Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=O)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(OP([CH2:31][C:32]#[N:33])(=O)OCC)C.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].COC1C=C(C(C2C=CC=C(OC)C=2)=CC#N)C=C(OC)C=1>C1COCC1>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:31][C:32]#[N:33])[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccc(C(=O)c2ccccc2)cc1OC1CCCC1
Reactant: CCOP(=O)(CC#N)OCC
Agent: COc1cccc(C(=CC#N)c2cc(OC)cc(OC)c2)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(C(=CC#N)c2ccccc2)cc1OC1CCCC1
Yield: 75.5 %

Procedure:
(3-Cyclopentyloxy-4-methoxy-phenyl)-phenyl-methanone (0.5 g, 1.7 mmol), cyanomethylphosphonic acid diethyl ester (0.3 ml, 1.9 mmol) in anhydrous THF (10 ml), and lithium bis(trimethylsilyl)amide (1.3 M solution in THF, 1.4 ml, 1.9 mmol) were treated in the same manner as described above for the synthesis of 3-(3,5-dimethoxy-phenyl)-3-(3-methoxy-phenyl)-acrylonitrile. The crude was purified by flash column chromatography to give 3-(3-cyclopentyloxy-4-methoxy-phenyl)-3-phenyl-acrylonitrile as a solid (0.41 g, 76%): mp, 90.6-93° C.; 1H NMR (CDCl3) δ 7.54-7.24 (m, 10H), 7.05-6.73 (m, 6H), 5.66 (s, 1H), 5.60 (s, 1H), 4.81-4.62 (m, 2H), 3.89 (s, 3H), 3.87 (s, 3H), 2.00-1.45 (m, 16H); 13C NMR (CDCl3) δ 162.8, 162.8, 152.2, 151.6, 147.4, 147.3, 139.5, 137.2, 130.2, 129.9, 129.6, 129.3, 128.7, 128.5, 128.4, 123.0, 121.8, 118.4, 118.3, 116.1, 114.8, 111.3, 93.2, 92.7, 80.6, 56.0, 32.8, 32.7, 24.1, 24.0; Anal. Calcd. For C21H21NO2: C, 78.97; H, 6.63; N, 4.39. Found: C, 78.85; H, 6.59; N, 4.31.
Reaction SMILES: [NH:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9]([CH3:12])(=[O:11])=[O:10])=[CH:5][N:4]=1)[NH2:2].[F:13][C:14]([F:29])([F:28])[C:15](=O)[CH2:16][C:17]([C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=1[Cl:26])=O.S(=O)(=O)(O)O>C(O)C(F)(F)F>[Cl:26][C:20]1[CH:21]=[C:22]([Cl:25])[CH:23]=[CH:24][C:19]=1[C:17]1[N:1]([C:3]2[CH:8]=[CH:7][C:6]([S:9]([CH3:12])(=[O:10])=[O:11])=[CH:5][N:4]=2)[N:2]=[C:15]([C:14]([F:29])([F:13])[F:28])[CH:16]=1
Reactant: O=C(CC(=O)C(F)(F)F)c1ccc(Cl)cc1Cl
Reactant: CS(=O)(=O)c1ccc(NN)nc1
Agent: O=S(=O)(O)O
Solvent: OCC(F)(F)F
Product: CS(=O)(=O)c1ccc(-n2nc(C(F)(F)F)cc2-c2ccc(Cl)cc2Cl)nc1
Temperature: 25 °C
Yield: 8.3 %

Procedure:
To a mixture of the 2-hydrazino-5-(methylsulfonyl)pyridine (106 mg, 4.05 mmol) and 4,4,4-trifluoro-1-(2,4-dichlorophenyl)-1,3-butanedione (105 mg, 3.68 mmol) in dry trifluoroethanol (6 ml) was added a catalytic amount of concentrated sulfuric acid (about 0.25 ml) and the mixture was refluxed overnight. The reaction mixture was cooled to room temperature, concentrated, and diluted with water (25 ml) and neutralized with saturated NaHCO3 to pH about 7 and then extracted with EtOAc (50ml×3). The organic layer was washed with brine (100 ml), dried (MgSO4) and concentrated to give the crude solid. The solid was purified by flash chromatography eluting with ethyl acetate/hexane (1/4) to give the desired product as a white solid (134 mg, 83% yield).
Reaction SMILES: [CH:1]1([CH2:6][C@@H:7]([C:20]([NH:22][NH:23][C:24]2[C:29]([F:30])=[C:28]([N:31]3[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][C@@H:32]3[CH3:38])[N:27]=[C:26]([CH3:39])[N:25]=2)=[O:21])[CH2:8][N:9]([O:12]CC2C=CC=CC=2)[CH:10]=[O:11])[CH2:5][CH2:4][CH2:3][CH2:2]1>CO>[CH:1]1([CH2:6][C@@H:7]([C:20]([NH:22][NH:23][C:24]2[C:29]([F:30])=[C:28]([N:31]3[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][C@@H:32]3[CH3:38])[N:27]=[C:26]([CH3:39])[N:25]=2)=[O:21])[CH2:8][N:9]([OH:12])[CH:10]=[O:11])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1nc(NNC(=O)[C@H](CC2CCCC2)CN(C=O)OCc2ccccc2)c(F)c(N2CCN(C)C[C@@H]2C)n1
Solvent: CO
Product: Cc1nc(NNC(=O)[C@H](CC2CCCC2)CN(O)C=O)c(F)c(N2CCN(C)C[C@@H]2C)n1
Yield: 89.6 %

Procedure:
A solution of [(2R)-2-(cyclopentylmethyl)-3-(2-{6-[(2S)-2,4-dimethyl-1-piperazinyl]-5-fluoro-2-methyl-4-pyrimidinyl}hydrazino)-3-oxopropyl][(phenylmethyl)oxy]formamide (0.118 g, 0.22 mmol) and Pd(C) (0.018 g) in MeOH (10 mL) was treated as in General Procedure A, Part C, to provide [(2R)-2-(cyclopentylmethyl)-3-(2-{6-[(2S)-2,4-dimethyl-1-piperazinyl]-5-fluoro-2-methyl-4-pyrimidinyl}hydrazino)-3-oxopropyl]hydroxyformamide as a white solid (0.089 g, 91%). LCMS: (M+H)+=452.4.
Reaction SMILES: Cl[CH2:2][C:3](=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[H-].[Na+].[CH:13]1([OH:20])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1>COCCOC>[CH2:8]([O:7][C:5](=[O:6])[CH2:4][C:3](=[O:10])[CH2:2][O:20][CH:13]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)[CH3:9]
Reactant: OC1CCCCCC1
Reactant: CCOC(=O)CC(=O)CCl
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CCOC(=O)CC(=O)COC1CCCCCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 84.2 %

Procedure:
Ethyl 4-chloroacetoacetate (3.00 mL, 22.1 mmol) was added dropwise to an ice-cooled suspension of sodium hydride (60% dispersion in oil, 2.04 g, 51.0 mmol) in DME (20 mL). Immediately cycloheptanol (3.00 mL, 24.9 mmol) was added dropwise and the resultant reaction mixture was allowed to warm slowly to ambient temperature and then stirred at this temperature for 18 h. The reaction mixture was quenched with aqueous 2M hydrochloric acid (100 mL) and extracted with ethyl acetate (100 mL). The aqueous phase was discarded and the organic phase washed with brine (100 mL) and dried (MgSO4). The residue was purified by flash column chromatography (4:1 hexane:ethyl acetate) to afford the tide compound (4.51 g, 84%). 1H NMR (CDCl3) 4.23-4.16 (2H, m), 4.07 (2H, s), 3.55 (2H, s), 3.50-3.47 (1H, m), 1.88-1.87 (2H, m), 1.67-1.53 (8H, m), 1.31-1.26 (5H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C:16]3[C:17](=[O:28])[N:18]([CH3:27])[C:19]4[C:24]([C:25]=3[OH:26])=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].C([O-])([O-])=O.[Cs+].[Cs+].Cl[C:36]([F:42])([F:41])C(OC)=O>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C:16]3[C:17](=[O:28])[N:18]([CH3:27])[C:19]4[C:24]([C:25]=3[O:26][CH:36]([F:42])[F:41])=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: Cn1c(=O)c(Cc2ccc(-c3ccc(F)c(Cl)c3)cc2)c(O)c2ccccc21
Reactant: COC(=O)C(F)(F)Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1c(=O)c(Cc2ccc(-c3ccc(F)c(Cl)c3)cc2)c(OC(F)F)c2ccccc21
Temperature: 100 °C
Reaction time: 3 h

Procedure:
A solution of example 145, Cs2CO3 (2 eq) in DMF (0.2M) was heated at 100° C. (open flask) then methyl chlorodifluoroacetate (2 eq) was added and the mixture stirred at 90-110° C. for 3 h. After cooling to rt, the mixture was diluted with water, extracted with ethyl acetate and the solvent evaporated. The residue was purified by crystallisation in hexane\ether to give the title compound as a white powder.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18]([O:19][CH3:20])=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][NH:13][C:14]2=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>O1CCCC1>[CH2:1]([O:8][C:9]1[C:18]([O:19][CH3:20])=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][NH:13][CH2:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc2c(c1OCc1ccccc1)CCNC2=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc2c(c1OCc1ccccc1)CCNC2
Temperature: 0 °C

Procedure:
Into a 50-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 5-(benzyloxy)-6-methoxy-1,2,3,4-tetrahydroisoquinolin-1-one (1 g, 3.53 mmol, 1.00 equiv), oxolane (20 mL) and LiAlH4 (400 mg, 11.79 mmol, 3.00 equiv). The resulting solution was heated to reflux for 2 hr. The reaction mixture was cooled to 0° C. with a water/ice bath. The reaction was then quenched by the addition of 0.4 mL of water. The solids were filtered out. The resulting mixture was concentrated under vacuum. This resulted in 0.8 g (crude) of 5-(benzyloxy)-6-methoxy-1,2,3,4-tetrahydroisoquinoline as light yellow oil. MS (ESI) m/z 270 ([M+H]+).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][C:3]1=[O:11].[Cl:12][CH2:13][CH2:14][C:15](Cl)=[O:16].Cl>>[CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:15](=[O:16])[CH2:14][CH2:13][Cl:12])=[CH:10][C:5]=2[O:4][C:3]1=[O:11]
Reactant: Cn1c(=O)oc2ccccc21
Reactant: O=C(Cl)CCCl
Agent: Cl
Product: Cn1c(=O)oc2cc(C(=O)CCCl)ccc21
Temperature: 75 °C
Reaction time: 0.5 h

Procedure:
The flask is equipped with a reflux condenser and taken to an oil bath at a temperature in the region of 40°-45° C. 0.04 mole of 3-methylbenzoxazolinone and 0.44 mole of 3-chloropropionic acid chloride are introduced. The mixture is heated to a temperature in the region of 75° C. for 2 hours 30 minutes. After cooling, the reaction mixture is poured into 300 g of ice, acidified with concentrated hydrochloric acid and stirred for hour 30 minutes. The precipitate obtained is drained, washed with water and dried. The product is recrystallized in ethanol.
Reaction SMILES: [CH2:1]([N:8]=[C:9]=[S:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:11]=[N+:12]=[N-:13].[Na+]>>[CH2:1]([N:8]1[C:9]([SH:10])=[N:13][N:12]=[N:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: S=C=NCc1ccccc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Product: Sc1nnnn1Cc1ccccc1
Yield: 7 %

Procedure:
Benzyl isothiocyanate (0.020 mol) and sodium azide (0.030 mol) were reacted substantially as described in Example 1C above to yield 0.27 g (7%) white needles: mp 141°-142° (chloroform/pet. ether).
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[CH2:7][CH2:6][CH:5]([C:8]2[S:20][C:11]3[N:12]=[C:13]([CH3:19])[N:14]=[C:15]([C:16](O)=[O:17])[C:10]=3[CH:9]=2)[CH2:4][CH2:3]1.[CH3:22][C:23]1([OH:29])[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH4+].[Cl-]>CN1C(=O)CCC1>[CH3:21][C:2]1([CH3:1])[CH2:7][CH2:6][CH:5]([C:8]2[S:20][C:11]3[N:12]=[C:13]([CH3:19])[N:14]=[C:15]([C:16]([N:26]4[CH2:27][CH2:28][C:23]([OH:29])([CH3:22])[CH2:24][CH2:25]4)=[O:17])[C:10]=3[CH:9]=2)[CH2:4][CH2:3]1
Reactant: CC1(O)CCNCC1
Reactant: Cc1nc(C(=O)O)c2cc(C3CCC(C)(C)CC3)sc2n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(C(=O)N2CCC(C)(O)CC2)c2cc(C3CCC(C)(C)CC3)sc2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.6 %

Procedure:
To a mixture of 6-(4,4-dimethylcyclohexyl)-2-methylthieno[2,3-d]pyrimidine-4-carboxylic acid (150 mg), 4-methylpiperidin-4-ol (68 mg), HATU (262 mg), and NMP (2.1 mL) was added DIPEA (244 μL), followed by stirring at room temperature overnight. To the reaction mixture was added a saturated aqueous NH4Cl solution, followed by extraction with EtOAc. The organic layer was washed sequentially with water and brine, dried over MgSO4, and then concentrated under reduced pressure. The residue was purified by silica gel column. The obtained purified product was suspended in IPE, collected by filtration, and then dried under reduced pressure to obtain [6-(4,4-dimethylcyclohexyl)-2-methylthieno[2,3-d]pyrimidin-4-yl](4-hydroxy-4-methylpiperidin-1-yl)methanone (120 mg).
Reaction SMILES: [C:1]([CH:6]([NH:15][NH:16]C(OC(C)(C)C)=O)[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([O:3][CH2:4][CH3:5])=[O:2].[F:24][C:25]([F:30])([F:29])[C:26]([OH:28])=[O:27]>>[F:24][C:25]([F:30])([F:29])[C:26]([OH:28])=[O:27].[C:9]1([CH2:8][CH2:7][CH:6]([NH:15][NH2:16])[C:1]([O:3][CH2:4][CH3:5])=[O:2])[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CCOC(=O)C(CCc1ccccc1)NNC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C(CCc1ccccc1)NN
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of ethyl 4-phenyl-2-oxobutanoate (2.06 g; 10 mmol) and t-butylcarbazate (1.32 g; 10 mmol) in THF (50 ml) can be warmed at reflux for 8 hours. Solvent can be evaporated and the residue taken up in anhydrous ethanol (25 ml). Sodium cyanoborohydride (0.31 g; 5 mmol) can be added, and the solution stirred for 4 hrs. The residue, after evaporation, can be stirred with EtOAc (50 ml) and hydrochloric acid (0.5 N: 20 ml) for 30 minutes. The aqueous layer can be neutralized by addition of K2CO3 and extracted with EtOAc (3×25 ml). The combined organic portions can be washed with H2O and brine and dried (MgSO4). The residue, upon evaporation, can be purified by chromatography on silica gel, affording N-(1-carboethoxy-3-phenylpropyl)-N'-BOC-hydrazine. An ice-cold solution of the above hydrazine in trifluoroacetic acid can be allowed to stand for 1 hr. Removal of solvent can provide hydrazine (56) as the trifluoroacetic acid salt.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:8][CH2:7][NH:6][C:5]1=[N:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[N:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1.[C:22](OC(=O)C)(=[O:24])[CH3:23]>ClCCl>[C:22]([O:1][CH2:2][CH2:3][N:4]1[CH2:8][CH2:7][NH:6][C:5]1=[N:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[N:16]1[CH2:17][CH2:18][O:19][CH2:20][CH2:21]1)(=[O:24])[CH3:23]
Reactant: OCCN1CCNC1=Nc1ccccc1N1CCOCC1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Product: CC(=O)OCCN1CCNC1=Nc1ccccc1N1CCOCC1

Procedure:
Reaction of 4-(2-[1-(2-hydroxyethyl)-2-imidazolidinylideneamino]phenyl)morpholine (3 g prepared as described in Example 175) in dichloromethane (20 ml) with acetic anhydride (0.86 g) yielded 4-(2-[1-(2-acetyloxyethyl)-2-imidazolidinylideneamino]phenyl)morpholine (m.p. 89°-91° C.) which was recrystallised from hexane.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([NH:10][C:11](=[O:36])[C@@H:12]([NH:20][C:21](=[O:35])[CH:22]([NH2:34])[C:23]2[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][O:32][CH3:33])=[CH:25][CH:24]=2)[CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[S:8][CH:9]=1)=[O:4].C(N(C(C)C)CC)(C)C.[O:46]=[C:47](Cl)OC(Cl)(Cl)Cl.O>ClCCl>[CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([NH:10][C:11](=[O:36])[C@@H:12]([N:20]2[C:21](=[O:35])[CH:22]([C:23]3[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][O:32][CH3:33])=[CH:25][CH:24]=3)[NH:34][C:47]2=[O:46])[CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[S:8][CH:9]=1)=[O:4]
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: COCCOc1ccc(C(N)C(=O)N[C@@H](Cc2ccccc2)C(=O)Nc2nc(C(=O)OC)cs2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O
Product: COCCOc1ccc(C2NC(=O)N([C@@H](Cc3ccccc3)C(=O)Nc3nc(C(=O)OC)cs3)C2=O)cc1

Procedure:
To a solution of 2-((S)-2-{2-amino-2-[4-(2-methoxy-ethoxy)-phenyl]-acetylamino}-3-phenyl-propionylamino)-thiazole-4-carboxylic acid methyl ester (a mixture of two epimers R/S=85:15) (0.16 g , 0.31 mmol) and diisopropylethylamine (0.31 mL, 1.78 mmol) in dichloromethane (20 mL) was added to a solution of diphosgene (0.03 μL, 0.25 mmol) in dichloromethane (30 mL) over a period of 10 minute at −10° C. The mixture was stirred at −10° C. for 15 minutes Water was added to quench the reaction, then the mixture was extracted with ethyl acetate. The organic layer was separated, washed with water, brine, dried over sodium sulfate and concentrated. The residue was purified by chromatography over silica gel eluted with ethyl acetate to give 2-((S)-2-{4-[4-(2-methoxy-ethoxy)-phenyl]-2,5-dioxo-imidazolidin-1-yl}-3-phenyl-propionylamino)-thiazole-4-carboxylic acid methyl ester as a white solid (a mixture of two epimers R/S=85:15) (0.075 g, 87%).
Reaction SMILES: [F:1][C:2]([F:18])([C:9]([F:17])([F:16])[C:10]([F:15])([F:14])[CH:11]([F:13])[F:12])[CH2:3][CH:4]([C:7]#[N:8])[C:5]#[N:6].FC(F)(F)S(O[CH2:25][C:26]([F:34])([F:33])[CH:27]([F:32])[C:28]([F:31])([F:30])[F:29])(=O)=O.C(=O)([O-])[O-].[K+].[K+].Cl>COCCOC>[F:33][C:26]([F:34])([CH:27]([F:32])[C:28]([F:31])([F:30])[F:29])[CH2:25][C:4]([CH2:3][C:2]([F:18])([F:1])[C:9]([F:16])([F:17])[C:10]([F:14])([F:15])[CH:11]([F:13])[F:12])([C:7]#[N:8])[C:5]#[N:6]
Reactant: O=S(=O)(OCC(F)(F)C(F)C(F)(F)F)C(F)(F)F
Reactant: N#CC(C#N)CC(F)(F)C(F)(F)C(F)(F)C(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: N#CC(C#N)(CC(F)(F)C(F)C(F)(F)F)CC(F)(F)C(F)(F)C(F)(F)C(F)F
Temperature: 25 °C
Reaction time: 7 h
Yield: 2.7 %

Procedure:
1.4 g of 2-(2,2,3,3,4,4,5,5-octafluoropentyl)malononitrile and 3.1 g of 2,2,3,4,4,4-hexafluorobutyl trifluoromethanesulfonate were dissolved in 10 ml of ethylene glycol dimethyl ether, 0.97 g of potassium carbonate was added, and the mixture was stirred at room temperature for 7 hours. Thereafter, dilute hydrochloric acid was added to the reaction mixture, followed by extraction with methyl tert-butyl ether. The organic layer was washed successively with water, aqueous saturated sodium hydrogen carbonate and aqueous saturated sodium chloride, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.06 g of 2-(2,2,3,4,4,4-hexafluorobutyl)-2-(2,2,3,3,4,4,5,5-octafluoropentyl)malononitrile (hereinafter, referred to as the present compound (81)).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].Cl.[F:13][C:14]1([F:20])[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:13][C:14]1([F:20])[CH2:19][CH2:18][N:17]([C:2]2[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=2)[C:5]([O:7][CH3:8])=[O:6])[CH2:16][CH2:15]1
Reactant: COC(=O)c1cccc(Br)c1
Reactant: FC1(F)CCNCC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Product: COC(=O)c1cccc(N2CCC(F)(F)CC2)c1
Temperature: 130 °C

Procedure:
In a microwave reaction vessel, a solution of 500 mg (2.33 mmol) of methyl 3-bromobenzoate and 366 mg (2.33 mmol) of 4,4-difluoropiperidine hydrochloride in 15 ml of dioxane was deoxygenated by passing through argon. 52 mg (0.233 mmol) of palladium(II) acetate, 202 mg (0.349 mmol) of 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (xantphos) and 2.27 g (6.98 mmol) of caesium carbonate were then added. The microwave vessel was closed with a crimp closure and, with magnetic stirring, heated in a microwave oven (Biotage Initiator, with Dynamic Field Tuning) at 120-140° C. for 1.5 hours. After the reaction had ended the reaction mixture was filtered through a little kieselguhr and then evaporated to dryness. The residue was separated into its components by preparative HPLC (Method 33). Evaporation of the product fractions and drying of the residue under high vacuum gave 342 mg (57% of theory) of the title compound.
Reaction SMILES: Cl[C:2]1([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[O:3]1.C(N(CC)CC)C.[CH2:26]([NH2:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[CH:30]1[CH:31]=[CH:32][C:27]([CH2:26][N:33]2[C:2]([OH:3])([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=3)[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[C:4]2=[O:11])=[CH:28][CH:29]=1
Reactant: O=C1OC(Cl)(c2ccc(Cl)cc2)c2ccccc21
Reactant: NCc1ccccc1
Solvent: CCN(CC)CC
Product: O=C1c2ccccc2C(O)(c2ccc(Cl)cc2)N1Cc1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 77.1 %

Procedure:
Distilled THF (25 mL) was added to 3-chloro-3-(4-chlorophenyl)-3H-isobenzofuran-1-one (1.042 g, 3.84 mmol) followed by triethylamine (777.1 mg, 7.68 mmol, 1.06 mL)) and benzylamine (616 mg, 5.76 mmol, 0.79 mL) resulting in the formation of a yellow/cream precipitate. The mixture was stirred at room temperature under nitrogen for 4 hours and monitored by TLC. Upon completion the mixture was then extracted with EtOAc (15 mL) and washed with saturated sodium bicarbonate (3×10 mL), water (3×10 mL) and dried (Na2SO4). Recrystallisation of the cream precipitate from a minimum amount of boiling ethyl acetate and excess petrol to yielded the title product as a white crystalline solid (1.0378 g, 2.96 mmol, 77% yield). 1H NMR: (300 Hz, CDCl3) δ ppm 4.24 (d, 1H, J=15.48 Hz, H9), 4.42 (d, 1H, J=15.48 Hz, H9′), 7.16 (m, 5H, H10-H14), 7.25 (m, 5H, H1-H5), 7.56 (m, 2H, H6-H7), 7.75 (d, 1H, H8). 13C NMR: (75 Hz, DMSO); δ 42.80 (N—CH2), 90.60 (O—C—N), 122.95, 123.18, 126.78, 128.07, 128.35, 128.41, 128.51, 129.70, 130.81, 132.97, 133.07, 138.42, 139.46, 149.59 (Ar), 167.20 (C═O). IR: 1463, 1664, 2936, 3285 cm−1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[N:12][N:11]3[C:14](=[O:17])[NH:15][N:16]=[C:10]3[C:9]=2[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.[O:25]1[C@H:27]([CH2:28][CH2:29][CH2:30][CH3:31])[CH2:26]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[N:12][N:11]3[C:14](=[O:17])[N:15]([CH2:26][C@H:27]([OH:25])[CH2:28][CH2:29][CH2:30][CH3:31])[N:16]=[C:10]3[C:9]=2[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[CH:4][CH:3]=1
Reactant: CCCC[C@@H]1CO1
Reactant: O=c1[nH]nc2c(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)cnn12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCC[C@@H](O)Cn1nc2c(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)cnn2c1=O
Temperature: 85 °C
Reaction time: 8 h
Yield: 32.4 %

Procedure:
To a solution of 7,8-bis(4-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one, (20 mg, 0.056 mmol), prepared as described in Example 1, in 0.6 mL of DMF was added (R)-(+)-1,2-epoxyhexane (5.6 mg, 0.056 mmol), followed by K2CO3 (15.5 mg, 0.112 mmol). The mixture was heated at 85° C. After stirring overnight, the reaction was allowed to cool to RT The reaction mixture was filtered to remove excess of K2CO3. The collected solution was concentrated under reduced pressure. The crude product was purified using silica gel column chromatography using an automated system, eluting with a gradient of (0% to 60% EtOAc/hexanes for 30 min followed by 60% EtOAc/hexanes to 100% EtOAc for 10 min. The title compound, (R)-7,8-Bis(4-chlorophenyl)-2-(2-hydroxyhexyl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one (8.3 mg, 32% yield) was obtained as a yellow oil. MS [M+H]+: found 457; 1H NMR (CDCl3, 400 MHz) δ 8.12 (s, 1H), 7.28-7.19 (m, 6H), 7.06-7.02 (m, 2H), 4.13-4.08 (m, 1H), 4.00-3.90 (m, 2H), 1.49-1.24 (m, 6H), 0.83 (t, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=1.[CH3:9][O:10][C:11](=[O:17])[CH2:12][C:13](=O)[CH2:14]Cl>C1(C)C=CC=CC=1>[CH3:9][O:10][C:11](=[O:17])[CH2:12][C:13]1[N:1]=[C:2]2[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]2[CH:14]=1
Reactant: COC(=O)CC(=O)CCl
Reactant: Nc1ccc(Cl)cn1
Solvent: Cc1ccccc1
Product: COC(=O)Cc1cn2cc(Cl)ccc2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 31 %

Procedure:
1.28 g (10 mmol) 2-Amino-5-chloropyridine and 1.18 mL (1 eq) 4-chloro-3-oxo-butyric acid methyl ester are heated to 115° C. in 15 mL toluene for 18 h. The resulting brown suspension is evaporated and heated 1 h to 90° C. under high vacuum, then cooled to room temperature and stirred in 100 mL dichloromethane, 10 mL saturated aqueous sodium bicarbonate solution and 40 mL water at 0° C. for one hour. The organic phase is then separated and evaporated to yield a brownish solid that is column chromatographed (silica gel, ethyl acetate/petroleum ether 4:1) to yield 700 mg (31 %) desired product as a beige powder. MS(EI+): 225-227 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][CH:22]=[CH:21][C:3]=1[C:4]([NH:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([S:17](Cl)(=[O:19])=[O:18])=[CH:9][CH:8]=1)=[O:5].[N:25]([CH:28]([CH3:30])C)=[C:26]=[O:27]>C(N(CC)CC)C>[C:26]([N:25]1[CH2:28][CH2:30][CH:4]([NH:6][S:17]([C:10]2[C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:7]([NH:6][C:4](=[O:5])[C:3]3[CH:21]=[CH:22][CH:23]=[CH:24][C:2]=3[F:1])=[CH:8][CH:9]=2)(=[O:19])=[O:18])[CH2:3][CH2:2]1)(=[O:27])[CH2:8][CH2:7][CH3:16]
Reactant: CC(C)N=C=O
Reactant: O=C(Nc1ccc(S(=O)(=O)Cl)c2ccccc12)c1ccccc1F
Solvent: CCN(CC)CC
Product: CCCC(=O)N1CCC(NS(=O)(=O)c2ccc(NC(=O)c3ccccc3F)c3ccccc23)CC1

Procedure:
The title compound was prepared following the general procedure in Scheme 5 beginning with 4-(2-fluoro-benzoylamino)-naphthalene-1-sulfonyl chloride and substituting butyryl chloride and triethylamine for 2-isocyanato-propane. 1H NMR (300 MHz, DMSO) δ 10.73 (s, 1H), 8.69 (d, 1H), 8.28 (d, 1H), 8.21 (d, 1H), 8.11 (d, 1H), 7.99 (d, 1H), 7.83 (t, 1H), 7.76 (m, 2H), 7.64 (m, 1H), 7.40 (q, 2H), 4.00 (d, 1H), 0.60 (d, 1H), 3.26 (m, 1H), 2.93 (t, 1H), 2.59 (m, 2H), 2.17 (t, 2H), 1.46 (m, 2H), 1.43 (q, 2H), 1.17 (m, 1H), 0.82 (t, 3H); LC/MS m/z 496 (M−H)−, 498 (M+H)+.