Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[N:6][C:7]([CH:11]=[O:12])=[CH:8][CH:9]=2)[CH2:4][O:3]1.[CH2:13](O)[CH2:14][OH:15].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C([O-])(O)=O.[Na+]>C1C=CC=CC=1>[O:12]1[CH2:13][CH2:14][O:15][CH:11]1[C:7]1[N:6]=[C:5]2[CH2:4][O:3][C:2](=[O:1])[C:10]2=[CH:9][CH:8]=1
Reactant: O=Cc1ccc2c(n1)COC2=O
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O
Product: O=C1OCc2nc(C3OCCO3)ccc21
Temperature: 25 °C
Yield: 33.2 %

Procedure:
To a solution of 5-oxo-5,7-dihydro-furo[3,4-b]pyridine-2-carbaldehyde (100 mg, 0.61 mmol) in anhydrous benzene (5 mL) is added ethylene glycol (0.1 mL, 1.77 mmol), a catalytic amount p-toluenesulfonic acid monohydrate and 4 Å mole sieves. The reaction mixture is heated at a reflux temperature for 20 h. The reaction mixture is allowed to cool to room temperature and saturated. aqueous NaHCO3 solution is added. The resulting mixture is filtered through celite, washed with saturated aqueous NaHCO3 and EtOAc. The isolated organic layer is washed with brine (1×), dried with anhydrous Na2SO4, and concentrated. The residue is treated with EtOAc-Hexane (1:4) and the light brown solid which forms is collected by filtration and dried to give the title compound (42 mg, 33%).
Reaction SMILES: F[C:2]1[CH:16]=[CH:15][C:5]([C:6]([C:8]2[CH:13]=[C:12]([CH3:14])[CH:11]=[CH:10][N:9]=2)=[O:7])=[CH:4][CH:3]=1.[N-:17]=[N+]=[N-].[Na+].O>CS(C)=O>[NH2:17][C:2]1[CH:16]=[CH:15][C:5]([CH:6]([C:8]2[CH:13]=[C:12]([CH3:14])[CH:11]=[CH:10][N:9]=2)[OH:7])=[CH:4][CH:3]=1
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccnc(C(=O)c2ccc(F)cc2)c1
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: Cc1ccnc(C(O)c2ccc(N)cc2)c1
Reaction time: 8 h
Yield: 113 %

Procedure:
2-(4-fluorobenzoyl)-4-methylpyridine (1.6 g) and sodium azide (2.4 g) were suspended in dimethylsulfoxide (15 ml) under nitrogen atmosphere 90° C., and the mixture was heated with stirring overnight. The mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off. The residue was dissolved in tetrahydrofuran (50 ml), and to the solution was added aluminum lithium hydride (0.66 g) under ice-cooling, and the mixture was stirred overnight at room temperature under nitrogen atmosphere. To the solution were added water (0.66 ml), 15% aqueous solution of sodium hydroxide (0.66 ml) and water (1.98 ml) under ice-cooling, the mixture was stirred and dried over anhydrous magnesium sulfate. After filtration, the solvent of the filtrate was distilled off, to give (4-aminophenyl)(4-methylpyridin-2-yl)methanol (1.8 g) as pale yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:37]=[CH:36][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]2[C:15]([CH3:35])=[N:16][O:17][C:18]=2[C@@H:19]([NH:28][S@@](C(C)(C)C)=O)[CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=O)=[CH:4][CH:3]=1.CCO.C(Cl)(=O)C>C([O-])(O)=O.[Na+].CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]2[C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[C:14]3[C:15]([CH3:35])=[N:16][O:17][C:18]=3[C@H:19]([CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:25])[CH3:26])=[O:22])[N:28]=2)=[CH:36][CH:37]=1
Reactant: Cc1noc([C@H](CC(=O)OC(C)(C)C)N[S@](=O)C(C)(C)C)c1-c1ccccc1C(=O)c1ccc(Cl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)Cl
Solvent: CCOC(C)=O
Product: Cc1noc2c1-c1ccccc1C(c1ccc(Cl)cc1)=N[C@H]2CC(=O)OC(C)(C)C
Temperature: 60 °C
Yield: 77.2 %

Procedure:
To a resealable vial was added (3S)-tert-butyl 3-(4-(2-(4-chlorobenzo yl)phenyl)-3-methylisoxazol-5-yl)-3-((R)-1,1-dimethylethylsulfinamido)propanoate (0.043 g, 0.079 mmol), EtOH (3 mL), and acetyl chloride (0.017 mL, 0.237 mmol). The vial was sealed and heated to 60° C. for 1.75 h before being cooled to room temperature and diluting with saturated NaHCO3 and EtOAc. The layers were separated and the aqueous was extracted with EtOAc. The combined organics were washed with brine, dried over Na2SO4, filtered, and concentrated. The crude residue was purified via Biotage (EtOAc/hex) to afford tert-butyl 2-((4S)-6-(4-chlorophenyl)-1-methyl-4H-benzo[c]isoxazolo[4,5-e]azepin-4-yl)acetate (0.026 g, 0.061 mmol). 1H NMR (400 MHz, Acetone-d6) δ 7.87-7.83 (m, 1H), 7.76-7.70 (m, 1H), 7.51-7.41 (m, 2H), 7.40 (s, 4H), 4.40 (br. s, 1H), 3.32 (d, J=7.19 Hz, 2H), 2.54 (s, 3H), 1.48 (s, 9H); LC/MS m/z 423 [M+H]+.
Reaction SMILES: [ClH:1].[C:2]1([C@H:8]2[CH2:12][CH2:11][CH2:10][C@H:9]2[NH2:13])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.COC1[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][N:22]=1.Cl.C1([C@H]2CCC[C@H]2N)CCCCC1.COC1CCCCN=1>>[ClH:1].[CH:2]1([C@H:8]2[CH2:12][CH2:11][CH2:10][C@H:9]2[N:13]=[C:21]2[CH2:20][CH2:19][CH2:18][CH2:17][NH:22]2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: COC1=NCCCCC1
Reactant: N[C@@H]1CCC[C@@H]1c1ccccc1
Agent: COC1=NCCCC1
Agent: Cl
Agent: N[C@@H]1CCC[C@@H]1C1CCCCC1
Product: C1CCC([C@H]2CCC[C@H]2N=C2CCCCN2)CC1

Procedure:
Following the procedure of Example 1, only substituting for cis-2-phenylcyclopentylamine hydrochloride and O-methylcaprolactim, appropriate amounts of cis-2-(cyclohexyl)cyclopentylamine hydrochloride and O-methylvalerolactim respectively the desired product was obtained. M.P. 195.5°-197° C.
Reaction SMILES: [CH3:1][C:2]1[C:7]2[C:8](=[O:13])[NH:9][S:10](=[O:12])(=[O:11])[C:6]=2[CH:5]=[CH:4][C:3]=1[N+:14]([O-])=O.[H][H]>O.[Pd]>[CH3:1][C:2]1[C:7]2[C:8](=[O:13])[NH:9][S:10](=[O:12])(=[O:11])[C:6]=2[CH:5]=[CH:4][C:3]=1[NH2:14]
Reactant: [H][H]
Reactant: Cc1c([N+](=O)[O-])ccc2c1C(=O)NS2(=O)=O
Agent: [Pd]
Solvent: O
Product: Cc1c(N)ccc2c1C(=O)NS2(=O)=O
Temperature: 45 °C

Procedure:
33.6 g (0.13 mol) of 4-methyl-5-nitro-1,1,3-trioxo-2,3-dihydro-1λ6 benz[d]isothiazole are dissolved in 1.2 l of water with warming to 45° C. and 5 g of Pd/C (10 percent on active carbon) are added. Hydrogen gas is then passed in with vigorous stirring (pressureless hydrogenation). 9 l of H2 are absorbed in the course of 4.5 hours. After cooling to 25° C., the catalyst is filtered off, and the filtrate is concentrated to a volume of 200 ml (on a Rotavapor) and then acidified to pH 1. The deposited precipitate is filtered off with suction, washed with water and dried under reduced pressure at 50° C. 23.4 g (0.11 mol=85% of theory) of a white solid of m.p.: 272°-273° C. are obtained.
Reaction SMILES: [C:1]([C:6]1[S:7][CH:8]=[C:9]([CH:11]([CH3:13])[CH3:12])[N:10]=1)(OCC)=[O:2].C(O)C.[BH4-].[Na+]>O>[CH3:12][CH:11]([C:9]1[N:10]=[C:6]([CH2:1][OH:2])[S:7][CH:8]=1)[CH3:13]
Reactant: CCOC(=O)c1nc(C(C)C)cs1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(C)c1csc(CO)n1
Yield: 112.7 %

Procedure:
A solution of 4.5 g of 2-carboethoxy-4-(1-methylethyl)thiazole, 100 ml of ethyl alcohol and 1.1 g of sodium borohydride was heated to reflux for 4 hr. The reaction mixture was then condensed to one half of the original volume in vacuo, diluted with 150 ml of water and extracted with methylene chloride. The combined extracts were washed with water, dried (MgSO4) and condensed in vacuo to give 4.0 g of 4-(1-methylethyl)-2-thiazole methanol; m.p. 80°-82° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]3[N:14]=[C:15]([C:17]4[CH:22]=[CH:21][C:20]5[NH:23][C:24]([NH:32][C:19]=5[CH:18]=4)=[C:25]4[CH:31]=[CH:30][C:28](=[O:29])[CH:27]=[CH:26]4)[NH:16][C:10]=3[CH:9]=2)[CH2:4][CH2:3]1.I[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][O:40][C:41]1[C:50]2[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=2)[C:44](=[O:51])[C:43](=[O:52])[CH:42]=1>CO.CN(C=O)C.O>[O:51]=[C:44]1[C:45]2[C:50](=[CH:49][CH:48]=[CH:47][CH:46]=2)[C:41]([O:40][CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][O:29][C:28]2[CH:30]=[CH:31][C:25]([C:24]3[NH:23][C:20]4[CH:21]=[CH:22][C:17]([C:15]5[NH:14][C:11]6[CH:12]=[CH:13][C:8]([N:5]7[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]7)=[CH:9][C:10]=6[N:16]=5)=[CH:18][C:19]=4[N:32]=3)=[CH:26][CH:27]=2)=[CH:42][C:43]1=[O:52]
Reactant: CN1CCN(c2ccc3nc(-c4ccc5c(c4)NC(=C4C=CC(=O)C=C4)N5)[nH]c3c2)CC1
Reactant: O=C1C=C(OCCCCCCI)c2ccccc2C1=O
Solvent: CN(C)C=O
Solvent: O
Solvent: CO
Product: CN1CCN(c2ccc3[nH]c(-c4ccc5[nH]c(-c6ccc(OCCCCCCOC7=CC(=O)C(=O)c8ccccc87)cc6)nc5c4)nc3c2)CC1
Reaction time: 0.25 h
Yield: 30.1 %

Procedure:
Hoechst 33258 (3.0 g, 5 mmol) was dissolved in a hot mixture of isopropanol-water (24 mL/12 mL) and neutralized with ammonium hydroxide (3 mL). The precipitate was filtered, triturated with Et2O and dried in vacuo to obtain the free base of bisbenzimidazole. A 1.0 M solution of Bu4NOH in MeOH (0.6 mL, 0.6 mmol) was added to the solution of bisbenzimidazole (1.635 g, 3.85 mmol) in MeOH (30 mL), stirred for 15 min and concentrated to dryness in vacuo. Iodonaphthoquinone 505 (1.485 g, 3.87 mmol) in DMF (30 mL) was added to the tetrabutyl ammonium salt and the mixture was stirred for 48 h. The reaction mixture was suspended in H2O, the crude product was filtered, washed with H2O, dried and purified by flash chromatography (MeOH/CHCl3 1:9, 1:5) to afford 514 as a yellow solid (790 mg, 30%). 1H NMR (CDCl3/MeOH-d4) 8.21 (s, 1H), 8.09 (d, J=7.6 Hz, 1H), 8.05 (d, J=8.7 Hz, 2H), 7.85-7.95 (m, 2H), 7.48-7.75 (m, 4H), 7.14 (bs, 1H), 7.10-6.98 (m 3H), 4.21 (t, J=6.3 Hz, 2H), 4.08 (t, J=6.2 Hz, 2H), 2.65-2.75 (m, 4H), 2.40 (s, 3H), 1.80-2.15 (m, 4H), 1.60-1.75 (m, 4H). MS (LSIMS, 3-NBA) 725.2 (M++1).
Reaction SMILES: [OH:1][C:2]([C:9](=[O:27])[NH:10][C@@H:11]1[C:17](=[O:18])[NH:16][C:15]2[CH:19]=[CH:20][CH:21]=[CH:22][C:14]=2[C:13]2[CH:23]=[CH:24][CH:25]=[CH:26][C:12]1=2)([CH2:6][CH2:7][CH3:8])[C:3](O)=[O:4].[F:28][C:29]([F:36])([C:32]([F:35])([F:34])[F:33])[CH2:30]N.O.O[N:39]1C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.Cl.CN(C)CCCN=C=NCC>O1CCCC1>[OH:1][C:2]([CH2:6][CH2:7][CH3:8])([C:3]([NH2:39])=[O:4])[C:9]([N:10]([C@@H:11]1[C:17](=[O:18])[NH:16][C:15]2[CH:19]=[CH:20][CH:21]=[CH:22][C:14]=2[C:13]2[CH:23]=[CH:24][CH:25]=[CH:26][C:12]1=2)[CH2:30][C:29]([F:36])([F:28])[C:32]([F:35])([F:34])[F:33])=[O:27]
Reactant: On1nnc2ccccc21
Reactant: NCC(F)(F)C(F)(F)F
Reactant: CCCC(O)(C(=O)O)C(=O)N[C@@H]1C(=O)Nc2ccccc2-c2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCCC(O)(C(N)=O)C(=O)N(CC(F)(F)C(F)(F)F)[C@@H]1C(=O)Nc2ccccc2-c2ccccc21
Reaction time: 8 h
Yield: 63.2 %

Procedure:
A solution of 70.0 mg (0.19 mmol) 2-hydroxy-2-((S)-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-ylcarbamoyl)-pentanoic acid and 31.2 mg (0.21 mmol) 2,2,3,3,3-pentafluoropropylamine in 3 ml tetrahydrofuran were cooled to 0° C. and 28.2 mg (0.21 mmol) 1-hydroxy-benzotriazole hydrate, 72 μl (0.42 mmol) diisopropylethylamine and 40.1 mg (0.21 mmol) N-(3-dimethylaminopropyl)-N′-ethyl-carbodiimide hydrochloride were added. Stirring was continued overnight. Removal of the solvent by distillation and chromatography on silicagel with heptane/ethylacetate (gradient 90:10 to 50:50) yielded 60.0 mg (63%) (R/S)-2-hydroxy-N-((S)-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-N-(2,2,3,3,3-pentafluoro-propyl)-2-propyl-malonamide: MS (m/e): 500.4 (M+H)+.
Reaction SMILES: [NH:1]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C@H:2]([C:11]([OH:13])=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8]C(O)=CC=1.[CH3:21]I.[H-].[Na+].[CH2:25]1[CH2:29][O:28][CH2:27][CH2:26]1>>[C:17]([O:16][C:14]([N:1]([CH3:21])[C@H:2]([C:11]([OH:13])=[O:12])[CH2:3][C:4]1[CH:26]=[CH:25][C:29]([O:28][CH3:27])=[CH:8][CH:9]=1)=[O:15])([CH3:18])([CH3:19])[CH3:20]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)O
Reactant: CI
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Product: COc1ccc(C[C@@H](C(=O)O)N(C)C(=O)OC(C)(C)C)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
A solution of BocTyrOH (5.30 g, 18.8 mmol) and methyl iodide (2.57 mL, 41.4 mmol) in 80 mL of dry THF was cooled at 0° C. and sodium hydride (60% dispersion, 2.47 g, 62.0 mmol) was added. The reaction was allowed to stir at 0° C. for 1 hour, then at rt overnight. Excess sodium hydride was quenched by the dropwise addition of 10 mL of THF/H2O (1:1) and the solvents were removed in vacuo. After removal of the solvents, the deep orange gel was diluted with 30 mL of water and washed with pentane (2×30 mL). The aqueous phase was acidified with solid citric acrd (pH 2). Ethyl acetate was used for extraction. The combined extracts were washed with brine, dried (MgSO4) and concentrated in vacuo. The crude residue was purified by silica gel column chromatography eluting with ethyl ether to afford the desired compound as a yellow oil (5.22 g, 90%); [α]29 D-15.7° (c 1.0, MeOH), Lit.14b[α]22 D-16.9° (c 1.0, MeOH) 1H NMR 300 MHz, CDCl3) δ 7.18 & 7.12 (2H, two d), 6.85 (2H,d), 4,58 (1H, two t), 3.80 (3H, s), 3.24 & 3.13 (1H, 2dd), 2.76 & 2.68 (3H, 2s), 1.43 & 1.38 (9H, 2s); FABMS 619.3 (2M+H), 310.2 (M+H), 210.2 (M−Boc); HRFABMS Calcd for C16H24MO5 (M+H) 310.1654, Found 310.1648.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]=[N:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([O-])=O.[H][H]>O>[C:12]1([N:11]2[N:10]=[C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]3=[N:1]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccccc1N=Nc1ccccc1
Solvent: O
Product: c1ccc(-n2nc3ccccc3n2)cc1

Procedure:
An o-nitroazobenzene derivative which is selected as a starting material is dissolved in a solvent contained in a reaction vessel into which water, a hydrogenation catalyst and a basic substance are then placed. After the air in the reaction vessel has been replaced by hydrogen, a given amount of hydrogen is charged into the reaction vessel, and the reaction is then allowed to proceed under atmospheric pressure or a given pressure at a temperature of room temperature to 170° C. under agitation. After the reaction has been completed, the catalyst is filtered off, the solvent layer is washed with water, and the solvent is distilled off. The crude product is then purified by recrystallization to obtain the corresponding 2-phenylbenzotriazole as a pure product.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][N:10]([CH2:13][C:14]([C:16]3[CH:27]=[C:26]([C:28]([CH3:31])([CH3:30])[CH3:29])[C:19]([O:20][CH2:21][C:22]([O:24]C)=[O:23])=[C:18]([C:32]([CH3:35])([CH3:34])[CH3:33])[CH:17]=3)=[O:15])[CH2:9][CH2:8]2)=[CH:3][CH:2]=1.Cl>O1CCOCC1.O>[N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:8][CH2:9][N:10]([CH2:13][C:14]([C:16]3[CH:27]=[C:26]([C:28]([CH3:30])([CH3:29])[CH3:31])[C:19]([O:20][CH2:21][C:22]([OH:24])=[O:23])=[C:18]([C:32]([CH3:35])([CH3:34])[CH3:33])[CH:17]=3)=[O:15])[CH2:11][CH2:12]2)=[CH:3][CH:2]=1
Reactant: COC(=O)COc1c(C(C)(C)C)cc(C(=O)CN2CCN(c3ccncc3)CC2)cc1C(C)(C)C
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)c1cc(C(=O)CN2CCN(c3ccncc3)CC2)cc(C(C)(C)C)c1OCC(=O)O
Temperature: 100 °C

Procedure:
A solution of methyl 4-(2-[4-(4-pyridyl)piperazin-1-yl]acetyl)-2,6-di-tert-butylphenoxyacetate (241 mg) in dioxane (2.0 ml) was treated with 1N hydrochloric acid and the mixture heated at 100° C. for 20 hours. The mixture was cooled, diluted with water, filtered and the filtrate freeze-dried. The solid residue was purified by flash chromatography on silica eluting with toluene/ethyl acetate/0.880 ammonia/ethanol (60:20:10:35 v/v/v/v). The fractions containing the desired product were evaporated, the residue treated with dioxane, filtered and the filtrate diluted with water and freeze dried to give a white foam, which on drying at 55° C. gave the title compound, 90 mg: NMR (d6DMSO) δ8.16 (2H, d), 7.97 (2H, s), 6.84 (2H, d), 4.22 (2H, s), 3.86 (2H, s), 3.37 (4H, t), 2.64 (4H, t), 1.39 (18H, s); m/e 468 (M+H)+ ; calculated for C27H37N3O4.2H2O: C, 64.4; H, 8.2; N, 8.3. found C, 64.6; H, 7.9; N, 7.9%.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([CH:21]4[CH2:23][CH2:22]4)[N:19]=3)[N:14](COCC[Si](C)(C)C)[CH:13]=2)=[O:11])[CH:6]=[CH:7][CH:8]=1)#[N:2].FC(F)(F)C(O)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([CH:21]4[CH2:23][CH2:22]4)[N:19]=3)[NH:14][CH:13]=2)=[O:11])[CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: C[Si](C)(C)CCOCn1cc(C(=O)Nc2cccc(C#N)c2)c2nc(C3CC3)cnc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1cccc(NC(=O)c2c[nH]c3ncc(C4CC4)nc23)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 27.9 %

Procedure:
To a solution of 2-cyclopropyl-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (3-cyano-phenyl)-amide (113 mg, 0.26 mmol) in CH2Cl2 (2.6 mL) was added trifluoroacetic acid (1 mL). Stirred at room temperature for 2 h then neutralized with aqueous NaHCO3 and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4 and concentrated. The residue was dissolved in EtOH and NaOAc (0.7 g) was added. The reaction mixture was stirred at 60° C. overnight then cooled to room temperature and water and EtOAc were added. The aqueous layer was extracted with EtOAc and the combined organics were washed with brine, dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography (MeOH/CH2Cl2) to give 22 mg (28%) of 2-cyclopropyl-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (3-cyano-phenyl)-amide. MS: (M+H)+=304; mp=272.0-274.0.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[C:6]([C:9]1[O:10][C:11]2[C:17]([N+:18]([O-:20])=[O:19])=[CH:16][CH:15]=[CH:14][C:12]=2[N:13]=1)(=O)[NH2:7]>CN(C)C=O>[C:6]([C:9]1[O:10][C:11]2[C:17]([N+:18]([O-:20])=[O:19])=[CH:16][CH:15]=[CH:14][C:12]=2[N:13]=1)#[N:7]
Reactant: NC(=O)c1nc2cccc([N+](=O)[O-])c2o1
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: N#Cc1nc2cccc([N+](=O)[O-])c2o1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
26.14 g (17.22 mmoles) of phosphorus oxychloride is added to 100 ml dimethylformamide at 0° C. and stirred at 0° C. for 15 minutes at room temperature for 30 minutes. 6.5 g (34.45 mmoles) 2-carbamyl-7-nitrobenzoxazole is added and the mixture stirred at room temperature overnight, then poured into ice water and is allowed to stand for 1 hour at room temperature. The resulting precipitate is filtered off, redissolved in ethyl acetate, decolorized with carbon, filtered and the filtrate concentrated in vacuo to give 2-cyano-7-nitro-benzoxazole.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[C:4]([O:14][CH3:15])[CH:3]=1.[CH2:16]([N:23]1[C:28](=[O:29])[C:27]([CH3:30])=[CH:26][N:25]([CH2:31][CH2:32][CH2:33]Cl)[C:24]1=[O:35])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[ClH:1].[CH2:16]([N:23]1[C:28](=[O:29])[C:27]([CH3:30])=[CH:26][N:25]([CH2:31][CH2:32][CH2:33][N:11]2[CH2:10][CH2:9][N:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=3[O:14][CH3:15])[CH2:13][CH2:12]2)[C:24]1=[O:35])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: COc1cc(Cl)ccc1N1CCNCC1
Reactant: Cc1cn(CCCCl)c(=O)n(Cc2ccccc2)c1=O
Product: COc1cc(Cl)ccc1N1CCN(CCCn2cc(C)c(=O)n(Cc3ccccc3)c2=O)CC1
Product: Cl

Procedure:
substituting 1-(4-chloro-2-methoxyphenyl)piperazine and 3-benzyl-1-(3-chloropropyl)-5-methyl-2,4(1H,3H)-pyrimidinedione gave 3-benzyl-1-{3-[4-(4-chloro-2-methoxyphenyl)piperazin-1-yl]propyl}-5-methyl-2,4(1H,3H)-pyrimidinedione hydrochloride, m.p. 194°-195° C.; Anal.: Calcd. for C26H31ClN4O3.(HCl)2 : C, 55.63; H, 6.03; N, 9.98%; Found: C, 55.82; H, 5.94; N, 9.85%;
Reaction SMILES: [CH3:1][C:2]([CH3:8])([C:4](=[O:7])[CH2:5]Cl)[CH3:3].[F:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:1][C:2]([CH3:8])([C:4](=[O:7])[CH2:5][O:16][C:13]1[CH:14]=[CH:15][C:10]([F:9])=[CH:11][CH:12]=1)[CH3:3]
Reactant: Oc1ccc(F)cc1
Reactant: CC(C)(C)C(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)(C)C(=O)COc1ccc(F)cc1
Temperature: 25 °C
Yield: 17.2 %

Procedure:
418.3 g (3.11 mol) of 2,2-dimethyl-4-chloro-butan-3-one were added dropwise to a suspension, heated to the boil, of 315 g (2.8 mol) of 4-fluorophenol and 386.4 g (2.8 mol) of potassium carbonate in 1,500 ml of acetone. The mixture was stirred under reflux for 4 hours. After cooling to room temperature, the salt which had separated out was filtered off and the filtrate was concentrated in vacuo. The oil which remained was distilled in vacuo. 101.5 g (86.2% of theory) of 2,2-dimethyl-4-(4-fluorophenoxy)-butan-3-one of boiling point 83°-84° C./0.05 mm Hg (nD20 =1.4919) were obtained. ##STR75##
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:12][CH3:13])[CH:6]=1)=[O:4].[CH3:14][N:15]1[CH:19]=[CH:18][N:17]=[CH:16]1>C(#N)C.CO>[Br-:1].[CH3:14][NH+:15]1[CH:19]=[CH:18][N:17]([CH2:2][C:3]([C:5]2[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:12][CH3:13])[CH:6]=2)=[O:4])[CH2:16]1
Reactant: CCOc1cccc(C(=O)CBr)c1
Reactant: Cn1ccnc1
Solvent: CC#N
Solvent: CO
Product: CCOc1cccc(C(=O)CN2C=C[NH+](C)C2)c1
Product: [Br-]
Temperature: 25 °C
Reaction time: 18 h
Yield: 6.9 %

Procedure:
A solution of 2.9 g (0.012 mol) of 1-bromo-2-(3-ethoxyphenyl)-2-oxoethane in 20 ml of acetonitrile was combined with 1.03 g (0.013 mol) of 1-methylimidazole and the resulting mixture was stirred at room temperature for approximately 18 hours. The mixture was diluted with methanol and the volatiles were evaporated under reduced pressure to a volume of approximately 15 ml. This solution was diluted with ethyl acetate and the precipitated brown solid was collected by filtration. The collected solid was washed with ethyl acetate and dissolved in hot acetonitrile. The mixture was purified with charcoal and upon cooling the solid was collected. The solid was recrystallized from acetonitrile/diethyl ether to provide two crops which were combined and recrystallized three times from isopropyl alcohol to afford 0.27 g of 1-methyl-3-[2-(3-ethoxyphenyl)-2-oxoethyl]-1H-imidazolium bromide as pale yellow flakes. (7% yield) mp=137°-138° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][C@H:15]([O:17][CH2:18][C:19]2[CH:20]=[CH:21][C:22]3[O:27][CH2:26][CH2:25][N:24]([CH2:28][CH2:29][CH2:30][O:31][CH3:32])[C:23]=3[CH:33]=2)[C@@H:14]([C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=2)[CH2:13][C@H:12]1[C:42]([OH:44])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([N:47](CC)CC)C.ClC(OC(C)C)=O.N>ClCCl>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][C@H:15]([O:17][CH2:18][C:19]2[CH:20]=[CH:21][C:22]3[O:27][CH2:26][CH2:25][N:24]([CH2:28][CH2:29][CH2:30][O:31][CH3:32])[C:23]=3[CH:33]=2)[C@@H:14]([C:34]2[CH:35]=[CH:36][C:37]([O:40][CH3:41])=[CH:38][CH:39]=2)[CH2:13][C@H:12]1[C:42](=[O:44])[NH2:47])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COCCCN1CCOc2ccc(CO[C@H]3CN(C(=O)OCc4ccccc4)[C@H](C(=O)O)C[C@@H]3c3ccc(OC)cc3)cc21
Reactant: CCN(CC)CC
Agent: CC(C)OC(=O)Cl
Agent: N
Solvent: ClCCl
Product: COCCCN1CCOc2ccc(CO[C@H]3CN(C(=O)OCc4ccccc4)[C@H](C(N)=O)C[C@@H]3c3ccc(OC)cc3)cc21
Reaction time: 0.17 h

Procedure:
To a solution of 0.51 g of (2S,4R,5R)-4-(4-methoxy-phenyl)-5-[4-(3-methoxy-propyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-piperidine-1,2-dicarboxylic acid 1-benzyl ester (from example 3b) in 1 ml of dichlormethane are added 1.2 ml of triethylamine and 0.79 ml of isopropyl chloroformate. The reaction mixture is stirred for 10 minutes, followed by addition of 2 ml of conc. ammonia 25%. After an additional 10 minutes the reaction mixture is diluted with dichloromethane, washed with 0.5N hydrochloric acid and the organic phase is dried over sodium sulfate and concentrated under reduced pressure. The residue is purified by flash chromatography (SiO2 60 F) to afford the title compound as a yellow oil. Rf=0.50 (dichlormethane-methanol 9:1); Rt=4.50.