Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:7][C:8]([CH:10]2[C:18]3[C:13](=[CH:14][N:15]=[CH:16][CH:17]=3)[NH:12][C:11]2=[O:19])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:20](=[O:26])=[N:21]S(Cl)(=O)=O.C(#N)C.ClS(NC=O)(=O)=O>CS(C)=O>[C:1]1([CH2:7][C:8]([CH:10]2[C:18]3[C:13](=[CH:14][N:15]=[CH:16][CH:17]=3)[N:12]([C:20]([NH2:21])=[O:26])[C:11]2=[O:19])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C=NS(=O)(=O)Cl
Reactant: O=C(Cc1ccccc1)C1C(=O)Nc2cnccc21
Agent: O=CNS(=O)(=O)Cl
Solvent: CS(C)=O
Solvent: CC#N
Product: NC(=O)N1C(=O)C(C(=O)Cc2ccccc2)c2ccncc21

Procedure:
The title compound was prepared from 3-phenylacetyl-6-azaoxindole according to the procedure of Example 2C, using 3-phenylacetyl-6-azaoxindole (1.0 g, 3.9 mmol), N-chlorosulfonyl isocyanate (0.41 mL, 4.7 mmol) and acetonitrile (40 mL). Reaction time: 4 hours. The crude N-chlorosulfonyl carboxamide was hydrolysed by stirring in DMSO (6 mL) for 1 hour in a flask open to the air. After dilution with water, the product was collected by filtration, dried, and recrystallized from acetic acid. Yield: 172 mg (15%). M.p. 131°-133° C. (dec.).
Reaction SMILES: [OH:1][CH:2]([C:13]1[CH:14]=[CH:15][C:16]2[O:20][CH:19]=[C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:17]=2[CH:27]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[N+:28]([O-:33])([N+]([O-])=O)=[O:29].[OH-].[Na+].Cl>ClCCl.C(OCC)C>[N+:28]([C:19]1[O:20][C:16]2[CH:15]=[CH:14][C:13]([CH:2]([OH:1])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[CH:27][C:17]=2[C:18]=1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([O-:33])=[O:29]
Reactant: O=[N+]([O-])[N+](=O)[O-]
Reactant: CCCCCCCCCCC(O)c1ccc2occ(-c3ccccc3)c2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: ClCCl
Product: CCCCCCCCCCC(O)c1ccc2oc([N+](=O)[O-])c(-c3ccccc3)c2c1
Reaction time: 16 h

Procedure:
To the solution of product from step A is added 2 g. of dinitrogen tetraoxide dissolved in dichloromethane, and the mixture is stirred for about 16 hours. Evaporation provides a residue which is mixed with ice and 10 percent sodium hydroxide solution. The mixture is stirred for 15 minutes, then cold 6N hydrochloric acid and diethyl ether are added. The ether layer is separated, then washed with saturated sodium chloride solution and dried. The solution is chromatographed on silica gel, eluting first with carbon tetrachloride, then dichloromethane. The later fractions are evaporated to provide 1-(2-nitro-3-phenyl-5-benzofuranyl)undecan-1-ol as a yellow solid, m.p. 84°-85° C. after recrystallization from hexane.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[NH2:8].C(N(CC)CC)C.[C:16](Cl)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>O1CCCC1>[F:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[NH:8][C:16](=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Nc1ccncc1F
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Nc1ccncc1F)c1ccccc1
Reaction time: 2 h

Procedure:
A solution of 3-fluoropyridin-4-amine (2.20 kg, 19.6 mol) in anhydrous tetrahydrofuran (25 L) was cooled to −5° C. and flushed with nitrogen. This solution was charged with triethylamine (3.99 kg/5.5 L, 39.4 mol). Benzoylchloride (3.173 kg/2.62 l, 22.57 mol) was added drop-wise via an addition funnel over two hours while the internal temperature was maintained between −5° C. to 5° C. and the reaction mixture was left to stand for an additional two hours. The reaction mixture was then filtered and washed with dry tetrahydrofuran (5×20 L). The tetrahydrofuran solution was concentrated under vacuum to give crude product which was recrystallized from ethyl acetate and hexane, filtered and dried to afford N-(3-fluoro-pyridin-4-yl)-benzamide, 3.90 kg, (92%). 1H NMR (400 MHz, CDCl3): δ 8.51 (1H, t, J=5.46 Hz), 8.45 (1H, d, J=2.34 Hz), 8.39 (1H, d, J=5.46 Hz), 8.30 (1H, s), 7.89 (2H, d, J=8.20 Hz), 7.62 (1H, t, J=7.03 Hz), 7.53 (2H, t, J=7.81 Hz).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[N:6][CH:5]=[C:4](Cl)[N:3]=1.[F:9][C:10]1[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][CH:11]=1>>[F:9][C:10]1[CH:15]=[CH:14][C:13]([C:4]2[N:3]=[C:2]([NH2:1])[CH:7]=[N:6][CH:5]=2)=[CH:12][CH:11]=1
Reactant: Nc1cncc(Cl)n1
Reactant: OB(O)c1ccc(F)cc1
Product: Nc1cncc(-c2ccc(F)cc2)n1

Procedure:
Prepared in analogy to example 1d, starting from 2-amino-6-chloropyrazine and 4-fluorobenzeneboronic acid. The title compound was obtained as a slightly brown solid (yield: 91%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1)#[N:2].[Na].[CH3:10][NH:11][NH:12][C:13](=O)[C:14]1[CH:19]=[CH:18][CH:17]=[N:16][CH:15]=1>CO>[CH3:10][N:11]1[C:1]([C:3]2[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=2)=[N:2][C:13]([C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)=[N:12]1
Reactant: CNNC(=O)c1cccnc1
Reactant: N#Cc1ccncc1
Agent: [Na]
Solvent: CO
Product: Cn1nc(-c2cccnc2)nc1-c1ccncc1
Reaction time: 0.5 h

Procedure:
To 4-cyanopyridine (2 g.) in methanol (30 ml.) is added sodium (0.1 g.). The solution is allowed to stand 0.5 hours at ambient temperature and is then added to a solution of 1-methyl-2-nicotinoyl-hydrazine (3 g.) in methanol (30 ml.). The reaction mixture is heated 5 hours at reflux and is concentrated to an oil which solidifies. After chromatography on silica gel and recrystallization from acetonitrile 0.8 g. of 1-methyl-3-(3-pyridyl)-5-(4-pyridyl)-1,2,4-triazole melting 132°-133°C is obtained.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:11]=[CH:12][C:13]([CH2:16][CH2:17][C:18]3[CH:19]=[C:20]([CH2:23][CH2:24][C:25]([O:27]C)=O)[S:21][CH:22]=3)=[N:14][CH:15]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].O.[NH2:30][NH2:31].C(Cl)(Cl)[Cl:33]>CO>[ClH:33].[ClH:33].[ClH:33].[C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:11]=[CH:12][C:13]([CH2:16][CH2:17][C:18]3[CH:19]=[C:20]([CH2:23][CH2:24][C:25]([NH:30][NH2:31])=[O:27])[S:21][CH:22]=3)=[N:14][CH:15]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: COC(=O)CCc1cc(CCc2ccc(N3CCN(C(C)=O)CC3)cn2)cs1
Reactant: NN
Reactant: ClC(Cl)Cl
Solvent: CO
Solvent: O
Product: CC(=O)N1CCN(c2ccc(CCc3csc(CCC(=O)NN)c3)nc2)CC1
Product: Cl
Temperature: 47.5 °C
Reaction time: 48 h
Yield: 75.8 %

Procedure:
To a solution of methyl 3-(4-{2-[5-(4-acetylpiperazin-1-yl)pyridin-2-yl]ethyl}thiophen-2-yl)propanoate (360.0 mg, 0.897 mmol) in anhydrous methanol (14 ml) was added hydrazine monohydrate (449 mg, 8.97 mmol), and the mixture was stirred at 45 to 50° C. for 2 days. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in 10% methanol-dichloromethane mixture and filtered through aminopropylated silica gel. The filtrate was concentrated under reduced pressure, and the residue was purified by aminopropylated silica gel column chromatography (2% methanol-dichloromethane mixture) to give a colorless oil. This was dissolved in anhydrous chloroform (30 ml), and 1M hydrogen chloride diethyl ether solution (4.0 ml, 4.0 mmol) was added dropwise. After stirring for 15 min, the reaction mixture was concentrated under reduced pressure. Anhydrous chloroform (30 ml) was added to the residue, and the mixture was concentrated under reduced pressure. This operation was repeated 3 times to removed excess hydrogen chloride azeotropically. The residue was suspended in anhydrous chloroform (30 ml), filtered, washed with anhydrous chloroform, anhydrous diethyl ether and ethyl acetate, and dried under reduced pressure to give the title compound (347.5 mg, yield 75.8%) as a slightly yellow white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[I:10]N1C(=O)CCC1=O.C1C(=O)N(I)C(=O)C1.CN(C=O)C>CN(C)C=O>[NH2:1][C:2]1[CH:9]=[CH:8][C:7]([I:10])=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1ccccc1N
Reactant: O=C1CCC(=O)N1I
Solvent: CN(C)C=O
Product: N#Cc1cc(I)ccc1N
Temperature: 0 °C
Reaction time: 8 h

Procedure:
2-Aminobenzonitrile (2.0 g, 16.9 mmol, 1 equiv.) was dissolved in dry N,N-dimethylformamide (30 mL), and the solution was cooled to 0° C. A solution of N-iodosuccinimide, NIS (3.81 g, 16.9 mmol, 1 equiv.) in 30 mL of DMF was added dropwise with an addition funnel. After the NIS/DMF solution was, added, the ice bath was removed, and the reaction was stirred at room temperature overnight. The reaction was quenched by pouring into 3N NaOH (300 mL) and diluted with an additional 200 mL of water. 2-Amino-5-iodobenzonitrile formed as a precipitate, which was collected by filtration.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[C:9]2[C:5]([CH2:6][C:7]([CH2:16][CH:17]=[C:18]([Cl:20])[CH3:19])([CH2:13][CH2:14][CH3:15])[C:8]2=[O:12])=[CH:4][C:3]=1[CH:21]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[C:22]([O:24][CH2:25][CH3:26])=[O:23].[H-].[Na+].Br[CH2:35][C:36]([O:38][CH3:39])=[O:37].C(O)(=O)C>C1(C)C=CC=CC=1.CN(C)C=O>[CH3:39][O:38][C:36]([CH2:35][C:21]([C:3]1[CH:4]=[C:5]2[C:9](=[C:10]([Cl:11])[C:2]=1[Cl:1])[C:8](=[O:12])[C:7]([CH2:16][CH:17]=[C:18]([Cl:20])[CH3:19])([CH2:13][CH2:14][CH3:15])[CH2:6]2)([C:27]([O:29][CH2:30][CH3:31])=[O:28])[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[O:37]
Reactant: COC(=O)CBr
Reactant: CCCC1(CC=C(C)Cl)Cc2cc(C(C(=O)OCC)C(=O)OCC)c(Cl)c(Cl)c2C1=O
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CCCC1(CC=C(C)Cl)Cc2cc(C(CC(=O)OC)(C(=O)OCC)C(=O)OCC)c(Cl)c(Cl)c2C1=O
Temperature: 0 °C
Yield: 89 %

Procedure:
Diethyl 2-[6,7-dichloro-2-(3-chloro-2-butenyl)-2,3-dihydro-1-oxo-2-propyl-1H-inden-5-yl]-malonate (10.7 g, 0.0218 mole) dissolved in toluene (45 ml) was added dropwise with stirring under N2 at 25° C. to a suspension of 56% sodium hydride/mineral (1.22 g, 0.0284 mole) in dimethylformamide (45 ml). Methyl bromoacetate (4.34 g, 0.0284 mole) was added in one portion 40 minutes after the previous addition and the mixture was heated at 65° for 41/2 hours. The mixture was then cooled, and after acetic acid (3 ml) was added, poured into ice water and extracted with diethyl ether. The organic extracts were washed with water, dried over MgSO4, concentrated under vacuum, and the residue was chromatographed on silica eluting the methlene chloride/hexane, 4/1 to obtain 10.9 g of the product as an oil.
Reaction SMILES: [BrH:1].C([NH:5][CH:6]1[CH2:15][CH2:14][C:9]2[N:10]=[C:11]([NH2:13])[S:12][C:8]=2[CH2:7]1)(=O)C>Br>[BrH:1].[BrH:1].[NH2:13][C:11]1[S:12][C:8]2[CH2:7][CH:6]([NH2:5])[CH2:15][CH2:14][C:9]=2[N:10]=1
Reactant: CC(=O)NC1CCc2nc(N)sc2C1
Agent: Br
Product: Nc1nc2c(s1)CC(N)CC2

Procedure:
3 g (0.01 Mol) of 6-acetylamino-2-amino-4,5,6,7-tetrahydro-benzthiazole-hydrobromide are dissolved in 20 ml of semi-concentrated hydrobromic acid and refluxed for 6 hours. The solution is then concentrated by evaporation and the residue recrystallized from methanol.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:10])[CH3:9])=[CH:4][C:3]=1[NH:11][S:12]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH3:24])[CH:16]=1)(=[O:14])=[O:13]>C(Cl)Cl.C1COCC1.O=[Mn]=O>[C:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([NH:11][S:12]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH3:24])[CH:16]=2)(=[O:14])=[O:13])[CH:4]=1)(=[O:10])[CH3:9]
Reactant: COc1ccc(S(=O)(=O)Nc2cc(C(C)O)ccc2Cl)cc1OC
Agent: O=[Mn]=O
Solvent: C1CCOC1
Solvent: ClCCl
Product: COc1ccc(S(=O)(=O)Nc2cc(C(C)=O)ccc2Cl)cc1OC
Temperature: 25 °C
Reaction time: 7 h

Procedure:
A solution of N-[2-chloro-5-(1-hydroxy-ethyl)-phenyl]-3,4-dimethoxy-benzenesulfonamide (1.85 g, 5 mmol) in DCM/THF (1:1, 10 mL) was treated with MnO2 (10.8 g, 25 eq). The mixture was stirred at RT for 7 h, filtered over Celite and concentrated. The residue was purified by chromatography on SiO2 (hex/EA 1:1). The product was recovered as a colourless foam (1.58 g, 86%).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[C@@H:15]([C:16]([OH:18])=[O:17])[CH2:14][NH:13][C:12]1=[O:19])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1[CH:25]=[CH:24][CH:23]=CC=1.P(Cl)(Cl)(Cl)=O.[C:31]([O-])(=O)C.[Na+]>C(Cl)(Cl)Cl.C(O)(C)(C)C>[C:24]([O:17][C:16]([C@@H:15]1[N:11]([C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:10])[C:12](=[O:19])[NH:13][CH2:14]1)=[O:18])([CH3:23])([CH3:25])[CH3:31]
Reactant: c1ccncc1
Reactant: CC(=O)[O-]
Reactant: O=C(O)[C@H]1CNC(=O)N1C(=O)OCc1ccccc1
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC(C)(C)O
Solvent: O=P(Cl)(Cl)Cl
Product: CC(C)(C)OC(=O)[C@H]1CNC(=O)N1C(=O)OCc1ccccc1

Procedure:
To a solution of (R)-2-oxoimidazolidine-1,5-dicarboxylic acid 1-benzyl ester (534 mg) in chloroform (2.6 ml) were sequentially added pyridine (1.0 ml) and tert-butylalcohol (1.5 ml) at room temperature, and the mixture was stirred. This reaction solution was iced, and phosphorous oxychloride (0.23 ml) was added thereto, and then the mixture was stirred at room temperature for 5 hours. This reaction solution was iced, and a 20 wt % aqueous solution of sodium acetate (20 ml) was added thereto, and then chloroform (5 ml) was further added at room temperature, and the mixture was stirred for 30 minutes. This mixed solution was extracted with chloroform, and the resulting organic layer was washed with a 0.1M aqueous solution of hydrochloric acid, water, a saturated aqueous solution of sodium hydrogen carbonate and a saturated aqueous solution of sodium chloride, and then dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude product of the titled compound (467 mg).
Reaction SMILES: Cl.[NH:2]([C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7])[NH2:3].C(N(CC)CC)C.C[O:21][C:22](=O)[N:23]=[C:24](SC)[C:25]([C:39]1[CH:44]=[C:43]([O:45][CH3:46])[C:42]([O:47][CH3:48])=[CH:41][C:40]=1[F:49])=[N:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]2[N:37]=[C:36]([CH3:38])[O:35][N:34]=2)=[CH:29][CH:28]=1.Cl>CN(C)C=O>[F:49][C:40]1[CH:41]=[C:42]([O:47][CH3:48])[C:43]([O:45][CH3:46])=[CH:44][C:39]=1[C:25](=[N:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]2[N:37]=[C:36]([CH3:38])[O:35][N:34]=2)=[CH:29][CH:28]=1)[C:24]1[NH:23][C:22](=[O:21])[N:2]([C:4]2[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=2[C:6]([OH:8])=[O:7])[N:3]=1
Reactant: COC(=O)N=C(SC)C(=Nc1ccc(-c2noc(C)n2)cc1)c1cc(OC)c(OC)cc1F
Reactant: NNc1ccccc1C(=O)O
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc(F)c(C(=Nc2ccc(-c3noc(C)n3)cc2)c2nn(-c3ccccc3C(=O)O)c(=O)[nH]2)cc1OC
Temperature: 85 °C
Reaction time: 21 h
Yield: 95.1 %

Procedure:
After adding 240 mg of 2-hydrazinobenzoic acid hydrochloride and 0.295 ml of triethylamine to a solution of 500 mg of [2-(2-fluoro-4,5-dimethoxyphenyl)-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylimino]-1-methylsulfanylethylidene]carbamic acid methyl ester in 10 ml of N,N-dimethylformamide (hereinafter, “DMF”), the mixture was stirred at 85° C. for 21 hours under a nitrogen atmosphere. After cooling the reaction mixture to room temperature, dilute hydrochloric acid (pH 3-4) was added and extraction was performed with ethyl acetate. The organic layer was then washed with dilute hydrochloric acid (pH 3-4) and saturated brine, and dried over anhydrous sodium sulfate. The desiccating agent was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by NAM silica gel column chromatography (methanol-ethyl acetate) to give the title compound (548 mg) as a light yellow solid.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[CH:11]([O:12][CH3:13])[C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[CH2:8][O:7][C:6]=2[CH:18]=1.C([Li])CCC.[CH3:24]CCCCC.[C:30](=[O:32])=[O:31].S(=O)(=O)(O)O>O1CCCC1.CO>[CH3:13][O:12][CH:11]1[C:10]2[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=2[CH2:8][O:7][C:6]2[CH:18]=[C:2]([C:30]([O:32][CH3:24])=[O:31])[CH:3]=[CH:4][C:5]1=2
Reactant: O=C=O
Reactant: CCCCCC
Reactant: COC1c2ccccc2COc2cc(Br)ccc21
Agent: O=S(=O)(O)O
Agent: [Li]CCCC
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1ccc2c(c1)OCc1ccccc1C2OC
Temperature: -78 °C
Reaction time: 0.67 h

Procedure:
3-Bromo-11-methoxy-6,11-dihydrodibenz[b,e]oxepine, 30 g, was dissolved in 500 ml of tetrahydrofuran. After cooling to -78° C., 65 ml of 1.6N n-butyl lithium/hexane solution was dropwise added to the solution in a nitrogen atmospher followed by stirring at -78° C. for further 40 minutes. The reaction solution was dropwise added onto 100 g of dry ice, which was allowed to stand to elevate to room temperature. The solvent was distilled off under reduced pressure. To the residue obtained, were added 500 ml of methanol and 10 ml of conc. sulfuric acid. The mixture was heated to reflux for 2 hours. After allowing to cool, the solvent was distilled off under reduced pressure. The residue was extracted with 500 ml of ethyl acetate. After washing successively with saturated sodium chloride aqueous solution, saturated sodium bicarbonate aqueous solution and saturated sodium chloride aqueous solution, the extract was dried over anhydrous magnesium sulfate. The solvent was then distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (eluting solvent; hexane:ethyl acetate=1:1) to give 19.3 g of the product as pale yellow oil.
Reaction SMILES: [CH:1]([NH:3][CH:4](P(OCC)(OCC)=O)[C:5]([O:7][CH2:8][C:9]([Cl:12])([Cl:11])[Cl:10])=[O:6])=[S:2].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:28][C:29](=O)[CH2:30][O:31][CH2:32][O:33][CH3:34]>CC(C)=O.C(Cl)Cl>[CH3:34][O:33][CH2:32][O:31][CH2:30][C:29]1[CH2:28][S:2][CH:1]=[N:3][C:4]=1[C:5]([O:7][CH2:8][C:9]([Cl:10])([Cl:11])[Cl:12])=[O:6]
Reactant: CCOP(=O)(OCC)C(NC=S)C(=O)OCC(Cl)(Cl)Cl
Reactant: COCOCC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: ClCCl
Product: COCOCC1=C(C(=O)OCC(Cl)(Cl)Cl)N=CSC1
Reaction time: 4 h

Procedure:
A solution of 2,2,2-trichloroethyl α-thioformamidodiethylphosphonoacetate (3.87 g.) in acetone (50 ml.) is treated with powdered potassium carbonate (4.15 g) and 1-chloro-3-methoxymethyloxy-propan-2-one (1.60 g.). The mixture is stirred for 4 hrs. at room temperature under a nitrogen atmosphere, then filtered. Evaporation of the filtrate leaves a residue which is dissolved in methylene chloride. The solution is washed with dilute aqueous dipotassium hydrogen phosphate and water, dried over magnesium sulfate, filtered and evaporated in vacuo affording 2,2,2-trichloroethyl 5-methoxymethyloxymethyl-6H-1,3-thiazine-4-carboxylate.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([F:28])([F:27])[C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][CH:21]=3)[N:18]=[CH:17][C:16]([O:22][CH2:23][CH2:24][O:25][CH3:26])=[CH:15]4)=[N:9][N:10]=2)[N:7]=1.[F:29][C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[C:34]([F:36])[CH:35]=1.FC1C=C(C2C=C(F)C3N(C(C(F)(F)C4C=C5C(=CC=4)N=CC(OC)=C5)=NN=3)C=2)C=C(F)C=1>>[F:29][C:30]1[CH:31]=[C:32]([C:2]2[CH:3]=[CH:4][C:5]3[N:6]([C:8]([C:11]([F:28])([F:27])[C:12]4[CH:13]=[C:14]5[C:19](=[CH:20][CH:21]=4)[N:18]=[CH:17][C:16]([O:22][CH2:23][CH2:24][O:25][CH3:26])=[CH:15]5)=[N:9][N:10]=3)[N:7]=2)[CH:33]=[C:34]([F:36])[CH:35]=1
Reactant: COCCOc1cnc2ccc(C(F)(F)c3nnc4ccc(Cl)nn34)cc2c1
Reactant: OB(O)c1cc(F)cc(F)c1
Agent: COc1cnc2ccc(C(F)(F)c3nnc4c(F)cc(-c5cc(F)cc(F)c5)cn34)cc2c1
Product: COCCOc1cnc2ccc(C(F)(F)c3nnc4ccc(-c5cc(F)cc(F)c5)nn34)cc2c1

Procedure:
The title compound was synthesized from 6-((6-chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)difluoromethyl)-3-(2-methoxyethoxy)quinoline and 3,5-difluorophenylboronic acid in a similar manner as that described for 6-((6-(3,5-difluorophenyl)-8-fluoro-[1,2,4]triazolo[4,3-a]pyridin-3-yl)difluoromethyl)-3-methoxyquinoline. LRMS (ESI) m/z calcd for C24H18F4N5O2 (M+H) 484.1. found 484.2.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([C:14]2[S:23][C:22]3[C:21]4[N:24]=[C:25]([C:28]#[C:29][CH2:30][N:31]([CH3:33])[CH3:32])[CH:26]=[CH:27][C:20]=4[O:19][CH2:18][CH2:17][C:16]=3[CH:15]=2)=[N:12][CH:11]=[N:10]1>CO.[Pd]>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([C:14]2[S:23][C:22]3[C:21]4[N:24]=[C:25]([CH2:28][CH2:29][CH2:30][N:31]([CH3:33])[CH3:32])[CH:26]=[CH:27][C:20]=4[O:19][CH2:18][CH2:17][C:16]=3[CH:15]=2)=[N:12][CH:11]=[N:10]1
Reactant: CN(C)CC#Cc1ccc2c(n1)-c1sc(-c3ncnn3-c3ccc(F)cc3F)cc1CCO2
Agent: [Pd]
Solvent: CO
Product: CN(C)CCCc1ccc2c(n1)-c1sc(-c3ncnn3-c3ccc(F)cc3F)cc1CCO2
Temperature: 25 °C
Reaction time: 8 h
Yield: 12.9 %

Procedure:
The mixture of (3-{2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulen-9-yl}-prop-2-ynyl)-dimethyl-amine (200 mg, 0.43 mmol), 10% Pd/C (20 mg) in MeOH (20 mL) was stirred under H2 atmosphere (50 psi) at room temperature for overnight. Filtered and concentrated to give 246 (26 mg, yield: 13%). 1H NMR (CDCl3, 400 MHz): δ8.08 (s, 1H), 7.58-7.52 (m, 1H), 7.19 (d, J=8.0 Hz, 1H), 7.15-7.07 (m, 2H), 6.94 (d, J=8.0 Hz, 1H), 6.90 (s, 1H), 4.29 (t, J=4.4 Hz, 2H), 3.12 (t, J=4.4 Hz, 2H), 2.82-2.77 (m, 4H), 2.57 (s, 6H), 2.15-2.08 (m, 2H). ESI-MS: (m/z)=468 [M+H]+
Reaction SMILES: [S:1]1C=CC=[C:2]1CC(O)=O.[C:10](=[O:13])([O-])[O-].[K+].[K+].C(O)C.Br[CH2:20][CH2:21][CH2:22][C:23]#[N:24]>O>[SH:1][CH2:2][C:10]([CH2:20][CH2:21][CH2:22][C:23]#[N:24])=[O:13]
Reactant: O=C([O-])[O-]
Reactant: N#CCCCBr
Reactant: O=C(O)Cc1cccs1
Agent: [K+]
Solvent: O
Solvent: CCO
Product: N#CCCCC(=O)CS
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Thiolacetic acid (49 mL, 0.69 mol) is added to potassium carbonate (93.4 g, 0.68 mol) dissolved in water (150 mL). Ethanol (260 mL) is added and then 4-bromobutyronitrile is added at 15° to 28° C. and the reaction mixture stirred at room temperature for 16 hours. The resulting inorganic solids are filtered off and the filtrate extracted with toluene. The organic layer is separated, dried over anhydrous Na2SO4 and concentrated to give the desired 4-mercaptoacetyl butyronitrile as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](O)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.P(Cl)(Cl)([Cl:14])=O>>[NH2:1][C:2]1[N:7]=[C:6]([Cl:14])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Nc1ncc([N+](=O)[O-])c(O)n1
Product: Nc1ncc([N+](=O)[O-])c(Cl)n1

Procedure:
A suspension of 2-amino-4-hydroxy-5-nitropyrimidine (5.0 g, 32.1 mmol) in phosphorous oxychloride (100 mL) was refluxed overnight, and the excess phosphorous oxychloride was evaporated under reduced pressure. The residue was mixed with ice (100 g) in an ice-bath, and the mixture was neutralized with concentrated aqueous sodium carbonate solution. A yellow precipitate was collected by filtration and washed with water: yield, 1.39 g (25%); mp 191-194° C. dec.; 1H NMR d 8.45 (br s, 2 H, NH2, exchange with D2O), 9.03 (s, 1 H, H-6); MS (EI) calcd. m/z for C4H3N4O235Cl 173.9944, found 173.9934; calcd. m/z for C4H3N4O237Cl 175.9915, found 175.9916.
Reaction SMILES: [CH2:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:14]=[C:13]([S:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:12]3([CH:26]=[CH:25][C:24](=[O:27])[CH:23]=[CH:22]3)[N:11]=2)[CH2:6][CH2:5]1)[CH:2]=[CH2:3].ClC1C=CC(Cl)=CC=1Cl.[C:37]([OH:42])(=[O:41])[C:38]([OH:40])=[O:39]>C(Cl)(Cl)Cl.CC(C)=O>[C:37]([OH:42])(=[O:41])[C:38]([OH:40])=[O:39].[C:37]([OH:42])(=[O:41])[C:38]([OH:40])=[O:39].[CH2:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[N:11]3[CH:26]=[CH:25][C:24](=[O:27])[CH:23]=[CH:22][C:12]3=[C:13]([S:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:14]=2)[CH2:6][CH2:5]1)[CH:2]=[CH2:3]
Reactant: C=CCN1CCN(C2=NC3(C=CC(=O)C=C3)C(Sc3ccccc3)=C2)CC1
Agent: O=C(O)C(=O)O
Solvent: CC(C)=O
Solvent: Clc1ccc(Cl)c(Cl)c1
Solvent: ClC(Cl)Cl
Product: C=CCN1CCN(c2cc(Sc3ccccc3)c3ccc(=O)ccn23)CC1
Yield: 41.6 %

Procedure:
By working as in Example 5, but starting with 2-(4-allyl-1-piperazinyl)-4-phenylthio-1-azaspiro[4.5]deca-1,3,6,9-tetraen-8-one (15.2 g) and 1,2,4-trichlorobenzene (150 cc), a residue is obtained which is redissolved in chloroform (300 cc). The solution obtained is poured into silica (300 g) contained in a column 4.2 cm in diameter. Elution is first performed with chloroform (1 liter) and this eluate is rejected. Elution is then performed with a mixture of chloroform and methanol (90:10 by volume) (3 liters) and the corresponding eluate is evaporated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at 40° C. The residue obtained is dissolved in acetone (15 cc). Oxalic acid (1.9 g), dissolved in acetone (15 cc), is added to the solution obtained. The precipitate formed is separated by filtration and washed with ethyl ether (10 cc). 3-(4-Allyl-1-piperazinyl)-1-phenylthio-7H-pyrrolo[1,2-a]azepin- 7-one dioxalate (2.45 g), m.p. 225° C., is thereby obtained.