Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[C:10]([F:41])=[C:11]([CH:15]2[C:19]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=3[F:29])([C:20]#[N:21])[CH:18]([CH2:30][C:31]3([CH3:37])[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]3)[NH:17][CH:16]2[C:38](O)=[O:39])[CH:12]=[CH:13][CH:14]=1.[NH2:42][C:43]1[CH:52]=[CH:51][C:46]([C:47]([O:49][CH3:50])=[O:48])=[CH:45][CH:44]=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>C(Cl)Cl>[CH3:50][O:49][C:47](=[O:48])[C:46]1[CH:51]=[CH:52][C:43]([NH:42][C:38]([C@H:16]2[C@H:15]([C:11]3[CH:12]=[CH:13][CH:14]=[C:9]([Cl:8])[C:10]=3[F:41])[C@:19]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=3[F:29])([C:20]#[N:21])[C@H:18]([CH2:30][C:31]3([CH3:37])[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36]3)[NH:17]2)=[O:39])=[CH:44][CH:45]=1
Reactant: CC1(CC2NC(C(=O)O)C(c3cccc(Cl)c3F)C2(C#N)c2ccc(Cl)cc2F)CCCCC1
Reactant: COC(=O)c1ccc(N)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1ccc(NC(=O)[C@@H]2N[C@@H](CC3(C)CCCCC3)[C@](C#N)(c3ccc(Cl)cc3F)[C@H]2c2cccc(Cl)c2F)cc1
Yield: 40.2 %

Procedure:
In a manner similar to the method described in Examples 1e, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(1-methyl-cyclohexylmethyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 102c (0.41 g, 0.66 mmol) was reacted with methyl 4-aminobenzoate (0.2 g, 1.3 mmol), HATU (0.45 g, 1.2 mmol) and iPr2NEt (0.29 mL, 1.7 mmol) in CH2Cl2 at room temperature to give rac-4-{[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(1-methyl-cyclohexylmethyl)-pyrrolidine-2-carbonyl]-amino}-benzoic acid methyl ester as a white solid (0.17 g, 41%).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[N:13]=[CH:12][C:11]3[CH:14]=[N:15][NH:16][C:10]=3[CH:9]=2)[CH:5]=[N:4][CH:3]=1.Br[C:18]1[N:23]=[C:22]([N:24]2[C:29](=[O:30])[CH2:28][CH2:27][C@H:26]([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[CH2:25]2)[CH:21]=[CH:20][CH:19]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:1][C:2]1[N:7]=[C:6]([C:8]2[N:13]=[CH:12][C:11]3[CH:14]=[N:15][N:16]([C:18]4[N:23]=[C:22]([N:24]5[C:29](=[O:30])[CH2:28][CH2:27][C@H:26]([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:36])([CH3:35])[CH3:37])[CH2:25]5)[CH:21]=[CH:20][CH:19]=4)[C:10]=3[CH:9]=2)[CH:5]=[N:4][CH:3]=1
Reactant: Cc1cncc(-c2cc3[nH]ncc3cn2)n1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCC(=O)N(c2cccc(Br)n2)C1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: Cc1ccccc1
Product: Cc1cncc(-c2cc3c(cn2)cnn3-c2cccc(N3C[C@@H](NC(=O)OC(C)(C)C)CCC3=O)n2)n1
Temperature: 100 °C
Yield: 27.7 %

Procedure:
A mixture of 6-(6-methylpyrazin-2-yl)-1H-pyrazolo[4,3-c]pyridine (75 mg, 0.36 mmol), tert-butyl N-[(3S)-1-(6-bromo-2-pyridyl)-6-oxo-3-piperidyl]carbamate (158 mg, 0.426 mmol), tris(dibenzylideneacetone)dipalladium(0) (32 mg, 0.036 mmol), xantphos (42 mg, 0.071 mmol), and sodium tert-butoxide (70 mg, 0.71 mmol) in toluene 6.0 mL was stirred at 100° C. 18 h. The reaction was filtered through celite. The crude product was purified by flash chromatography (EtOAc/Heptane eluted at 100% EtOAc) to give tert-butyl N-[(3S)-1-[6-[6-(6-methylpyrazin-2-yl)pyrazolo[4,3-c]pyridin-1-yl]-2-pyridyl]-6-oxo-3-piperidyl]carbamate (50 mg) in 28% yield.
Reaction SMILES: [Br:1]Br.[C:3]([C:6]1[CH:7]=[C:8]([CH:11]=[C:12]([O:14][CH2:15][CH2:16][O:17][CH3:18])[CH:13]=1)[C:9]#[N:10])(=[O:5])[CH3:4]>CCOCC>[Br:1][CH2:4][C:3]([C:6]1[CH:7]=[C:8]([CH:11]=[C:12]([O:14][CH2:15][CH2:16][O:17][CH3:18])[CH:13]=1)[C:9]#[N:10])=[O:5]
Reactant: COCCOc1cc(C#N)cc(C(C)=O)c1
Reactant: BrBr
Solvent: CCOCC
Product: COCCOc1cc(C#N)cc(C(=O)CBr)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 94.2 %

Procedure:
Br2 (31.5 mmol) was dropped into the solution of 3-acetyl-5-(2-methoxyethoxy)benzonitrile (30 mmol) in 150 ml ether at 0° C., then stirred at room temperature for 5 h. The solution was washed with brine, dried (MgSO4), filtered, and concentrated to afford 3-(2-bromoacetyl)-5-(2-methoxyethoxy)benzonitrile (94.2%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:28])[C:10]2[CH:15]=[C:14]([N+:16]([O-])=O)[C:13]([NH:19][CH3:20])=[CH:12][C:11]=2[N:21]2[CH2:26][CH2:25][CH:24]([F:27])[CH2:23][CH2:22]2)=[CH:4][C:3]=1[Cl:29]>[Ni].C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:28])[C:10]2[CH:15]=[C:14]([NH2:16])[C:13]([NH:19][CH3:20])=[CH:12][C:11]=2[N:21]2[CH2:26][CH2:25][CH:24]([F:27])[CH2:23][CH2:22]2)=[CH:4][C:3]=1[Cl:29]
Reactant: CNc1cc(N2CCC(F)CC2)c(C(=O)Nc2ccc(F)c(Cl)c2)cc1[N+](=O)[O-]
Agent: [Ni]
Solvent: C1CCOC1
Product: CNc1cc(N2CCC(F)CC2)c(C(=O)Nc2ccc(F)c(Cl)c2)cc1N
Reaction time: 4 h

Procedure:
A mixture of N-(4-fluoro-3-chloro-phenyl)-2-(4-fluoro-piperidinyl)-4-methylamino-5-nitro-benzoic acid amide (90 mg, 0.21 mmol), Ra—Ni (30 mg) and THF (10 mL) is stirred under 50 psi H2-atmosphere for 4 h. The mixture is filtered, and the filtrate is concentrated.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH2:8][CH2:9][O:10][C:11](=[O:16])[CH2:12][C:13]([CH3:15])=O)[CH:2]=1.[NH3:17]>C(O)(C)C.Cl>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH2:8][CH2:9][O:10][C:11]([C:12]2[CH:2]([CH2:3][CH2:4][CH3:5])[C:12]([C:11]([O:10][CH2:9][CH2:8][CH2:7][C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)=[O:16])=[C:13]([CH3:15])[NH:17][C:13]=2[CH3:15])=[O:16])[CH:2]=1
Reactant: CC(=O)CC(=O)OCCCc1cccnc1
Reactant: N
Agent: Cl
Solvent: CC(C)O
Product: CCCC1C(C(=O)OCCCc2cccnc2)=C(C)NC(C)=C1C(=O)OCCCc1cccnc1

Procedure:
2.2 g of acetoacetic acid 3-(3-pyridyl)propyl ester and 0.36 g of n-butylaldehyde were heated and refluxed in the presence of 1 ml of concentrated ammonia solution in 20 ml of isopropanol for 7 hours. After the reaction, the reaction solution was condensed to dryness under reduced pressure, the residue was dissolved in 1N hydrochloric acid, washed with ethyl acetate, then made alkaline by sodium hydroxide and extracted by ethyl acetate. The extracted solution was rinsed, then dried over anhydrous sodium sulfate and condensed to dryness under reduced pressure, then the oily substance was refined by silica gel column chromatography to obtain the target compound in an amount of 1.24 g (51.9%).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:11][CH2:10][C:9](=O)[C:8]2[N:13]([CH3:16])[CH:14]=[CH:15][C:7]=2[S:6]1(=[O:18])=[O:17].Cl.[NH2:20][OH:21].C([O-])(=O)C.[Na+]>CO>[Cl:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:11][CH2:10][C:9](=[N:20][OH:21])[C:8]2[N:13]([CH3:16])[CH:14]=[CH:15][C:7]=2[S:6]1(=[O:18])=[O:17]
Reactant: Cn1ccc2c1C(=O)CCN(CCCCl)S2(=O)=O
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: Cn1ccc2c1C(=NO)CCN(CCCCl)S2(=O)=O
Yield: 79.5 %

Procedure:
A suspension of 404 mg (1.39 mmol) of Compound 18, 290 mg (4.17 mmol) of hydroxylamine hydrochloride and 342 mg (4.17 mmol) of sodium acetate in 40 ml of methanol was refluxed for 22 hours. To the reaction mixture, 97 mg (1.39 mmol) of hydroxylamine hydrochloride and 114 mg (1.39 mmol) of sodium acetate were added, followed by further refluxing for 19 hours. The reaction mixture was concentrated under reduced pressure and a half-saturated aqueous solution of potassium carbonate was added to the residue. The thus-obtained mixture was extracted with chloroform (3 times). The organic layer was washed successively with water and a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column (eluent: chloroform), whereby 338 mg of the title compound were obtained (yield: 80%).
Reaction SMILES: [Na].[C:2]([O:8][CH2:9][CH3:10])(=[O:7])[CH2:3][C:4]([CH3:6])=[O:5].[CH:11](=O)/[CH:12]=[CH:13]/[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.Cl>C(O)C>[CH2:9]([O:8][C:2]([CH:3]1[CH:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:12][CH:11]=[CH:6][C:4]1=[O:5])=[O:7])[CH3:10]
Reactant: O=C/C=C/c1ccccc1
Reactant: CCOC(=O)CC(C)=O
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C1C(=O)C=CCC1c1ccccc1
Temperature: 25 °C
Reaction time: 65 h

Procedure:
Under a nitrogen atmosphere, 0.1 gram (0.004 mole) of sodium metal was reacted in 40 mL of ethanol. The solution was stirred, and 13.0 grams (0.100 mole) of ethyl acetoacetate was added. The reaction mixture was cooled in an ice bath, and 13.2 grams (0.100 mole) of trans-cinnamaldehyde in 10 mL of ethanol was added dropwise during a 10 minute period. Upon completion of addition, the reaction mixture was allowed to warm to ambient temperature where it stirred for about 18 hours. After this time the reaction mixture was saturated with gaseous hydrochloric acid and then was allowed to stand for about 65 hours. The reaction mixture was concentrated under reduced pressure to yield 2-ethoxycarbonyl-3-phenylcyclohex-5-enone. A 100% yield (24.4 grams) of product was assumed.
Reaction SMILES: [NH:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=[O:5])[C:2]1=[O:3].Cl.[CH:13]([N:16]([CH:20]([CH3:22])[CH3:21])[CH2:17][CH2:18]Cl)([CH3:15])[CH3:14].[H-].[Na+]>C1(C)C=CC=CC=1.CN(C)C=O>[CH:13]([N:16]([CH:20]([CH3:22])[CH3:21])[CH2:17][CH2:18][N:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=[O:5])[C:2]1=[O:3])([CH3:15])[CH3:14]
Reactant: O=C1Nc2ccccc2C1=O
Reactant: CC(C)N(CCCl)C(C)C
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CC(C)N(CCN1C(=O)C(=O)c2ccccc21)C(C)C
Temperature: 80 °C

Procedure:
2.94 Grams of isatin and 4.00 g of 2-diisopropylaminoethyl chloride hydrochloride were suspended in a mixture of 50 ml of dry toluene and 10 ml of dry N,N-dimethylformamide, and 1.60 g of sodium hydride (60% dispersion in mineral oil) was added to the suspension with stirring under ice-cooling. The mixture was stirred for 30 minutes at room temperature, and then heated at 80° C. for 19 hours. The reaction mixture was concentrated under reduced pressure, and water was added to the residue. The mixture was extracted with benzene, and the benzene layer was washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was recrystallized from hexane to obtain 4.62 g of 1-(2-diisopropylaminoethyl)isatin having a melting point of 60°-61° C.
Reaction SMILES: [C:1]([CH:3]([N:10]([C:12]1[CH:17]=[CH:16][C:15]([CH2:18][N:19]2[C:23]3=[N:24][C:25]([CH3:29])=[CH:26][C:27]([CH3:28])=[C:22]3[N:21]=[C:20]2[CH2:30][CH3:31])=[CH:14][CH:13]=1)[CH3:11])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)#[N:2].C[Sn]([N:36]=[N+:37]=[N-:38])(C)C>C1(C)C=CC=CC=1>[NH:36]1[C:1]([CH:3]([N:10]([C:12]2[CH:13]=[CH:14][C:15]([CH2:18][N:19]3[C:23]4=[N:24][C:25]([CH3:29])=[CH:26][C:27]([CH3:28])=[C:22]4[N:21]=[C:20]3[CH2:30][CH3:31])=[CH:16][CH:17]=2)[CH3:11])[C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)=[N:2][N:38]=[N:37]1
Reactant: CCc1nc2c(C)cc(C)nc2n1Cc1ccc(N(C)C(C#N)c2ccccc2)cc1
Reactant: C[Sn](C)(C)N=[N+]=[N-]
Solvent: Cc1ccccc1
Product: CCc1nc2c(C)cc(C)nc2n1Cc1ccc(N(C)C(c2ccccc2)c2nnn[nH]2)cc1
Yield: 79.5 %

Procedure:
To a solution of 101 mg (0.25 mmol) of the product of Step A dissolved in 5.0 mL toluene was added 154 mg (0.75 mmol) of trimethylstannyl azide, and the mixture was stirred and heated at reflux for 24 hours. The reaction mixture was evaporated in vacuo, the residue was redissolved in 5.0 mL THF and then treated with 0.5 mL of a 1.0N HCl solution at 0° C. After stirring for 10 minutes, the reaction mixture was concentrated in vacuo, and the water was removed by azeotropic distillation with toluene. After evaporation, the residue was purified on a silica gel preparative layer chromatography plate eluted with CHCl3 /MeOH/NH4OH (80:20:2). The product bands were collected and the product removed from the silica gel by elution with 10% methanol/chloroform. Evaporation of the filtrate and recrystallization of the residue from dichloromethane/hexanes afforded 90 mg (80%) of the title compound as a white powder.
Reaction SMILES: Cl.O1CCOCC1.[NH2:8][C:9]1[N:14]=[CH:13][N:12]=[C:11]2[N:15]([CH2:32][C@@H:33]3[CH2:37][CH2:36][CH2:35][N:34]3[C:38](=[O:59])[C:39]([C:57]#[N:58])=[CH:40][C:41]([N:44]3[CH2:49][CH2:48][N:47](C(OC(C)(C)C)=O)[CH2:46][CH2:45]3)([CH3:43])[CH3:42])[N:16]=[C:17]([C:18]3[CH:23]=[CH:22][C:21]([O:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[CH:20][C:19]=3[F:31])[C:10]=12>C1COCC1>[NH2:8][C:9]1[N:14]=[CH:13][N:12]=[C:11]2[N:15]([CH2:32][C@@H:33]3[CH2:37][CH2:36][CH2:35][N:34]3[C:38]([C:39](=[CH:40][C:41]([CH3:43])([N:44]3[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]3)[CH3:42])[C:57]#[N:58])=[O:59])[N:16]=[C:17]([C:18]3[CH:23]=[CH:22][C:21]([O:24][C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)=[CH:20][C:19]=3[F:31])[C:10]=12
Reactant: CC(C)(C)OC(=O)N1CCN(C(C)(C)C=C(C#N)C(=O)N2CCC[C@H]2Cn2nc(-c3ccc(Oc4ccccc4)cc3F)c3c(N)ncnc32)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: CC(C)(C=C(C#N)C(=O)N1CCC[C@H]1Cn1nc(-c2ccc(Oc3ccccc3)cc2F)c2c(N)ncnc21)N1CCNCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 78 %

Procedure:
To a solution of 4N HCl in dioxane (0.5 mL, 0.050 mmol) in THF (1 mL) in the ice bath, was added tert-butyl 4-[4-[(2S)-2-[[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]methyl]pyrrolidin-1-yl]-3-cyano-1,1-dimethyl-4-oxo-but-2-enyl]piperazine-1-carboxylate (32.9 mg, 0.050 mmol). The ice bath was removed, the reaction mixture was stirred for 4 h at room temperature at which point TLC and LC-MS showed the reaction was finished. The mixture was concentrated in vacuo, adjusted with NaHCO3 to pH 6-7, and the aq. layer extracted with CH2Cl2. The combined organic layer was washed by brine, dried over Na2SO4, filtered, and the solvent removed to get product 2-[(2S)-2-[[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]methyl]-pyrrolidine-1-carbonyl]-4-methyl-4-piperazin-1-yl-pent-2-enenitrile (24 mg, 0.039 mmol, 85% yield) as an off white powder. LC-MS (ES, m/z): 610 [M+H]
Reaction SMILES: [Cl:1][C:2]1[N:3]([CH2:28][CH2:29][CH3:30])[C:4](=[O:27])[C:5]2[NH:6][C:7]([C:11]3[CH:12]=[N:13][N:14]([CH2:16][C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=4)[CH:15]=3)=[N:8][C:9]=2[N:10]=1.[C:31]([O-])([O-])=O.[K+].[K+].CI.CN(C=O)C>O>[Cl:1][C:2]1[N:3]([CH2:28][CH2:29][CH3:30])[C:4](=[O:27])[C:5]2[N:6]([CH3:31])[C:7]([C:11]3[CH:12]=[N:13][N:14]([CH2:16][C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=4)[CH:15]=3)=[N:8][C:9]=2[N:10]=1
Reactant: CCCn1c(Cl)nc2nc(-c3cnn(Cc4cccc(C(F)(F)F)c4)c3)[nH]c2c1=O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CI
Product: CCCn1c(Cl)nc2nc(-c3cnn(Cc4cccc(C(F)(F)F)c4)c3)n(C)c2c1=O
Temperature: 60 °C
Reaction time: 2 h
Yield: 57.9 %

Procedure:
A mixture of 2-Chloro-1-propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-1,7-dihydro-purin-6-one (200 mg, 0.46 mmol), K2CO3 (95 mg, 0.69 mmol), MeI (85 mg, 0.60 mmol) and DMF (2 ml) were stirred at 60° C. for 2 hours. Reaction mixture was cooled, diluted with water (10 ml) and extracted with ethyl acetate (2×5 ml). The organic layer was washed with brine (2×10 ml), dried over Na2SO4 and evaporated to obtain 2-Chloro-7-methyl-1-propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-1,7-dihydro-purin-6-one (120 mg, 58%)
Reaction SMILES: [CH3:1][NH:2][N:3]=[CH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C(O[CH:14]=[C:15]([C:21](=[O:25])[CH:22]([F:24])[F:23])[C:16]([O:18][CH2:19][CH3:20])=[O:17])C>C1(C)C=CC=CC=1>[F:24][CH:22]([F:23])[C:21](=[O:25])[C:15](=[CH:14][N:2]([CH3:1])[N:3]=[CH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[C:16]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: CCOC=C(C(=O)OCC)C(=O)C(F)F
Reactant: CNN=Cc1ccccc1
Solvent: Cc1ccccc1
Product: CCOC(=O)C(=CN(C)N=Cc1ccccc1)C(=O)C(F)F
Yield: 74.1 %

Procedure:
13.8 g (0.1 mol) of benzaldehyde methylhydrazone and 62.2 g of toluene were admixed with 23.7 g (0.1 mol) of ethyl 2-ethoxymethylene-4,4-difluoro-3-oxo-butyrate, as a result of which the internal temperature rose to 35° C. The reaction mixture was stirred at reflux temperature for 1.25 hours and then stirred at 25° C. for 15 hours. The precipitated solid was filtered off with a suction filter and washed twice with 25 m; each time of toluene. After drying at 40-50° C. under reduced pressure, 23 g of product were obtained.
Reaction SMILES: C([O:5][C:6](=[O:28])[CH2:7][C@H:8]([C:18]1[O:19][CH:20]=[C:21]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[N:22]=1)[CH2:9][CH2:10][CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)(C)(C)C.[F:29][C:30]([F:35])([F:34])[C:31]([OH:33])=[O:32]>ClCCl>[F:29][C:30]([F:35])([F:34])[C:31]([OH:33])=[O:32].[CH:12]1([CH2:11][CH2:10][CH2:9][C@@H:8]([C:18]2[O:19][CH:20]=[C:21]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[N:22]=2)[CH2:7][C:6]([OH:28])=[O:5])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]1
Reactant: CCOC(=O)c1coc([C@H](CCCC2CCCCC2)CC(=O)OC(C)(C)C)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)c1coc([C@H](CCCC2CCCCC2)CC(=O)O)n1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of ethyl 2-{(1R)-1-[2-(tert-butoxy)-2-oxoethyl]-4-cyclohexylbutyl}-1,3-oxazole-4-carboxylate (Preparation 62) (1.58 g, 4.01 mmol) in anhydrous dichloromethane (25 ml) was treated with trifluoroacetic acid (7 ml) and the resulting mixture was stirred at room temperature under a nitrogen atmosphere for 4 hours. The solvent was removed under reduced pressure and the residue azeotroped from dichloromethane to afford the title compound (1.66 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([CH2:32][CH2:33][CH2:34][OH:35])[O:13][C:12](=[O:14])[N:11]([C@H:15]([C:17]3[CH:22]=[CH:21][C:20](B4OC(C)(C)C(C)(C)O4)=[CH:19][CH:18]=3)[CH3:16])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Cl[C:37]1[N:42]=[CH:41][CH:40]=[CH:39][N:38]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C@:8]2([CH2:32][CH2:33][CH2:34][OH:35])[O:13][C:12](=[O:14])[N:11]([C@H:15]([C:17]3[CH:22]=[CH:21][C:20]([C:37]4[N:42]=[CH:41][CH:40]=[CH:39][N:38]=4)=[CH:19][CH:18]=3)[CH3:16])[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: Clc1ncccn1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CCCO)(c2ccc(F)cc2)OC1=O
Product: C[C@@H](c1ccc(-c2ncccn2)cc1)N1CC[C@](CCCO)(c2ccc(F)cc2)OC1=O

Procedure:
The title compound was prepared (R)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one and 2-chloropyrimidine following procedures analogous to those described in Example 1 Step 2. LC-MS Method 2 tR=1.401, m/z=436.1; 1H NMR (CDCl3) 1.53 (d, 3H), 1.62 (m, 1H), 1.81-1.98 (m, 3H), 2.15 (m, 2H), 2.31 (m, 1H), 2.76 (m, 1H), 3.51 (t, 2H), 5.67 (m, 1H), 6.92 (m, 4H), 7.11 (m, 1H), 7.19 (m, 1H), 8.15 (d, 2H), 8.71 (d, 2H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:17])[CH3:16])=[CH:11][C:10]=1[CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([N-]C(C)C)(C)C.[Li+].[CH3:27][C:28]1[N:29]=[C:30]([C:35]2[CH:40]=[CH:39][C:38]([C:41]([F:44])([F:43])[F:42])=[CH:37][CH:36]=2)[S:31][C:32]=1[CH:33]=O.C1(C)C(S(O)(=O)=O)=CC=CC=1>O1CCCC1.C(O)(=O)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:17])[CH:16]=[CH:33][C:32]2[S:31][C:30]([C:35]3[CH:36]=[CH:37][C:38]([C:41]([F:44])([F:42])[F:43])=[CH:39][CH:40]=3)=[N:29][C:28]=2[CH3:27])=[CH:11][C:10]=1[CH3:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)c1ccc(OCc2ccccc2)c(C)c1
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1C=O
Agent: CC(C)[N-]C(C)C
Agent: Cc1ccccc1S(=O)(=O)O
Agent: [Li+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: Cc1cc(C(=O)C=Cc2sc(-c3ccc(C(F)(F)F)cc3)nc2C)ccc1OCc1ccccc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A mixture of 1-[4-(benzyloxy)-3-methylphenyl]ethanone (intermediate 8, 1.15 g) in dry tetrahydrofuran (15 ml) at −78° C. was treated dropwise with lithium diisopropylamide (2.6 ml of 2M solution in heptane/tetrahydrofuran/ethylbenzene) under nitrogen. The reaction mixture was warmed to 0° C. for 30 minutes. The mixture was cooled to −78° C. and 4-methyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazole-5-carbaldehyde (intermediate 2, 1.08 g) in dry tetrahydrofuran (15 ml) was added drop-wise at −78° C. and the reaction mixture stirred at 21° C. for 2 hours. Acetic acid (4 ml) in dry tetrahydrofuran (4 ml) was added followed by toluenesulphonic acid (0.1 g) and the reaction mixture was heated at 50° C. for 1 hour and then concentrated. The residue was partitioned between saturated bicarbonate solution and ethyl acetate; the aqueous layer separated and extracted thrice more with ethyl acetate. The organic solutions were combined and were dried with brine and over magnesium sulfate and concentrated. The product isolated after evaporation of the solvent was further purified by flash chromatography using cyclohexane:ethyl acetate (6:1) as eluent to give the title compound as a yellow solid.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[C:35]([O:36][CH3:37])=[CH:34][C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][C:7]=2[CH:6]=1)[N:14]=[CH:13][C:12]([C:17]#[N:18])=[C:11]3[NH:19][C:20]1[CH:25]=[CH:24][C:23]([S:26][C:27]2[N:28]([CH3:32])[CH:29]=[CH:30][N:31]=2)=[C:22]([Cl:33])[CH:21]=1.[CH3:38][N:39]1[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1.[I-].[Na+]>>[Cl:33][C:22]1[CH:21]=[C:20]([NH:19][C:11]2[C:10]3[C:15](=[CH:16][C:7]4[CH:6]=[C:5]([O:4][CH2:3][CH2:2][N:42]5[CH2:43][CH2:44][N:39]([CH3:38])[CH2:40][CH2:41]5)[C:35]([O:36][CH3:37])=[CH:34][C:8]=4[CH:9]=3)[N:14]=[CH:13][C:12]=2[C:17]#[N:18])[CH:25]=[CH:24][C:23]=1[S:26][C:27]1[N:28]([CH3:32])[CH:29]=[CH:30][N:31]=1
Reactant: COc1cc2cc3c(Nc4ccc(Sc5nccn5C)c(Cl)c4)c(C#N)cnc3cc2cc1OCCCl
Reactant: CN1CCNCC1
Agent: [I-]
Agent: [Na+]
Product: COc1cc2cc3c(Nc4ccc(Sc5nccn5C)c(Cl)c4)c(C#N)cnc3cc2cc1OCCN1CCN(C)CC1

Procedure:
Following procedure 1 of Example 149, a mixture of 0.15 g (0.3 mmol) of 8-(2-chloroethoxy)-4-[3-chloro-4-(1-methyl-1H-imidazol-2-ylsulfanyl)phenylamino]-7-methoxybenzo[g]quinoline-3-carbonitrile, 0.5 mL of 1-methylpiperazine and 0.02 g of sodium iodide is heated under reflux for 16 hours. Purification of the material is carried out by silica gel flash chromatography, utilizing a 90:10 to 85:15 gradient of methylene chloride/methanol to give 0.052 g of 4-[3-chloro-4-(1-methyl-1H-imidazol-2-ylsulfanyl)phenylamino]-7-methoxy-8-[2-(4-methylpiperazin-1-yl)ethoxy]-benzo[g]quinoline-3-carbonitrile as a yellow solid, mp 184-186° C.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH3:11])=[N:9][N:10]=2)[N:7]=1.[CH3:12][NH:13][C@@H:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH3:15]>CN1C(=O)CCC1>[CH3:12][N:13]([C@@H:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH3:15])[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH3:11])=[N:9][N:10]=2)[N:7]=1
Reactant: Cc1nnc2ccc(Cl)nn12
Reactant: CN[C@H](C)c1ccccc1
Solvent: CN1CCCC1=O
Product: Cc1nnc2ccc(N(C)[C@H](C)c3ccccc3)nn12
Temperature: 200 °C

Procedure:
6-Chloro-3-methyl-[1,2,4]triazolo[4,3-b]pyridazine (150 mg, 0.890 mmol; commercially available or prepared according to patent WO2006/039325A2), (R)-N-methyl-1-phenylethanamine (481 mg, 3.56 mmol; available from Aldrich) and anhydrous NMP (1 mL) were charged into a microwave tube equipped with a magnetic stirbar. After the vessel was sealed, the mixture was heated at 200° C. for 60 min using microwave irradiation. The reaction was purified by normal phase (gradient of 0% to 20% MeOH in CH2Cl2 as eluent) and by reverse phase chromatography before being lyophilized to give the (R)-N,3-dimethyl-N-(1-phenylethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-amine (Compound 3) as an off-white solid (115 mg; 48% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.01 (d, J=10.1 Hz, 1H), 7.23-7.41 (m, 6H), 5.71 (q, J=6.8 Hz, 1H), 2.83 (s, 3H), 2.54 (s, 3H), 1.58 (d, J=7.1 Hz, 3H). LRMS [M+H]+: 268 m/z.