Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([N+:13]([O-:15])=[O:14])=[C:4]([CH3:12])[C:5]([CH3:11])=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[Br:16]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:16][CH2:12][C:4]1[C:5]([CH3:11])=[CH:6][C:7]([N+:8]([O-:10])=[O:9])=[C:2]([Cl:1])[C:3]=1[N+:13]([O-:15])=[O:14]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc([N+](=O)[O-])c(Cl)c([N+](=O)[O-])c1C
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1cc([N+](=O)[O-])c(Cl)c([N+](=O)[O-])c1CBr
Temperature: 25 °C
Reaction time: 2 h
Yield: 21.8 %

Procedure:
A mixture of 4-chloro-3,5-dinitro-o-xylene (4.62 g; 0.02 mol), N-bromosuccinimide (3.90 g; 0.022 mol) and carbon tetrachloride (100 ml) is stirred and heated at reflux for 4 hours. The reaction mixture is then irradiated with a light source (60 watt) and refluxing continued for 2 hours. Next, 100 mg of initiator [2,2-azobis(2-methylpropionitrile)] is added and the mixture refluxed for one more hour. The reaction mixture is then cooled to room temperature and stirred under a light source for 48 hours, and filtered. The filtrate is evaporated to dryness in vacuo, and the solid residue recrystallized twice from ethanol to afford 1.35 g of title product.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]1[N:15]=[C:14]([OH:16])[C:13]([C:17]([OH:19])=O)=[CH:12][N:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C(ON1N=N[C:30]2[CH:31]=[CH:32][CH:33]=[N:34][C:29]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH2:1]([O:8][CH2:9][C:10]1[N:15]=[C:14]([OH:16])[C:13]([C:17]([NH:34][CH2:33][C:32]2[CH:5]=[CH:4][C:3]3[C:30](=[CH:29][CH:6]=[CH:7][CH:2]=3)[CH:31]=2)=[O:19])=[CH:12][N:11]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: O=C(O)c1cnc(COCc2ccccc2)nc1O
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: O=C(NCc1ccc2ccccc2c1)c1cnc(COCc2ccccc2)nc1O
Temperature: 25 °C

Procedure:
To a stirred suspension of compound 2-e (5 g, 19.2 mmol) in DMF (50 mL) was added HATU (8.04 g, 21.1 mmol) and EIPEA (2.73 g, 21.1 mmol). The reaction mixture was stirred at ambient temperature until all dissolved. To this stirred solution was added compound 2-22-a (3.17 g, 20.2 mmol) in DMF (20 mL) via syringe. The solution was stirred at room temperature overnight. The reaction mixture was poured into ice-water and extracted with DCM and then concentrated to give a residue. The residue was purified by column chromatography with the eluent DCM:MeOH=60:1 to afford product, 2-22-b, (5.2 g, 68%). 1H NMR (300 MHz, CDCl3): δ 9.38 (s, 1H), 8.90 (s, 1H), 7.81-7.75 (m, 4H), 7.43-7.34 (m, 8H), 4.77 (d, J=6.0 Hz, 2H), 4.67 (s, 2H), 4.56 (s, 2H). LC-MS: (M+H)+ 400.
Reaction SMILES: C(OC([NH:8][CH:9]([C@@H:16]1[CH2:20][CH2:19][NH:18][CH2:17]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1)=O)(C)(C)C.C(#N)C.[NH2:24][C:25]1[C:34]([F:35])=[C:33](F)[C:32]([F:37])=[C:31]2[C:26]=1[C:27](=[O:45])[C:28]([C:42]([OH:44])=[O:43])=[CH:29][N:30]2[C@@H:38]1[CH2:40][C@@H:39]1[F:41]>C(N(CC)CC)C>[NH2:24][C:25]1[C:34]([F:35])=[C:33]([N:18]2[CH2:19][CH2:20][C@@H:16]([CH:9]([NH2:8])[C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=3)[CH2:17]2)[C:32]([F:37])=[C:31]2[C:26]=1[C:27](=[O:45])[C:28]([C:42]([OH:44])=[O:43])=[CH:29][N:30]2[C@@H:38]1[CH2:40][C@@H:39]1[F:41]
Reactant: CC(C)(C)OC(=O)NC(c1ccccn1)[C@@H]1CCNC1
Reactant: Nc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2[C@@H]1C[C@@H]1F
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Nc1c(F)c(N2CC[C@@H](C(N)c3ccccn3)C2)c(F)c2c1c(=O)c(C(=O)O)cn2[C@@H]1C[C@@H]1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 53.8 %

Procedure:
3-(R)-[1-Tert-butoxycarbonylamino-1-(2-pyridyl)methyl]pyrrolidine [F2] (0.535 mmol) was added to an acetonitrile suspension (5 ml) of 5-amino-6,7,8-trifluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (169 mg, 0.534 mmol), and the mixture was heated under reflux for 19 hours in the presence of triethylamine (0.5 ml). After cooling, the solvent of the reaction solution was evaporated under a reduced pressure. The resulting residue was dissolved in chloroform (50 ml), this was washed with 10% citric acid (40 ml) and saturated brine (40 ml) and dried over anhydrous sodium sulfate, and then the solvent was evaporated under a reduced pressure. The resulting residue was mixed with concentrated hydrochloric acid (5 ml) under ice-cooling, further mixed with 1 mol/l hydrochloric acid aqueous solution (5 ml) at roam temperature and then washed with chloroform (50 ml×5). This hydrochloric acid aqueous solution was adjusted to an alkaline liquid property by adding 10 mol/l sodium hydroxide aqueous solution and then stirred at room temperature for 1 hour. This suspension was adjusted to a liquid property of pH 7.4 by adding concentrated hydrochloric acid and 1 mol/l hydrochloric acid and then extracted with chloroform (150 ml×3). The resulting organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated under a reduced pressure to obtain the crude title compound as light yellow crystals. This was purified by recrystallizing from ethanol to obtain 136 mg (54%) of the title compound.
Reaction SMILES: [CH3:1][N:2]([C:11]1[S:12][CH:13]=[C:14]([C:16](=[O:22])[C:17]([O:19]CC)=[O:18])[N:15]=1)[C:3]([O:5][C:6]([CH2:9][CH3:10])([CH3:8])[CH3:7])=[O:4].[OH-].[Na+]>C(O)C>[CH3:1][N:2]([C:11]1[S:12][CH:13]=[C:14]([C:16](=[O:22])[C:17]([OH:19])=[O:18])[N:15]=1)[C:3]([O:5][C:6]([CH2:9][CH3:10])([CH3:7])[CH3:8])=[O:4]
Reactant: CCOC(=O)C(=O)c1csc(N(C)C(=O)OC(C)(C)CC)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCC(C)(C)OC(=O)N(C)c1nc(C(=O)C(=O)O)cs1
Yield: 84.7 %

Procedure:
To a solution of ethyl 2-[2-(N-methyl-N-tert-pentyloxycarbonylamino)-1,3-thiazol-4-yl]glyoxylate (3.1 g.) in ethanol (40 ml.) was added 1N sodium hydroxide aqueous solution (14.2 ml.) under ice-cooling and stirring, and the mixture was further stirred for 30 minutes at the same temperature. After the reaction, ethanol was distilled off from the reaction mixture below 20° C. under reduced pressure. To the residue was added water (50 ml.), and after layering with ethyl acetate, the mixture was adjusted to pH 3 with 2N hydrochloric acid. The ethyl acetate layer was separated from the mixture, washed with water, dried over magnesium sulfate and then treated with an activated charcoal. The solvent is distilled off from the resulting ethyl acetate layer to give solid of 2-[2-(N-methyl-N-tert-pentyloxycarbonylamino)-1,3-thiazol-4-yl]glyoxylic acid (2.4 g.).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([O:8]C)=O.[H-].[Na+].[CH3:12][C:13]([CH3:15])=[O:14].Cl>C(OCC)C>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([CH2:12][C:13](=[O:14])[CH3:15])=[O:8]
Reactant: CC(C)=O
Reactant: COC(=O)c1ccco1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Product: CC(=O)CC(=O)c1ccco1
Yield: 99.6 %

Procedure:
4.27 ml (5.04 g, 40 mmol) methyl 2-furoate was added to a suspension of NaH (made from 3.83 g commercial NaH slurry by removal of the mineral oil with pentane) in 30 ml anhydrous diethyl ether. To this was added, so as to maintain the temperature below 30° C., 5.87 ml (4.64 g, 80 mmol) acetone (dried over CaCl2). This mixture was heated under reflux for 2 h, cooled, and divided between diethyl ether and 3M HCl. The ether layer was washed with brine, dried (MgSO4), and concentrated to yield 6.06 g of a red oil (raw yield 99%) which was purified by vacuum distillation (b.p. 85°-90° C./1 torr).
Reaction SMILES: [BH4-].[Li+].[N+:3]([C:6]1[CH:7]=[C:8]([CH:12]([CH3:17])[C:13](OC)=[O:14])[CH:9]=[CH:10][CH:11]=1)([O-:5])=[O:4]>C1COCC1>[N+:3]([C:6]1[CH:7]=[C:8]([CH:12]([CH3:17])[CH2:13][OH:14])[CH:9]=[CH:10][CH:11]=1)([O-:5])=[O:4]
Reactant: COC(=O)C(C)c1cccc([N+](=O)[O-])c1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(CO)c1cccc([N+](=O)[O-])c1
Reaction time: 18 h
Yield: 100.6 %

Procedure:
A solution of lithium borohydride (2M, THF, 2.0 equiv. 3.4 ml) was added to a solution of methyl 2-(3-nitrophenyl)propanoate (0.7 g) in THF. The resulting mixture was stirred for 18 hours then concentrated and poured into hydrochloric acid (10%) at 0□ C. The mixture was extracted with ether. The combined organic phases were dried over sodium sulfate, filtered and concentrated to afford the title compound as yellow oil (0.610 g, 100% yield).
Reaction SMILES: [CH2:1]([C:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)=[C:8]([NH2:17])[NH:7][N:6]=1)[CH2:2][CH2:3][CH3:4].[F:18][C:19]1[CH:24]=[CH:23][C:22]([C:25](=O)[CH2:26][C:27](OCC)=[O:28])=[CH:21][CH:20]=1>N1C=CC=CC=1>[CH2:1]([C:5]1[C:9]([C:10]2[CH:11]=[CH:12][C:13]([CH3:16])=[CH:14][CH:15]=2)=[C:8]2[NH:17][C:27](=[O:28])[CH:26]=[C:25]([C:22]3[CH:23]=[CH:24][C:19]([F:18])=[CH:20][CH:21]=3)[N:7]2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1n[nH]c(N)c1-c1ccc(C)cc1
Reactant: CCOC(=O)CC(=O)c1ccc(F)cc1
Solvent: c1ccncc1
Product: CCCCc1nn2c(-c3ccc(F)cc3)cc(=O)[nH]c2c1-c1ccc(C)cc1
Temperature: 25 °C
Yield: 65.7 %

Procedure:
3-Butyl-4-(4-methylphenyl)-1H-pyrazol-5-amine (200 mg) and ethyl 3-(4-fluorophenyl)-3-oxopropanoate (250 mg) are stirred overnight in a pyridine (10 mL) solvent at 95° C. After cooling to room temperature, the reaction solvent is removed by distillation under reduced pressure. The remainder is extracted with ethyl acetate and water. The extracted organic layer is washed with brine and dehydrated with anhydrous MgSO4. The dehydrated organic layer is distilled under reduced pressure and 215 mg of the target compound is yielded by column chromatography.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15](=[O:17])[CH3:16])[CH:10]=2)=[CH:5][CH:4]=1.[BH4-].[Na+]>O.CCO>[F:1][C:2]([F:18])([F:19])[C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]([OH:17])[CH3:16])[CH:10]=2)=[CH:7][CH:8]=1
Reactant: CC(=O)c1cccc(-c2ccc(C(F)(F)F)cc2)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(O)c1cccc(-c2ccc(C(F)(F)F)cc2)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 90.3 %

Procedure:
A mixture of 1-[4′-(trifluoromethyl)-3-biphenylyl]ethanone (300 mg, 1.14 mmol) in water (1 mL) and EtOH (5 mL) was treated portion-wise with sodium borohydride (57 mg, 1.50 mmol) and then stirred at rt for 1.5 hours. The reaction was then quenched by the addition of saturated aqueous NH4Cl, diluted with CHCl3 and the layers separated. The organic layer was then dried (Na2SO4), filtered and reduced to give the title compound (274 mg).
Reaction SMILES: CS(O[CH:6]1[CH2:9][N:8]([C:10]2[S:11][C:12]3[CH:18]=[C:17]([Br:19])[CH:16]=[CH:15][C:13]=3[N:14]=2)[CH2:7]1)(=O)=O.[NH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[Br:19][C:17]1[CH:16]=[CH:15][C:13]2[N:14]=[C:10]([N:8]3[CH2:9][CH:6]([N:20]4[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]4)[CH2:7]3)[S:11][C:12]=2[CH:18]=1
Reactant: CS(=O)(=O)OC1CN(c2nc3ccc(Br)cc3s2)C1
Reactant: C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Brc1ccc2nc(N3CC(N4CCCCC4)C3)sc2c1
Temperature: 92.5 °C
Reaction time: 48 h

Procedure:
A mixture of 1-(6-bromobenzo[d]thiazol-2-yl)azetidin-3-yl methanesulfonate (Reference Example 12b, 61.7 mg, 0.17 mmol), piperidine (0.250 mL, 2.5 mmol), and potassium carbonate (0.062 g, 0.44 mmol) in N,N-dimethylformamide (1 mL) was stirred at 90-95° C. for two days. The reaction mixture was cooled to room temperature, diluted with water (10 mL), and extracted with dichloromethane (2×4 mL). The combined organic extracts were washed with water (2×5 mL), then dried (Na2SO4) and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel chromatography (90:10:0 to 88:10:2 dichloromethane/ethyl acetate/methanol). A second column was run with the same eluent gradient. Fractions containing product were combined and concentrated under reduced pressure to give 6-bromo-2-(3-(piperidin-1-yl)azetidin-1-yl)benzo[d]thiazole. 1H NMR (300 MHz, CD3OD) δ ppm 1.47-1.58 (m, 2H), 1.64 (pentet, J=5 Hz, 1H), 2.35-2.45 (m, 4H), 3.36-3.46 (m, 1H), 4.02-4.08 (m, 2H), 4.24 (t, J=8 Hz, 2H), 7.35 (d, J=8 Hz, 1H), 7.42 (dd, J=2, 8 Hz, 1H), 7.83 (d, J=2 Hz, 1H); MS (ESI) m/z 352 (M+H)+.
Reaction SMILES: N#N.[CH3:3][C:4]1([C:9]2[CH:10]=[C:11]([CH2:14]O)[S:12][CH:13]=2)[O:8][CH2:7][CH2:6][O:5]1.CCN(CC)CC.S([Cl:27])(C)(=O)=O>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Cl:27][CH2:14][C:11]1[S:12][CH:13]=[C:9]([C:4]2([CH3:3])[O:8][CH2:7][CH2:6][O:5]2)[CH:10]=1
Reactant: CS(=O)(=O)Cl
Reactant: CC1(c2csc(CO)c2)OCCO1
Agent: CN(C)c1ccncc1
Agent: N#N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(c2csc(CCl)c2)OCCO1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of [4-(2-methyl-[1,3]dioxolan-2-yl)-thiophen-2-yl]-methanol (256 mg, 1.28 mmol) in dry CH2Cl2 (5.0 mL) was treated at 0° C. with Et3N (0.23 mL, 1.64 mmol) followed by DMAP (16 mg, 0.13 mmol) and Ms-Cl (0.12 mL, 1.55 mmol). After stirring at 0° C. for 30 min and at rt for 1 h, the reaction mixture was quenched with water (10 mL), extracted with CH2Cl2 (10 mL) and the combined org. extracts were dried over Na2SO4, filtered, and the solvents were removed under reduced pressure to give crude 2-(5-chloromethyl-thiophen-3-yl)-2-methyl-[1,3]dioxolane (TLC:rf (1:1 EA-Hept)=0.61). A solution of the crude material in DMF (3 mL) was treated at rt with a solution of (4-nitro-2H-[1,2,3]triazole (124 mg, 1.07 mmol) in DMF (2.0 mL) pre-treated for 30 min with DIPEA (0.40 mL, 2.34 mmol). The resulting mixture was stirred for two weeks at rt. Water (10 mL), followed by EA (10 mL) were added. The org. extract was washed with water (10 mL), dried over Na2SO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (hept to 1:1 hept-EA) gave the title compound as a yellow oil: TLC:rf (1:1 hept-EA)=0.48.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][C:5]([CH2:11][S+:12]([O-:24])[C:13]2[NH:14][C:15]3[CH:16]=[CH:17][C:18]([O:22][CH3:23])=[CH:19][C:20]=3[N:21]=2)=[C:6]([CH3:10])[C:7]=1[O:8][CH3:9]>CO>[CH3:1][C:2]1[C:7]([O:8][CH3:9])=[C:6]([CH3:10])[C:5]([CH2:11][N:14]2[C:13]([S:12]([CH2:11][C:5]3[C:6]([CH3:10])=[C:7]([O:8][CH3:9])[C:2]([CH3:1])=[CH:3][N:4]=3)=[O:24])=[N:21][C:20]3[CH:19]=[C:18]([O:22][CH3:23])[CH:17]=[CH:16][C:15]2=3)=[N:4][CH:3]=1
Reactant: COc1ccc2[nH]c([S+]([O-])Cc3ncc(C)c(OC)c3C)nc2c1
Solvent: CO
Product: COc1ccc2c(c1)nc(S(=O)Cc1ncc(C)c(OC)c1C)n2Cc1ncc(C)c(OC)c1C

Procedure:
For standards, 100 μg/mL concentration of omeprazole in methanol for a marker was prepared. A 0.1 μg/mL concentration of omeprazole was then prepared to set one-half the minimal detection limit. Then, a 1 μg/mL concentration of omeprazole impurity D in methanol was prepared. The chromatographic conditions were: Mobile Phase: 75% Na2PO4 pH 7.6, 25% acetonitrile; Flow Rate: 1.0 mL/min; Run Time: 30 min; Injection Volume: 20 μL; Detector: U.V., 280 nm; Column: Waters SymmetryShield RP8.
Reaction SMILES: [CH:1]1([CH:7]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH3:18])[CH:15]=3)[CH2:10][CH2:9][N:8]2[C:19](=[O:34])[CH2:20][NH:21][CH2:22][CH2:23][O:24][C@@H:25]2[CH2:29][CH2:28][CH2:27][C@@H:26]2[O:30]COC)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.CCOC(C)=O>CO>[CH:1]1([CH:7]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH3:18])[CH:15]=3)[CH2:10][CH2:9][N:8]2[C:19](=[O:34])[CH2:20][NH:21][CH2:22][CH2:23][O:24][C@H:25]2[CH2:29][CH2:28][CH2:27][C@H:26]2[OH:30])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COCO[C@H]1CCC[C@H]1OCCNCC(=O)N1CCc2ccc(OC)cc2C1C1CCCCC1
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1ccc2c(c1)C(C1CCCCC1)N(C(=O)CNCCO[C@H]1CCC[C@H]1O)CC2
Temperature: 60 °C
Reaction time: 5 h
Yield: 83.8 %

Procedure:
2-(1-cyclohexyl-7-methoxy-3,4-dihydroisoquinolin-2(1H)-yl)-N-(2-{[cis-2-(methoxymethoxy)cyclopentyl]oxy}ethyl)-2-oxoethanamine (500 mg) was dissolved in MeOH (8 mL). To the reaction liquid was added 4 M HCl/EtOAc (0.8 mL) under ice-cooling, followed by stirring at 60° C. for 5 hours. The solvent was evaporated and saturated aqueous sodium bicarbonate was added to the resulting residue, followed by extraction with chloroform. The extract was washed with saturated brine, and then dried over magnesium sulfate. The solvent was evaporated and the resulting residue was purified by silica gel column chromatography (chloroform-MeOH) to obtain cis-2-(2-{[2-(1-cyclohexyl-7-methoxy-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl]amino}ethoxy)cyclopentanol (380 mg).
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([C:9]([CH3:13])([CH3:12])[C:10]#[N:11])[CH:6]=[CH:7][CH:8]=1.[CH3:14][C:15]1[NH:16][C:17]2[C:22]([C:23]=1[CH3:24])=[CH:21][C:20]([C:25]([O:27][CH2:28][CH:29]=[CH2:30])=[O:26])=[CH:19][CH:18]=2>>[C:10]([C:9]([C:5]1[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=1)[CH2:2][N:16]1[C:17]2[C:22](=[CH:21][C:20]([C:25]([O:27][CH2:28][CH:29]=[CH2:30])=[O:26])=[CH:19][CH:18]=2)[C:23]([CH3:24])=[C:15]1[CH3:14])([CH3:13])[CH3:12])#[N:11]
Reactant: CC(C)(C#N)c1cccc(CBr)c1
Reactant: C=CCOC(=O)c1ccc2[nH]c(C)c(C)c2c1
Product: C=CCOC(=O)c1ccc2c(c1)c(C)c(C)n2Cc1cccc(C(C)(C)C#N)c1

Procedure:
The title compound was prepared following the same general protocol as described in Step 2, Example 1, using 2-(3-(bromomethyl)phenyl)-2-methylpropanenitrile and allyl 2,3-dimethyl-1H-indole-5-carboxylate. ESI-MS (m/z): 387 [M+H]+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[CH2:12][CH2:11][C:10](=[O:13])[NH:9][C:8]2=[O:14])[CH2:3][CH2:2]1.C1C=CC2N(O)N=NC=2C=1.[Cl:25][C:26]1[CH:27]=[C:28]2[C:33](=[CH:34][CH:35]=1)[CH:32]=[C:31]([S:36]([CH2:39][C@@H:40]([OH:44])[C:41](O)=[O:42])(=[O:38])=[O:37])[CH:30]=[CH:29]2.CCN=C=NCCCN(C)C>CN(C=O)C>[Cl:25][C:26]1[CH:27]=[C:28]2[C:33](=[CH:34][CH:35]=1)[CH:32]=[C:31]([S:36]([CH2:39][C@@H:40]([OH:44])[C:41]([N:1]1[CH2:2][CH2:3][CH:4]([N:7]3[CH2:12][CH2:11][C:10](=[O:13])[NH:9][C:8]3=[O:14])[CH2:5][CH2:6]1)=[O:42])(=[O:37])=[O:38])[CH:30]=[CH:29]2
Reactant: O=C(O)[C@H](O)CS(=O)(=O)c1ccc2cc(Cl)ccc2c1
Reactant: O=C1CCN(C2CCNCC2)C(=O)N1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: O=C1CCN(C2CCN(C(=O)[C@H](O)CS(=O)(=O)c3ccc4cc(Cl)ccc4c3)CC2)C(=O)N1
Temperature: 25 °C
Reaction time: 72 h
Yield: 9.1 %

Procedure:
To a solution of 1-piperidin-4-yl-dihydropyrimidin-2,4(1H,3H)-dione (105 mg) obtained in Example 4 5e), HOBt (83 mg) and (2S)-3-[(6-chloro-2-naphthyl)sulfonyl]-2-hydroxypropionic acid (170 mg) in DMF (10 mL) was added WSC (105 mg) at room temperature. The mixture was stirred at room temperature for 3 days, and DMF was distilled off under reduced pressure. The residue was diluted with chloroform, washed with an aqueous saturated sodium bicarbonate solution and saturated saline solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate to ethyl acetate/methanol=10/1), and recrystallized from ethanol to obtain the title compound (24 mg, 9%) as a white powder.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:11]=[C:10]2[C:6]([N:7]=[CH:8][N:9]2[C@H:12]2[C@@H:16]3[O:17]C(C)(C)[O:19][C@@H:15]3[C@@H:14]([C:22]([NH:24][CH2:25][CH3:26])=[O:23])[O:13]2)=[C:5]([NH:27][CH2:28][CH:29]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[N:4]=1.C(N(CC)CC)C.[C:49]1([C:59]2[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=2)[CH:54]=[CH:53][C:52]([S:55](Cl)(=[O:57])=[O:56])=[CH:51][CH:50]=1>ClCCl>[C:49]1([C:59]2[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=2)[CH:54]=[CH:53][C:52]([S:55]([NH:1][CH2:2][C:3]2[N:11]=[C:10]3[C:6]([N:7]=[CH:8][N:9]3[C@@H:12]3[O:13][C@H:14]([C:22]([NH:24][CH2:25][CH3:26])=[O:23])[C@@H:15]([OH:19])[C@H:16]3[OH:17])=[C:5]([NH:27][CH2:28][CH:29]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=3)[N:4]=2)(=[O:57])=[O:56])=[CH:51][CH:50]=1
Reactant: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CN)nc32)[C@@H]2OC(C)(C)O[C@@H]21
Reactant: O=S(=O)(Cl)c1ccc(-c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CNS(=O)(=O)c4ccc(-c5ccccc5)cc4)nc32)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 18 h
Yield: 60 %

Procedure:
A solution of (3aS,4S,6R,6aR)-6-{2-(aminomethyl)-6-[(2,2-diphenylethyl)amino]-9H-purin-9-yl}-N-ethyl-2,2-dimethyltetrahydrofuro[3,4-][1,3]dioxole4-carboxamide (Preparation 10) (140 mg, 0.25 mmol) and triethylamine (0.05 ml, 0.36 mmol) in anhydrous dichloromethane (1 ml) was treated with a solution of [1,1′-biphenyl]-4-sulfonyl chloride (J. Pharm. Sci., 1964, 53, 73) (71 mg, 0.28 mmol) in anhydrous dichloromethane (1 ml). The mixture was stirred at room temperature for 18 hours during which time the solvent was allowed to evaporate off freely. The residue was dissolved in ethanol (1 ml), treated with hydrochloric acid (1M, 1 ml) and heated at 60° C. for 15 hours. The solvent was removed under reduced pressure and the residue was azeotroped with ethanol (×2). The residue was then purified by column chromatography on silica gel eluting with a gradient system of dichloromethane: methanol (95:5 by volume) gradually changing to dichloromethane:methanol (90:10 by volume) to give a solid which was triturated with diethyl ether, diluted with pentane, filtered and dried to afford the title compound as a solid (110 mg).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH:4](O)[CH2:5][CH2:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10].N1C=CC=CC=1.S(Cl)([Cl:21])=O>C1(C)C=CC=CC=1>[Cl:21][CH:4]([CH2:3][CH2:2][Cl:1])[CH2:5][CH2:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10]
Reactant: O=C(O)CCCCC(O)CCCl
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: O=C(O)CCCCC(Cl)CCCl
Temperature: 25 °C

Procedure:
To a solution of 2.4 g (11.0 mmoles) of the methyl ester of (+)-8-chloro-6hydroxy-octanoic acid (+)-(VIII) (R=Me) and 0.04 g (0.5 mmoles) of pyridine in 8 ml toluene, 1.6 g (13.5 mmoles) of thionyl chloride in 5 ml of toluene were added slowly. The mixture was then refluxed for 1 hour. After cooling to room temperature, the reaction mixture was added to 20 ml ice water and the organic phase was separated and washed with 10 mL of water and dried over magnesium sulfate. After that, the solvent was evaporated under vacuum. The methyl ester of (-)-6,8-Dichloro-octanoic acid (-)-(III), (R=Me) was obtained in a yield of 2.0 g (81% of the theoretical yield). [α]D20 =-30.0° (c=1, benzene).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:14])[C:10]([F:13])([F:12])[F:11])[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].O.O1CCC[CH2:19]1>>[Br:1][C:2]1[CH:3]=[C:4]([N:8]([CH3:19])[C:9](=[O:14])[C:10]([F:11])([F:13])[F:12])[CH:5]=[CH:6][CH:7]=1
Reactant: C1CCOC1
Reactant: O=C(Nc1cccc(Br)c1)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CN(C(=O)C(F)(F)F)c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
N-(3-Bromophenyl)-2,2,2-trifluoroacetamide (J. Chem. Soc., 1952, 4014) in tetrahydrofuran (3 ml) was added dropwise to sodium hydride (0.16 g) in tetrahydrofuran (5 ml). The reaction mixture was stirred for 30 minutes at room temperature. lodomethane (0.25 ml) was added dropwise to the reaction mixture and it was stirred overnight at room temperature. Water was added and the product extracted with ethyl acetate. The combined extracts were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography over silica gel eluting with iso-hexane: dichloromethane (1: 1) to give the sub-title compound as an oil (0.385 g).
Reaction SMILES: [CH2:1]([NH2:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[CH3:14][C:15]1[C:24]([N:25]=[C:26]=[O:27])=[C:23]2[C:18]([C:19](=[O:28])[CH2:20][CH2:21][O:22]2)=[CH:17][CH:16]=1>C(OCC)(=O)C>[CH2:1]([NH:13][C:26]([NH:25][C:24]1[C:15]([CH3:14])=[CH:16][CH:17]=[C:18]2[C:23]=1[O:22][CH2:21][CH2:20][C:19]2=[O:28])=[O:27])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: Cc1ccc2c(c1N=C=O)OCCC2=O
Reactant: CCCCCCCCCCCCN
Solvent: CCOC(C)=O
Product: CCCCCCCCCCCCNC(=O)Nc1c(C)ccc2c1OCCC2=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 78.4 %

Procedure:
95 mg of dodecylamine was added to a solution of 100 mg of 7-methyl-4-chromanon-8-ylisocyanate in 5 ml of ethyl acetate, and the mixture was stirred at room temperature for 12 hr. The solvent was removed by distillation under reduced pressure, and the residue was recrystallized from ethyl acetate to afford 150 mg of the intended title compound.