Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)=[CH:13][S:14][CH:15]=2)=[CH:7][CH:6]=1)(=O)=O.[CH3:23]C1C=C(F)C=CC=1B(O)O>C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+].C(O)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:1][S:2][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=3[CH3:23])=[CH:13][S:14][CH:15]=2)=[CH:7][CH:6]=1
Reactant: Cc1cc(F)ccc1B(O)O
Reactant: CS(=O)(=O)c1ccc(-c2cscc2-c2ccc(F)cc2)cc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CSc1ccc(-c2cscc2-c2ccc(F)cc2C)cc1
Yield: 74.2 %

Procedure:
The mono-substituted thiophene from Example 14 (1.8 mmol, 520 mg) was combined with the 2-methyl-4-fluorophenyl boronic acid (2 eq, 3.6 mmol, 562 mg) in 8.0 ml of toluene, 4.3 ml of 2 M sodium carbonate, 10 ml of ethanol and tetrakis(triphenylphosphine)-palladium(0) (1.0 g) and was stirred at reflux overnight. The reaction was concentrated in vacuo and the residue was partitioned between toluene and water. The toluene layer was dried (MgSO4) and reconcentrated in vacuo. The residue was purified via silica chromatography (Waters, LC-2000) in 97% hexane/ethyl acetate to give 3-(4-methylthiophenyl)-4-(2-methyl-4-fluorophenyl)thiophene (420 mg) as a semi-solid. NMR (CDCl3) δ1.90(s, 3H), 2.43(s, 3H), 6.8-6.9(m, 2H), 7.05(q, J=8 Hz, 4H), 7.12-7.18(m, 2H), 7.33(d, J=2 Hz, 1H).
Reaction SMILES: [CH:1]1([N:7]2[CH2:13][CH2:12][C:11](O[Si](C)(C)C)=[C:10](O[Si](C)(C)C)[CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Br.Br.[NH2:26][CH2:27][C:28]([NH2:30])=[NH:29]>>[NH2:30][C:28]1[CH:27]=[N:26][C:11]2[CH2:12][CH2:13][N:7]([CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[CH2:8][CH2:9][C:10]=2[N:29]=1
Reactant: C[Si](C)(C)OC1=C(O[Si](C)(C)C)CCN(C2CCCCC2)CC1
Reactant: N=C(N)CN
Agent: Br
Product: Nc1cnc2c(n1)CCN(C1CCCCC1)CC2

Procedure:
This compound was prepared analogous to Example 1 from 1-cyclohexyl-2,3,6,7-tetrahydro-4,5-bis(trimethylsilyloxy)azepine and 2-amino-acetamidine dihydrobromide.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[C:11]([O:15][C:16](=[O:22])[NH:17][CH2:18][CH2:19][CH2:20][NH2:21])([CH3:14])([CH3:13])[CH3:12].C(=O)([O-])[O-].[K+].[K+].C(#N)C>O.C(OCC)(=O)C>[N+:8]([C:7]1[C:2]([NH:21][CH2:20][CH2:19][CH2:18][NH:17][C:16](=[O:22])[O:15][C:11]([CH3:13])([CH3:12])[CH3:14])=[N:3][CH:4]=[CH:5][CH:6]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: CC(C)(C)OC(=O)NCCCN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC(C)(C)OC(=O)NCCCNc1ncccc1[N+](=O)[O-]
Reaction time: 4 h
Yield: 108.2 %

Procedure:
To 2-chloro-3-nitropyridine (92 mg), tert-butyl(3-aminopropyl)carbamate (102 mg) and potassium carbonate (161 mg), acetonitrile (1.2 mL) was added at room temperature, and the mixture was stirred at the same temperature for 4 hours. To the reaction mixture, ethyl acetate and water were added. The organic layer was separated, washed with saturated aqueous sodium chloride, and then 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 to 0% hexane in ethyl acetate) to obtain tert-butyl (3-((3-nitropyridin-2-yl)amino)propyl)carbamate (C42, 186 mg).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH:11]1[N:16]2[C:17](=[O:26])[N:18]([CH:23]([CH3:25])[CH3:24])[C:19](=[O:22])[C:20]([OH:21])=[C:15]2[C:14](=[O:27])[N:13]([CH2:28][C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)[CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[CH3:45][C:46]([CH3:51])([CH3:50])[C:47](Cl)=[O:48].CO>ClCCl>[C:47]([O:21][C:20]1[C:19](=[O:22])[N:18]([CH:23]([CH3:25])[CH3:24])[C:17](=[O:26])[N:16]2[CH:11]([CH2:10][CH2:9][O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:12][N:13]([CH2:28][C:29]3[CH:30]=[CH:31][C:32]([F:35])=[CH:33][CH:34]=3)[C:14](=[O:27])[C:15]=12)(=[O:48])[C:46]([CH3:51])([CH3:50])[CH3:45]
Reactant: CC(C)(C)C(=O)Cl
Reactant: CC(C)n1c(=O)c(O)c2n(c1=O)C(CCOCc1ccccc1)CN(Cc1ccc(F)cc1)C2=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: CC(C)n1c(=O)c(OC(=O)C(C)(C)C)c2n(c1=O)C(CCOCc1ccccc1)CN(Cc1ccc(F)cc1)C2=O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 4-[2-(benzyloxy)ethyl]-2-(4-fluorobenzyl)-9-hydroxy-7-isopropyl-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,6,8(7H)-trione (Example 9, Step 6, 1.18 g, 2.46 mmol) in anhydrous dichloromethane (20 mL) at 0° C. were added diisopropylethylamine (856 μL, 4.91 mmol), trimethylacetyl chloride (454 μL, 3.69 mmol), and N,N-dimethylaminopyridine (60 mg, 0.49 mmol). The mixture was stirred at ambient temperature under inert atmosphere for 1.5 h. Addition of methanol resulted in the precipitation of the title compound as a white solid. 1H NMR (CDCl3, 400 MHz): δ 7.39-7.26 (m, 5 H), 7.07-7.03 (m, 2 H), 6.97-6.93 (m, 2 H), 5.18-5.12 (m, 1 H), 4.79 (m, 1 ), 4.64-4.58 (m, 1 H), 4.47-4.34 (m, 3 H), 3.66-3.54 (m, 1 H), 3.45-3.27 (m, 3 H), 1.88 (m, 1 H), 1.77-1.72 (m, 1 H), 1.46-1.44 (m, 6 H), 1.40 (s, 9 H). ES MS (M+1)=566.7.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5](F)=[C:6]([CH:9]=1)[C:7]#[N:8].C([O-])([O-])=O.[K+].[K+].[CH3:17][N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1>CS(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:21]2[CH2:22][CH2:23][N:18]([CH3:17])[CH2:19][CH2:20]2)=[C:6]([CH:9]=1)[C:7]#[N:8]
Reactant: CN1CCNCC1
Reactant: N#Cc1cc(Cl)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CN1CCN(c2ccc(Cl)cc2C#N)CC1
Temperature: 100 °C
Reaction time: 6 h
Yield: 87.2 %

Procedure:
A mixture of 5-chloro-2-fluoro-benzonitrile (500 mg, 3.21 mmol), K2CO3 (1.32 g, 9.64 mmol) and 1-methyl-piperazine (482 mg, 4.81 mmol) in DMSO (6.4 ml) was stirred at 100° C. for 6 h and then partitioned between water and Et2O. The organic phase was dried over Na2SO4 and evaporated in vacuo. The crude mixture was purified by column chromatography (eluent: DCM/MeOH/NH4OH 98:2:0.1) to give 660 mg of 5-chloro-2-(4-methyl-piperazin-1-yl)-benzonitrile.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:12]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)=[N:13]O)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.C([O-])(=O)C.[NH4+]>CCO.[NH4+].[OH-].[Zn]>[F:1][C:2]1[CH:3]=[C:4]([CH:12]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[NH2:13])[CH:5]=[C:6]([C:8]([F:10])([F:11])[F:9])[CH:7]=1
Reactant: ON=C(c1ccc(F)cc1)c1cc(F)cc(C(F)(F)F)c1
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [OH-]
Solvent: CCO
Product: NC(c1ccc(F)cc1)c1cc(F)cc(C(F)(F)F)c1
Temperature: 25 °C
Yield: 93.3 %

Procedure:
To a suspension of (3-fluoro-5-(trifluoromethyl)phenyl)(4-fluorophenyl)methanone oxime (904 mg, 3.0 mmol) in EtOH (3 mL) and conc. NH4OH (15 mL) was added ammonium acetate (120 mg, 1.6 mmol) followed by zinc powder (1.05 g, 16.2 mmol) and the reaction mixture was heated at reflux for 2 h. The reaction mixture was allowed to cool to rt then filtered. The filtered solid was washed with 10 N NaOH (15 mL) and EtOAc (15 mL). The combined filtrate was extracted with EtOAc (2×30 mL). The combined organic fractions were washed with sat. NaCl (2×10 mL) then dried over MgSO4, filtered and concentrated under reduced pressure to yield (3-fluoro-5-(trifluoromethyl)phenyl)(4-fluorophenyl)methanamine (804 mg, 93% yield) as a clear, colorless oil. LCMS: RT=0.96 min [M-NH2]271.0 (2 min Phenomenex Luna C18 column, 4.6×30 mm eluting with 10-90% acetonitrile/H2O over 2 minutes containing 0.1% TFA; 5 mL/min, monitoring at 220 nm); NMR: 400 MHz 1H (CDCl3) δ ppm 1.68 (bs, 2H), 5.25 (s, 1H), 7.03 (t, J=8.57 Hz, 2H), 7.19 (d, J=7.91 Hz, 1H), 7.29-7.35 (m, 3H), 7.48 (s, 1H).
Reaction SMILES: Cl.Cl.[Br:3][C:4]1[C:9]2[N:10]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:11]([C@@H:13]([NH2:15])[CH3:14])=[N:12][C:8]=2[CH:7]=[CH:6][CH:5]=1.Cl[C:23]1[N:31]=[CH:30][N:29]=[C:28]2[C:24]=1[N:25]=[CH:26][N:27]2[CH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][O:33]1.CCN(C(C)C)C(C)C>CC(O)C>[Br:3][C:4]1[C:9]2[N:10]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:11]([C@@H:13]([NH:15][C:23]3[N:31]=[CH:30][N:29]=[C:28]4[C:24]=3[N:25]=[CH:26][N:27]4[CH:32]3[CH2:37][CH2:36][CH2:35][CH2:34][O:33]3)[CH3:14])=[N:12][C:8]=2[CH:7]=[CH:6][CH:5]=1
Reactant: C[C@H](N)c1nc2cccc(Br)c2n1-c1ccccc1
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Agent: Cl
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Nc1ncnc2c1ncn2C1CCCCO1)c1nc2cccc(Br)c2n1-c1ccccc1
Yield: 67.1 %

Procedure:
(S)-1-(7-Bromo-1-phenyl-1H-benzoimidazol-2-yl)ethylamine dihydrochloride (1 g, 2.5 mmol), 6-chloro-9-(tetrahydropyran-2-yl)-9H-purine (0.736 g, 3.1 mmol) and DIPEA (2.26 mL, 13 mmol) in IPA (4 mL) were heated in a sealed tube for 4 h. The cooled reaction mixture was concentrated in vacuo; the residue dissolved in EtOAc and the resulting solution washed with water, brine, dried (Na2SO4) and concentrated in vacuo. The residue was purified on silica (Si—PCC, 0-10% MeOH in DCM) to give the product as a white solid (870 mg, 67%). LCMS (Method B): RT 3.48 min; m/z [M+H]+ 518/520
Reaction SMILES: C[O:2][C:3]([C:5]12[CH2:12][CH2:11][C:8]([C:13]3[NH:21][C:20]4[C:19](=[O:22])[N:18]([CH2:23][CH2:24][CH3:25])[C:17](=[O:26])[N:16]([CH2:27][CH2:28][CH3:29])[C:15]=4[N:14]=3)([CH2:9][CH2:10]1)[CH2:7][CH2:6]2)=[O:4].O.C1(C)C=CC=CC=1>[OH-].[K+]>[O:26]=[C:17]1[N:16]([CH2:27][CH2:28][CH3:29])[C:15]2[N:14]=[C:13]([C:8]34[CH2:11][CH2:12][C:5]([C:3]([OH:4])=[O:2])([CH2:10][CH2:9]3)[CH2:6][CH2:7]4)[NH:21][C:20]=2[C:19](=[O:22])[N:18]1[CH2:23][CH2:24][CH3:25]
Reactant: CCCn1c(=O)c2[nH]c(C34CCC(C(=O)OC)(CC3)CC4)nc2n(CCC)c1=O
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: CCCn1c(=O)c2[nH]c(C34CCC(C(=O)O)(CC3)CC4)nc2n(CCC)c1=O
Temperature: 17.5 °C
Reaction time: 0.17 h

Procedure:
4-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]octane-1-carboxylic acid methyl ester (VIII, Example 84a) in the potassium hydroxide environment is heated at reflux for 2 to 3 hr until complete as measured by NMR. The mixture is then cooled to 10 to 25° C. Water (11.16 vol) is added followed by toluene (1.25 vol) and the contents are stirred vigorously for 5 to 15 minutes. The layers are separated. Toluene (1.25 vol) is added to the aqueous layer and the mixture is stirred vigorously for a 5 to 15 minutes. The layers are separated. Toluene (1.25 vol) is added to the aqueous layer, stirred vigorously for 5 to 15 minutes and the layers are separated. The aqueous phase is then cooled to between 0 and 10° C. and acidified with concentrated hydrochloric acid. (0.74 vol), maintaining the temperature below 10° C. The mixture is stirred at between 0 and 10° C. for 60 to 90 minutes. The solid is collected by filtration and dried under reduced pressure to give the title compound.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:14][CH2:13][CH:12]([OH:15])[CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].Cl[C:17]1[C:22]([NH2:23])=[CH:21][N:20]=[CH:19][N:18]=1>O1CCCC1>[NH2:23][C:22]1[C:17]([O:15][CH:12]2[CH2:13][CH2:14][N:10]([C:8]([O:7][C:3]([CH3:6])([CH3:4])[CH3:5])=[O:9])[CH2:11]2)=[N:18][CH:19]=[N:20][CH:21]=1
Reactant: Nc1cncnc1Cl
Reactant: CC(C)(C)OC(=O)N1CCC(O)C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2ncncc2N)C1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
At room temperature, NaH (71 mg, 2.94 mmol) was added to a solution of tert-butyl-3-hydroxypyrrolidine-1-carboxylate (1B2) (500 mg, 2.67 mmol) in THF (tetrahydrofuran) (10 mL) and stirred for 1 hour. 4-chloropyrimidin-5-amine (H) (348 mg, 2.67 mmol) was then added. The reaction mixture was then heated to 100° C. under nitrogen and stirred for 4 hours, cooled to room temperature (20-30° C.) and concentrated in vacuo. The residue was purified with flash column (eluent: 10-30% ethyl acetate/petroleum ether) to obtain the product 1D3 (336 mg, 1.2 mmol).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:18][CH:17]2[CH:12]([CH2:13][CH2:14][CH2:15][CH2:16]2)[CH2:11][CH:10]1[OH:19])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.C(O)(=O)C>C(Cl)Cl>[C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:18][CH:17]2[CH:12]([CH2:13][CH2:14][CH2:15][CH2:16]2)[CH2:11][C:10]1=[O:19])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1CC2CCCCC2CC1O
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1CC2CCCCC2CC1=O
Temperature: 25 °C
Reaction time: 0.83 h

Procedure:
Under argon to a solution of 3-tert-butoxycarbonylaminodecahydro-2-naphthalenol (0.27 g) in methylene chloride (5 ml) was added pyridinium dichromate (572 mg), molecular sieves 3A powder (791 mg) and acetic acid (100 μl). The reaction mixture was stirred for 50 minutes at room temperature. The black mixture was filtered through a silica gel column (60 g, elution with ethyl acetate:cyclohexane, 1:4) to give, after evaporation of solvents, the title compound as a viscous oil (165 mg).
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].[CH3:7][O:8][CH2:9][CH2:10][O:11][CH2:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=1>CO>[C:17]([C:16]1[CH:19]=[CH:20][C:13]([CH2:12][O:11][CH2:10][CH2:9][O:8][CH3:7])=[CH:14][CH:15]=1)#[CH:1]
Reactant: COCCOCc1ccc(C=O)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#Cc1ccc(COCCOC)cc1
Reaction time: 16 h
Yield: 67.2 %

Procedure:
Dimethyl[(2-diazo-3-oxo)propyl] phosphonate was added in 4 portions to a suspension of potassium carbonate (4.96 g, 36 mmol), the product of Step B (3.78 g, 18 mmol), and methanol (50 mL). The reaction was stirred for 16 hours. and concentrated in vacuo. The residue was taken up in ether, washed with water (3×), dried (potassium carbonate), and concentrated. The crude product was purified by silica gel chromatography (hexane:ethyl acetate) to provide the title compound (2.3 g).
Reaction SMILES: [CH3:1][N:2]([CH2:10][CH2:11][CH:12]1[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]1)[C:3]([C:5]1[N:6]=[N:7][NH:8][CH:9]=1)=[O:4].Cl.O1CCOCC1>CCOC(C)=O>[CH3:1][N:2]([CH2:10][CH2:11][CH:12]1[CH2:13][CH2:14][NH:15][CH2:16][CH2:17]1)[C:3]([C:5]1[N:6]=[N:7][NH:8][CH:9]=1)=[O:4]
Reactant: CN(CCC1CCN(C(=O)OC(C)(C)C)CC1)C(=O)c1c[nH]nn1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CN(CCC1CCNCC1)C(=O)c1c[nH]nn1
Reaction time: 0.5 h

Procedure:
To tert-butyl 4-(2-(N-methyl-1H-1,2,3-triazole-4-carboxamido)ethyl)piperidine-1-carboxylate (step 2) (190 mg, 0.563 mmol) in EtOAc (5 ml) was added 4N HCl in dioxane (5 ml, 20.00 mmol). The mixture was stirred for 30 mins and concentrated under reduced pressure to give crude N-methyl-N-(2-(piperidin-4-yl)ethyl)-1H-1,2,3-triazole-4-carboxamide as a gum. This was used in the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[O:8][CH2:9][CH2:10][O:11][C:6]=2[C:5]([C:12]([O:14][CH2:15][CH:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)=[O:13])=[CH:4][C:3]=1[Cl:22].[C:23](#[N:26])[CH:24]=[CH2:25]>CC(C)=O>[NH2:1][C:2]1[C:7]2[O:8][CH2:9][CH2:10][O:11][C:6]=2[C:5]([C:12]([O:14][CH2:15][CH:16]2[CH2:17][CH2:18][N:19]([CH2:25][CH2:24][C:23]#[N:26])[CH2:20][CH2:21]2)=[O:13])=[CH:4][C:3]=1[Cl:22]
Reactant: C=CC#N
Reactant: Nc1c(Cl)cc(C(=O)OCC2CCNCC2)c2c1OCCO2
Solvent: CC(C)=O
Product: N#CCCN1CCC(COC(=O)c2cc(Cl)c(N)c3c2OCCO3)CC1
Yield: 16.8 %

Procedure:
4-Piperidinylmethyl 8-amino-7-chloro-1,4-benzodioxan-5-carboxylate (0.180 g, 0.55 mmol) was dissolved in acetone (10 ml) and treated with acrylonitrile (0.040 ml; 0.61 mmol). The solution was heated at reflux (18 hours), cooled and evaporated in vacuo to an orange gum. The gum was purified by flash silica-gel chromatography with CHCl3 →2% MeOH/CHCl3 as eluant to yield the title compound as a colourless oil (0.035g; 17%) which was converted to the oxalate salt, mp 101°-103° C.
Reaction SMILES: O1CCCCC1[O:7][CH2:8][CH:9]1[CH2:14][CH2:13][C:12]2[CH:15]=[C:16]([NH:19][C:20](=[O:22])[CH3:21])[CH:17]=[CH:18][C:11]=2[O:10]1.CO.Cl>O>[OH:7][CH2:8][CH:9]1[CH2:14][CH2:13][C:12]2[CH:15]=[C:16]([NH:19][C:20](=[O:22])[CH3:21])[CH:17]=[CH:18][C:11]=2[O:10]1
Reactant: CC(=O)Nc1ccc2c(c1)CCC(COC1CCCCO1)O2
Agent: Cl
Solvent: CO
Solvent: O
Product: CC(=O)Nc1ccc2c(c1)CCC(CO)O2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74 %

Procedure:
To a stirred solution of 27 parts of N-[3,4-dihydro-2-[[(tetrahydro-2H-pyran-2-yl)oxy]methyl]-2H-1-benzopyran-6-yl]-acetamide in 240 parts of methanol were added 100 parts of a hydrochloric acid solution 10% in water. The whole was stirred for 30 minutes at room temperature. The reaction mixture was evaporated till all traces of methanol were removed. After cooling, the product was filtered off from the aqueous phase, washed with water and crystallized from acetonitrile. The product was filtered off and dried, yielding 14.4 parts (74%) of N-[3,4-dihydro-2-(hydroxymethyl)-2H-1-benzopyran-6-yl]acetamide; mp. 156.5° C. (intermediate 12).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][NH:4][C:5]([NH:7][C@@H:8]1[O:16][C@H:15]([CH2:17][OH:18])[C@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6].[N:19]([O-])=[O:20].[Na+].C(OCC)C>C(O)=O>[Cl:1][CH2:2][CH2:3][N:4]([N:19]=[O:20])[C:5]([NH:7][C@@H:8]1[O:16][C@H:15]([CH2:17][OH:18])[C@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6]
Reactant: O=N[O-]
Reactant: O=C(NCCCl)N[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O
Agent: [Na+]
Solvent: CCOCC
Solvent: O=CO
Product: O=NN(CCCl)C(=O)N[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O

Procedure:
To a solution of 300 mg of 1-(2-chloroethyl)-3-(β-D-galactopyranosyl)urea in 2 ml of 99% formic acid was slowly added 150 mg of sodium nitrite in an icebath under stirring. The mixture was stirred for 1 hour under ice-cooling to complete the nitrosation. The reaction mixture was admixed with 50 ml of ethyl ether to deposit an oily substance. The ethyl ether phase was separated from the oily substance by decantation. The operation of adding ethyl ether to and separating the ethyl ether phase from the oily substance by decantation was repeated three times, using 50 ml, 20 ml and 20 ml of the ether, respectively. Thereafter, the oily substance was taken up into 30 ml of methyl alcohol, and the resultant solution was admixed with 3 ml of Amberlite IR-120 (H+ form). The admixture was filtered to remove cation-exchange resin, and the filtrate was concentrated under a reduced pressure, depositing crystals of the titled compound. Yield 210 mg (63.6%). mp. 145° C. (decomposition with foaming). [α]D21.0 +13.0° (c 0.5, H2O).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:15])[CH:9]([CH3:14])[CH2:10][C:11]([OH:13])=[O:12])=[CH:4][C:3]=1[N+:16]([O-:18])=[O:17].[CH2:19]([NH2:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(O)C>[CH2:19]([NH:26][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:15])[CH:9]([CH3:14])[CH2:10][C:11]([OH:13])=[O:12])=[CH:4][C:3]=1[N+:16]([O-:18])=[O:17])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: NCc1ccccc1
Reactant: CC(CC(=O)O)C(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Solvent: CCO
Product: CC(CC(=O)O)C(=O)c1ccc(NCc2ccccc2)c([N+](=O)[O-])c1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
4-(4-Chloro-3-nitro-phenyl)-3-methyl-4-oxo-butyric acid E-4.1′″ (800 mg; 2.95 mmol) is placed in 8 ml ethanol and heated up to 50° C. to get solved. Benzylamine (1.61 ml; 14.73 mmol) is added and the reaction mixture stirred for 3 hours at 100° C. The crude product is purified by using reversed phase chromatography
Reaction SMILES: [CH2:1]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1I)[CH:2]=[CH2:3].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>CC#N.CCN(CC)CC.CCOCC.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH2:3]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][O:4][CH2:1]1
Reactant: C=CCOCc1ccccc1I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: C=C1COCc2ccccc21
Temperature: 80 °C

Procedure:
1-[(allyloxy)methyl]-2-iodobenzene (23 g, 83.9 mmol) was dissolved in 100 ml of CH3CN and 58 ml of Et3N. The solution was vacuum degassed (3 cycles) followed by the addition of Pd(OAc)2 (0.9 g, 4.2 mmol) and PPh3 (2.2 g, 8.4 mmol). The mixture was heated to 80° C. until HPLC indicated complete reaction. The mixture was cooled to room temperature and diluted with Et2O (200 ml). The mixture was washed with 1N HCl (2×50 ml); NaHCO3 (2×50 ml); brine (1×50 ml); dried over Na2SO4 and concentrated in vacuo to yield 4-methylene-3,4-dihydro-1H-isochromene (Heterocycles 1994, 39, 497) as an oil. HRMS (ESI+) calcd for C10H10O m/z 146.0732 (M+H)+. Found 146.0728. The crude oil was dissolved in 1:1 CH3OH/CH2Cl2 (500 ml) and 5 ml of pyridine added. The mixture was chilled to −78° C. and ozone was bubbled through the mixture for 1 h, at which time TLC indicated complete reaction. The mixture was purged with N2 at −78° C. and treated with Me2S, then allowed to warm to room temperature and stir for 3 h. The reaction was then diluted with CH2Cl2 and washed with H2O and brine. The organic layer was dried over Na2SO4 and concentrated in vacuo to yield 5.1 g of 1H-isochromen-4(3H)-one as a slight yellow oil after flash chromatography (10% EtOAc/Hexanes) Rf=0.25. 1H NMR (400 MHz, CDCl3) δ 8.05 (d, J=7.88 Hz, 1H), 7.59 (m, 1H), 7.43 (appt, J=7.36 Hz, 1H), 7.24 (d, J=7.67 Hz, 1H), 4.91 (s, 2H), 4.39 (s, 2H. Anal calcd for C9H8O2; C, 72.96; H, 5.44; found C, 72.50; H, 5.29. MS (ESI+) for C9H8O2 m/z 148.8 (M+H)+.
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: CCOCC
Solvent: ClCCl
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): δ2.15-2.4(2H,m); 3.25(3H,s); 4.4-4.8(1H,m); 4.85(1H,t); 8.9(1H,2xs). 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. Biological Data
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:11][CH2:10][C:9]2[C:4](=[C:5]([N:12]3[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]3)[CH:6]=[CH:7][CH:8]=2)[CH2:3]1.C(N(CC)CC)C.[C:26]1([CH2:32][CH2:33][C:34](Cl)=[O:35])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C(Cl)Cl>[CH3:18][N:15]1[CH2:16][CH2:17][N:12]([C:5]2[CH:6]=[CH:7][CH:8]=[C:9]3[C:4]=2[CH2:3][C@H:2]([NH:1][C:34](=[O:35])[CH2:33][CH2:32][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:11][CH2:10]3)[CH2:13][CH2:14]1
Reactant: O=C(Cl)CCc1ccccc1
Reactant: CN1CCN(c2cccc3c2C[C@H](N)CC3)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN1CCN(c2cccc3c2C[C@H](NC(=O)CCc2ccccc2)CC3)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To an ice-cooled solution of (R)-2-amino-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalene (99 mg, 0.40 mmol) and triethylamine (83 μL, 0.42 mmol) in methylene chloride (20 mL) was added dropwise 3-phenylpropionyl chloride (72 mg, 0.42 mmol) in methylene chloride (5 mL). After the addition, the reaction was allowed to stir at ambient temperature for 15 min and then washed with water. The phases were separated and the organic phase was dried (Na2SO4), filtered and evaporated in vacuo to give a crude product which was purified on a silica gel column using chloroform/ethanol saturated with NH3 (100:4) as the eluent. Yield: 120 mg (61%) of the title compound as white crystals: mp 184-186° C.; [α]21D +6.5° (c 1.0, chloroform); EIMS (70 eV) m/z (relative intensity) 374 (54, M+).