Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][CH:5]=[C:4](Cl)[N:3]=1.Cl.Cl.[F:14][C:15]1[CH:20]=[CH:19][C:18]([C:21](=[O:31])[CH2:22][CH2:23][CH2:24][N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].O>C(O)CC>[F:14][C:15]1[CH:20]=[CH:19][C:18]([C:21](=[O:31])[CH2:22][CH2:23][CH2:24][N:25]2[CH2:26][CH2:27][N:28]([C:4]3[N:3]=[C:2]([NH2:1])[C:7]([NH2:8])=[CH:6][CH:5]=3)[CH2:29][CH2:30]2)=[CH:17][CH:16]=1
Reactant: Nc1nc(Cl)ccc1[N+](=O)[O-]
Reactant: O=C(CCCN1CCNCC1)c1ccc(F)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCO
Solvent: O
Product: Nc1ccc(N2CCN(CCCC(=O)c3ccc(F)cc3)CC2)nc1N
Reaction time: 0.17 h

Procedure:
6 g 2-amino-6-chloro-3-nitropyridine, 12.6 g 1-(4-fluorophenyl)-4-(1-piperazinyl)-1-butanone dihydrochloride and 20 g potassium carbonate in 120 ml n-propanol are stirred under reflux for 21/2 hours. The mixture is then treated with 400 ml water, stirred for further 10 minutes and cooled in an ice bath. The resulting precipitate is filtered off, washed with water, dissolved in methylene chloride, dried over sodium sulphate and evaporated. The resulting 1-(4-fluorophenyl)-4-[4-(2-amino-3-nitro-pyridin-6-yl)-1-piperazinyl]-1-butanone, m.p. 128°-130°, is without further purification dissolved in 400 ml methanol. 3 g palladium on charcoal (5%) are added to the solution and the mixture is hydrogenated under normal conditions. The catalyst is filtered off and the solvent distilled off to give 1-(4-fluorophenyl)-4-[4-(2,3-diaminopyridin-6-yl)-1-piperazinyl]-1-butanone which is used without further purification.
Reaction SMILES: [C:1]([C:5]1[C:14]2[CH:13]=[C:12]([CH:15]=[O:16])[C:11]([O:17][CH2:18][CH3:19])=[CH:10][C:9]=2[C:8]([CH3:21])([CH3:20])[CH2:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:22]([Mg]Cl)[CH3:23]>C1COCC1.CN1CCCN(C)C1=O>[C:1]([C:5]1[C:14]2[CH:13]=[C:12]([CH:15]([OH:16])[CH2:22][CH3:23])[C:11]([O:17][CH2:18][CH3:19])=[CH:10][C:9]=2[C:8]([CH3:20])([CH3:21])[CH2:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC[Mg]Cl
Reactant: CCOc1cc2c(cc1C=O)C(C(C)(C)C)=CCC2(C)C
Solvent: CN1CCCN(C)C1=O
Solvent: C1CCOC1
Product: CCOc1cc2c(cc1C(O)CC)C(C(C)(C)C)=CCC2(C)C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 8-tert-butyl-3-ethoxy-5,5-dimethyl-5,6-dihydro-naphthalene-2-carbaldehyde (Compound A-27, 450 mg, 1.57 mmol) in THF (7 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU, 0.3 mL) was added ethylmagnesium chloride (2 M in THF, 1.6 mL, 3.1 mmol). After stirring at 0° C. for 30 min, the reaction was quenched with 1N HCl. The resulting mixture was diluted with water, extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried (MgSO4), filtered, and concentrated under reduced pressure to give the title compound as a colorless oil after purification by flash chromatography (silica gel, 10% ethyl acetate in hexane).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[H-].[Na+].[CH:8]([N:11]([CH:23]([CH3:25])[CH3:24])[C:12](=[O:22])[CH:13](Cl)[C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)([CH3:10])[CH3:9]>CN(C)C=O>[CH:23]([N:11]([CH:8]([CH3:10])[CH3:9])[C:12](=[O:22])[CH:13]([C:14]1[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=1)[N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1)([CH3:24])[CH3:25]
Reactant: CC(C)N(C(=O)C(Cl)c1ccc(Cl)cc1)C(C)C
Reactant: c1c[nH]cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)N(C(=O)C(c1ccc(Cl)cc1)n1ccnc1)C(C)C

Procedure:
While stirring, a solution of 4.5 g of imidazole in 30 ml of dimethylformamide is dripped into a suspension of 1.3 g of sodium hydride in 30 ml of dimethylformamide. When no more gas evolves, a solution of 13.6 g of α-chloro-α-(4-chlorophenyl)-acetic acid-diisopropyl amide (see d)) in 100 ml of dimethylformamide is dripped in and the mixture is stirred overnight at room temperature. The oil which remains after the solvent has been evaporated off is taken up in 100 ml of dichloromethane and shaken 5 times, each time with 100 ml of 5% strength sodium chloride solution. The organic phase is then concentrated and chromatographed on silica gel (25×6 cm) using dichloromethane/acetone (9:1). After 2 l of first runnings have been separated off, the product fractions are obtained from which, after concentration and trituration with 10 ml of diisopropyl ether, 8.9 g of colorless crystals (m.p.: 112° C.) are isolated.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:11]([CH3:29])([CH3:28])[CH2:12][O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:16]=2)[CH:5]=[CH:6][C:7]=1[O:8]CC.[OH-].[K+].CN1CCN(C)C1=O.Cl>O>[Cl:1][C:2]1[CH:3]=[C:4]([C:11]([CH3:29])([CH3:28])[CH2:12][O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:16]=2)[CH:5]=[CH:6][C:7]=1[OH:8]
Reactant: CCOc1ccc(C(C)(C)COCc2cccc(Oc3ccccc3)c2)cc1Cl
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCN(C)C1=O
Solvent: O
Product: CC(C)(COCc1cccc(Oc2ccccc2)c1)c1ccc(O)c(Cl)c1
Temperature: 150 °C
Yield: 48.9 %

Procedure:
One hundred grams of 3-phenoxybenzyl 2-(3-chloro-4-ethoxyphenyl)-2-methylpropyl ether and 25 g of potassium hydroxide were added to 300 ml of 1,3-dimethyl-2-imidazolidinone (to be abbreviated as DMI hereinafter), and the mixture was stirred at 150° C. for hours. The reaction mixture was cooled to room temperature, poured into water, acidified with a concentrated hydrochloric acid, and extracted with benzene. The benzene solution was washed with water, and dried. Benzene was evaporated under reduced pressure. The resulting oily residue was purified by column chromatography (silica gel; eluent: benzene) to give 45.6 g 3-phenoxybenzyl 2-(3-chloro-4-hydroxyphenyl)-2-methylpropyl ether having a melting point of 68° to 69° C.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:4]=1[CH2:5][O:6][C:7]1[CH:14]=[CH:13][C:10]([CH:11]=O)=[CH:9][C:8]=1[O:15][CH3:16].[S:27]1[CH2:33][C:31](=[O:32])[NH:30][C:28]1=[S:29].CCO>CCOC(C)=O>[F:1][C:2]([F:25])([F:26])[C:3]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:4]=1[CH2:5][O:6][C:7]1[CH:14]=[CH:13][C:10]([CH:11]=[C:33]2[S:27][C:28](=[S:29])[NH:30][C:31]2=[O:32])=[CH:9][C:8]=1[O:15][CH3:16]
Reactant: COc1cc(C=O)ccc1OCc1ccc(C(F)(F)F)cc1C(F)(F)F
Reactant: O=C1CSC(=S)N1
Solvent: CCO
Solvent: CCOC(C)=O
Product: COc1cc(C=C2SC(=S)NC2=O)ccc1OCc1ccc(C(F)(F)F)cc1C(F)(F)F
Temperature: 65 °C
Reaction time: 14 h
Yield: 22 %

Procedure:
To a flask was added 4-(2,4-bis(trifluoromethyl)benzyloxy)-3-methoxybenzaldehyde from Step A (164 mg, 433 μmol), rhodanine (58 mg, 433 μmol), absolute EtOH (7 mL), and TEA (120 μL, 870 μmol). The reaction solution was allowed to stir at 65° C. for 14 h. The reaction solution was diluted with EtOAc (100 mL), washed with sat. NH4Cl (75 mL×3), dried over Na2SO4, filtered, and concentrated to ⅓ the original volume. The yellow precipitates were isolated by filtration under reduced pressure, washed with EtOAc (50 mL) and Et2O (50 mL) to afford the title compound (47 mg, 23%). 1H NMR (DMSO-d6) δ 13.25 (1H, br s), 7.90 (1H, d, J=8.1 Hz), 7.86 (1H, s), 7.80 (1H, d, J=8.60 Hz), 7.48 (1H, s), 6.99 (1H, dd, J=2.0 Hz, 8.6 Hz), 6.96 (1H, d, J=2.0 Hz), 6.86 (1H, d, J=8.3 Hz), 5.35 (2H, s), 3.88 (3H, s); MS (ESI) 494 (MH+).
Reaction SMILES: [C:1]([CH:4]1[CH2:8][CH:7]([CH2:9][CH2:10][CH2:11][CH3:12])[O:6][C:5]1=[O:13])(=O)[CH3:2].[OH-].[Na+].O.C(=O)[C:18]1[CH:23]=[CH:22]C=[CH:20][CH:19]=1>C1(C)C=CC=CC=1>[C:2]1(/[CH:1]=[C:4]2/[C:5](=[O:13])[O:6][CH:7]([CH2:9][CH2:10][CH2:11][CH3:12])[CH2:8]/2)[CH:22]=[CH:23][CH:18]=[CH:19][CH:20]=1
Reactant: CCCCC1CC(C(C)=O)C(=O)O1
Reactant: O=Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCC1C/C(=C\c2ccccc2)C(=O)O1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 34.7 %

Procedure:
To a mixture of 36.8 g (0.200 mole) of 3-acetyl-5-butyldihydro-2(3H)-furanone in 200 mL of toluene charged to a 500 mL flask fitted with a mechanical stirrer, Dean-Stark trap and an addition funnel was added 8.00 g (0.200 mole) of sodium hydroxide at once. The mixture was vigorously stirred for 10 mins. at room temperature and then heated under reflux for 1 hour while water was removed in the Dean-Stark trap. After the one hour period 23.9 g (0.225 mole) of benzaldehyde was added to the refluxing solution in 4-5 ml aliquats in 1 hour. The reaction was further heated under reflux for an additional 2.5 hours. The reaction mixture was then cooled to room temperature and washed with 3×80 ml of water. The water layer was extracted with 50 ml of toluene and the toluene layers combined. The toluene solution was then washed with 100 ml of saturated sodium chloride and dried over Na2SO4 and concentrated to 35.4 gms of an orange oil under rotoevaporation. 19.0 gms of this oil was subjected to simple straight takeover distillation (0.04 mm Hg: 25°-147° C.) to leave 16 g (64.5% yield) of (E)-3-(phenylmethylene)-5-butyldihydro-2 (3H)-furanone as a viscous liquid. 1HNMR (CDCl3) δ7.5 (m, 6H), 4.56 (pentet, 1H), 3.3 (ddd, 1H), 2.8 (ddd, 1H), 1.9-1.2 (m, 6H), 0.86 (t, 3H).
Reaction SMILES: [CH:1]([C@@H:4]1[N:9]2[C:10]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[N+:13]([O-])=[CH:12][C:11]=3[N:21]=[C:8]2[CH2:7][O:6][CH2:5]1)([CH3:3])[CH3:2].[OH-].[NH4+:23].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>C(Cl)Cl.O>[CH:1]([C@@H:4]1[N:9]2[C:10]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[N:13]=[C:12]([NH2:23])[C:11]=3[N:21]=[C:8]2[CH2:7][O:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: [NH4+]
Reactant: CC(C)[C@H]1COCc2nc3c[n+]([O-])c4ccccc4c3n21
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: CC(C)[C@H]1COCc2nc3c(N)nc4ccccc4c3n21
Reaction time: 2 h

Procedure:
(11S)-11-Isopropyl-10,11-dihydro-8H-[1,4]oxazino[4′,3′:1,2]imidazo[4,5-c]quinoline 5-oxide (1.20 g, 4.23 mmol) was dissolved in 50 mL of CH2Cl2 and treated with 5 mL of concentrated ammonium hydroxide solution. The mixture was stirred rapidly and then p-toluenesulfonyl chloride (849 mg, 4.45 mmol) was carefully added. Rapid stirring was continued for 2 hours. The reaction mixture was then diluted with 25 mL of CH2Cl2 and 25 mL of H2O. The layers were separated and the organic portion was washed with 2% Na2CO3 solution (3×25 mL), H2O and brine. The organic portion was dried over Na2SO4, filtered and concentrated under reduced pressure. Chromatography (SiO2, 5-25% CMA/CHCl3) gave an off-white powder. Crystallization from ethyl acetate gave (11S)-11-isopropyl-10,11-dihydro-8H-[1,4]oxazino[4′,3′:1,2]imidazo[4,5-c]quinolin-6-amine (479 mg) as amber crystals, mp 249.0-250.0° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([NH2:11])[C:7]=1[C:8]([OH:10])=[O:9].[F:12][C:13]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[C:14]=1[C:15](Cl)=O.C(NC1C=CC2N=C(C3C(F)=CC=CC=3F)OC(=O)C=2C=1)(=O)C>C(N(CC)CC)C.C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:7]2[C:8](=[O:10])[O:9][C:15]([C:14]3[C:13]([F:12])=[CH:21][CH:20]=[CH:19][C:18]=3[F:22])=[N:11][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1c(F)cccc1F
Reactant: Nc1cccc(Cl)c1C(=O)O
Agent: CC(=O)Nc1ccc2nc(-c3c(F)cccc3F)oc(=O)c2c1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=c1oc(-c2c(F)cccc2F)nc2cccc(Cl)c12

Procedure:
6-Chloroanthranilic acid (0.566 g), 2,6-difluorobenzoyl chloride (0.93 mL) and triethyl amine/toluene (1/1) (18 mL) were reacted as described under (10). Reaction time 2 days. Extraction between ethyl acetate (100 mL) and HCl (2N, 100 mL), followed by separation of the organic layer, drylng over MgSO4, filtering and evaporation gave a crude product which was dissolved in warm THF (20 mL) and precipitated with hexane. The resulting mixture was further purified on a silicagel column using dichloromethane as eluent. The isolated fraction was dissolved in warm THF (20 mL) and precipitated with hexane, ylelding 5-chloro-2-(2,6-difluoro-phenyl)-benzo[d][1,3]oxazin-4-one (0.65 g) mp. 176 C, MS m/e: 293/295 M+.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2.[Br:24][C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=1)[C:28](O)=[O:29]>>[Br:24][C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=1)[C:28]([NH:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2)=[O:29]
Reactant: Cc1nc(C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CN)c(-c2cccc(Cl)c2)s1
Reactant: O=C(O)c1cccc(Br)c1
Product: Cc1nc(C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2cccc(Br)c2)c(-c2cccc(Cl)c2)s1

Procedure:
prepared by reaction of ((1S,2S,5R)-2-Aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-[5-(3-chloro-phenyl)-2-methyl-thiazol-4-yl]-methanone with 3-Bromo-benzoic acid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([CH3:11])[C:7](Br)=[N:8][CH:9]=1)=[O:4].[F:12][C:13]([F:24])([F:23])[C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O1CCCC1.O.C(=O)([O-])[O-].[Na+].[Na+].O>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH3:11])[C:7]([C:17]2[CH:18]=[CH:19][C:14]([C:13]([F:24])([F:23])[F:12])=[CH:15][CH:16]=2)=[N:8][CH:9]=1)=[O:4]
Reactant: COC(=O)c1cnc(Br)n1C
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1cnc(-c2ccc(C(F)(F)F)cc2)n1C
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 94.4 %

Procedure:
To 2-bromo-3-methyl-3H-imidazole-4-carboxylic acid methyl ester (800 mg) were added 4-(trifluoromethyl)phenylboronic acid (1.04 g), and tetrakis(triphenylphosphine)palladium(0) (422 mg), and tetrahydrofuran (9 ml), saturated sodium carbonate water (3 ml), and water (1.5 ml) as solvents, and stirred at 120° C. for 30 minutes under microwave radiation. After completion of the reaction, to the reaction solution 6 was added water, and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was evaporated. The obtained residue was purified with silica gel column chromatography (n-hexane/ethyl acetate) to give 3-methyl-2-[4-(trifluoromethyl)phenyl]-3H-imidazole-4-carboxylic acid methyl ester (980 mg) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)[CH2:14][CH2:13]2)=[C:4]([N+:9]([O-])=O)[C:5]([NH2:8])=[N:6][CH:7]=1.CCO.[N:28]1([CH2:34][C:35]2[CH:42]=[CH:41][C:38]([CH:39]=O)=[CH:37][CH:36]=2)[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1.[O-]S(S([O-])=O)=O.[Na+].[Na+]>C(OCC)C>[Cl:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)[CH2:14][CH2:13]2)=[C:4]2[N:9]=[C:39]([C:38]3[CH:37]=[CH:36][C:35]([CH2:34][N:28]4[CH2:33][CH2:32][O:31][CH2:30][CH2:29]4)=[CH:42][CH:41]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Nc1ncc(Cl)c(N2CCN(Cc3cccnc3)CC2)c1[N+](=O)[O-]
Reactant: O=Cc1ccc(CN2CCOCC2)cc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CCO
Product: Clc1cnc2[nH]c(-c3ccc(CN4CCOCC4)cc3)nc2c1N1CCN(Cc2cccnc2)CC1
Temperature: 80 °C
Reaction time: 20 h

Procedure:
To a mixture of 5-chloro-3-nitro-4-(4-pyridin-3-ylmethyl-piperazin-1-yl)-pyridin-2-ylamine (0.031 g, 0.09 mmol) and EtOH (3.0 ml) was added 4-morpholin-4-ylmethyl-benzaldehyde (0.025 g, 0.12 mmol) followed by a freshly prepared aqueous solution of Na2S2O4 (1M; 0.36 ml, 0.36 mmol). The reaction mixture was stirred at 80° C. for 20 h, then allowed to cool to room temperature and concentrated in vacuo. The resulting residue was absorbed on silica, and the free-running powder was placed on a 10 g isolute silica column. Elution with a gradient of methanol (2 to 13%) in ethyl acetate/dichloromethane (v:v; 4:1) afforded a yellow solid. The title compound was obtained as a pale yellow solid after trituration with diethyl ether (0.014 g, 30%); 1H-NMR (500 MHz, DMSO-d6) 2.38 (br s, 4H) and 3.59 (t, J=4.5 Hz, 4H) (morpholine N(CH2)2 and morpholine O(CH2)2), 2.62 (br s, 4H, piperazine N(CH2)2), 3.53 (s, 2H) and 3.61 (s, 2H) (NCH2-pyridyl and C6H4CH2N), 3.71 (br s, 4H, piperazine N(CH2)2), 7.39 (dd, J=5.30, 8.2 Hz, pyridine 5-H), 7.47 (d, J=8.2 Hz, 2H) and 8.12 (d, J=8.7 Hz, 2H) (3,5-C6H4— and 2,6-C6H4—), 7.78 (d, J=6.9 Hz, 1H, pyridine 4-H), 8.14 (s, 1H, imidazo[4,5-b]pyridine 5-H), 8.50 (dd, J=1.50, 4.6 Hz, 1H, pyridine 6-H), 8.56 (d, J=1.5 Hz, 1H, pyridine 2-H), 13.42 (br s, 1H, imidazo[4,5-b]pyridine N—H);
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]#[C:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[CH:5]=[CH:4][N:3]=1.[C:17]([NH2:21])([CH3:20])([CH3:19])[CH3:18]>O>[C:17]([NH:21][C:2]1[N:7]=[C:6]([C:8]#[C:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[CH:5]=[CH:4][N:3]=1)([CH3:20])([CH3:19])[CH3:18]
Reactant: Fc1ccc(C#Cc2ccnc(Cl)n2)cc1
Reactant: CC(C)(C)N
Solvent: O
Product: CC(C)(C)Nc1nccc(C#Cc2ccc(F)cc2)n1
Temperature: 25 °C

Procedure:
A solution of 2-chloro-4-(4-fluoro-phenylethynyl)-pyrimidine (1 equiv.) in tert-butylamine (0.2 M) is heated at 80° C. in a sealed tube for 24 h. The mixture is cooled to rt, diluted with water, and extracted with EtOAc. The organic layer is concentrated and the residue purified by column chromatography to provide the title compound.
Reaction SMILES: [CH2:1]([C:5]1[C:9]([CH2:10][O:11][C:12]2[CH:20]=[CH:19][C:15]([C:16]([OH:18])=O)=[CH:14][N:13]=2)=[C:8]([CH3:21])[O:7][N:6]=1)[CH2:2][CH2:3][CH3:4].[CH3:22][N:23]([CH3:25])[NH2:24].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH3:22][N:23]([CH3:25])[NH:24][C:16](=[O:18])[C:15]1[CH:19]=[CH:20][C:12]([O:11][CH2:10][C:9]2[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[N:6][O:7][C:8]=2[CH3:21])=[N:13][CH:14]=1
Reactant: CCCCc1noc(C)c1COc1ccc(C(=O)O)cn1
Reactant: CN(C)N
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCCCc1noc(C)c1COc1ccc(C(=O)NN(C)C)cn1
Yield: 33.6 %

Procedure:
To a stirred solution of 6-(3-butyl-5-methyl-isoxazol-4-ylmethoxy)-nicotinic acid (100 mg, 0.34 mmol) in DMF (5 mL) at room temperature under argon was added N,N-dimethylhydrazine (23 mg, 0.38 mmol), 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (122 mg, 0.38 mmol) and N,N-diisopropylethylamine (223 mg, 1.7 mmol). After 15 h the reaction mixture was concentrated, diluted with water and extracted with ethyl acetate. The combined organic extracts were dried over sodium sulfate, filtered and concentrated. Purification by chromatography (silica, dichloromethane:methanol 1:0 to 97.5:2.5) afforded the title compound (38 mg, 33%) as a colourless gum. MS: m/e=333.3 [M+H]+.
Reaction SMILES: N(CCC1C=CC(F)=CC=1)=[N+]=[N-].[N:13]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=1)=[N+:14]=[N-:15].[CH2:27]([NH:34][C:35]([C:37]1[S:41][C:40]([C:42]#[CH:43])=[N:39][C:38]=1[CH3:44])=[O:36])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[CH2:27]([NH:34][C:35]([C:37]1[S:41][C:40]([C:42]2[N:15]=[N:14][N:13]([CH2:16][C:17]3[CH:18]=[CH:19][C:20]([C:23]([F:25])([F:24])[F:26])=[CH:21][CH:22]=3)[CH:43]=2)=[N:39][C:38]=1[CH3:44])=[O:36])[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: C#Cc1nc(C)c(C(=O)NCc2ccccc2)s1
Reactant: [N-]=[N+]=NCc1ccc(C(F)(F)F)cc1
Agent: [N-]=[N+]=NCCc1ccc(F)cc1
Product: Cc1nc(-c2cn(Cc3ccc(C(F)(F)F)cc3)nn2)sc1C(=O)NCc1ccccc1
Yield: 81 %

Procedure:
Following the procedure as described in Example 1, making variations as necessary to replace 1-(2-azidoethyl)-4-fluorobenzene with 1-(azidomethyl)-4-(trifluoromethyl)benzene to react with N-benzyl-2-ethynyl-4-methylthiazole-5-carboxamide, the title compound was obtained as a white solid in 81% yield: mp 131-132° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, CDCl3) δ 7.98 (s, 1H), 7.65-7.53 (m, 2H), 7.45-7.34 (m, 2H), 7.28-7.19 (m, 5H), 6.60 (t, J=5.6 Hz, 1H), 5.57 (s, 2H), 4.54 (d, J=5.6 Hz, 2H), 2.61 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 161.9, 157.6, 155.5, 143.1, 137.9, 137.8, 131.3, 128.8, 128.6, 127.8, 127.6, 126.5, 125.2, 123.7, 121.7, 53.8, 44.1, 17.2; MS (ES+) m/z 458.3 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[C:6]2[CH3:13].[NH2-].[Na+].C1(C)C=CC=CC=1.[CH2:23]([O:25][C:26](=O)[O:27]CC)[CH3:24]>C(OCC)C>[CH2:23]([O:25][C:26](=[O:27])[CH2:13][C:6]1[C:5]2[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=2)[N:9]=[CH:8][CH:7]=1)[CH3:24]
Reactant: COc1ccc2nccc(C)c2c1
Reactant: CCOC(=O)OCC
Agent: [NH2-]
Agent: [Na+]
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CCOC(=O)Cc1ccnc2ccc(OC)cc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 16 %

Procedure:
6-Methoxy-4-methyl-quinoline (0.791 g, 4.572 mmol) was dissolved in anhydrous diethyl ether and cooled to 0° C. under an argon atmosphere. To the stirred mixture was added sodamide as a 50% w/w slurry in toluene (0.36 g, 4.57 mmol). The resulting slurry was allowed to warm to room temperature and was stirred for 1 hour. To this was added diethylcarbonate (0.28 ml, 2.29 mmol). The reaction mixture was then stirred at reflux for 10 hours after which time it was quenched with water (2 ml). The mixture was partitioned between ethyl acetate (2×100 ml) and water (20 ml). The organic phases were combined and dried over magnesium sulfate. The volatiles were removed under reduced pressure and the residue subjected to purification on silica gel using an ethyl acetate-hexane gradient. This provided the desired product as a brown oil (90 mg, 7%).
Reaction SMILES: [C:1]([N:5]1[C:29](=[O:30])[C:28]2[N:13]3[CH2:14][CH2:15][C:16]4[CH:17]=[C:18]([O:26][CH3:27])[C:19]([O:22][CH:23]([CH3:25])[CH3:24])=[CH:20][C:21]=4[C:12]3=[CH:11][C:10]=2[CH2:9][O:8][CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[Br:31]N1C(=O)CCC1=O.O>CN(C=O)C.[O-]S([O-])(=S)=O.[Na+].[Na+]>[C:1]([N:5]1[C:29](=[O:30])[C:28]2[N:13]3[CH2:14][CH2:15][C:16]4[CH:17]=[C:18]([O:26][CH3:27])[C:19]([O:22][CH:23]([CH3:24])[CH3:25])=[CH:20][C:21]=4[C:12]3=[C:11]([Br:31])[C:10]=2[CH2:9][O:8][CH2:7][CH2:6]1)([CH3:3])([CH3:2])[CH3:4]
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1cc2c(cc1OC(C)C)-c1cc3c(n1CC2)C(=O)N(C(C)(C)C)CCOC3
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2c(cc1OC(C)C)-c1c(Br)c3c(n1CC2)C(=O)N(C(C)(C)C)CCOC3
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81.6 %

Procedure:
To a solution of 180 mg of 18c in 2 ml of DMF was added 85 mg of N-bromosuccinimide. The mixture was stirred for ½ hr at RT. 3 ml of water was added and two drops of sat. aq. Na2S2O3 and the mixture was stirred for ½ hr. The precipitate was filtered and washed with water, dried and then triturated with diisopropyl ether, to provide 175 mg of 18d as white crystalline material. Mp 160-162° C.
Reaction SMILES: [CH2:1]([O:5][C:6]1[C:9](=[O:10])[C:8](=[O:11])[C:7]=1[NH:12][CH2:13][CH2:14][CH2:15]O)[CH2:2][CH2:3][CH3:4].[CH3:17][S:18](Cl)(=[O:20])=[O:19].O>N1C=CC=CC=1>[CH2:1]([O:5][C:6]1[C:9](=[O:10])[C:8](=[O:11])[C:7]=1[NH:12][CH2:13][CH2:14][CH2:15][S:18]([CH3:17])(=[O:20])=[O:19])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1c(NCCCO)c(=O)c1=O
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: O
Product: CCCCOc1c(NCCCS(C)(=O)=O)c(=O)c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 66 %

Procedure:
A solution of 1-butoxy-2-(3-hydroxypropylamino)-1-cyclobutene-3,4-dione [prepared in Example 7] (1.0 g, 4.4 mmol) in 5 mL of pyridine was cooled to 0° C. and treated dropwise with 0.36 mL (4.6 mmol) of methanesulfonyl chloride. The mixture was stirred at ambient temperature for 1 hour then poured into 80 mL of water and extracted with 20 mL of ethyl acetate. The organic phase was washed 4 times with water, dried and evaporated to give 0.84 g of title compound.