Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5]Br.[NH2:7][C@H:8]([CH3:11])[CH2:9][OH:10]>>[N:7]1([C@H:8]([CH3:11])[CH2:9][OH:10])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: BrCCCCBr
Reactant: C[C@@H](N)CO
Product: C[C@H](CO)N1CCCC1

Procedure:
The title compound was synthesized as described in Intermediate 9 using 1,4-dibromobutane and (R)-2-aminopropan-1-ol as starting materials. 1H NMR (CDCl3): δ 3.61 (m, 1H), 3.38 (m, 1H), 2.97 (br s, 1H), 2.72 (m, 1H), 2.60 (br s, 4H), 1.78 (br s, 4H), 1.06 (d, 3H).
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[CH:5][C:6]([O:31][CH2:32][O:33][CH3:34])=[C:7]([CH:30]=1)[C:8]([NH:10][C:11]1[CH:23]=[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:21]=[CH:20][C:12]=1[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[O:9].[CH3:35][N:36]([CH3:41])[CH2:37][CH2:38][NH:39][CH3:40]>CC(C)=O>[CH3:35][N:36]([CH3:41])[CH2:37][CH2:38][N:39]([CH2:2][C:3]1[CH:4]=[CH:5][C:6]([O:31][CH2:32][O:33][CH3:34])=[C:7]([CH:30]=1)[C:8]([NH:10][C:11]1[CH:23]=[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:21]=[CH:20][C:12]=1[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[O:9])[CH3:40]
Reactant: COCOc1ccc(CBr)cc1C(=O)Nc1cc(-c2ccccc2)ccc1C(=O)OC(C)(C)C
Reactant: CNCCN(C)C
Solvent: CC(C)=O
Product: COCOc1ccc(CN(C)CCN(C)C)cc1C(=O)Nc1cc(-c2ccccc2)ccc1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Under ice-cooling, tert-butyl 2-(5-(bromomethyl)-2-(methoxymethoxy)benzamido)-4-phenylbenzoate (0.12 g) was added to an acetone (1.8 mL) solution of N,N,N′-trimethylethylenediamine (0.089 mL), followed by stirring at room temperature for 1 hour. The solvent was evaporated under reduced pressure, and a saturated aqueous solution of sodium bicarbonate and chloroform were added to the residue. The organic layer was separated and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: 100-90% chloroform/methanol] to obtain 0.070 g of tert-butyl 2-(5-(((2-(dimethylamino)ethyl)(methyl)amino)methyl)-2-(methoxymethoxy)benzamido)-4-phenylbenzoate.
Reaction SMILES: C(Cl)Cl.[C:4]([NH:12][CH2:13][CH:14]([C:19](=[O:21])[CH3:20])[C:15]([O:17][CH3:18])=[O:16])(=[O:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>CCN(CC)CC>[C:4]([NH:12][CH2:13][C@H:14]([C@@H:19]([OH:21])[CH3:20])[C:15]([O:17][CH3:18])=[O:16])(=[O:11])[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: COC(=O)C(CNC(=O)c1ccccc1)C(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@H](CNC(=O)c1ccccc1)[C@H](C)O
Temperature: 45 °C
Reaction time: 24 h
Yield: 90.1 %

Procedure:
In a 100 ml-volume autoclave whose atmosphere had been displaced with nitrogen was added a methylene chloride solution of 2.5 g of methyl 2-(N-benzoylamino)methyl-3-oxobutanoate and 84.5 mg (0.05 mmole) of Ru2Cl4 ((-)-BINAP2 (NEt3), and a reaction was conducted by stirring at 45° C. under a hydrogen pressure of 70 kg/cm2 for 24 hours. The reaction mixture was taken out, and the solvent was removed by distillation under reduced pressure of 20 mmHg at 30° C. The residue was purified by silica gel column chromatography using a 7/3 (by volume) mixture of hexane and isopropanol as an eluent to obtain 2.27 g (yield: 91%) of methyl (2R, 3S)-2-(N-benzoylamino)methyl-3-hydroxybutanoate having an optical purity of 97 %ee.
Reaction SMILES: CN(C)C=O.[CH3:6][O:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:17]=1[OH:18])[N:14]=[CH:13][CH:12]=[C:11]2[O:19][C:20]1[C:21]([CH3:30])=[N:22][C:23]2[C:28]([CH:29]=1)=[CH:27][CH:26]=[CH:25][CH:24]=2.Br[CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34].C(=O)([O-])[O-].[K+].[K+]>O>[CH3:6][O:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:17]=1[O:18][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[N:14]=[CH:13][CH:12]=[C:11]2[O:19][C:20]1[C:21]([CH3:30])=[N:22][C:23]2[C:28]([CH:29]=1)=[CH:27][CH:26]=[CH:25][CH:24]=2
Reactant: CCOC(=O)CBr
Reactant: COc1cc2c(Oc3cc4ccccc4nc3C)ccnc2cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)COc1cc2nccc(Oc3cc4ccccc4nc3C)c2cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.2 %

Procedure:
N,N-Dimethylformamide (1.5 ml) was added to 6-methoxy-4-(2-methyl-quinolin-3-yloxy)-quinolin-7-ol (compound 352) (50 mg), ethyl bromoacetate (75 mg), and potassium carbonate (62 mg), and the mixture was stirred at room temperature overnight. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water and was then dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give the title compound (31 mg, yield 49%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:12]=[CH:11][NH:10][C:9](=O)[N:8]=2)=[CH:3][CH:2]=1.S(Cl)([Cl:16])=O.CN(C)C=O>>[Cl:16][C:9]1[N:8]=[C:7]([C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)[CH:12]=[CH:11][N:10]=1
Reactant: O=c1nc(-c2ccncc2)cc[nH]1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: Clc1nccc(-c2ccncc2)n1

Procedure:
With ice-bath cooling under argon, 4-(4-pyridyl)-2(1H)-pyrimidinone (13.45 g, 77.7 mmol) and thionyl chloride (92 ml) were combined. N,N-Dimethylformamide (13.2 ml, 170.5 mmol) was added slowly and the mixture was heated to reflux for 1 h. It was evaporated and co-distilled with toluene. At 0° C., water was added to the remainder, then 10% ammonium hydroxide until neutral followed by extraction with dichloromethane. Drying of the organic solution was followed by evaporation and the resultant solid was recrystallized from acetone. MS (m/z): 192.1,194.0 (M+H)+; C9H6ClN3 requir. 191.6.
Reaction SMILES: N1C=CC=CC=1.[OH:7][N:8]1[C:12](=[O:13])[C:11]2=[CH:14][CH:15]=[CH:16][CH:17]=[C:10]2[C:9]1=[O:18].[Cl:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1>C(Cl)Cl>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([O:7][N:8]2[C:9](=[O:18])[C:10]3=[CH:17][CH:16]=[CH:15][CH:14]=[C:11]3[C:12]2=[O:13])=[CH:22][CH:21]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: O=C1c2ccccc2C(=O)N1O
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C1c2ccccc2C(=O)N1Oc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Pyridine (0.37 mL, 4.6 mmol) was added to a suspension of N-hydroxyphthalimide (664 mg, 4.1 mmol), 4-chlorophenylboronic acid (635 mg, 4.1 mmol), and powdered 4 Å molecular sieves (1.02 g) in CH2Cl2 (20 mL). Cupric acetate monohydrate (812 mg, 4.1 mmol) was added, and the mixture was stirred open to the atmosphere at room temperature for 18 hours. Silica gel (10 g) was added, and the slurry was concentrated to dryness under vacuum. The residue was applied to the top of a flash chromatography column, and eluted with hexanes:ethyl acetate (80:20) to provide the title compound. 1H NMR (300 MHz, CDCl3) δ 7.11-7.17 (m, 2 H), 7.27-7.34 (m, 2 H), 7.79-7.87 (m, 2 H), 7.88-7.95 ppm (m, 2 H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:13]2[S:14][C:15]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:16]([CH3:18])[N:17]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH:10]([CH3:12])[CH3:11].[F:24][C:25]([F:30])([F:29])C([O-])=O.[Na+]>CN1CCCC1=O>[CH2:9]([O:8][C:7]1[CH:6]=[CH:5][C:4]([C:13]2[S:14][C:15]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:16]([CH3:18])[N:17]=2)=[CH:3][C:2]=1[C:25]([F:30])([F:29])[F:24])[CH:10]([CH3:12])[CH3:11]
Reactant: CCOC(=O)c1sc(-c2ccc(OCC(C)C)c(Br)c2)nc1C
Reactant: O=C([O-])C(F)(F)F
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: CCOC(=O)c1sc(-c2ccc(OCC(C)C)c(C(F)(F)F)c2)nc1C
Temperature: 140 °C
Yield: 82.3 %

Procedure:
100 mg of Ethyl 2-(3-bromo-4-isobutyloxyphenyl)-4-methyl-5-thiazolecarboxylate, 95 mg of cuprous iodide and 140 mg of sodium trifluoroacetate were suspended in 2 ml of N-methylpyrrolidone, and the mixture was heated in a nitrogen atmosphere at 140° C. for 4 hours. After completion of the reaction, the product was extracted with ethyl acetate, and the organic layer was concentrated to give a crude crystal. The resulting crystal was purified by silica gel chromatography to give 80 mg of ethyl 2-(4-isobutyloxy-3-trifluoromethylphenyl)-4-methyl-5-thiazolecarboxylate. The product was hydrolyzed by a conventional process, following by recrystallization from hexane-ether to give 50 mg of 2-(4-isobutyloxy-3-trifluomethylphenyl)-4-methyl-5-thiazolecarboxylic acid (yield: 56%).
Reaction SMILES: FC(F)(F)C(O)=O.[O:8]1[C:12]2[CH:13]=[CH:14][C:15]([C:17]3([C:20]([NH:22][C:23]4[CH:24]=[C:25]5[C:29](=[CH:30][CH:31]=4)[NH:28][C:27]([C:32]([CH3:43])([CH3:42])[CH2:33][NH:34]C(=O)OC(C)(C)C)=[CH:26]5)=[O:21])[CH2:19][CH2:18]3)=[CH:16][C:11]=2[O:10][CH2:9]1>ClCCl>[NH2:34][CH2:33][C:32]([C:27]1[NH:28][C:29]2[C:25]([CH:26]=1)=[CH:24][C:23]([NH:22][C:20]([C:17]1([C:15]3[CH:14]=[CH:13][C:12]4[O:8][CH2:9][O:10][C:11]=4[CH:16]=3)[CH2:19][CH2:18]1)=[O:21])=[CH:31][CH:30]=2)([CH3:42])[CH3:43]
Reactant: CC(C)(C)OC(=O)NCC(C)(C)c1cc2cc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)ccc2[nH]1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(CN)c1cc2cc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)ccc2[nH]1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 84.6 %

Procedure:
Trifluoroacetic acid (0.75 mL) was added to a solution of tert-butyl 2-(5-(1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-1H-indol-2-yl)-2-methylpropylcarbamate (77 mg, 0.16 mmol) in dichloromethane (3 mL) and the mixture was stirred at room temperature for 1.5 h. The mixture was evaporated, dissolved in dichloromethane, washed with saturated sodium bicarbonate solution, dried over magnesium sulfate and evaporated to dryness to give N-(2-(1-amino-2-methylpropan-2-yl)-1H-indol-5-yl)-1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide (53 mg, 86%). 1H NMR (400 MHz, CDCl3) δ 9.58 (s, 1H), 7.60 (d, J=1.6 Hz, 1H), 7.18-7.15 (m, 2H), 7.02-6.94 (m, 3H), 6.85 (d, J=7.8 Hz, 1H), 6.14 (d, J=1.2 Hz, 1H), 6.02 (s, 2H), 2.84 (s, 2H), 1.68 (dd, J=3.6, 6.7 Hz, 2H), 1.32 (s, 6H), 1.08 (dd, J=3.7, 6.8 Hz, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:17]([OH:19])=O)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([N-]C(C)C)(C)C.[Li+].Cl.O.[CH2:30]([Cl:32])[Cl:31]>O1CCCC1.CCCCCCC.C(C1C=CC=CC=1)C>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:17](=[O:19])[CH:30]([Cl:32])[Cl:31])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reactant: ClCCl
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: CCCCCCC
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)C(Cl)Cl
Reaction time: 1 h
Yield: 46 %

Procedure:
Methyl ester (1.40 g) of N-tert-butoxycarbonyl-L-phenylalanine was dissolved in dehydrated tetrahydrofuran (27 ml) and methylene chloride (0.80 ml), and the obtained solution was cooled to −20° C. 2M solution (6.25 ml) of lithium diisopropylamide in heptane, tetrahydrofuran and ethylbenzene were added thereto, and they were stirred for 1 hour. 2 N Hydrochloric acid (12.5 ml) and water (12.5 ml) were added to the reaction mixture to terminate the reaction. The temperature was elevated to room temperature. After the extraction with ethyl acetate and water, the obtained solution in ethyl acetate was analyzed by HPLC to find that the intended (3S)-3-tert-butoxycarbonylamino-1,1-dichloro-4-phenyl-2-butanone (0.94 g) was obtained in a yield of 57%. The obtained solution in ethyl acetate was dried over anhydrous magnesium sulfate. Magnesium sulfate was filtered off. The solvent was evaporated under reduced pressure. Ethyl acetate was added to the residue to form a slurry. The crystals thus formed were separated from the slurry and dried to obtain the intended (3S)-3-tert-butoxycarbonylamino-1,1-dichloro-4-phenyl-2-butanone (0.77 g) in a yield of 46%.
Reaction SMILES: [ClH:1].Cl.[NH2:3][C:4]1[CH:17]=[CH:16][C:7]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH2:15])[CH:10]=2)=[C:6]([F:18])[CH:5]=1.[F:19][C:20]1[CH:33]=[CH:32][C:23]([CH2:24][S:25]([CH2:28][C:29](O)=[O:30])(=[O:27])=[O:26])=[CH:22][CH:21]=1>>[ClH:1].[F:19][C:20]1[CH:33]=[CH:32][C:23]([CH2:24][S:25]([CH2:28][C:29]([NH:3][C:4]2[CH:17]=[CH:16][C:7]([O:8][C:9]3[CH:14]=[CH:13][N:12]=[C:11]([NH2:15])[CH:10]=3)=[C:6]([F:18])[CH:5]=2)=[O:30])(=[O:26])=[O:27])=[CH:22][CH:21]=1
Reactant: Nc1ccc(Oc2ccnc(N)c2)c(F)c1
Reactant: O=C(O)CS(=O)(=O)Cc1ccc(F)cc1
Agent: Cl
Product: Nc1cc(Oc2ccc(NC(=O)CS(=O)(=O)Cc3ccc(F)cc3)cc2F)ccn1
Yield: 45.6 %

Procedure:
4-(4-Amino-2-fluorophenoxy)pyridin-2-amine dihydrochloride (50 mg, 0.17 mmol) was coupled with 2-(4-fluorobenzylsulfonyl)acetic acid (33 mg, 0.14 mmol) in a manner similar to that which is described in Step C of Example 1 to give 2-(4-fluorobenzylsulfonyl)-N-(4-(2-aminopyridin-4-yloxy)-3-fluorophenyl)acetamide, hydrochloride salt (30 mg, 45% yield). 1H NMR (DMSO-d6) δ 13.40 (s, 1H), 11.15 (s, 1H), 7.97 (d, 1H, J=7.0 Hz), 7.80-7.90 (m, 3H), 7.47 (m, 4H), 7.26 (t, 2H, J=8.5 Hz), 6.72 (d, 1H, J=7.0 Hz), 6.14 (d, 1H, J=2.0 Hz), 4.69 (s, 2H), 4.27 (s, 2H); MS (ESI+): m/z 434.15 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][NH:6][CH2:5][CH2:4][NH:3]1.I[CH2:9][CH3:10].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:9]([N:6]1[CH2:5][CH2:4][NH:3][C:2](=[O:1])[CH2:7]1)[CH3:10]
Reactant: O=C1CNCCN1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCN1CCNC(=O)C1
Temperature: 55 °C
Reaction time: 3 h
Yield: 72.3 %

Procedure:
A mixture of 2-oxopiperazine (1.07 g), iodoethane (1.72 g) and potassium carbonate (2.76 g) in acetonitrile (50 mL) was stirred at 55° C. for 3 hours. After cooling, the mixture was filtered and the filtrate was concentrated in vacuo. The residue was triturated with DCM and filtered and the filtrate was concentrated in vacuo. The residue was purified by chromatography on silica, eluting with a mixture of methanol and DCM with a gradient of 0-40% to give 4-ethylpiperazin-2-one (0.991 g) as a colourless oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][C:15]=2[F:23])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>CCO.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][C:15]=2[F:23])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc([N+](=O)[O-])cc2F)CC1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(N)cc2F)CC1
Reaction time: 2.5 h

Procedure:
A solution of 4-(2-fluoro-4-nitro-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (9.30 g, 28.6 mmol) in EtOH (80 mL) was treated with hydrogen (H2, 50 psi) in the presence of 10% Pd/C (0.50 g). After 2.5 h, the reaction mixture was filtered and the filtrate was concentrated to yield the title compound.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[C:13]([O:17][CH2:18][CH3:19])(=[O:16])[C:14]#[CH:15].[CH:20]([O:23][C:24]1[C:25]([O:35][CH3:36])=[CH:26][C:27]([N+:32]([O-:34])=[O:33])=[C:28]([CH:31]=1)[CH:29]=[O:30])([CH3:22])[CH3:21].C(O)(=O)C>O1CCCC1.O>[CH:20]([O:23][C:24]1[C:25]([O:35][CH3:36])=[CH:26][C:27]([N+:32]([O-:34])=[O:33])=[C:28]([CH:29]([OH:30])[C:15]#[C:14][C:13]([O:17][CH2:18][CH3:19])=[O:16])[CH:31]=1)([CH3:22])[CH3:21]
Reactant: C#CC(=O)OCC
Reactant: COc1cc([N+](=O)[O-])c(C=O)cc1OC(C)C
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCOC(=O)C#CC(O)c1cc(OC(C)C)c(OC)cc1[N+](=O)[O-]
Reaction time: 1 h
Yield: 114.6 %

Procedure:
1.5 N butyl lithium (22.6 ml, 33.8 mmol) was added to a solution of diisopropylamine (5.0 ml, 36.0 mmol) in tetrahydrofuran (75 ml) under an argon atmosphere at −78° C., and the mixture was stirred for one hr. Ethyl propiolate (2.9 ml, 28.2 mmol) and a solution of 5-isopropoxy-4-methoxy-2-nitrobenzaldehyde (4.5 g, 18.8 mmol) in tetrahydrofuran (50 ml) were then added thereto in that order, and the mixture was stirred at −78° C. for additional 1.5 hr. A solution of acetic acid (5.9 ml, 102 mmol) in tetrahydrofuran (20 ml) was added to the reaction solution. Water was then added thereto, followed by extraction with ethyl acetate. The organic layer was washed with dilute hydrochloric acid, water, a saturated aqueous sodium hydrogencarbonate solution, and saturated brine solution. The organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give ethyl 4-(5-isopropoxy-4-methoxy-2-nitrophenyl)-4-hydroxy-2-butynoate (7.27 g). The resultant ethyl 4-(5-isopropoxy-4-methoxy-2-nitrophenyl)-4-hydroxy-2-butynoate was dissolved in toluene (60 ml). 4-Methoxybenzyl azide (9.2 g, 56.4 mmol) was added to the solution. The mixture was heated at 100° C. with stirring overnight. The reaction solution was cooled to room temperature. The solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=1:2) to give a 1:1 mixture (7.01 g, 75%) of ethyl 4-(1-hydroxy-(5-isopropoxy-4-methoxy-2-nitrophenyl)methyl)-1-(4-methoxybenzyl)-1H-1,2,3-triazole-5-carboxylate (a-1: low polar product (LP)) and ethyl 5-(1-hydroxy-(5-isopropoxy-4-methoxy-2-nitrophenyl)methyl)-1-(4-methoxybenzyl)-1H-1,2,3-triazole-4-carboxylate (a-2: high polar product (MP)).
Reaction SMILES: [SH:1][CH2:2][C@@H:3]([CH3:14])[C:4]([N:6]1[CH2:13][CH2:12][CH2:11][C@H:7]1[C:8]([OH:10])=[O:9])=[O:5].FC1C([O:22][C:23](=O)[CH2:24][CH2:25][CH2:26][O:27][N+:28]([O-:30])=[O:29])=C(F)C(F)=C(F)C=1F>CN(C1C=CN=CC=1)C>[N+:28]([O:27][CH2:26][CH2:25][CH2:24][C:23]([S:1][CH2:2][C@@H:3]([CH3:14])[C:4]([N:6]1[CH2:13][CH2:12][CH2:11][C@H:7]1[C:8]([OH:10])=[O:9])=[O:5])=[O:22])([O-:30])=[O:29]
Reactant: C[C@H](CS)C(=O)N1CCC[C@H]1C(=O)O
Reactant: O=C(CCCO[N+](=O)[O-])Oc1c(F)c(F)c(F)c(F)c1F
Agent: CN(C)c1ccncc1
Product: C[C@H](CSC(=O)CCCO[N+](=O)[O-])C(=O)N1CCC[C@H]1C(=O)O

Procedure:
Using the same procedure described in Example 1 but starting from 1-[(2S)-3-mercapto-2-methyl-1-oxopropyl]-L-proline (Captopril)(0.41 g, 1.9 mmol), 4-(nitrooxy)butanoic acid pentafluorophenyl ester (0.60 g, 1.9 mmol) TEA (0.26 ml, 1.9 mmol) and DMAP (0.23 g, 1.9 mmol) after purification with Flash chromatography of the residue (CH2Cl2/Acetone 80:20) the title compound (0.140 g, 20%) was obtained as a white foam.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:18]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)=[N:17][C:9]2[C@H:10]3[N:14]([C:15](=[O:16])[C:8]=2[C:7]=1[C:27]1[CH:35]=[CH:34][C:30]([C:31](O)=[O:32])=[CH:29][CH:28]=1)[CH2:13][CH2:12][CH2:11]3)=[O:5])[CH3:2].[N:36]1([NH2:45])[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[CH2:38][CH2:37]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[N:36]1([NH:45][C:31]([C:30]2[CH:29]=[CH:28][C:27]([C:7]3[C:8]4[C:15](=[O:16])[N:14]5[C@H:10]([C:9]=4[N:17]=[C:18]([CH2:19][C:20]4[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=4)[C:6]=3[C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:11][CH2:12][CH2:13]5)=[CH:35][CH:34]=2)=[O:32])[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[CH2:38][CH2:37]1
Reactant: NN1CCc2ccccc21
Reactant: CCOC(=O)c1c(Cc2ccc(F)cc2)nc2c(c1-c1ccc(C(=O)O)cc1)C(=O)N1CCC[C@@H]21
Agent: CCN=C=NCCCN(C)C
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CCOC(=O)c1c(Cc2ccc(F)cc2)nc2c(c1-c1ccc(C(=O)NN3CCc4ccccc43)cc1)C(=O)N1CCC[C@@H]21
Reaction time: 12 h
Yield: 83 %

Procedure:
A solution of 4-[(9aS)-3-(ethoxycarbonyl)-2-(4-fluorobenzyl)-5-oxo-7,8,9,9a-tetrahydro-5H-pyrido[2,3-α]pyrrolizin-4yl]benzoic acid (0.200 g, 0.42 mmol, 1 equiv) in CH2Cl2 (1.0 mL) was treated with the 1-indolinamine (ref. Wijngaarden, I. et al., J Med Chem, 1993, 36, 3693–99) (0.113 g, 0.84 mmol, 2 equiv), EDCI (0.113 g, 0.59 mmol, 1.4 equiv), and HOBt (0.080 g, 0.59 mmol, 1.4 equiv). After 12 h at ambient temperature, the diluted with CH2Cl2 (1.0 mL) and treated with saturated aqueous NaHCO3. The organic potion was the washed with 1N HCl (1 mL) followed by brine (1 mL). Concentration gave a brown oil the was chromatographed radially (SiO2, 2 mm plate, 50% hexanes-EtOAc) to provide the title compound as a white solid (0.206 g, 83%): 1H NMR (CDCl3, 400 MHz) δ 7.86 (d, J=8.2 Hz, 2H), 7.68 (s, 1H), 7.45 (d, J=8.0 Hz, 2H ), 7.25–7.21 (m, 2H), 7.15–7.10 (m, 2H), 6.94 (t, J=8.6 Hz, 2H), 6.86 (t, J=7.4 Hz, 1H), 6.71 (d, J=7.7 Hz, 1H), 4.74 (dd, J=10.4, 6.2 Hz, 1H), 4.35 (d, J=14.3 Hz, 1H), 4.29 (d, J=14.3 Hz, 1H), 3.90 (q, J=6.8 Hz, 2H), 3.69–3.61 (m, 3H), 3.36–3.31 (m, 1H), 3.09–3.05 (m, 2H), 2.53–2.47 (m, 1H), 2.35–2.27 (m, 2H), 1.45–1.34 (m, 1H), 0.84 (t, J=7.1 Hz, 3H).
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[CH:12]=[CH:11][S:10][CH:9]=1)(=O)=O.[NH:13]1[CH:17]=[N:16][CH:15]=[N:14]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[S:10]1[CH:11]=[CH:12][C:8]([CH2:7][CH2:6][N:13]2[CH:17]=[N:16][CH:15]=[N:14]2)=[CH:9]1
Reactant: CS(=O)(=O)OCCc1ccsc1
Reactant: c1nc[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: c1ncn(CCc2ccsc2)n1
Yield: 82.7 %

Procedure:
A mixture of 3-thiopheneethanol methanesulfonate (ester) (0.286 mol), 1,2,4-triazole (0.571 mol) and potassium carbonate (39.47 g) in acetonitrile (1100 ml) was refluxed overnight. The mixture was filtered off and the filtrate was evaporated. The residue was taken up in water and extracted with dichloromethane. The organic layer was dried (MgSO4), filtered off and evaporated. The residue (49.08 g) was purified by column chromatography over silica gel (eluent: CH2Cl2 /CH3OH/NH4OH 99/1/0.1 to 97/3/0.1) (35-70 μm). The pure fractions were collected and evaporated, yielding 42.4 g (83%) of 1-[2-(3-thienyl)ethyl]-1H-1,2,4-triazole (interm. 1).
Reaction SMILES: [CH2:1]([Si:7]([CH3:10])(Cl)Cl)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH:11]1[C:23]2[CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]=2[CH:14]=[CH:13][CH:12]=1>C1COCC1>[CH2:1]([Si:7]([CH3:10])([CH:22]1[C:23]2[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=2[C:16]2[C:21]1=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:22]1[C:21]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:15]2[C:23]1=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: c1ccc2c(c1)Cc1ccccc1-2
Reactant: CCCCCC[Si](C)(Cl)Cl
Solvent: C1CCOC1
Product: CCCCCC[Si](C)(C1c2ccccc2-c2ccccc21)C1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
n-Hexylmethyldichlorosilane (30.4 g, 0.152 mol) and 300 mL of dry THF were charged to a one liter Schlenk equipped with an addition funnel. Fluorene anion (52.4 g, 0.305 mol) was dissolved in approximately 200 mL of dry THF and charged to the addition funnel. The temperature of the stirring solution was lowered to -78° C. under positive nitrogen pressure. The fluorene anion was added dropwise over two hours. After the anion addition was complete, the reaction mixture was allowed to warm to room temperature. The solution was allowed to stir overnight. The solution was washed with three 200 mL aliquots of water, retaining the organic layer after each washing. The organic layer was dried with magnesium sulfate and filtered. The product was recrystallized from hexane. The yield of this reaction is 19.6%.
Reaction SMILES: [C:1]1([CH:7]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:8][NH:9][C:10]2[C:11]3[N:12]=[CH:13][N:14]([C:24]=3[N:25]=[CH:26][N:27]=2)[C@@H:15]2[O:23][C@H:20]([CH2:21][OH:22])[C@@H:18]([OH:19])[C@H:16]2[OH:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O[C:38](=[O:40])[CH3:39])(=O)C>N1C=CC=CC=1>[C:16]([O:17][C@@H:16]1[C@H:18]([O:19][C:18](=[O:19])[CH3:20])[C@@H:20]([CH2:21][O:22][C:38](=[O:40])[CH3:39])[O:23][C@H:15]1[N:14]1[C:24]2[N:25]=[CH:26][N:27]=[C:10]([NH:9][CH2:8][CH:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:11]=2[N:12]=[CH:13]1)(=[O:17])[CH3:15]
Reactant: OC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)ncnc32)[C@H](O)[C@@H]1O
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)ncnc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O

Procedure:
N6 -(2,2-Diphenylethyl)adenosine (4.6 g, 0.01 mole) and acetic anhydride (2.9 mL, 306 mol%) are mixed in pyridine at room temperature under nitrogen for 20 hours, and the reaction is evaporated in vacuo. The residue is dissolved in chloroform, washed twice with aqueous ice-cold 5% sodium carbonate, and the organic layer is dried (MgSO4) and evaporated in vacuo. Chromatography over silica gel eluting with 5/1 chloroform/methanol affords the title compound after evaporation in vacuo of appropriate fractions; mp 75°-80° C.