Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]12[CH2:8][C:5]([C:9]([O:11][CH2:12][CH3:13])=[O:10])([CH2:6][CH2:7]1)[CH2:4][CH2:3]2.C(=O)([O-])[O-].[K+].[K+].Br[CH2:21][C:22]([N:24]1[CH2:28][C@@H:27]([F:29])[CH2:26][C@H:25]1[C:30]#[N:31])=[O:23]>CN(C)C=O>[CH2:12]([O:11][C:9]([C:5]12[CH2:8][C:2]([NH:1][CH2:21][C:22]([N:24]3[CH2:28][C@@H:27]([F:29])[CH2:26][C@H:25]3[C:30]#[N:31])=[O:23])([CH2:3][CH2:4]1)[CH2:7][CH2:6]2)=[O:10])[CH3:13]
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CBr
Reactant: CCOC(=O)C12CCC(N)(CC1)C2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C12CCC(NCC(=O)N3C[C@@H](F)C[C@H]3C#N)(CC1)C2
Reaction time: 1 h
Yield: 96.7 %

Procedure:
Ethyl 4-aminobicyclo[2.2.1]heptane-1-carboxylate (50.0 mg) was dissolved in N,N-dimethylformamide (2 mL) and potassium carbonate (40.0 mg) was added to the solution. (2S,4S)-1-(2-Bromoacetyl)-4-fluoropyrrolidine-2-carbonitrile (64.2 mg) in N,N-dimethylformamide (1 mL) was then added dropwise at room temperature and the mixture was stirred for 1 hour. The insoluble materials were filtered and the filtrate was concentrated. The resulting residue was purified by silica gel column chromatography (NH silica, eluant:ethyl acetate) to give (2S,4S)-1-[[N-(4-ethoxycarbonylbicyclo[2.2.1]hept-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (89.0 mg).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:9][C@@H:8]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][CH:11]=2)[O:7][C:6]1=[O:22].[N:23]1[S:27][N:26]=[C:25]2[CH:28]=[C:29]([CH:32]=O)[CH:30]=[CH:31][C:24]=12.CO.[BH4-].[Na+]>C(OCC)(=O)C.C(Cl)Cl>[N:23]1[S:27][N:26]=[C:25]2[CH:28]=[C:29]([CH2:32][NH:1][CH2:2][CH2:3][CH2:4][N:5]3[CH2:9][C@@H:8]([C:10]4[C:19]5[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH3:21])[CH:18]=5)[N:13]=[CH:12][CH:11]=4)[O:7][C:6]3=[O:22])[CH:30]=[CH:31][C:24]=12
Reactant: O=Cc1ccc2nsnc2c1
Reactant: COc1ccc2nccc([C@@H]3CN(CCCN)C(=O)O3)c2c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COc1ccc2nccc([C@@H]3CN(CCCNCc4ccc5nsnc5c4)C(=O)O3)c2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 66.7 %

Procedure:
A mixture of (R)-3-(3-amino-propyl)-5-(6-methoxy-quinolin-4-yl)-oxazolidin-2-one (0.15 g, 0.5 mmol), benzo[1,2,5]thiadiazole-5-carbaldehyde (92 mg, 0.56 mmol), methanol (0.5 ml), methylene chloride (1.8 ml), 3 Å dry molecular sieve (1 g) was stirred at room temperature for 16 hours. Sodium borohydride (28 mg, 0.76 mmol) was added and the mixture was stirred for 3 hours. After concentration of the solvent the residue was dissolved in ethyl acetate and the organic phase was washed with water, dried over magnesium sulfate and concentrated. The residue was chromatographed on silicagel eluting with methylene chloride-methanol (99-1 first, then 90-10) to give (R)-3-{3-[(benzo[1,2,5]thiadiazol-5-ylmethyl)-amino]-propyl}-5-(6-methoxyquinolin-4-yl)-oxazolidin-2-one (150 mg, 59%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[N:16]=[C:15]([O:17][C@@H:18]([C@H:20]3[CH2:24][N:23]([C@@H](C4C=CC(OC)=CC=4)C)[C:22](=[O:35])[CH2:21]3)[CH3:19])[C:14]3[N:36](COCC[Si](C)(C)C)[C:37]([CH3:39])=[N:38][C:13]=3[CH:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]>C(O)(C(F)(F)F)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[N:16]=[C:15]([O:17][C@@H:18]([C@H:20]3[CH2:24][NH:23][C:22](=[O:35])[CH2:21]3)[CH3:19])[C:14]3[NH:36][C:37]([CH3:39])=[N:38][C:13]=3[CH:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc([C@@H](C)N2C[C@H]([C@@H](C)Oc3nc(-c4ccc(OC)c(OC)c4)cc4nc(C)n(COCC[Si](C)(C)C)c34)CC2=O)cc1
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(-c2cc3nc(C)[nH]c3c(O[C@H](C)[C@H]3CNC(=O)C3)n2)cc1OC
Temperature: 60 °C
Reaction time: 6 h

Procedure:
(R)-4-((R)-1-(6-(3,4-dimethoxyphenyl)-2-methyl-3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[4,5-c]pyridin-4-yloxy)ethyl)-1-((R)-1-(4-methoxyphenyl)ethyl)pyrrolidin-2-one was dissolved in TFA. Reaction was heated to 60° C. After 6 h, reaction was cooled to r.t. and was concentrated in vacuo. The resulting residue was diluted with EtOAc, brine, and saturated NaHCO3. The phases were separated, and the aqueous phase was extracted with EtOAc. The organic layer was dried over MgSO4, filtered, and concentrated to afford (R)-4-((R)-1-(6-(3,4-dimethoxyphenyl)-2-methyl-3H-imidazo[4,5-c]pyridin-4-yloxy)ethyl)pyrrolidin-2-one 2.66 that was used without further purification. [M+H]+ calcd C21H24N4O4: 397.18; found 397.1.
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][N:9]([CH:13]1[CH2:18][CH2:17][N:16]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:15][CH2:14]1)[CH:10]([CH3:12])[CH3:11].[Br:26]P(Br)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>ClCCl>[Br:26][CH2:2][CH2:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][N:9]([CH:13]1[CH2:18][CH2:17][N:16]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:15][CH2:14]1)[CH:10]([CH3:12])[CH3:11]
Reactant: BrP(Br)(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)N(CCOCCCCO)C1CCN(Cc2ccccc2)CC1
Solvent: ClCCl
Product: CC(C)N(CCOCCCCBr)C1CCN(Cc2ccccc2)CC1

Procedure:
4-[N-(7-Hydroxy-3-oxahept-1-yl)-N-(isopropyl)amino]-1-benzylpiperidine (3.7 g, 10.6 mmol) was treated with dibromotriphenylphosphorane (11.2 g, 26.6 mmol) in dichloromethane for 2 h. The reaction mixture was then was washed with 1 N sodium hydroxide, saturated sodium bicarbonate, brine, dried over magnesium sulfate and concentrated to give the title intermediate, which was used without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][NH:11][C:12]([C:14]23[CH2:23][CH:18]4[CH2:19][CH:20]([CH2:22][C:16]([C:24]5[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=5)([CH2:17]4)[CH2:15]2)[CH2:21]3)=[O:13])[CH:5]=[CH:6][C:7]=1[OH:8]>C(OC(=O)CC)(=O)CC.OS(O)(=O)=O>[C:2]([O:8][C:7]1[CH:6]=[CH:5][C:4]([CH2:9][CH2:10][NH:11][C:12]([C:14]23[CH2:21][CH:20]4[CH2:19][CH:18]([CH2:17][C:16]([C:24]5[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][CH:29]=5)([CH2:22]4)[CH2:15]2)[CH2:23]3)=[O:13])=[CH:3][C:2]=1[O:1][C:12](=[O:13])[CH2:14][CH3:15])(=[O:1])[CH2:7][CH3:6]
Reactant: O=C(NCCc1ccc(O)c(O)c1)C12CC3CC(C1)CC(c1ccc(Cl)cc1)(C3)C2
Agent: CCC(=O)OC(=O)CC
Agent: O=S(=O)(O)O
Product: CCC(=O)Oc1ccc(CCNC(=O)C23CC4CC(C2)CC(c2ccc(Cl)cc2)(C4)C3)cc1OC(=O)CC
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Compound 1 was dissolved in propionic anhydride with a catalytic amount of 98% H2SO4 and stirred under N2 for 3 days at room temperature. The solution was then concentrated under a vacuum and filtered to give the product Compound 3, with a melting point of 114-115° C. 1H NMR (500 MHz, CDCl3) δ 1.24-1.30 (m, 6H, 2CH3), 1.74 (m, 2H, Admant-H), 1.84-1.87 (m, 8H, Admant-H), 1.93 (s, 2H, Admant-H), 2.26 (m, 2H, Admant-H), 2.53-2.61 (m, 4H, 2COCH2), 2.82-2.85 (t, J=7.5 Hz, 2H, CH2), 3.50-3.54 (q, 2H, NCH2), 5.40 (s, 1H, NH), 7.01-7.02 (d, J=5 Hz, 1H, Ar—H), 7.06-7.08 (d, d, 1H, H—Ar), 7.13-7.15 (d, J=10 Hz, 1H, Ar—H), 7.30 (s, 4H, Ar—H); 13C NMR (500 MHz, CDCl3) δ 9.1, 27.5, 28.8, 35.0, 35.5, 36.5, 38.3, 40.3, 41.7, 42.0, 44.5, 123.5, 123.9, 126.4, 126.8, 128.3, 131.5, 137.8, 140.7, 142.1, 148.4, 171.7, 171.8, 177.4; MS m/z (relative intensity) 538.61 (MH+, 100), 539.61 (38), 540.61 (45).
Reaction SMILES: [NH:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8].[H-].[Na+].[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][C:29]=1[O:30][CH3:31])[C:24](Cl)=[O:25]>C1C=CC=CC=1>[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][C:29]=1[O:30][CH3:31])[C:24]([N:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8])=[O:25]
Reactant: O=C1CC[C@@H](C(=O)OCc2ccccc2)N1
Reactant: COc1ccc(C(=O)Cl)cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Product: COc1ccc(C(=O)N2C(=O)CC[C@H]2C(=O)OCc2ccccc2)cc1OC
Reaction time: 1 h

Procedure:
A solution of 24.1 g (0.11 mol) of benzyl (L)-pyroglutamate, prepared according to Example II(1), in 200 ml of benzene is added over 11/2 hours to a suspension of 5.28 g (0.11 mol) of sodium hydride in 20 ml of dry benzene. After stirring for 1 hour at ordinary temperature, a solution of 22.1 g (0.11 mol) of 3,4-dimethoxybenzoyl chloride in 180 ml of benzene is run in.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.[Mg+].[C:24]([O:30][CH2:31][CH3:32])(=[O:29])[CH2:25]C([O-])=O.Cl>O1CCCC1.O.C(OCC)(=O)C>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](=[O:6])[CH2:25][C:24]([O:30][CH2:31][CH3:32])=[O:29]
Reactant: O=C(O)c1ccccc1F
Reactant: CCOC(=O)CC(=O)[O-]
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Mg+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)CC(=O)c1ccccc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 160.3 %

Procedure:
To a solution of 2-fluorobenzoic acid (25.3 g, 181 mmol) in tetrahydrofuran (300 ml) was added 1,1′-carbonylbis-1H-imidazole (32.2 g, 198 mmol) and the mixture was stirred at room temperature for 30 min. To the reaction solution was added monoethyl malonate magnesium salt (27.1 g, 94.7 mmol) and the mixture was heated under reflux for 30 min. Ethyl acetate (50 ml) and water (50 ml) were added to the reaction solution, and conc. hydrochloric acid was added until the aqueous layer showed acidic pH. The reaction solution was extracted with ethyl acetate (200 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) to give ethyl 3-(2-fluorophenyl)-3-oxopropionate (31.9 g, 84%) as a colorless oil.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][CH2:5][N:6]1[CH:13]=[C:12]([F:14])[C:10](=[O:11])[NH:9][C:7]1=[O:8].[C:15](OC(=O)C)(=[O:17])[CH3:16]>N1C=CC=CC=1>[C:15]([O:1][CH2:2][CH2:3][O:4][CH2:5][N:6]1[CH:13]=[C:12]([F:14])[C:10](=[O:11])[NH:9][C:7]1=[O:8])(=[O:17])[CH3:16]
Reactant: CC(=O)OC(C)=O
Reactant: O=c1[nH]c(=O)n(COCCO)cc1F
Solvent: c1ccncc1
Product: CC(=O)OCCOCn1cc(F)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
1-(2-Hydroxyethoxy)methyl-5-fluorouracil (1 g) prepared in Example 1 was dissolved in a mixture of acetic anhydride (5 ml) and pyridine (5 ml) and the solution was stirred at room temperature for 3 hours. The reaction mixture was poured into ice-water and the resulting oil was extracted with chloroform (30 ml). The extract was washed with hydrochloric acid, aqueous sodium bicarbonate and then water, dried over magnesium sulfate and the solvent was evaporated off under reduced pressure. The residue was treated with methanol to give 0.9 g of crystalline 1-(2-acetoxyethoxy)methyl-5-fluorouracil.
Reaction SMILES: [CH2:1]1[CH2:11][C:9](=[O:10])[C:8]2[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:2]1.S(=O)(=O)(O)O.[N+:17]([O-])([OH:19])=[O:18]>O>[N+:17]([C:6]1[CH:7]=[C:8]2[C:3]([CH2:2][CH2:1][CH2:11][C:9]2=[O:10])=[CH:4][CH:5]=1)([O-:19])=[O:18]
Reactant: O=C1CCCc2ccccc21
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C1CCCc2ccc([N+](=O)[O-])cc21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
5 g of alpha-tetralone are added to 18.2 ml of sulfuric acid cooled to 0° C., while maintaining the temperature <10° C. A mixture of 1.87 ml of nitric acid at 70% in water and of 3.65 ml of sulfuric acid is added while maintaining the temperature <10° C. The reaction medium is stirred for 30 minutes at a temperature <10° C. and then stirred for one hour at ambient temperature. The reaction medium is poured into ice-cold water (250 ml). The insoluble material is filtered off under vacuum and dried, so as to give 5.2 g of 7-nitro-3,4-dihydronaphthalen-1(2H)-one in the form of a beige solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:13]1[CH:18]=[CH:17][C:16]([C:19]2([OH:23])[CH2:22][CH2:21][CH2:20]2)=[CH:15][CH:14]=1.CC(=CC)C.Cl([O-])=[O:30].[Na+].O.OP([O-])(O)=O.[Na+].[NH4+].[Cl-]>CC#N.C(O)(C)(C)C.O>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([OH:30])=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:13]1[CH:14]=[CH:15][C:16]([C:19]2([OH:23])[CH2:22][CH2:21][CH2:20]2)=[CH:17][CH:18]=1
Reactant: [O-][Cl+][O-]
Reactant: O=Cc1c[nH]c2cc(Cl)c(-c3ccc(C4(O)CCC4)cc3)cc12
Agent: CC=C(C)C
Agent: O=P([O-])(O)O
Agent: [Cl-]
Solvent: CC#N
Solvent: O
Solvent: CC(C)(C)O
Product: O=C(O)c1c[nH]c2cc(Cl)c(-c3ccc(C4(O)CCC4)cc3)cc12
Temperature: 25 °C
Reaction time: 13 h
Yield: 71.2 %

Procedure:
To a solution of 6-chloro-5-[4-(1-hydroxy-cyclobutyl)-phenyl]-1H-indole-3-carbaldehyde (4.88 g, 15.0 mmol) in MeCN (212 mL) and tert-butanol (212 mL) at 0° C. was added 2-methyl-2-butene (120 mL, 1.15 mol), followed by a solution of sodium chlorite (25.5 g, 300 mmol) and sodium phosphate monobasic hydrate (42.5 g, 308 mmol) in water (212 mL) dropwise via addition funnel. The ice bath was removed and the reaction mixture was stirred vigorously at room temperature. After 13 hours, additional 2-methyl-2-butene (50 mL, 480 mmol) was added, followed by sodium chlorite (10.6 g, 125 mmol) and sodium phosphate monobasic hydrate (17.7 g, 125 mmol) as solids. The reaction mixture was stirred at room temperature for an additional 5 hours, and treated with additional 2-methyl-2-butene (25 mL, 240 mmol), solid sodium chlorite (5.3 g, 73 mmol) and solid sodium phosphate monobasic hydrate (8.8 g, 73 mmol). After an additional 4 hours, the reaction mixture was poured into a 4:1 mixture of saturated aqueous NH4Cl solution/water (500 mL), and extracted with EtOAc (3×400 mL). The combined organic layers were dried over Na2SO4 and concentrated in vacuo. The resulting material was loaded onto a silica gel plug and eluted, first with heptane/EtOAc (4:1, 1.5 L), followed by 1:4 heptane/EtOAc (3 L) then EtOAc (1 L). The filtrates from the second and third elutions were combined and concentrated in vacuo. The resulting tan solid was partially dissolved in 4:1 DMF/DCM, loaded onto an Isco silica gel cartridge, and purified by flash chromatography (20-80% EtOAc/heptane, with 0.2% formic acid modifier) to give the title compound (3.65 g, 71%) as a white solid. MS (ES+) 340.2 (M−H)+. 1H NMR (500 MHz, DMSO-d6) δ 12.10 (s, 1 H), 11.95 (s, 1 H), 8.08 (s, 1 H), 7.95 (s, 1 H), 7.64 (s, 1 H), 7.57 (d, J=7.1 Hz, 2 H), 7.41 (d, J=7.1 Hz, 2 H), 5.52 (s, 1 H), 2.48-2.40 (m, 2 H), 2.35-2.26 (m, 2 H), 1.97-1.90 (m, 1 H), 1.76-1.62 (m, 1H).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([C:10]2[C:19]([N:20]([CH3:24])[CH:21]([CH3:23])[CH3:22])=[N:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:25]([O:27][CH2:28][C:29]4[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=4)=[O:26])[CH:16]=3)[N:11]=2)[CH:6]=[CH:7][C:8]=1[OH:9])=O.[NH2:37]OS(O)(=O)=O.CO>O>[O:9]1[C:8]2[CH:7]=[CH:6][C:5]([C:10]3[C:19]([N:20]([CH3:24])[CH:21]([CH3:23])[CH3:22])=[N:18][C:17]4[C:12](=[CH:13][CH:14]=[C:15]([C:25]([O:27][CH2:28][C:29]5[CH:30]=[CH:31][C:32]([O:35][CH3:36])=[CH:33][CH:34]=5)=[O:26])[CH:16]=4)[N:11]=3)=[CH:4][C:3]=2[CH:1]=[N:37]1
Reactant: COc1ccc(COC(=O)c2ccc3nc(-c4ccc(O)c(C=O)c4)c(N(C)C(C)C)nc3c2)cc1
Reactant: NOS(=O)(=O)O
Solvent: CO
Solvent: O
Product: COc1ccc(COC(=O)c2ccc3nc(-c4ccc5oncc5c4)c(N(C)C(C)C)nc3c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 26.6 %

Procedure:
To a solution of (4-methoxyphenyl)methyl 2-(3-formyl-4-hydroxyphenyl)-3-[methyl(propan-2-yl)amino]quinoxaline-6-carboxylate (190 mg, 0.39 mmol) in water (5 mL) was added aminooxysulfonic acid (83 mg, 0.48 mmol) and methanol (5 mL). The resulting solution was stirred overnight at 25° C. Then the reaction was quenched by the addition of water (200 mL) and extracted with ethyl acetate (3×50 mL), dried over anhydrous sodium sulfate and concentrated in vacuo to give a residue, which was purified by silica gel column chromatography eluting with 1% to 5% ethyl acetate in petroleum to afford (4-methoxyphenyl)methyl 2-(1,2-benzoxazol-5-yl)-3-[methyl(propan-2-yl)amino]quinoxaline-6-carboxylate as a yellow solid (50 mg, 26%).
Reaction SMILES: [NH:1]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C@H:2]([C:7]([OH:9])=O)[C@H:3]([CH2:5][CH3:6])[CH3:4].[NH:17]1[CH2:32][CH2:31][CH2:30][CH2:29][CH:18]1[C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20].Cl.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC>CN(C=O)C>[NH:1]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C@H:2]([C:7]([N:17]1[CH2:32][CH2:31][CH2:30][CH2:29][CH:18]1[C:19]([O:21][CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)=[O:20])=[O:9])[C@H:3]([CH2:5][CH3:6])[CH3:4]
Reactant: CC[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: O=C(OCc1ccccc1)C1CCCCN1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCCCC1C(=O)OCc1ccccc1
Reaction time: 8 h
Yield: 115 %

Procedure:
Boc-L-Ile-OH ½ H2O (3.92 g, 16.8 mmol), H-D,L-Pip-OBzl HCl (3.57 g, 12 mmol) and HATU (7.75 g, 18 mmol) were dissolved in DMF (15 ml), mixed with Et3N (4.76 ml, 30 mmol) under ice cooling, and then stirred overnight. The reaction mixture was concentrated, extracted with ethyl acetate (120 ml), and washed twice with 10% citric acid, 4% NaHCO3 and then brine, respectively. After drying over magnesium sulfate, ethyl acetate was distilled off. The residue was vacuum dried and purified by flash chromatography (3.5×20 cm) with CHCl3/MeOH (99:1) to yield Boc-L-Ile-D,L-Pip-OBzl (5.90 g, 13.8 mmol; yield 97%) as an oil.
Reaction SMILES: [Mg].II.Br[C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][CH:6]=1.[CH2:12]([N:19]1[CH2:24][CH2:23][C:22](=[O:25])[CH2:21][CH2:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C1COCC1.O>[CH2:12]([N:19]1[CH2:24][CH2:23][C:22]([C:5]2[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][CH:6]=2)([OH:25])[CH2:21][CH2:20]1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: Brc1ccc(Br)cc1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Agent: II
Agent: [Mg]
Solvent: O
Solvent: C1CCOC1
Product: OC1(c2ccc(Br)cc2)CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of magnesium (1.77 g) and iodine (0.81 g) in THF (60 mL) was added a solution of 1,4-dibromobenzene (8.94 mL) in THF (5 mL), and the mixture was stirred at room temperature for 30 min. The reaction mixture was cooled to 0° C., a solution of 1-benzylpiperidin-4-one (13.2 mL) in THF (5 mL) was slowly added dropwise thereto, and the reaction mixture was stirred at room temperature for 2 hr. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (9.19 g).
Reaction SMILES: C1(P(=O)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.[Cl:36][C:37]1[S:41][C:40]([S:42]([NH:45][C:46]2[CH:47]=[CH:48][CH:49]=[C:50]3[C:54]=2[NH:53][C:52]([C:55]([NH:57][CH2:58][CH2:59][S:60]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=O)=[CH:51]3)(=[O:44])=[O:43])=[CH:39][CH:38]=1>ClCCl>[Cl:36][C:37]1[S:41][C:40]([S:42]([NH:45][C:46]2[CH:47]=[CH:48][CH:49]=[C:50]3[C:54]=2[NH:53][C:52]([C:55]2[S:60][CH2:59][CH2:58][N:57]=2)=[CH:51]3)(=[O:44])=[O:43])=[CH:39][CH:38]=1
Reactant: O=C(NCCSC(c1ccccc1)(c1ccccc1)c1ccccc1)c1cc2cccc(NS(=O)(=O)c3ccc(Cl)s3)c2[nH]1
Agent: O=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: O=S(=O)(Nc1cccc2cc(C3=NCCS3)[nH]c12)c1ccc(Cl)s1
Reaction time: 0.17 h
Yield: 37.5 %

Procedure:
To a solution of triphenylphosphine oxide (3.57 g) in dichloromethane (20 mL) was slowly added trifluoromethanesulfonic anhydride (1.10 mL) at 0° C. The mixture was stirred for 10 min, and 7-{[(5-chloro-2-thienyl)sulfonyl]amino}-N-[2-(tritylthio)ethyl]-1H-indole-2-carboxamide (1.41 g) was added. The reaction mixture was stirred at room temperature for 3 hr and concentrated. Saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography and the title compound (0.32 g, yield 37%) was obtained as colorless crystals from a fraction eluted with ethyl acetate-hexane (1:20→1:1, volume ratio). melting point>210° C. (decomposition).
Reaction SMILES: [C:1]1([NH2:15])[N:2]=[C:3]([NH2:14])[N:4]=[C:5]2[C:10]=1[C:9]1[CH:11]=[CH:12][NH:13][C:8]=1[CH:7]=[CH:6]2.CN(C)C=O.[H-].[Na+].F[C:24]1[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[CH:26][CH:25]=1>C(O)(=O)C>[C:28]([C:27]1[CH:30]=[CH:31][C:24]([N:13]2[C:8]3[CH:7]=[CH:6][C:5]4[C:10](=[C:1]([NH2:15])[N:2]=[C:3]([NH2:14])[N:4]=4)[C:9]=3[CH:11]=[CH:12]2)=[CH:25][CH:26]=1)#[N:29]
Reactant: Nc1nc(N)c2c(ccc3[nH]ccc32)n1
Reactant: N#Cc1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: N#Cc1ccc(-n2ccc3c4c(N)nc(N)nc4ccc32)cc1

Procedure:
A solution of 15.94 g. 7H-pyrrolo[3,2-f]quinazoline-1,3-diamine in 800 ml. dry dimethylformamide is stirred, under nitrogen, with 4.61 g. ca. 50% sodium hydride-mineral oil dispersion for 1.5 hours. Addition of 10.66 g. 4-fluorobenzonitrile is followed by heating of the reaction mixture at 95° for 6 hours. Glacial acetic acid (40 ml.) is added and the solvent is removed in vacuo. The residue is stirred thoroughly with excess aqueous potassium carbonate solution, collected, washed with water and dried. Two recrystallizations of the crude product from dimethylformamide, followed by washing with a small amount of dimethylformamide, with methanol and thorough drying, yield the title compound, m.p. 344° (dec.), NMR (dDMSO): δ 7.17 (doublet, J=9Hz, 5 or 6H), 7.42 (doublet, J=3Hz, 9H), 7.76-7.95 (four protons multiplet, 5 or 6H, 8H and two protons meta to the cyano group), 8.09 (two proton doublet, J= 8Hz, two protons ortho to the cyano group) p.p.m.
Reaction SMILES: [CH2:1]1[O:12][C:11]2[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH2:8])=[CH:4][C:3]=2[O:2]1.[CH3:13][O:14][C:15](=[O:35])[C:16]1[CH:21]=[CH:20][C:19]([C:22]2[N:23]=[C:24](Cl)[C:25]3[CH:30]=[C:29]([N+:31]([O-:33])=[O:32])[S:28][C:26]=3[N:27]=2)=[CH:18][CH:17]=1>>[CH3:13][O:14][C:15](=[O:35])[C:16]1[CH:21]=[CH:20][C:19]([C:22]2[N:23]=[C:24]([NH:8][CH2:7][CH2:6][C:5]3[CH:9]=[CH:10][C:11]4[O:12][CH2:1][O:2][C:3]=4[CH:4]=3)[C:25]3[CH:30]=[C:29]([N+:31]([O-:33])=[O:32])[S:28][C:26]=3[N:27]=2)=[CH:18][CH:17]=1
Reactant: NCCc1ccc2c(c1)OCO2
Reactant: COC(=O)c1ccc(-c2nc(Cl)c3cc([N+](=O)[O-])sc3n2)cc1
Product: COC(=O)c1ccc(-c2nc(NCCc3ccc4c(c3)OCO4)c3cc([N+](=O)[O-])sc3n2)cc1

Procedure:
The reaction procedure as above wherein 3,4-methylenedioxyphenethylamine is reacted with 4-(4-chloro-6-nitro-thieno-[2,3-d]-pyrimidin-2-yl)-benzoic acid methylester yields 4-[4-(3,4-methylenedioxyphenethylamino)-6-nitro-thieno-[2,3-d]-pyrimidin-2-yl]-benzoic acid methylester.
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[C:14]2[C:9]([N:10]=[CH:11][CH:12]=[CH:13]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[Br:16][CH2:17][C:18](Br)=[O:19]>C(#N)C>[Br:16][CH2:17][C:18]([C:6]1[CH:5]=[CH:4][C:3]2[C:8](=[C:9]3[C:14](=[CH:15][C:2]=2[NH2:1])[CH:13]=[CH:12][CH:11]=[N:10]3)[N:7]=1)=[O:19]
Reactant: Nc1cc2cccnc2c2ncccc12
Reactant: O=C(Br)CBr
Solvent: CC#N
Product: Nc1cc2cccnc2c2nc(C(=O)CBr)ccc12

Procedure:
5-Amino-1,10-phenanthroline (2) (Preparation 1; 1.28 g; 6.54 mmol) was dissolved with heating in 200 ml anhydrous acetonitrile. Into this solution, was added bromoacetyl bromide (Aldrich; 6.60 g; 32.7 mmol) in 7.2 ml anhydrous acetonitrile.