Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[C:4]([N+:9]([O-:11])=[O:10])[C:5]([Cl:8])=[N:6][CH:7]=1.[NH3:13]>O1CCOCC1>[Br:1][C:2]1[C:3]([NH2:13])=[C:4]([N+:9]([O-:11])=[O:10])[C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: O=[N+]([O-])c1c(Cl)ncc(Br)c1Cl
Reactant: N
Solvent: C1COCCO1
Product: Nc1c(Br)cnc(Cl)c1[N+](=O)[O-]
Temperature: 30 °C
Yield: 46 %

Procedure:
A 250 mL round bottom flask was charged with 5-bromo-2,4-dichloro-3-nitropyridine (3.5 g, 12.6 mmol) and a solution of ammonia in 1,4-dioxane (150 mL). The mixture was heated at 30° C. for 4 h. Work-up: the reaction mixture was concentrated in vacuo. The residue was poured into saturated aqueous NaHCO3 and extracted with EtOAc. The combined organic layers were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was further purified by flash column chromatography on silica gel with 20% EtOAc in petroleum ether, to afford 1.5 g (46%) of the product as a white solid. MS m/z: 252 (M+H+).
Reaction SMILES: CN(C)[CH:3]=[C:4]([C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][C:14]=1[N+:20]([O-])=O)[CH:5]=[C:6]1[C:10](=[O:11])[O:9][C:8]([CH3:12])=[N:7]1.C(OC(=O)C)(=O)C.[H][H]>[Pt].C(O)(=O)C>[CH3:19][C:16]1[CH:15]=[C:14]2[C:13]([C:4](/[CH:5]=[C:6]3\[N:7]=[C:8]([CH3:12])[O:9][C:10]\3=[O:11])=[CH:3][NH:20]2)=[CH:18][CH:17]=1
Reactant: CC1=NC(=CC(=CN(C)C)c2ccc(C)cc2[N+](=O)[O-])C(=O)O1
Reactant: [H][H]
Agent: [Pt]
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: CC1=N/C(=C\c2c[nH]c3cc(C)ccc23)C(=O)O1
Yield: 35 %

Procedure:
A 500-ml. Parr bottle was charged with 3.17 g. (10 mmol) of 4-[3-dimethylamino-2-(4-methyl-2-nitrophenyl)-2-propen-1-ylidene]-2-methyl-2-oxazolin-5-one, 5 ml. of acetic anhydride, 95 ml. of glacial acetic acid, and 600 mg. of 10% platinum on charcoal, and was shaken under 3 atmospheres of hydrogen for 12 hours. During this time, 34 mmol of hydrogen were absorbed. The reaction was treated as in Example 4. 0.83 g. (35%) of (Z)-4-(6-methylindol-3-ylmethylene)-2-methyl-2-oxazolin-5-one (mp 194°-196° C.) was thereby obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:3]=1[C:4]([OH:6])=[O:5].[CH2:12]=[C:13]1[O:17][C:15](=O)[CH2:14]1.C(Cl)(Cl)(Cl)Cl.C(OC(=O)C)(=O)C>CC(C)=O>[CH3:11][C:7]1[C:3]2[C:4](=[O:6])[O:5][C:15]([CH2:14][C:13](=[O:17])[CH3:12])=[N:1][C:2]=2[CH:10]=[CH:9][CH:8]=1
Reactant: C=C1CC(=O)O1
Reactant: Cc1cccc(N)c1C(=O)O
Solvent: CC(=O)OC(C)=O
Solvent: ClC(Cl)(Cl)Cl
Solvent: CC(C)=O
Product: CC(=O)Cc1nc2cccc(C)c2c(=O)o1
Temperature: 25 °C
Reaction time: 8 h
Yield: 48 %

Procedure:
To a solution of 2-amino-6-methylbenzoic acid (20 g, 0.132 mol) in acetone (100 mL), diketene (15.3 mL, 0.198 mol) was added dropwise at room temperature, and the mixture was stirred overnight at room temperature. The reaction solvent and excess diketene was evaporated under reduced pressure. To the residue, carbon tetrachloride (80 mL) and subsequently acetic anhydride (27 g, 0.265 mol) were added, and the mixture was heated under reflux for 3 hours. The reaction solvent and excess acetic anhydride were evaporated and concentrated under reduced pressure, and the resulting powder was collected by filtration and washed with diethylether to give crude 5-methyl-2-(2-oxopropyl)-4H-3,1-benzoxazin-4-one (13.75 g, 48% yield). A solution of the compound (12.99 g, 0.06 mol) and 2-hydrazinopyridine (7.18 g, 0.066 mol) in ethanol (100 mL) was heated under reflux for 1 hour. The reaction solution was allowed to cool to room temperature, and the reaction solvent was evaporated and concentrated under reduced pressure. A solution of the residue in phosphorous oxychloride (45.8 g, 0.3 mol) was heated and stirred at 100° C. for 1 hour. After the reaction solution was cooled to room temperature, the reaction solvent was evaporated and concentrated under reduced pressure, and the residue was poured into iced water, which was made basic by the addition of a sodium hydroxide solution, and organic matter was extracted with chloroform. The extract was washed with saturated brine and water, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue thus obtained was purified by silica gel column chromatography (ethyl acetate:methanol=98:2) to give the title compound (4.4 g, 24% yield).
Reaction SMILES: C[O:2][C:3]1[C:8]([N+:9]([O-:11])=[O:10])=[C:7]([O:12]C)[C:6]([N+:14]([O-:16])=[O:15])=[C:5]([O:17]C)[C:4]=1[N+:19]([O-:21])=[O:20].N.[C:23]1([NH2:40])[C:28]([N+:29]([O-:31])=[O:30])=[C:27]([NH2:32])[C:26]([N+:33]([O-:35])=[O:34])=[C:25]([NH2:36])[C:24]=1[N+:37]([O-:39])=[O:38]>>[N+:9]([C:8]1[C:3]([OH:2])=[C:4]([N+:19]([O-:21])=[O:20])[C:5]([OH:17])=[C:6]([N+:14]([O-:16])=[O:15])[C:7]=1[OH:12])([O-:11])=[O:10].[C:23]1([NH2:40])[C:24]([N+:37]([O-:39])=[O:38])=[C:25]([NH2:36])[C:26]([N+:33]([O-:35])=[O:34])=[C:27]([NH2:32])[C:28]=1[N+:29]([O-:31])=[O:30]
Reactant: COc1c([N+](=O)[O-])c(OC)c([N+](=O)[O-])c(OC)c1[N+](=O)[O-]
Agent: N
Agent: Nc1c([N+](=O)[O-])c(N)c([N+](=O)[O-])c(N)c1[N+](=O)[O-]
Product: O=[N+]([O-])c1c(O)c([N+](=O)[O-])c(O)c([N+](=O)[O-])c1O

Procedure:
One method of synthesizing TATB from phloroglucinol is described in GB 2355715. Phloroglucinol, also known as 1,3,5-trihydroxybenzene, is nitrated using sodium nitrite and nitric acid, forming trinitrophloroglucinol (“TNPG”), which is also known as 1,3,5-trihydroxy-2,4,6-trinitrobenzene. The nitric acid is added sequentially or in multiple additions. When cooled, a solid is produced, which is filtered, washed with 3 M hydrochloric acid (“HCl”), and dried, yielding a solid product that is a monohydrate of TNPG. The monohydrate of TNPG is a free-flowing solid. The TNPG is alkoxylated using a trialkyl orthoformate, such as trimethyl orthoformate, forming 1,3,5-trimethoxy-2,4,6-trinitrobenzene. Methanol and methyl formate are also formed and are removed by distillation. The solution of 1,3,5-trimethoxy-2,4,6-trinitrobenzene is concentrated, yielding 1,3,5-trimethoxy-2,4,6-trinitrobenzene as a solid, which is recrystallized from ethanol. The purified 1,3,5-trimethoxy-2,4,6-trinitrobenzene is then aminated using liquid ammonia or gaseous ammonia, filtered, washed with N-methylpyrrolidinone and methanol, and dried, yielding crystals of the TATB. To conduct the amination reaction, a solution of the 1,3,5-trimethoxy-2,4,6-trinitrobenzene is cooled to −10° C. and ammonia gas is introduced. If liquid ammonia is used, the animation reaction is conducted at room temperature and a pressure of 8-9 bar, or at atmospheric pressure and −33° C. If gaseous ammonia is used, the animation reaction is conducted at atmospheric pressure or at a pressure of 8-9 bar. At higher temperatures, the method is described as being less energy efficient. The TATB synthesis utilizes multiple drying and isolation acts to produce solid products of TNPG, TETNB, and TATB.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([N:9]2[CH2:15][CH2:14][CH2:13][N:12](C(O)=O)[CH2:11][CH2:10]2)=[N:5][CH:6]=[CH:7][CH:8]=1.[ClH:19].O1CCOCC1>CO>[ClH:19].[ClH:19].[CH3:1][O:2][C:3]1[C:4]([N:9]2[CH2:15][CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[N:5][CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccnc1N1CCCN(C(=O)O)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: COc1cccnc1N1CCCNCC1
Reaction time: 15 h

Procedure:
To 4-(3-methoxypyridin-2-yl)-[1,4]diazepane-1-carboxylic acid tent-butyl ester (335 mg, 1.1 mmol) was added MeOH (3 mL) followed by 4M HCl in dioxane (5 mL, 20 mmol). This was stirred for 15 hours, then concentrated to give the title compound. MS (ES) m/z 208 (M+H+).
Reaction SMILES: [SH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][N:3]=1.Cl.[CH3:12][C@@H:13]([NH2:18])[C:14]([F:17])([F:16])[F:15].CCOC1N(C(OCC)=O)C2C(=CC=CC=2)C=C1.C(N(CC)CC)C>CN(C=O)C.O>[SH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:18][C@H:13]([CH3:12])[C:14]([F:17])([F:16])[F:15])=[O:8])=[CH:4][N:3]=1
Reactant: O=C(O)c1ccc(S)nc1
Reactant: C[C@@H](N)C(F)(F)F
Agent: CCOC(=O)N1c2ccccc2C=CC1OCC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: C[C@@H](NC(=O)c1ccc(S)nc1)C(F)(F)F
Yield: 17.1 %

Procedure:
Combine 6-mercapto-nicotinic acid (655 mg, 4.2 mmol), (R)-1-methyl-2,2,2-trifluoro-ethylamine hydrochloride (634 mg, 4.2 mmol) and EEDQ (1.06 g, 4.3 mmol) in anhydrous DMF (3 mL). Add triethylamine (0.6 mL, 4.3 mmol) and stir at room temperature for 16 h. Dilute the reaction mixture with water and extract with EtOAc (4×40 mL). Wash the combined organic extracts with brine, dry over MgSO4, filter and concentrate in vacuo. Purify the crude mixture by chromatography on silica gel eluting with hexane/EtOAc (3:2) to obtain the title compound as a yellow solid (180 mg, 18%). MS (ES+) m/z: 251.2 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][C:8](=[O:11])[N:7]([CH3:12])[C:6]=2[CH:13]=1.[F:14][C:15]([F:26])([F:25])[C:16]1[CH:17]=[CH:18][C:19]([CH2:22][CH2:23][NH2:24])=[N:20][CH:21]=1>>[CH3:12][N:7]1[C:6]2[CH:13]=[C:2]([NH:24][CH2:23][CH2:22][C:19]3[CH:18]=[CH:17][C:16]([C:15]([F:26])([F:14])[F:25])=[CH:21][N:20]=3)[CH:3]=[CH:4][C:5]=2[O:10][CH2:9][C:8]1=[O:11]
Reactant: CN1C(=O)COc2ccc(Br)cc21
Reactant: NCCc1ccc(C(F)(F)F)cn1
Product: CN1C(=O)COc2ccc(NCCc3ccc(C(F)(F)F)cn3)cc21

Procedure:
In analogy to the procedure described for the synthesis example 71 (step 1), the title compound 4-methyl-6-[2-(5-trifluoromethyl-pyridin-2-yl)-ethylamino]-4H-benzo[1,4]oxazin-3-one (MS m/e: 352.2 [M+H]+) was prepared from 6-bromo-4-methyl-4H-benzo[1,4]oxazin-3-one instead of 6-bromo-2,3-dihydro-benzofuran and 2-(5-trifluoromethyl-pyridin-2-yl)-ethylamine instead of 2-(6-trifluoromethyl-pyridin-3-yl)-ethylamine.
Reaction SMILES: OCC(C)(C)C(=O)CC#N.C[O:12][CH2:13][C:14]([C:17]1[O:21][N:20]=[C:19]([NH2:22])[CH:18]=1)([CH3:16])[CH3:15]>>[NH2:22][C:19]1[CH:18]=[C:17]([C:14]([CH3:16])([CH3:15])[CH2:13][OH:12])[O:21][N:20]=1
Reactant: COCC(C)(C)c1cc(N)no1
Agent: CC(C)(CO)C(=O)CC#N
Product: CC(C)(CO)c1cc(N)no1
Yield: 49 %

Procedure:
Prepared from 5-hydroxy-4,4-dimethyl-3-oxopentanenitrile (1 g, 7.90 mmol) according to the method described for 5-(1-methoxy-2-methylpropan-2-yl)isoxazol-3-amine. Purification via recrystallisation from diethyl ether afforded 2-(3-aminoisoxazol-5-yl)-2-methylpropan-1-ol as a colorless solid (600 mg, 49%). 1H NMR (300 MHz, CDCl3) δ 5.64 (s, 1H), 3.65 (s, 2H), 2.30 (brs, 2H), 1.31 (s, 6H).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[NH:14][CH:13]=[C:12]([CH:15]=[O:16])[CH:11]=1.C1OCCOCCOCCOCCOC1.[N:32]1[CH:37]=[CH:36][CH:35]=[C:34]([S:38](Cl)(=[O:40])=[O:39])[CH:33]=1>>[Br:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[N:14]([S:38]([C:34]2[CH:33]=[N:32][CH:37]=[CH:36][CH:35]=2)(=[O:40])=[O:39])[CH:13]=[C:12]([CH:15]=[O:16])[CH:11]=1
Reactant: O=S(=O)(Cl)c1cccnc1
Reactant: O=Cc1c[nH]c(-c2ccccc2Br)c1
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Product: O=Cc1cc(-c2ccccc2Br)n(S(=O)(=O)c2cccnc2)c1

Procedure:
By a similar operation as in Reference Example 154 and using sodium hydride (60% in oil, 91.0 mg), 5-(2-bromophenyl)-1H-pyrrole-3-carbaldehyde (396 mg), 15-crown-5 (418 mg) and pyridin-3-ylsulfonyl chloride (309 mg), the title compound was obtained as a pale-yellow solid (yield 560 mg, 91%).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]([NH:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11](Cl)=[O:12])=[O:4].[CH:16]1[C:27]2[CH:26]=[CH:25][C:24]3[CH:28]=[CH:29][CH:30]=[CH:31][C:23]=3[CH2:22][NH:21][C:20]=2[CH:19]=[CH:18][CH:17]=1.N1C=CC=CC=1>C(Cl)Cl>[CH:16]1[C:27]2[CH:26]=[CH:25][C:24]3[CH:28]=[CH:29][CH:30]=[CH:31][C:23]=3[CH2:22][N:21]([C:11](=[O:12])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][NH:5][C:3](=[O:4])[C:2]([F:15])([F:14])[F:1])[C:20]=2[CH:19]=[CH:18][CH:17]=1
Reactant: C1=Cc2ccccc2NCc2ccccc21
Reactant: O=C(Cl)CCCCCNC(=O)C(F)(F)F
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(CCCCCNC(=O)C(F)(F)F)N1Cc2ccccc2C=Cc2ccccc21
Reaction time: 0.5 h
Yield: 70.7 %

Procedure:
6-(trifluoroacetamido)hexanoyl chloride (Clark et al., Chem. Soc. Perkin Trans. 1 2001:3312-3324) (0.984 g, 4.52 mmol) was added to a solution of 2 (0.75 g, 3.62 mmol) and pyridine (0.859 g, 10.86 mmol) in CH2Cl2 (approximately 10 ml) at room temperature, and stirred for 30 minutes. The reaction mixture was diluted with CH2Cl2 (approximately 20 mL), washed with water (2×30 mL), dried over anhydrous MgSO4 and the solvent was removed under reduced pressure. The residue was purified by chromatography (hexanes:ethyl acetate 2:3) to provide 1.064 g (2.56 mmol, 71%) of 3 as yellowish oil. 1H: δ 7.32-7.22 (m, 4H), 7.19-7.11 (m, 4H), 6.77 (d, J=13.2 Hz, 1H), 6.58 (d, J=13.2 Hz, 1H), 5.46 (d, J=14.8 Hz, 1H), 4.20 (d, J=14.8 Hz, 1H), 3.29-3.15 (m, 2H), 2.09-2.02 (m, 1H), 1.93-1.85 (m, 1H), 1.51-1.32 (m, 4H), 1.25-1.04 (m, 2H); 13C: 172.7, 157.5, 141.1, 136.1, 135.8, 134.8, 132.4, 131.8, 130.5, 128.5, 128.2, 128.1, 128.0, 127.3, 127.2, 117.5, 114.6, 54.8, 39.6, 34.3, 28.2, 25.9, 24.3; FIRMS (ESI+) m/z calcd for C23H24F3N2O2 [M+H]+ 417.1790. found 417.1783.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:15]=[CH:14][C:10]([C:11]([O-:13])=O)=[CH:9][CH:8]=2)=[CH:3][CH:2]=1.[Na+].C(Cl)(=O)C(Cl)=O.[C:23]([O:27][C:28]([NH:30][C:31]1[CH:36]=[CH:35][N:34]=[CH:33][C:32]=1[NH2:37])=[O:29])([CH3:26])([CH3:25])[CH3:24].[OH-].[Na+]>C(Cl)Cl.O1CCCC1.C(OCC)(=O)C.N1C=CC=CC=1.CN(C)C=O>[C:23]([O:27][C:28]([NH:30][C:31]1[CH:36]=[CH:35][N:34]=[CH:33][C:32]=1[NH:37][C:11](=[O:13])[C:10]1[CH:9]=[CH:8][C:7]([C:4]2[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=2)=[CH:15][CH:14]=1)=[O:29])([CH3:26])([CH3:24])[CH3:25]
Reactant: O=C([O-])c1ccc(-c2ccncc2)cc1
Reactant: CC(C)(C)OC(=O)Nc1ccncc1N
Agent: O=C(Cl)C(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)Nc1ccncc1NC(=O)c1ccc(-c2ccncc2)cc1
Reaction time: 0.75 h
Yield: 10 %

Procedure:
A suspension of sodium 4-(4-pyridyl)benzoate (425 mg, 1.92 mmol) in methylene chloride was treated with oxalyl chloride (0.840 mL, 9.60 mmol), followed by dimethylformamide (0.01 mL)). After 0.75 h, the mixture was concentrated in vacuo. The residue was then dissolved in methylene chloride and added dropwise to a solution of N4-(tert-butyloxycarbonyl)-3,4-pyridinediamine (400 mg, 1.92 mmol) and pyridine (0.31 mL) in methylene chloride (2 mL) and tetrahydrofuran (1 mL). After 16 h, the mixture was poured into ethyl acetate and 1 N aqueous sodium hydroxide. The organic layer was washed once with 1 N aqueous sodium hydroxide, once with saturated sodium chloride solution, dried (potassium carbonate), and filtered. The residue was purified by flash chromatography (silica gel, ethyl acetate/hexanes) to yield 75 mg (10%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH3:21])[N:14]([CH2:15][CH2:16][CH2:17][C:18](=O)[CH3:19])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.Cl.[NH2:23][OH:24].[OH-].[Na+]>C(O)C.O>[NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH3:21])[N:14]([CH2:15][CH2:16][CH2:17][C:18](=[N:23][OH:24])[CH3:19])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1
Reactant: CC(=O)CCCn1c(C)nc2c(N)nc3ccccc3c21
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(CCCn1c(C)nc2c(N)nc3ccccc3c21)=NO
Reaction time: 0.5 h

Procedure:
A solution of 5-(4-amino-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)pentan-2-one, 2.20 g, 7.80 mmol) in ethanol (50 mL) was heated at reflux, and a solution of hydroxylamine hydochloride (1.08 g, 15.6 mmol) in water (10 mL) was added, followed by a solution of sodium hydroxide (0.94 g, 23.5 mmol) in water (10 mL). After 30 minutes, the reaction mixture was cooled in an ice bath to cause crystallization of the product, which was isolated by filtration and recrystallized from aqueous DMSO to provide 5-(4-amino-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)pentan-2-one oxime in about a 16 to 1 mixture of E and Z isomers as yellow crystals, mp 264-266° C.
Reaction SMILES: C([O:3][CH2:4][CH2:5][O:6][NH:7][C:8]([C:10]1[C:11]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([Br:26])=[CH:22][C:21]=2[F:27])=[CH:12][C:13]2[N:14]([CH:16]=[CH:17][N:18]=2)[N:15]=1)=[O:9])=C.BrC1C=CC(NC2C(C(O)=O)=NN3C=CN=C3C=2)=C(F)C=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.C(OCCON)=C.CCN(CC)CC>CC(N(C)C)=O.CCOC(C)=O>[OH:3][CH2:4][CH2:5][O:6][NH:7][C:8]([C:10]1[C:11]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([Br:26])=[CH:22][C:21]=2[F:27])=[CH:12][C:13]2[N:14]([CH:16]=[CH:17][N:18]=2)[N:15]=1)=[O:9]
Reactant: C=COCCONC(=O)c1nn2ccnc2cc1Nc1ccc(Br)cc1F
Agent: C=COCCON
Agent: CCN=C=NCCCN(C)C
Agent: O=C(O)c1nn2ccnc2cc1Nc1ccc(Br)cc1F
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: O=C(NOCCO)c1nn2ccnc2cc1Nc1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Preparation of 7-(4-bromo-2-fluorophenylamino)-imidazo[1,2-b]pyridazine-6-carboxylic acid (2-vinyloxyethoxy)-amide: A mixture of 7-(4-bromo-2-fluorophenylamino)-imidazo[1,2-b]pyridazine-6-carboxylic acid (1.00 equiv), EDCI (1.50 equivalents), and HOBt (1.50 equivalents) in DMA is stirred for 30 minutes at room temperature under N2. O-(2-vinyloxy-ethyl)-hydroxylamine (3.00 equivalents) is added followed by Et3N (2.50 equivalents). After the reaction mixture is stirred for 16 hours at room temperature, it is diluted with EtOAc and washed with saturated NH4Cl solution, saturated NaHCO3 solution and saturated NaCl. The organic layer is dried (Na2SO4) and concentrated under reduced pressure to yield the desired product. The product may be purified by flash column chromatography if further purification is necessary.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:18][CH:17]([C:19]([N:21]2[CH2:25][CH2:24][C@@H:23]([OH:26])[CH2:22]2)=[O:20])[CH2:16]1)=O)(C)(C)C>ClCCl>[NH:15]1[CH2:18][CH:17]([C:19]([N:21]2[CH2:25][CH2:24][C@@H:23]([OH:26])[CH2:22]2)=[O:20])[CH2:16]1
Reactant: CC(C)(C)OC(=O)N1CC(C(=O)N2CC[C@@H](O)C2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(C1CNC1)N1CC[C@@H](O)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.3 %

Procedure:
Trifluoroacetic acid (3 mL) was added to a solution of 3-((R)-3-hydroxypyrrolidine-1-carbonyl)azetidine-1-carboxylic acid tert-butyl ester (420 mg, 1.55 mmol) in dichloromethane (12 mL) The resulting reaction mixture was stirred at RT for 2 h. The solvents were reduced in vacuo. The resulting residue was loaded onto an Isolute® SCX-2 cartridge (10 g). The cartridge was washed with DCM/MeOH, the desired product was subsequently eluted using a mixture of 2M NH3 in MeOH and DCM to afford Azetidin-3-yl-((R)-3-hydroxypyrrolidin-1-yl)methanone as colourless oil (225 mg, 85%). 1H NMR (400 MHz, DMSO, d6): δ 4.26-4.22 (1 H, m), 3.47-3.44 (10 H, m), 2.13-2.09 (1 H, m), 1.81 (2 H, m)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[CH2:5][O:6][C:7]1[CH:18]=[CH:17][C:10]2[CH2:11][C:12](=[O:16])[NH:13][CH2:14][CH2:15][C:9]=2[CH:8]=1.[C:22]([O-])(=[O:24])[CH3:23].[Na+].O.ClCCl>C(OC(=O)C)(=O)C>[C:22]([N:13]1[CH2:14][CH2:15][C:9]2[CH:8]=[C:7]([O:6][CH2:5][C:4]3[CH:19]=[CH:20][CH:21]=[C:2]([Cl:1])[CH:3]=3)[CH:18]=[CH:17][C:10]=2[CH2:11][C:12]1=[O:16])(=[O:24])[CH3:23]
Reactant: O=C1Cc2ccc(OCc3cccc(Cl)c3)cc2CCN1
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: O
Solvent: ClCCl
Product: CC(=O)N1CCc2cc(OCc3cccc(Cl)c3)ccc2CC1=O
Temperature: 145 °C
Yield: 65.4 %

Procedure:
A mixture of 50 mg (0.2 mmol) of 7-(3-chloro-benzyloxy)-1,3,4,5-tetrahydro-benzo[d]azepin-2-one and 33 mg (0.4 mmol) of sodium acetate in 0.12 ml of acetic acid anhydride was heated to 145° C. during 4.5 hours. For the working-up, the reaction mixture was cooled and treated with water and dichloromethane. The organic layer was separated, washed with a saturated solution of sodium hydrogencarbonate, and, finally, evaporated. For purification, the crude material obtained was chromatographed on silica gel using a 4:1-mixturet of heptane and ethyl acetate as the eluent. There were obtained 45 mg (79% of theory) of 3-acetyl-7-(3-chloro-benzyloxy)-1,3,4,5-tetrahydro-benzo[d]azepin-2-one as a white foam; MS: m/e=344 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[NH:10][C:9]2[C:8](=[O:11])[N:7]([CH2:12][C:13]#[N:14])[C:6](=[O:15])[N:5]([CH2:16][CH2:17][CH3:18])[C:4]=2[N:3]=1.ClC1N(CC=C)[C:27]2C(=O)NC(=O)N(CCC3CC3)[C:22]=2N=1>>[Cl:1][C:2]1[NH:10][C:9]2[C:8](=[O:11])[N:7]([CH2:12][C:13]#[N:14])[C:6](=[O:15])[N:5]([CH2:16][CH2:17][CH:18]3[CH2:27][CH2:22]3)[C:4]=2[N:3]=1
Reactant: C=CCn1c(Cl)nc2c1c(=O)[nH]c(=O)n2CCC1CC1
Reactant: CCCn1c(=O)n(CC#N)c(=O)c2[nH]c(Cl)nc21
Product: N#CCn1c(=O)c2[nH]c(Cl)nc2n(CCC2CC2)c1=O

Procedure:
Prepared as (8-chloro-2,6-dioxo-3-propyl-2,3,6,7-tetrahydro-1H-purin-1-yl)acetonitrile (example 23) using 8-chloro-3-(2-cyclopropylethyl)-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione.
Reaction SMILES: [C:1](O)(=O)CCC/C=C\C/C=C\C/C=C\C/C=C\CCCCC.C([Li])CCC.[C:28]([O:49][CH2:50][CH3:51])(=[O:48])[CH2:29][CH2:30][CH2:31]/[CH:32]=[CH:33]\[CH2:34]/[CH:35]=[CH:36]\[CH2:37]/[CH:38]=[CH:39]\[CH2:40]/[CH:41]=[CH:42]\[CH2:43][CH2:44][CH2:45][CH2:46][CH3:47].CI>>[CH3:1][CH:29]([CH2:30][CH2:31]/[CH:32]=[CH:33]\[CH2:34]/[CH:35]=[CH:36]\[CH2:37]/[CH:38]=[CH:39]\[CH2:40]/[CH:41]=[CH:42]\[CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])[C:28]([O:49][CH2:50][CH3:51])=[O:48]
Reactant: CCCCC/C=C\C/C=C\C/C=C\C/C=C\CCCC(=O)OCC
Reactant: CCCCC/C=C\C/C=C\C/C=C\C/C=C\CCCC(=O)O
Agent: [Li]CCCC
Solvent: CI
Product: CCCCC/C=C\C/C=C\C/C=C\C/C=C\CCC(C)C(=O)OCC

Procedure:
The instant compounds having the 5, 8, 11 and 14 double bonds are prepared preferably by alkylating the appropriate alkyl ester of arachidonic acid with an alkyl iodide in the presence of a base, such as a secondary amine, and n-alkyl lithium, i.e. n-butyl lithium. Typically, ethyl arachidonate is added to n-isopropylcyclohexylamine containing n-butyl lithium at a low temperature, e.g. -78°C., and then methyl iodide is added to yield ethyl 2-methylarachidonate. That same procedure then is repeated with ethyl 2-methylarachidonate in place of ethyl arachidonate to yield ethyl 2,2-dimethylarachidonate. The ester moiety can be cleaved with lithium iodide in an aromatic amine, e.g. collidine, to yield the corresponding acid. For example, methyl 2,2-dimethylarachidonate, when treated with lithium iodide in collidine, affords 2,2-dimethyl arachidonic acid.
Reaction SMILES: [CH:1]1[N:5]([CH2:6][O:7][CH2:8][CH2:9][OH:10])[C:4]2[N:11]=[C:12]([NH2:16])[N:13]=[C:14]([OH:15])[C:3]=2[N:2]=1.[H-].[Na+].Br[CH2:20][C:21]([C:23]1[CH:28]=[CH:27][C:26]([Br:29])=[CH:25][CH:24]=1)=O.N>CN(C=O)C>[OH:10][CH2:9][CH2:8][O:7][CH2:6][N:5]1[C:4]2[N:11]=[C:12]3[N:13]([CH:20]=[C:21]([C:23]4[CH:28]=[CH:27][C:26]([Br:29])=[CH:25][CH:24]=4)[NH:16]3)[C:14](=[O:15])[C:3]=2[N:2]=[CH:1]1
Reactant: O=C(CBr)c1ccc(Br)cc1
Reactant: Nc1nc(O)c2ncn(COCCO)c2n1
Agent: N
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=c1c2ncn(COCCO)c2nc2[nH]c(-c3ccc(Br)cc3)cn12
Temperature: 25 °C
Reaction time: 3 h
Yield: 53 %

Procedure:
A solution of 2.7 g acyclovir, 70 mL DMF, and 800 mg sodium hydride (80%) was stirred at room temperature for 15 min, then 4 g 2,4′-dibromo-acetophenone was added into the solution. The solution was stirred at room temperature for 3 hr, added 15 mL ammonia, and was continuously stirred overnight. The solvent was removed to obtain a residue, which was washed with 50 mL of water and acetone to produce a product, 3-(2-hydroxy-ethoxymethyl)-6-(4-bromophenyl)-3,5-dihydro-1,3,4,5,7a-pentaaza-s-indacen-8-one, 2.55 g (yellow, yield 53%).