Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:18])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH3:17])([C:14]([NH2:16])=O)[CH2:6][CH2:5]2.Cl>C1COCC1>[NH2:16][CH2:14][C:7]1([CH3:17])[CH2:6][CH2:5][C:4]2[C:9](=[C:10]([CH3:13])[C:11]([CH3:12])=[C:2]([OH:1])[C:3]=2[CH3:18])[O:8]1
Reactant: Cc1c(C)c2c(c(C)c1O)CCC(C)(C(N)=O)O2
Agent: Cl
Solvent: C1CCOC1
Product: Cc1c(C)c2c(c(C)c1O)CCC(C)(CN)O2
Yield: 55 %

Procedure:
To a solution of 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxamide (1.0 g, 4.0 mmol) in THF (30 mL) was added borane-methyl sulfide complex (10M, 1.9 mL, 19 mmol). The resultant mixture was refluxed for 7 h. To the resultant reaction mixture was added 1N hydrochloric acid (9.6 mL) under ice-cooling, and the resultant mixture was further refluxed for 2 h followed by concentration under reduced pressure. The residue was extracted with ethyl acetate after addition of 1N aqueous solution of sodium hydroxide. The organic layer was washed with 10% aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica-gel column chromatography to give an amine, 2-aminomethyl-6-hydroxy-2,5,7,8-tetramethylchroman (yield 55%).
Reaction SMILES: CO[C:3](=[O:15])[C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:13]Br.[NH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.N1C=CC=CC=1>C(O)C>[N+:10]([C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:4]=1[C:3](=[O:15])[N:16]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:13]2)([O-:12])=[O:11]
Reactant: COC(=O)c1c(CBr)cccc1[N+](=O)[O-]
Reactant: Nc1ccccc1
Solvent: c1ccncc1
Solvent: CCO
Product: O=C1c2c(cccc2[N+](=O)[O-])CN1c1ccccc1
Temperature: 25 °C
Yield: 62 %

Procedure:
A solution of 2-bromomethyl-6-nitro-benzoic acid methyl ester (0.40 g, 1.46 mmol) and aniline (0.23 g, 2.44 mmol) in ethanol (20 ml) was added with pyridine (0.15 g, 1.95 mmol), and the mixture was refluxed by heating for 30 hours. The reaction solution was cooled to room temperature, and then poured into ice water, and the deposited crystals were collected by filtration, washed with ethanol and water, and dried. The resulting crystals were recrystallized (acetone) to obtain 7-nitro-2-phenyl-2,3-dihydro-isoindol-1-one as pale yellow crystals (0.23 g, yield: 62.9%).
Reaction SMILES: Br[C:2]1[C:3]([OH:8])=[N:4][CH:5]=[CH:6][CH:7]=1.[CH3:9][N:10]1[C:18]2[C:13](=[CH:14][C:15](B(O)O)=[CH:16][CH:17]=2)[CH:12]=[N:11]1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.O.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:9][N:10]1[C:18]2[C:13](=[CH:14][C:15]([C:2]3[C:3](=[O:8])[NH:4][CH:5]=[CH:6][CH:7]=3)=[CH:16][CH:17]=2)[CH:12]=[N:11]1
Reactant: Cn1ncc2cc(B(O)O)ccc21
Reactant: Oc1ncccc1Br
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1ncc2cc(-c3ccc[nH]c3=O)ccc21
Temperature: 90 °C

Procedure:
The suspension of 3-bromo-2-hydroxypyridine (80 mg, 0.46 mmol), 1-methyl-1H-indazol-5-ylboronic acid (121 mg, 0.69 mmol) and sodium carbonate (146 mg, 1.38 mmol) in DMF (2.0 mL) and H2O (0.4 mL) was degassed with N2 for 5 minutes. To the mixture was added bis(triphenylphosphine)palladium (II) dichloride (67 mg, 0.09 mmol), and the resulting mixture was heated at 90° C. for 2 h. The reaction mixture was filtered and purified by reverse phase HPLC (Gemini, 5 to 100% ACN/H2O+0.1% TFA) to give the product. LCMS-ESI+ (m/z): [M+H]+ calcd for C13H12N3O: 226.25; Found: 226.2.
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12](O)=[O:13])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].S(Cl)([Cl:20])=O>>[Si:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([Cl:20])=[O:13])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc(C(=O)O)c1
Product: CC(C)(C)[Si](C)(C)Oc1cccc(C(=O)Cl)c1

Procedure:
Into a 100 mL round bottom flask a mixture of 5 parts of 3-tert-butyldimethylsilyloxybenzoic acid and 25 mL of thionyl chloride was heated at reflux for 90 mins. The reaction mixture was concentrated under reduced pressure to give an oil, yield 5.77 parts of the following structure.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:23]=[CH:22][CH:21]=[CH:20][C:6]=1[C:7]([NH:9][C:10]1[CH:18]=[C:17]([NH2:19])[CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=[O:13])=[O:8])(=[O:3])[CH3:2].[C:24]([O:27][C:28]1[CH:36]=[CH:35][CH:34]=[CH:33][C:29]=1[C:30](Cl)=[O:31])(=[O:26])[CH3:25]>>[C:1]([O:4][C:5]1[CH:23]=[CH:22][CH:21]=[CH:20][C:6]=1[C:7]([NH:9][C:10]1[CH:18]=[C:17]([NH:19][C:30](=[O:31])[C:29]2[CH:33]=[CH:34][CH:35]=[CH:36][C:28]=2[O:27][C:24](=[O:26])[CH3:25])[CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=[O:13])=[O:8])(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1ccccc1C(=O)Cl
Reactant: CC(=O)Oc1ccccc1C(=O)Nc1cc(N)ccc1C(=O)O
Product: CC(=O)Oc1ccccc1C(=O)Nc1ccc(C(=O)O)c(NC(=O)c2ccccc2OC(C)=O)c1

Procedure:
By the procedure similar to that described in Example 23, 2-(2'-acetoxybenzamido)-4-aminobenzoic acid and 2-acetoxybenzoylchloride were allowed to react and were treated to obtain crude crystals. Recrystallization from methanol-water gave 2,4-bis(2'-acetoxybenzamido)-benzoic acid having a melting point between 194° - 195°C. The product wass confirmed to be identical to that obtained in Example 18.
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH2:5][NH:6][C:7]1[C:16]2[C:17](=[O:24])[C:18]3[C:23]([C:15]=2[C:14]2[C:9](=[CH:10][C:11]([O:25]C)=[CH:12][CH:13]=2)[N:8]=1)=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH3:3].Br>C(O)(=O)C>[CH3:3][N:2]([CH2:4][CH2:5][NH:6][C:7]1[C:16]2[C:17](=[O:24])[C:18]3[C:23]([C:15]=2[C:14]2[C:9](=[CH:10][C:11]([OH:25])=[CH:12][CH:13]=2)[N:8]=1)=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH3:1]
Reactant: COc1ccc2c3c(c(NCCN(C)C)nc2c1)C(=O)c1ccccc1-3
Agent: Br
Solvent: CC(=O)O
Product: CN(C)CCNc1nc2cc(O)ccc2c2c1C(=O)c1ccccc1-2
Yield: 73.2 %

Procedure:
To a solution of 6-(((dimethylamino)ethyl)amino)-3-methoxy-7H-indeno[2,1-c]quinoline-7-on obtained in example 1 (3 g, 8.6 mmol) in acetic acid (40 ml) was added 47% aqueous hydrobromic acid (40 ml), and the mixture was refluxed with heat for 60 hours. The reaction mixture was distilled to dryness. To the residue was added water and the solution was adjusted to a pH of about 8 with aqueous ammonia, and subsequently extracted with chloroform. The chloroform layer was dried over magnesium sulfate and evaporated. The residue was purified by silica gel column chromatography (eluent; chloroform:methanol:water=8:3:1(v/v/v)) and crystallized from cyclohexane to give 2.1 g (yield: 73.0%) of title compound. The physicochemical properties thereof are shown in table 1.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:14])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[H-].[Na+].[CH3:17]I.O>CN(C=O)C>[I:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([O:14][CH3:17])[CH2:9][CH2:10][O:11][CH2:12][CH2:13]2)=[CH:4][CH:3]=1
Reactant: CI
Reactant: OC1(c2ccc(I)cc2)CCOCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC1(c2ccc(I)cc2)CCOCC1
Temperature: 25 °C
Reaction time: 1.25 h

Procedure:
Under an argon atmosphere, a solution of tetrahydro-4-(4-iodophenyl)-2H-pyran-4-ol (2.99 g) in anhydrous DMF (10 ml) was added dropwise to a suspension of sodium hydride (60 wt %) (432 mg) in anhydrous DMF (20 ml) at room temperature, and the resulting mixture was stirred at room temperature for 75 minutes. Methyl iodide (0.92 ml) was added dropwise to the reaction solution and the resulting mixture was stirred at room temperature for 8.5 hours. Water was added thereto and the resulting mixture was extracted twice with ethyl acetate. Organic layers were washed with saturated brine, and dried over anhydrous sodium sulfate. After removing anhydrous sodium sulfate by filtration, the filtrate was concentrated. The residue was purified by column chromatography (silica gel, eluent: cyclohexane/ethyl acetate=10/1) to obtain tetrahydro-4-(4-iodophenyl)-4-methoxy-2H-pyran (2.87 g). NMR (H1, CDCl3): δ 1.90-2.02 (4H, m), 2.97 (3H, s), 3.80-3.88 (4H, m), 7.14 (1H, d, J=8.5 Hz), 7.70 (1H, d, J=8.5 Hz)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]([NH:13]C(=O)OC(C)(C)C)([CH3:12])[CH2:9][NH:10][CH3:11])[CH:5]=[CH:6][CH:7]=1>C(O)(C(F)(F)F)=O.C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([C:8]([NH2:13])([CH3:12])[CH2:9][NH:10][CH3:11])[CH:5]=[CH:6][CH:7]=1
Reactant: CNCC(C)(NC(=O)OC(C)(C)C)c1cccc(Br)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNCC(C)(N)c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.4 %

Procedure:
tert-Butyl 2-(3-bromophenyl)-1-(methylamino)propan-2-ylcarbamate (CD3; R1=Me, R4=Me) (0.62 g, 1.8 mmol) was dissolved in 25% TFA in DCM (25 mL) and the mixture was left stirring at RT for 1 h. The mixture was concentrated in vacuo and the residue was redissolved in CHCl3 (20 mL). The solution was washed with 15% NaOH (10 mL) and the aqueous layer was extracted with CHCl3 (3×10 mL). The combined organic layer was dried over MgSO4 and concentrated in vacuo to give 0.33 g (76%) of crude 2-(3-bromophenyl)-N1-methylpropan-1,2-diamine as a colorless oil. 1H NMR (CDCl3) δ 7.65 (t, J=1.7 Hz, 1H), 7.41-7.34 (m, 2H), 7.21 (t, J=7.8 Hz, 1H), 2.86 (dd, J=11.7, 0.6 Hz, 1H), 2.64 (dd, J=11.7, 0.6 Hz, 1H), 2.38 (s, 3H), 1.54 (bs, 3H), 1.43 (s, 9H). MS (ESI) m/e 242.9 (M+H)+. The compound was used in the next step without further purification.
Reaction SMILES: [Si]([O:8][NH:9][C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]1[CH:23]=[CH:22][C:21]([CH2:24][N:25]2[C:33]3[C:28](=[CH:29][C:30]([C:34]([NH:36][C@H:37]([C:39]4[CH:44]=[CH:43][CH:42]=[C:41]([CH:45]([CH3:47])[CH3:46])[CH:40]=4)[CH3:38])=[O:35])=[CH:31][CH:32]=3)[C:27]([CH3:48])=[C:26]2[CH3:49])=[CH:20][CH:19]=1)=[O:11])(C(C)(C)C)(C)C>C(Cl)Cl.C(O)(C(F)(F)F)=O>[OH:8][NH:9][C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]1[CH:19]=[CH:20][C:21]([CH2:24][N:25]2[C:33]3[C:28](=[CH:29][C:30]([C:34]([NH:36][C@H:37]([C:39]4[CH:44]=[CH:43][CH:42]=[C:41]([CH:45]([CH3:46])[CH3:47])[CH:40]=4)[CH3:38])=[O:35])=[CH:31][CH:32]=3)[C:27]([CH3:48])=[C:26]2[CH3:49])=[CH:22][CH:23]=1)=[O:11]
Reactant: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)NO[Si](C)(C)C(C)(C)C)cc2)c2ccc(C(=O)N[C@@H](C)c3cccc(C(C)C)c3)cc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)NO)cc2)c2ccc(C(=O)N[C@@H](C)c3cccc(C(C)C)c3)cc12

Procedure:
The solution of (S)-1-((2′-(((tert-Butyldimethylsilyl)oxy)carbamoyl)-[1,1′-biphenyl]-4-yl)methyl)-N-(1-(3-isopropylphenyl)ethyl)-2,3-dimethyl-1H-indole-5-carboxamide in DCM (3 mL) and TFA (0.5 mL) was stirred for 1 h at rt. The solvent was removed and the residue was purified by reverse phase prep-HPLC (MeOH/Acetonitrile/water) to obtain the title compound. ESI-MS (m/z): 560 [M+H]+.
Reaction SMILES: C(=O)=O.CC(C)=O.[C:8]([S:12][C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][CH:14]=1)([CH3:11])([CH3:10])[CH3:9].[Br:20]N1C(=O)CCC1=O>C(Cl)Cl>[C:8]([S:12][C:13]1[CH:14]=[CH:15][C:16]([NH2:17])=[C:18]([Br:20])[CH:19]=1)([CH3:11])([CH3:9])[CH3:10]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)Sc1ccc(N)cc1
Agent: O=C=O
Solvent: CC(C)=O
Solvent: ClCCl
Product: CC(C)(C)Sc1ccc(N)c(Br)c1
Reaction time: 8 h

Procedure:
To a cold (dry ice - acetone bath) stirred solution of 4-tert-butylthioaniline (25.6 g., 0.14 mole) in methylene chloride is added a slurry of N-bromosuccinimide (25.0 g., 0.14 mole) in methylene chloride in three equal portions. The reaction is allowed to come to room temperature with stirring overnight. The methylene chloride solution is washed with dilute aqueous sodium carbonate and water and then evaporated to give the desired product as a brown oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][C:15]=1[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[C:5]([N:7]1[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1)=[O:6].[CH3:22][O:23][C:24]([C:26]1[CH:33]=[CH:32][C:29]([CH:30]=O)=[CH:28][CH:27]=1)=[O:25].O>C(O)(=O)C>[CH2:16]([C:15]1[CH:14]=[CH:13][C:4]([C:5]([N:7]2[CH2:8][CH2:9][O:10][CH2:11][CH2:12]2)=[O:6])=[CH:3][C:2]=1[NH:1][CH2:30][C:29]1[CH:28]=[CH:27][C:26]([C:24]([O:23][CH3:22])=[O:25])=[CH:33][CH:32]=1)[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCCCCc1ccc(C(=O)N2CCOCC2)cc1N
Reactant: COC(=O)c1ccc(C=O)cc1
Solvent: O
Solvent: CC(=O)O
Product: CCCCCCc1ccc(C(=O)N2CCOCC2)cc1NCc1ccc(C(=O)OC)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
The compound ([5]-(55)-75) (600 mg) prepared in Example 63 was dissolved in acetic acid (6.0 ml). Then, 4-methoxycarbonylbenzaldehyde (373 mg) was added. The mixture was stirred at room temperature for 4 hours. Then, boranediethylamine complex (146 mg) was added to the solution. The mixture was stirred at room temperature for 30 minutes. After the reaction was completed, water was added to the solution. The solution was extracted with ethyl acetate, washed with distilled water, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (Kieselgel 60=30 g, hexane/ethyl acetate=1/1) to obtain the above-captioned compound ([5]-(57)-75') (841 mg) as a white solid.
Reaction SMILES: C[O:2][C:3](=[O:16])[CH2:4][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[CH:11][C:12]=2[Cl:14])[NH:7][C:6]=1[CH3:15].[H-].[Na+].[CH3:19][S:20]([C:23]1[CH:30]=[CH:29][C:26]([CH2:27]Br)=[CH:25][CH:24]=1)(=[O:22])=[O:21]>CN(C=O)C.O>[Cl:14][C:12]1[CH:11]=[CH:10][N:9]=[C:8]2[N:7]([CH2:27][C:26]3[CH:25]=[CH:24][C:23]([S:20]([CH3:19])(=[O:22])=[O:21])=[CH:30][CH:29]=3)[C:6]([CH3:15])=[C:5]([CH2:4][C:3]([OH:2])=[O:16])[C:13]=12
Reactant: CS(=O)(=O)c1ccc(CBr)cc1
Reactant: COC(=O)Cc1c(C)[nH]c2nccc(Cl)c12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(CC(=O)O)c2c(Cl)ccnc2n1Cc1ccc(S(C)(=O)=O)cc1
Temperature: 0 °C
Reaction time: 5 h

Procedure:
To a cooled (0° C.) stirred solution of (4-chloro-2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-acetic acid methyl ester (0.1 g, 0.42 mmol) in dry DMF (2.5 ml) is added sodium hydride (0.019 g of a 60% dispersion in mineral oil, 0.47 mmol). After stirring at room temperature for 5 hours, the reaction mixture is re-cooled to 0° C. and treated with 4-methylsulfonylbenzyl bromide (0.105 g, 0.42 mmol). The resulting mixture is stirred and allowed to warm to room temperature overnight. The reaction mixture is diluted with water (3 ml) and extracted with ether (3×15 ml). The organic portions are combined, washed with water, dried (Na2SO4) and concentrated in vacuo. The resulting crude residue is loaded on a pre-packed Isolute™ silica column and eluted with iso-hexane:ethyl acetate (1:8) to yield the titled compound as a white powder. (MH+ 407).
Reaction SMILES: [CH3:1][C:2]([NH:10][C:11]([C:13]1[S:14][C:15]2[N:20](C(OC(C)(C)C)=O)[N:19]=[C:18]([NH:28][C:29](=[O:42])[C:30]3[CH:35]=[CH:34][C:33]([N:36]4[CH2:41][CH2:40][O:39][CH2:38][CH2:37]4)=[CH:32][CH:31]=3)[C:16]=2[N:17]=1)=[O:12])([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:3].Cl.[Cl-].[Na+]>C(O)C.O1CCOCC1>[CH3:3][C:2]([NH:10][C:11]([C:13]1[S:14][C:15]2[NH:20][N:19]=[C:18]([NH:28][C:29](=[O:42])[C:30]3[CH:35]=[CH:34][C:33]([N:36]4[CH2:41][CH2:40][O:39][CH2:38][CH2:37]4)=[CH:32][CH:31]=3)[C:16]=2[N:17]=1)=[O:12])([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)[CH3:1]
Reactant: CC(C)(C)OC(=O)n1nc(NC(=O)c2ccc(N3CCOCC3)cc2)c2nc(C(=O)NC(C)(C)c3ccccc3)sc21
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCO
Product: CC(C)(NC(=O)c1nc2c(NC(=O)c3ccc(N4CCOCC4)cc3)n[nH]c2s1)c1ccccc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 61.8 %

Procedure:
0.19 g (0.32 mmol) of tert-butyl 5-(1-methyl-1-phenylethylcarbamoyl)-3-(4-morpholin-4-ylbenzoylamino)-1H-pyrazolo[4,3-d]thiazole-1-carboxylate dissolved in 7 ml of ethanol is placed in a 50 ml round-bottomed flask. 1.6 ml (6.4 mmol) of a 4M solution of hydrochloric acid in dioxane are then added and the reaction mixture is stirred for 15 hours at 25° C. A further 1.6 ml (6.4 mmol) of a 4M solution of hydrochloric acid in dioxane are then added and the mixture is stirred for 15 hours at 25° C. The reaction medium is then concentrated to dryness under reduced pressure (40° C.) and the residue is taken up in 40 ml of dichloromethane and 40 ml of water, and basified with 0.1N sodium hydroxide solution. The emulsion obtained is resorbed by saturation with sodium chloride. After separation of the phases by settling, the organic phase is dried over magnesium sulfate and concentrated to dryness under reduced pressure (40° C.). The yellow residue is purified by flash chromatography (msilica=30 g; eluent: 97/3 dichloromethane/methanol). 0.097 g of N-(1-methyl-1-phenylethyl)-3-(4-morpholin-4-ylbenzoylamino)-1H-pyrazolo[4,3-d]thiazole-5-carboxamide is thus obtained in the form of a yellow foam. m.p.K=266° C. 1H NMR (400 MHz, DMSO-d6): δ ppm 1.70 (s, 6H); 3.29 (masked m, 4H); 3.75 (m, 4H); 7.04 (d, J=8.5 Hz, 2H); 7.20 (t, J=7.5 Hz, 1H); 7.31 (t, J=7.5 Hz, 2H); 7.41 (d, J=7.5 Hz, 2H); 7.99 (d, J=8.5 Hz, 2H); 8.50 (broad s, 1H); 10.8 (broad m, 1H); 13.6 (broad m, 1H).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]([OH:8])=O)[N:3]=[N:2]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:42][N:43]([CH3:69])[CH2:44][CH2:45][O:46][C:47](=[O:68])[C@@:48]([CH2:66][OH:67])([CH3:65])[CH2:49][C@H:50]([NH2:64])[CH2:51][C:52]1[CH:57]=[CH:56][C:55]([C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=2)=[CH:54][CH:53]=1>CN(C=O)C>[CH3:69][N:43]([CH3:42])[CH2:44][CH2:45][O:46][C:47](=[O:68])[C@@:48]([CH2:66][OH:67])([CH3:65])[CH2:49][C@H:50]([NH:64][C:6]([C:4]1[NH:3][N:2]=[N:1][CH:5]=1)=[O:8])[CH2:51][C:52]1[CH:53]=[CH:54][C:55]([C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=2)=[CH:56][CH:57]=1
Reactant: CN(C)CCOC(=O)[C@](C)(CO)C[C@H](N)Cc1ccc(-c2ccccc2)cc1
Reactant: O=C(O)c1c[nH]nn1
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: CN(C)C=O
Product: CN(C)CCOC(=O)[C@](C)(CO)C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)c1cnn[nH]1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 26.1 %

Procedure:
1,2,3-Triazole-4-carboxylic acid (0.0274 g, 0.242 mmol), DIPEA (169 μL, 969 μmol) and HATU (92 mg, 242 μmol) were combined in DMF (0.2 mL) and stirred for 5 minutes at room temperature. This was then combined with (2S,4R)-4-amino-5-biphenyl-4-yl-2-hydroxymethyl-2-methyl-pentanoic acid 2-dimethylamino-ethyl ester (93 mg, 240 μmol), predissolved in DMF (0.2 mL) and DIPEA (0.5 eq.). The resulting mixture was stirred for 15 minutes and the reaction was quenched with AcOH. The product was purified by preparative HPLC and lyophilized to yield the title compound (30 mg; purity 95%). MS m/z [M+H]+ calc'd for C26H33N5O4, 480.25. found 480.4.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]([NH:10][CH2:11][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][C:17]=2[C:18]([F:21])([F:20])[F:19])[N:3]=1.[CH3:22][NH:23][C:24]([CH:26]1[CH2:31][CH2:30][CH:29]([NH2:32])[CH2:28][CH2:27]1)=[O:25].N12CCCN=C1CCCCC2>C1COCC1>[C:8]([C:7]1[C:2]([NH:32][C@@H:29]2[CH2:28][CH2:27][C@H:26]([C:24]([NH:23][CH3:22])=[O:25])[CH2:31][CH2:30]2)=[N:3][C:4]([NH:10][CH2:11][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][C:17]=2[C:18]([F:21])([F:20])[F:19])=[N:5][CH:6]=1)#[N:9]
Reactant: CNC(=O)C1CCC(N)CC1
Reactant: N#Cc1cnc(NCc2cnccc2C(F)(F)F)nc1Cl
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: CNC(=O)[C@H]1CC[C@@H](Nc2nc(NCc3cnccc3C(F)(F)F)ncc2C#N)CC1
Temperature: 60 °C

Procedure:
4-Chloro-2-(((4-(trifluoromethyl)pyridin-3-yl)methyl)amino)pyrimidine-5-carbonitrile (1.0 equiv.) was placed in a sealable flask with (1s,4s)-4-amino-N-methylcyclohexanecarboxamide (1.0 equiv.), 1,8-diazabicyclo[5.4.0]undec-7-ene (1.2 equiv.), and THF (0.1 M). The flask was purged with nitrogen and sealed. The reaction mixture was heated to 60° C. for 18 h. Standard work-up afforded cis-4-((5-cyano-2-(((4-(trifluoromethyl)pyridin-3-yl)methyl)amino)pyrimidin-4-yl)amino)-N-methylcyclohexanecarboxamide (48.2% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm) 8.73 (d, J=5.08 Hz, 1H), 8.64-8.69 (m, 1H), 8.29 (t, J=5.66 Hz, 1H), 8.21 (s, 1H), 7.72 (d, J=5.08 Hz, 1H), 7.53-7.66 (m, 1H), 7.00-7.12 (m, 1H), 4.62-4.73 (m, 2H), 3.69 (br. s., 1H), 2.53-2.61 (m, 3H), 2.15-2.30 (m, 1H), 1.70-1.97 (m, 2H), 1.42-1.62 (m, 3H), 1.15-1.27 (m, 3H). MS (ESI) m/z 434.3 [M+1]+
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:12]=[C:11]2[C:6]([C:7]([NH:13][C:14]3[CH:27]=[CH:26][C:17]([C:18]([N:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)=[O:19])=[CH:16][CH:15]=3)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.Cl[C:31]1[N:36]=[C:35]([O:37][CH3:38])[N:34]=[C:33]([O:39][CH3:40])[CH:32]=1.C(N(CC)CC)C>C(O)CO>[CH3:38][O:37][C:35]1[N:36]=[C:31]([N:23]2[CH2:24][CH2:25][N:20]([C:18](=[O:19])[C:17]3[CH:26]=[CH:27][C:14]([NH:13][C:7]4[C:6]5[C:11](=[CH:12][C:3]([C:2]([F:1])([F:28])[F:29])=[CH:4][CH:5]=5)[N:10]=[CH:9][CH:8]=4)=[CH:15][CH:16]=3)[CH2:21][CH2:22]2)[CH:32]=[C:33]([O:39][CH3:40])[N:34]=1
Reactant: COc1cc(Cl)nc(OC)n1
Reactant: O=C(c1ccc(Nc2ccnc3cc(C(F)(F)F)ccc23)cc1)N1CCNCC1
Solvent: OCCO
Solvent: CCN(CC)CC
Product: COc1cc(N2CCN(C(=O)c3ccc(Nc4ccnc5cc(C(F)(F)F)ccc45)cc3)CC2)nc(OC)n1
Temperature: 100 °C
Yield: 43.2 %

Procedure:
A mixture of 3.70 g (0.00924 mol) of 4-[4-[[7-(trifluoromethyl)-4-quinolinyl]amino]benzoyl]piperazine, 1.61 g (0.00924 mol) of 6-chloro-2,4-dimethoxypyrimidine, 1.29 ml (0.00924 mol) of triethylamine and 125 ml of ethylene glycol is heated at 100° C. for 6 hours. After cooling, the precipitated solid is collected on a sintered glass funnel and dried in the air over the weekend. The solid is chromatographed on silica gel, eluting with 6% methanol/methylene chloride, to give 2.15 g (43%) of 1-(2,6-dimethoxy-4-pyrimidinyl)-4-[4-[[7-(trifluoromethyl)-4-quinolinyl]amino]benzoyl]piperazine of melting point 260°-262° C., after crystallization from methanol/methylene chloride.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH3:8])[C:5]([Br:9])=[CH:4][N:3]=1.Cl.[NH:11]1[CH2:14][CH:13]([OH:15])[CH2:12]1.C(N(CC)CC)C>C(O)C>[Br:9][C:5]1[C:6]([CH3:8])=[N:7][C:2]([N:11]2[CH2:14][CH:13]([OH:15])[CH2:12]2)=[N:3][CH:4]=1
Reactant: OC1CNC1
Reactant: Cc1nc(Br)ncc1Br
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1nc(N2CC(O)C2)ncc1Br
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of the product from example 135 step (i) (0.75 g), azetidin-3-ol hydrochloride (0.66 g) and triethylamine (0.9 ml) in ethanol (10 ml) was stirred at RT for 2 h. The solvent was removed under reduced pressure and the residue purified by chromatography on silica eluting with 60% diethylether/isohexane as eluant, yield 0.7 g.
Reaction SMILES: CN.[CH2:3]([N:6]1[CH2:11][CH2:10][CH2:9][N:8]([C:12]2[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:19])C1=S)C=C>C(O)C.ClCCl>[Cl:18][C:17]1[C:12]([NH:8][CH2:9][CH2:10][CH2:11][NH:6][CH3:3])=[C:13]([CH3:19])[CH:14]=[CH:15][CH:16]=1
Reactant: C=CCN1CCCN(c2c(C)cccc2Cl)C1=S
Agent: CN
Solvent: CCO
Solvent: ClCCl
Product: CNCCCNc1c(C)cccc1Cl
Temperature: 25 °C
Reaction time: 17 h
Yield: 59.9 %

Procedure:
To an 8.03 M solution of methylamine in ethanol (31 mL) was added the hydrobromide salt of Example 12, Step B (8.6 g) and the mixture was stirred at ambient temperature for 17 hours. The ethanol was removed in vacuo and the residue was partitioned between dichloromethane and 1N sodium hydroxide. The organic phase was washed with brine, dried over sodium sulfate, and concentrated in vacuo to give a yellow oil. The crude material was dissolved in dichloromethane and absorbed onto a column of Merck-60 flash silica gel. Elution with a solvent gradient (from 98:2 to 80:20 dichloromethane-methanol containing 0.2% ammonium hydroxide) gave the title compound (3.9 g, 84.1%) as a pale yellow oil, which was used as such in the next step.