Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=[C:2]1[C:9]2[CH:8]=[C:7]([C:10]([O:12][CH3:13])=[O:11])[NH:6][C:5]=2[CH2:4][CH2:3]1.[C:14]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:19]=[CH:18][C:17]([Mg]Br)=[CH:16][CH:15]=1>>[C:14]1([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:19]=[CH:18][C:17]([CH:2]2[C:9]3[CH:8]=[C:7]([C:10]([O:12][CH3:13])=[O:11])[NH:6][C:5]=3[CH2:4][CH2:3]2)=[CH:16][CH:15]=1
Reactant: Br[Mg]c1ccc(-c2ccccc2)cc1
Reactant: COC(=O)c1cc2c([nH]1)CCC2=O
Product: COC(=O)c1cc2c([nH]1)CCC2c1ccc(-c2ccccc2)cc1

Procedure:
The title compound was synthesized in two steps. First, methyl 4-oxo-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate (300 mg, 1.67 mmol) and biphenyl-4-ylmagnesium bromide (13.4 mL, 6.70 mmol; 0.5 M in THF) were reacted according to General Procedure 3 to give the endo olefin-containing compound methyl 4-(biphenyl-4-yl)-1,6-dihydrocyclopenta[b]pyrrole-2-carboxylate, which was then hydrogenated according to General Procedure 6 (with 10% Pd/C), and was purified column chromatography (Isco CombiFlash) eluting with a gradient of 0-40% EtOAc/heptane to afford the title compound. 430 mg. 1H NMR (400 MHz, ACETONE-d6) δ ppm 2.23-2.33 (m, 1H), 2.74-2.84 (m, 1H), 2.85-3.01 (m, 2H), 3.75 (s, 3H), 4.26 (t, J=7.20 Hz, 1H), 6.55 (d, J=1.76 Hz, 1H), 7.29-7.36 (m, 3H), 7.41-7.47 (m, 2H), 7.55-7.60 (m, 2H), 7.62-7.66 (m, 2H), 10.66 (s, 1H); LCMS-MS (ESI+) 340.2 (M+Na).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][CH:16]=1)[NH:6][C:7]1[S:8][CH:9]=[C:10]([CH:12]=O)[N:11]=1.[S:19]1[CH2:25][C:23](=[O:24])[N:22]([CH2:26][C:27]([OH:29])=[O:28])[C:20]1=[S:21].[Cl-].[NH4+].N>C(O)C>[F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][CH:16]=1)[NH:6][C:7]1[S:8][CH:9]=[C:10]([CH:12]=[C:25]2[S:19][C:20](=[S:21])[N:22]([CH2:26][C:27]([OH:29])=[O:28])[C:23]2=[O:24])[N:11]=1
Reactant: O=C(O)CN1C(=O)CSC1=S
Reactant: O=Cc1csc(Nc2cccc(C(F)(F)F)c2)n1
Agent: N
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: O=C(O)CN1C(=O)C(=Cc2csc(Nc3cccc(C(F)(F)F)c3)n2)SC1=S

Procedure:
The reaction described in Example 1 was repeated, but using 1 g of 2-(m-trifluoromethylanilino)thiazole-4-carbaldehyde, 0.7 g of rhodanine-3-acetic acid, 0.5 g of ammonium chloride, 0.5 ml of 28% v/v aqueous ammonia, and 10 ml of ethanol, giving the title compound as yellowish-orange prisms.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[NH:12][C:11](=[O:13])[C:10]([CH3:14])=[N:9]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[C:22]1[CH:27]=[CH:26][N:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=1>CN(C)C=O.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[N:12]=[C:11]([O:13][C:22]3[CH:27]=[CH:26][N:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=3)[C:10]([CH3:14])=[N:9]2)=[CH:6][CH:7]=1
Reactant: FC(F)(F)c1cc(Cl)ccn1
Reactant: Cc1nn(-c2ccc(F)cc2)[nH]c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nn(-c2ccc(F)cc2)nc1Oc1ccnc(C(F)(F)F)c1
Temperature: 100 °C

Procedure:
To a solution of 2-(4-fluorophenyl)-2,3-dihydro-5-methyl-4H-1,2,3-triazol-4-one (i.e. the product of Step C, 3.1 g, 16 mmol) in N,N-dimethylformamide (70 mL) was added anhydrous potassium carbonate (6.2 g, 45 mmol) under an atmosphere of nitrogen. 4-Chloro-2-trifluoromethyl-pyridine (2.9 g, 16 mmol) was added and the mixture was heated to 100° C. for 20 h. The reaction mixture was diluted with water, then extracted with diethyl ether. The organic layer was washed successively with water and saturated aqueous sodium chloride solution, dried (MgSO4), filtered, and concentrated under reduced pressure. The crude material was purified by chromatography on silica gel eluting with 0 to 20% ethyl acetate in hexanes to obtain the title compound (4.2 g) as a viscous light yellow oil that solidified upon standing to form an off-white solid.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][CH2:8][CH3:9])[CH:2]1[O:4][CH2:3]1.[SH-:10].[Na+].[NH4+].[Cl-]>C(O)(C)C.O>[S:10]([CH2:3][CH:2]([OH:4])[CH2:1][O:5][CH2:6][CH2:7][CH2:8][CH3:9])[CH2:3][CH:2]([OH:4])[CH2:1][O:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: [SH-]
Reactant: CCCCOCC1CO1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Product: CCCCOCC(O)CSCC(O)COCCCC
Temperature: 90 °C
Reaction time: 3 h

Procedure:
A solution of butyl glycidyl ether (2.91 g, 22.39 mmol) in isopropanol (5 mL) and H2O (1 mL) was added to sodium bisulfide (0.628 g, 11.20 mmol) under nitrogen in a 100 mL 3-neck round bottom flask equipped with a N2 inlet, a rubber septum, glass stopper and a magnetic stir bar. The mixture was heated at 90° C. and monitored for completion by gas chromatography/mass spectrometry for disappearance of starting materials and formation of the product. After 3 h, the reaction was judged to be complete. The mixture was cooled to ambient temperature and treated with saturated NH4Cl (5.0 mL) and extracted into ethyl acetate (50 mL). The solvent was dried (MgSO4), filtered, and evaporated in-vacuo to give the product, 1,1′-thiobis(3-butoxypropan-2-ol), which was identified by mass spectrometry as well as 1H and 13C NMR.
Reaction SMILES: [CH3:1][N:2]1[C:7]2[C:8](C)=[CH:9][NH:10][C:6]=2[C:5](=[O:12])[N:4]([CH3:13])[C:3]1=[O:14].Br[CH2:16][C:17]([NH:19][C:20]1[S:21][CH:22]=[C:23]([C:25]2[CH:30]=[C:29]([Cl:31])[C:28]([O:32][CH2:33][CH2:34][C:35]([F:41])([F:40])[C:36]([F:39])([F:38])[F:37])=[C:27]([Cl:42])[CH:26]=2)[N:24]=1)=[O:18].[H-].[Na+]>CN(C=O)C>[Cl:42][C:27]1[CH:26]=[C:25]([C:23]2[N:24]=[C:20]([NH:19][C:17](=[O:18])[CH2:16][N:10]3[C:6]4[C:5](=[O:12])[N:4]([CH3:13])[C:3](=[O:14])[N:2]([CH3:1])[C:7]=4[CH:8]=[CH:9]3)[S:21][CH:22]=2)[CH:30]=[C:29]([Cl:31])[C:28]=1[O:32][CH2:33][CH2:34][C:35]([F:41])([F:40])[C:36]([F:38])([F:39])[F:37]
Reactant: O=C(CBr)Nc1nc(-c2cc(Cl)c(OCCC(F)(F)C(F)(F)F)c(Cl)c2)cs1
Reactant: Cc1c[nH]c2c(=O)n(C)c(=O)n(C)c12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c(=O)c2c(ccn2CC(=O)Nc2nc(-c3cc(Cl)c(OCCC(F)(F)C(F)(F)F)c(Cl)c3)cs2)n(C)c1=O

Procedure:
The title compound was prepared according to the general procedure (Method A) by coupling Intermediate 1 (50 mg, 0.279 mmol) with 2-bromo-N-{4-[3,5-dichloro-4-(3,3,4,4,4-pentafluorobutoxy)phenyl]-1,3-thiazol-2-yl}acetamide (176 mg, 0.332 mmol) in the presence of NaH (16 mg, 0.666 mmol) in dry DMF (5.0 mL) to give 58 mg of the product as an off-white solid; 1H NMR (δ ppm, DMSO-d6, 300 MHz) 2.80-2.86 (m, 2H), 3.17 (s, 3H), 3.39 (s, 3H), 4.25-4.32 (m, 2H), 5.32 (s, 2H), 6.23 (s, 1H), 7.35 (s, 1H), 7.88 (s, 1H), 8.03 (s, 2H), 12.70 (br s, 1H); ESI-MS (m/z) 626.18 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][N:5]=[C:4]2[N:9]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[C:10]([C:12]3[CH:13]=[N:14][N:15]([CH3:17])[CH:16]=3)=[CH:11][C:3]=12.[Br:26][C:27]1[CH:28]=[N:29][NH:30][CH:31]=1.C(=O)([O-])[O-].[K+].[K+]>CN1CCCC1=O>[Br:26][C:27]1[CH:28]=[N:29][N:30]([C:2]2[C:7]([Cl:8])=[CH:6][N:5]=[C:4]3[N:9]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[C:10]([C:12]4[CH:13]=[N:14][N:15]([CH3:17])[CH:16]=4)=[CH:11][C:3]=23)[CH:31]=1
Reactant: Cn1cc(-c2cc3c(Cl)c(Cl)cnc3n2COCC[Si](C)(C)C)cn1
Reactant: Brc1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: Cn1cc(-c2cc3c(-n4cc(Br)cn4)c(Cl)cnc3n2COCC[Si](C)(C)C)cn1
Temperature: 150 °C

Procedure:
A solution of Example 113E (0.194 g, 0.488 mmol) and 4-bromo-1H-pyrazole (0.115 g, 0.781 mmol) in 1-methyl-2-pyrrolidinone (0.8 mL) was treated with potassium carbonate (0.169 g, 1.22 mmol), and the reaction was heated at 150° C. for 2.5 hours. The reaction was cooled to ambient temperature, and partitioned between water and ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by flash chromatography on a silica gel column, eluting with a gradient of 0% to 1% methanol in dichloromethane, to provide the title compound. MS ESI(+) m/z 509.0 [M+H]+.
Reaction SMILES: C([NH:5][S:6]([C:9]1[S:10][C:11]([C:14]2[CH:19]=[C:18]([C:20]3[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[C:22]([C:30]4[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][CH:31]=4)[N:21]=3)[CH:17]=[CH:16][N:15]=2)=[CH:12][CH:13]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>>[F:29][C:26]([F:27])([F:28])[C:24]1[CH:23]=[C:22]([C:30]2[CH:35]=[CH:34][C:33]([C:36]([F:38])([F:39])[F:37])=[CH:32][CH:31]=2)[N:21]=[C:20]([C:18]2[CH:17]=[CH:16][N:15]=[C:14]([C:11]3[S:10][C:9]([S:6]([NH2:5])(=[O:8])=[O:7])=[CH:13][CH:12]=3)[CH:19]=2)[CH:25]=1
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(-c2cc(-c3cc(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)n3)ccn2)s1
Solvent: O=C(O)C(F)(F)F
Product: NS(=O)(=O)c1ccc(-c2cc(-c3cc(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)n3)ccn2)s1
Temperature: 23 °C
Reaction time: 16 h
Yield: 59.7 %

Procedure:
To 5-[4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-[2,4′]bipyridinyl-2′-yl]-thiophene-2-sulfonic acid tert-butylamide (example 319) (0.180 g, 0.307 mmol) was added TFA (3 mL) and the reaction mixture was stirred at 23° C. for 16 h. The mixture was evaporated to dryness and partitioned between EtOAc and saturated NaHCO3 solution, the organic layer was dried over Na2SO4. Removal of the solvent in vacuum left a crude product which was triturated with diethyl ether to give the title compound as a white solid (0.097 g, 60%). MS (ISP) 530.2 [(M+H)+]; mp 97° C. (dec.).
Reaction SMILES: N[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[CH:4][CH:3]=1.N([O-])=[O:12].[Na+].C([O-])([O-])=O.[Na+].[Na+]>Cl.O>[OH:12][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: Nc1ccc2cn[nH]c2c1
Reactant: O=N[O-]
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: Oc1ccc2cn[nH]c2c1
Temperature: 2.5 °C
Reaction time: 0.75 h

Procedure:
To a stirred suspension of 6-aminoindazole (20 mmol) in concentrated HCl (6 mL) at 0° C. was added a solution of NaNO2 (22 mmol) in water (12 mL) in portions. During the addition, the temperature of the reaction mixture was maintained at 0-5° C., and the stirring continued for additional 45 min. The contents were then added into a flask containing 1% aqueous HCl (200 mL), and heated at 100° C. The reaction mixture was then stirred at 100° C. for 5 h. The contents were cooled to RT, neutralized to pH 7 using 5% aqueous Na2CO3, and extracted with EtOAc (2×70 mL). Combined organic layers were washed with brine and dried over anhydrous Na2SO4. Removal of solvent under vacuum provided 6-hydroxyindazole as dark brown solid, which was used for further transformation without any purification.
Reaction SMILES: [N:1]([C@@H:4]1[CH2:13][CH2:12]C[C:10]2[CH:9]=[C:8]([CH2:14][N:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)[CH:7]=[CH:6][C:5]1=2)=[N+:2]=[N-:3].N([C@H]1C2C(=CC(C=O)=CC=2)[O:27]CC1)=[N+]=[N-]>>[N:1]([C@H:4]1[C:5]2[C:10](=[CH:9][C:8]([CH2:14][N:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)=[CH:7][CH:6]=2)[O:27][CH2:12][CH2:13]1)=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=N[C@@H]1CCCc2cc(CN3CCCCC3)ccc21
Reactant: [N-]=[N+]=N[C@@H]1CCOc2cc(C=O)ccc21
Product: [N-]=[N+]=N[C@@H]1CCOc2cc(CN3CCCCC3)ccc21

Procedure:
Using the same procedure described for (20), and using (R)-4-azido-3,4-dihydro-2H-chromene-7-carbaldehyde afforded (R)-1-((4-Azido-3,4-dihydro-2H-chromen-7-yl)methyl)piperidine (26) MS m/z: 273.6 (M+H) (Calc'd for C15H20N4O−272.35); and
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:12]=[CH:11][C:7]([C:8](O)=[O:9])=[CH:6][C:5]=1[CH3:13].Cl.CN(C)CCCN=C=NCC.[CH3:27][Si:28]([CH2:31][NH2:32])([CH3:30])[CH3:29]>ClCCl>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:12]=[CH:11][C:7]([C:8]([NH:32][CH2:31][Si:28]([CH3:30])([CH3:29])[CH3:27])=[O:9])=[CH:6][C:5]=1[CH3:13]
Reactant: COC(=O)c1ccc(C(=O)O)cc1C
Reactant: C[Si](C)(C)CN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: COC(=O)c1ccc(C(=O)NC[Si](C)(C)C)cc1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-methyl-terephthalic acid 1-methylester (preparation see WO 2000/021920) (1.43 g) in dichloromethane (10 ml) was added N-(−3-dimethylaminopropyl)-N′-ethylcarbodiimid hydrochloride (1.84 g), N,N-dimethylaminopyridine (0.41 g) and trimethylsilylmethylamine (1 ml). The reaction mixture was stirred at ambient temperature. for 2 hours. The reaction mixture was concentrated and the residue purified by chromatography on silica gel (eluent: ethyl acetate/heptanes 1:3) to give 2-methyl-N-trimethylsilanylmethyl-terephthalamic acid methyl ester (1.85 g). 1H-NMR (400 MHz, CDCl3): 7.72 (d, 1H), 7.45 (s, 1H), 7.40 (d, 1H), 5.85 (s, 1H), 3.78 (s, 3H), 2.84 (d, 2H), 2.49 (s, 3H), 0.00 (s, 9H) ppm. 2-Methyl-N-trimethylsilanylmethyl-terephthalamic acid tert-butyl ester was obtained using a similar procedure. 1H-NMR (400 MHz, CDCl3): 7.82 (d, 1H), 7.48 (s, 1H), 7.39 (d, 1H), 5.70 (s, 1H), 2.82 (d, 2H), 2.48 (s, 3H), 1.48 (s, 9H), 0.00 (s, 9H) ppm.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][N:5]1[CH2:9][CH2:8][CH2:7][CH2:6]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(C)C=CC=CC=1.[CH2:25]([O:32][C:33]1[CH:60]=[CH:59][C:58](Br)=[CH:57][C:34]=1[C:35]([NH:37][C:38]1[CH:50]=[C:49]([C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[CH:48]=[CH:47][C:39]=1[C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])=[O:36])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=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].C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C(Cl)(Cl)Cl.O>[CH2:25]([O:32][C:33]1[CH:60]=[CH:59][C:58]([N:2]([CH3:1])[CH2:3][CH2:4][N:5]2[CH2:9][CH2:8][CH2:7][CH2:6]2)=[CH:57][C:34]=1[C:35]([NH:37][C:38]1[CH:50]=[C:49]([C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[CH:48]=[CH:47][C:39]=1[C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])=[O:36])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cc(Br)ccc1OCc1ccccc1
Reactant: CNCCN1CCCC1
Agent: [Pd+2]
Agent: [Pd]
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Solvent: O
Solvent: ClC(Cl)Cl
Product: CN(CCN1CCCC1)c1ccc(OCc2ccccc2)c(C(=O)Nc2cc(-c3ccccc3)ccc2C(=O)OC(C)(C)C)c1
Temperature: 25 °C
Yield: 59.6 %

Procedure:
N-Methyl-2-(pyrrolidin-1-yl)ethylamine (0.086 g), tripotassium phosphate (0.17 g), tris(dibenzylideneacetone)dipalladium(0) (2.5 mg), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (6.4 mg), and palladium(II) acetate (1.2 mg) were added to a toluene (2.3 mL) solution of tert-butyl 2-(2-(benzyloxy)-5-bromobenzamido)-4-phenylbenzoate (0.15 g), followed by heating to reflux under a nitrogen atmosphere for 1 hour and 30 minutes. The reaction mixture was cooled to room temperature, and then N-methyl-2-(pyrrolidin-1-yl)ethylamine (0.017 g), tripotassium phosphate (0.029 g), tris(dibenzylideneacetone)dipalladium(0) (2.5 mg), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (6.4 mg), and palladium(II) acetate (1.2 mg) were added to the reaction mixture, followed by heating to reflux under a nitrogen atmosphere for 7 hours and 30 minutes. The reaction mixture was cooled to room temperature, and then N-methyl-2-(pyrrolidin-1-yl)ethylamine (0.017 g), tripotassium phosphate (0.029 g), tris(dibenzylideneacetone)dipalladium(0) 2.5 mg, 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (6.4 mg), and palladium(II) acetate (1.2 mg) were added to the reaction mixture, followed by heating to reflux under a nitrogen atmosphere for 3 hours. The reaction mixture was cooled to room temperature, and water and chloroform were added thereto. The insoluble substance was removed by filtration. The organic layer was separated and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: 100-90% chloroform/methanol] to obtain 0.097 g of tert-butyl 2-(2-(benzyloxy)-5-(methyl(2-(pyrrolidin-1-yl)ethyl)amino)benzamido)-4-phenylbenzoate.
Reaction SMILES: Br[C:2]1[CH:31]=[CH:30][C:5]([CH2:6][N:7]([C:17]2[CH:18]=[CH:19][C:20]3[C:25](=[O:26])[O:24][C:23]([CH3:28])([CH3:27])[O:22][C:21]=3[CH:29]=2)[C:8](=[O:16])[CH2:9][CH2:10][CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[CH:4][CH:3]=1.[C:32]1([CH2:38][CH2:39][CH2:40][C:41]#[CH:42])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[CH:11]1([CH2:10][CH2:9][C:8]([N:7]([C:17]2[CH:18]=[CH:19][C:20]3[C:25](=[O:26])[O:24][C:23]([CH3:28])([CH3:27])[O:22][C:21]=3[CH:29]=2)[CH2:6][C:5]2[CH:4]=[CH:3][C:2]([C:42]#[C:41][CH2:40][CH2:39][CH2:38][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[CH:31][CH:30]=2)=[O:16])[CH2:12][CH2:13][CH2:14][CH2:15]1
Reactant: C#CCCCc1ccccc1
Reactant: CC1(C)OC(=O)c2ccc(N(Cc3ccc(Br)cc3)C(=O)CCC3CCCC3)cc2O1
Product: CC1(C)OC(=O)c2ccc(N(Cc3ccc(C#CCCCc4ccccc4)cc3)C(=O)CCC3CCCC3)cc2O1

Procedure:
The titled compound was prepared following the procedure N using N-(4-bromobenzyl)-3-cyclopentyl-N-(2,2-dimethyl-4-oxo-4H-1,3-benzodioxin-7-yl)propanamide and 5-phenyl-1-pentyne as a yellow oil (54%). M+ (ESI): 550.2. HPLC, Rt: 5.96 min (Purity: 94.9%).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:5]([C:7]([N:9]2[C@H:14]([CH2:15][NH2:16])[CH2:13][C@H:12]3[C@@H:10]2[CH2:11]3)=[O:8])[N:6]=1.[CH3:24][C:25]1[N:26]2[CH:35]=[CH:34][N:33]=[C:27]2[S:28][C:29]=1[C:30](O)=[O:31]>>[NH2:1][C:2]1[S:3][C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:5]([C:7]([N:9]2[C@H:14]([CH2:15][NH:16][C:30]([C:29]3[S:28][C:27]4=[N:33][CH:34]=[CH:35][N:26]4[C:25]=3[CH3:24])=[O:31])[CH2:13][C@H:12]3[C@@H:10]2[CH2:11]3)=[O:8])[N:6]=1
Reactant: Cc1c(C(=O)O)sc2nccn12
Reactant: NC[C@@H]1C[C@@H]2C[C@@H]2N1C(=O)c1nc(N)sc1-c1cccc(F)c1
Product: Cc1c(C(=O)NC[C@@H]2C[C@@H]3C[C@@H]3N2C(=O)c2nc(N)sc2-c2cccc(F)c2)sc2nccn12

Procedure:
prepared by reaction of [2-amino-5-(3-fluoro-phenyl)-thiazol-4-yl]-((1S,3S,5S)-3-aminomethyl-2-aza-bicyclo[3.1.0]hex-2-yl)-methanone with 3-methyl-imidazo[2,1-b]thiazole-2-carboxylic acid. LC-MS (basic): tR=0.74 min; [M+H]+=497.2.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C@@H:10]([NH2:13])[CH2:11][CH3:12])[N:7]([C:14]3[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=3)[C:6]=2[CH:20]=1.Cl[C:22]1[N:30]=[CH:29][N:28]=[C:27]2[C:23]=1[N:24]=[CH:25][N:26]2C1CCCCO1.CCN(C(C)C)C(C)C>C(O)CCC>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([CH:10]([NH:13][C:22]3[N:30]=[CH:29][N:28]=[C:27]4[C:23]=3[N:24]=[CH:25][NH:26]4)[CH2:11][CH3:12])[N:7]([C:14]3[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=3)[C:6]=2[CH:20]=1
Reactant: CC[C@H](N)c1nc2ccc(F)cc2n1-c1cccnc1
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: CCC(Nc1ncnc2[nH]cnc12)c1nc2ccc(F)cc2n1-c1cccnc1
Temperature: 100 °C
Yield: 41.5 %

Procedure:
A mixture of (S)-1-(6-fluoro-1-pyridin-3-yl-1H-benzoimidazol-2-yl)propylamine (243 mg, 0.90 mmol), 6-chloro-9-(tetrahydropyran-2-yl)-9H-purine (210 mg, 0.90 mmol) and DIPEA (780 μL, 4.5 mmol) in n-butanol (3 mL) was heated at 100° C. in a sealed vial for 18 h. After cooling to RT, the volatiles were removed under reduced pressure and the resulting residue loaded onto an Isolute® SCX-2 cartridge and washed with MeOH followed by 2M NH3/MeOH. The product containing fractions were combined and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-10% 2M NH3/MeOH in DCM) to afford 205 (145 mg, 42%). LCMS (Method K): RT 2.96 min [M+H]+ 389.1. 1H NMR (DMSO-d6, 400 MHz): δ 12.65 (1H, s), 8.81 (1H, d, J=2.47 Hz), 8.67 (1H, br s), 8.21-8.01 (3H, m), 7.91 (1H, br s), 7.73 (1H, dd, J=8.81, 4.84 Hz), 7.56 (1H, br s), 7.18-7.08 (1H, m), 6.95 (1H, dd, J=8.88, 2.48 Hz), 5.35 (1H, br s), 2.19-2.01 (2H, m), 0.90 (3H, t, J=7.32 Hz)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]1[N:15]2[N:16]=[CH:17][C:18]([C:19]([OH:21])=O)=[C:14]2[N:13]=[CH:12][C:11]=1[C:22]([N:24]1[CH2:29][CH2:28][CH:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:26][CH2:25]1)=[O:23].[CH:36]1([S:39]([NH2:42])(=[O:41])=[O:40])[CH2:38][CH2:37]1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]1[N:15]2[N:16]=[CH:17][C:18]([C:19]([NH:42][S:39]([CH:36]3[CH2:38][CH2:37]3)(=[O:41])=[O:40])=[O:21])=[C:14]2[N:13]=[CH:12][C:11]=1[C:22]([N:24]1[CH2:29][CH2:28][CH:27]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH2:26][CH2:25]1)=[O:23]
Reactant: Cc1ccc(F)c(Nc2c(C(=O)N3CCC(c4ccccc4)CC3)cnc3c(C(=O)O)cnn23)c1
Reactant: NS(=O)(=O)C1CC1
Product: Cc1ccc(F)c(Nc2c(C(=O)N3CCC(c4ccccc4)CC3)cnc3c(C(=O)NS(=O)(=O)C4CC4)cnn23)c1
Yield: 59.7 %

Procedure:
In the same manner as in Example 1, step 6 and using 7-(2-fluoro-5-methylphenylamino)-6-(4-phenylpiperidine-1-carbonyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (87 mg, 0.18 mmol) obtained in Example 59, step 2 and cyclopropanesulfonamide (109 mg, 0.90 mmol), the title compound (62 mg, 59%) was obtained.
Reaction SMILES: [CH:1]1([C:4]([C:6]2[S:7][C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([NH:17][C:18]4[N:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[CH:20][N:19]=4)[CH:12]=3)=[CH:9][N:10]=2)=[O:5])[CH2:3][CH2:2]1.[F:28][C:29]([Si](C)(C)C)([F:31])[F:30].[F-].C[N+](C)(C)C.CC([O-])(C)C.[K+].CCCC[N+](CCCC)(CCCC)CCCC.[F-].Cl>O1CCCC1.CCCC[N+](CCCC)(CCCC)CCCC.[F-].CCOCC>[CH:1]1([C:4]([C:6]2[S:7][C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([NH:17][C:18]4[N:23]=[C:22]([C:24]([F:25])([F:26])[F:27])[CH:21]=[CH:20][N:19]=4)[CH:12]=3)=[CH:9][N:10]=2)([OH:5])[C:29]([F:31])([F:30])[F:28])[CH2:3][CH2:2]1
Reactant: O=C(c1ncc(-c2cccc(Nc3nccc(C(F)(F)F)n3)c2)s1)C1CC1
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CC(C)(C)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: C[N+](C)(C)C
Solvent: CCOCC
Solvent: C1CCOC1
Product: OC(c1ncc(-c2cccc(Nc3nccc(C(F)(F)F)n3)c2)s1)(C1CC1)C(F)(F)F
Temperature: 25 °C
Reaction time: 4 h
Yield: 67.6 %

Procedure:
TBAF (1 M, 3.71 μL, 3.71 μmol) was added to a stirred, cooled (0° C.) mixture of cyclopropyl[5-(3-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]methanone (29 mg, 0.074 mmol) and (trifluoromethyl)trimethylsilane (14.24 μL, 0.089 mmol) in tetrahydrofuran (0.2 mL) and the mixture was stirred at room temperature for 4 h. Additional TMSCF3 (20 μL) and tetramethyammonium fluoride (0.811 mg, 7.43 μmol) were added and the mixture was left to stir overnight. Additional TMSCF3 (22 μL) and KOtBu (1M in TIM, 74 μL) were added to the mixture and left to stir for 2 days. The mixture was treated with TBAF (74 μL), ether and HCl, and extracted with ethyl acetate. The combined organics were concentrated, and purified by flash chromatography to give 1-cyclopropyl-2,2,2-trifluoro-1-[5-(3-{[4-(trifluoromethyl)-pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]ethanol (23 mg, 0.050 mmol, 67.2% yield). APCI: [M+H]+ m/z 461.1. 1H NMR (400 MHz, CDCl3): δ 8.72 (d, J=4.9 Hz, 1H); 8.19 (s, 1H); 7.97 (s, 1H); 7.52 (d, J=8.3 Hz, 1H); 7.48-7.40 (m, 2H); 7.32 (d, J=7.8 Hz, 1H); 7.12 (d, J=4.9 Hz, 1H); 4.53 (s, 1H); 1.58-1.51 (m, 1H); 1.01-0.94 (m, 1H); 0.77-0.67 (m, 1H); 0.59-0.51 (m, 2H). rhSYK activity=+++
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[CH:6][CH:5]=1)=[O:3].[Br:11]N1C(=O)CCC1=O>CC#N>[NH2:10][C:7]1[CH:8]=[CH:9][C:4]([C:2](=[O:3])[CH3:1])=[CH:5][C:6]=1[Br:11]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(=O)c1ccc(N)cc1
Solvent: CC#N
Product: CC(=O)c1ccc(N)c(Br)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 85 %

Procedure:
To a solution of 4-aminoacetophenone (5.67 g, 0.0419 mol) in 30 mL of CH3CN at 0° C. was added N-bromosuccinimide (7.83 g, 0.0439 mol) in 20 mL of CH3CN dropwise. The reaction was allowed to warm to room temperature and concentrated in vacuo after stirring 16 h. The crude residue was dissolved in EtOAc (100 mL), washed with saturated aqueous NaHCO3 (1×100 mL), brine (1×100 mL) and dried (Na2SO4). The solvent was removed under vacuum to afford the title compound (7.62 g, 85%) as a yellow solid. Mass spectrum (ESI, m/z): Calcd. for C8H8BrNO, 213.9 (M+H). found 214.0.