Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:9])=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].Br[CH2:11][CH2:12][CH2:13][C:14](Cl)=[O:15].[H-].[Na+]>C(Cl)Cl>[Br:1][C:2]1[C:3]([CH3:9])=[C:4]([NH:5][C:14]([CH:13]2[CH2:11][CH2:12]2)=[O:15])[CH:6]=[CH:7][CH:8]=1
Reactant: Cc1c(N)cccc1Br
Reactant: O=C(Cl)CCCBr
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Product: Cc1c(Br)cccc1NC(=O)C1CC1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 32.9 %

Procedure:
A solution of 3-bromo-2-methylaniline (2.00 g, 10.75 mmol) in DCM (20 mL) was treated with TEA (3.00 mL, 21.50 mmol) and then with a solution of 4-bromobutanoyl chloride (2.392 g, 12.90 mmol) in DCM (10 mL), and the resulting mixture was stirred at rt. After 2.5 h, the mixture was diluted with DCM, washed with NaHCO3 (aq) and water, and dried and concentrated. The residue was dissolved in THF (20 mL) and treated with hexane-washed sodium hydride (60% oil dispersion, 0.860 g, 21.50 mmol). The mixture was stirred at rt for 1.5 h, then was concentrated. The residue was dissolved in DCM, washed with water, 1 M hydrochloric acid and brine, and dried and concentrated. The residue was purified by column chromatography (eluting with a gradient from 80:20 hexane-EtOAc to EtOAc) to provide N-(3-bromo-2-methylphenyl)cyclopropanecarboxamide (900 mg, 33%) as a white solid. Mass spectrum m/z 254, 256 (M+H)+.
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.[CH3:14][C:15]([C:19]1[N:23]([CH2:24][CH:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[C:22]2[CH:31]=[CH:32][C:33]([S:35]([N:38]3[CH:42]=[C:41]([C:43](O)=[O:44])[CH:40]=[N:39]3)(=[O:37])=[O:36])=[CH:34][C:21]=2[N:20]=1)([CH3:18])[CH2:16][CH3:17].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH:1]1([NH:4][C:43]([C:41]2[CH:40]=[N:39][N:38]([S:35]([C:33]3[CH:32]=[CH:31][C:22]4[N:23]([CH2:24][CH:25]5[CH2:30][CH2:29][O:28][CH2:27][CH2:26]5)[C:19]([C:15]([CH3:14])([CH3:18])[CH2:16][CH3:17])=[N:20][C:21]=4[CH:34]=3)(=[O:37])=[O:36])[CH:42]=2)=[O:44])[CH2:3][CH2:2]1
Reactant: NC1CC1
Reactant: CCC(C)(C)c1nc2cc(S(=O)(=O)n3cc(C(=O)O)cn3)ccc2n1CC1CCOCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCC(C)(C)c1nc2cc(S(=O)(=O)n3cc(C(=O)NC4CC4)cn3)ccc2n1CC1CCOCC1
Yield: 42.3 %

Procedure:
Following the same procedure in Example 24, Step A, using cyclopropylamine (21 mg, 25 uL, 0.36 mmol), DIPEA (104 uL, 77 mg, 0.59 mmol), 1-{[2-(1,1-dimethylpropyl)-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5-yl]sulfonyl}-1H-pyrazole-4-carboxylic acid (0.18 mmol) and HATU (109 mg, 0.29 mmol) in DMF (3 mL). The crude product was purified by MPLC using Hex/EtOAc (1:4) on silica gel to give 38 mg (42%) of a white solid as the title compound. 1H NMR (400 MHz, METHANOL-D4) δ 0.54-0.61 (m, 2 H), 0.74-0.82 (m, 5 H), 1.42-1.58 (m, 4 H), 1.60 (s, 6 H), 1.96 (q, J=7.55 Hz, 2 H), 2.22-2.36 (m, 1 H), 2.73-2.80 (m, 1 H), 3.26-3.36 (m, 2 H), 3.86-3.95 (m, 2 H), 4.42 (d, J=7.42 Hz, 2 H), 7.92 (d, J=8.8 Hz, 1 H), 7.98 (dd, J=8.8, 1.8 Hz, 1 H), 8.05 (s, 1 H), 8.34 (d, J=1.76 Hz, 1 H), 8.76 (s, 1 H); MS (ESI) (M+H)+=500.0; Anal. Calcd for C25H33N5O4S+0.6 TFA+1.0H2O (586.07): C, 53.70; H, 6.12; N, 11.95. Found: C, 53.65; H, 5.98; N, 12.02.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8](F)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[NH2:11][C@H:12]([C:20]([OH:22])=[O:21])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>CS(C)=O>[Cl:1][C:2]1[CH:9]=[C:8]([NH:11][C@H:12]([C:20]([OH:22])=[O:21])[CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Reactant: N#Cc1ccc(F)cc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: N#Cc1ccc(N[C@@H](Cc2ccccc2)C(=O)O)cc1Cl
Temperature: 90 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a solution of 2-chloro-4-fluorobenzonitrile (5.0 g) in dimethyl sulfoxide (100 mL) were added phenylalanine (6.37 g) and cesium carbonate (13.6 g), and the mixture was stirred at 90° C. overnight. After allowing to room temperature, ethyl acetate was added, and the mixture was extracted 3 times with saturated aqueous sodium hydrogen carbonate solution. The aqueous layers were combined, and acidified with citric acid, and the mixture was extracted twice with ethyl acetate. The organic layers were combined, washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure to give the title compound as a brown oil (yield: 9.67 g, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9](=[N:22][O:23][CH3:24])[CH2:10][N:11]1C(=O)C2=CC=CC=C2C1=O.O.NN.O>C(O)C>[CH3:24][O:23][N:22]=[C:9]([C:3]1[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=1[Cl:1])[CH2:10][NH2:11]
Reactant: CON=C(CN1C(=O)c2ccccc2C1=O)c1ccc(Cl)cc1Cl
Agent: NN
Solvent: CCO
Solvent: O
Product: CON=C(CN)c1ccc(Cl)cc1Cl
Temperature: 60 °C
Reaction time: 2 h
Yield: 83.8 %

Procedure:
To 316 mg of N-[2-(2,4-dichlorophenyl)-2-(methoxyimino)ethyl]phthalimide in 10 ml of ethanol, 108 mg of hydrazine monohydrate was added, and the mixture was stirred at 60° C. for 2 hours. After completion of the reaction, the reaction mixture was allowed to cool to room temperature, mixed with 30 ml of water and extracted with ethyl acetate (40 ml×1). The resulting organic layer was dried over saturated aqueous sodium chloride and then anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain 170 mg of the desired crude product as a colorless oil. The oil was used in the next step without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][NH:13][CH2:12]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C[Si]([N:21]=[C:22]=[O:23])(C)C>ClCCl>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][N:13]([C:22]([NH2:21])=[O:23])[CH2:12]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCC1CCCNC1
Reactant: C[Si](C)(C)N=C=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCC1CCCN(C(N)=O)C1
Temperature: 25 °C
Reaction time: 3.35 h
Yield: 70.3 %

Procedure:
3-(2-tert-Butoxycarbonylaminoethyl)piperidine (500 mg, 2.19 mmoles) was dissolved in anhydrous dichloromethane (10 mL) and trimethylsilylisocyanate (2.96 mL, 21.9 mmoles) was added. The mixture was stirred under argon at 25° C. for 3.35 h. The mixture was diluted with dichloromethane and washed with saturated aqueous sodium bicarbonate. The organic layer was dried (MgSO4), filtered, evaporated to dryness and chromatographed on a silica gel column (15×5 cm) using 5% (10% conc. ammonium hydroxide in methanol)-dichloromethane as the eluant to give 3-(2-tert-butoxycarbonylaminoethyl)piperidine-1-carboxamide (417.7 mg, 70%): FABMS: m/z 272.0 (MH+); HRFABMS: m/z 272.1979 (MH+). Calcd. for C13H26O3: m/z (9H, s, —COOC(CH3)3), 1.68 (1H, m, CH2), 1 84 (1H, m, CH2), 2.54 (1H, dd, CH2), 2.73 (1H, m, CH2), 3.08 (1H, m, CH2), 3.42 (1H, m, CH2), 4.02 (1H, m, CH2), 410 (1H, m, CH2), 4.84 (1H, m, NH) and 4.96 ppm (2H, bm, CONH2); δc (CDCl3) CH3: 28.5, 28.5, 28.5; CH2: 25.2, 31.7, 34.9, 37.3, 44.6, 50.3; CH: 32.9; C: 79.5, 156.4, 158.2.
Reaction SMILES: [CH2:1]([OH:6])[CH2:2][CH:3]([OH:5])[CH3:4].[F:7][C:8]1[C:13]([S:14](Cl)(=[O:16])=[O:15])=[C:12]([F:18])[C:11]([F:19])=[C:10]([F:20])[C:9]=1[F:21].C([O-])(O)=O.[Na+].C(OCC)(=O)C>C(Cl)Cl>[F:7][C:8]1[C:9]([F:21])=[C:10]([F:20])[C:11]([F:19])=[C:12]([F:18])[C:13]=1[S:14]([O:6][CH2:1][CH2:2][CH:3]([OH:5])[CH3:4])(=[O:16])=[O:15]
Reactant: O=S(=O)(Cl)c1c(F)c(F)c(F)c(F)c1F
Reactant: CC(O)CCO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(O)CCOS(=O)(=O)c1c(F)c(F)c(F)c(F)c1F
Temperature: 25 °C
Reaction time: 6 h
Yield: 40.6 %

Procedure:
To a solution of 1,3-butane diol (0.9 g, 10 mmol) and TEA (0.61 g, 6 mmol) in CH2Cl2 (4 mL) at 0° C. was added pentafluorobenzenesulfonyl chloride (0.53 g, 2 mmol) dissolved in CH2Cl2 (4 mL). The solution was stirred for 6 h over which time the solution slowly warmed to rt. Saturated aqueous NaHCO3 (25 mL) was added to the solution and the mixture was stirred at rt for 30 min. The organics were extracted with CH2Cl2 (50 mL) and washed with 0.5 M HCl (3×20 mL), saturated aqueous NaHCO3 (1×20 mL) and saturated aqueous NaCl (1×20 mL). The organics were dried over Na2SO4 and concentrated to give a crude mixture. Silica gel chromatography with ethyl acetate in hexanes yielded the desired product (0.26 g, 40%). 1H NMR (400 MHz CDCl3) δ 4.62 (m, 2H), 4.13 (m, 1H), 2.11 (m, 1H), 1.94 (m, 1H), 1.40 (d, 3H, J=6.2 Hz). Anal. Calcd. For C10H9F5O4S: C, 37.51; H, 2.83. Found: C, 37.70; H, 2.93.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]2[C:6]3[C:20](=O)[NH:19][C:18]([CH3:22])=[N:17][C:7]=3[CH2:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:4]=2[CH:3]=1.P(Cl)(Cl)([Cl:27])=O>C(Cl)Cl>[Cl:27][C:20]1[C:6]2[C:5]3[CH:23]=[CH:24][C:2]([Cl:1])=[CH:3][C:4]=3[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[N:9][CH2:8][C:7]=2[N:17]=[C:18]([CH3:22])[N:19]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1nc2c(c(=O)[nH]1)-c1ccc(Cl)cc1C(c1ccccc1)=NC2
Solvent: ClCCl
Product: Cc1nc(Cl)c2c(n1)CN=C(c1ccccc1)c1cc(Cl)ccc1-2

Procedure:
A solution of 3.5 g (10.4 mmol) of 9-chloro-3-methyl-7-phenyl-5H-pyrimido[4,5-d][2]benzazepin-1(2H)-one and 22 mL of phosphorous oxychloride in 100 mL of methylene chloride was stirred at room temperature for 18 hr. The reaction mixture was concentrated at reduced pressure to a solid residue. The residue was partitioned between ice cold saturated aqueous sodium bicarbonate and methylene chloride. The methylene chloride solution was dried over anhydrous sodium sulfate and concentrated at reduced pressure to a yellow residue. Purification by column chromatography (silica gel, 40.0 g; eluent: methylene chloride ether, 10:1) gave a pale yellow solid, mp 190°-192°. A portion was recrystallized from a mixture of ether and petroleum ether to yield colorless prisms, mp 191°-193°.
Reaction SMILES: [C:1]1([CH3:16])[CH:6]=[CH:5][C:4]([C:7]2[S:8][C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=3[CH:11]=2)=[CH:3][CH:2]=1.[C:17]([OH:27])(=[O:26])[C:18]1[CH:25]=[CH:24][C:21]([CH:22]=O)=[CH:20][CH:19]=1.CC(C)([O-])C.[K+]>C(O)(=O)C>[C:17]([C:18]1[CH:25]=[CH:24][C:21]([CH:22]=[CH:16][C:1]2[CH:2]=[CH:3][C:4]([C:7]3[S:8][C:9]4[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=4[CH:11]=3)=[CH:5][CH:6]=2)=[CH:20][CH:19]=1)([OH:27])=[O:26]
Reactant: Cc1ccc(-c2cc3ccccc3s2)cc1
Reactant: O=Cc1ccc(C(=O)O)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)O
Product: O=C(O)c1ccc(C=Cc2ccc(-c3cc4ccccc4s3)cc2)cc1
Temperature: 35 °C
Reaction time: 2 h

Procedure:
A stirred solution of 2.24 g (0.01 mole) of 2-(p-tolyl)benzothiophene and 2.25 g (0.01 mole) of the anil derivative of terephthalaldehydic acid in 150 ml of freshly distilled, dry dimethylformamide was flushed with nitrogen for 10 minutes. The solution was heated to 35°C and 6.72 g (0.06 mole) of potassium tert-but-oxide was added. The color of the reaction mixture changed from violet to brown. Analysis of an aliquot by ultraviolet spectroscopy showed that the reaction was completed after 2 hours of stirring. Glacial acetic acid was added in amount sufficient to neutralize excess potassium tert-butoxide, and the reaction mixture was heated to reflux and filtered while hot to collect the resulting precipitate. The filter cake was washed with hot dimethylformamide containing two percent aniline, then slurried in hot ten percent aqueous hydrochloric acid and refiltered. The collected precipitate was washed on the filter with water until free of acid and then dried in vacuo. The product was finally purified by sublimation to obtain 2-[4-(4-carboxystyryl)phenyl]benzothiophene which remained unmelted at 350°C. The wavelength of maximum excitation of this compound was 367 nm and the wavelength of maximum emission was 423 nm.
Reaction SMILES: [CH2:1]([O:6][N:7]=[C:8]([C:14](=O)[CH2:15]Cl)[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:2][CH2:3][CH2:4][CH3:5].[NH2:18][C:19]([NH2:21])=[S:20].O.O.O.C([O-])(=O)C.[Na+].C(O)C>O>[NH2:21][C:19]1[S:20][CH:15]=[C:14]([C:8](=[N:7][O:6][CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[C:9]([O:11][CH2:12][CH3:13])=[O:10])[N:18]=1
Reactant: NC(N)=S
Reactant: CCCCCON=C(C(=O)CCl)C(=O)OCC
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCCCCON=C(C(=O)OCC)c1csc(N)n1
Yield: 52.1 %

Procedure:
Ethyl 2-pentyloxyimino-4-chloro-3-oxobutyrate (syn isomer, 51.1 g.), thiourea (14.7 g.), sodium acetate trihydrate (26.4 g.), ethanol (175 ml.) and water (125 ml.) were treated in a similar manner to that of Example F-(3) to give ethyl 2-(2-aminothiazol-4-yl)-2-pentyloxyiminoacetate (syn isomer, 28.7 g.), mp 86° to 88° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([C:16]2[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:23])[CH:11]=2)[CH:6]=1.[C:25]1([S:31](Cl)(=[O:33])=[O:32])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(N(C(C)C)CC)(C)C>C1COCC1>[CH3:1][O:2][C:3](=[O:24])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([C:16]2[CH:21]=[CH:20][C:19]([NH:22][S:31]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)(=[O:33])=[O:32])=[CH:18][CH:17]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:23])[CH:11]=2)[CH:6]=1
Reactant: COC(=O)Cc1cc2ccc(Cl)cc2c(-c2ccc(N)cc2)c1C
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COC(=O)Cc1cc2ccc(Cl)cc2c(-c2ccc(NS(=O)(=O)c3ccccc3)cc2)c1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 77.6 %

Procedure:
To a solution of [4-(4-amino-phenyl)-6-chloro-3-methyl-naphthalen-2-yl]-acetic acid methyl ester (100 mg, 0.29 mmol) and benzenesulfonyl chloride (105 mg, 0.59 mmol) in THF (5.5 mL) was added diisopropylethylamine (0.15 ml, 0.85 mmol) at 0° C. under nitrogen. After addition, the reaction mixture was warmed to room temperature and stirred for 3 hours. The solvent was removed under vacuum and the residue was diluted with water (10 mL). Then, the mixture was extracted with ethyl acetate (2×20 mL). The combined organic extracts were washed with brine solution (30 mL) and dried over anhydrous magnesium sulfate. Filtration of the drying agent and concentration of the solvent under vacuum gave the crude residue which was purified using an ISCO (40 g) column, eluting with 5-25% ethyl acetate in hexanes, to afford [4-(4-benzenesulfonylamino-phenyl)-6-chloro-3-methyl-naphthalen-2-yl]-acetic acid methyl ester (108 mg, 76%) as a white foam. HRMS calcd. for C26H21ClNO4S [(M−H)−] 478.0885, obsd. 478.0884.
Reaction SMILES: [CH:1]1([CH2:6][NH:7][C:8](=[O:21])[CH2:9][C:10]2[CH:18]=[C:17]3[C:13]([C:14]([CH:19]=[O:20])=[CH:15][NH:16]3)=[CH:12][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Br[CH2:23][C:24]1[CH:36]=[CH:35][C:27]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[CH:26][C:25]=1[O:37][CH3:38].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH:1]1([CH2:6][NH:7][C:8]([CH2:9][C:10]2[CH:18]=[C:17]3[C:13]([C:14]([CH:19]=[O:20])=[CH:15][N:16]3[CH2:23][C:24]3[CH:36]=[CH:35][C:27]([C:28]([O:30][C:31]([CH3:34])([CH3:32])[CH3:33])=[O:29])=[CH:26][C:25]=3[O:37][CH3:38])=[CH:12][CH:11]=2)=[O:21])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=Cc1c[nH]c2cc(CC(=O)NCC3CCCC3)ccc12
Reactant: COc1cc(C(=O)OC(C)(C)C)ccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(C(=O)OC(C)(C)C)ccc1Cn1cc(C=O)c2ccc(CC(=O)NCC3CCCC3)cc21
Reaction time: 48 h
Yield: 97.5 %

Procedure:
A mixture of N-cyclopentylmethyl-3-formylindole-6-acetamide (0.52 g), t-butyl 4-bromomethyl-3-methoxybenzoate (0.66 g), and potassium carbonate (0.37 g) in N,N-dimethylformamide (10 ml) was stirred for 48 hr under a nitrogen atmosphere. Water was added to give a precipitate which was collected by filtration and purified by flash chromatography, eluting with 1:49 methanol:chloroform, to give t-butyl 4-[6-(cyclopentylmethylcarbamoyl)methyl-3-formylindol-1-ylmethyl]-3-methoxybenzoate (0.90 g, 97%) as a white solid; partial NMR (80 MHz, CDCl3): 1.56 (s, 9H, C(CH3)3), 3.09(t, 2H, NHCH2), 3.65(s, 2H, COCH2), 3.93(s, 3H, OCH3), 9.98(s, 1H, CHO).
Reaction SMILES: [CH2:1]([N:3]1[C:7]([C:8]2[S:9][C:10]3[N:11]=[CH:12][N:13]=[C:14](SC)[C:15]=3[N:16]=2)=[C:6]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:5]=[CH:4]1)[CH3:2].C([N:27]1C(C2SC3N=CN=C(SC)C=3C=2)=C(C2C=CC=CC=2)N=C1)C>>[CH2:1]([N:3]1[C:7]([C:8]2[S:9][C:10]3[N:11]=[CH:12][N:13]=[C:14]([NH2:27])[C:15]=3[N:16]=2)=[C:6]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:5]=[CH:4]1)[CH3:2]
Reactant: CCn1cnc(-c2ccccc2)c1-c1cc2c(SC)ncnc2s1
Reactant: CCn1cnc(-c2ccccc2)c1-c1nc2c(SC)ncnc2s1
Product: CCn1cnc(-c2ccccc2)c1-c1nc2c(N)ncnc2s1

Procedure:
The title compound was prepared by a similar process to that described for Example 56 but using 2-(1-ethyl-4-phenyl-1H-imidazol-5-yl)-7-(methylthio)[1,3]thiazolo[5,4-d]pyrimidine (Intermediate 78) in place of 6-(1-ethyl-4-phenyl-1H-imidazol-5-yl)-4-(methylthio)thieno-[2,3-d]pyrimidine (Intermediate 70). Yellow solid (60 mg, 64%);
Reaction SMILES: C[Si](Br)(C)C.[F:6][CH:7]([P:17]([OH:20])(=[O:19])[OH:18])[CH2:8][CH:9]([O:15]C)[C:10]1[N:14]=[CH:13][NH:12][N:11]=1>ClCCl.CCOCC>[F:6][CH:7]([P:17]([OH:20])(=[O:18])[OH:19])[CH2:8][CH:9]([OH:15])[C:10]1[N:14]=[CH:13][NH:12][N:11]=1
Reactant: COC(CC(F)P(=O)(O)O)c1nc[nH]n1
Agent: C[Si](C)(C)Br
Solvent: ClCCl
Solvent: CCOCC
Product: O=P(O)(O)C(F)CC(O)c1nc[nH]n1

Procedure:
A solution of this material in dichloromethane was treated with trimethylsilyl bromide as described in Example 24 to give, after ion-exchange chromatography, 1-fluoro-3-methoxy-3(1,2,4-triazol-3-yl) propane phosphonic acid (Compound No. 46 in Table 1) also as a mixture of diastereoisomers in a ratio of 3:1 or 1:3. NMR(D2O): δ 2.15-2.4(2H,m); 3.25(3H,s); 4.4-4.8(1H,m); 4.85(1H,t); 8.9(1H,2 xs). FAB M/S: MH+ 240. More vigorous deprotection, for example in the presence of iodide ion, will result in ether cleavage to give 1-fluoro-3-hydroxy-3(1,2,4-triazol-3-yl)propane phosphonic acid (Compound No. 45 in Table 1), also as a mixture of diastereoisomers.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][O:4][C:3]2[CH:7]=[C:8]([C:11]([O:13][CH3:14])=[O:12])[CH:9]=[CH:10][C:2]1=2.[N+:15]([O-])([OH:17])=[O:16]>C(O)(=O)C>[N+:15]([C:9]1[C:8]([C:11]([O:13][CH3:14])=[O:12])=[CH:7][C:3]2[O:4][CH2:5][CH2:6][O:1][C:2]=2[CH:10]=1)([O-:17])=[O:16]
Reactant: O=[N+]([O-])O
Reactant: COC(=O)c1ccc2c(c1)OCCO2
Solvent: CC(=O)O
Product: COC(=O)c1cc2c(cc1[N+](=O)[O-])OCCO2
Temperature: 25 °C
Reaction time: 1 h
Yield: 92 %

Procedure:
To a solution of methyl 2,3-dihydrobenzo[b][1,4]dioxine-6-carboxylate (780 mg, 4.0 mmol) in acetic acid (3 mL) was added dropwise conc. HNO3 (4 mL) while keeping the temperature below 20° C. and the resulting reaction mixture was warmed to room temperature. After stirring for 1 hr, the mixture was poured onto ice-water with vigorous stirring. The resulting white precipitate was collected by vacuum filtration and dried under reduced pressure to yield methyl 7-nitro-2,3-dihydrobenzo[b][1,4]dioxine-6-carboxylate (889 mg, 92%). 1H NMR (DMSO-d6, 600 MHz) δ 7.64 (s, 1H), 7.30 (s, 1H), 4.41-4.38 (m, 4H), 3.80 (s, 3H); MS (ES+) m/z 240.0 (M+H)+
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([NH:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[CH:6]=[N:5][C:4]=1[C:19]1[CH:24]=[CH:23][C:22]([O:25][C:26]([F:29])([F:28])[F:27])=[CH:21][C:20]=1[O:30][CH3:31].[Br:32]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[Br:32][C:6]1[C:7]([NH:9][CH2:10][C:11]2[CH:12]=[CH:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=2)=[N:8][C:3]([O:2][CH3:1])=[C:4]([C:19]2[CH:24]=[CH:23][C:22]([O:25][C:26]([F:27])([F:29])[F:28])=[CH:21][C:20]=2[O:30][CH3:31])[N:5]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1ccc(CNc2cnc(-c3ccc(OC(F)(F)F)cc3OC)c(OC)n2)cc1
Solvent: ClC(Cl)Cl
Product: COc1ccc(CNc2nc(OC)c(-c3ccc(OC(F)(F)F)cc3OC)nc2Br)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.4 %

Procedure:
A solution of {6-methoxy-5-[2-methoxy-4-(trifluoromethoxy)phenyl]pyrazin-2yl}[(4-methoxyphenyl)methyl]amine (870 mg, 2.0 mmol) in chloroform (10 mL) is cooled to 0 C and N-bromosuccinimide (356 mg, 2.0 mmol) is added in portions. After the addition, the mixture is further stirred for 1 hour while being allowed to warm to room temperature. The mixture is washed with saturated aqueous sodium bicarbonate, aqueous sodium chloride, dried (magnesium sulfate), filtered, and evaporated to give {3-bromo-6-methoxy-5-[2methoxy-4-(trifluoromethoxy)phenyl]pyrazin-2-yl} [(4-methoxyphenyl)methyl]amine (920 mg), a yellow solid.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[C:11](=[O:20])[CH:10]2[CH2:21][CH2:22][CH:23]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[OH:24])=[CH:5][CH:4]=1.[OH:32][CH:33]([CH:47]([OH:54])[CH:48]([OH:53])[CH:49]([OH:52])[CH2:50][OH:51])[CH2:34][NH:35][CH2:36][C:37]1[CH:42]=[CH:41][C:40]([CH2:43][C:44](O)=[O:45])=[CH:39][CH:38]=1>>[F:19][C:16]1[CH:15]=[CH:14][C:13]([N:12]2[C:11](=[O:20])[CH:10]([CH2:21][CH2:22][CH:23]([C:25]3[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=3)[OH:24])[CH:9]2[C:6]2[CH:7]=[CH:8][C:3]([CH2:2][NH:1][C:44](=[O:45])[CH2:43][C:40]3[CH:39]=[CH:38][C:37]([CH2:36][NH:35][CH2:34][CH:33]([OH:32])[CH:47]([OH:54])[CH:48]([OH:53])[CH:49]([OH:52])[CH2:50][OH:51])=[CH:42][CH:41]=3)=[CH:4][CH:5]=2)=[CH:18][CH:17]=1
Reactant: O=C(O)Cc1ccc(CNCC(O)C(O)C(O)C(O)CO)cc1
Reactant: NCc1ccc(C2C(CCC(O)c3ccc(F)cc3)C(=O)N2c2ccc(F)cc2)cc1
Product: O=C(Cc1ccc(CNCC(O)C(O)C(O)C(O)CO)cc1)NCc1ccc(C2C(CCC(O)c3ccc(F)cc3)C(=O)N2c2ccc(F)cc2)cc1

Procedure:
The synthesis was carried out analogously to Example XVe), starting [lacuna]70 mg of 4-(4-aminomethylphenyl)-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-azetidin-2-one and 110 mg of {4-[(2,3,4,5,6-pentahydroxyhexylamino)-methyl]-phenyl}-acetic acid. This gave the product of molecular weight 733.82 (C40H45F2N3O8+); MS (ESI) 734.32 (M +H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([SH:9])=[CH:5][CH:4]=1.[CH2:10]([NH:13][OH:14])[CH2:11][CH3:12]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9][C:3]2[O:2][C:11]([CH:10]=[N+:13]([CH2:5][CH2:6][CH3:7])[O-:14])=[CH:12][CH:4]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(S)cc1
Reactant: CCCNO
Product: CCC[N+]([O-])=Cc1ccc(Sc2ccc(OC)cc2)o1

Procedure:
The title compound was prepared according to the procedure described in Example 1 using 4-methoxybenzenethiol and N-n-propylhydroxylamine. The title compound was isolated in 76.6% yield as slightly yellowish crystals, m.p. 63.0° C. (Rf=0.17 on a silica gel plate using hexanes/EtOAc, 2:1, v:v, as the eluant).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([NH2:9])=[C:4]([NH2:10])[CH:3]=1.O.[NH:12]1[C:20](=[O:21])[C:18](=O)[C:16](=O)[NH:15][C:13]1=[O:14].B(O)(O)O>C(O)(=O)C>[CH:3]1[C:2]([Cl:1])=[C:7]([Cl:8])[CH:6]=[C:5]2[N:9]=[C:16]3[NH:15][C:13](=[O:14])[NH:12][C:20](=[O:21])[C:18]3=[N:10][C:4]=12
Reactant: O=C1NC(=O)C(=O)C(=O)N1
Reactant: Nc1cc(Cl)c(Cl)cc1N
Agent: OB(O)O
Solvent: O
Solvent: CC(=O)O
Product: O=c1[nH]c(=O)c2nc3cc(Cl)c(Cl)cc3nc2[nH]1
Yield: 99.9 %

Procedure:
A solution of 10 g of 4,5-dichloro-o-phenylenediamine, 9 g of alloxan hydrate, 1.5 g of boric acid and 250 ml of glacial acetic acid was stirred overnight at room temperature to obtain a brown-black solution which was filtered. The yellow-buff crystalline solid was well washed with water to obtain 15.9 g of 7,8-dichloro-alloxazine melting at >370° C. A solution of 2 g of 7,8-dichloro-alloxazine in 10 ml of concentrated sulfuric acid was slowly heated to 240° C. and held there for 10 minutes. The mixture was cooled and poured onto ice and the mixture was made alkaline with sodium hydroxide addition. The mixture was extracted several times with ether to obtain 0.73 g of 2-amino-6,7-dichloro-quinoxaline as an orange crystalline solid melting at 220° C.