Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][N:12]([CH:20]3[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][N:28]4[C:37]5[C:32](=[C:33]([OH:38])[CH:34]=[CH:35][CH:36]=5)[CH:31]=[CH:30][C:29]4=[O:39])[CH2:22][CH2:21]3)[C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:47][C:48]([O:50][CH2:51][CH3:52])=[O:49].Cl>O.CN(C)C=O>[C:15]([O:14][C:13]([N:12]([CH2:11][C:9]1[CH:8]=[CH:7][C:6]2[O:1][CH2:2][CH2:3][O:4][C:5]=2[CH:10]=1)[CH:20]1[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][N:28]2[C:37]3[C:32](=[C:33]([O:38][CH2:47][C:48]([O:50][CH2:51][CH3:52])=[O:49])[CH:34]=[CH:35][CH:36]=3)[CH:31]=[CH:30][C:29]2=[O:39])[CH2:22][CH2:21]1)=[O:19])([CH3:18])([CH3:17])[CH3:16]
Reactant: CCOC(=O)CBr
Reactant: CC(C)(C)OC(=O)N(Cc1ccc2c(c1)OCCO2)C1CCN(CCn2c(=O)ccc3c(O)cccc32)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)COc1cccc2c1ccc(=O)n2CCN1CCC(N(Cc2ccc3c(c2)OCCO3)C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 3 mL of an N,N-dimethylformamide solution containing 166 mg of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(5-hydroxy-2-oxoquinolin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate, 65 mg of potassium carbonate and 43 μL of ethyl bromoacetate were added, and stirred at room temperature for 2 hours. After water was added to the reaction mixture and acidified with hydrochloric acid, the mixture was extracted with a mixture of ethyl acetate:toluene=5:1. The extracts were washed with aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [Silica Gel; Kanto Chemical Co., Inc., Silica Gel 60, eluent; chloroform:methanol=20:1], to give 196 mg of ethyl (1-(2-(4-((tert-butoxycarbonyl)(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino)piperidin-1-yl)ethyl)-2-oxo-1,2-dihydroquinolin-5-yloxy)acetate as a pale brown oil.
Reaction SMILES: [C:1]([NH:5][NH:6][C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1)=[O:8])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].[C:17](Cl)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C1(C)C=CC=CC=1>[C:1]([N:5]([C:17](=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[NH:6][C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1)=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(C)(C)NNC(=O)c1ccccn1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CC(C)(C)N(NC(=O)c1ccccn1)C(=O)c1ccccc1
Reaction time: 8 h

Procedure:
A solution of N'-t-butyl-N-(2-pyridinecarbonyl)hydrazine (1.0 g, 0.00518 mol) in 20 ml of toluene at 23° C. was treated sequentially with 50% sodium hydroxide (1.3 g) and benzoyl chloride (0.728 g). The mixture was stirred overnight. The solids were removed by filtration and washed with water to afford N'-t-butyl-N-(2-pyridinecarbonyl)-N'-benzoylhydrazine.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:13])[NH:7][C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1.ClC1C=C2C(C(O[Si](C)(C)C)=NC(O[Si](C)(C)C)=N2)=CC=1.Cl[CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38].[Br-].[Li+]>>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:13])[NH:7][C:8](=[O:12])[N:9]2[CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])=[CH:4][CH:3]=1
Reactant: O=c1[nH]c(=O)c2ccc(Cl)cc2[nH]1
Reactant: CCOC(=O)CCl
Agent: C[Si](C)(C)Oc1nc(O[Si](C)(C)C)c2ccc(Cl)cc2n1
Agent: [Br-]
Agent: [Li+]
Product: CCOC(=O)Cn1c(=O)[nH]c(=O)c2ccc(Cl)cc21
Reaction time: 18 h

Procedure:
7-Chloro-2,4-dioxo-1,2,3,4-tetrahydroquinazoline (10 g) was treated as in Example 1 to give a concentrate containing 7-chloro-2,4-bis(trimethylsilyloxy)quinazoline. To this concentrate was added an oil prepared from ethyl chloroacetate (15 ml) and lithium bromide (2.21 g), and the reaction was carried out at an internal temperature of 115˜130° C. for 18 hours. This reaction mixture was cooled to ≦70° C. and worked up as in Example 4 to provide ethyl 2-(7-chloro-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-1-yl)acetate (13.66 g).
Reaction SMILES: [CH:1]([O:14][C:15]([C:17]1[N:18]2[CH:21]([S:22][CH2:23][C:24]=1[C:25]1[S:29][C:28]([NH:30][CH3:31])=[N:27][CH:26]=1)[CH:20]([NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])O2)=[O:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CNC(N)=S.[CH:45]([O:58]C(C1N2C(SCC=1C=CN(C)C)C(NC(OC(C)(C)C)=O)C2=O)=O)(C1C=CC=CC=1)C1C=CC=CC=1>>[CH:1]([O:14][C:15]([C:17]1[N:18]2[CH:21]([S:22][CH2:23][C:24]=1[C:25]1[S:29][C:28]([NH:30][CH3:31])=[N:27][CH:26]=1)[CH:20]([NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[C:45]2=[O:58])=[O:16])([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CNc1ncc(C2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3OC(NC(=O)OC(C)(C)C)C3SC2)s1
Reactant: CN(C)C=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)OC(C)(C)C)C2SC1
Agent: CNC(N)=S
Product: CNc1ncc(C2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)C(NC(=O)OC(C)(C)C)C3SC2)s1

Procedure:
2-Benzhydryloxycarbonyl-7-t-butoxycarbonylamino-3-(2-methylamino-thiazol-5-yl)-8-oxa-5-thia-1-azabicyclo[4.2.0]oct-2-ene can be prepared by following the working method of Example 2, but replacing the thiourea by N-methylthiourea (4 g). Starting from 2-benzhydryloxycarbonyl-7-t-butoxycarbonylamino-3-(2-dimethylamino-vinyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene (E-form)(20 g), and following purification by chromatography on a column (height: 45 cm, diameter: 4 cm) of silica gel (0.2-0.06 mm), elution being carried out with mixtures of cyclohexane and ethyl acetate, successively 50:50 by volume (1.5 liters), 40:60 by volume (1 liter) and 20:80 by volume (1.5 liters), and then with ethyl acetate (1 liter), and the fractions containing the expected product (according to thin layer chromatography) being combined and evaporated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 30° C., 2-benzhydryloxycarbonyl-7-t-butoxycarbonylamino-3-(2-methylamino-thiazol-5-yl)-8-oxo-5-thia- 1-azabicyclo[4.2.0]oct-2-ene (4.74 g) is obtained in the form of a pale brown froth.
Reaction SMILES: [Cl:1][C:2]([O:5]C(=O)OC(Cl)(Cl)Cl)(Cl)Cl.N1C=CC=CC=1.[O:19]1[CH2:24][CH2:23][CH:22]([OH:25])[CH2:21][CH2:20]1>O1CCCC1>[C:2]([Cl:1])(=[O:5])[O:25][CH:22]1[CH2:23][CH2:24][O:19][CH2:20][CH2:21]1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: OC1CCOCC1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: O=C(Cl)OC1CCOCC1
Yield: 92.9 %

Procedure:
To a solution (40 mL) of bis(trichloromethyl)carbonate (2.97 g) in tetrahydrofuran was dropwise added a solution (10 mL) of pyridine (2.43 mL) in tetrahydrofuran under ice-cooling. After stirring under ice-cooling for 10 min., a solution (20 mL) of tetrahydropyran-4-ol (1.91 g) in tetrahydrofuran was dropwise added slowly. After stirring at room temperature for 2 hrs., the mixture was concentrated under reduced pressure, and ethyl acetate (50 mL) and water (50 mL) were added to the residue. The ethyl acetate layer was separated and taken, washed with 0.2N hydrochloric acid (20 mL) and saturated brine (50 mL), and dried over anhydrous magnesium sulfate. Concentration under reduced pressure gave tetrahydropyran-4-yl chlorocarbonate (1.53 g). To a mixture of tert-butyl 2-hydroxyethyl(methyl)carbamate (1.40 g) obtained in Reference Example 1 and tetrahydrofuran (20 mL) was added pyridine (0.78 mL), and a solution (10 mL) of tetrahydropyran-4-yl chlorocarbonate (1.53 g) obtained above in tetrahydrofuran was dropwise added, and the mixture was stirred overnight at room temperature. After concentration of the reaction mixture under reduced pressure, water (50 mL) was added, the mixture was extracted with ethyl acetate (50 mL). The residue was washed with a 5% aqueous citric acid solution (50 mL) and saturated brine (50 mL), and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (eluted with ethyl acetate:hexane=4:1, then 3:2). The obtained colorless oil (2.03 g) was dissolved in diethyl ether (2 mL), and a 4N hydrogen chloride-ethyl acetate solution (5 mL) was added. After stirring at room temperature for 30 min., diethylether (10 mL) was added and the mixture was stirred overnight. The precipitated solid was collected by filtration and dried under reduced pressure to give the title compound (1.20 g) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][C@H:17]4[CH2:19][O:18]4)=[CH:11][CH:10]=3)=[N:7][O:8][C:4]=2[CH:3]=1.[CH3:22][N:23]([CH3:26])C=O>CNC1CCCCC1.C(O)C>[CH:22]1([N:23]([CH3:26])[CH2:19][C@@H:17]([OH:18])[CH2:16][O:15][C:12]2[CH:13]=[CH:14][C:9]([C:6]3[C:5]4[CH:20]=[CH:21][C:2]([F:1])=[CH:3][C:4]=4[O:8][N:7]=3)=[CH:10][CH:11]=2)[CH2:20][CH2:21][CH2:2][CH2:3][CH2:4]1
Reactant: Fc1ccc2c(-c3ccc(OC[C@H]4CO4)cc3)noc2c1
Reactant: CN(C)C=O
Solvent: CCO
Solvent: CNC1CCCCC1
Product: CN(C[C@@H](O)COc1ccc(-c2noc3cc(F)ccc23)cc1)C1CCCCC1

Procedure:
The title compound is prepared from a mixture of (R)-6-fluoro-3-(4-oxiranylmethoxy-phenyl)-benzo[d]isoxazole in dimethylformamide and N-methylcyclohexylamine in ethanol essentially as described above in Example 21. Purity by LC/MS=100%, [M+H]+=399.
Reaction SMILES: N1C=CN=C1.[CH2:6]([Si:8](Cl)([CH2:11][CH3:12])[CH2:9][CH3:10])[CH3:7].[OH:14][C@@H:15]([C@@H:17]1[C@@H:20]([C@@H:21]([CH3:40])[C:22]([C:24]2[S:28][C:27]3=[C:29]([C:32]([C:34]4[CH:35]=[N:36][CH:37]=[CH:38][CH:39]=4)=[O:33])[N:30]=[CH:31][N:26]3[CH:25]=2)=[O:23])[NH:19][C:18]1=[O:41])[CH3:16]>CN(C)C=O.C(OCC)(=O)C>[CH2:6]([Si:8]([CH2:11][CH3:12])([CH2:9][CH3:10])[O:14][C@@H:15]([C@@H:17]1[C@@H:20]([C@@H:21]([CH3:40])[C:22]([C:24]2[S:28][C:27]3=[C:29]([C:32]([C:34]4[CH:35]=[N:36][CH:37]=[CH:38][CH:39]=4)=[O:33])[N:30]=[CH:31][N:26]3[CH:25]=2)=[O:23])[NH:19][C:18]1=[O:41])[CH3:16])[CH3:7]
Reactant: CC[Si](Cl)(CC)CC
Reactant: C[C@@H](O)[C@H]1C(=O)N[C@@H]1[C@@H](C)C(=O)c1cn2cnc(C(=O)c3cccnc3)c2s1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC[Si](CC)(CC)O[C@H](C)[C@H]1C(=O)N[C@@H]1[C@@H](C)C(=O)c1cn2cnc(C(=O)c3cccnc3)c2s1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Imidazole (0.15 g) and 0.36 ml of triethylsilylchloride were added to a solution of 0.32 g of (3S,4R)-3-[(1R)-1-hydroxyethyl]-4-[(1R)-1-methyl-2-[7-(pyridin-3-yl)carbonylimidazo[5,1-b]thiazol-2-yl]-2-oxoethyl]azetidin-2-one in 3.2 ml of dimethylformamide under ice cooling, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with 80 ml of ethyl acetate, and the diluted reaction mixture was washed three times with 20 ml of a 10% aqueous sodium chloride solution and was then washed with an a saturated aqueous sodium chloride solution and was dried over anhydrous magnesium sulfate. The solvent was removed by evaporation, the resultant solid was suspended in 4 ml of a hexane:ethyl acetate=1:1 solution and was collected by filtration to give 0.33 g of (3S,4R)-3-[(1R)-1-(triethylsilyloxy)ethyl]-4-[(1R)-1-methyl-2-[7-(pyridin-3-yl)carbonylimidazo[5,1-b]thiazol-2-yl]-2-oxoethyl]azetidin-2-one.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:13][O:14][C:15]1[CH:23]=[C:22]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[CH:21]=[CH:20][C:16]=1[C:17]([OH:19])=O.[NH2:30][C@H:31]1[CH2:36][C:35]2[C:37]([N:41]3[CH2:46][CH2:45][N:44]([CH3:47])[CH2:43][CH2:42]3)=[CH:38][CH:39]=[CH:40][C:34]=2[O:33][CH2:32]1>CN(C)C=O>[CH3:47][N:44]1[CH2:45][CH2:46][N:41]([C:37]2[C:35]3[CH2:36][C@H:31]([NH:30][C:17](=[O:19])[C:16]4[CH:20]=[CH:21][C:22]([N:24]5[CH2:29][CH2:28][O:27][CH2:26][CH2:25]5)=[CH:23][C:15]=4[O:14][CH3:13])[CH2:32][O:33][C:34]=3[CH:40]=[CH:39][CH:38]=2)[CH2:42][CH2:43]1
Reactant: CN1CCN(c2cccc3c2C[C@H](N)CO3)CC1
Reactant: COc1cc(N2CCOCC2)ccc1C(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: COc1cc(N2CCOCC2)ccc1C(=O)N[C@@H]1COc2cccc(N3CCN(C)CC3)c2C1
Temperature: 25 °C
Reaction time: 120 h
Yield: 32.7 %

Procedure:
A stirred solution of 1,1′-carbonyldiimidazole (222 mg, 1.37 mmol) and 2-methoxy-4-morpholinobenzoic acid (176 mg, 0.740 mmol) in anhydrous N,N-dimethylformamide (5 mL) was heated at 75° C. for 2 h, and was then allowed to cool. A solution of (S)-3-amino-5-(4-methylpiperazin-1-yl)-3,4-dihydro-2H-1-benzopyran (183 mg, 0.740 mmol) in anhydrous N,N-dimethylformamide (4 mL) was added. The reaction mixture was stirred at room temperature for 5 days. The solvent was removed in vacuo, and the residue was partitioned between ethyl acetate (50 mL) and a 2 M NH3 solution (15 mL). The organic layer was dried (MgSO4), and the solvent was removed in vacuo. The residue was purified by column chromatography on silica (eluent: chloroform/ethanol, 93:7+0.5% conc. NH3) affording 113 mg (30% yield) of the title compound as an uncolored foam: [α]21D−141° (c 0.5, chloroform); EIMS (70 eV) m/z (relative intensity) 466 (20, M+).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][C@H:3]1[F:15].[Cl:16][C:17]1[N:18]=[C:19]([C:24](O)=[O:25])[NH:20][C:21]=1[CH2:22][CH3:23].O.ON1C2C=CC=CC=2N=N1.CCN=C=NCCCN(C)C.Cl.C(N(CC)CC)C>>[Cl:16][C:17]1[N:18]=[C:19]([C:24]([NH:1][C@@H:2]2[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:12])([CH3:14])[CH3:13])=[O:9])[CH2:4][C@H:3]2[F:15])=[O:25])[NH:20][C:21]=1[CH2:22][CH3:23]
Reactant: CCc1[nH]c(C(=O)O)nc1Cl
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](N)[C@H](F)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Product: CCc1[nH]c(C(=O)N[C@@H]2CCN(C(=O)OC(C)(C)C)C[C@H]2F)nc1Cl
Yield: 72.1 %

Procedure:
The same operation as in Example (196d) was performed using tert-butyl trans(±)-4-amino-3-fluoropiperidine-1-carboxylate obtained in Example (197a) (30.0 mg, 0.137 mmol), 4-chloro-5-ethyl-1H-imidazole-2-carboxylic acid obtained in Example (1d) (28.8 mg, 0.165 mmol), 1-hydroxybenzotriazole hydrate (27.9 mg, 0.206 mmol), WSC hydrochloride (39.5 mg, 0.206 mmol) and triethylamine (28.7 μL, 0.206 mmol), to obtain 37.0 mg of the title compound (72%) as a pale yellow foamy substance.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)=[C:7]([CH:10]=1)[C:8]#[N:9].Cl[C:23]1[CH:24]=[C:25]2[N:32]([CH:33]3[CH2:35][CH2:34]3)[CH2:31][CH2:30][N:26]2[C:27](=[O:29])[N:28]=1>>[CH:33]1([N:32]2[C:25]3[N:26]([C:27](=[O:29])[N:28]=[C:23]([O:1][CH2:2][C:3]4[CH:4]=[CH:5][C:6]([O:11][C:12]5[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:19])([F:20])[F:21])[CH:13]=5)=[C:7]([CH:10]=4)[C:8]#[N:9])[CH:24]=3)[CH2:30][CH2:31]2)[CH2:35][CH2:34]1
Reactant: O=c1nc(Cl)cc2n1CCN2C1CC1
Reactant: N#Cc1cc(CO)ccc1Oc1cccc(C(F)(F)F)c1
Product: N#Cc1cc(COc2cc3n(c(=O)n2)CCN3C2CC2)ccc1Oc1cccc(C(F)(F)F)c1

Procedure:
The title compound was prepared by a procedure similar to that described for E9 starting from 5-(hydroxymethyl)-2-(3-(trifluoromethyl)phenoxy)benzonitrile and 7-chloro-1-cyclopropyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one.
Reaction SMILES: [Mg].II.[CH3:4][O:5][C:6]1[CH:7]=[C:8]([Mg]Br)[CH:9]=[C:10]([O:12][CH3:13])[CH:11]=1.[CH3:16][O:17][C:18]1[CH:25]=[CH:24][C:21]([CH:22]=[O:23])=[CH:20][C:19]=1[N+:26]([O-:28])=[O:27]>C1COCC1>[CH3:4][O:5][C:6]1[CH:7]=[C:8]([CH:22]([C:21]2[CH:24]=[CH:25][C:18]([O:17][CH3:16])=[C:19]([N+:26]([O-:28])=[O:27])[CH:20]=2)[OH:23])[CH:9]=[C:10]([O:12][CH3:13])[CH:11]=1
Reactant: COc1cc(OC)cc([Mg]Br)c1
Reactant: COc1ccc(C=O)cc1[N+](=O)[O-]
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Product: COc1cc(OC)cc(C(O)c2ccc(OC)c([N+](=O)[O-])c2)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Grignard reagent was prepared in an oven-dried three necked flask outfitted with a reflux condenser, dropping funnel, and magnetic stirrer. Approximately ¼ of a solution of 3,5-bromoveratrole (10 g, 46.1 mmol) in anhydrous THF (60 mL) was added to a mixture of magnesium turnings (1.12 g, 46.1 mmol) in THF (10 mL) with a small piece of iodine. As soon as the solution became colorless (heating sometimes necessary), the remaining 3,5-bromoveratrole solution was added dropwise to the reaction mixture under mild reflux, over 30 min. The resulting mixture was refluxed for 3 h then cooled to room temperature for 30 min. The (3,5-dimethoxy-phenyl) magnesium bromide was then added slowly to a stirred solution of 4-methoxy-3-nitro-benzaldehyde (6.95 g, 38.4 mmol) in THF (60 mL) at 0° C. After complete addition, the reaction mixture was stirred at cold for 10 min and then at room temperature for 2 h. The solution was cooled to 0° C. and quenched with saturated NH4Cl solution (90 mL). The aqueous layer was extracted with ether (3×90 mL). The combined organic layers were washed with water (2×120 mL), brine (120 mL) and dried (MgSO4). Removal of solvent gave the crude (3,5-dimethoxy-phenyl)-(4-methoxy-3-nitro-phenyl)-methanol, which was used in the next step without further purification.
Reaction SMILES: Br[C:2]1[N:6]2[C:7]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:8]=3[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=3)=[N:10][CH2:11][C:5]2=[N:4][N:3]=1.[OH:23][CH2:24][CH2:25][N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>>[F:22][C:19]1[CH:20]=[CH:21][C:7]2[N:6]3[C:2]([N:29]4[CH2:30][CH2:31][N:26]([CH2:25][CH2:24][OH:23])[CH2:27][CH2:28]4)=[N:3][N:4]=[C:5]3[CH2:11][N:10]=[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=3)[C:8]=2[CH:18]=1
Reactant: Fc1ccc2c(c1)C(c1ccccn1)=NCc1nnc(Br)n1-2
Reactant: OCCN1CCNCC1
Product: OCCN1CCN(c2nnc3n2-c2ccc(F)cc2C(c2ccccn2)=NC3)CC1

Procedure:
In the manner given in Example 1, 1-bromo-8-fluoro-6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine is heated with excess 1-(β-hydroxyethyl)piperazine to give 8-fluoro-1-[4-(β-hydroxyethyl)piperazino]-6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: C([Si](C)(C)[O:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2([CH2:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[O:21][C:20](=[O:22])[CH:19]=[C:18]([OH:23])[CH2:17]2)=[CH:12][CH:11]=1)(C)(C)C.[C:34]([C:38]1[CH:43]=[C:42]([O:44][CH2:45][CH2:46][O:47][Si](C(C)(C)C)(C)C)[C:41]([CH3:55])=[CH:40][C:39]=1[S:56]S(C1C=CC(C)=CC=1)(=O)=O)([CH3:37])([CH3:36])[CH3:35].C([O-])([O-])=O.[K+].[K+].Cl>CO.CN(C=O)C>[C:34]([C:38]1[CH:43]=[C:42]([O:44][CH2:45][CH2:46][OH:47])[C:41]([CH3:55])=[CH:40][C:39]=1[S:56][C:19]1[C:20](=[O:22])[O:21][C:16]([C:13]2[CH:14]=[CH:15][C:10]([O:9][CH2:8][CH2:7][OH:6])=[CH:11][CH:12]=2)([CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:17][C:18]=1[OH:23])([CH3:37])([CH3:36])[CH3:35]
Reactant: Cc1ccc(S(=O)(=O)Sc2cc(C)c(OCCO[Si](C)(C)C(C)(C)C)cc2C(C)(C)C)cc1
Reactant: CC(C)(C)[Si](C)(C)OCCOc1ccc(C2(CCc3ccccc3)CC(O)=CC(=O)O2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CN(C)C=O
Product: Cc1cc(SC2=C(O)CC(CCc3ccccc3)(c3ccc(OCCO)cc3)OC2=O)c(C(C)(C)C)cc1OCCO

Procedure:
To a round bottom flask equipped with a magnetic stirrer were added 6-{4-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-phenyl} -4-hydroxy-6-phenethyl-5,6-dihydro-pyran-2-one (prepared in Example SS; 0.260 g, 0.555 mmol), toluene-4-thiosulfonic acid S-{2-tert-butyl-4-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-5-methyl-phenyl) ester (prepared in Example PPP; 0.282 g, 0.555 mmol), K2CO3 (0.346 g, 2.50 mmol), and DMF (5 mL), as described in General Method 9. The mixture was stirred at room temperature for 2 days at which time MeOH (150 mL) was added and the solution taken to pH 3.0 with conc. HCl. The reaction was quenched with H2O (500 mL) and extracted with EtOAc. The organics were dried over MgSO4 and concentrated; the residue was taken up in a small amount of EtOAc and triturated with hexane. The solid was filtered and dried under high vacuum to yield the title compound, m.p. >190° C. (dec.). 1H NMR (DMSO-d6) δ 1.45 (s, 9 H), 1.68 (s, 3 H), 2.22 (br m, 4 H), 2.51 (br m, partially obscured by DMSO, 2 H), 3.34 (d of ABX q, partially obscured by H2 0, 1 H), 3.40 (d of ABX q, partially obscured by H2O, 1 H), 3.67 (br m, 2 H), 3.72 (br m, 2 H)3.91 (t, 2 H), 3.98 (t, 2 H), 6.76 (s, 1 H), 6.96 (s, 1 H), 6.99 (d, 2 H), 7.08-7.22 (m, 1 H), 7.10 (d, 2 H), 7.24 (d, 2 H), 7.30 (d, 2 H).
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:20]C)[CH:16]=3)[C:11]=2[O:22][C:23]2[CH:37]=[CH:36][C:26]([O:27][CH2:28][CH2:29][N:30]3[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]3)=[CH:25][CH:24]=2)[CH:6]=[C:7]([F:9])[CH:8]=1.B(Br)(Br)Br.CO>ClCCl>[F:9][C:7]1[CH:6]=[C:5]([C:10]2[C:11]([O:22][C:23]3[CH:24]=[CH:25][C:26]([O:27][CH2:28][CH2:29][N:30]4[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]4)=[CH:36][CH:37]=3)=[C:12]3[C:17](=[CH:18][CH:19]=2)[CH:16]=[C:15]([OH:20])[CH:14]=[CH:13]3)[CH:4]=[C:3]([F:2])[CH:8]=1
Reactant: COc1ccc2c(Oc3ccc(OCCN4CCCCC4)cc3)c(-c3cc(F)cc(F)c3)ccc2c1
Agent: BrB(Br)Br
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: Oc1ccc2c(Oc3ccc(OCCN4CCCCC4)cc3)c(-c3cc(F)cc(F)c3)ccc2c1
Yield: 96.8 %

Procedure:
Dissolve 1-(2-{4-[2-(3,5-difluoro-phenyl)-6-methoxy-naphthalen-1-yloxy]-phenoxy}-ethyl)-piperidine hydrochloride (410 mg, 0.76 mmol) in dichloromethane (10 mL) and cool in an ice bath. Add boron tribromide (0.22 mL, 2.28 mmol) and stir for 2.5 hours. Add methanol (5 mL), warm to ambient temperature, dilute with dichloromethane and wash with saturated aqueous sodium bicarbonate, dry with solid magnesium sulfate, filter and remove solvent under vacuum. Chromatograph on silica gel with dichloromethane/methanol mixtures to give 350 mg of the title compound (96%).
Reaction SMILES: C(#N)C.N1C=CC=CC=1.F.[C:11]([C:14]1[CH2:28][C@@H:27]([O:29][Si](C(C)(C)C)(C)C)[C@H:26](/[CH:37]=[CH:38]/[C@@H:39]([O:47][Si](C(C)(C)C)(C)C)[CH2:40][C@H:41]([CH3:46])[CH2:42][CH2:43][CH2:44][CH3:45])[C:15]=1[S:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])(=[O:13])[CH3:12]>N1C=CC=CC=1>[C:11]([C:14]1[CH2:28][C@@H:27]([OH:29])[C@H:26](/[CH:37]=[CH:38]/[C@@H:39]([OH:47])[CH2:40][C@H:41]([CH3:46])[CH2:42][CH2:43][CH2:44][CH3:45])[C:15]=1[S:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])(=[O:13])[CH3:12]
Reactant: CCCC[C@@H](C)C[C@@H](/C=C/[C@@H]1C(SCCCCCC(=O)OC)=C(C(C)=O)C[C@H]1O[Si](C)(C)C(C)(C)C)O[Si](C)(C)C(C)(C)C
Agent: F
Solvent: CC#N
Solvent: c1ccncc1
Product: CCCC[C@@H](C)C[C@H](O)/C=C/[C@@H]1C(SCCCCCC(=O)OC)=C(C(C)=O)C[C@H]1O
Reaction time: 15 h
Yield: 38.2 %

Procedure:
To a solution of ice-cooled acetonitrile (1 mL) and pyridine (0.1 mL) was added a hydrogen fluoride-pyridine solution (0.1 mL). To this solution was added methyl (11R,12S,13E,15S,17R)-9-acetyl-11,15-bis(tert-butyldimethylsiloxy)-17,20-dimethyl-7-thiaprosta-8,13-dienoate (12 mg, 0.019 mmol) in pyridine (0.1 mL). The ice bath was removed and the solution was agitated for 15 hours, while returning it to room temperature. The reaction solution was poured into a mixture of ethyl acetate and a saturated aqueous sodium hydrogencarbonate. The desired product was extracted from this mixed solution of ethyl acetate. The extract was washed with brine, then dried over anhydrous sodium sulfate. The solution was concentrated under reduced pressure, then subjected to thin layer chromatography for separation (ethyl acetate:hexane=3:1) to obtain methyl (11R,12S,13E,15S,17R)-9-acetyl-11,15-dihydroxy-17,20-dimethyl-7-thiaprosta-8,13-dienoate (3.2 mg, 39%).
Reaction SMILES: [CH2:1]([NH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=2)[N:8]=[C:7](Cl)[N:6]=1)[CH:2]=[CH2:3].[CH2:19]([NH2:22])[CH2:20][CH3:21]>O>[CH2:1]([NH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=2)[N:8]=[C:7]([NH:22][CH2:19][CH2:20][CH3:21])[N:6]=1)[CH:2]=[CH2:3]
Reactant: C=CCNc1nc(Cl)nc2ccc([N+](=O)[O-])cc12
Reactant: CCCN
Solvent: O
Product: C=CCNc1nc(NCCC)nc2ccc([N+](=O)[O-])cc12
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 77.3 %

Procedure:
A mixture of 250 mg (0.95 mmol) of 4-allylamino-2-chloro-6-nitroquinazoline and 719 mg (12.16 mmol) of propylamine were stirred at room temperature for 2.5 hours. Water was added to the reaction mixture, followed by extraction with ethyl acetate, washing with brine and drying over anhydrous sodium sulfate. After the solvent was distilled off, the residue was purified by a silica gel column to give 211 mg (yield: 77.7%) of the title compound.