Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.C([O:9][C:10]1[CH:19]=[C:18]2[C:13]([C:14]([NH:20][C:21]3[CH:26]=[CH:25][C:24]([Br:27])=[CH:23][C:22]=3[F:28])=[N:15][CH:16]=[N:17]2)=[CH:12][C:11]=1[O:29][CH3:30])C1C=CC=CC=1>C(O)(C(F)(F)F)=O>[Br:27][C:24]1[CH:25]=[CH:26][C:21]([NH:20][C:14]2[C:13]3[C:18](=[CH:19][C:10]([OH:9])=[C:11]([O:29][CH3:30])[CH:12]=3)[N:17]=[CH:16][N:15]=2)=[C:22]([F:28])[CH:23]=1
Reactant: COc1cc2c(Nc3ccc(Br)cc3F)ncnc2cc1OCc1ccccc1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc2c(Nc3ccc(Br)cc3F)ncnc2cc1O
Yield: 81.4 %

Procedure:
A solution of 7-benzyloxy-4-(4-bromo-2-fluorophenylamino)-6-methoxyquinazoline hydrochloride (9.4 g, 19.1 mmol) in TFA (90 ml) was heated at reflux for 50 minutes. The mixture was allowed to cool and was poured on to ice. The resulting precipitate was collected by filtration and dissolved in methanol (70 ml). The solution was adjusted to pH 9–10 with concentrated aqueous ammonia solution. The mixture was concentrated to half initial volume by evaporation. The resulting precipitate was collected by filtration, washed with water and then ether, and dried under vacuum to give 4-(4-bromo-2-fluorophenylamino)-7-hydroxy-6-methoxyquinazoline (5.66 g, 82%).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[N-:10]=[N+:11]=[N-:12].[Na+].[Cl-].[NH4+]>CN(C)C=O>[NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]1[NH:12][N:11]=[N:10][N:5]=1
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1ccccc1N
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Nc1ccccc1-c1nnn[nH]1
Temperature: 120 °C
Yield: 65.2 %

Procedure:
2-Aminobenzonitrile (9.44 g, 80 mmol), sodium azide, (6.24 g, 0.1 mol), ammonium chloride (5.12 g, 0.1 mol) and dimethylformamide (50 mL) were mixed and heated at 120° C. overnight. The solvent was evaporated and the residue taken up in water. The crude product was isolated by filtration and re-crystallised from water. A yield of 8.4 g of pure product was obtained
Reaction SMILES: [Li][CH2:2]CCC.[CH3:6][CH2:7][C:8]([C:10]1[CH:15]=[CH:14][C:13]([Br:16])=[CH:12][CH:11]=1)=O>CCOCC.[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Br:16][C:13]1[CH:14]=[CH:15][C:10]([C:8](=[CH2:2])[CH2:7][CH3:6])=[CH:11][CH:12]=1
Reactant: CCC(=O)c1ccc(Br)cc1
Reactant: [Li]CCCC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: CCOCC
Product: C=C(CC)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 32.9 %

Procedure:
To a solution of n-BuLi (2.79 ml, 1.6M solution in hexane, 4.46 mmol) in ether was added solid methyltriphenylphosphonium bromide (1.59 g, 4.46 mmol) in three portions. The mixture was stirred at rt for 4 h, and then a solution of 4-bromopropio-phenone (1.00 g, 4.69 mmol) in ether was added and the mixture was gently refluxed overnight. The mixture was filtered and the filtrate was washed with water and brine, dried (MgSO4), filtered and concentrated in vacuo to give a residue which was purified by flash column chromatography to give 1-bromo-4-(1-methylenepropyl)-benzene (310 mg, 31%) as a colorless oil. 1H NMR (CDCl3, 300 MHz): δ 7.45 (d, J=9.0 Hz, 2H), 7.28 (d, J=9.0 Hz, 2H), 5.26 (m, 1H), 5.07 (m, 1H), 2.48 (q, J=7.5 Hz, 2H), 1.09 (t, J=7.5 Hz, 3H).
Reaction SMILES: BrC[CH2:3][C:4]([C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=1)=O.[CH2:16]([O:18][C:19](=[O:23])[C:20]([NH2:22])=[S:21])[CH3:17]>CCO>[CH:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:14]=[CH:15][C:6]=1[C:4]1[N:22]=[C:20]([C:19]([O:18][CH2:16][CH3:17])=[O:23])[S:21][CH:3]=1
Reactant: O=C(CCBr)c1ccc2ccccc2c1
Reactant: CCOC(=O)C(N)=S
Solvent: CCO
Product: CCOC(=O)c1nc(-c2ccc3ccccc3c2)cs1
Temperature: 25 °C
Yield: 48 %

Procedure:
A mixture of bromoethyl-2-naphthyl ketone (1.78 g, 6.8 mmol), 2-thio-oxalamic acid ethyl ester (1 g, 7.5 mmol) in EtOH (absolute) was kept under reflux for 6 h. The mixture was cooled to room temperature. The product separated as a solid, which was filtered, washed with ethanol and dried to provide the desired ester, ethyl 4-(2-naphthyl)-1,3-thiazole-2-carboxylate, (IIIb) (0.862 g, 48% yield). MS: 284 (M+H). To a mixture of the ester, (IIIb) (800 mg, 2.82 mmol) in dry methylacetate (10 mL) was added NaH (60% dispersion in mineral oil, 135 mg, 3.37 mmol). The mixture was stirred at room temperature for 0.5 h and at reflux for 2 h. The mixture was poured into cold water and was neutralized with conc. HCl. After saturating the mixture with NaCl, the mixture was extracted from dichloromethane (twice). The combined extract was washed with brine. After drying over magnesium sulphate, solvent was evaporated to furnish the β-ketoester, ethyl 3-(4-(2-naphthyl)(1,3-thiazol-2-yl))-3-oxopropanoate, which was used for the next step without further purification. To the above β-ketoester was added absolute ethanol (10 mL) and hydrazine hydrate (1 mL, excess). The mixture was kept under reflux for 4 h. After cooling, solvent was evaporated from the reaction mixture. The resulting mixture was chromatographed over silica gel and was eluted with EtOAc. The product pyrazolone (VIg) was isolated as a solid which was further purified via washing with diethyl ether (i.e. stirring in ˜50 mL of diethyl ether followed by filtration and washing with diethyl ether). Yield 287 mg, (35% in two steps). MS: 294 (M+H).
Reaction SMILES: C1C[O:4][CH2:3]C1.C(N1C=CN=C1)(N1C=CN=C1)=O.[Cl:18][C:19]1[C:28]([NH2:29])=[C:27]([NH:30][C@H:31]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH3:32])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]=1.O>N1C=CC=CC=1>[Cl:18][C:19]1[C:28]2[N:29]=[C:3]([OH:4])[N:30]([C@H:31]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH3:32])[C:27]=2[C:26]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[N:20]=1
Reactant: C[C@H](Nc1c(N)c(Cl)nc2ccccc12)c1ccccc1
Reactant: C1CCOC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: c1ccncc1
Product: C[C@@H](c1ccccc1)n1c(O)nc2c(Cl)nc3ccccc3c21
Temperature: 90 °C
Reaction time: 8 h

Procedure:
THF (100 mL) and 1,1′-carbonyldiimidazole (10.6 g, 65.6 mmol) were sequentially added to a solution of 2-chloro-N4-[(1S)-1-phenylethyl]quinoline-3,4-diamine (13.0 g, 43.7 mmol) in pyridine (100 mL), and the reaction was heated at 90° C. for one hour. An analysis by LC/MS indicated the presence of starting material, and additional 1,1′-carbonyldiimidazole (3 equivalents) was added as heating at 90° C. was continued overnight. The reaction was still incomplete, and additional 1,1′-carbonyldiimidazole (3 equivalents) was added in portions as heating at 90° C. was continued for a second night. The reaction was cooled to approximately 0° C., and water (300 mL) was added. The mixture was stirred for two hours. A precipitate was present and was isolated by filtration, washed with water, and dried overnight in a vacuum oven to provide 9.98 g of 4-chloro-1-[(1S)-1-phenylethyl]-1H-imidazo[4,5-c]quinolin-2-ol.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)=[CH:3][CH:2]=1.[C:13]([C:15]1[CH:23]=[CH:22][C:18]([C:19](Cl)=[O:20])=[CH:17][CH:16]=1)#[N:14]>ClCCl.C(N(CC)CC)C>[N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:8][CH2:9][N:10]([C:19](=[O:20])[C:18]3[CH:22]=[CH:23][C:15]([C:13]#[N:14])=[CH:16][CH:17]=3)[CH2:11][CH2:12]2)=[CH:3][CH:2]=1
Reactant: c1cc(N2CCNCC2)ccn1
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N#Cc1ccc(C(=O)N2CCN(c3ccncc3)CC2)cc1
Reaction time: 2 h
Yield: 28.5 %

Procedure:
A solution of 1-(4-pyridyl)piperazine (0.49 g) in dry dichloromethane (20 ml) and triethylamine (0.7 ml) was treated slowly with a solution of 4-cyanobenzoyl chloride (0.50 g) in dry dichloromethane (30ml). The reaction mixture was then stirred under argon for 2 hours. The dichloromethane solvent was removed by evaporation and the residue dissolved in ethyl acetate. The organic extracts were then washed with aqueous sodium hydrogen carbonate solution, water, brine, dried (Na2SO4) and evaporated to give a colourless oil which was crystallised from ethyl acetate/isohexane to afford 1-(4-pyridyl)4-(4-cyanobenzoyl)piperazine (0.25 g) as a solid, m.p. 164-165° C.; microanalysis, found: C, 69.7; H, 5.6; N, 18.5%; C17H16N4O requires: C, 69.8; H, 5.52; N, 19.2%; NMR: (CDCl3) 3.38(bs,4H), 3.75(bs,4H), 6.67(dd,2H), 7.56(dd,2H), 7.76(dd,2H), 8.32(dd,2H): MS: m/z 293 (MH)+.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][C:4](=O)[CH:5]([CH2:7][CH2:8][CH3:9])O.[CH2:11]([SH:16])[CH:12]([SH:15])[CH2:13][CH3:14].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:13]([CH:12]1[CH2:11][S:16][C:4]([CH2:3][CH2:2][CH3:1])=[C:5]([CH2:7][CH2:8][CH3:9])[S:15]1)[CH3:14]
Reactant: CCCC(=O)C(O)CCC
Reactant: CCC(S)CS
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CCCC1=C(CCC)SC(CC)CS1

Procedure:
Butyroin (12.2 g), butane-1,2-dithiol (14.4 g) and p-toluenesulfonic acid (0.5 g) were dissolved in toluene (50 g) and the solution refluxed under a Dean-Stark trap. It was worked up as in Example 3 to give 2-ethyl-2,3-dihydro-5,6-dipropyl-1,4-dithiin as a clear greenish liquid, boiling range 92°-105°/0.025 mm, yield 8.5 g (44%). NMR(CDCl3), 0.78-1.14 δ (overlapping triplets), 1.21-1.80 δ (multiplet) 2.07-2.37 δ (complex quartet), 2.6-3.4 δ (multiplet).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[O:11][CH:10]2C(OCC)=O)=[C:5]([CH3:17])[CH:4]=1)#[N:2].CC[O-].[Na+].O>C(O)C>[CH3:17][C:5]1[CH:4]=[C:3]([CH:8]=[CH:7][C:6]=1[CH2:9][CH:10]=[O:11])[C:1]#[N:2]
Reactant: CCOC(=O)C1OC1c1ccc(C#N)cc1C
Agent: CC[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cc1cc(C#N)ccc1CC=O
Reaction time: 0.17 h
Yield: 20.4 %

Procedure:
A solution of ethyl 3-(4-cyano-2-methylphenyl)oxirane-2-carboxylate (927 mg, 4.0 mmol) in 10 mL of dry ethanol was cooled to 0° C. Freshly prepared EtONa (12.4 mmol) in 8 mL of ethanol was added and stirred at 0 for 10 min. Then dropwise addition of 0.1 g of water, stirred at 0° C. for 2 hours, and the sodium salt of the epoxy compound was filtered. The sodium salt of the epoxy compound was then dissolved in 5 mL of water and added 5 mL of 1 N of HCl and 20 mL of toluene. The mixture was heated to reflux for 2 hours. The organic phase was separated, washed by saturated sodium chloride, dried over Na2SO4 and distilled off solvent to afford 130 mg of crude 3-methyl-4-(2-oxoethyl)benzonitrile. MS m/z: 160 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[C:9]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])=[N:8][CH:7]=[C:6]([Cl:18])[C:3]=1[C:4]#[N:5].[C:19](OC(=O)C)(=[O:21])[CH3:20]>>[Cl:1][C:2]1[C:9]([N:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])[C:19](=[O:21])[CH3:20])=[N:8][CH:7]=[C:6]([Cl:18])[C:3]=1[C:4]#[N:5]
Reactant: Cc1ccccc1Nc1ncc(Cl)c(C#N)c1Cl
Reactant: CC(=O)OC(C)=O
Product: CC(=O)N(c1ccccc1C)c1ncc(Cl)c(C#N)c1Cl
Temperature: 180 °C
Yield: 86.8 %

Procedure:
A mixture of 3,5-dichloro-2-(o-tolylamino)isonicotinonitrile (700 mg, 2.52 mmol) and acetic anhydride (10 mL, 106 mmol) was heated in a sealed tube to 180° C. for 20 h. The mixture was cooled to room temperature and concentrated. Silica gel chromatography, loading with dichloromethane-hexanes (1:1) and eluting with 5 to 30% ethyl acetate in hexanes, gave N-(3,5-dichloro-4-cyanopyridin-2-yl)-N-o-tolylacetamide (700 mg, 87% yield). 1H NMR (400 MHz, CDCl3) δ ppm 8.44 (1H, s), 7.28-7.43 (4H, m), 2.41 (3H, br. s), 2.04 (3H, s); MS (ES+) m/z: 320 (M+H); LC retention time: 3.38 min (analytical HPLC Method A).
Reaction SMILES: [CH:1](O)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1.S(=O)(=O)(O)O>>[C:2]1([CH:1]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]2=[O:15])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Oc1ccccn1
Reactant: OC(c1ccccc1)c1ccccc1
Agent: O=S(=O)(O)O
Product: O=c1ccccn1C(c1ccccc1)c1ccccc1

Procedure:
Combine 92.1 g (0.5 mole) of benzhydrol with 142.7 g. (1.5 mole) of 2-hydroxypyridine and heat to 190° C. with stirring. Add 1.5 ml. of concentrated sulfuric acid and follow the procedure of Example III, step A to obtain thereby the product of this step yield 68 g., m.p. 142°-145° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].Br[CH2:10][CH:11]1[O:15][CH2:14][CH2:13][O:12]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][CH2:10][CH:11]1[O:15][CH2:14][CH2:13][O:12]1
Reactant: Sc1ccccc1Br
Reactant: BrCC1OCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Brc1ccccc1SCC1OCCO1
Reaction time: 8 h

Procedure:
To a mixture of 2-bromothiophenol (5 g) and 2-bromomethyl-1,3-dioxolane (2.98 mL) in N,N-dimethylformamide (50 mL) was added potassium carbonate (5.48 g) at room temperature, and the mixture was stirred overnight. The reaction mixture was poured into water, and the mixture was extracted with diethyl ether. The extract washed with water, 1 mol/L sodium hydroxide aqueous solution, water and brine successively, and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to give (2-bromophenylthiomethyl)-1,3-dioxolane (7.25 g). To a mixture of poly phosphoric acid (20 g) and chlorobenzene (40 mL) was added a solution of (2-bromophenylthiomethyl)-1,3-dioxolene (7.25 g) in chlorobenzene (20 mL), and the mixture was refluxed for 8 hours. The reaction mixture was cooled to room temperature and supernatant solution was collected by decantation. Toluene was added to the residue, and the supernatant was collected by decantation after the mixture was stirred. The supernatant was combined and concentrated under reduced pressure. The residue was dissolved in ethyl acetate, and the solution washed with a saturated sodium hydrogencarbonate aqueous solution, water and brine and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: n-hexane) to give the title compound (2.27 g).
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[C:6]1([C@H:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15][CH2:14][NH:13]2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(=O)([O-])O.[Na+]>CCOC(C)=O.O>[Cl:1][CH2:2][C:3]([N:13]1[CH2:14][CH2:15][C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[C@@H:12]1[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)=[O:4]
Reactant: O=C(Cl)CCl
Reactant: c1ccc([C@@H]2NCCc3ccccc32)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(CCl)N1CCc2ccccc2[C@@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.2 %

Procedure:
A mixture of chloroacetyl chloride (1.03 g) and EtOAc (5 mL) was added dropwise with stirring to a mixture of (1S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline (1.58 g), sodium hydrogen carbonate (960 mg), water (25 mL) and EtOAc (25 mL), followed by stirring at room temperature for 2 hours. The reaction liquid was extracted with EtOAc, and the extract was washed sequentially with saturated aqueous sodium bicarbonate and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane-AcOEt, 4:1) to obtain (1S)-2-(chloroacetyl)-1-phenyl-1,2,3,4-tetrahydroisoquinoline (2.14 g).
Reaction SMILES: [O:1]=[C:2]([CH:4]=[C:5]([CH3:7])[CH3:6])[CH3:3].[C:8]([C:12]1[CH:17]=[C:16]([SH:18])[CH:15]=[C:14]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:13]=1[OH:23])([CH3:11])([CH3:10])[CH3:9].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:6][C:5]([S:18][C:16]1[CH:15]=[C:14]([C:19]([CH3:20])([CH3:21])[CH3:22])[C:13]([OH:23])=[C:12]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:17]=1)([CH3:7])[CH2:4][C:2](=[O:1])[CH3:3]
Reactant: CC(C)(C)c1cc(S)cc(C(C)(C)C)c1O
Reactant: CC(=O)C=C(C)C
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(=O)CC(C)(C)Sc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reaction time: 2 h

Procedure:
8.48 Grams of mesityl oxide (0.084 moles) is added dropwise to a solution of 21.0 grams of 2,6 di-tert-butyl-4-mercaptophenol (0.088 moles) and one gram of triethylamine in 30 ml of toluene. The mixture is heated at 50°-55° C. for six hours. The solvent is then stripped off under vacuum and the residue retained at 60°-65° C. and 0.20 mm. Hg. for two hours. The residue is dissolved in toluene and purified by flash chromatography using silica gel. The product is isolated from solution by distilling off the volatiles under vacuum to a final pressure of 0.10 mm. Hg for five hours.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[N:3]=1.[C:12]1([CH2:22][NH2:23])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[Cl:11][C:4]1[N:3]=[C:2]([NH:23][CH2:22][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14][CH:13]=2)[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1Cl
Reactant: NCc1cccc2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccc(Cl)nc1NCc1cccc2ccccc12
Temperature: 80 °C
Reaction time: 3 h
Yield: 51.2 %

Procedure:
A mixture of 2,6-dichloro-3-nitropyridine (3.86 g, 20 mmol), naphthalen-1-ylmethanamine (3.14 g, 20 mmol) and K2CO3 (4.14 g, 30 mmol) in DMF (100 mL) was stirred at 80° C. for 3 h. It was cooled to room temperature and poured into water (500 mL). It was extracted with EtOAc (300 mL×2). The combined organic layers were washed with brine (300 mL×3), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel eluted with EtOAc/Pet ether=1/6 to afford the desired product as a yellow solid (3.21 g, 51%); LC/MS: MS (ES+) m/e 314 (MH+); 1H NMR (300 MHz, DMSO-d6) δ ppm 5.21 (d, J=6.0 Hz, 2H), 6.80 (d, J=8.7 Hz, 1H), 7.43-7.63 (m, 4H), 7.85 (d, J=8.1 Hz, 1H), 7.97 (d, J=8.1 Hz, 1H), 8.26 (d, J=8.1 Hz, 1H), 8.46 (d, J=8.7 Hz, 1H), 9.20 (t, J=5.7 Hz, 1H).
Reaction SMILES: Br[CH2:2][C:3]#[N:4].[Br:5][C:6]1[CH:11]=[C:10]([C:12]2[C:21]3[C:22]4[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=4[S:24][C:20]=3[C:19]([Br:29])=[C:18]3[C:13]=2[CH:14]=[CH:15][CH:16]=[CH:17]3)[CH:9]=[C:8]([Br:30])[C:7]=1[OH:31].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[Br:5][C:6]1[CH:11]=[C:10]([C:12]2[C:21]3[C:22]4[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=4[S:24][C:20]=3[C:19]([Br:29])=[C:18]3[C:13]=2[CH:14]=[CH:15][CH:16]=[CH:17]3)[CH:9]=[C:8]([Br:30])[C:7]=1[O:31][CH2:2][C:3]#[N:4]
Reactant: Oc1c(Br)cc(-c2c3ccccc3c(Br)c3sc4ccccc4c23)cc1Br
Reactant: N#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: N#CCOc1c(Br)cc(-c2c3ccccc3c(Br)c3sc4ccccc4c23)cc1Br
Reaction time: 2.5 h
Yield: 96.1 %

Procedure:
Bromoacetonitrile (0.25 mL, 3.56 mmol) was added to a room temperature, stirred suspension of 2,6-dibromo-4-(6-bromo-benzo[b]naphtho[2,3-d]thiophen-11-yl)-phenol (1.0 g, 1.78 mmol) and potassium carbonate (0.615 g, 4.45 mmol) in DMF (5 mL). After 2.5 h, the reaction mixture was added to water, filtered, washed with water and triturated with petroleum ether. The solid was dried in vacuo at 80° C. to provide the title compound as a white solid (1.03 g, 96%): NMR (DMSO-d6); δ8.29 (d, J=8 Hz, 1 H), 8.08 (d, J=8 Hz, 1 H), 7.92 (s, 2 H), 7.80 (ddd, J=8, 7, 1 Hz, 1 H), 7.65-7.51 (m, 3 H), 7.27 (ddd, J=8, 7, 1 Hz, 1 H), 6.68 (d, J=8 Hz, 1 H), 5.36 (s, 2 H); MS (+FAB): [M+], 3 bromine isotope pattern, 599, 601, 603, 605; Anal. Calc. for C24H12Br3NOS: C, 47.87, H, 2.01, N, 2.33. Found: C, 47.83, H, 1.92, N, 2.32.
Reaction SMILES: [NH2:1][C:2]1[C:7](=[O:8])[NH:6][C:5](=[S:9])[N:4]([CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[C:3]=1[NH:15][C:16]([CH:18]1[CH2:21][CH2:20][CH2:19]1)=O.[OH-].[Na+]>O.CO>[CH:18]1([C:16]2[NH:1][C:2]3[C:7](=[O:8])[NH:6][C:5](=[S:9])[N:4]([CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[C:3]=3[N:15]=2)[CH2:21][CH2:20][CH2:19]1
Reactant: CCCCCn1c(NC(=O)C2CCC2)c(N)c(=O)[nH]c1=S
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCCCCn1c(=S)[nH]c(=O)c2[nH]c(C3CCC3)nc21
Temperature: 70 °C
Reaction time: 1 h
Yield: 74.3 %

Procedure:
The mixture of N-(5-amino-6-oxo-3-pentyl-2-thioxo-1,2,3,6-tetrahydropyrimidin-4-yl)cyclobutanecarboxamide (720 mg, 2.3 mmol) and 2.5 M of sodium hydroxide in water (25 mL) and methanol (25 mL) was stirred at 70° C. for 1 hour. After cooling to room temperature, the reaction mixture was concentrated to remove methanol and then acidified to pH=5. The precipitate formed was filtered and dried to yield the desired product (500 mg, 73.7%). LCMS calculated for C14H21N4OS(M+H): 293.1; found: 293.1.
Reaction SMILES: [CH:1]([Mg]Cl)=[CH:2][CH2:3][CH3:4].[Cl-].[NH4+].C([O:11][CH2:12][CH3:13])C>[Cu]Cl>[CH2:4]([C@@H:4]1[CH2:3][CH2:2][CH2:1][C@@:12]1([CH3:13])[OH:11])[CH2:3][CH:2]=[CH2:1]
Reactant: CCC=C[Mg]Cl
Reactant: CCOCC
Agent: Cl[Cu]
Agent: [Cl-]
Agent: [NH4+]
Product: C=CCC[C@@H]1CCC[C@@]1(C)O
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a 0° C. solution of butenyl magnesium chloride (45.6 mL, 0.5 M) was added copper(I) chloride (0.113 g) followed by methylcyclopropane oxide (1.12 g) in diethyl ether (5 ml). The reaction mixture was warmed to room temperature and stirred for 20 hours. The mixture was cooled back to 0° C. before pouring into a saturated solution of ammonium chloride (at 0° C.). The mixture was extracted with ethyl acetate (3×). The combined organic fractions were dried over magnesium sulfate, filtered and concentrated carefully. The residue was purified by flash chromatography (ISCO, 0 to 30% ethyl acetate in hexanes) to give the desired product (1.3 g). 1H NMR (400 MHz, CDCl3): δ (ppm) 5.86-5.79 (m, 1H), 5.05-4.99 (m, 1H), 4.97-4.93 (m, 1H), 2.20-2.09 (m, 1H), 2.02-1.92 (m, 2H), 1.73-1.50 (m, 7H), 1.31-1.10 (m, 5H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[C:8](F)[C:7]([C:11]([F:14])([F:13])[F:12])=[CH:6][C:5]=1[N+:15]([O-:17])=[O:16].[NH:19]1[CH2:24][CH2:23][S:22][CH2:21][CH2:20]1>O1CCCC1>[CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[C:8]([N:19]2[CH2:24][CH2:23][S:22][CH2:21][CH2:20]2)[C:7]([C:11]([F:14])([F:13])[F:12])=[CH:6][C:5]=1[N+:15]([O-:17])=[O:16]
Reactant: COC(=O)c1cc(F)c(C(F)(F)F)cc1[N+](=O)[O-]
Reactant: C1CSCCN1
Solvent: C1CCOC1
Product: COC(=O)c1cc(N2CCSCC2)c(C(F)(F)F)cc1[N+](=O)[O-]
Yield: 98.3 %

Procedure:
A solution of 240 mg (0.90 mmol) of 5-fluoro-2-nitro-4-trifluoromethyl-benzoic acid methyl ester and 0.189 ml (2.00 mmol) of thiomorpholine in 2.5 ml of tetrahydrofuran is heated at reflux for 2 hours. After evaporation of the tetrahydrofuran the residue is distributed between water and ethyl acetate, the organic phase separated and washed with water and brine, dried over Na2SO4 and concentrated yielding 310 mg of 2-nitro-5-thiomorpholin-4-yl-4-trifluoromethyl-benzoic acid methyl ester as brown powder, m.p. 68-82° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:20]=1.Cl[C:22]1[N:27]=[C:26]([CH3:28])[N:25]=[C:24]([C:29]([C:31]2[CH:40]=[C:39]([CH3:41])[C:34]3[NH:35][C:36](=[O:38])[O:37][C:33]=3[CH:32]=2)=[O:30])[CH:23]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][N:17]([C:22]4[CH:23]=[C:24]([C:29]([C:31]5[CH:40]=[C:39]([CH3:41])[C:34]6[NH:35][C:36](=[O:38])[O:37][C:33]=6[CH:32]=5)=[O:30])[N:25]=[C:26]([CH3:28])[N:27]=4)[CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:20]=1
Reactant: COc1ccc2c(c1)CCN(C1CCNCC1)C(=O)N2
Reactant: Cc1nc(Cl)cc(C(=O)c2cc(C)c3[nH]c(=O)oc3c2)n1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(C(=O)c4cc(C)c5[nH]c(=O)oc5c4)nc(C)n3)CC1)C(=O)N2

Procedure:
83 mg (0.30 mmol) 7-methoxy-3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one, 91 mg (0.30 mmol) 6-(6-chloro-2-methyl-pyrimidine-4-carbonyl)-4-methyl-3H-benzoxazol-2-one and 0.11 mL (0.60 mmol) DIPEA were stirred together in 3 mL DMF overnight at RT. Then the reaction mixture was purified by preparative HPLC-MS. The fractions containing the product were combined and the organic solvent was evaporated down. The residue was neutralised with 4N aqueous sodium hydroxide solution, the precipitate formed was suction filtered, washed with water and dried i. vac.