Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[CH:14]=[C:13]([NH:15][CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)[N:12]3[N:22]=[CH:23][C:24]([CH:25]=[C:26]4[NH:30][C:29](=[O:31])[NH:28][C:27]4=[O:32])=[C:11]3[N:10]=2)[CH:5]=[CH:6][CH:7]=1.Cl[CH2:34][CH:35]([OH:37])[CH3:36].[I-].[K+]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[CH:14]=[C:13]([NH:15][CH:16]3[CH2:21][CH2:20][N:19]([CH2:34][CH:35]([OH:37])[CH3:36])[CH2:18][CH2:17]3)[N:12]3[N:22]=[CH:23][C:24]([CH:25]=[C:26]4[NH:30][C:29](=[O:31])[NH:28][C:27]4=[O:32])=[C:11]3[N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(O)CCl
Reactant: O=C1NC(=O)C(=Cc2cnn3c(NC4CCNCC4)cc(Nc4cccc(Cl)c4)nc23)N1
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(O)CN1CCC(Nc2cc(Nc3cccc(Cl)c3)nc3c(C=C4NC(=O)NC4=O)cnn23)CC1
Temperature: 120 °C
Reaction time: 8 h

Procedure:
To 5-((5-(3-chlorophenylamino)-7-(piperidin-4-ylamino)pyrazolo[1,5-a]pyrimidin-3-yl)methylene)imidazolidine-2,4-dione (30 mg, 0.066 mmol) in DMF was added 1-chloro2-propanol (7 μL, 0.13 mmol) and potassium iodide (11.0 mg, 0.066 mmol). The mixture was heated to 120° C. and stirred for overnight. The reaction mixture was concentrated, diluted with MeOH, and purified by prep HPLC to yield 5-((5-(3-chlorophenylamino)-7-(1-(2-hydroxypropyl)piperidin-4-ylamino)pyrazolo[1,5-a]pyrimidin-3-yl)methylene)imidazolidine-2,4-dione. LCMS (M+1=511)
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=2)[C:5]2[S:10](=[O:11])[CH2:9][CH2:8][C:6]=2[N:7]=1.[N:20]1([C:26]2[CH:36]=[CH:35][C:29]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:28][CH:27]=2)[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.C(N(C(C)C)CC)(C)C.O>O1CCOCC1>[Cl:19][C:15]1[CH:14]=[C:13]([NH:12][C:4]2[C:5]3[S:10](=[O:11])[CH2:9][CH2:8][C:6]=3[N:7]=[C:2]([N:23]3[CH2:22][CH2:21][N:20]([C:26]4[CH:27]=[CH:28][C:29]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:35][CH:36]=4)[CH2:25][CH2:24]3)[N:3]=2)[CH:18]=[CH:17][CH:16]=1
Reactant: CCOC(=O)c1ccc(N2CCNCC2)cc1
Reactant: O=S1CCc2nc(Cl)nc(Nc3cccc(Cl)c3)c21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CCOC(=O)c1ccc(N2CCN(c3nc4c(c(Nc5cccc(Cl)c5)n3)S(=O)CC4)CC2)cc1
Temperature: 160 °C
Yield: 77.8 %

Procedure:
5.44 g (2-chloro-5-oxo-6,7-dihydro-5H-5λ4-thieno[3,2-d]pyrimidin-4-yl)-(3-chloro-phenyl)-amine (prepared from 2,4-dichloro-6,7-dihydro-thieno[3,2-d]pyrimidine and 3-chloroaniline as described in Example 28, see scheme 2), 8.00 g ethyl 4-piperazin-1-yl-benzoate and 4.80 ml diisopropylethylamine are placed in 54 ml dioxane, then heated to 160° C. in the microwave for 0.7 hours. Then the reaction mixture is cooled and mixed with water. The precipitate formed is suction filtered and stirred with petroleum ether/ethyl acetate 1:1, suction filtered and dried. 6.90 g of the product are obtained as a powder.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[C:7]([O:11][C:12]([N:14]1[CH2:19][CH2:18][CH:17]([C:20](=[O:25])N(OC)C)[CH2:16][CH2:15]1)=[O:13])([CH3:10])([CH3:9])[CH3:8].OS([O-])(=O)=O.[K+]>C1COCC1>[C:7]([O:11][C:12]([N:14]1[CH2:19][CH2:18][CH:17]([CH:20]=[O:25])[CH2:16][CH2:15]1)=[O:13])([CH3:10])([CH3:9])[CH3:8]
Reactant: CON(C)C(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: O=S(=O)([O-])O
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 108 %

Procedure:
A solution of 5.46 g (143.8 mmol) of LAH in 600 ml THF was cooled (−50° C.) and treated during 25 min with a solution of 35.6 g (130.7 mmol) of 4-(Methoxy-methyl-carbamoyl)-piperidine-1-carboxylic acid tert-butyl ester in 600 ml THF. The reaction was warmed up to RT for 3.5 h, cooled (−78° C.) and hydrolyzed with a suspension of 35 g MgSO4.7H2O, 35 g silicagel in 130 ml aqueous 10% KHSO4. The cooling bath was removed, THF was added, the mixture was stirred for 30 min and filtered. After evaporation, the residue was dissolved in CH2Cl2, dried (Na2SO4) and evaporated to give 30.1 g (quantitative) of 4-Formyl-piperidine-1-carboxylic acid tert-butyl ester, MS: 213 (M).
Reaction SMILES: [CH2:1]([O:3][CH2:4][N:5]1[C:13]2[C:12](=[O:14])[NH:11][C:10](=[O:15])[N:9]([CH3:16])[C:8]=2[N:7]=[CH:6]1)[CH3:2].Br[CH2:18][CH2:19][CH2:20][P:21]([O:26][CH2:27][CH3:28])(=[O:25])[O:22][CH2:23][CH3:24]>>[CH2:1]([O:3][CH2:4][N:5]1[C:13]2[C:12](=[O:14])[N:11]([CH2:18][CH2:19][CH2:20][P:21](=[O:25])([O:26][CH2:27][CH3:28])[O:22][CH2:23][CH3:24])[C:10](=[O:15])[N:9]([CH3:16])[C:8]=2[N:7]=[CH:6]1)[CH3:2]
Reactant: CCOP(=O)(CCCBr)OCC
Reactant: CCOCn1cnc2c1c(=O)[nH]c(=O)n2C
Product: CCOCn1cnc2c1c(=O)n(CCCP(=O)(OCC)OCC)c(=O)n2C

Procedure:
The title substance was prepared from 0.048 mol of 7-ethoxymethyl-3-methylxanthine and 0.058 mol of diethyl 3-bromopropanephosphonate analogously to Example 32 and chromatographed on silica gel (eluent: ethyl acetate/methanol 10:1).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]([CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20])[CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].C(OC1C=CC(N(CC=C(C)C)C2CCNCC2)=CC=1)C1C=CC=CC=1.[CH3:48][C:49]([CH3:54])([CH3:53])[CH2:50][CH:51]=O>>[CH3:48][C:49]([CH3:54])([CH3:53])[CH2:50][CH2:51][N:14]1[CH2:15][CH2:16][CH:11]([N:10]([C:7]2[CH:6]=[CH:5][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:9][CH:8]=2)[CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20])[CH2:12][CH2:13]1
Reactant: CC(C)=CCN(c1ccc(C(C)C)cc1)C1CCNCC1
Reactant: CC(C)(C)CC=O
Agent: CC(C)=CCN(c1ccc(OCc2ccccc2)cc1)C1CCNCC1
Product: CC(C)=CCN(c1ccc(C(C)C)cc1)C1CCN(CCC(C)(C)C)CC1

Procedure:
The preparation of Example 26: [1-(3,3-Dimethyl-butyl)-piperidin-4-yl]-(4-isopropyl-phenyl)-(3-methyl-but-2-enyl)-amine was prepared in accordance with the methods of Step 4 in Example 1, except that (4-Isopropyl-phenyl)-(3-methyl-but-2-enyl)-piperidin4-yl-amine (26c) was used instead of (4-Benzyloxy-phenyl-(3-methyl-but-2-enyl)-piperidin-4-yl-amine (Ic) and 3,3-dimethylbutyraldehyde was used instead of isovaleraldehyde.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[CH:12][C:11]([C:14]([OH:16])=O)=[CH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.C(Cl)(=O)C(Cl)=O.[NH2:23][N:24]1[CH2:29][CH2:28][N:27]([CH2:30][CH2:31][OH:32])[CH2:26][CH2:25]1.CN1C(=O)CCC1>C(Cl)Cl.CN(C=O)C>[OH:32][CH2:31][CH2:30][N:27]1[CH2:28][CH2:29][N:24]([NH:23][C:14]([C:11]2[CH:12]=[N:13][C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)=[N:9][CH:10]=2)=[O:16])[CH2:25][CH2:26]1
Reactant: NN1CCN(CCO)CC1
Reactant: O=C(O)c1cnc(-c2cccc(F)c2)nc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CN1CCCC1=O
Solvent: ClCCl
Product: O=C(NN1CCN(CCO)CC1)c1cnc(-c2cccc(F)c2)nc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 46.3 %

Procedure:
To a solution of 2-(3-fluoro-phenyl)-pyrimidine-5-carboxylic acid (0.28 g, 1.4 mmol) in anhydrous DCM (10 mL) at 0° C. is added the oxalyl chloride (0.18 mL, 1.4 mmol) followed by the addition of DMF (0.11 mL). The mixture is stirred at 0° C. for 30 min, and then allowed to warm up to rt and stirred for 30 min. The mixture is concentrated in vacuo. The residue is dissolved in anhydrous DCM (10 mL). 2-(4-Amino-piperazin-1-yl)-ethanol (0.145 g, 1 mmol) is added at rt followed by the addition of NMP (0.19 mL, 2 mmol). The mixture is stirred at rt for 2 h and the mixture is then concentrated in vacuo. The residue is triturated in Et2O and the resulting solid is collected by filtration to afford 2-(3-fluoro-phenyl)-pyrimidine-5-carboxylic acid-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-amide (0.16 g). MS: 346 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10]([C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)=O)=[CH:4][CH:3]=1.O.[NH2:18][NH2:19]>C(O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[NH:19][NH:18][C:10]([C:12]3[S:13][CH:14]=[CH:15][CH:16]=3)=[CH:9]2)=[CH:4][CH:3]=1
Reactant: O=C(C=Cc1ccc(F)cc1)c1cccs1
Reactant: NN
Solvent: CCO
Solvent: O
Product: Fc1ccc(C2C=C(c3cccs3)NN2)cc1
Temperature: 25 °C
Yield: 97 %

Procedure:
3-(4-Fluorophenyl)-1-(2-thienyl)-2-propen-1-one (3.5 g, 15 mM) and hydrazine hydrate (1.5 g, 30 mM) were added to ethanol (30 ml) and heated under reflux for 3 hours. After the mixture was allowed to cool to room temperature, the solvent was distilled off to obtain 3.6 g (98%) of the desired 5-(4-fluorophenyl)-3-(2-thienyl)-pyrazoline in the form of a pale-yellow oil, nD20=1.6364.
Reaction SMILES: [SH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[C:7](=[O:13])[CH2:6][CH2:5]2.Cl[C:15]1[S:16][C:17]([C@@:20]2([O:27][CH3:28])[CH2:25][CH2:24][O:23][C@@H:22]([CH3:26])[CH2:21]2)=[CH:18][N:19]=1>>[CH3:28][O:27][C@:20]1([C:17]2[S:16][C:15]([S:1][C:2]3[CH:3]=[C:4]4[C:9](=[CH:10][CH:11]=3)[N:8]([CH3:12])[C:7](=[O:13])[CH2:6][CH2:5]4)=[N:19][CH:18]=2)[CH2:25][CH2:24][O:23][C@@H:22]([CH3:26])[CH2:21]1
Reactant: CN1C(=O)CCc2cc(S)ccc21
Reactant: CO[C@]1(c2cnc(Cl)s2)CCO[C@@H](C)C1
Product: CO[C@]1(c2cnc(Sc3ccc4c(c3)CCC(=O)N4C)s2)CCO[C@@H](C)C1

Procedure:
Using an analogous procedure to that described in Example 1, 6-mercapto-1-methyl-1,2,3,4-tetrahydroquinolin-2-one was reacted with (2S,4R)-4-(2-chlorothiazol-5-yl)-4-methoxy-2-methyltetrahydropyran to give (2S,4R)-4-methoxy-2-methyl-4-[2-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-ylthio)thiazol-5-yl]tetrahydropyran in 95Z yield as a foam;
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH2:5][NH2:6].[Br:12][C:13]1[CH:24]=[C:17]2[C:18](OC(=O)[NH:22][C:16]2=[CH:15][CH:14]=1)=[O:19].O.C(OCC)(=O)C>CN(C)C=O>[NH2:22][C:16]1[CH:15]=[CH:14][C:13]([Br:12])=[CH:24][C:17]=1[C:18]([NH:6][CH2:5][C:4]1[CH:7]=[CH:8][C:9]([O:10][CH3:11])=[C:2]([Cl:1])[CH:3]=1)=[O:19]
Reactant: COc1ccc(CN)cc1Cl
Reactant: O=c1[nH]c2ccc(Br)cc2c(=O)o1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccc(CNC(=O)c2cc(Br)ccc2N)cc1Cl
Temperature: 25 °C
Yield: 53.5 %

Procedure:
A solution of 3-chloro-4-methoxybenzylamine (234 mg) in N,N-dimethylformamide (5 mL) was added dropwise to a solution of 5-bromoisatoic anhydride (300 mg) in N,N-dimethylformamide (3 mL). The reaction mixture was stirred for an hour at ambient temperature. The mixture was poured into a mixture of water and ethyl acetate. The precipitates were collected by filtration and washed with 2-propanol to give 2-amino-5-bromo-N-(3-chloro-4-methoxybenyl)benzamide (245 mg) as white powders.
Reaction SMILES: N1C=CC=CC=1.[CH3:7][C:8]1[C:13]([OH:14])=[C:12]([CH:15]([OH:17])[CH3:16])[C:11]([CH:18]=[CH2:19])=[CH:10][N:9]=1>[O-2].[O-2].[O-2].[Cr+6].C(Cl)Cl>[CH3:7][C:8]1[C:13]([OH:14])=[C:12]([C:15](=[O:17])[CH3:16])[C:11]([CH:18]=[CH2:19])=[CH:10][N:9]=1
Reactant: C=Cc1cnc(C)c(O)c1C(C)O
Agent: [Cr+6]
Agent: [O-2]
Solvent: ClCCl
Solvent: c1ccncc1
Product: C=Cc1cnc(C)c(O)c1C(C)=O
Reaction time: 0.33 h

Procedure:
To 750 ml. of dry methylene chloride containing 47.5 ml. of dry pyridine was added with stirring and cooling 29.6 g. of chromium trioxide. The mixture was aged 20 minutes at room temperature and then treated with a solution of 10.96 g. of the product from Example 10, Step B, in 250 ml. of dry methylene chloride over 15 minutes. After one hour at room temperature, the reaction mixture was filtered and the residue was washed with 2 × 100 ml. of methylene chloride. The methylene chloride filtrates were extracted with 3 × 500 ml. of 5% (w/w) aqueous sodium hydroxide solution, dried over magnesium sulfate and evaporated to dryness. The residue was crystallized from hexane to give 2-methyl-3-hydroxy-4-acetyl-5-vinylpyridine.
Reaction SMILES: [CH3:1][CH:2]([C@H:4]([NH:8][C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])[C:5]([OH:7])=O)[CH3:3].[C:19]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])(=[O:21])[CH3:20].[Li+].CC([N-]C(C)C)C.[N-]1C=CN=C1>O1CCCC1>[C:23]([O:22][C:19](=[O:21])[CH2:20][C:5](=[O:7])[C@@H:4]([NH:8][C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])[CH:2]([CH3:1])[CH3:3])([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: CC(=O)OC(C)(C)C
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: c1c[n-]cn1
Solvent: C1CCOC1
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)CC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 98.9 %

Procedure:
To an ice-cooled solution of Z-Valine (5 g, 19.9 mmol) in 60 ml tetrahydrofuran was added N,N'-carbonyldiimidazole (3.55 g, 22.3 mmol) in one portion and the resulting mixture stirred for 3 h. t-Butyl acetate (13.5 ml, 100 mmol) was added dropwise to a solution of LDA (90 mmol in tetrahydrofuran (270 ml) at -78° C. After 30 min, the imidazolide solution was added dropwise via double-ended needle to the enolate. The resulting mixture was stirred for 2 h until the temperature rose to -15° C. The reaction was quenched with 400 ml saturated aqueous NH4Cl and extracted with ether (3×200 ml). The combined organic extracts were washed with 2N aqueous HCl (50 ml), saturated aqueous NaHCO3 (2×50 ml), dried over magnesium sulfate and evaporated to dryness in vacuo. The residue was purified by column chromatography on silica gel using ethyl acetate-hexane (1:4) as an eluent to give the product as a colorless oil (6.88 g).
Reaction SMILES: [SH:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][C:9]([CH3:12])([CH3:11])[CH:8]=[CH:7][C:6]=2[CH:13]=1.[H-].[Na+].[F:16][C:17](I)([F:22])[C:18]([F:21])([F:20])[F:19].Cl>CN(C)C=O>[CH3:12][C:9]1([CH3:11])[CH:8]=[CH:7][C:6]2[CH:13]=[C:2]([S:1][C:17]([F:22])([F:16])[C:18]([F:21])([F:20])[F:19])[CH:3]=[CH:4][C:5]=2[O:10]1
Reactant: CC1(C)C=Cc2cc(S)ccc2O1
Reactant: FC(F)(F)C(F)(F)I
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C)C=Cc2cc(SC(F)(F)C(F)(F)F)ccc2O1
Reaction time: 0.25 h
Yield: 82 %

Procedure:
A solution of 1.463 g of 6-mercapto-2,2-dimethyl-2H-1-benzopyran (prepared as described in Preparation 6) in 15 ml of dimethylformamide was added dropwise, whilst ice-cooling, to a suspension of 0.366 g of sodium hydride (as a 55% w/w dispersion in mineral oil) in 15 ml of dimethylformamide under an atmosphere of nitrogen. After the reaction mixture had been stirred for 15 minutes, 5.53 g of perfluoroethyl iodide were added to it. The reaction mixture was then stirred whilst ice-cooling for 1 hour and then at room temperature for 2 hours. At the end of this time, the reaction mixture was poured into 150 ml of dilute aqueous hydrochloric acid and extracted with ethyl acetate. The extract was washed with water, with an aqueous solution of sodium hydrogencarbonate and with a saturated aqueous solution of sodium chloride, in that order, after which it was dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, and the resulting residue was purified by column chromatography through silica gel, using a 20:1 by volume mixture of cyclohexane and ethyl acetate as the eluent, to afford 1.935 g of the title compound as an oil.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([Cl:26])[CH:19]=1)=[CH:13][C:12]([C:27]#[N:28])=[CH:11][C:10]=2[CH2:29][CH3:30])=O)C.C(O[AlH-](OC(C)(C)C)OC(C)(C)C)(C)(C)C.[Li+].C1COCC1>C1COCC1>[Cl:26][C:20]1[CH:19]=[C:18]([CH2:17][NH:16][C:15]2[C:14]3[C:9](=[C:10]([CH2:29][CH3:30])[CH:11]=[C:12]([C:27]#[N:28])[CH:13]=3)[N:8]=[CH:7][C:6]=2[CH2:4][OH:3])[CH:23]=[CH:22][C:21]=1[O:24][CH3:25]
Reactant: CCOC(=O)c1cnc2c(CC)cc(C#N)cc2c1NCc1ccc(OC)c(Cl)c1
Agent: CC(C)(C)O[AlH-](OC(C)(C)C)OC(C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCc1cc(C#N)cc2c(NCc3ccc(OC)c(Cl)c3)c(CO)cnc12
Yield: 83.2 %

Procedure:
To a suspension of 100 mg (0.236 mmol) of 4-[[(3-chloro-4-methoxyphenyl)methyl]amino]-6-cyano-8-ethylquinoline-3-carboxylic acid ethyl ester in 2.8 mL anhydrous THF under nitrogen, was added 1.2 mL (5.0 eq) of 1M lithium tri-t-butoxyaluminohydride/THF. The resulting mixture was refluxed overnight with stirring. The reaction was quenched with 1 mL of MeOH and partitioned between 75 mL 1M NaOH and 100 mL CH2Cl2. The organic phase was washed with 1M NaOH (2×30 mL) and dried over MgSO4. Removal of the solvent under reduced pressure gave 75 mg (84% yield) of the title compound as a light yellow solid. The analytical sample was obtained by trituration in ether: mp: 188–189° C. LC: 3.15′; MH+: 382.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([CH3:19])[C:9]([N:11]1[CH2:16][CH2:15][S:14](=[O:18])(=[O:17])[CH2:13][CH2:12]1)=[O:10])(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:7][CH:8]([CH3:19])[C:9]([N:11]1[CH2:16][CH2:15][S:14](=[O:18])(=[O:17])[CH2:13][CH2:12]1)=[O:10]
Reactant: CC(NC(=O)OC(C)(C)C)C(=O)N1CCS(=O)(=O)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(N)C(=O)N1CCS(=O)(=O)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 159.8 %

Procedure:
To a solution of [2-(1,1-Dioxo-1lambda*6*-thiomorpholin-4-yl)-1-methyl-2-oxo-ethyl]-carbamic acid tert-butyl ester (5.6 g, 18.2 mmol) in CH2Cl2 (70 mL) was added trifluoroacetic acid (5 mL) at 0° C. The reaction mixture was allowed to warm to room temperature and was stirred for 3 hours. After removal of CH2Cl2 and excess trifluoroacetic acid under reduced pressure, 2-Amino-1-(1,1-dioxo-1lambda*6*-thiomorpholin-4-yl)-propan-1-one (6.0 g, yield 100%) was obtained as a white solid. MS (M+H)=207.
Reaction SMILES: COC1C=C2C(=CC=1)C=C(B(O)O)C=C2.FC(F)(F)S(OC1C=C(F)C=CC=1[N+]([O-])=O)(=O)=O.[F:34][C:35]1[CH:36]=[CH:37][C:38]([N+:53]([O-])=O)=[C:39]([CH:41]2[CH2:50][CH2:49][C:48]3[C:43](=[CH:44][CH:45]=[C:46]([O:51][CH3:52])[CH:47]=3)[CH2:42]2)[CH:40]=1>>[F:34][C:35]1[CH:36]=[CH:37][C:38]([NH2:53])=[C:39]([C:41]2[CH:50]=[CH:49][C:48]3[C:43](=[CH:44][CH:45]=[C:46]([O:51][CH3:52])[CH:47]=3)[CH:42]=2)[CH:40]=1
Reactant: COc1ccc2c(c1)CCC(c1cc(F)ccc1[N+](=O)[O-])C2
Agent: COc1ccc2cc(B(O)O)ccc2c1
Agent: O=[N+]([O-])c1ccc(F)cc1OS(=O)(=O)C(F)(F)F
Product: COc1ccc2cc(-c3cc(F)ccc3N)ccc2c1
Yield: 95.4 %

Procedure:
Synthesized from (6-methoxynaphthalen-2-yl)boronic acid and 5-fluoro-2-nitrophenyl trifluoromethanesulfonate according to an analogous synthetic method to Example 24, 2-(5-fluoro-2-nitrophenyl)-6-methoxy-1,2,3,4-tetrahydronaphthalene (1.3 g) was used according to an analogous synthetic method to Example 22 to provide the title compound (1.1 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]([C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[NH:22][C:21]([C:26]([OH:28])=O)=[CH:20]3)=[O:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[F:30][C:31]1([F:37])[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1.Cl.C(N=C=NCCCN(C)C)C>C(N(CC)CC)C>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]([C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[NH:22][C:21]([C:26]([N:34]2[CH2:35][CH2:36][C:31]([F:37])([F:30])[CH2:32][CH2:33]2)=[O:28])=[CH:20]3)=[O:16])[CH2:10][CH2:9]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCCN(C(=O)c2ccc3[nH]c(C(=O)O)cc3c2)CC1
Reactant: FC1(F)CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCCN(C(=O)c2ccc3[nH]c(C(=O)N4CCC(F)(F)CC4)cc3c2)CC1

Procedure:
The title compound was synthesized in analogy to Example 1, from 5-(4-tert-butoxycarbonyl-[1,4]diazepane-1-carbonyl)-1H-indole-2-carboxylic acid, 4,4-difluoropiperidine hydrochloride, triethylamine and 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride, to afford the product as a yellow solid (87%).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]([CH3:25])[C:9](=[O:24])[C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=1.[O:26]1[CH2:31][CH:30]=[C:29](OS(C(F)(F)F)(=O)=O)[CH2:28][CH2:27]1>>[O:26]1[CH2:27][CH:28]=[C:29]([C:2]2[CH:7]=[CH:6][N:5]=[CH:4][C:3]=2[N:8]([CH3:25])[C:9](=[O:24])[C:10]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=2)[CH2:30][CH2:31]1
Reactant: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnccc1I
Reactant: O=S(=O)(OC1=CCOCC1)C(F)(F)F
Product: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnccc1C1=CCOCC1

Procedure:
The title compound was prepared in analogy to example 73, from N-(4-iodo-pyridin-3-yl)-N-methyl-3,5-bis-trifluoromethyl-benzamide (example 98, intermediate a) and trifluoro-methanesulfonic acid 3,6-dihydro-2H-pyran-4-yl ester (CAS RN 188975-30-6). The compound was purified by silica gel chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of n-heptane:EtOAc (100:0 to 40:60). Colorless solid (56%). MS (ESI): m/z=431.177 [M+H]+.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][NH2:10])=[CH:5][CH:4]=1.Br[C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:14][CH:13]=1.CC([O-])(C)C.[Na+].C(NC(C)C)(C)C>CC([O-])=O.CC([O-])=O.[Pd+2].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>[F:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]([C:21]2[CH:22]=[CH:23][C:18]([C:15]3[CH:16]=[CH:17][CH:12]=[CH:13][CH:14]=3)=[CH:19][CH:20]=2)[NH2:10])=[CH:5][CH:4]=1
Reactant: Brc1ccc(-c2ccccc2)cc1
Reactant: NNc1ccc(F)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: CC(C)NC(C)C
Product: NN(c1ccc(F)cc1)c1ccc(-c2ccccc2)cc1
Temperature: 50 °C
Yield: 78 %

Procedure:
4-Fluorophenylhydrazine hydrochloride (1.2 equiv., 0.6 mmol, 98 mg), 4-bromobiphenyl (1.0 equiv., 0.5 mmol, 117 mg), Pd(OAc)2 (0.05 equiv., 0.025 mmol, 6 mg), BINAP (0.05 equiv., 0.025 mmol, 16 mg), NaOtBu (1.4 equiv., 0.7 mmol, 67 mg) and diisopropylamine (2 mL) were added to an oven dried test tube which was capped with a septum and purged briefly with argon (a 1 min.), and then heated to 50° C. under argon for 7 hours. The reaction was then cooled to room temperature, diluted with Et2O (2 mL), filtered through Celite and concentrated under vacuum. The crude mixture was purified by flash column chromatography (10% EtOAc/Hex) to give the title product as a white solid (110 mg, 0.39 mmol, 79% yield).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[C:11]([NH:15][C:16]3[N:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][N:17]=3)[CH:12]=[CH:13][CH:14]=2)O1.Br[C:28]1[S:32][CH:31]=[N:30][CH:29]=1.C(=O)([O-])[O-].[Na+].[Na+]>O.CCOC(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[S:32]1[C:28]([C:9]2[CH:10]=[C:11]([NH:15][C:16]3[N:21]=[C:20]([C:22]([F:23])([F:24])[F:25])[CH:19]=[CH:18][N:17]=3)[CH:12]=[CH:13][CH:14]=2)=[CH:29][N:30]=[CH:31]1
Reactant: Brc1cncs1
Reactant: CC1(C)OB(c2cccc(Nc3nccc(C(F)(F)F)n3)c2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CCOC(C)=O
Product: FC(F)(F)c1ccnc(Nc2cccc(-c3cncs3)c2)n1
Temperature: 80 °C
Yield: 73.7 %

Procedure:
Pd(dppf)Cl2 (1.01 g, 1.23 mmol) and Intermediate 6 (9.0 g, 25 mmol) were combined in a flask and were evacuated and back-filled with nitrogen (×3). Added 2-Me THF (90 mL), 5-bromothiazole (4.45 g, 27.1 mmol), and aqueous sodium carbonate (24.7 mL, 49.3 mmol) sequentially. Sealed the flask and heated to 80° C. for 15 h. The brown solution was allowed to cool to rt, then diluted with water and EtOAc. The layers were separated, and the aqueous portion was extracted with EtOAc (2×). The combined organic portions were washed with saturated aqueous NaHCO3, then Brine, then dried over Na2SO4 and concentrated in vacuo. Trituration with CH2Cl2 and collection of the beige solid via filtration provided 5.94 g of the desired product. The mother liquor was concentrated in vacuo and subsequent purification via silica gel column chromatography (CH2Cl2-40% EtOAc:CH2Cl2) provided an additional 1.41 g of the desired product. In total, N-[3-(1,3-thiazol-5-yl)phenyl]-4-(trifluoromethyl)pyrimidin-2-amine (7.35 g, 22.8 mmol, 93%) was isolated as a beige solid. MS APCI: [M+H]+ m/z 323. 1H NMR (600 MHz, DMSO-D6, ppm) δ 10.32 (s, 1H), 9.06 (s, 1H), 8.82 (d, J=4.8, 1H), 8.20 (d, J=8.2, 1H), 8.20 (s, 1H), 7.64 (d, J=7.5, 1H), 7.40-7.31 (m, 2H), 7.27 (d, J=4.9, 1 H). rhSYK activity=++.