Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)/[C:4](=[N:13]/[S:14]([C:17]2[S:18][CH:19]=[CH:20][CH:21]=2)(=[O:16])=[O:15])/[CH:3]=1.[CH3:22][NH:23][CH3:24]>C1COCC1>[CH3:22][N:23]([CH3:24])[C:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[N:13][S:14]([C:17]2[S:18][CH:19]=[CH:20][CH:21]=2)(=[O:16])=[O:15])[CH:3]=1
Reactant: CNC
Reactant: O=C1C(Cl)=C/C(=N\S(=O)(=O)c2cccs2)c2ccccc21
Solvent: C1CCOC1
Product: CN(C)C1=CC(=NS(=O)(=O)c2cccs2)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 100 %

Procedure:
33.5 mg (E)-N-(3-chloro-4-oxonaphthalen-1(4H)-ylidene)thiophene-2-sulfonamide was dissolved in 2 ml THF, to which was added 0.4 ml dimethylamine in THF solution (2 M). The wine-red solution was stirred at r.t. for 10 min and concentrated. The residue was suspended in 50 ml ethyl acetate and washed with water and brine. Dried over Na2SO4, the organic phase was filtered and the filtrate was concentrated to dryness affording the title compound 36 mg (100%) as a wine-red solid, m.p.: 183-185° C.
Reaction SMILES: CON(C)C(=O)[C:5]1[CH:10]=[CH:9][CH:8]=[N:7][C:6]=1[O:11][CH:12]([F:14])[F:13].[CH3:17][Mg]Br.Cl.[C:21](=[O:24])([O-])O.[Na+]>O1CCCC1>[F:14][CH:12]([F:13])[O:11][C:6]1[CH:5]=[CH:10][C:9]([C:21](=[O:24])[CH3:17])=[CH:8][N:7]=1
Reactant: C[Mg]Br
Reactant: O=C([O-])O
Reactant: CON(C)C(=O)c1cccnc1OC(F)F
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)c1ccc(OC(F)F)nc1
Yield: 98 %

Procedure:
N-methoxy-N-methyl-2-difluoromethoxynicotinamide (336 mg, 1.45 mmol) was dissolved in tetrahydrofuran (7.3 mL). 0.93 M methylmagnesium bromide (2.4 mL, 2.18 mmol) was added dripwise at 0° C. under an argon atmosphere. The resultant mixture was stirred for 10 minutes and added with 1N hydrochloric acid at the same temperature. Subsequently, the reaction solution was added with a saturated aqueous solution of sodium hydrogen carbonate, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, concentrated in vacuo, and purified using silica-gel column chromatography (n-hexane/ethyl acetate=4/1). 1-(2-(Difluoromethoxy)pyridin-5-yl)ethanone (264 mg, yield 98%) was obtained as a yellow oil.
Reaction SMILES: Br[C:2]1[C:3]([CH:16]=[O:17])=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1.[CH:18]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH2:19].C(N(CC)CC)C.O>CN(C)C=O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:23][S:20]([CH:18]=[CH:19][C:2]1[C:3]([CH:16]=[O:17])=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1)(=[O:22])=[O:21]
Reactant: C=CS(C)(=O)=O
Reactant: CC1(C)CCC(C)(C)c2cc(C=O)c(Br)cc21
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC1(C)CCC(C)(C)c2cc(C=CS(C)(=O)=O)c(C=O)cc21
Yield: 61.6 %

Procedure:
A solution of 0.537 g (1.82 mmol) of 3-bromo-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthaldehyde, 0.579 g (5.46 mmol) of methyl vinyl sulfone, 0.191 g (0.27 mmol) of tetrakis(triphenylphosphine) palladium and 5.23 g (51.7 mmol) of triethylamine in 12 ml dimethylformamide was heated to 100° C. under argon for 5 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The crude material was purified by flash chromatography (elution with 25% ethyl acetate/hexane) to afford 0.359 g (62%) of 3-(2-methylsulfonylvinyl)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthaldehyde (M+1=321).
Reaction SMILES: O.O.[Sn](Cl)Cl.[N+:6]([C:9]1[CH:34]=[CH:33][C:12]2[C:13](=[O:32])[C:14]3[CH:21]=[CH:20][C:19]([NH:22][C:23]4[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=4[O:30][CH3:31])=[CH:18][C:15]=3[O:16][CH2:17][C:11]=2[CH:10]=1)([O-])=O>C(O)C>[NH2:6][C:9]1[CH:34]=[CH:33][C:12]2[C:13](=[O:32])[C:14]3[CH:21]=[CH:20][C:19]([NH:22][C:23]4[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=4[O:30][CH3:31])=[CH:18][C:15]=3[O:16][CH2:17][C:11]=2[CH:10]=1
Reactant: COc1cc(F)ccc1Nc1ccc2c(c1)OCc1cc([N+](=O)[O-])ccc1C2=O
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCO
Product: COc1cc(F)ccc1Nc1ccc2c(c1)OCc1cc(N)ccc1C2=O

Procedure:
In accordance with general method Y, 0.30 g (1.32 mmol) of tin(II) chloride dihydrate is dissolved in 15 ml of ethanol, and 0.07 g (0.19 mmol) of (16) is added. Yield: 0.042 g (60.6%); melting point: 38.9° C.; C21H17FN2O3 (Mr=364.38); LC 18.82 min
Reaction SMILES: [C:1]([C:5]1[S:9][C:8]([NH:10][C:11]([CH2:13][C:14]2[N:15]=[C:16]([NH2:19])[S:17][CH:18]=2)=[O:12])=[N:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2]>C(OC(=O)CC)(=O)CC>[C:1]([C:5]1[S:9][C:8]([NH:10][C:11]([CH2:13][C:14]2[N:15]=[C:16]([NH:19][C:11](=[O:12])[CH2:13][CH3:14])[S:17][CH:18]=2)=[O:12])=[N:7][N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1nnc(NC(=O)Cc2csc(N)n2)s1
Agent: CCC(=O)OC(=O)CC
Product: CCC(=O)Nc1nc(CC(=O)Nc2nnc(C(C)(C)C)s2)cs1
Yield: 67.2 %

Procedure:
A mixture of 4.8 g (0.016 mole) of 4-(5-tert-butyl-1,3,4-thiadiazol-2-ylcarbamoylmethyl)-2-aminothiazole dissolved 20 ml of propionic anhydride was heated for 1 hour at 90°. The reaction solution was cooled and the precipitate was collected. The crude solid was recrystallized from chloroform-hexane. There was obtained 1.9 g of product, m.p. 210°-12°. N.M.R. (CDCl3) ∂ 1.1-1.4 (CH3, triplet), 1.4 [C(CH3)3 ], 2.3-2.7 (CH2, quartet), 3.9 (CH2, singlet), 6.8 (hetero-aromatic).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][NH:6][C:5](=[O:8])[NH:4][C:3]1=[O:9].[CH2:10]=[C:11]=[O:12].[C:13]([O-])(=[O:15])[CH3:14].[Na+]>C(OCC)(=O)C>[C:11]([N:6]1[CH2:7][CH:2]([CH3:1])[C:3](=[O:9])[N:4]([C:13](=[O:15])[CH3:14])[C:5]1=[O:8])(=[O:12])[CH3:10]
Reactant: CC(=O)[O-]
Reactant: CC1CNC(=O)NC1=O
Reactant: C=C=O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CC(=O)N1CC(C)C(=O)N(C(C)=O)C1=O

Procedure:
As described in IV, 18.2 gm (0.14 mol) of 5-methyl-5,6-dihydrouracil were reacted with ketene in boiling ethyl acetate in the presence of sodium acetate. The product recrystallized from isopropanol had the following analysis values and a melting point of 130° C to 131° C:
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:8]([OH:15])=[C:7]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH:6]=1)=[O:4].[OH-].[K+].[N:22]1[N:23]([C:31]2[CH:36]=[C:35]([CH3:37])[CH:34]=[CH:33][C:32]=2[O-:38])[N:24]=[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=12>C(#N)C>[N:22]1[N:23]([C:31]2[CH:36]=[C:35]([CH3:37])[CH:34]=[CH:33][C:32]=2[O:38][CH2:2][C:3]([C:5]2[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:8]([OH:15])=[C:7]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH:6]=2)=[O:4])[N:24]=[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=12
Reactant: CC(C)(C)c1cc(C(=O)CBr)cc(C(C)(C)C)c1O
Reactant: Cc1ccc([O-])c(-n2nc3ccccc3n2)c1
Agent: [K+]
Agent: [OH-]
Solvent: CC#N
Product: Cc1ccc(OCC(=O)c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)c(-n2nc3ccccc3n2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 72.6 %

Procedure:
6.54 g (20 mmol) of 2-bromo-1-(4-hydroxy-3,5-di-tert-butylphenyl)-ethanone and 1.98 g (30 mmol) of potassium hydroxide are dissolved in 150 ml of acetonitrile and stirred under inert atmosphere at room temperature for 30 minutes. Then 5.27 g (20 mmol) of 2-benzotriazol-2-yl-4-methyl-phenolate is added in portions. Stirring at room temperature is continued for additional 3 hours. After adjusting the pH to 6-7 the mixture is extracted with ethyl acetate. The collected organic phases are washed with water, dried and evaporated. Crystallization of the crude product from methanol gives 6.85 g of compound 106, m.p. 155-157° C.
Reaction SMILES: Cl.[CH3:2][Si:3]([CH3:11])([CH2:8][CH2:9][NH2:10])[Si:4]([CH3:7])([CH3:6])[CH3:5].[C:12](Cl)(Cl)=[O:13]>C1(C)C=CC=CC=1>[CH3:2][Si:3]([CH3:11])([CH2:8][CH2:9][N:10]=[C:12]=[O:13])[Si:4]([CH3:7])([CH3:6])[CH3:5]
Reactant: C[Si](C)(C)[Si](C)(C)CCN
Reactant: O=C(Cl)Cl
Agent: Cl
Solvent: Cc1ccccc1
Product: C[Si](C)(C)[Si](C)(C)CCN=C=O

Procedure:
50 g of 2-(pentamethyldisilanyl)ethylamine hydrochloride is suspended in 100 ml of dry toluene in a 250 ml two-neck flask fitted with a gas inlet tube and reflux condenser. A powerful stream of gaseous phosgene is then passed through the solution while stirring. At the same time the solution is heated to boiling. The conversion of the hydrochloride to the isocyanate is terminated when a clear toluene solution has been produced. Subsequently, the excess toluene is distilled off in a water-jet vacuum and the residue left behind is fractionated in an oil-pump vacuum.
Reaction SMILES: CCN(C(C)C)C(C)C.Cl.Cl.[Br:12][C:13]1[N:17]2[N:18]=[C:19]([N:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH:23]3[CH3:28])[CH:20]=[CH:21][C:16]2=[N:15][CH:14]=1.Cl[C:30]([O:32][CH:33]([CH3:35])[CH3:34])=[O:31]>C(OCC)(=O)C.C1(C)C=CC=CC=1>[Br:12][C:13]1[N:17]2[N:18]=[C:19]([N:22]3[CH2:27][CH2:26][N:25]([C:30]([O:32][CH:33]([CH3:35])[CH3:34])=[O:31])[CH2:24][CH:23]3[CH3:28])[CH:20]=[CH:21][C:16]2=[N:15][CH:14]=1
Reactant: CC(C)OC(=O)Cl
Reactant: CC1CNCCN1c1ccc2ncc(Br)n2n1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(C)OC(=O)N1CCN(c2ccc3ncc(Br)n3n2)C(C)C1
Reaction time: 17 h

Procedure:
Hunig's base [7087-68-5] (2.1 mL, 12.1 mmol) was added to an ambient temperature, stirred suspension of 3-bromo-6-(2-methylpiperazin-1-yl)imidazo[1,2-b]pyridazine dihydrochloride (1.1 g, 3.0 mmol) in ethyl acetate (150 mL). The suspension was stirred for 1.5 h then a 1.0M solution of isopropyl chloroformate in toluene (3.0 mL) was slowly added and the reaction allowed to proceed for 17 h then washed with brine. The ethyl acetate phase was dried (MgSO4) and evaporated. Product was purified by preparative RP-HPLC to provide 52.1 mg of racemic isopropyl 4-(3-bromoimidazo[1,2-b]pyridazin-6-yl)-3-methylpiperazine-1-carboxylate as a light yellow solid, mp. 52-54° C. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.11 (d, J=6.57 Hz, 3H) 1.15-1.25 (m, 6H) 2.51 (dt, J=3.73, 1.80 Hz, 2H) 3.15 (dd, J=12.88, 2.78 Hz, 2H) 3.86 (d, J=13.39 Hz, 1H) 3.98 (d, J=13.39 Hz, 2H) 4.47 (br. s., 1H) 4.78-4.87 (m, 1H) 7.23 (d, J=10.10 Hz, 1H) 7.64 (s, 1H) 7.91 (d, J=10.11 Hz, 1H). 13C NMR (100 MHz, DMSO-d6) δ ppm 13.53, 21.90, 42.71, 48.04, 68.05, 99.42, 110.59, 126.00, 131.15, 136.33, 154.41, 154.71. LRMS (ESI) m/z 382.0/384.0 [(M+H)]+, calc'd for C16H20BrN6O2: 382.26.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.S([NH:19][NH2:20])(C1C=CC(C)=CC=1)(=O)=O.[OH-].[Na+].[CH2:23]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[C:24]#[CH:25]>CCO.O.CCOC(C)=O>[N:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:1]2[CH:25]=[C:24]([CH2:23][NH:26][C:27](=[O:33])[O:28][C:29]([CH3:30])([CH3:32])[CH3:31])[NH:20][N:19]=2)[CH:3]=1
Reactant: C#CCNC(=O)OC(C)(C)C
Reactant: Cc1ccc(S(=O)(=O)NN)cc1
Reactant: O=Cc1cccnc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)NCc1cc(-c2cccnc2)n[nH]1
Reaction time: 0.33 h
Yield: 36.2 %

Procedure:
(See FIG. 11.) To a solution of nicotinaldehyde (150 μL, 1.59 mmol) in 95% EtOH (5 mL) was added 2-tosylhydrazine (296 mg, 1.59 mmol) and the resultant solution was stirred at room temperature for 2 h. To the solution was added aqueous sodium hydroxide (5 N, 0.32 mL, 1.59 mmol) and the solution was stirred for 20 min. To the solution was added a solution of tert-butyl prop-2-ynylcarbamate (1.23 g, 7.95 mmol) and the resultant solution was warmed to 50° C. and stirred under an argon atmosphere for 96 h. The solution was poured into a water/EtOAc mixture (1:1, 100 mL), the organic fraction was collected and the aqueous fraction was extracted with EtOAc (2×20 mL). The combined organic fractions were dried (Na2SO4), filtered and the solvent was removed in vacuo. The crude material was chromatographed on silica gel (EtOAc/Hex, 50/50, Rf=0.08) to afford the title compound 31 (158 mg, 36% yield) as a white solid: mp=185-187° C.; 1H NMR. (CDCl3) δ 8.92 (m, 1H), 8.50 (m, 1H), 8.01 (m, 1H), 7.28 (m, 1H), 6.47 (s, 1H); 5.62 (br s, 1H); 4.34 (d, J=6 Hz, 1H), 1.45 (s, 9H); LRMS (ESI) m/z calcd for C14H19N4O2 [M+H]+ 275. found 275.
Reaction SMILES: [C:1]1([S:7]([N:10]2[CH2:12][CH:11]2[C:13]([N:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:26]=[C:25]([CH3:27])[CH:24]=[CH:23][C:22]=3[CH3:28])[CH2:17][CH2:16]2)=[O:14])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[I-].[Na+].[CH:31]1([N:36]=[C:37]=[O:38])[CH2:35][CH2:34][CH2:33][CH2:32]1>>[C:1]1([S:7]([N:10]2[CH2:12][CH:11]([C:13]([N:15]3[CH2:20][CH2:19][N:18]([C:21]4[CH:26]=[C:25]([CH3:27])[CH:24]=[CH:23][C:22]=4[CH3:28])[CH2:17][CH2:16]3)=[O:14])[N:36]([CH:31]3[CH2:35][CH2:34][CH2:33][CH2:32]3)[C:37]2=[O:38])(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1ccc(C)c(N2CCN(C(=O)C3CN3S(=O)(=O)c3ccccc3)CC2)c1
Reactant: O=C=NC1CCCC1
Agent: [I-]
Agent: [Na+]
Product: Cc1ccc(C)c(N2CCN(C(=O)C3CN(S(=O)(=O)c4ccccc4)C(=O)N3C3CCCC3)CC2)c1

Procedure:
In analogy to example 2, (RS)-(1-benzenesulfonyl-aziridin-2-yl)-[4-(2,5-dimethyl-phenyl)-piperazin-1-yl]-methanone (example 2, step 3) was reacted with sodium iodide and cyclopentyl isocyanate to give the title compound as a colorless solid. MS: 511.1 ([M+H]+)
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[CH:10]=[CH:9][NH:8][C:7]=12.[F:11][C:12]1[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[CH:14][C:13]=1[OH:21].C([O-])([O-])=O.[K+].[K+]>O(C1C=CC=CC=1)C1C=CC=CC=1>[F:11][C:12]1[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[CH:14][C:13]=1[O:21][C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[CH:10]=[CH:9][NH:8][C:7]=12
Reactant: O=[N+]([O-])c1ccc(O)c(F)c1
Reactant: Clc1nccc2cc[nH]c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccc(Oc2ccccc2)cc1
Product: O=[N+]([O-])c1ccc(Oc2nccc3cc[nH]c23)c(F)c1
Temperature: 200 °C
Yield: 44.2 %

Procedure:
A mixture of 259 (420 mg, 2.76 mmol), 2-fluoro-4-nitrophenol (651 mg, 4.14 mmol) and K2CO3 (1.14 g, 8.28 mmol) in Ph2O (15 mL) was heated at 200° C. for 6 hours, cooled to room temperature and partitioned between EtOAc and water. Organic phase was collected, dried and concentrated. The residue was purified by flash column chromatography with gradient elution from hexane to hexane/EtOAc (3:1), to afford the title compound 260 (333 mg, 44% yield) as a yellowish solid. MS (m/z): 274.1(M+H) (found).
Reaction SMILES: Cl[CH:2]1[C:10]2[C:5](=[C:6]([N+:11]([O-:13])=[O:12])[CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.CCN(C(C)C)C(C)C.Cl.[CH3:24][O:25][C:26]([N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)=[O:27]>C(#N)C.CCOC(C)=O>[N+:11]([C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:5]=1[CH2:4][CH2:3][CH:2]2[N:31]1[CH2:32][CH2:33][N:28]([C:26]([O:25][CH3:24])=[O:27])[CH2:29][CH2:30]1)([O-:13])=[O:12]
Reactant: COC(=O)N1CCNCC1
Reactant: O=[N+]([O-])c1cccc2c1CCC2Cl
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)N1CCN(C2CCc3c2cccc3[N+](=O)[O-])CC1
Temperature: 79 °C
Yield: 69.9 %

Procedure:
To a room temperature solution of 1-Chloro-4-nitro-2,3-dihydro-1H-indene (221 mg, 1.12 mmol, 1.0 equiv) and DIPEA (430 μL, 2.46 mmol, 2.2 equiv) in dry acetonitrile (1.6 mL) was added methylpiperazine carboxylate hydrochloride salt (444 mg, 2.46 mmol, 2.2 equiv) as a solid in one portion. The resulting reaction mixture was heated to 79° C. overnight. The reaction mixture was allowed to cool to RT and diluted with EtOAc. The organic layer was extracted with 1 M HCl (3×20 mL), and the combined aqueous layers were treated with 3 N NaOH until the pH=10. The resulting solution was extracted three times with EtOAc, and the combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to provide the title compound as a brown oil (239 mg, 78%). LCMS [M+H]+=306.1.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]([Cl:11])[CH:8]=[C:7]([CH3:12])[C:3]=1[C:4]([OH:6])=[O:5].C(N)(N)=[O:14].OO.FC(F)(F)C(OC(=O)C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[N+:10]([O-:14])=[C:9]([Cl:11])[CH:8]=[C:7]([CH3:12])[C:3]=1[C:4]([OH:6])=[O:5]
Reactant: NC(N)=O
Reactant: Cc1cc(Cl)nc(Cl)c1C(=O)O
Agent: OO
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(Cl)[n+]([O-])c(Cl)c1C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 40.7 %

Procedure:
2,6-Dichloro-4-methyl-nicotinic acid (0.234 g, 1.14 mmol) and hydrogen peroxide-urea adduct (0.537 g, 5.70 mmol) were suspended in CH2Cl2 to give a white slurry. Trifluoroacetic anhydride (0.65 ml, 4.67 mmol) was added dropwise over 5 minutes and the resulting pale yellow solution was stirred overnight at rt. The reaction mixture was quenched with water (10 ml) and then dry loaded onto silica gel and purified using column chromatography (MeCN/MeOH/NH4OH, 8:1:1, v/v/v) to give 2,6-dichloro-4-methyl-nicotinic acid-N-oxide as a pale yellow crystalline solid (0.103 g, 41%). 1H NMR (CD3OD) δ 2.37 (s, 3H), 7.60 (s, 1H).
Reaction SMILES: O[CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C:3]1=[O:8].[CH3:9][C:10]1C(=O)CC(C(C)=C)[CH2:12][CH:11]=1.O[C:21](O)=O.C(O)(=O)C(O)=O>>[CH3:21][C:2]1[C:3](=[O:8])[CH2:4][CH2:5][C:6]2[C:7]=1[CH2:12][CH2:11][CH2:10][CH:9]=2
Reactant: C=C(C)C1CC=C(C)C(=O)C1
Reactant: O=C1CCCCC1O
Reactant: O=C(O)O
Agent: O=C(O)C(=O)O
Product: CC1=C2CCCC=C2CCC1=O

Procedure:
This material is prepared according to the procedure for Preparation 6 wherein 2-hydroxycyclohexanone is substituted for carvone. The resulting hydroxyketone is converted to the semicarbazone before dehydration with aqueous oxalic acid.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5](Cl)=[O:6].[NH2:8][C:9]1[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[C:10]=1[CH2:11][NH:12][C:13]1[C:14]2[N:15]([C:19]([CH3:23])=[C:20]([CH3:22])[N:21]=2)[CH:16]=[CH:17][CH:18]=1.N1C=CC=CC=1.C(=O)([O-])O.[K+]>ClCCl.O>[Cl:1][CH2:2][CH2:3][CH2:4][C:5]([NH:8][C:9]1[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[C:10]=1[CH2:11][NH:12][C:13]1[C:14]2[N:15]([C:19]([CH3:23])=[C:20]([CH3:22])[N:21]=2)[CH:16]=[CH:17][CH:18]=1)=[O:6]
Reactant: O=C(Cl)CCCCl
Reactant: Cc1cccc(N)c1CNc1cccn2c(C)c(C)nc12
Agent: O=C([O-])O
Agent: [K+]
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O
Product: Cc1cccc(NC(=O)CCCCl)c1CNc1cccn2c(C)c(C)nc12
Temperature: 10 °C
Reaction time: 2 h
Yield: 86.1 %

Procedure:
0.88 ml (7.85 mmol) of 4-chlorobutyryl chloride is added dropwise at 0-5° C. with stirring to a solution of 2.2 g (7.85 mmol) of 8-(2-amino-6-methylbenzylamino)-2,3-dimethylimidazo[1,2-a]pyridine and 0.63 ml (7.85 mmol) of pyridine in 30 ml of dichloromethane and the mixture is stirred for a further 2 h at 0-20° C. It is treated with water and potassium hydrogen carbonate to pH 7, the mixture is extracted with shaking, and the organic layer is dried with magnesium sulfate and concentrated in vacuo. The residue is recrystallized from toluene and petroleum ether (50/70° C.). 2.6 g (86%) of the title compound are obtained. M.p. 138-140° C.
Reaction SMILES: C[O:2][C:3]([C:5]1([NH:12][C:13](=[O:22])[C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([OH:21])[CH:15]=2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:4].[C:23]1([CH3:32])[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29][CH2:30]O)[CH:24]=1>>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([C:13]([NH:12][C:5]2([C:3]([OH:2])=[O:4])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]2)=[O:22])=[CH:15][C:16]=1[O:21][CH2:30][CH2:29][C:25]1[CH:24]=[C:23]([CH3:32])[CH:28]=[CH:27][CH:26]=1
Reactant: COC(=O)C1(NC(=O)c2ccc(Cl)c(O)c2)CCCCCC1
Reactant: Cc1cccc(CCO)c1
Product: Cc1cccc(CCOc2cc(C(=O)NC3(C(=O)O)CCCCCC3)ccc2Cl)c1

Procedure:
The compound of step 3 was etherified with 2-m-tolylethanol in analogy to step 1 of example 1, and the intermediate was hydrolyzed in analogy to step 4 of example 1 to yield the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[N:12]([CH3:16])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:5]([C:17]([O:19][CH3:20])=[O:18])[C:4]=2[CH:3]=1.[CH3:21][N:22]([CH3:26])[CH2:23][CH2:24]Cl.O>O1CCCC1>[Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[N:12]([CH3:16])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([C:17]([O:19][CH3:20])=[O:18])([CH2:24][CH2:23][N:22]([CH3:26])[CH3:21])[C:4]=2[CH:3]=1
Reactant: CN(C)CCCl
Reactant: COC(=O)C1c2ccccc2N(C)c2ccc(Cl)cc21
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)C1(CCN(C)C)c2ccccc2N(C)c2ccc(Cl)cc21
Temperature: 45 °C
Reaction time: 1 h
Yield: 86.3 %

Procedure:
3.9 gm of 2-chloro-9-methoxycarbonyl-10-methyl-acridane were dissolved in 10 cc of tetrahydrofuran and 5 cc of hexamethyl phosphortriamide and the solution was heated to 45°C and 3.4 gm of potassium tert.-butylate were added thereto. After stirring the mixture for 1 hour at 45°-47°C, 4.5 gm of β-dimethylaminoethyl chloride were added thereto and the mixture was stirred for 16 hours at 46°-48°C. After cooling the mixture, 150 cc of water were added and the mixture was extracted with ether. The organic phases were washed with an aqueous solution of sodium chloride, dried over magnesium sulfate, treated with charcoal, filtered and evaporated to dryness to obtain 4.2 gm of raw 2-chloro-9 -methoxycarbonyl-9-(β -dimethylaminoethyl)-10-methyl-acridane.
Reaction SMILES: CO[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[CH2:8][CH2:7][CH2:6]2.Cl.[NH2:15][OH:16].[C:17](=O)([O-])[O-].[Na+].[Na+]>C(O)C>[CH3:17][O:13][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:10]=1[CH2:11][CH2:12][CH2:3]/[C:4]/2=[N:15]/[OH:16]
Reactant: COc1ccc2c(c1)CCCC2=O
Reactant: O=C([O-])[O-]
Reactant: NO
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: COc1cccc2c1CCC/C2=N/O
Temperature: 80 °C
Yield: 97.7 %

Procedure:
A solution of 6-methoxy-1-tetralone (5.0 g) in ethanol (100 mL) was treated with hydroxylamine hydrochloride (2.0 g) and sodium carbonate (3.6 g). The reaction mixture was heated overnight at 80° C. Cooled to room temperature after twenty hours, transferred to a 300 mL flask and concentrated. The residue was triturated in water and filtered to yield the title product as a brown solid (5.3 g) 1H NMR (400 MHz, CDCl3) 1.84–1.87(m, 2H), 2.72(t, J=6.2 Hz, 2H), 2.79(t, J=6.6 Hz, 2H), 3.80(s, 3H), 6.65(d, J=2.6 Hz, 1H), 6.76(dd, J=11.5, 2.7 Hz, 1H), 7.86 (d, J=8.8 Hz, 1H)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([OH:14])[CH:12]=2)[NH:7][CH:6]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[C:22]([O:25][CH2:26][CH2:27]Br)(=[O:24])[CH3:23]>CC(C)=O>[CH3:1][O:2][C:3](=[O:15])[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:14][CH2:27][CH2:26][O:25][C:22](=[O:24])[CH3:23])[CH:12]=2)[NH:7][CH:6]=1
Reactant: COC(=O)Cc1c[nH]c2ccc(O)cc12
Reactant: CC(=O)OCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: COC(=O)Cc1c[nH]c2ccc(OCCOC(C)=O)cc12

Procedure:
To a solution of (5-hydroxy-1H-indol-3-yl)-acetic acid methyl ester (670 mg, 3.26 mmol) in acetone (15 mL) was added cesium carbonate (1.17 g, 3.59 mmol) and 2-bromoethyl acetate (395 μL, 3.59 mmol). The suspension was refluxed overnight under nitrogen. Acetone was concentrated and the residue was dissolved in water and extracted twice with EtOAc. The combined organic layers were dried over Na2SO4, filtered and concentrated. The crude residue was purified by flash column chromatography on silica gel (c-hexane to c-hexane/EtOAc 6:4) to give the desired material. TLC, Rf (c-hexane/EtOAc 1:1)=0.45; MS (LC-MS): 292.1 [M+H]+, 314.0 [M+Na]+, 290.0 [M−H]−; tR (HPLC conditions f): 1.70 min.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][C:8]([F:11])=[CH:7][C:3]=1[C:4](O)=[O:5].C[N:13](C=O)C.C(Cl)(=O)C(Cl)=O>C(Cl)Cl>[Cl:1][C:2]1[N:10]=[CH:9][C:8]([F:11])=[CH:7][C:3]=1[C:4]([NH2:13])=[O:5]
Reactant: O=C(O)c1cc(F)cnc1Cl
Reactant: CN(C)C=O
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: NC(=O)c1cc(F)cnc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 900.2 %

Procedure:
To a solution of 2-chloro-5-fluoronicotinic acid 6 (50 g, 285 mmol) and DMF (2 mL, 28 mmol) in DCM (400 mL) at 0° C. was added oxalyl chloride (64 mL, 741 mmol) dropwise. The reaction mixture was stirred at room temperature overnight and concentrated in vacuo. The resulting yellow liquid was dissolved in 1,4-dioxane (600 mL), cooled at 0° C. and NH3 (g) was bubbled through the solution for 30 minutes. The mixture was stirred at room temperature overnight. The resulting mixture was filtered and the filtrate was concentrated to give compound 3 (44 g, 89%) as a beige solid. 1H NMR (DMSO-d6, 300 MHz): δ 7.84 (s, 1H), 7.96 (dd, 1H), 8.09 (s, 1H), 8.49 (d, 1H).