=O)CCCN5CCOCC5)CC4)c3c2)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.9 %

Procedure:
To a solution of 5-(5-formyl-2-thienyl)-3-(1-{[3-(4-morpholinyl)propyl]sulfonyl}-4-piperidinyl)-1H-indole-7-carboxamide (20 mg, 0.04 mmol) in MeOH/CH2Cl2 (1 mL/1 mL) was added ethyl amine (0.13 mL, 0.24 mmol). The reaction mixture was stirred at room temperature for 2 hours before NaBH4(10.5 mg, 0.24 mmol) was added. The reaction mixture was stirred at room temperature overnight and evaporated all the solvent. The residue was purified by using a Gilson semi-preparative HPLC system, eluting with 10% B to 80% B, where A=H2O (0.1% trifluoroacetic acid) and B=CH3CN (0.1% trifluoroacetic acid) pumped at 25 mL/min to give the title compound (11 mg, 52%)