Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@@H:2]1[CH2:21][CH2:20][C@@:19]2([CH3:22])[C@@H:4]([CH2:5][CH2:6][C@@H:7]3[C:18]2=[CH:17][CH2:16][C@@:15]2([CH3:23])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:12](=[O:14])[CH3:13])[CH2:3]1.BrN1C(=[O:30])CCC1=O.Cl(O)(=O)(=O)=O.[OH-].[Na+]>O1CCOCC1.O.C(O)(=O)C>[O:30]1[C@@H:17]2[C@:18]31[C@H:7]([C@H:8]1[C@:15]([CH3:23])([CH2:16]2)[C@@H:11]([C:12](=[O:14])[CH3:13])[CH2:10][CH2:9]1)[CH2:6][CH2:5][C@@H:4]1[C@:19]3([CH3:22])[CH2:20][CH2:21][C@@H:2]([OH:1])[CH2:3]1
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)CC[C@]4(C)C3=CC[C@]12C
Reactant: O=C1CCC(=O)N1Br
Agent: [Na+]
Agent: [O-][Cl+3]([O-])([O-])O
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Solvent: C1COCCO1
Product: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)CC[C@]4(C)[C@@]34O[C@H]4C[C@]12C
Reaction time: 0.08 h
Yield: 25.5 %

Procedure:
3α-Hydroxy-5α-pregn-9(11)-en-20-one (500 mg.) was dissolved in dioxan (50 ml.) and water (12.5 ml.) under nitrogen; N-bromosuccinimide (325 mg.) was added followed by perchloric acid (60% w/v; 0.175 ml.) in water (5 ml.) and the reaction was allowed to stand at room temperature for 5 min. The pH was adjusted to 11.7 with 2N sodium hydroxide and the reaction mixture was allowed to stand at room temperature for a further 15 mins. The pH was adjusted to 6 with glacial acetic acid and the mixture was poured into water. The steroid was extracted with chloroform and triturated with ether to give a white solid; crystallisation from ether followed by crystallisation from methyl acetate-petrol gave the title compound (134 mg.), m.p. 160°-162°, [α]D + 101°.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([C:17]2[C:25]3[C:20](=[C:21]([C:26]([F:29])([F:28])[F:27])[CH:22]=[CH:23][CH:24]=3)[N:19]([CH:30]3[CH2:34][CH2:33][CH2:32][CH2:31]3)[N:18]=2)=[O:16])=[CH:11][CH:10]=1)C1C=CC=CC=1>[Pd].C(O)C.C1CCCCC=1>[CH:30]1([N:19]2[C:20]3[C:25](=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]([F:28])([F:29])[F:27])[C:17]([C:15]([C:12]3[CH:11]=[CH:10][C:9]([OH:8])=[CH:14][CH:13]=3)=[O:16])=[N:18]2)[CH2:31][CH2:32][CH2:33][CH2:34]1
Reactant: O=C(c1ccc(OCc2ccccc2)cc1)c1nn(C2CCCC2)c2c(C(F)(F)F)cccc12
Agent: [Pd]
Solvent: CCO
Solvent: C1=CCCCC1
Product: O=C(c1ccc(O)cc1)c1nn(C2CCCC2)c2c(C(F)(F)F)cccc12
Temperature: 70 °C
Yield: 81.1 %

Procedure:
A mixture of [4-(benzyloxy)phenyl][1-cyclopentyl-7-(trifluoromethyl)-1H-indazol-3-yl]methanone (0.13 g, 0.28 mmol) and 10% palladium on carbon(0.10 g) in 10 mL ethanol/cyclohexene (3:1, v/v) was heated at 70° C. for 0.5 hours. The catalyst was filtered (celite) and the filtrate concentrated in vacuo to give crude product. The residue was crystallized from Et2O/hexane to give 0.085 g of product as a white solid (mp 225-226° C.).
Reaction SMILES: [CH3:1][N:2]1[C:15]([C:16](OCCCC)=[O:17])=[C:14]([OH:23])[C:5]2[N:6]([CH3:13])[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[C:4]=2[S:3]1(=[O:25])=[O:24].[F:26][C:27]1[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29][CH:28]=1>C1(C)C(C)=CC=CC=1>[CH3:1][N:2]1[C:15]([C:16]([NH:31][C:30]2[CH:32]=[CH:33][C:27]([F:26])=[CH:28][CH:29]=2)=[O:17])=[C:14]([OH:23])[C:5]2[N:6]([CH3:13])[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[C:4]=2[S:3]1(=[O:25])=[O:24]
Reactant: Nc1ccc(F)cc1
Reactant: CCCCOC(=O)C1=C(O)c2c(c3ccccc3n2C)S(=O)(=O)N1C
Solvent: Cc1ccccc1C
Product: CN1C(C(=O)Nc2ccc(F)cc2)=C(O)c2c(c3ccccc3n2C)S1(=O)=O
Yield: 68 %

Procedure:
2,5-Dihydro-2,5-dimethyl-N-(4-fluoro-phenyl)-4-hydroxy-1,2-thiazino[5,6-b]indole-3-carboxamide-1,1-dioxide was prepared analogous to Example 9 from n-butyl 2,5-dihydro-2,5-dimethyl-4-hydroxy-1,2-thiazino[5,6-b]indole-3-carboxylate-1,1-dioxide and 4-fluoro-aniline in xylene; M.p.: 271°-272° C. (decomp.); Yield: 68% of theory;
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]#[CH:10])=[CH:5][CH:4]=1.I[C:12]1[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=1>O1CCCC1.C(N(CC)CC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]#[C:10][C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)=[CH:5][CH:4]=1
Reactant: C#Cc1ccc(OC)cc1
Reactant: Ic1ccncc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccc(C#Cc2ccncc2)cc1

Procedure:
A mixture of 4-methoxyphenylacetylene (2.86 g, 21.7 mmol), 4-iodopyridine (4.44 g, 21.7 mmol), cuprous iodide (206 mg, 1.08 mmol), bis(triphenylphosphine)palladium(II) dichloride (758 mg, 1.08 mmol) in tetrahydrofuran (40 mL) and triethylamine (20 mL) was heated at reflux for 2 h. The mixture was filtered, concentrated, and the residue chromaptographed on silica in 1:1 ethyl acetate-hexanes giving 2.45 g (54%) of a yellow solid. 1H NMR (CDCl3, 400 mHz) δ 9.2 (very broad, 2H), 7.57 (br, 2H), 7.48 (d, 2H, J=8.7 Hz), 6.88 (d, 2H, J=8.7 Hz), 3.82 (s, 3H). MS (AP+) m/e 210 (MH+).
Reaction SMILES: Cl[CH:2]([C:10]1[CH:22]=[C:21]2[C:13]([CH:14]=[CH:15][C:16]3[O:17][C:18](=[O:25])[C:19](C)(C)[C:20]=32)=[CH:12][CH:11]=1)[C:3]1[CH:8]=[CH:7][C:6]([Cl:9])=[CH:5][CH:4]=1.[NH:26]1[CH:30]=[N:29][CH:28]=[N:27]1.C(=O)([O-])[O-].[K+].[K+].C(#N)C>O>[Cl:9][C:6]1[CH:7]=[CH:8][C:3]([CH:2]([C:10]2[CH:22]=[C:21]3[C:13]([CH:14]=[CH:15][C:16]4[O:17][C:18](=[O:25])[CH2:19][C:20]=43)=[CH:12][CH:11]=2)[N:26]2[CH:30]=[N:29][CH:28]=[N:27]2)=[CH:4][CH:5]=1
Reactant: CC1(C)C(=O)Oc2ccc3ccc(C(Cl)c4ccc(Cl)cc4)cc3c21
Reactant: c1nc[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: O=C1Cc2c(ccc3ccc(C(c4ccc(Cl)cc4)n4cncn4)cc23)O1

Procedure:
A mixture of 8-(α,4-dichlorobenzyl)-1,1-dimethyl-2(1H)-naphtho[2,1-b]furanone, 1,2,4-triazole (0.3 g), potassium carbonate (0.3 g) and acetonitrile (5 ml) was heated under reflux for 18 h. The mixture was treated with water (20 ml) and extracted with ethyl acetate. The ethyl acetate extract was dried and then evaporated to dryness, and the residue was purified by flash chromatography eluting with methanol:chloroform, 1:99 v/v, to give 8-[4-chloro-α-(1H-1,2,4-triazol-1-yl)benzyl]-2(1H)-naphtho[2,1-b]furanone. Nmr in deuteriochloroform: δ8.12(2H,s); 7.94(1H,d); 7.36-7.46(4H,m); 7.15-7.25(3H,m); 6.92(1H,s); 1.62(3H,s); 1.60(3H,s).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[N:9]=[CH:8][NH:7][C:6]=2[CH:5]=[C:4]([C:11]([O:13][CH3:14])=[O:12])[CH:3]=1.N1C=CC=CC=1.[Cl:21][CH2:22][CH2:23][CH2:24][CH2:25][S:26](Cl)(=[O:28])=[O:27]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Cl:21][CH2:22][CH2:23][CH2:24][CH2:25][S:26]([NH:1][C:2]1[C:10]2[N:9]=[CH:8][NH:7][C:6]=2[CH:5]=[C:4]([C:11]([O:13][CH3:14])=[O:12])[CH:3]=1)(=[O:28])=[O:27]
Reactant: O=S(=O)(Cl)CCCCCl
Reactant: COC(=O)c1cc(N)c2nc[nH]c2c1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1cc(NS(=O)(=O)CCCCCl)c2nc[nH]c2c1
Reaction time: 1 h
Yield: 50.2 %

Procedure:
To a solution of methyl 4-amino-1H-benzimidazole-6-carboxylate (D251) (1.1 g, 5.76 mmol, 1 equiv) in CH2Cl2 (80 ml) at room temperature were added pyridine (1.02 ml, 12.67 mmol, 2.2 equiv), 4-chloro-1-butanesulfonyl chloride (D20) (2.31 g, 12.1 mmol, 2.1 equiv) and DMAP (704 mg, 5.76 mmol, 1 equiv) and the resulting mixture was stirred for 1 h then concentrated in vacuo. The residue was diluted with AcOEt and the organic phase was washed with a 2N aqueous HCl solution and brine, then dried over MgSO4 and concentrated in vacuo. Purification of the residue by flash chromatography on silica gel (AcOEt/iso-hexane: 2/3) gave methyl 4-{[(4-chlorobutyl)sulfonyl]amino}-1H-benzimidazole-6-carboxylate (D252) (1 g, 50%) as a colorless oil. [M+H]+=346.1, RT=2.97 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:14]=O)[C:6](=[CH:10][C:11]=1[O:12][CH3:13])[C:7](O)=[O:8].O.[NH2:17][NH2:18]>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:6](=[CH:10][C:11]=1[O:12][CH3:13])[C:7](=[O:8])[NH:18][N:17]=[CH:14]2
Reactant: COc1cc(C=O)c(C(=O)O)cc1OC
Reactant: NN
Solvent: CCO
Solvent: O
Product: COc1cc2cn[nH]c(=O)c2cc1OC

Procedure:
4,5-Dimethoxyphthalaldehydic acid (10 g.) and hydrazine hydrate (2.4 ml.) in ethanol (150 ml.) were heated under reflux for 20 hours during which time a white crystalline solid formed. The mixture was cooled in an ice bath, filtered and the resulting product dried to give crude 6,7-dimethoxyphthalazin-1-one (7 g.). A sample was crystallized from water yielding colorless needles, m.p. 254°-256° C.
Reaction SMILES: N[C:2]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[N:12]1C=CC=CC=1.[F:18][C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21](Cl)=[O:22].Cl>C(Cl)(Cl)Cl>[F:18][C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21]([C:2]1[C:10]([NH2:12])=[CH:9][C:8]([Br:11])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5])=[O:22]
Reactant: c1ccncc1
Reactant: O=C(Cl)c1ccccc1F
Reactant: NC(=O)c1cc(Br)ccc1N
Agent: Cl
Solvent: ClC(Cl)Cl
Product: NC(=O)c1cc(Br)cc(N)c1C(=O)c1ccccc1F
Temperature: 0 °C
Reaction time: 1 h
Yield: 57.4 %

Procedure:
2-Amino-5-bromo-benzamide (2 g, 9.3 mmol) was dissolved in chloroform (40 ml) in a 50 ml round bottomed flask and cooled to 0° C. Pyridine (0.8 ml, 9.3 mmol) was added followed by 2-fluoro-benzoyl chloride (1.3 ml, 10 mmol) and the mixture was magnetically stirred for 1 hr at this temperature. 10% Hydrochloric acid (50 ml) was added and the precipitated solid was filtered, washed with water and dried to yield pure title compound (1.8 g, 57%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:25]=[CH:24][C:13]3[C:14]4([CH3:23])[CH:19]([CH2:20][CH2:21][C:12]=3[CH:11]=2)[NH:18][C:17](=[O:22])[CH2:16][CH2:15]4)=[C:6]([C:26]([F:29])([F:28])[F:27])[CH:5]=1)([O-:3])=[O:2].[C:30](O)(C)(C)C.CC(C)([O-])C.[K+].CI>C(OCC)(=O)C>[CH3:30][N:18]1[C@H:19]2[C@@:14]([CH3:23])([C:13]3[CH:24]=[CH:25][C:10]([C:7]4[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][C:6]=4[C:26]([F:29])([F:27])[F:28])=[CH:11][C:12]=3[CH2:21][CH2:20]2)[CH2:15][CH2:16][C:17]1=[O:22]
Reactant: CC12CCC(=O)NC1CCc1cc(-c3ccc([N+](=O)[O-])cc3C(F)(F)F)ccc12
Reactant: CC(C)(C)O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CI
Solvent: CCOC(C)=O
Product: CN1C(=O)CC[C@]2(C)c3ccc(-c4ccc([N+](=O)[O-])cc4C(F)(F)F)cc3CC[C@@H]12
Temperature: 25 °C
Reaction time: 4 h
Yield: 70 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-10bR)-8-(4-nitro-2-trifluoromethylphenyl)-10b-methyl-1,2,3,4, 4a,5,6,10b-octahydrobenzo[f]quinolin-3-one (48 mg, 0.12 mmol), 0.3 mL of t-butanol, and potassium t-butoxide (40 mg, 0.36 mmol). Methyl iodide ! 0.022 mL, 0.36 mmol) was added and the mixture was stirred at room temperature for 4 h. The mixture was diluted with ethyl acetate, and purified by silica gel chromatography (ethyl acetate eluent) to give 35 mg (70%) of the title compound as a white solid. mp 128°-130°. FDMS: m/e=418.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][C:24](Cl)=[O:25])=[CH:19][CH:18]=1>ClCCl>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][C:24]([O:8][C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=2)=[O:25])=[CH:19][CH:18]=1
Reactant: O=C(Cl)Cc1ccc(Cl)cc1
Reactant: Oc1ccc(Br)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Cc1ccc(Cl)cc1)Oc1ccc(Br)cc1
Temperature: 10 °C
Reaction time: 8 h

Procedure:
A cooled (10° C.) stirred solution of 4-bromophenol (3 g) and triethylamine (2.5 ml) in dichloromethane (100 ml) was treated with 4-chlorophenylacetyl chloride (3.3 g) in dichloromethane (50 ml). The mixture was stirred at room temperature overnight. The solution was washed with water, dried over magnesium sulfate, filtered and evaporated under reduced pressure. The residue was purified by silica gel chromatography to give 4-bromophenyl 4-chlorophenylacetate.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[S:7][CH:8]=[CH:9][CH:10]=1.C(N(CC)CC)C.[C:18](Cl)(=[O:20])[CH3:19]>C1COCC1>[C:18]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[S:7][CH:8]=[CH:9][CH:10]=1)(=[O:20])[CH3:19]
Reactant: OCCCCc1cccs1
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)OCCCCc1cccs1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The crude product from Step A was dissolved in 100 ml of THF and the mixture was cooled in an ice-water bath. Triethylamine (7.5 ml, 54 mmol) was added followed by dropwise addition of 3.8 ml of acetyl chloride (54 mmol). The mixture was allowed to stir overnight at ambient temperature. The solution was filtered and concentrated on a rotary evaporator. The residue was partitioned between ethyl acetate and dilute, cold 1N HCl. The organic phase was washed with saturated NaHCO3 solution, brine and then dried (Na2SO4). Evaporation of the solvent left 10.48 g of the desired acetate (98%) the solvent left 10.48 g of the desired acetate (98%) as a light yellow oil. 1H-NMR (CDCl3)δ7.2-6.6 (3H, m); 2.9 (2H, t); 2.45 (2H, t); 2.15 (3H, s); 2.0 (4H, m).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([CH2:7][CH2:8][NH:9][C:10](=O)[CH3:11])=[CH:4][CH:3]=1.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>>[CH3:1][C:2]1[O:6][C:5]2[CH2:7][CH2:8][N:9]=[C:10]([CH3:11])[C:4]=2[CH:3]=1
Reactant: CC(=O)NCCc1ccc(C)o1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Product: CC1=NCCc2oc(C)cc21

Procedure:
In close analogy to the procedure described above, N-[2-(5-Methyl-furan-2-yl)-ethyl]-acetamide is reacted with phosphorus pentoxide to provide the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([CH3:23])[C:17]=1[CH3:24].Cl[C:26](Cl)([O:28][C:29](=[O:35])OC(Cl)(Cl)Cl)Cl.[N:37]1([CH2:43]CO)[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:29](=[O:35])[O:28][CH2:26][CH2:43][N:37]2[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]2)=[C:18]([CH3:23])[C:17]=1[CH3:24]
Reactant: COc1cc2nccc(Oc3ccc(N)c(C)c3C)c2cc1OC
Reactant: OCCN1CCCCC1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc2nccc(Oc3ccc(NC(=O)OCCN4CCCCC4)c(C)c3C)c2cc1OC
Yield: 112.3 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,3-dimethylaniline (50 mg) was added to toluene (5 ml), and triethylamine (0.5 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (68 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, 2-piperidino-1-ethanol (30 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, and the extract was washed with water and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (83 mg, yield 100%).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]([N:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[C:13]([O:16]C)[CH:14]=[CH:15][C:8]=2[CH2:7][CH2:6]1)=[O:4].B(Br)(Br)Br>ClCCl>[F:19][C:2]([F:1])([F:18])[C:3]([N:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[C:13]([OH:16])[CH:14]=[CH:15][C:8]=2[CH2:7][CH2:6]1)=[O:4]
Reactant: COc1ccc2c(c1)CCN(C(=O)C(F)(F)F)CC2
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=C(N1CCc2ccc(O)cc2CC1)C(F)(F)F
Yield: 90.9 %

Procedure:
Dissolve 2,2,2-trifluoro-1-(7-methoxy-1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)ethanone (10.0 g, 36.6 mmol) in dichloromethane (750 mL). Add BBr3 (11.0 mL, 116 mmol) and stir for 4 hours. Quench the reaction mixture with water (350 mL). Filter the suspension, then separate the two layers. Extract the aqueous layer with dichloromethane (2×300 mL). Dry the combined organic extracts over MgSO4, filter and concentrate to give the title compound (8.62 g, 91%): MS ES+ 260 (M+H)+, ES− 258 (M−H)−; HPLC [YMC-Pack Pro C-18 (150×4.6 mm, S-5 microm), acetonitrile in water containing 0.01% concentrated HCl at 1.0 mL/min, 30-99% over 19 min], tR=8.8 min, 100% purity.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([N:18]3[CH2:23][CH2:22][CH:21]([NH:24][NH2:25])[CH2:20][CH2:19]3)=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.S.O1[CH2:31][CH2:30][CH2:29][CH2:28]1>>[C:29]1([C:28]2[NH:18][C:16](=[O:15])[N:24]([CH:21]3[CH2:22][CH2:23][N:18]([C:16]([O:15][CH2:14][CH:12]4[C:13]5[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=5[C:6]5[C:11]4=[CH:10][CH:9]=[CH:8][CH:7]=5)=[O:17])[CH2:19][CH2:20]3)[N:25]=2)[CH:30]=[CH:31][CH:13]=[CH:1][CH:2]=1
Reactant: C1CCOC1
Reactant: NNC1CCN(C(=O)OCC2c3ccccc3-c3ccccc32)CC1
Agent: S
Product: O=C(OCC1c2ccccc2-c2ccccc21)N1CCC(n2nc(-c3ccccc3)[nH]c2=O)CC1

Procedure:
The solutions of 5.56 g (0.0165 mol) of [1-(9H-fluoren-9-ylmethoxycarbonyl)-4-piperidinyl]-hydrazine in 60 ml of tetrahydrofuran and 3.7 g (0.0177 mol) of N-(ethoxycarbonyl)-benzothionamide in 30 ml of tetrahydrofuran were combined and refluxed for 1 hour, whereupon hydrogen sulphide was released. The solvent was distilled off in vacuo, the oily residue remaining was boiled with a little acetonitrile. The mixture was allowed to cool, then additionally cooled from outside with ice water and the resulting precipitate was suction filtered. 4.0 g (52% of theory) of colourless crystals were obtained, melting point 142° C. and Rf=0.38 (eluant 4).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=2[F:12])[N:5]=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2SC)[C:3]=1[CH3:22].O[O:24][S:25]([O-:27])=O.[K+].[CH2:29]1COCC1>O.CCOC(C)=O>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=2[F:12])[N:5]=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[S:25]([CH3:29])(=[O:27])=[O:24])[C:3]=1[CH3:22]
Reactant: O=S([O-])OO
Reactant: CSc1ccccc1-c1nc2cc(F)cc(F)c2c(Cl)c1C
Reactant: C1CCOC1
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1c(-c2ccccc2S(C)(=O)=O)nc2cc(F)cc(F)c2c1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirring solution of 4-chloro-5,7-difluoro-3-methyl-2-(2-(methylthio)phenyl)-quinoline (0.940 g, 2.80 mmol) in THF (20 mL) and water (6.7 mL) was added oxone (4.3 g, 7.00 mmol). The reaction was stirred at rt for 2 h, then 75 mL water was added and the mixture was stirred for 10 min. The resulting precipitate was isolated by filtration, then dissolved in EtOAc, dried over MgSO4, and concentrated to give 4-chloro-5,7-difluoro-3-methyl-2-(2-(methylsulfonyl)phenyl)-quinoline. Mass Spectrum (ESI) m/e=368.0 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12](O)([CH3:13])[O:11][C:10](=O)[C:9]=2[C:16]2[C:21]([F:22])=[CH:20][C:19]([F:23])=[CH:18][C:17]=2[F:24])=[CH:4][CH:3]=1.O.[NH2:26][NH2:27]>C(O)CCC>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH3:13])=[N:27][NH:26][C:10](=[O:11])[C:9]=2[C:16]2[C:21]([F:22])=[CH:20][C:19]([F:23])=[CH:18][C:17]=2[F:24])=[CH:4][CH:3]=1
Reactant: NN
Reactant: CC1(O)OC(=O)C(c2c(F)cc(F)cc2F)=C1c1ccc(Cl)cc1
Solvent: O
Solvent: CCCCO
Product: Cc1n[nH]c(=O)c(-c2c(F)cc(F)cc2F)c1-c1ccc(Cl)cc1
Temperature: 90 °C
Reaction time: 3 h
Yield: 41.5 %

Procedure:
17.03 g of 4-(4-chlorophenyl)-5-hydroxy-5-methyl-3-(2,4,6-trifluorophenyl)-2(5H)-furanone, 2.64 g of hydrazine monohydrate and 240 ml of 1-butanol were mixed, and stirred at 90° C. for 3 hours. Then, the reaction mixture was cooled to 0° C. The resulting solid was collected by filtration. The collected solid was washed using hexane and t-butyl methyl ether, and dried under reduced pressure to obtain 6.99 g of 5-(4-chlorophenyl)-6-methyl-4-(2,4,6-trifluorophenyl)-2H-pyridazin-3-one.
Reaction SMILES: CO.[CH3:3][C:4]1([CH3:12])[CH2:10][C:9](=[O:11])[NH:8][C:6](=[O:7])[CH2:5]1.[OH-].[K+].S(C1C=CC(C)=CC=1)(O)(=O)=O.O[CH2:27][CH2:28][N:29]1[C:33]([N+:34]([O-:36])=[O:35])=[CH:32][N:31]=[C:30]1[CH3:37]>C1(C)C=CC=CC=1.CN(C)C=O>[CH3:37][C:30]1[N:29]([CH2:28][CH2:27][N:8]2[C:9](=[O:11])[CH2:10][C:4]([CH3:12])([CH3:3])[CH2:5][C:6]2=[O:7])[C:33]([N+:34]([O-:36])=[O:35])=[CH:32][N:31]=1
Reactant: Cc1ncc([N+](=O)[O-])n1CCO
Reactant: CC1(C)CC(=O)NC(=O)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CO
Solvent: Cc1ccccc1
Product: Cc1ncc([N+](=O)[O-])n1CCN1C(=O)CC(C)(C)CC1=O

Procedure:
A solution is prepared from 240 parts of methanol, 14 parts of 3,3-dimethylglutarimide, and 6.5 parts of potassium hydroxide. The solvent is evaporated to leave a residual syrup which is mixed with 95 parts of dimethylformamide, Then, a solution of 32 parts of 1-(2-hydroxyethyl)-2-methyl-5-nitroimidazole tosylate in 190 parts of dimethylformamide is added. The mixture becomes dark green-black immediately. It is then stirred and warmed at 90°-110° C. for about 1 hour before it is cooled and diluted slowly to a total volume of 100 parts with toluene. The precipitate which forms is removed by filtration and washed. The solvent is evaporated from the toluene-dimethylformamide filtrate under reduced pressure and the residue is dissolved in 80 parts of acetone, diluted with 280 parts of ether, mixed with charcoal, and filtered. The solvent is evaporated from the filtrate under reduced pressure and the residual oil is diluted with 140 parts of ether and made to crystallize. The precipitate which forms is separated by filtration and dried. The solid is then dissolved in an excess of warm acetone and treated with charcoal. The resulting filtrate is diluted with 35 parts of ether and crystallization is initiated. The precipitate which forms is separated by filtration, washed with ether and then with acetone. The resulting filtrate is then concentrated to a volume of 40 parts and cooled. The precipitate which forms is separated by filtration, washed, and then dried to give N-[2-(2-methyl-5-nitro-1-imidazolyl)ethyl]-3,3-dimethylglutarimide melting at about 153°-154.5° C.
Reaction SMILES: [C:1]([C:3]1[CH:27]=[CH:26][C:6]([O:7][C:8]2[CH:9]=[C:10]([CH:14]=[C:15]([O:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[CH:20][CH:19]=3)[CH:16]=2)[C:11](O)=[O:12])=[CH:5][CH:4]=1)#[N:2].[C:28]([O:32][C:33]([N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1)=[O:34])([CH3:31])([CH3:30])[CH3:29]>>[C:28]([O:32][C:33]([N:35]1[CH2:40][CH2:39][N:38]([C:11](=[O:12])[C:10]2[CH:9]=[C:8]([O:7][C:6]3[CH:26]=[CH:27][C:3]([C:1]#[N:2])=[CH:4][CH:5]=3)[CH:16]=[C:15]([O:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[CH:20][CH:19]=3)[CH:14]=2)[CH2:37][CH2:36]1)=[O:34])([CH3:31])([CH3:29])[CH3:30]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: N#Cc1ccc(Oc2cc(Oc3ccc(C#N)cc3)cc(C(=O)O)c2)cc1
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2cc(Oc3ccc(C#N)cc3)cc(Oc3ccc(C#N)cc3)c2)CC1
Yield: 75.6 %

Procedure:
Following the procedure of Example 5(c) 3,5-bis-(4-cyano-phenoxy)-benzoic acid 0.45 g (1.26 mmol) and piperazine-1-carboxylic acid tert-butyl ester (0.23 g, 1.26 mmol) were used to afford 0.5 g of the required product. 1H NMR (DMSO-d6): δ 1.40 (9H, sm), 3.35 (6H, m), 3.55 (2H, m) 7.02 (2H, d), 7.08 (1H, t), 7.26 (2H, d), 7.88 (2H, d).
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[C:12]([N+:15]([O-:17])=[O:16])=[C:11]([CH3:18])[N:10]=[C:9]1/[N:19]=[CH:20]/[N:21]([CH3:23])[CH3:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CN(C=O)C>[CH2:1]([N:8]1[C:13](=[O:14])[C:12]([N+:15]([O-:17])=[O:16])=[C:11](/[CH:18]=[CH:1]/[N:8]([CH3:13])[CH3:9])[N:10]=[C:9]1/[N:19]=[CH:20]/[N:21]([CH3:22])[CH3:23])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1nc(/N=C/N(C)C)n(Cc2ccccc2)c(=O)c1[N+](=O)[O-]
Solvent: CN(C)C=O
Product: CN(C)/C=C/c1nc(/N=C/N(C)C)n(Cc2ccccc2)c(=O)c1[N+](=O)[O-]
Temperature: 65 °C
Reaction time: 3 h

Procedure:
To a solution of (E)-N′(1-benzyl-4-methyl-5-nitro-6-oxo-1,6-dihydropyrimidin-2-yl)-N,N-dimethylformimidamide (64.7 g, 0.2 mol) in DMF (254 mL) was added DMF-dimethylacetal (54.5 mL, 0.41 mol). The reaction mixture was stirred for 3 h at 65° C., cooled, and the solvent was removed under reduced pressure. The residue was triturated with ethanol, and the solid was collected by vacuum filtration (69.2 g, 91%) and used in the next step without further purification.