Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][CH:6]=[C:5]2[S:13][CH:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1.[CH:27]1([CH2:30]Br)[CH2:29][CH2:28]1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:30][CH:27]1[CH2:29][CH2:28]1)[CH:6]=[C:5]2[S:13][CH:14]1[CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:18][CH2:19]1
Reactant: BrCC1CC1
Reactant: CC(C)(C)OC(=O)N1CCC(Sc2c[nH]c(=O)c3ccc(Br)cc23)CC1
Product: CC(C)(C)OC(=O)N1CCC(Sc2cn(CC3CC3)c(=O)c3ccc(Br)cc23)CC1

Procedure:
The subtitle compound was prepared from tert-butyl 4-[(6-bromo-1-oxo-1,2-dihydroisoquinolin-4-yl)sulfanyl]piperidine-1-carboxylate (Example 58b) and cyclopropylmethylbromide using the method of example 58c.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([CH2:30][CH:31]=C)[CH2:11][CH2:10][CH:9]([O:12][Si:13]([C:26]([CH3:29])([CH3:28])[CH3:27])([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:8][CH2:7]1)=[O:5])C.C(OCC)(=[O:35])C>CC(O)C.O.O=[Os](=O)(=O)=O>[CH3:1][O:3][C:4]([C:6]1([CH2:30][CH:31]=[O:35])[CH2:7][CH2:8][CH:9]([O:12][Si:13]([C:26]([CH3:27])([CH3:28])[CH3:29])([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:10][CH2:11]1)=[O:5]
Reactant: CCOC(C)=O
Reactant: C=CCC1(C(=O)OCC)CCC(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CC1
Agent: O=[Os](=O)(=O)=O
Solvent: CC(C)O
Solvent: O
Product: COC(=O)C1(CC=O)CCC(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 87 %

Procedure:
1-Allyl-4-(tert-butyl-diphenyl-silanyloxy)-cyclohexanecarboxylic acid ethyl ester (5 g, 11.1 mmol) was dissolved in 2-propanol (100 mL) and water (50 mL). To this was added an aqueous solution of NaIO4 (5.94 g, 27.8 mmol) in water (50 mL), followed by addition of OsO4 (0.025 g, crystals, in one portion). The reaction mixture was allowed to stir for 16 hours at rt. The reaction mixture was poured into ice water (50 mL) and ethyl acetate (EtOAc) (60 mL). The layers were separated and the aqueous layer was extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine, and concentrated to dryness. The material was then purified over silica gel column eluting with ethyl acetate in heptanes (0-60%) to afford 4.45 g (87%) of the title compound.
Reaction SMILES: Br[CH2:2][C:3]([NH:5][C:6]1[S:7][C:8]([C:16]([CH:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[O:17])=[C:9]([C:11]2[O:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1)=[O:4].Cl.[CH3:25][O:26][CH:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1.C(N(CC)CC)C>C1COCC1>[O:12]1[CH:13]=[CH:14][CH:15]=[C:11]1[C:9]1[N:10]=[C:6]([NH:5][C:3](=[O:4])[CH2:2][N:30]2[CH2:31][CH2:32][CH:27]([O:26][CH3:25])[CH2:28][CH2:29]2)[S:7][C:8]=1[C:16]([CH:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)=[O:17]
Reactant: O=C(CBr)Nc1nc(-c2ccco2)c(C(=O)C2CCOCC2)s1
Reactant: COC1CCNCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC1CCN(CC(=O)Nc2nc(-c3ccco3)c(C(=O)C3CCOCC3)s2)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 73.8 %

Procedure:
Compound 531 (120 mg, 0.300 mmol) and 4-methoxypiperidine hydrochloride (139 mg, 0.900 mmol) were suspended in THF (4 mL), and triethylamine (0.140 mL, 0.990 mmol) was added dropwise thereto, followed by stirring at room temperature for 1.5 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified through silica gel column chromatography (chloroform:methanol=49:1), followed by reslurrying with a mixed solvent of diisopropyl ether and diethyl ether to afford the entitled Compound 545 (96.0 mg, 74%) as a white solid.
Reaction SMILES: C([C:4]1[CH:5]=[CH:6][C:7]([O:12][CH2:13][CH2:14][CH3:15])=[C:8]([CH:11]=1)[C:9]#[N:10])(=O)C.S(OOS([O-])(=O)=O)([O-])(=O)=[O:17].[NH4+].[NH4+].S(=O)(=O)(O)O>C(O)(=O)C>[OH:17][C:4]1[CH:5]=[CH:6][C:7]([O:12][CH2:13][CH2:14][CH3:15])=[C:8]([CH:11]=1)[C:9]#[N:10]
Reactant: CCCOc1ccc(C(C)=O)cc1C#N
Reactant: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [NH4+]
Solvent: CC(=O)O
Product: CCCOc1ccc(O)cc1C#N
Temperature: 45 °C
Reaction time: 0.5 h
Yield: 73.4 %

Procedure:
5-acetyl-2-n-propoxybenzonitrile (20.3 g, 0.10 mol) was dissolved in glacial acetic acid (100 ml), followed by addition of ammonium persulfate (60 g, 0.26 mol). After sulphuric acid solution (H2SO4 10 ml/H2O 14 ml) was slowly added dropwise under ice-water bath, the reaction temperature was raised to 45° C. for 3 h. The reaction mixture was poured into ice water to generate precipitates, stirred for 0.5 h, filtered, and dried to give the title compound (13.0 g, yield: 73%). 1H NMR (CDCl3) δ: 8.00 (1H, d), 7.04 (1H, dd), 6.90 (1H, d), 4.05 (2H, t), 1.78 (2H, m), 1.01 (3H, t).
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[O:11][CH2:10][C:9](=[O:12])[N:8]([CH2:13][CH2:14][CH2:15][O:16][CH3:17])[C:7]=2[CH:18]=1.[Br:19][Si](C)(C)C>C(Cl)(Cl)Cl>[Br:19][CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[O:11][CH2:10][C:9](=[O:12])[N:8]([CH2:13][CH2:14][CH2:15][O:16][CH3:17])[C:7]=2[CH:18]=1
Reactant: C[Si](C)(C)Br
Reactant: COCCCN1C(=O)COc2ccc(CO)cc21
Solvent: ClC(Cl)Cl
Product: COCCCN1C(=O)COc2ccc(CBr)cc21
Reaction time: 0.5 h

Procedure:
To a solution of 74.0 g of 6-hydroxymethyl-4-(3-methoxy-propyl)-4H-benzo[1,4]oxazin-3-one (from example 1 g) in 600 ml of chloroform are added 58 ml of bromotrimethylsilane at room temperature. The reaction mixture is stirred for 30 minutes and concentrated under reduced pressure. The residue is purified by flash chromatography (SiO2 60 F) to afford the title compound as an off white solid. Rf=0.46 (EtOAc-heptane 1:1); Rt=4.03.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][N:12]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]OS(C)(=O)=O)[C:13]([NH:15][C:16]2[C:21]([Cl:22])=[CH:20][C:19]([Cl:23])=[CH:18][C:17]=2[Cl:24])=[O:14])=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[Cl-:36].[K+]>CS(C)=O>[CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][N:12]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][Cl:36])[C:13]([NH:15][C:16]2[C:21]([Cl:22])=[CH:20][C:19]([Cl:23])=[CH:18][C:17]=2[Cl:24])=[O:14])=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ccc(CN(CCCCCCOS(C)(=O)=O)C(=O)Nc2c(Cl)cc(Cl)cc2Cl)cc1
Reactant: [Cl-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCCCc1ccc(CN(CCCCCCCl)C(=O)Nc2c(Cl)cc(Cl)cc2Cl)cc1
Yield: 64.7 %

Procedure:
A mixture of 1.9 g of 1-[(4-butylphenyl)methyl]-1-[6-[(methylsulfonyl)oxy]hexyl]-3-(2,4,6-trichlorophenyl)urea, 0.6 g of potassium chloride, and 3.0 ml of dried dimethyl sulfoxide was heated at an oil bath temperature of 60°-70° C. for 20 hours. The extraction and chromatography procedures of Example 521 were followed to give 1.1 g of the desired product as a colorless oil.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([CH3:20])=[CH:18][C:17]([CH2:21][CH2:22][CH3:23])=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.C(OCC)(=O)C.[OH-].[Na+]>C(Cl)(Cl)Cl>[CH3:20][C:19]1[C:14]([N:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)=[N:15][CH:16]=[C:17]([CH2:21][CH2:22][CH3:23])[CH:18]=1
Reactant: CCCc1cnc(N2CCN(C(=O)OC(C)(C)C)CC2)c(C)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: CCCc1cnc(N2CCNCC2)c(C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.4 %

Procedure:
To a mixture of 4-(5-bromo-3-methylpyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (6.7 g), bis(tricyclohexylphosphine)palladium (II) dichloride (148 mg), tripotassium phosphate (13 g) and cis-1-propene-1-boronic acid (2.6 g) were added toluene (60 mL) and water (3 mL), and the mixture was refluxed for 8 hr. After cooling, the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated. The residue was purified by column chromatography (hexane:ethyl acetate) to give 4-[3-methyl-5-propenylpyridin-2-yl]piperazine-1-carboxylic acid tert-butyl ester (6 g). 4-[3-Methyl-5-propenylpyridin-2-yl]piperazine-1-carboxylic acid tert-butyl ester (6 g) was dissolved in ethanol (40 mL), 5% palladium carbon-ethylenediamine complex (1.2 g) was added, and the mixture was stirred under a hydrogen atmosphere at room temperature overnight. After celite filtration, the solvent in the filtrate was evaporated to give 4-[3-methyl-5-propylpyridin-2-yl]piperazine-1-carboxylic acid tert-butyl ester (6 g). 4-[3-Methyl-5-propylpyridin-2-yl]piperazine-1-carboxylic acid tert-butyl ester (6 g) was dissolved in chloroform (10 mL), 4N hydrogen chloride/ethyl acetate (10 mL) was added, and the mixture was stirred at room temperature overnight. To the reaction mixture was added 1N aqueous sodium hydroxide solution (40 mL), and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, and the solvent was evaporated to give the title compound (2.9 g).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]#[N:16])=[CH:5][CH:4]=1.[CH2:17]([NH2:20])[CH2:18][CH3:19]>C(Cl)Cl>[C:15]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[C:6]1[CH:7]=[CH:8][C:3]([CH2:2][NH:20][CH2:17][CH2:18][CH3:19])=[CH:4][CH:5]=1)#[N:16]
Reactant: N#Cc1ccccc1-c1ccc(CBr)cc1
Reactant: CCCN
Solvent: ClCCl
Product: CCCNCc1ccc(-c2ccccc2C#N)cc1
Reaction time: 0.5 h

Procedure:
10.84 g of 4-bromomethyl-2'-cyano-biphenyl are mixed at room temperature with 20 ml of propylamine. The mixture is stirred for 30 minutes, during which heating to reflux temperature occurs, is then diluted with 400 ml of CH2Cl2 and washed with 200 ml of NaHCO3 solution. The organic phase is dried over Na2SO4 and freed of the solvents in vacuo to leave a yellow oil. Purification of the latter by chromatography on silica gel 60 (40-63 μm) using CH2Cl2 /CH3OH (98:2) as eluant yields pure N-(2'-cyanobiphenyl-4-ylmethyl)-N-propyl-amine that has an Rf value of 0.15 [CH2Cl2 /CH3OH (95:5)].
Reaction SMILES: [O:1]([CH2:8][C:9]1[CH:20]=[CH:19][C:12]([O:13][CH:14]([CH3:18])[C:15](N)=[O:16])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C(O)(=[O:24])C>O>[O:1]([CH2:8][C:9]1[CH:20]=[CH:19][C:12]([O:13][CH:14]([CH3:18])[C:15]([OH:24])=[O:16])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(Oc1ccc(COc2ccccc2)cc1)C(N)=O
Reactant: CC(=O)O
Agent: Cl
Solvent: O
Product: CC(Oc1ccc(COc2ccccc2)cc1)C(=O)O

Procedure:
A mixture of 1 g. of 2-(4-phenoxymethylphenoxy)-propionamide, 2 ml. of concentrated hydrochlorid acid, and 2 ml. of acetic acid is refluxed for 48 hours and, after adding water, worked up as usual, yielding 2-(4-phenoxymethylphenoxy)-propionic acid.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[F:6][C:7](=[C:17]([F:19])[F:18])[CH2:8][CH2:9][S:10][CH:11]1[NH:15][C:14](=O)[CH2:13][O:12]1.N1C=CC=CC=1>ClCCl>[Cl:3][C:14]1[N:15]=[C:11]([S:10][CH2:9][CH2:8][C:7]([F:6])=[C:17]([F:19])[F:18])[O:12][CH:13]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=C1COC(SCCC(F)=C(F)F)N1
Solvent: c1ccncc1
Solvent: ClCCl
Product: FC(F)=C(F)CCSc1nc(Cl)co1
Temperature: 75 °C
Reaction time: 3 h
Yield: 65.3 %

Procedure:
2 g of phosphorus oxychloride were added dropwise to a mixture of 1 g of 2-(3,4,4-trifluoro-3-butenylthio)oxazolidin-4-one and 0.35 g of pyridine under ice cooling and stirred at 70-80° C. for 3 hours. After addition of ice water to the reaction mixture and stirring for 30 minutes, the mixture was extractred with dichloromethane. The extracted layer was washed with water, dried with anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography (eluent: dichloromethane) to obtain 0.7 g of 4-chloro-2-(3,4,4-trifluoro-3-butenylthio)oxazole (yield 65%). n20D=1.4813.
Reaction SMILES: Br[CH2:2][CH:3]1[O:8][C:7]2[CH:9]=[C:10]([S:13]([CH3:16])(=[O:15])=[O:14])[CH:11]=[CH:12][C:6]=2[CH2:5][O:4]1.[CH2:17]([NH2:20])[CH2:18][CH3:19]>CCO>[CH3:16][S:13]([C:10]1[CH:11]=[CH:12][C:6]2[CH2:5][O:4][CH:3]([CH2:2][NH:20][CH2:17][CH2:18][CH3:19])[O:8][C:7]=2[CH:9]=1)(=[O:15])=[O:14]
Reactant: CS(=O)(=O)c1ccc2c(c1)OC(CBr)OC2
Reactant: CCCN
Solvent: CCO
Product: CCCNCC1OCc2ccc(S(C)(=O)=O)cc2O1
Temperature: 140 °C
Yield: 120.4 %

Procedure:
A mixture of 2-(bromomethyl)-7-(methylsulfonyl)-4H-1,3-benzodioxine (0.50 g, 1.63 mmol), propan-1-amine (2.0 ml, 24.3 mmol), EtOH (3.0 ml) was heated in a micro wave oven at 140° C. for 30 min. The mixture was evaporated to dryness. The residue was chromathographed on a silica column using EtOAc:MeOH (5:1) as eluent, affording the title compound as a light-yellow solid (0.56 g). The product was washed with several portions of ethyl acetate to give a pure white powder as the title compound (0.43 g, 90%). 0.24 g of the title compound was converted into the hydrochloric acid salt and crystallized from EtOH/DEE. M.p. 213° C. MS m/z (rel. intensity, 70 eV) 285 (M+, 1), 123 (10), 77 (15), 72 (bp), 51 (12).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([OH:11])[CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:6]2[CH3:12].[H-].[Na+].F[C:21]1[CH:28]=[CH:27][C:24]([CH:25]=[O:26])=[CH:23][CH:22]=1>CN(C)C=O>[Cl:1][C:2]1[CH:10]=[C:9]([O:11][C:21]2[CH:28]=[CH:27][C:24]([CH:25]=[O:26])=[CH:23][CH:22]=2)[CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:6]2[CH3:12]
Reactant: O=Cc1ccc(F)cc1
Reactant: CCOC(=O)c1cc2c(Cl)cc(O)cc2n1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2c(Cl)cc(Oc3ccc(C=O)cc3)cc2n1C
Temperature: 25 °C
Yield: 64.6 %

Procedure:
After 1.00 g (3.94 mmol) of ethyl 4-chloro-6-hydroxy-1-methyl-2-indolecarboxylate was added to a suspension of 0.16 g (3.94 mmol) of 60% sodium hydride and 30 ml of dimethylformamide, the suspension was stirred at room temperature until the mixture became an almost transparent solution. Then 0.54 g (4.34 mmol) of 4-fluoro-benzaldehyde was added to the solution at room temperature followed by stirring for 10 hours at 70° C. The reaction mixture was poured onto ice water. The resulting mixture was then extracted three times with ethyl acetate. The combined extracts were washed with water. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure and the residue was isolated and purified by silica gel column chromatography to give 0.91 g (64.5%) of ethyl 4-chloro-6-(4-formylphenoxy)-1-methyl-2-indolecarboxylate.
Reaction SMILES: C(OP([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])(OCC)=O)C.[H-].[Na+].[F:17][C:18]1[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[CH:22][C:19]=1[CH:20]=O.O>O1CCCC1>[F:17][C:18]1[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[CH:22][C:19]=1/[CH:20]=[CH:9]/[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: COc1ccc(C=O)c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)/C=C/c1ccc(OC)cc1F
Reaction time: 0.25 h
Yield: 97.3 %

Procedure:
To a solution of ice-cooled ethyl diethylphosphonoacetate (9.45 g, 42.1 mmol) in tetrahydrofuran (50 mL) was added sodium hydride (60% in oil, 1.54 g, 38.5 mmol) and the mixture was stirred for 15 min. A solution of 2-fluoro-4-methoxybenzaldehyde (5.00 g, 32.4 mmol) in tetrahydrofuran (30 mL) was added dropwise. The mixture was stirred at room temperature for 2 hr, and water was added. The mixture was extracted with ethyl acetate. The extract washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (20% ethyl acetate/hexane) to give the title compound (7.07 g, yield 97%) as a colorless oil. 1H NMR (CDCl3) δ: 1.33 (3H, t, J=7.1 Hz), 3.83 (3H, s), 4.26 (2H, q, J=7.1 Hz), 6.41 (1H, d, J=16.2 Hz), 6.61-6.73 (2H, m), 7.45 (1H, t, J=8.6 Hz), 7.75 (1H, d, J=16.2 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[NH:11][C:10](=[O:14])[O:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[F:22][C:23]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[C:24]=1[C:25](Cl)=[O:26]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12](=[O:13])[N:11]([C:25](=[O:26])[C:24]3[C:23]([F:22])=[CH:31][CH:30]=[CH:29][C:28]=3[F:32])[C:10](=[O:14])[O:9]2)=[CH:6][CH:7]=1
Reactant: O=c1[nH]c(=O)n(-c2ccc(Cl)cc2)o1
Reactant: O=C(Cl)c1c(F)cccc1F
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=C(c1c(F)cccc1F)n1c(=O)on(-c2ccc(Cl)cc2)c1=O
Reaction time: 24 h

Procedure:
2-(4-Chlorophenyl)-1,2,4-oxadiazolidin-3,5-dione (0.03 mole), toluene (100 ml) and triethylamine (5 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. 2,6-Difluorobenzoyl chloride (0.03 mole) dissolved in toluene (20 ml) is then added to the reaction flask and the resulting mixture is heated at reflux with stirring for a period of about 24 hours. After this time the reaction mixture is filtered and the filtrate is washed with water, dilute hydrochloric acid and with aqueous sodium bicarbonate. The washed solution is then dried over anhydrous magnesium sulfate. The dried solution is stripped of solvent under reduced pressure leaving a solid residue. The residue is recrystallized to yield the desired product 2-(4-chlorophenyl)-4-(2,6-difluorobenzoyl)-1,2,4-oxadiazolidin-3,5-dione.
Reaction SMILES: Cl[C:2]1[N:6]2[N:7]=[C:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[CH:9]=[CH:10][C:5]2=[N:4][N:3]=1.[N:18]1([CH2:24][CH2:25][NH:26][C:27]([NH:29][C:30]2[S:31][C:32]3[CH:38]=[C:37]([SH:39])[CH:36]=[CH:35][C:33]=3[N:34]=2)=[O:28])[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1.[BH4-].[Na+]>C(N(CC)CC)C>[F:17][C:14]1[CH:15]=[CH:16][C:11]([C:8]2[CH:9]=[CH:10][C:5]3[N:6]([C:2]([S:39][C:37]4[CH:36]=[CH:35][C:33]5[N:34]=[C:30]([NH:29][C:27]([NH:26][CH2:25][CH2:24][N:18]6[CH2:23][CH2:22][O:21][CH2:20][CH2:19]6)=[O:28])[S:31][C:32]=5[CH:38]=4)=[N:3][N:4]=3)[N:7]=2)=[CH:12][CH:13]=1
Reactant: Fc1ccc(-c2ccc3nnc(Cl)n3n2)cc1
Reactant: O=C(NCCN1CCOCC1)Nc1nc2ccc(S)cc2s1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCN(CC)CC
Product: O=C(NCCN1CCOCC1)Nc1nc2ccc(Sc3nnc4ccc(-c5ccc(F)cc5)nn34)cc2s1

Procedure:
The 1-(6-{[6-(4-fluorophenyl)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulphanyl}-1,3-benzothiazol-2-yl)-3-(2-morpholin-4-ylethyl)urea was prepared according to the method described in Example 1a, but using 240 mg of 3-chloro-6-(4-fluorophenyl)-1,2,4-triazolo[4,3-b]pyridazine, 338 mg of 1-(2-morpholin-4-ylethyl)-3-(6-sulphanyl-1,3-benzothiazol-2-yl)urea, 0.14 cm3 of triethylamine and 38 mg of sodium borohydride. The crude obtained is chromatographed on a Merck cartridge (30 g of silica 15-40 μm), elution being carried out with dichloromethane. 117 mg of 1-(6-{[6-(4-fluorophenyl)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulphanyl}-1,3-benzothiazol-2-yl)-3-(2-morpholin-4-ylethyl)urea are thus recovered in the form of a beige solid, the characteristics of which are as follows:
Reaction SMILES: [C:1]([NH:4][CH2:5][CH:6]([NH:10][C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])[C:7]([OH:9])=O)(=[O:3])[CH3:2].C(Cl)CCl.[C:25]([CH:27]=[P:28]([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)#[N:26]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH2:14]([O:13][C:11](=[O:12])[NH:10][CH:6]([CH2:5][NH:4][C:1](=[O:3])[CH3:2])[C:7](=[O:9])[C:27]([C:25]#[N:26])=[P:28]([C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: N#CC=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(=O)NCC(NC(=O)OCc1ccccc1)C(=O)O
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: ClCCl
Product: CC(=O)NCC(NC(=O)OCc1ccccc1)C(=O)C(C#N)=P(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 70.3 %

Procedure:
This intermediate was prepared generally according to the method of Wasserman et al., J. Org. Chem. (1994), vol. 59, 4364. In particular, to a solution of (3-acetylamino-2-benzyloxycarbonylaminopropionic acid (1.40 g, 5.0 mmol, 1 equiv) in CH2Cl2 (50 mL) at 0° C. were added EDC (1.00 g, 5.25 mmol, 1.05 equiv) and DMAP (61 mg, 0.5 mmol, 0.1 equiv). A solution of (cyanomethylene)triphenylphosphorane (prepared as described in Freudenreich et al., J. Am. Chem. Soc. (1984), vol. 106, 3344) (2.50 g, 8.30 mmol, 1.66 equiv) in CH2Cl2 (16 mL) was added to the acid solution dropwise over 20 min. After stirring 2 h at 0° C., the reaction mixture was partitioned between deionized water (30 mL) and CH2Cl2 (3×50 mL). The combined organic layers were washed with brine (30 mL), dried over MgSO4, filtered, and concentrated. The residue was purified by flash column chromatography (5% CH3OH in CH2Cl2) to give [1-(acetylaminomethyl)-3-cyano-2-oxo-3-(triphenyl-λ5-phosphanylidene)propyl]-carbamic acid benzyl ester (1.98 g, 70% yield) as a colorless foam. Rf=0.40 (10% CH3OH in CH2Cl2). IR (cm−1) 3312, 2175, 1716, 1437. 1H NMR (CDCl3) δ1.91 (s, 3H), 3.66-3.79 (m, 2H), 5.04-5.06 (m, 1H), 5.10 (s, 2H), 5.94 (br s, 1H), 6.21 (br s, 1H), 7.26-7.70 (m, 21H).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[NH:9][CH:8]=[N:7][C:6]=2[C:5]([CH3:11])=[CH:4][C:3]=1[N:12]=[C:13]=[S:14].CO.[CH2:17]([NH2:20])[CH2:18][NH2:19]>C(Cl)Cl>[CH3:1][C:2]1[C:10]2[NH:9][CH:8]=[N:7][C:6]=2[C:5]([CH3:11])=[CH:4][C:3]=1[NH:12][C:13]([NH:19][CH2:18][CH2:17][NH2:20])=[S:14]
Reactant: NCCN
Reactant: Cc1cc(N=C=S)c(C)c2[nH]cnc12
Solvent: CO
Solvent: ClCCl
Product: Cc1cc(NC(=S)NCCN)c(C)c2[nH]cnc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 4,7-dimethyl-5-benzimidazolylisothiocyanate (0.59 g) in CH2Cl2 (50 mL)/methanol (5 mL) is added dropwise over 20 minutes to ethylenediamine (1 mL) in solution in CH2Cl2 (150 mL). The mixture is stirred for 2 hours at room temperature. The resulting suspension is filtered and the solid is dried overnight in vacuo to afford N-(4,7-dimethyl-5-benzimidazolyl)-N'-2-aminoethylthiourea as a white solid.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:12][C:11](=[O:13])[NH:10][C:9]2=[O:14])[CH:5]=[CH:6][CH:7]=1.Br[CH2:16][C:17]([NH2:19])=[O:18].[H-].[Na+].P([O-])([O-])([O-])=O>CN(C=O)C>[I:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:12][C:11](=[O:13])[N:10]([CH2:16][C:17]([NH2:19])=[O:18])[C:9]2=[O:14])[CH:5]=[CH:6][CH:7]=1
Reactant: NC(=O)CBr
Reactant: O=C1CN(c2cccc(I)c2)C(=O)N1
Agent: O=P([O-])([O-])[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: NC(=O)CN1C(=O)CN(c2cccc(I)c2)C1=O
Yield: 77.7 %

Procedure:
1-(3-Iodophenyl)imidazolidine-2,4-dione (0.302 g) was taken up in dry DMF (15 ml) and treated with bromoacetamide (0.399 g) and then with sodium hydride (60% oil dispersion, 48 mg). After 3 h pH 6.4 phosphate buffer (50 ml) was added and the reaction mixture extracted with EtOAc (3×25 ml), dried (MgSO4) and evaporated under reduced pressure. Thee residue was purified by Flash chromatography (Merck 9385, EtOAc then 9:1 EtOAc:MeOH) to give the title compound (0.279 g). LCMS RT=2.62 min.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:7][CH2:6][CH2:5][C@@H:4]1[NH:8][C:9](=[O:22])[C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][C:11]=1[N:17]1[N:21]=[CH:20][CH:19]=[N:18]1.Cl[C:24]1[CH:29]=[N:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][N:25]=1.CCN(C(C)C)C(C)C>CS(C)=O>[CH3:16][C:14]1[CH:13]=[CH:12][C:11]([N:17]2[N:18]=[CH:19][CH:20]=[N:21]2)=[C:10]([CH:15]=1)[C:9]([NH:8][C@H:4]1[CH2:5][CH2:6][CH2:7][C@@H:3]1[NH:2][C:24]1[CH:29]=[N:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][N:25]=1)=[O:22]
Reactant: Cc1ccc(-n2nccn2)c(C(=O)N[C@H]2CCC[C@@H]2N)c1
Reactant: FC(F)(F)c1cnc(Cl)cn1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: Cc1ccc(-n2nccn2)c(C(=O)N[C@H]2CCC[C@@H]2Nc2cnc(C(F)(F)F)cn2)c1

Procedure:
A microwave vial was charged with N-[(1S,2S)-2-aminocyclopentyl]-5-methyl-2-(2H-1,2,3-triazol-2-yl)benzamide hydrochloride (Intermediate 7; 450 mg, 1.40 mmol), 2-chloro-5-(trifluoromethyl)pyrazine (CAS number 799557-87-2; 306 mg, 1.68 mmol) and DIPEA (733 μl, 4.20 mmol) in dry DMSO (4.7 ml). The reaction was subjected to microwave irradiation at 140° C. for 2 hours and then partitioned between ethyl acetate and water, washed with water, brine and concentrated in vacuo. The crude product was then purified by column chromatography (basic silica, 0-100% ethyl acetate/petrol) to give a cream solid which was then recrystallised from a mixture of ethyl acetate and pentane to afford the title compound.