Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[OH:10].C(=O)([O-])[O-].[K+].[K+].[CH2:17]([O:19][CH:20]([O:23][CH2:24][CH3:25])[CH2:21]Br)[CH3:18].C(OCC)(=O)C>CN(C)C=O.[OH-].[Na+]>[CH2:17]([O:19][CH:20]([O:23][CH2:24][CH3:25])[CH2:21][O:10][C:3]1[CH:4]=[C:5]([O:8][CH3:9])[CH:6]=[CH:7][C:2]=1[Br:1])[CH3:18]
Reactant: COc1ccc(Br)c(O)c1
Reactant: CCOC(CBr)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(COc1cc(OC)ccc1Br)OCC
Temperature: 142 °C

Procedure:
A mixture of 16.0 gm (78.8 mMol) 2-bromo-5-methoxyphenol, 10.9 gm (78.8 mMol) potassium carbonate, and 15.5 gm (78.8 mMol) bromoacetaldehyde diethyl acetal in 300 mL dimethylformamide was heated at 142° C. for 16 hours. The reaction mixture was then cooled to room temperature and diluted with 100 mL 2N sodium hydroxide followed by 500 mL ethyl acetate. This mixture was washed twice with 1 L of water. The combined aqueous washes were extracted twice with 300 mL portions of ethyl acetate. All organic phases were combined, washed with 1 L of water, washed with 1 L of saturated aqueous sodium chloride, dried over magnesium sulfate and concentrated under reduced pressure to provide the desired compound as a dark amber oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]([C:11]2[NH:12][C:13]([C:16]3[C:24]4[C:19](=[CH:20][CH:21]=[C:22]([N+:25]([O-:27])=[O:26])[CH:23]=4)[NH:18][N:17]=3)=[CH:14][CH:15]=2)=[O:10])[CH:5]=[CH:6][CH:7]=1.[C:28]1(C)C=CC=CC=1>CNN.CN1CCCC1=O>[F:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]([C:11]2[NH:12][C:13]([C:16]3[C:24]4[C:19](=[CH:20][CH:21]=[C:22]([N+:25]([O-:27])=[O:26])[CH:23]=4)[N:18]([CH3:28])[N:17]=3)=[CH:14][CH:15]=2)=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Nc1cccc(F)c1)c1ccc(-c2n[nH]c3ccc([N+](=O)[O-])cc23)[nH]1
Reactant: Cc1ccccc1
Agent: CNN
Solvent: CN1CCCC1=O
Product: Cn1nc(-c2ccc(C(=O)Nc3cccc(F)c3)[nH]2)c2cc([N+](=O)[O-])ccc21
Temperature: 120 °C

Procedure:
A mixture of 5-(2-chloro-5-nitro-benzoyl)-1H-pyrrole-2-carboxylic acid (3-fluoro-phenyl)-amide (250 mg, 0.6 mmol) (Example 47), methyl hydrazine (4 drops), toluene (0.6 mL) and 1-methyl-pyrrolin-2-one (0.2 mL) was heated at 120° C. for 2 hours. The reaction was concentrated, triturated with DCM and hexane to give 55 mg of the titled compound as a yellow solid.
Reaction SMILES: Cl[C:2]1[C:10]2[C:6](=[CH:7][S:8][CH:9]=2)[NH:5][C:4](=[O:11])[C:3]=1[C:12]#[N:13].[N:14]1([C:20]([C:22]2[S:23][CH:24]=[CH:25][CH:26]=2)=[O:21])[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1>>[O:11]=[C:4]1[C:3]([C:12]#[N:13])=[C:2]([N:17]2[CH2:18][CH2:19][N:14]([C:20]([C:22]3[S:23][CH:24]=[CH:25][CH:26]=3)=[O:21])[CH2:15][CH2:16]2)[C:10]2[C:6](=[CH:7][S:8][CH:9]=2)[NH:5]1
Reactant: O=C(c1cccs1)N1CCNCC1
Reactant: N#Cc1c(Cl)c2cscc2[nH]c1=O
Product: N#Cc1c(N2CCN(C(=O)c3cccs3)CC2)c2cscc2[nH]c1=O

Procedure:
To yield a compound of structure (II) with R2 as carbonitrile, R3 as thiophene, and R1 as defined above, the intermediate 7-chloro-5-oxo-4,5-dihydro-2-thia-4-aza-indene-6-carbonitrile, depicted by formula (33), was reacted with piperazin-1-yl-thiophene-2-yl-methanone to yield 5-oxo-7-[4-(thiophene-2-carbonyl)-piperazin-1-yl]-4,5-dihydro-2-thia-4-aza-indene-6-carbonitrile, depicted by formula (34), which was either reacted with an appropriate halide (R1—X) or boronic acid (R1—B(OH)2) to yield target compounds of structure (II) with R2 as carbonitrile, R3 as thiophene, and R1 as defined above, as shown in Scheme 16.
Reaction SMILES: [N+:1]([O-:4])([O-])=[O:2].[K+].[C:6]([C:10]1[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=1[NH2:12])([CH3:9])([CH3:8])[CH3:7]>OS(O)(=O)=O>[C:6]([C:10]1[CH:16]=[CH:15][C:14]([N+:1]([O-:4])=[O:2])=[CH:13][C:11]=1[NH2:12])([CH3:9])([CH3:7])[CH3:8]
Reactant: O=[N+]([O-])[O-]
Reactant: CC(C)(C)c1ccccc1N
Agent: O=S(=O)(O)O
Agent: [K+]
Product: CC(C)(C)c1ccc([N+](=O)[O-])cc1N
Temperature: -10 °C
Reaction time: 1 h
Yield: 62.8 %

Procedure:
To KNO3 (7.5 g, 73.8 mmol) in conc. H2SO4 (50 mL) was slowly added to a mixture of 2-tert-butylaniline (11.0 g, 73.8 mmol) in conc. H2SO4 (50 mL) at −10° C. The mixture was stirred at −10° C. for 1 hour and poured into ice-water. The mixture was extracted with EtOAc (150 mL×3). The combined organics were washed with brine, dried over anhydrous Na2SO4, and purified by chromatography on silica gel to obtain 2-tert-butyl-5-nitroaniline (9.0 g, 63%). 1H NMR (400 MHz, CDCl3) δ 7.53 (dd, J=2.8, 8.8 Hz, 1 H), 7.46 (d, J=2.8 Hz, 1 H), 7.34 (d, J=8.8 Hz, 1 H), 4.12 (br s, 2 H), 1.44 (s, 9 H).
Reaction SMILES: [CH2:1]([C:8]([NH:28]C(=O)OC(C)(C)C)([CH3:27])[CH2:9][O:10][CH2:11][C:12]1[CH:17]=[C:16]([N:18]([S:22]([CH3:25])(=[O:24])=[O:23])[CH2:19][CH2:20][CH3:21])[N:15]=[C:14](Cl)[CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:36][CH:37]1[CH2:39][CH:38]1[CH2:40][NH2:41].C(O)(C(F)(F)F)=O.C(NS(C)(=O)=O)CC>CCO>[NH2:28][C:8]([CH3:27])([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH2:9][O:10][CH2:11][C:12]1[CH:13]=[C:14]([NH:41][CH2:40][CH:38]2[CH2:39][CH:37]2[CH3:36])[N:15]=[C:16]([N:18]([CH2:19][CH2:20][CH3:21])[S:22]([CH3:25])(=[O:23])=[O:24])[CH:17]=1
Reactant: CC1CC1CN
Reactant: CCCN(c1cc(COCC(C)(Cc2ccccc2)NC(=O)OC(C)(C)C)cc(Cl)n1)S(C)(=O)=O
Agent: CCCNS(C)(=O)=O
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Product: CCCN(c1cc(COCC(C)(N)Cc2ccccc2)cc(NCC2CC2C)n1)S(C)(=O)=O

Procedure:
N-(4-[(2-amino-2-methyl-3-phenylpropoxy)methyl]-6-{[(2-methylcyclopropyl)methyl]amino}pyridin-2-yl)-N-propylmethanesulfonamide was prepared from intermediate VI and [(2-methylcyclopropyl)methyl]amine (prepared from N-benzyl-1-(2-trans-methylcyclopropyl)methenamine by hydrogenation on Pd(OH)2, in EtOH, in the presence of TFA), following a similar procedure as described for the preparation of N-4-[(2-amino-2-methyl-3-phenylpropoxy)methyl]-6-{benzyl[(2-methylcyclopropyl)methyl]amino}pyridin-2-yl)-N-propylmethanesulfonamide. HRMS (ES, M+H) calcd. for C25H38N4O3S: 475.2737, found: 475.2719.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[C:5](=[CH:10][C:11]([NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[I:29])=[C:12]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[I:21])[CH:13]=1)[C:6]([O:8]C)=O.[NH3:31]>C(O)CO.[Cl-].[Na+].O>[I:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[NH:22][C:11]1[CH:10]=[C:5]2[C:6](=[O:8])[NH:31][C:3](=[O:2])[C:4]2=[CH:13][C:12]=1[NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[I:21]
Reactant: N
Reactant: COC(=O)c1cc(Nc2ccccc2I)c(Nc2ccccc2I)cc1C(=O)OC
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: OCCO
Product: O=C1NC(=O)c2cc(Nc3ccccc3I)c(Nc3ccccc3I)cc21

Procedure:
Analogously to Example 1, 1.48 g (2.36 mmol) of 4,5bis(2-iodoanilino)phthalic acid dimethyl ester in 25 ml of ethylene glycol are heated at 120° and, with stirring, ammonia gas is passed through the mixture for 19 hours. The reaction mixture is cooled, diluted with brine and extracted with ethyl acetate. The ethyl acetate phases are washed in succession three times with water and once with saturated sodium chloride solution, dried with sodium sulfate and concentrated by evaporation. The residue obtained after concentration by evaporation is filtered through silica gel with dichloromethane and the product fractions are combined and concentrated by evaporation. The residue obtained after concentration by evaporation is crystallized from boiling dichloromethane, yielding the title compound in the form of yellow crystals, m.p. 108°-110° C., FAB-MS: 582 [M+ +H].
Reaction SMILES: [N+](=[CH:3][CH3:4])=[N-].[C:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH:14]1[CH:18]([S:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:17][CH2:16][C:15]1=[O:27])([OH:7])=[O:6].C(O)C.Cl>CCOCC>[C:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH:14]1[CH:18]([S:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:17][CH2:16][C:15]1=[O:27])([O:7][CH2:3][CH3:4])=[O:6]
Reactant: CCCCCCCSC1CCC(=O)C1CCCCCCC(=O)O
Reactant: CC=[N+]=[N-]
Agent: Cl
Solvent: CCO
Solvent: CCOCC
Product: CCCCCCCSC1CCC(=O)C1CCCCCCC(=O)OCC
Temperature: 0 °C

Procedure:
At room temperature, 70 ml. of a 0.2N diazoethane solution in ether is added to a solution of 3.4 g. of 2-(6-carboxyhexyl)-3-heptylthio-cyclopentanone in 25 ml. of dry ethanol. The reaction mixture is poured into 100 ml. of ice water, containing 5 ml. of concentrated HCl, agitated, the organic phase separated, the aqueous phase extracted three times with respectively 30 ml. of chloroform, and the combined organic phases are washed with water, dried over Na2SO4, the solvent is distilled off, and chromatographic purification of the residue (silica gel/chloroform) produces 2-(6-carbethoxyhexyl)-3-heptylthio-cyclopentanone. Rf = 0.7 (silica gel/chloroform).
Reaction SMILES: [CH2:1]([C:5]1[C:6]2[N:17]=[C:16]([C:18]3[CH:32]=[C:31]([CH3:33])[C:21]([O:22][CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[C:20]([CH3:34])[CH:19]=3)[O:15][C:7]=2[N:8]=[C:9](S(C)(=O)=O)[N:10]=1)[CH:2]([CH3:4])[CH3:3].[F:35][C:36]([F:41])([F:40])[CH2:37][CH2:38][OH:39]>>[CH2:1]([C:5]1[C:6]2[N:17]=[C:16]([C:18]3[CH:32]=[C:31]([CH3:33])[C:21]([O:22][CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[C:20]([CH3:34])[CH:19]=3)[O:15][C:7]=2[N:8]=[C:9]([O:39][CH2:38][CH2:37][C:36]([F:41])([F:40])[F:35])[N:10]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: Cc1cc(-c2nc3c(CC(C)C)nc(S(C)(=O)=O)nc3o2)cc(C)c1OCC(=O)OC(C)(C)C
Reactant: OCCC(F)(F)F
Product: Cc1cc(-c2nc3c(CC(C)C)nc(OCCC(F)(F)F)nc3o2)cc(C)c1OCC(=O)OC(C)(C)C
Yield: 10 %

Procedure:
Analogously to example 2 (a), the reaction of 95 mg of tert-butyl [4-(7-isobutyl-5-methanesulfonyloxazolo[5,4-d]pyrimidin-2-yl)-2,6-dimethylphenoxy]acetate with 3,3,3-trifluoropropan-1-ol gave 10 mg (10%) of the title compound.
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:37])[NH:5][C:6](=[O:36])[N:7]([CH:35]=1)[C@@H:8]1[O:34][C@H:12]([CH2:13][O:14][C:15]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C@@H:10]([OH:11])[CH2:9]1)[CH3:2].[OH-].[K+].[CH2:40](I)[CH3:41]>C1C=CC=CC=1.O1CCOCC1>[CH2:40]([O:11][C@@H:10]1[C@@H:12]([CH2:13][O:14][C:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[O:34][C@@H:8]([N:7]2[CH:35]=[C:3]([CH2:1][CH3:2])[C:4](=[O:37])[NH:5][C:6]2=[O:36])[CH2:9]1)[CH3:41]
Reactant: CCc1cn([C@H]2C[C@H](O)[C@@H](COC(c3ccccc3)(c3ccccc3)c3ccccc3)O2)c(=O)[nH]c1=O
Reactant: CCI
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: c1ccccc1
Product: CCO[C@H]1C[C@H](n2cc(CC)c(=O)[nH]c2=O)O[C@@H]1COC(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
A mixture of 6 g of 2'-deoxy-5-ethyl-5'-O-trityluridine, 1.347 g of powdered potassium hydroxide and 1.95 ml of ethyl iodide in a mixture of 60 ml of benzene and 20 ml of dioxane was stirred and heated under reflux for 14 hours. The solvents were removed by evaporation, the residue was taken up in 6 ml of methanol and the solution was poured into 250 ml of water. The resulting mixture was extracted four times with 150 ml of chloroform each time and the combined chloroform extracts were evaporated to give 2'-deoxy-3'-O-ethyl-5-ethyl-5'-O-trityluridine which was used directly in the next step.
Reaction SMILES: [Br:1][C:2]1[CH:12]=[CH:11][C:5]2[O:6][C:7]([F:10])([F:9])[O:8][C:4]=2[C:3]=1[Cl:13].[N+:14]([O-])([OH:16])=[O:15]>S(=O)(=O)(O)O>[N+:14]([C:12]1[C:2]([Br:1])=[C:3]([Cl:13])[C:4]2[O:8][C:7]([F:10])([F:9])[O:6][C:5]=2[CH:11]=1)([O-:16])=[O:15]
Reactant: O=[N+]([O-])O
Reactant: FC1(F)Oc2ccc(Br)c(Cl)c2O1
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1cc2c(c(Cl)c1Br)OC(F)(F)O2
Temperature: -10 °C
Reaction time: 2 h
Yield: 57 %

Procedure:
The solution of 5-bromo-4-chloro-2,2-diflouro-1,3-benzodioxole (1.5 g, 5.53 mmol) in 10 mL conc. sulfuric acid was cooled to −10° C. Then a solution of 1 mL fuming nitric acid and 2 mL of conc. sulfuric acid was added drop wise. The resulting solution was stirred at −10° C. for ˜2 h. Then the reaction mixture was poured into ice water and a yellow solid precipitated out. Filtered off the solid, rinsed with water and collected the solid. The crude solid was purified by flash chromatography (SiO2, 0-5% ethyl acetate in hexanes) to afford pure 6-nitro-5-bromo-4-chloro-2,2-diflouro-1,3-benzodioxole (1.0 g, 3.16 mmol, 57%). MS: (ES) m/z calculated for C7HBrClF2NO4 [M+H]+ 316.0. found 316.
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)(C)=O.[F:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[C:17](=[O:27])[C@H:18]([O:20][CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][O:22]1)[CH3:19]>CS(C)=O>[F:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[C:17]1([C@H:18]([O:20][CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][O:22]2)[CH3:19])[CH2:4][O:27]1
Reactant: C[C@@H](OC1CCCCO1)C(=O)c1cc(F)ccc1F
Reactant: C[S+](C)(C)=O
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Product: C[C@@H](OC1CCCCO1)C1(c2cc(F)ccc2F)CO1
Temperature: 25 °C
Reaction time: 3 h
Yield: 97.1 %

Procedure:
To a stirred mixture of NaH (60% in oil, 9.1 g, 0.228 mol) in DMSO (300ml) was added portionwise trimethylsulfoxonium iodide (53.9 g, 0.245 mol ) at the inner temperature with the range from 15° C. to 18° C. over 20 min. The ice bath was removed and the mixture was stirred at r.t. for 3 hrs. The mixture was cooled down to 10° C. To this mixture was added a solution of (2R)-2′,5′-Difluoro-2-(3,4,5,6-tetrahydro-2H-pyran-2-yloxy)-propiophenone (47.3 g, 0.175 mol) in DMSO (150 ml) dropwise over 20 min. The resulting mixture was stirred at r.t. for 4 hrs. The reaction mixture was poured into ice-water (800 ml). The whole was extracted with EtOAc (400 ml+200 ml×2). The combined organic layer was washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was chromatograkkphed on silicagel (n-hexane: EtOAc=8:1˜5:1) to give 2-(2,5-Difluorophenyl)-2-[(1R)-1-(3,4,5,6,-tetrahydro-2H-pyran-2-yloxy)ethyl]oxirane (48.3 g, 97% ).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:13]([C:14](O)=[O:15])=[C:12]([Br:17])[N:11]([CH:18]([CH3:20])[CH3:19])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.Cl>O1CCCC1>[CH2:1]([O:8][C:9]1[C:13]([CH2:14][OH:15])=[C:12]([Br:17])[N:11]([CH:18]([CH3:20])[CH3:19])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)n1nc(OCc2ccccc2)c(C(=O)O)c1Br
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: CC(C)n1nc(OCc2ccccc2)c(CO)c1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 68 %

Procedure:
3-Benzyloxy-5-bromo-1-isopropylpyrazole-4-carboxylic acid (4.6 g) was dissolved in tetrahydrofuran (30 mL) and to the stirred solution was added dropwise 1M solution of borane-tetrahydrofuran complex in tetrahydrofuran (21 mL) under ice cooling. The mixture was stirred at room temperature for 1 hour. The reaction mixture was cooled with ice bath and to the reaction mixture was dropwise added 50 mL of water. Then 1 mol/L hydrochloric acid (20 mL) was added dropwise to the mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure and the obtained residue was purified by column chromatography on silica gel (eluent: ethyl acetate/hexane=1/5) to give 3.0 g of the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[Cl:14])[NH:10][C:9](=[O:15])[C:8](=[O:16])[NH:7]2)([O-])=O.Cl[Sn]Cl>C(O)C>[NH2:1][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[Cl:14])[NH:10][C:9](=[O:15])[C:8](=[O:16])[NH:7]2
Reactant: O=c1[nH]c2cc(Cl)c([N+](=O)[O-])cc2[nH]c1=O
Agent: Cl[Sn]Cl
Solvent: CCO
Product: Nc1cc2[nH]c(=O)c(=O)[nH]c2cc1Cl
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 45.6 %

Procedure:
To a stirred mixture of 6-nitro-7-chloro-1,4-dihydro-2,3-quinoxalinedione (35 mg, 0.145 mMol) in ethanol (2 mL) was added SnCl2 ·2H2O (163 mg, 0.724 mMol) in one portion. The mixture was refluxed at 80° C. (oil bath 90° C.) with stirring for 0.5 h to form a clear solution and continually refluxed for another 0.5 h. It was then cooled to room temperature and the yellow precipitate was collected by filtration, followed by washing with cold ethanol (1×1 mL) to give 25 mg (82%) of crude title compound (contains minor impurities by NMR). Crystallization from DMSO/H2O gave 14 mg of pure title compound as bright yellow needles, mp:>350° C. (dec. from 335° C.). IR (KBr, cm-1): 3406, 3356, 3212, 1668, 1637, 1518, 1437. NMR (1H, DMSO-d6): d 5.306 (s, 2H); 6.551 (s, 1H); 6.940 (s, 1H); 11.606 (s, 1H); 11.788 (s, 1H). HRMS: calcd for C8H6N3O2Cl (M+) m/z: 211.0147; found 211.0159. Potency relative to DCK: 28.0%.
Reaction SMILES: [F:1][C:2]1[C:11]2[NH:10][C:9](=[O:12])[C:8]3[CH2:13][CH2:14][CH2:15][C:7]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1.[Mg]>>[F:1][C:2]1[C:11]2[NH:10][C:9](=[O:12])[CH:8]3[CH2:13][CH2:14][CH2:15][CH:7]3[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=c1[nH]c2c(F)cccc2c2c1CCC2
Agent: [Mg]
Product: O=C1Nc2c(F)cccc2C2CCCC12
Yield: 56.8 %

Procedure:
Analogously to Example 7, 6-fluoro-1,2,3,5-tetrahydrocyclopenta[c]quinolin-4-one (494 mg, 2.4 mmol) is reacted with magnesium (1.22 g, 50.0 mmol) to form 280 mg (56%) of product.
Reaction SMILES: Br.[CH2:2]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:17]=[C:18]([NH2:21])[S:19][CH:20]=2)=[CH:12][CH:11]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:22]1([CH3:32])[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1.Cl>N1C=CC=CC=1>[CH2:2]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:17]=[C:18]([NH:21][S:28]([C:25]3[CH:26]=[CH:27][C:22]([CH3:32])=[CH:23][CH:24]=3)(=[O:30])=[O:29])[S:19][CH:20]=2)=[CH:12][CH:11]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1nc(-c2ccc(OCc3ccccc3)cc2)cs1
Agent: Br
Agent: Cl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)Nc2nc(-c3ccc(OCc4ccccc4)cc3)cs2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 36.6 %

Procedure:
A mixture of 0.5 g of 4-(4-benzyloxy-phenyl)-thiazol-2-ylamine hydrobromide with 0.29 g of p-toluenesulfonyl chloride was stirred for 4 hours with 2 ml of pyridine. The resulting, red colored suspension was poured into 30 ml of 1N hydrochloric acid and the mixture was extracted with methylene chloride. The organic phase was dried with magnesium sulphate and concentrated. The residue was dissolved in a mixture of 20 ml of ethanol and 20 ml of 2N sodium hydroxide solution. After the addition of 0.7 g of active charcoal the mixture was stirred at room temperature for 30 minutes and subsequently the active charcoal was filtered off. After neutralization with concentrated hydrochloric acid the mixture was concentrated and the residue was chromatographed on 100 g of Kieselgel 60 with diethyl ether as the eluent. The product-containing fractions were concentrated and, after recrystallization from ethyl acetate, yielded 0.22 g of N-[4-(4-benzyloxy-phenyl)-thiazol-2-yl]-4-methyl-benzenesulfonamide as colorless crystals.
Reaction SMILES: [OH:1][C:2]([CH3:19])([CH3:18])[CH2:3][C:4]1[CH:9]=[CH:8][N:7]=[C:6]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH:5]=1.[H-].[Na+].F[C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26]([N+:33]([O-:35])=[O:34])=[CH:25][CH:24]=1>CN(C=O)C>[CH3:18][C:2]([O:1][C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26]([N+:33]([O-:35])=[O:34])=[CH:25][CH:24]=1)([CH3:19])[CH2:3][C:4]1[CH:9]=[CH:8][N:7]=[C:6]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:14])([CH3:16])[CH3:15])[CH:5]=1
Reactant: O=[N+]([O-])c1ccc(F)c2ccccc12
Reactant: CC(C)(O)Cc1ccnc(NC(=O)OC(C)(C)C)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1cc(CC(C)(C)Oc2ccc([N+](=O)[O-])c3ccccc23)ccn1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 16.4 %

Procedure:
To a stirred solution of tert-butyl 4-(2-hydroxy-2-methylpropyl)pyridin-2-ylcarbamate (26) (292 mg, 1.10 mmol) in DMF (5.0 mL), at 0° C. under nitrogen, was added sodium hydride (132 mg, 3.29 mmol, 60 wt %). The resulting orange mixture was stirred at 0° C. for 45 min, and then a solution of 1-fluoro-4-nitronaphthalene (210 mg, 1.10 mmol) in DMF (5.0 mL) was added dropwise, over 2 min. The dark-brown mixture was stirred at 0° C. for 5 min, and then at RT. After 90 min, the reaction was quenched by addition of 4.0 mL aqueous NH4Cl solution. Diethyl ether (40 mL), EtOAc (40 mL) and water (40 mL) were added, and the layers separated. The aqueous layer was extracted with a mixture of diethyl ether and EtOAc (1:1, 30 mL×2). The combined organic extracts were washed with brine (50 mL), dried and the solvents removed under reduced pressure. The crude mixture was purified by column chromatography (40 g) eluting with 0 to 70% EtOAc in iso-hexane, to give tert-butyl 4-(2-methyl-2-(4-nitronaphthalen-1-yloxy)propyl)pyridin-2-ylcarbamate (27) (79 mg, 15%) as an orange foam: m/z 438 (M+H)+ (ES+).
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][NH2:10])=[CH:4][CH:3]=1.[C:11](O)(=[O:18])/[C:12](=[C:14](\[CH:16]=O)/[Br:15])/[Br:13].Cl>C(O)C>[Br:13][C:12]1[C:11](=[O:18])[N:9]([CH2:8][C:5]2[CH:6]=[CH:7][N:2]=[CH:3][CH:4]=2)[N:10]=[CH:16][C:14]=1[Br:15]
Reactant: NNCc1ccncc1
Reactant: O=C/C(Br)=C(/Br)C(=O)O
Agent: Cl
Solvent: CCO
Product: O=c1c(Br)c(Br)cnn1Cc1ccncc1
Yield: 59 %

Procedure:
4-Picolylhydrazine hydrochloride (500 mg, 3.13 mmol), mucobromic acid (807 mg, 3.13 mmol) and concentrated hydrochloric acid (500 μL) in ethanol (5 mL) were stirred at 90° C. for 1 day. After completion of the reaction, the resulting crystals were collected by filtration, washed with methanol and dried to give the desired product (59% yield).
Reaction SMILES: [C:1](#[N:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].N[CH2:15][CH:16]([NH2:18])[CH3:17].NC(N)(C)C>CC(C)[O-].CC(C)[O-].CC(C)[O-].CC(C)[O-].[Ti+4].O>[CH2:2]([C:1]1[NH:13][CH2:15][CH:16]([CH3:17])[N:18]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCC#N
Reactant: CC(N)CN
Agent: [Ti+4]
Agent: CC(C)(N)N
Agent: CC(C)[O-]
Solvent: O
Product: CCCCCCCCCCCC1=NC(C)CN1
Temperature: 120 °C
Yield: 92 %

Procedure:
In a 500 ml four-necked flask equipped with a reflux condenser and a thermometer were charged 181 g of lauronitrile and 2 g of titanium tetraisopropoxide. Further, 1 g of water was added with stirring and the mixture was heated up to about 120° C. with stirring for 10 minutes. Thereafter, while maintaining the temperature at about 120° C., the mixture was heated for 30 minutes under a reduced pressure to remove isopropanol formed in situ and unreacted water therefrom. After heating the mixture up to 200°-210° C., 74 g of 1,2-diaminopropane were added dropwise for 120 hours with stirring while maintaining the temperature at 200° C. or above. After the addition of the diaminopropane had been completed, the reaction mixture was heated at 210°-220° C. for 4 hours for the completion of the reaction. The resulting mixture was then subjected to vacuum distillation at 1.0 mmHg and at 160°-165° C. to obtain 219 g of 2-undecyl-4-methyl-2-imidazoline with a yield of 92%.
Reaction SMILES: C([O:3][C:4]([C:6]1[O:10][N:9]=[C:8]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]3[C:20]([Cl:25])=[N:21][CH:22]=[CH:23][CH:24]=3)=[CH:13][CH:12]=2)[CH:7]=1)=O)C.[NH3:26]>CCO>[Cl:25][C:20]1[C:19]([CH2:18][O:17][C:14]2[CH:15]=[CH:16][C:11]([C:8]3[CH:7]=[C:6]([C:4]([NH2:26])=[O:3])[O:10][N:9]=3)=[CH:12][CH:13]=2)=[CH:24][CH:23]=[CH:22][N:21]=1
Reactant: N
Reactant: CCOC(=O)c1cc(-c2ccc(OCc3cccnc3Cl)cc2)no1
Solvent: CCO
Product: NC(=O)c1cc(-c2ccc(OCc3cccnc3Cl)cc2)no1
Reaction time: 8 h
Yield: 14 %

Procedure:
3-[4-(2-Chloro-pyridin-3-ylmethoxy)-phenyl]-isoxazole-5-carboxylic acid ethyl ester (which may be prepared as described in Preparation of Intermediate 11; 57 mg, 0.16 mmol) was taken up in 2M NH3 in EtOH. The mixture was stirred overnight, transferred to a 20 mL scintillation vial and evaporated after several hours at room temperature. The residue was purified twice by chromatography, eluting first with 35-80% EtOAc/hexanes and then with 50-90% EtOAc/hexanes to give 3-[4-(2-chloro-pyridin-3-ylmethoxy)-phenyl]-isoxazole-5-carboxylic acid amide (7.2 mg, 14%). HRMS Calcd. for C16H13ClN3O3 (M+H)+, 330.0640. Found: 330.0637.