Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N[C:2]1[C:3](=[O:13])[NH:4][C:5]2[C:10]([CH:11]=1)=[C:9]([CH3:12])[N:8]=[CH:7][CH:6]=2.[OH-:14].[Na+]>C(O)(=O)C>[OH:14][C:2]1[C:3](=[O:13])[NH:4][C:5]2[C:10]([CH:11]=1)=[C:9]([CH3:12])[N:8]=[CH:7][CH:6]=2
Reactant: [OH-]
Reactant: Cc1nccc2[nH]c(=O)c(N)cc12
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1nccc2[nH]c(=O)c(O)cc12
Temperature: 25 °C

Procedure:
This compound was prepared by heating 3-amino-5-methyl-1,6-naphthyridin-2(1H)-one following in part the procedure described in Example E-4 without purification of 3-amino-5-methyl-1,6-naphthyridin-2(1H)-one by reacting said unpurified 3-amino compound with aqueous sodium hydroxide solution or by similarly reacting said purified 3-amino compound with aqueous sodium hydroxide solution. These procedures are described as follows. Following the procedure described in Example E-4 using 27 g of 1,2-dihydro-5-methyl-2-oxo-1,6-naphthyridine-3-carboxylic acid hydrazide, 60 ml of concentrated sulfuric acid, 200 ml of water and 9.1 g of sodium nitrite and after conentrating the reaction mixture to dryness on a rotary evaporator, the residue containing the corresponding said 3-amino compound was treated with 75 ml of 35% sodium hydroxide solution and 100 ml of water and the resulting aqueous mixture was heated on a steam bath for 30 hours and then acidified with acetic acid. The acidified mixture was allowed to stand at room temperature overnight and the resulting product that separated was collected, washed with water and air-dried. It was then recrystallized from 400 ml of boiling dimethylformamide, filtering off the insoluble material, concentrating the filtrate to a volume of about 200 ml and then allowing it to stand at room temperature for 3 hours. The yellow crystalline solid was collected, washed with methanol and dried at 100° C. to yield 7.6 g of 3-hydroxy-5-methyl-1,6-naphthyridin-2-(1H)-one, m.p.>320° C. The same compound was also prepared by heating a mixture containing 3-amino-5-methyl-1,6-naphthyridin-2(1H)-one with 25 ml of 10% aqueous sodium hydroxide solution on a steam bath for 7 hours and then cooled to room temperature. The reaction mixture was acidified with acetic acid and the resulting white crystalline precipitate was collected, washed with water and dried at 95° C. to yield 1.2 g of 3-hydroxy-5-methyl-1,6-naphthyridin-2(1H)-one, m.p.>320° C.
Reaction SMILES: C([O:8][C:9]1[C:14](=[O:15])[CH:13]=[CH:12][N:11]([CH3:16])[C:10]=1[CH:17]([OH:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1)C1C=CC=CC=1>ClCCl.C(O)C>[OH:8][C:9]1[C:14](=[O:15])[CH:13]=[CH:12][N:11]([CH3:16])[C:10]=1[CH:17]([OH:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1
Reactant: Cn1ccc(=O)c(OCc2ccccc2)c1C(O)c1ccccn1
Solvent: CCO
Solvent: ClCCl
Product: Cn1ccc(=O)c(O)c1C(O)c1ccccn1

Procedure:
3-Benzyloxy-2-(hydrox-pyridin-2-yl-methyl-1-methyl-1H-pyridin-4-one: From 2.5 g of 3-benzyloxy-1-methyl-2-[pyridin-2-yl-(tetrahydropyran-2-yloxy)-methyl]-1H-pyridin-4-one there is obtained analogously to Example 7b: 3-benzyloxy-2-(hydroxy-pyridin-2-yl-methyl)-1-methyl-1H-pyridin-4-one. Yellow resin. Rf value: 0.52 (silica gel 60, dichloromethane/ethanol 4/1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][CH:9]=[CH:10][C:3]=12.[H-].[Na+].[CH3:13][Si:14]([CH3:21])([CH3:20])[CH2:15][CH2:16][O:17][CH2:18]Cl>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:18][O:17][CH2:16][CH2:15][Si:14]([CH3:21])([CH3:20])[CH3:13])[CH:9]=[CH:10][C:3]=12
Reactant: Brc1ccnc2[nH]ccc12
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1ccc2c(Br)ccnc21
Reaction time: 1 h
Yield: 94.4 %

Procedure:
A solution of 4-bromo-1H-pyrrolo[2,3-b]pyridine (10.0 g, 0.0508 mol) in DMF (40 mL) was cooled under nitrogen to 0° C. Sodium hydride (3.0 g, 0.075 mol) was added portionwise. The reaction was stirred for 1 hour. To this mixture, [2-(trimethylsilyl)ethoxy]methyl chloride (10.8 mL, 0.061 mol) was added slowly. After being stirred at 0° C. for 1 hour, the reaction was quenched with water and extracted with EtOAc twice. The combined extracts were washed with water, brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with 0-25% EtOAc/hexanes to afford 15.7 g (94.5%) of the desired product as a yellowish oil. LC/MS found: 327.1, 329.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:15](=N)[CH3:16])=[C:4]2[CH:13]=[CH:12][CH:11]=[C:10]3[C:5]2=[C:6]([CH:14]=1)[CH2:7][O:8][CH2:9]3.Cl.[O:19]1CCCC1>>[Cl:1][C:2]1[C:3]([C:15](=[O:19])[CH3:16])=[C:4]2[CH:13]=[CH:12][CH:11]=[C:10]3[C:5]2=[C:6]([CH:14]=1)[CH2:7][O:8][CH2:9]3
Reactant: CC(=N)c1c(Cl)cc2c3c(cccc13)COC2
Reactant: C1CCOC1
Agent: Cl
Product: CC(=O)c1c(Cl)cc2c3c(cccc13)COC2
Temperature: 80 °C

Procedure:
1-(5-Chloro-1H,3H-benzo[de]isochromen-6-yl)-ethylidene-amine (22 g) obtained in Step 1 described above was dissolved in tetrahydrofuran (200 mL), 5 N aqueous hydrochloric acid solution (200 mL) was added, and this was stirred while heating at 80° C. for 48 hours. After cooling the mixture to room temperature, the solvent was removed by using a rotary evaporator. The obtained residue was dissolved in ethyl acetate (400 mL), then washed with water (300 mL) and saturated sodium hydrogen carbonate solution successively, and then dried over sodium sulfate. A residue obtained after filtration and concentration was purified by silica gel column chromatography (developing solvent; n-hexane:dichloromethane:ethyl acetate=10:10:1), and thus, 1-(5-chloro-1H,3H-benzo[de]isochromen-6-yl)-ethanone (19.2 g) was obtained as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[O:12][CH3:13].[CH3:14][C:15]1([CH3:23])[O:20][C:19](=[O:21])[CH2:18][C:17](=[O:22])[O:16]1.[CH:24](OC)(OC)OC>>[CH3:14][C:15]1([CH3:23])[O:20][C:19](=[O:21])[C:18](=[CH:24][NH:1][C:2]2[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=2[O:12][CH3:13])[C:17](=[O:22])[O:16]1
Reactant: COC(OC)OC
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: COC(=O)c1ccc(N)c(OC)c1
Product: COC(=O)c1ccc(NC=C2C(=O)OC(C)(C)OC2=O)c(OC)c1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
Into a 250-mL round-bottom flask, was placed methyl 4-amino-3-methoxybenzoate (10 g, 55.19 mmol, 1.00 equip), 2,2-dimethyl-1,3-dioxane-4,6-dione (9.5 g, 65.91 mmol, 1.20 equip), (CH3O)3CH (100 mL). The resulting solution was stirred overnight at 100° C. The reaction mixture was cooled with a water/ice bath. The solids were collected by filtration to yield methyl 4-[[(2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-ylidene)methyl]amino]-3-methoxybenzoate as a light yellow solid. LCMS (ES, m/z) 336 [M+H]+
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][CH:10]([NH:13][C:14]2[N:19]=[C:18]([CH3:20])[C:17](/[CH:21]=[CH:22]/[C:23](O)=[O:24])=[CH:16][N:15]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH:27]1[O:32][NH2:33].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C.C(OCC)(C)=O.O>[CH2:1]([N:8]1[CH2:12][CH2:11][CH:10]([NH:13][C:14]2[N:19]=[C:18]([CH3:20])[C:17](/[CH:21]=[CH:22]/[C:23]([NH:33][O:32][CH:27]3[CH2:28][CH2:29][CH2:30][CH2:31][O:26]3)=[O:24])=[CH:16][N:15]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NOC1CCCCO1
Reactant: Cc1nc(NC2CCN(Cc3ccccc3)C2)ncc1/C=C/C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nc(NC2CCN(Cc3ccccc3)C2)ncc1/C=C/C(=O)NOC1CCCCO1
Temperature: 25 °C
Reaction time: 15 h
Yield: 22.3 %

Procedure:
A mixture of A mixture of (2E)-3-{2-[(1-benzyl-3-pyrrolidinyl)amino]-4-methyl-5-pyrimidinyl}acrylic acid (693 mg), O-(tetrahydro-2H-pyran-2-yl)hydroxylamine (264 mg), HOBt (290 mg) and EDCI (334 mg) in DMF (20 ml) was stirred at ambient temperature for 15 hours. The reaction mixture was poured into a mixture of AcOEt-H2O and the organic layer was washed with brine and dried over MgSO4. The solvent was evaporated in vacuo and the residue was chromatographed on silicagel eluting with AcOEt-MeOH (9:1). The eluted fractions containing the desired product were collected and evaporated in vacuo to give (2E)-3-{2-[(1-benzyl-3-pyrrolidinyl)amino]-4-methyl-5-pyrimidinyl}-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide (200 mg).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.[CH2:17]([O:21][C:22]1[CH:27]=[C:26](/[CH:28]=[C:29](\[CH3:35])/[C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH:25]=[CH:24][C:23]=1[C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([CH2:42][NH:43][CH3:44])[CH:37]=1)[CH2:18][CH2:19][CH3:20].C(N(CC)CC)C.Cl>CN(C)C1C=CN=CC=1.ClCCl>[C:1]([CH2:44][NH:43][CH2:42][C:38]1[CH:37]=[C:36]([C:23]2[CH:24]=[CH:25][C:26](/[CH:28]=[C:29](\[CH3:35])/[C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:27][C:22]=2[O:21][CH2:17][CH2:18][CH2:19][CH3:20])[CH:41]=[CH:40][CH:39]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CCCCOc1cc(/C=C(\C)C(=O)OCC)ccc1-c1cccc(CNC)c1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: CCCCOc1cc(/C=C(\C)C(=O)OCC)ccc1-c1cccc(CNCC(=O)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 92.7 %

Procedure:
142 μL of benzoyl chloride (1.2 mmol) are added to a solution of 0.36 g (0.6 mmol) of ethyl (E)-3-(2-butoxy-3′-methylaminomethylbiphenyl-4-yl)-2-methylacrylate trifluoroacetate, 6.5 mL of dichloromethane, 257 μL (1.84 mmol) of triethylamine and 7 mg (10 mol %) of 4-dimethylaminopyridine. The reaction medium is stirred at room temperature for 18 hours and then treated with 1 N hydrochloric acid solution and washed with water. The organic phase is dried over magnesium sulfate, filtered and evaporated. The crude residue obtained is purified by chromatography on a column of silica eluted with an 85/15 and then 70/30 heptane/ethyl acetate mixture. 270 mg (91%) of ethyl (E)-3-{3′-[(benzoylmethylamino)methyl]-2-butoxybiphenyl-4-yl}-2-methylacrylate are obtained in the form of a yellow oil.
Reaction SMILES: [C:1]1([CH3:10])[C:2]([C:7](Cl)=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1.O.[C-:12]#[N:13].[Na+]>ClCCl.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH3:10][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([C:12]#[N:13])=[O:8]
Reactant: [C-]#N
Reactant: Cc1ccccc1C(=O)Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: Cc1ccccc1C(=O)C#N
Reaction time: 2 h

Procedure:
To a stirred solution of o-toluoyl chloride (38.86 g) in dichloromethane (250 ml) at room temperature was added water (20.0 ml) followed immediately by tetrabutylammonium bromide (0.15 g) and sodium cyanide (13.0 g). The reaction mixture was stirred vigorously for 11/2 hours, then filtered. The filtrate was washed with water (2×100 ml) then dried (MgSO4) and evaporated under reduced pressure to give a golden oil. Distillation under vacuum gave 2-methylbenzoyl cyanide, as a colourless oil, bp 47-50°/0.05 mm. To 85% w/w sulphuric acid (140 ml) at room temperature was added sodium bromide (20 g) followed immediately by the dropwise addition of 2-methylbenzoyl cyanide (34.8 g). The reaction mixture was then heated gently until the exothermic reaction started and then maintained at 70° C. for 10 minutes by cooling. Methanol (400 ml) was added and the mixture heated under reflux for 1 hour, cooled and diluted with ice/water (500 ml). Extraction with diethyl ether gave a golden oil which was distilled under vacuum to give methyl oxo(o-tolyl)acetate, as a colourless oil, bp 75-85°/0.4 mm.
Reaction SMILES: [CH:1]([C:3]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][C:4]=1[C:5]([OH:7])=[O:6])=[O:2].C1C=CC=CC=1.CCCCCC.[C:26]1([C:32]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[N+]=[N-])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C(Cl)(Cl)Cl>[CH:1]([C:3]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][C:4]=1[C:5]([O:7][CH:32]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:6])=[O:2]
Reactant: COc1ccc(C=O)c(C(=O)O)c1
Reactant: [N-]=[N+]=C(c1ccccc1)c1ccccc1
Solvent: CCCCCC
Solvent: ClC(Cl)Cl
Solvent: c1ccccc1
Product: COc1ccc(C=O)c(C(=O)OC(c2ccccc2)c2ccccc2)c1
Temperature: 25 °C

Procedure:
4.87 g of 2-formyl-5-methoxybenzoic acid was dissolved in 30 ml of chloroform. With stirring at room temperature, a benzene/n-hexane (1:1) mixture solution of diphenyldiazomethane prepared in accordance with the procedure disclosed in Journal of the Chemical Society (Parkin I, pp. 2030-2033, 1975) was added to the above solution until the reaction solution showed a purplish red color. The resulting reaction solution was subjected to purification by silica gel column chromatography using a toluene/ethyl acetate mixture as an eluant to obtain 8.2 g of diphenylmethyl 2-formyl-5-methoxybenzoate as a viscous oil.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([S:8][CH2:9][CH3:10])[N:5]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]([F:22])([F:21])[F:20])=[CH:13][CH:12]=2)[C:4](=[O:23])[CH:3]=1.C([O-])(=O)C.[Na+].[Br:29]Br.O>C(O)(=O)C>[NH2:1][C:2]1[N:7]=[C:6]([S:8][CH2:9][CH3:10])[N:5]([C:11]2[CH:12]=[CH:13][C:14]([O:17][CH2:18][C:19]([F:21])([F:22])[F:20])=[CH:15][CH:16]=2)[C:4](=[O:23])[C:3]=1[Br:29]
Reactant: CCSc1nc(N)cc(=O)n1-c1ccc(OCC(F)(F)F)cc1
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCSc1nc(N)c(Br)c(=O)n1-c1ccc(OCC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 6-amino-2-(ethylsulfanyl)-3-[4-(2,2,2-trifluoroethoxy)phenyl]pyrimidin-4(3H)-one (0.5 g) and sodium acetate (0.143 g) in acetic acid (10 mL) was added dropwise bromine (0.09 mL), and the mixture was stirred at room temperature for 2 hr. To the reaction mixture was added water, and the precipitated crystals were collected by filtration to give the title compound (0.1 g).
Reaction SMILES: Cl.[CH2:2]([C:5]1[N:10]=[CH:9][C:8]([NH2:11])=[C:7]([NH2:12])[CH:6]=1)[CH2:3][CH3:4].N1C=CC=CC=1.[CH3:19][C:20](OC(C)=O)=[O:21].C([O-])(O)=O.[Na+]>C(Cl)Cl.CN(C=O)C>[NH2:12][C:7]1[CH:6]=[C:5]([CH2:2][CH2:3][CH3:4])[N:10]=[CH:9][C:8]=1[NH:11][C:20](=[O:21])[CH3:19]
Reactant: CCCc1cc(N)c(N)cn1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CCCc1cc(N)c(NC(C)=O)cn1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of 6-propyl-pyridine-3,4-diamine hydrochloride (prepared from ethyl butyrylacetate as described in Example 28, steps 1-9) (187 mg, 1.00 mmol) in CH2Cl2 (4 mL) at 0° C. under N2 is added pyridine (0.24 mL, 3.00 mmol) followed by DMF (2 mL) (for solubility). Next, Ac2O (0.104 mL, 1.1 mmol) is added. The reaction mixture is stirred for 3 h while slowly warming to rt. It is then poured into saturated aq NaHCO3 and extracted thrice with CH2Cl2. The combined extracts are dried over K2CO3 and concentrated to 114 mg of crude N-(4-amino-6-propyl-pyridin-3-yl)-acetamide, which was used without further purification. 1H NMR (CDCl3, 300 MHz) δ 8.73 (br, 1H), 8.00 (s, 1H), 8.43 (s, 1H), 4.63 (br, 2H), 2.54 (m, 2H), 2.13 (s, 3H), 1.63 (sextet, J=7.2 Hz, 2H), 0.89 (t, J=7.2 Hz, 3H) ppm. Electrospray MS: m/z 194 [M+1].
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:12])[CH2:5][NH:6][CH2:7][C:8]([O:10][CH3:11])=[O:9].CN1CCOCC1.[I:20][C:21]1[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[CH:23][CH:22]=1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C>[CH3:11][O:10][C:8](=[O:9])[CH2:7][N:6]([C:25](=[O:26])[C:24]1[CH:28]=[CH:29][C:21]([I:20])=[CH:22][CH:23]=1)[CH2:5][C:4]([O:3][CH3:2])=[O:12]
Reactant: COC(=O)CNCC(=O)OC
Reactant: O=C(O)c1ccc(I)cc1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CN1CCOCC1
Product: COC(=O)CN(CC(=O)OC)C(=O)c1ccc(I)cc1
Temperature: 45 °C
Reaction time: 0.08 h

Procedure:
Iminodiacetic dimethyl ester hydrochloride (624 mg, 3.24 mmol) was suspended in 5 mL of anhydrous DMF under nitrogen, and N-methylmorpholine (360 μL, 3.27 mmol) was added. After 5 minutes, 4-iodobenzoic acid (805 mg, 3.25 mmol) was added, followed by HOBt (450 mg, 3.33 mmol) and EDC (1.0 g, 5.28 mmol). The reaction was stirred overnight at 45° C. The solvent was removed and the residue was dissolved in EtOAc (20 mL) and washed with 0.5 M HCl, sat. NaHCO3 and water. The organic phase was collected, the solvent removed and the mixture purified by column chromatography (silica; hexanes:EtOAc 90:10-65:45), yielding the product as a white solid. MS (ES+): Cal'd. 392.00 (MH+), exp. 391.98 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][CH2:5][C:6]1[C:11]([OH:12])=[CH:10][CH:9]=[C:8]([C:13]#[C:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([O:23][CH3:24])=[O:22])=[CH:17][CH:16]=2)[N:7]=1.[CH2:26](Br)[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35]>>[CH3:1][O:2][C:3](=[O:25])[CH2:4][CH2:5][C:6]1[C:11]([O:12][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])=[CH:10][CH:9]=[C:8]([C:13]#[C:14][C:15]2[CH:16]=[CH:17][C:18]([C:21]([O:23][CH3:24])=[O:22])=[CH:19][CH:20]=2)[N:7]=1
Reactant: COC(=O)CCc1nc(C#Cc2ccc(C(=O)OC)cc2)ccc1O
Reactant: CCCCCCCCCCBr
Product: CCCCCCCCCCOc1ccc(C#Cc2ccc(C(=O)OC)cc2)nc1CCC(=O)OC
Yield: 75.1 %

Procedure:
Under the conditions of example 1 D, 500 mg of 3-{3-hydroxy-6-[2-(4-methoxycarbonylphenyl)-ethinyl]-2-pyridyl}-propionic acid methyl ester is reacted with 358 mg of 1-decyl bromide and worked up. 531 mg of 3-{6-[2-(4-methoxycarbonylphenyl)-ethinyl]-3-decyloxy-2-pyridyl}-propionic acid methyl ester of melting point 88°-90° C. is obtained.
Reaction SMILES: [CH:1]1([C:4]2[O:8][N:7]=[C:6]([C:9]3[N:10]=[CH:11][N:12]4[C:21]5[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=5)[NH:15][C:14](=O)[C:13]=34)[N:5]=2)[CH2:3][CH2:2]1.P(Cl)(Cl)(Cl)(Cl)[Cl:24]>P(Cl)(Cl)(Cl)=O>[Cl:24][C:14]1[C:13]2[N:12]([CH:11]=[N:10][C:9]=2[C:6]2[N:5]=[C:4]([CH:1]3[CH2:3][CH2:2]3)[O:8][N:7]=2)[C:21]2[C:16]([N:15]=1)=[CH:17][CH:18]=[CH:19][CH:20]=2
Reactant: O=c1[nH]c2ccccc2n2cnc(-c3noc(C4CC4)n3)c12
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Product: Clc1nc2ccccc2n2cnc(-c3noc(C4CC4)n3)c12
Temperature: 0 °C
Reaction time: 2 h
Yield: 83.9 %

Procedure:
A ground mixture of 3-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-4,5-dihydro-4-oxo-imidazo[1,5-a]quinoxaline (3.76 g, 13 mmol) and phosphorus pentachloride (2.67 g, 13 mmol) in phosphorus oxychloride (10 ml) was stirred for 2 h at 150°-160° C. The resulting solution while still warm was poured into 200 ml of ice and stirred for 1 h. The precipitate was collected by filtration, rinsed with water and dried to give 3.4 g of the title compound, m.p. 140°-150° C. (dec.). The crude product obtained in this way was processed without further purification. (Compound 1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[N:11]1[C:15]([CH3:16])=[N:14][CH:13]=[N:12]1.C(N(CC)CC)C.[H][H]>O1CCCC1.[Pd]>[F:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1[N:11]1[C:15]([CH3:16])=[N:14][CH:13]=[N:12]1
Reactant: [H][H]
Reactant: Cc1ncnn1-c1ccc([N+](=O)[O-])cc1F
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1ncnn1-c1ccc(N)cc1F
Yield: 75.2 %

Procedure:
1-(2-Fluoro-4-nitro-phenyl)-5-methyl-1H-[1,2,4]triazole (120 mg, 0.54 mmol) was dissolved in tetrahydrofurane (6 mL) and triethylamine (10 mL) and stirred for 4 hours with 10% palladium on carbon (50 mg) under 3 bar of hydrogen. The reaction mixture was filtered and the solvent was removed in vacuo to yield the title compound (78 mg, 75%) as a yellow solid. MS ISP (m/e): 193.3 [(M+H)+]. 1H NMR (CDCl3, 300 MHz): δ (ppm)=7.93 (s, 1H), 7.16 (dd, 1H), 6.51 (m, 2H), 4.03 (s broad, 2H), 2.38 (s, 3H). Mp 106-108° C.
Reaction SMILES: [H-].[Na+].[CH2:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5][NH:4]1.Cl[C:14]1[CH:19]=[CH:18][N:17]=[CH:16][C:15]=1[N+:20]([O-:22])=[O:21]>CN(C)C=O.O.C(OCC)(=O)C>[N+:20]([C:15]1[CH:16]=[N:17][CH:18]=[CH:19][C:14]=1[N:4]1[CH2:5][CH2:6][C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:3]1)([O-:22])=[O:21]
Reactant: c1ccc2c(c1)CCNC2
Reactant: O=[N+]([O-])c1cnccc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cnccc1N1CCc2ccccc2C1
Reaction time: 0.17 h
Yield: 62.4 %

Procedure:
Sodium hydride (60%, 386.4 mg, 9.66 mmol) was added at 0° C. to a solution of 1,2,3,4-tetrahydroisoquinoline (1.06 ml, 8.05 mmol) in N,N-dimethylformamide (30 ml) and stirred for 10 minutes at the same temperature. 4-Chloro-3-nitropyridine (1.124 g, 7.09 mmol) prepared in Step 1 was added to the reaction mixture, which was stirred for 2 hours at room temperature, diluted with a mixture of water (10 ml) and ethyl acetate (100 ml), and then washed with water (100 ml) twice. The separated organic layer was dried on anhydrous magnesium sulfate and concentrated under reduced pressure to give the titled compound as a yellow solid (1.13 g, 89.3%).
Reaction SMILES: Cl[C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[F:11][C:12]1[C:18]([C:19]([F:22])([F:21])[F:20])=[CH:17][CH:16]=[CH:15][C:13]=1[NH2:14]>>[N:6]1[C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[NH:3][C:2]=1[NH:14][C:13]1[CH:15]=[CH:16][CH:17]=[C:18]([C:19]([F:20])([F:21])[F:22])[C:12]=1[F:11]
Reactant: Clc1nc2ccccc2[nH]1
Reactant: Nc1cccc(C(F)(F)F)c1F
Product: Fc1c(Nc2nc3ccccc3[nH]2)cccc1C(F)(F)F

Procedure:
The title compound was prepared from 2-chlorobenzimidazole and 2-fluoro-3-(trifluoromethyl)aniline by Procedure A. The product was isolated by filtration and preparative LCMS to give the title compound as the free base (solid, mp 91-92° C.). MS(ES+) m/z 296 ([M+1]+, 100).
Reaction SMILES: [OH:1][N:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]3[CH:12]=[N:13][N:14]([CH:16]4[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][CH2:17]4)[CH:15]=3)[CH:9]=2)[CH:4]=[CH:3]1.Br[C:30]1[N:35]=[CH:34][CH:33]=[CH:32][N:31]=1>>[NH:19]1[CH2:20][CH2:21][CH:16]([N:14]2[CH:15]=[C:11]([C:8]3[CH:9]=[C:10]4[N:2]([O:1][C:30]5[N:35]=[CH:34][CH:33]=[CH:32][N:31]=5)[CH:3]=[CH:4][C:5]4=[N:6][CH:7]=3)[CH:12]=[N:13]2)[CH2:17][CH2:18]1
Reactant: Brc1ncccn1
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(-c3cnc4ccn(O)c4c3)cn2)CC1
Product: c1cnc(On2ccc3ncc(-c4cnn(C5CCNCC5)c4)cc32)nc1

Procedure:
The entitled compound is prepared from tert-butyl 4-[4-(1-hydroxy-1H-pyrrolo[3,2-b]pyridin-6-yl)-1H-pyrazol-1-yl]piperidine-1-carboxylate and 2-bromo-pyrimidine as described in the last 2 steps of Example 18.
Reaction SMILES: [Cl:1][C:2](Cl)([O:4]C(=O)OC(Cl)(Cl)Cl)Cl.N1C=CC=CC=1.[F:19][C:20]([F:34])([F:33])[C:21]1[CH:22]=[C:23]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[CH:24]=[CH:25][CH:26]=1>O1CCCC1>[F:34][C:20]([F:19])([F:33])[C:21]1[CH:22]=[C:23]([N:27]2[CH2:32][CH2:31][N:30]([C:2]([Cl:1])=[O:4])[CH2:29][CH2:28]2)[CH:24]=[CH:25][CH:26]=1
Reactant: FC(F)(F)c1cccc(N2CCNCC2)c1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: O=C(Cl)N1CCN(c2cccc(C(F)(F)F)c2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 78.7 %

Procedure:
A mixture of triphosgene (3.2 g, 10.85 mmol) in tetrahydrofuran (10 mL) was slowly treated with pyridine (1.72 g, 21.72 mmol) via syringe. The resulting white suspension was then treated portionwise with 1-[3-(trifluoromethyl)phenyl]piperazine (500 mg, 2.17 mmol). The reaction mixture was allowed to stir at 25° C. for 18 h. At this time, the reaction was slowly quenched by the addition of water. The aqueous layer was extracted with methylene chloride. The organics were washed with a saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated in vacuo to afford 4-(3-trifluoromethyl-phenyl)piperazine-1-carbonyl chloride (500 mg, 79%). The NMR spectrum obtained on the sample is compatible with its structure.