Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[C:3]([CH2:5]P(=O)(OCC)OCC)#[N:4].[CH2:14]([N:18]([CH2:40][CH2:41][CH2:42][CH3:43])[C:19]1[CH:24]=[CH:23][C:22]([CH:25]=[CH:26][C:27]2[CH2:32][C:31]([CH3:34])([CH3:33])[CH2:30][C:29](=O)[C:28]=2[O:36][CH3:37])=[C:21]([O:38][CH3:39])[CH:20]=1)[CH2:15][CH2:16][CH3:17].O>O1CCCC1.C(OCC)(=O)C>[CH2:14]([N:18]([CH2:40][CH2:41][CH2:42][CH3:43])[C:19]1[CH:24]=[CH:23][C:22]([CH:25]=[CH:26][C:27]2[CH2:32][C:31]([CH3:34])([CH3:33])[CH2:30][C:29](=[CH:5][C:3]#[N:4])[C:28]=2[O:36][CH3:37])=[C:21]([O:38][CH3:39])[CH:20]=1)[CH2:15][CH2:16][CH3:17]
Reactant: CCOP(=O)(CC#N)OCC
Reactant: CCCCN(CCCC)c1ccc(C=CC2=C(OC)C(=O)CC(C)(C)C2)c(OC)c1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CCCCN(CCCC)c1ccc(C=CC2=C(OC)C(=CC#N)CC(C)(C)C2)c(OC)c1
Temperature: 60 °C
Reaction time: 24 h
Yield: 52.9 %

Procedure:
To 0.18 g (7.5 mmol) of sodium hydride, 12 ml of tetrahydrofuran was added. To this mixture, 0.98 g (5.5 mmol) of diethyl cyanomethylphosphonate was added dropwise under ice cooling. To the mixture, 0.915 g (2.2 mmol) of 3-[2-(4-dibutylamino-2-methoxyphenyl)vinyl]-2-methoxy-5,5-dimethyl-2-cyclohexenone in tetrahydrofuran was added dropwise. After the mixture was stirred at 60° C. for 24 hours, water was added to the mixture and extraction with ethyl acetate was performed. The extract was washed with a saturated saline solution, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography to give 0.51 g of an orange oily matter (yield: 52.9%).
Reaction SMILES: [OH:1][C:2]([C:4](F)(F)F)=O.[NH2:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]2[S:22](=[O:24])(=[O:23])[N:21]([CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[C:20](=[O:31])[CH2:19]2)=[C:14]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:13]=1.C(N(C(C)C)CC)(C)C.C(Cl)(=O)C>C(Cl)Cl>[CH2:33]([O:32][C:14]1[CH:13]=[C:12]([CH2:11][CH2:10][CH2:9][NH:8][C:2](=[O:1])[CH3:4])[CH:17]=[CH:16][C:15]=1[N:18]1[CH2:19][C:20](=[O:31])[N:21]([CH2:25][CH2:26][Si:27]([CH3:28])([CH3:29])[CH3:30])[S:22]1(=[O:24])=[O:23])[C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: O=C(O)C(F)(F)F
Reactant: C[Si](C)(C)CCN1C(=O)CN(c2ccc(CCCN)cc2OCc2ccccc2)S1(=O)=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)Cl
Product: CC(=O)NCCCc1ccc(N2CC(=O)N(CC[Si](C)(C)C)S2(=O)=O)c(OCc2ccccc2)c1

Procedure:
To a solution of 5-[4-(3-aminopropyl)-2-benzyloxyphenyl]-1,1-dioxo-2-(2-trimethylsilanylethyl)-1,2,5-thiadiazolidin-3-one TFA salt (124 mg, 0.26 mmol) in methylene chloride (5 mL) is added diisopropylethylamine (0.1 mg, 0.781 mmol) then acetyl chloride (21 mg, 0.267 mmol) and the mixture is stirred at RT for 18 h. The solvent is removed under reduced pressure and 1 N HCl is added. The mixture is extracted with ether and the organic phase is dried over magnesium sulfate. The solvent is removed under reduced pressure and the residue is purified by flash chromatography using a gradient of 10-50% EtOAc/hexane as eluent to give the title compound.
Reaction SMILES: [CH3:1][C:2]([Si:5]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[O:6][CH2:7][C:8]1[N:12]([CH3:13])[N:11]=[N:10][C:9]=1[CH2:14][OH:15])([CH3:4])[CH3:3].Cl[C:29]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:32]2=[N:39][N:40]=[C:41]([C:42]3[CH:46]=[C:45]([CH3:47])[O:44][N:43]=3)[N:31]2[N:30]=1>>[CH3:4][C:2]([Si:5]([O:6][CH2:7][C:8]1[N:12]([CH3:13])[N:11]=[N:10][C:9]=1[CH2:14][O:15][C:29]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:32]2=[N:39][N:40]=[C:41]([C:42]3[CH:46]=[C:45]([CH3:47])[O:44][N:43]=3)[N:31]2[N:30]=1)([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([CH3:1])[CH3:3]
Reactant: Cc1cc(-c2nnc3c4ccccc4c(Cl)nn23)no1
Reactant: Cn1nnc(CO)c1CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Product: Cc1cc(-c2nnc3c4ccccc4c(OCc4nnn(C)c4CO[Si](c4ccccc4)(c4ccccc4)C(C)(C)C)nn23)no1
Yield: 95.9 %

Procedure:
The reaction was carried out according to Example 1 step 4 using [5-({[(1,1-dimethylethyl)(diphenyl)silyl]oxy}methyl)-1-methyl-1H-[1,2,3]triazol-4-yl]methanol (1.20 g, 3.14 mmol) and 6-chloro-3-(5-methylisoxazol-3-yl)-[1,2,4]triazolo[3,4-α]phthalazine (0.90 mg, 3.14 mmol). The crude residue was purified by column chromatography on silica using 1-2% MeOH/CH2Cl2 containing 1% NH3 to yield the desired phthalazine (1.90 g, 96%). 1H NMR (360 MHz, CDCl3) δ 8.68 (1H, d, J=7.9 Hz), 7.99 (1H, d, J=7.9 Hz), 7.91 (1H, t, J=7.9 Hz), 7.69 (1H, t, J=7.9 Hz), 7.55 (4H, d, J=7.9 Hz), 7.34-7.18 (6H, m), 6.90 (1H, s), 5.43 (2H, s), 4.90 (2H, s), 4.10 (3H, s), 2.58 (3H, s), 0.99 (9H, s). m/z (ES+) 632 (M+2H+).
Reaction SMILES: [NH:1]1[CH:9]=[C:7]([CH3:8])[C:5](=[O:6])[NH:4][C:2]1=[O:3].[C:10]([O:14][CH2:15]C)(=[O:13])[CH:11]=[CH2:12].[OH-].[Na+]>CO>[CH3:15][O:14][C:10](=[O:13])[CH2:11][CH2:12][N:1]1[CH:9]=[C:7]([CH3:8])[C:5](=[O:6])[NH:4][C:2]1=[O:3]
Reactant: Cc1c[nH]c(=O)[nH]c1=O
Reactant: C=CC(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COC(=O)CCn1cc(C)c(=O)[nH]c1=O

Procedure:
Thymine (14.0 g, 0.11 mol) was suspended in methanol. ethyl acrylate (39.6 ml, 0.44 mol) was added, along with catalytic amounts of sodium hydroxide. The solution was refluxed in the dark for 45 h, evaporated to dryness, in vacuo, and the residue dissolved in methanol (8 ml) with heating. After cooling on an ice bath, the product was precipitated by addition of ether (20 ml), isolated by filtration, washed with ether (3×15 ml), and dried over sicapent, in vacuo. Yield 11.23 g (48%). M.p. 112–119° C. Anal. for C9H12N2O4. found (calc.) C, 51.14 (50.94); H, 5.78 (5.70); N, 11.52 (13.20). The compound showed satisfactory 1H and 13C-NMR spectra.
Reaction SMILES: [CH2:1]([OH:18])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].[NH2:19][C:20](N)=[O:21]>[Ni]>[C:20](=[O:21])([O:18][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[NH2:19]
Reactant: CCCCCCCCCCCCCCCCCO
Reactant: NC(N)=O
Agent: [Ni]
Product: CCCCCCCCCCCCCCCCCOC(N)=O
Yield: 94 %

Procedure:
A mixture of 256 parts of heptadecyl alcohol, 60 parts of urea and 5 parts of a cation exchanger which is commercially available under the registered name Amberlite 200 and, having been treated in accordance with Example 1, contains nickel, is heated in a stirred vessel to 140°-145° C., whilst stirring. After filtering off the exchanger whilst the reaction solution is hot, 280 parts of heptadecyl carbamate are obtained. This corresponds to a yield of 94% of theory. The product has a melting point of 53°-54° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=2)[N:3]=1>CC(O)C>[CH:8]([O:12][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=2)[N:3]=1)([CH3:9])[CH3:7]
Reactant: COc1ccc2c(Cl)nc(Nc3cc(C)[nH]n3)cc2c1
Solvent: CC(C)O
Product: COc1ccc2c(OC(C)C)nc(Nc3cc(C)[nH]n3)cc2c1

Procedure:
Similar procedure as described in example 10 was used, starting from propan-2-ol and (1-chloro-6-methoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine to give (1-isopropoxy-6-methoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS m/e 313(MH+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:17]1[C:18](=[O:34])[N:19]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[CH:20]=[C:21]([N+:23]([O-])=O)[CH:22]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O1CCCC1.[F-].[K+]>O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:17]1[C:18](=[O:34])[N:19]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:31])([CH3:32])[CH3:33])[CH:20]=[C:21]([NH2:23])[CH:22]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)n1c(-c2cc([N+](=O)[O-])cn(COCC[Si](C)(C)C)c2=O)cc2ccccc21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)n1c(-c2cc(N)cn(COCC[Si](C)(C)C)c2=O)cc2ccccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 67 %

Procedure:
A round bottom flask was charged with intermediate (6b), 2-[5-nitro-2-oxo-1-(2-trimethylsilanyl-ethoxymethyl)-1,2-dihydro-pyridin-3-yl]-indole-1-carboxylic acid tert-butyl ester (0.485 g, 1 mmol), tetrahydrofuran (5 mL) and palladium acetate (11 mg, 5 mol %). The flask was sealed and purged with nitrogen. While purging the flask with nitrogen, a solution of potassium fluoride (116 mg, 2 mmol) in water (2 mL), which had been thoroughly degassed, was added via syringe. The nitrogen inlet was removed and replaced with a balloon of nitrogen. Poly(methylhydrosiloxane) (0.44 mL) was added drop wise and the reaction was stirred at ambient temperature for 18 hours. The reaction mixture was diluted with dichloromethane (20 mL) and aqueous saturated sodium bicarbonate solution (20 mL). The organic layer was separated, filtered through a bed of celite and concentrated in vacuo. The resultant crude product was purified by flash chromatography on SiO2 eluting with hexane—50% ethyl acetate/hexane (gradient) to afford the desired title compound as a brown solid 0.308 g, 67%.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])=[CH:28][CH:27]=2)[C:7](=[O:24])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([C:21]([OH:23])=O)=[CH:10][CH:9]=2)=[O:4].[Cl-].C[NH3+].Cl.[CH2:43]([N:45]=[C:46]=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1.Cl>C1COCC1.O.C(N(CC)CC)C>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:25][C:26]2[CH:27]=[CH:28][C:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])=[CH:30][CH:31]=2)[C:7](=[O:24])[C:8]2[C:13]([C:14]=1[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[CH:12][C:11]([C:21](=[O:23])[N:45]([CH3:46])[CH3:43])=[CH:10][CH:9]=2)=[O:4]
Reactant: COC(=O)c1c(-c2ccccc2)c2cc(C(=O)O)ccc2c(=O)n1Cc1ccc(C(=O)OC(C)(C)C)cc1
Reactant: CCN=C=NCCCN(C)C
Agent: C[NH3+]
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1c(-c2ccccc2)c2cc(C(=O)N(C)C)ccc2c(=O)n1Cc1ccc(C(=O)OC(C)(C)C)cc1
Temperature: 40 °C
Reaction time: 12 h
Yield: 50.7 %

Procedure:
To a solution of 2-(4-tert-butoxycarbonylbenzyl)-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3,6-dicarboxylic acid 3-methyl ester (300 mg) in THF (6 ml) were added methyl ammonium chloride (150 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (230 mg), 1-hydroxy-1H-benzotriazole monohydrate (180 mg) and triethylamine (1 ml) at room temperature. The reaction mixture was stirred at 40° C. for 12 hrs. Water and 1N-hydrochloric acid were added to acidify the aqueous layer and the mixture was extracted with ethyl acetate. The organic layer was washed with water, saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was crystallized from methanol to give the title compound (160 mg).
Reaction SMILES: [O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[CH2:3][CH2:2]1.[N-:12]=[N+]=[N-].[Na+].S(=O)(=O)(O)O.[OH-].[NH4+]>C(O)(=O)C>[O:1]1[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[C:4](=[O:11])[NH:12][CH2:3][CH2:2]1
Reactant: O=C1CCOc2ccccc21
Reactant: [N-]=[N+]=[N-]
Agent: O=S(=O)(O)O
Agent: [NH4+]
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C1NCCOc2ccccc21
Temperature: 50 °C
Reaction time: 24 h

Procedure:
To 4-chromanone (50 g, 340 mmol) in acetic acid (670 ml) was added sodium azide (66.31 g, 1.02 mol) and conc. sulfuric acid (100 ml) dropwise at 0° C. The mixture was heated to 50° C. for 4 h and then cooled to room temperature. The mixture was poured onto ice (1 l) and basified with conc. ammonium hydroxide. The mixture was stirred for 24 h and the solids were collected by filtration (30.43 g, 55%), MSm/z 164 [M+H]+.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[CH:7][C:8]([NH:11]C(=O)OC(C)(C)C)=[N:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O>ClCCl>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([NH2:11])=[N:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(C(C)(C)C)cn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)c1ccc(N)nc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a 0° C. solution of Example 59A (1.0 g, 40 mmol) in dichloromethane (3 mL) was added trifluoroacetic acid (3. mL, 40 mmol). The reaction mixture was stirred at ambient temperature for 3 hours then concentrated under reduced pressure. The residue was diluted with ethyl acetate (100 mL) and washed with saturated aqueous NaHCO3. The layers were separated and the aqueous phase was extracted with ethyl acetate (5×100 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to provide the title compound. MS (ESI+) m/z 151 (M+H)+.
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]=[C:17]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:18]([NH2:21])=[N:19][CH:20]=2)=[CH:11][CH:10]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Si:28]([O:35][C:36]1[CH:41]=[CH:40][C:39]([CH2:42][C:43](Cl)=[O:44])=[CH:38][CH:37]=1)([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29].O>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[Si:28]([O:35][C:36]1[CH:37]=[CH:38][C:39]([CH2:42][C:43]([NH:21][C:18]2[C:17]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[N:16][C:15]([C:12]3[CH:11]=[CH:10][C:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2])=[CH:14][CH:13]=3)=[CH:20][N:19]=2)=[O:44])=[CH:40][CH:41]=1)([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(CC(=O)Cl)cc1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(-c2cnc(N)c(-c3ccccc3)n2)cc1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: O
Product: CC(C)(C)[Si](C)(C)Oc1ccc(CC(=O)Nc2ncc(-c3ccc(O[Si](C)(C)C(C)(C)C)cc3)nc2-c2ccccc2)cc1
Temperature: 50 °C
Reaction time: 18 h
Yield: 75.4 %

Procedure:
Under an argon atmosphere, to a mixture of 5-[4-(tert-butyldimethylsilyloxy)phenyl]-3-phenylpyrazin-2-amine (7a) (504 mg, 1.33 mmol) and 4-(dimethylamino)pyridine (16.3 mg, 133 μmol) dissolved in anhydrous pyridine (20 mL) was added 2-[4-(tert-butyldimethylsilyloxy)phenyl]acetyl chloride (10) prepared above at 0° C. and the mixture was heated with stirring at 50° C. for 18 hours. After cooling to room temperature, to this was added water and the product was extracted with ethyl acetate (100 mL×3). The combined organic extract was washed successively with water (200 mL) and brine (200 mL), followed by drying over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the residue was purified by column chromatography (silica gel 50 g, n-hexane/ethyl acetate=4/1) to give Compound 11a (630 mg, 1.01 mmol, 75.4%) as a yellow foamy solid. Rf=0.33 (n-hexane/diethyl ether=2/3); 1H NMR (400 MHz, DMSO-d6) δ 0.18 (s, 6H), 0.23 (s, 6H), 0.94 (s, 9H), 0.96 (s, 9H), 3.47 (s, 2H), 6.72-6.79 (AA′BB′, 2H), 6.96-7.02 (AA′BB′, 2H), 7.03-7.09 (AA′BB′, 2H), 7.29-7.39 (m, 3H), 7.66-7.74 (m, 2H), 8.05-8.12 (AA′BB′, 2H), 8.98 (s, 1H), 10.54 (s, 1H); 13C NMR (75.5 MHz, DMSO-d6) δ −4.6 (4C), 17.9, 18.0, 25.50 (3C), 25.54 (3C), 41.7, 119.5 (2C), 120.3 (2C), 127.8 (2C), 127.9, 128.0 (2C), 128.2 (2C), 128.5, 128.9, 130.3 (2C), 130.5, 137.6, 142.8, 147.6, 148.0, 153.8, 156.7, 169.3; IR (KBr, cm−1) 523, 694, 781, 804, 839, 914, 1020, 1070, 1086, 1105, 1169, 1263, 1371, 1416, 1510, 1605, 1672, 2857, 2886, 2930, 2955, 3040, 3059, 3233; HRMS (ESI+) m/z 648.3043 ([M+Na]+, C36H47N3NaO3Si2+ requires 648.3048).
Reaction SMILES: [C:1]([N:9]([CH2:24][CH2:25][CH:26]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:10][CH2:11][CH2:12][C:13]1[CH:14]=[C:15]([CH:21]=[CH:22][CH:23]=1)[O:16][CH2:17][C:18]([OH:20])=[O:19])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+:40]>CO>[C:1]([N:9]([CH2:24][CH2:25][CH:26]([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH2:10][CH2:11][CH2:12][C:13]1[CH:14]=[C:15]([CH:21]=[CH:22][CH:23]=1)[O:16][CH2:17][C:18]([O-:20])=[O:19])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1.[Na+:40]
Reactant: O=C(O)COc1cccc(CCCN(CCC(c2ccccc2)c2ccccc2)C(=O)c2ccccc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C([O-])COc1cccc(CCCN(CCC(c2ccccc2)c2ccccc2)C(=O)c2ccccc2)c1
Reaction time: 0.5 h

Procedure:
To a solution of (3-{3-[benzoyl(3,3-diphenylpropyl)amino]propyl}phenoxy)acetic acid (110 mg) in MeOH (1 mL) was added 1M NaOH aqueous solution (0.217 mL) at ambient temperature. The mixture was stirred for 0.5 hours at the same temperature. The resulting mixture was evaporated in vacuo. The residue was triturated with diisopropylether to give a sodium (3-{3-[benzoyl(3,3-diphenylpropyl)amino]propyl}phenoxy)acetate.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]Br)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:17][N:18](C)[CH:19]=[O:20]>C(OCC)(=O)C>[CH2:3]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][N:18]1[CH2:17][C@H:9]([CH2:4][CH2:5][CH2:6][CH3:7])[CH2:8][C:19]1=[O:20])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CN(C)C=O
Reactant: BrCCCCCOCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CCCC[C@@H]1CC(=O)N(CCCCCOCc2ccccc2)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 95 %

Procedure:
To a solution of the compound of Example 2(c) (0.42 g, 2.9 mmol) in dry dimethylformamide (10 mL) under argon was slowly added sodium hydride (60% in mineral oil, 0.14 g, 3.5 mmol) at 0° C. After stirring at 0° C. for 30 minutes, 5-benzyloxypentyl bromide (0.9 g, 3.5 mmol) was dropwise added. The resulting mixture was stirred at room temperature overnight and then diluted with ethyl acetate (50 mL). The organic solution was washed with water (4×30 mL), brine (30 mL), dried (Na2SO4) and concentrated. The residue was purified by flash column chromatography (silica gel, 1:1 EtOAc/hexanes) to afford 0.73 g (95%) of the title compound as a clear oil: 1H NMR (CDCl3) δ 7.33 (m, 5H), 4.51 (s, 2H), 3.45 (m, 3H), 3.27 (t, 2H), 2.99 (dd, 1H), 2.52 (dd, 1H), 2.32 (m, 1H), 2.06 (m, 1H), 1.24-1.71 (m, 12H), 0.93 (t, 3H). MS(ES) m/e 318 [M+H]+.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:12])[O:10][CH3:11])=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14].[NH2:16][CH2:17][CH:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1>CCO>[N+:13]([C:3]1[CH:4]=[C:5]([NH:8][C:9](=[O:12])[O:10][CH3:11])[CH:6]=[CH:7][C:2]=1[NH:16][CH2:17][CH:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)([O-:15])=[O:14]
Reactant: NCC1CCOCC1
Reactant: COC(=O)Nc1ccc(F)c([N+](=O)[O-])c1
Solvent: CCO
Product: COC(=O)Nc1ccc(NCC2CCOCC2)c([N+](=O)[O-])c1

Procedure:
Methyl (4-fluoro-3-nitrophenyl)carbamate (2.0 g, 9.32 mmol) and 4-aminomethyl tetrahydropyran (1.28 g, 11.2 mmol) were stirred in 50 mL of EtOH containing TEA (2.0 mL, 14.0 mmol) at 75° C. for 48 h. The solvent was evaporated. The residue was dissolved in EtOAc and washed with aqueous 5% KHSO4, saturated aqueous NaHCO3 solution, brine and dried over anhydrous MgSO4. The crude product was purified by silica gel flash chromatography using 1:1/hexanes:EtOAc as eluent. Yield: 2.53 g (88%). 1H NMR (400 MHz, CHLOROFORM-D) δ 1.42 (m, 2 H), 1.73 (d, J=1.76 Hz, 1 H), 1.76 (d, J=1.95 Hz, 1 H), 1.88-2.01 (m, 1 H), 3.22 (dd, J=6.74, 5.57 Hz, 2 H), 3.42 (m, 2 H), 3.78 (s, 3 H), 4.01 (d, J=4.30 Hz, 1 H), 4.04 (d, J=3.51 Hz, 1 H), 6.48 (br.s, 1 H), 6.85 (d, J=9.37 Hz, 1 H), 7.65 (br.s, 1 H), 8.03-8.09 (m, 2 H).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1)[CH:2]=[CH2:3].[C:14]([C:16]1[CH:21]=[CH:20][C:19](O)=[CH:18][CH:17]=1)#[N:15].O>C(Cl)(Cl)Cl>[CH2:1]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([O:11][C:19]2[CH:20]=[CH:21][C:16]([C:14]#[N:15])=[CH:17][CH:18]=2)=[O:10])=[CH:7][CH:6]=1)[CH:2]=[CH2:3]
Reactant: N#Cc1ccc(O)cc1
Reactant: C=CCOc1ccc(C(=O)O)cc1
Solvent: O
Solvent: ClC(Cl)Cl
Product: C=CCOc1ccc(C(=O)Oc2ccc(C#N)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.1 %

Procedure:
15.0 g of PPE, 4.00 g (22.4 mmol) of the compound (12) and 2.66 g (22.3 mmol) of p-cyanophenol were dissolved in ml of chloroform under an argon gas atmosphere and the whole was stirred at room temperature overnight. After addition of water to the reaction mixture, the whole was extracted with methylene chloride. After removal of the solvent by distillation, the residue was purified by silica gel column chromatography to obtain 4.80 g of p-cyanophenyl p-allyloxybenzoate (17) as a white solid (yield: 76.7%).
Reaction SMILES: N[C:2]1[CH:3]=[CH:4][C:5]2[S:9][N:8]=[CH:7][C:6]=2[CH:10]=1.S(=O)(=O)(O)[OH:12].N([O-])=O.[Na+]>O>[S:9]1[C:5]2[CH:4]=[CH:3][C:2]([OH:12])=[CH:10][C:6]=2[CH:7]=[N:8]1
Reactant: O=S(=O)(O)O
Reactant: Nc1ccc2sncc2c1
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: Oc1ccc2sncc2c1
Temperature: 90 °C
Reaction time: 2 h
Yield: 30 %

Procedure:
5-Aminobenzo[d]isothiazole (217 mg, 1.45 mmol) was suspended/dissolved in water (20 mL) containing concentrated sulphuric acid (1.5 mL) and heated at 90° C. for 2 h. This solution was cooled to 0° C. and sodium nitrite (105 mg, 1.52 mmol) in water (1 mL) was added over 5 min and the mixture allowed to warm to ambient temperature. The diazonium salt was added dropwise over 20 min to a solution of concentrated sulphuric acid (1 mL) in water (12 mL) at 90° C. and stirred at this temperature for 2 h before hot filtering to remove an insoluble solid. The filtrate was extracted with dichloromethane (3×20 mL) and the combined organic extracts washed with brine (50 mL), dried (MgSO4) and concentrated in vacuo to give the title compound as a brown solid (65 mg, 30%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[N:17])([CH3:4])([CH3:3])[CH3:2].[OH-].[NH4+].[H][H]>[Ni].CO>[C:1]([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[CH2:16][NH2:17])([CH3:4])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)COc1ccc(Cl)cc1C#N
Agent: [Ni]
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)COc1ccc(Cl)cc1CN
Reaction time: 2 h
Yield: 630.9 %

Procedure:
Raney nickel (˜0.5 g) was added to a solution of 2-cyano-4-chlorophenoxy acetic acid-t-butyl ester (560 mg, 0.21 mmol) in methanol (25 mL) containing 1 mL of sat. ammonium hydroxide. The mixture was placed under 40 psi of hydrogen and shaken for two hours. The mixture was filtered and concentrated. The residue was partitioned between 1 N HCl and ether. The layers were separated and the aqueous layer was re-extracted with ether. The aqueous layer was basified to ˜pH with K2CO3 solution and extracted with ether (3×). The combined organic layers were dried (MgSO4), filtered and concentrated to afford 360 mg of the title compound as an oil. MS 272 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 7.22 (s, 1H); 7.12 (d, 1H, J=8.7 Hz); 6.61 (d, 1H, J=8.7 Hz); 4.5 (s, 2H); 3.85 (s, 2H); 2.62 (bs, 2H); 1.41 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:8]#[N:9])=[N:4][CH:5]=[CH:6][CH:7]=1.[NH2:10][C:11](N)=[O:12].O>C(OCCOCCO)C>[NH2:9][C:8]1[C:3]2[N:4]=[CH:5][CH:6]=[CH:7][C:2]=2[NH:1][C:11](=[O:12])[N:10]=1
Reactant: NC(N)=O
Reactant: N#Cc1ncccc1N
Solvent: O
Solvent: CCOCCOCCO
Product: Nc1nc(=O)[nH]c2cccnc12
Temperature: 205 °C

Procedure:
A slurry of 3-Amino-2-cyanopyridine (200 mg) and urea (400 mg) in 2-(2-ethoxyethoxy)ethanol (0.5 mL) was gradually heated to about 205° C., and maintained at 205° C. for 10 min. Heating was ceased and 6 mL of hot water was carefully added while shaking the mixture. The mixture was vacuum filtered to collect the precipitate. The precipitate was washed with water and ethyl acetate and allowed to dry to yield 4-Amino-pyrido[2,3-e]pyrimidin-2-one as a light yellow solid, m.p. >300° C.