Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][OH:9])[CH2:3][CH2:2]1.[O:10]1[CH:12]([CH2:13][C:14]([F:26])([F:25])[C:15]([F:24])([F:23])[C:16]([F:22])([F:21])[C:17]([F:20])([F:19])[F:18])[CH2:11]1>>[O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][O:9][CH2:11][CH:12]([OH:10])[CH2:13][C:14]([F:25])([F:26])[C:15]([F:23])([F:24])[C:16]([F:21])([F:22])[C:17]([F:18])([F:20])[F:19])[CH2:3][CH2:2]1
Reactant: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)CC1CO1
Reactant: OCCN1CCOCC1
Product: OC(COCCN1CCOCC1)CC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 80 °C
Reaction time: 10 h
Yield: 73 %

Procedure:
A mixture of 13.1 g of 2-morpholinoethanol and 27.6 g of 1,2-epoxy-4,4,5,5,6,6,7,7,7-nonafluoroheptane was stirred at 80° C. for 10 hours. The reaction mixture was directly purified by silica gel column chromatography. There was obtained 29.7 g of 1-(2-morpholinoethoxy)-4,4,5,5,6,6,7,7,7-nonafluoro-2-heptanol (yield 73%).
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][S:5][C:6]=1[NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11].C([Sn](CCCC)(CCCC)[C:20]1[N:21]=[CH:22][S:23][CH:24]=1)CCC>O1CCOCC1.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>[S:5]1[C:6]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[C:2]([C:20]2[N:21]=[CH:22][S:23][CH:24]=2)[N:3]=[CH:4]1
Reactant: CC(C)(C)OC(=O)Nc1scnc1Br
Reactant: CCCC[Sn](CCCC)(CCCC)c1cscn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)Nc1scnc1-c1cscn1
Temperature: 140 °C
Yield: 70.6 %

Procedure:
A mixture of tert-butyl 4-bromothiazol-5-ylcarbamate (590 mg, 2.1 mmol), tetrakis(triphenylphosphine)palladium(0) (240 mg, 0.21 mmol) and 4-tributylstannylthiazole (1.18 g, 3.2 mmol) in anhydrous dioxane (5 mL) was heated to 140° C. in a microwave reactor for 1 h. The reaction mixture was then concentrated in vacuo and purified by flash chromatography (EtOAc/hexanes elution) to give the desired product (420 mg, 71%). MH+ 283.9.
Reaction SMILES: [OH:1][C@H:2]([C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=1)[C@H:3]([NH:10][C:11](=[O:20])OCC1C=CC=CC=1)[CH2:4][N:5]1[CH2:9][CH2:8][CH2:7][CH2:6]1.Cl.[CH3:30][CH2:31][OH:32]>[Pd]>[OH:1][C@H:2]([C:21]1[CH:22]=[CH:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=1)[C@H:3]([NH:10][C:11](=[O:20])[CH2:30][CH2:31][O:32][C:24]1[CH:25]=[CH:26][C:21]([CH3:2])=[CH:22][CH:23]=1)[CH2:4][N:5]1[CH2:6][CH2:7][CH2:8][CH2:9]1
Reactant: CCO
Reactant: COc1ccc([C@@H](O)[C@@H](CN2CCCC2)NC(=O)OCc2ccccc2)cc1
Agent: [Pd]
Agent: Cl
Product: COc1ccc([C@@H](O)[C@@H](CN2CCCC2)NC(=O)CCOc2ccc(C)cc2)cc1
Reaction time: 2 h
Yield: 85 %

Procedure:
A mixture of benzyl(1R,2R)-1-hydroxy-1-(4-methoxyphenyl)-3-(pyrrolidin-1-yl)propan-2-ylcarbamate (0.10 g, 0.26 mmol) and Pd/C (5%, 21 mg) in EtOH (1 mL)/HCl (1 M, 50 μL) was degassed and hydrogen gas was added. The mixture was hydrogenated at atmospheric pressure for two hours. The mixture was filtered over celite and the solvent was removed to dryness. The product was obtained as a colorless oil (63.5 mg, 85% yield).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:7][O:8][C:9](=[O:19])[CH2:10][CH2:11][C:12]1[C:17]([OH:18])=[CH:16][CH:15]=[CH:14][N:13]=1.Br[CH2:21][CH2:22][CH2:23][CH2:24]/[CH:25]=[CH:26]/[C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=1>CN(C)C=O>[CH3:7][O:8][C:9](=[O:19])[CH2:10][CH2:11][C:12]1[C:17]([O:18][CH2:21][CH2:22][CH2:23][CH2:24]/[CH:25]=[CH:26]/[C:27]2[CH:28]=[CH:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=2)=[CH:16][CH:15]=[CH:14][N:13]=1
Reactant: COC(=O)CCc1ncccc1O
Reactant: COc1ccc(/C=C/CCCCBr)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)CCc1ncccc1OCCCC/C=C/c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 45.8 %

Procedure:
1.02 g of cesium carbonate is added to a solution of 300 mg of 3-(3-hydroxy-2-pyridyl)-propionic acid methyl ester and 450 mg of (1E)-6-bromo-1-(4-methoxyphenyl)-1-hexene in 6 ml of dimethylformamide, and the suspension is stirred under argon atmosphere for 20 hours at room temperature. The reaction mixture is filtered, the filter residue is washed with dichloromethane and the filtrate is concentrated by evaporation. The residue is added to water, shaken out with ethyl acetate, the organic phase is washed with saturated common salt solution, dried with sodium sulfate and concentrated by evaporation. The crude product is purified by high-pressure liquid chromatography on reversed-phase silica gel (Nova-Pak HR C18) with methanol/water=8/2. 280 mg of 3-{3-[6-(4-methoxyphenyl)-(5E)-5-hexenyloxy]-2-pyridyl}-propionic acid methyl ester is obtained as colorless oil.
Reaction SMILES: C(OC([NH:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([CH2:19][C:20]2[CH:25]=[CH:24][N:23]=[C:22]([NH:26]C(OC(C)(C)C)=O)[CH:21]=2)=[CH:11][CH:10]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([CH2:19][C:20]2[CH:25]=[CH:24][N:23]=[C:22]([NH2:26])[CH:21]=2)=[CH:11][CH:10]=1
Reactant: CC(C)(C)OC(=O)Nc1cc(Cc2ccc(NC(=O)OC(C)(C)C)c3ccccc23)ccn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1cc(Cc2ccc(N)c3ccccc23)ccn1
Temperature: 0 °C

Procedure:
To a solution of (4-(tert-butoxycarbonyl)aminonaphthalen-1-yl)(2-(tert-butoxycarbonyl)amino pyridin-4-yl)methane (270 mg, 0.60 mmol) in dry DCM (6.0 mL) under N2 at 0° C. was added TFA (2.0 mL, 25 mmol). The reaction was maintained at 0° C. for a further 20 min and was then warmed to RT for 4 hr. The mixture was evaporated in vacuo and the residue was subjected to SCX capture and release to afford the title compound, Intermediate H1, (150 mg, 100%); Rt 0.79 min (Method 2); m/z 250 (M+H)+ (ES+).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.[Br-].[F:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=1)[CH2:14][Zn+]>>[Br:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH2:14][C:13]2[CH:16]=[CH:17][CH:18]=[C:11]([F:10])[CH:12]=2)[N:3]=1
Reactant: Fc1cccc(C[Zn+])c1
Reactant: Brc1cccc(Br)n1
Agent: [Br-]
Product: Fc1cccc(Cc2cccc(Br)n2)c1

Procedure:
Prepared according to the procedure described in Example 84, Step 2, using 2,6-dibromo-pyridine and 3-fluoro-benzylzinc bromide.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([O:15][C:16]([N:18]1[CH2:23][CH2:22][N:21]([CH2:24][C:25]2([C:38]([O:40]C(C)(C)C)=[O:39])[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][CH2:26]2)[C:20](=[O:45])[CH2:19]1)=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C1(C)C=CC=CC=1>[CH2:8]([O:15][C:16]([N:18]1[CH2:23][CH2:22][N:21]([CH2:24][C:25]2([C:38]([OH:40])=[O:39])[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:36])([CH3:37])[CH3:35])=[O:32])[CH2:27][CH2:26]2)[C:20](=[O:45])[CH2:19]1)=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CN2CCN(C(=O)OCc3ccccc3)CC2=O)(C(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(CN2CCN(C(=O)OCc3ccccc3)CC2=O)(C(=O)O)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.6 %

Procedure:
Trifluoroacetic acid (100 ml) was added to a solution of 4-benzyloxycarbonyl-1-[1,4-bis(tert-butoxycarbonyl)-4-piperidylmethyl]-2-piperazinone (38.8 g) obtained in Reference Example 1 in toluene (100 ml), the mixture was stirred at room temperature for 1 hour, and concentrated under reduced pressure. Then, di-tert-butyl dicarbonate (17.6 ml) was added to a mixture of the residue, sodium carbonate (38.7 g), water (300 ml) and ethyl acetate (300 ml) at room temperature while stirring, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was separated into layers, the aqueous layer was adjusted to pH 3 with 1N hydrochloric acid, and extracted with ethyl acetate. The ethyl acetate layer was dried with magnesium sulfate, and concentrated under reduced pressure, and the residue was purified by silica gel chromatography (ethyl acetate:methanol=10/1) to obtain the title compound (29 g) as yellow powders.
Reaction SMILES: Cl.[NH2:2][C@:3]([CH3:24])([CH2:6][CH2:7][C:8]1[O:9][C:10]([C:13]#[C:14][CH2:15][CH2:16][O:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)=[CH:11][CH:12]=1)[CH2:4][OH:5].O.C(=O)([O-])O.[K+].Cl[C:32]([O:34][CH2:35][CH:36]=[CH2:37])=[O:33]>C(OCC)(=O)C>[CH2:35]([O:34][C:32]([NH:2][C@:3]([CH3:24])([CH2:6][CH2:7][C:8]1[O:9][C:10]([C:13]#[C:14][CH2:15][CH2:16][O:17][CH:18]2[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]2)=[CH:11][CH:12]=1)[CH2:4][OH:5])=[O:33])[CH:36]=[CH2:37]
Reactant: C=CCOC(=O)Cl
Reactant: C[C@](N)(CO)CCc1ccc(C#CCCOC2CCCCC2)o1
Agent: Cl
Agent: O=C([O-])O
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Product: C=CCOC(=O)N[C@@](C)(CO)CCc1ccc(C#CCCOC2CCCCC2)o1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92.6 %

Procedure:
To a suspension of (2R)-2-amino-2-methyl-4-[5-(4-cyclohexyloxybut-1-ynyl)furan-2-yl]butan-1-ol (0.5305 g, 1.66 mmol) obtained in Example 20 in a mixed solvent of ethyl acetate (16 ml) and water (16 ml) were added potassium hydrogencarbonate (0.1995 g, 1.99 mmol) first and then allyl chloroformate (0.21 ml, 1.98 mmol) with stirring, and the resulting mixture was stirred at room temperature for 30 minutes. After stirring, the reaction mixture was diluted with ethyl acetate and extracted with ethyl acetate. The extract was washed with saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. After filtration, the solvent was removed in vacuo to afford the title compound (0.6202 g, yield: 93%)
Reaction SMILES: [CH:1](=[N:8][N:9]([C:11]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[CH2:14][O:13][N:12]=1)[CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>C(O)C>[OH:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:11]1[N:9]([CH3:10])[N:8]=[C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[N:12]=1
Reactant: CN(N=Cc1ccccc1)C1=NOCc2ccccc21
Agent: Cl
Solvent: CCO
Product: Cn1nc(-c2ccccc2)nc1-c1ccccc1CO
Temperature: 0 °C
Yield: 96 %

Procedure:
A suspension of 1.2 g. of 4-(2-benzylidene-1-methylhydrazino)-1H-2,3-benzoxazine in 12 ml. of ethanol and 12 ml. of aqueous 5% HCl is heated on a water bath for three hours. The ethanol is removed by distillation and the residue, neutralized with aqueous NaHCO3, is cooled to about 0° C. The precipitate is filtered and crystallized from ethanol. M.p. 122° C. Yield 96%.
Reaction SMILES: [Br:1][CH2:2][C:3](=[O:25])[CH2:4][C:5]([NH:7][CH:8]1[C:23](=[O:24])[N:10]2[C:11]([C:20]([OH:22])=[O:21])=[C:12]([CH2:15][O:16][C:17](=[O:19])[NH2:18])[CH2:13][S:14][C@H:9]12)=[O:6].[N:26]([O-])=[O:27].[Na+]>C(O)(=O)C>[Br:1][CH2:2][C:3](=[O:25])[C:4](=[N:26][OH:27])[C:5]([NH:7][CH:8]1[C:23](=[O:24])[N:10]2[C:11]([C:20]([OH:22])=[O:21])=[C:12]([CH2:15][O:16][C:17](=[O:19])[NH2:18])[CH2:13][S:14][C@H:9]12)=[O:6]
Reactant: O=N[O-]
Reactant: NC(=O)OCC1=C(C(=O)O)N2C(=O)C(NC(=O)CC(=O)CBr)[C@H]2SC1
Agent: [Na+]
Solvent: CC(=O)O
Product: NC(=O)OCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NO)C(=O)CBr)[C@H]2SC1
Reaction time: 0.33 h

Procedure:
While a solution of 0.15 g of 7-(4-bromo-3-oxobutyrylamino)-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid in 2 ml of acetic acid was stirred at room temperature, 0.0.3 g of sodium nitrite was added dropwise over a period of five minutes. Then, the mixture was further stirred for 20 minutes, after which time it was concentrated to dryness under reduced pressure. The resultant vitreous solid was applied to a Merck silica gel plate No. 5715 and developed with ethyl acetate-acetic acid-water (8:1:1). The color reaction with a 0.5% solution of copper chloride gave a single yellow spot at Rf=0.327. Therefore, the product was assumed to be substantially the captioned compound and was subjected to the next reaction.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([O:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29](O)=[O:30])=[N:10][CH:11]=[C:12]([C:14](=[O:23])[NH:15][C@@H:16]3[CH2:21][CH2:20][CH2:19][CH2:18][C@H:17]3[OH:22])[CH:13]=2)=[CH:4][CH:3]=1.CN(C(O[N:40]1N=N[C:42]2[CH:43]=[CH:44]C=C[C:41]1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH2:41]([NH:40][C:29]([CH2:28][CH2:27][CH2:26][CH2:25][O:24][C:9]1[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)=[CH:13][C:12]([C:14]([NH:15][C@@H:16]2[CH2:21][CH2:20][CH2:19][CH2:18][C@H:17]2[OH:22])=[O:23])=[CH:11][N:10]=1)=[O:30])[CH2:42][CH2:43][CH3:44]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: O=C(O)CCCCOc1ncc(C(=O)N[C@@H]2CCCC[C@H]2O)cc1-c1ccc(Cl)cc1
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCCNC(=O)CCCCOc1ncc(C(=O)N[C@@H]2CCCC[C@H]2O)cc1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 93.5 %

Procedure:
5-[3-(4-Chloro-phenyl)-5-((1R,2R)-2-hydroxy-cyclohexylcarbamoyl)-pyridin-2-yloxy]-pentanoic acid (20 mg) was dissolved in DMF (1 mL). To the solution was added TBTU (16 mg), N,N-diisopropylethyl amine (0.038 mL, 42) and (N)-butylamine (0.005 mL). The reaction mixture was stirred for 16 h at room temperature. The solvent was evaporated in vacuo and the residue was purified by column chromatography on silica (dichloromethane/methanol gradient) to yield 21 mg of the title compound as a white solid, MS (ISP) 502.1, 504.1 (M+H)+.
Reaction SMILES: [S:1]([O-:11])([O:4][CH2:5][CH2:6][O:7][CH2:8][CH:9]=[CH2:10])(=[O:3])=[O:2].[C:12](I)([C:15]([C:18]([C:21]([C:24]([C:27]([C:30]([C:33]([F:36])([F:35])[F:34])([F:32])[F:31])([F:29])[F:28])([F:26])[F:25])([F:23])[F:22])([F:20])[F:19])([F:17])[F:16])([F:14])[F:13]>>[S:1]([OH:11])([O:4][CH2:5][CH2:6][O:7][CH2:8][CH:9]=[CH:10][C:12]([F:14])([F:13])[C:15]([F:16])([F:17])[C:18]([F:19])([F:20])[C:21]([F:22])([F:23])[C:24]([F:25])([F:26])[C:27]([F:29])([F:28])[C:30]([F:32])([F:31])[C:33]([F:36])([F:35])[F:34])(=[O:2])=[O:3]
Reactant: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)I
Reactant: C=CCOCCOS(=O)(=O)[O-]
Product: O=S(=O)(O)OCCOCC=CC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F

Procedure:
Crystalline allyloxyethyl sulfate (Na salt) from the preparation shown in example 2 was perfluoroalkylated using the procedure of example 7 and C8F17I to produce 2-(4,4,5,5,6,6,7,7,8,8,9,9,10,10,11,11,11-heptadecafluoroundec-2-enyloxy)ethyl hydrogen sulfate.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[C:6]([Cl:9])[N:5]2[N:10]=[CH:11][C:12]([CH:13]=[O:14])=[C:4]2[N:3]=1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.[CH2:32](O)[CH2:33][CH2:34][OH:35].O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:7]([CH3:8])=[C:6]([Cl:9])[N:5]2[N:10]=[CH:11][C:12]([CH:13]3[O:35][CH2:34][CH2:33][CH2:32][O:14]3)=[C:4]2[N:3]=1
Reactant: Cc1c(Cl)nc2c(C=O)cnn2c1Cl
Reactant: OCCCO
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1c(Cl)nc2c(C3OCCCO3)cnn2c1Cl

Procedure:
To 5,7-dichloro-6-methylpyrazolo[1,5-a]pyrimidine-3-carbaldehyde (290 mg) in toluene (40 mL) was added pyridinium p-toluenesulfonate (60 mg) and propan-1,3-diol. The mixture was then heated under reflux for 2 h, with azeotropic removal of water. The solution was cooled and evaporated under reduced pressure. The residue was chromatographed on silica gel using ethyl acetate/petroleum ether ⅔ as eluent to give the title compound (310 mg) as a white solid; 1H-NMR (400 MHz, CDCl3) d(ppm): 8.32 (1H, s, 2-H), 5.97 (1H, s, CHO2R), 4.25 (2H, br dd, OCHeq), 4.05 (2H, br t, OCHax), 2.50 (3H, s, 6-Me), 2.25 (1H, m, CCHeqHC), 1.48 (1H, br d, CCHHaxC).
Reaction SMILES: [CH3:1][C@H:2]1[NH:7][C@@H:6](C)[CH2:5][N:4]([CH2:9][C:10]2[S:18][C:17]3[C:16]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)=[N:15][C:14]([C:25]4[CH:33]=[C:32]([F:34])[CH:31]=[C:30]5[C:26]=4[CH:27]=[CH:28][NH:29]5)=[N:13][C:12]=3[CH:11]=2)[CH2:3]1.[CH3:35]N(C)C1CCNC1>>[F:34][C:32]1[CH:31]=[C:30]2[C:26]([CH:27]=[CH:28][NH:29]2)=[C:25]([C:14]2[N:15]=[C:16]([N:19]3[CH2:20][CH2:21][O:22][CH2:23][CH2:24]3)[C:17]3[S:18][C:10]([CH2:9][N:4]4[CH2:5][CH2:1][CH:2]([N:7]([CH3:6])[CH3:35])[CH2:3]4)=[CH:11][C:12]=3[N:13]=2)[CH:33]=1
Reactant: CN(C)C1CCNC1
Reactant: C[C@@H]1CN(Cc2cc3nc(-c4cc(F)cc5[nH]ccc45)nc(N4CCOCC4)c3s2)C[C@H](C)N1
Product: CN(C)C1CCN(Cc2cc3nc(-c4cc(F)cc5[nH]ccc45)nc(N4CCOCC4)c3s2)C1

Procedure:
Prepared according to the method used in the preparation of 6-(cis-3,5-dimethyl-piperazin-1-ylmethyl)-2-(6-fluoro-1H-indol-4-yl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine using dimethyl-pyrrolidin-3-yl-amine in place of 2,6-dimethyl-piperazine. The title compound was obtained as a white solid (21.8 mg, 36%).
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.[CH2:25]([O:29][CH2:30][CH3:31])[CH:26]1[O:28][CH2:27]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O>[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]([CH2:27][CH:26]([OH:28])[CH2:25][O: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: CCOCC1CO1
Reactant: O=c1[nH]nc2c(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)cnn12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOCC(O)Cn1nc2c(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)cnn2c1=O
Temperature: 85 °C
Reaction time: 8 h
Yield: 77.8 %

Procedure:
To a solution of 7,8-bis(4-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one, (300 mg, 0.84 mmol), prepared as described in Example 1, in 8 mL of DMF was added ethyl glycidyl ether (86 mg, 0.84 mmol), followed by K2CO3 (232 mg, 1.68 mmol). The mixture was heated at 85° C. After stirring overnight, the reaction was allowed to cool to RT The reaction mixture was diluted with EtOAc (200 mL). The resultant solution was washed with saturated aqueous NaCl (3×40 mL). The organic layer was dried over MgSO4, filtered, and 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 100% EtOAc for 40 min. The title compound, 7,8-bis(4-chlorophenyl)-2-(3-ethoxy-2-hydroxypropyl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one, (0.3 gm, 78% yield) as a yellow solid. MS [M+H]+: found 459; 1H NMR (CDCl3, 400 MHz) δ 8.20 (s, 1H), 7.34-7.25 (m, 6H), 7.09 (d, 2H), 4.29-4.24 (m, 2H), 4.18-4.13 (m, 1H), 3.57-3.49 (m, 4H), 1.17 (t, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[C:16]2[CH2:21][C:20]([CH3:23])([CH3:22])[CH2:19][C:18]([CH3:25])([CH3:24])[CH2:17]2)[C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:33][C:34]#[N:35]>CC(C)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[C:16]2[CH2:17][C:18]([CH3:25])([CH3:24])[CH2:19][C:20]([CH3:23])([CH3:22])[CH2:21]2)[C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:33][C:34]#[N:35])=[CH:11][CH:10]=2)=[CH:6][CH:7]=1
Reactant: N#CCBr
Reactant: CC1(C)CC(=C(c2ccc(O)cc2)c2ccc(F)cc2)CC(C)(C)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC1(C)CC(=C(c2ccc(F)cc2)c2ccc(OCC#N)cc2)CC(C)(C)C1
Temperature: 25 °C
Yield: 72.4 %

Procedure:
The o-alkylation procedure described for 10 (example 5, step 2) was employed. To a stirred suspension of 4-[(4-fluorophenyl)(3,3,5,5-tetramethylcyclohexylidene) methyl]phenol 9 (0.508 g, 1.5 mmol), K2CO3 (0.414 g, 3.0 mmol), and acetone (50 mL) was added, under N2 at RT, bromoacetonitrile (0.21 mL, 3.0 mmol). The reaction mixture was refluxed for 4 h, cooled to RT, and filtered. Standard work-up followed by purification afforded 0.410 g (72%) of the title compound 14 as a white foam. mp 100-101° C. 1H NMR (300 MHz, CDCl3): δ 7.18-7.11 (m, 4H), 6.99 and 6.97 (dd, J1=8.7 Hz, J2=8.7 Hz, 2H), 6.92 (d, J=8.7 Hz, 2H), 4.76 (s, 2H), 1.98 (s, 2H), 1.97 (s, 2H), 1.32 (s, 2H), 0.96 (s, 12H). LCMS (ESI): m/z 376 (M−H)−. Anal. Calcd for C25H28FNO, C, 79.54, H, 7.48; N, 3.71. Found: C, 79.21, H, 7.46; N, 3.73.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[C:6]([C@@:8]12[CH2:25][CH2:24][C:23]3[CH:22]=[C:21]([O:26][CH3:27])[CH:20]=[CH:19][C:18]=3[C@H:17]1[CH:16](O)[CH2:15][C@@:13]1([CH3:14])[C@H:9]2[CH2:10][CH2:11][C@@H:12]1[O:29][CH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][O:31]1)#[N:7].C(=O)(O)[O-].[Na+]>N1C=CC=CC=1>[C:6]([C@@:8]12[CH2:25][CH2:24][C:23]3[CH:22]=[C:21]([O:26][CH3:27])[CH:20]=[CH:19][C:18]=3[C:17]1=[CH:16][CH2:15][C@@:13]1([CH3:14])[C@H:9]2[CH2:10][CH2:11][C@@H:12]1[O:29][CH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][O:31]1)#[N:7]
Reactant: COc1ccc2c(c1)CC[C@@]1(C#N)[C@@H]3CC[C@H](OC4CCCCO4)[C@@]3(C)CC(O)[C@H]21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc2c(c1)CC[C@]1(C#N)C2=CC[C@]2(C)[C@@H](OC3CCCCO3)CC[C@H]21
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
27.6 ml of phosphorus oxychloride was added in drops to a solution of 27.6 g of 4 in 275 ml of pyridine at a temperature of 0-5° C., and it was stirred for another 1.5 hours at this temperature. Then, the mixture was moved into a dropping funnel and added in drops to an ice-cooled, saturated sodium bicarbonate solution. Then, it was extracted with dichloromethane, the collected organic phases were washed with brine, dried on magnesium sulfate, and the solvent was removed in a vacuum. In this way, 23.5 g (89%) of almost colorless, foamy 5 was obtained, which was used without further purification in the next stage.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([N:17]2[CH2:22][CH2:21][CH:20]([CH2:23]O)[CH2:19][CH2:18]2)=[O:16])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:25]N1C(=O)CCC1=O>C1C=CC=CC=1>[Br:25][CH2:23][CH:20]1[CH2:21][CH2:22][N:17]([C:15]([O:14][C:11]2[CH:12]=[CH:13][C:8]([O:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:9][CH:10]=2)=[O:16])[CH2:18][CH2:19]1
Reactant: O=C(Oc1ccc(Oc2ccccc2)cc1)N1CCC(CO)CC1
Reactant: O=C1CCC(=O)N1Br
Solvent: c1ccccc1
Product: O=C(Oc1ccc(Oc2ccccc2)cc1)N1CCC(CBr)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 210.1 %

Procedure:
The hydroxymethyl derivative produced in Example 30 (5.0 g, 15 mmol) and wiphenylphosphine (4.0 g, 15 mmol) were dissolved in 100 ml of benzene and the resulting solution put under a nitrogen atmosphere. N-Bromosuccinimide (2.7 g, 15 mmol) was added in portions to the above solution and the reaction stirred at room temperature overnight. The solvent was removed under reduced pressure to give 12.3 g of a brown oil. Purification of this oil by chromatography on 600 g of silica gel (230-400 mesh) using ethyl acetate-hexane as the eluent gave 4.52 g of a white solid. Recrystallization of this solid from diisopropyl ether gave the title compound as a white crystalline solid (4.12 g, 68%), mp 76°-78° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[C:5]([C:10]1[CH:15]=[CH:14][C:13]([NH2:16])=[C:12]([NH:17][CH3:18])[C:11]=1[C:19]#[N:20])([CH3:9])[C:6](=[O:8])[CH3:7])[CH3:2].[Br:22]Br>C(Cl)(Cl)Cl.C(OCC)(=O)C>[CH2:1]([O:3][C:4](=[O:21])[C:5]([C:10]1[CH:15]=[C:14]([Br:22])[C:13]([NH2:16])=[C:12]([NH:17][CH3:18])[C:11]=1[C:19]#[N:20])([CH3:9])[C:6](=[O:8])[CH3:7])[CH3:2]
Reactant: CCOC(=O)C(C)(C(C)=O)c1ccc(N)c(NC)c1C#N
Reactant: BrBr
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C(C)(C(C)=O)c1cc(Br)c(N)c(NC)c1C#N
Yield: 52.7 %

Procedure:
To a solution of 2-(4-amino-2-cyano-3-methylaminophenyl)-2-methyl-3-oxobutyric acid ethyl ester from Example 4 (9.02 g, 31.2 mmol) in CHCl3 (90 mL) was added bromine (4.98 g, 31.2 mmol) dropwise at ambient temperature. After the addition of bromine, the reaction mixture was diluted with ethyl acetate (800 mL). This solution was washed successively with sat. NaHCO3 solution and brine and dried. The residue after evaporation was purified by flash chromatography in hexanes/EtOAc 2:1 to yield 2-(4-amino-5-bromo-2-cyano-3-methylaminophenyl)-2-methyl-3-oxobutyric acid ethyl ester as an oil (6.06 g, 53%).