Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5](C(OCC)=O)[S:6][C:7]=1S(C)(=O)=O)#[N:2].O.[NH2:18][NH2:19].Cl.C(=O)([O-])O.[Na+].[CH2:26](O)[CH3:27]>>[CH2:26]([N:18]1[C:7]2[S:6][CH:5]=[CH:4][C:3]=2[C:1]([NH2:2])=[N:19]1)[CH3:27]
Reactant: NN
Reactant: CCO
Reactant: CCOC(=O)c1cc(C#N)c(S(C)(=O)=O)s1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CCn1nc(N)c2ccsc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A suspension of 16.4 g (0.063 mol) of ethyl 4-cyano-5-methylsulfonylthiophene-2-carboxylate in 160 mL of absolute ethanol is refluxed until the product has dissolved, and a solution of 6.2 mL (0.126 mol) of hydrazine hydrate in 40 mL of absolute ethanol is then added dropwise. The reaction mixture is stirred at reflux for 2 hours, and 4.6 mL (0.094 mol) of hydrazine hydrate are then added dropwise and stirring at reflux is continued for two hours. After cooling to a temperature in the region of 25° C., the mixture is concentrated to dryness under vacuum (2 kPa) at a temperature in the region of 40° C. The residue is taken up in 200 mL of ethanol and a solution of 13.2 mL (0.158 mol) of 12 N hydrochloric acid is added with stirring at a temperature in the region of 25° C. The reaction mixture is stirred at a temperature in the region of 25° C. for 4 hours, and then poured slowly into 500 mL of saturated sodium hydrogen carbonate solution precooled to 10° C. After stirring for 30 minutes, the mixture is extracted three times with 600 mL of ethyl acetate. The organic extracts are combined, washed twice with 300 mL of saturated brine, dried over magnesium sulfate, filtered and concentrated to dryness under vacuum (2 kPa) at a temperature in the region of 40° C. The residue is purified by chromatography on a column of 500 g of silica gel (0.020-0.045 mm), eluting with pure ethyl acetate. The fractions containing the expected product are combined and then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. 3.4 g of ethyl 3-amino-1H-thieno[2,3-c]pyrazole)-5-carboxylate are thus obtained in the form of a brown-colored powder, which product is used directly in the following step. MS-EI: 211 (+)=M(+).
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=2)[C:8]([NH:10][C:11](=[O:18])[NH:12][CH2:13][CH2:14][C:15]([OH:17])=[O:16])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:27]O>S(=O)(=O)(O)O.O>[CH3:27][O:16][C:15](=[O:17])[CH2:14][CH2:13][NH:12][C:11]([NH:10][C:8](=[O:9])[CH:7]([C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=1)[CH2:6][CH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)=[O:18]
Reactant: O=C(O)CCNC(=O)NC(=O)C(CC1CCCC1)c1ccc(Cl)c(Cl)c1
Reactant: CO
Agent: O=S(=O)(O)O
Solvent: O
Product: COC(=O)CCNC(=O)NC(=O)C(CC1CCCC1)c1ccc(Cl)c(Cl)c1
Temperature: 80 °C
Yield: 86 %

Procedure:
A solution of 3-{3-[3-cyclopentyl-2-(3,4-dichloro-phenyl)-propionyl]-ureido}-propionic acid (20 mg, 0.05 mmol) in methanol (5 mL) was treated with concentrated sulfuric acid (4 drops). This solution was heated to 80° C. for 8 h. At this time, the reaction was cooled to 25° C. and diluted with water (10 mL). This solution extracted with ethyl acetate (3×20 mL). The organics were washed with a saturated aqueous sodium bicarbonate solution (1×20 mL), a saturated aqueous sodium chloride solution (1×20 mL) and water (1×10 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 80/20 hexanes/ethyl acetate) afforded 3-{3-[3-cyclopentyl-2-(3,4-dichloro-phenyl)-propionyl]-ureido}-propionic acid methyl ester (18 mg, 86%) as a white solid: 93.6-95.8° C.: EI-HRMS m/e calcd for C19H24Cl2N2O4 (M+) 414.1113, found 414.1114.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][C:17]([OH:19])=O)=[CH:10][CH:9]=2)[CH2:7][CH2:6]1)=[O:4].C(Cl)(=O)C(Cl)=O>C(Cl)Cl.CN(C=O)C>[O:19]=[C:17]1[C:10]2[C:11](=[CH:12][CH:13]=[C:8]([C:5]3([C:3]([OH:2])=[O:4])[CH2:6][CH2:7]3)[CH:9]=2)[O:14][CH2:15][CH2:16]1.[O:19]=[C:17]1[C:10]2[C:11](=[CH:12][CH:13]=[C:8]([C:5]3([C:3]([O:2][CH3:1])=[O:4])[CH2:6][CH2:7]3)[CH:9]=2)[O:14][CH2:15][CH2:16]1
Reactant: COC(=O)C1(c2ccc(OCCC(=O)O)cc2)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)C1(c2ccc3c(c2)C(=O)CCO3)CC1
Product: O=C1CCOc2ccc(C3(C(=O)O)CC3)cc21
Temperature: 2.5 °C
Reaction time: 1 h
Yield: 38 %
Yield: 19 %

Procedure:
To a solution of 1-[4-(2-carboxy-ethoxy)-phenyl]-cyclopropanecarboxylic methyl ester (5.0 g, 20 mmol) in CH2Cl2 (50 mL) were added oxalyl chloride (4.8 g, 38 mmol) and two drops of DMF at 0° C. The mixture was stirred at 0-5° C. for 1 h and then evaporated under vacuum. To the resulting mixture was added CH2Cl2 (50 mL) at 0° C. and stirring was continued at 0˜5° C. for 1 h. The reaction was slowly quenched with water and was extracted with EtOAc (50 mL×3). The combined organic extracts were dried over anhydrous Na2SO4 and evaporated under vacuum to give the crude product, which was purified by column chromatography on silica gel (petroleum ether/ethyl acetate 20:1-2:1) to give 1-(4-oxochroman-6-yl)cyclopropanecarboxylic acid (830 mg, 19%) and methyl 1-(4-oxochroman-6-yl)cyclopropanecarboxylate (1.8 g, 38%). 1-(4-Oxochroman-6-yl)cyclopropane-carboxylic acid: 1H NMR (400 MHz, DMSO) δ 12.33 (br s, 1H), 7.62 (d, J=2.0 Hz, 1H), 7.50 (dd, J=2.4, 8.4 Hz, 1H), 6.95 (d, J=8.4 Hz, 1H), 4.50 (t, J=6.4 Hz, 2H), 2.75 (t, J=6.4 Hz, 2H), 1.44-1.38 (m, 2H), 1.10-1.07 (m, 2H). MS (ESI) m/z (M+H+) 231.4. 1-(4-Oxochroman-6-yl)cyclopropanecarboxylate: 1H NMR (400 MHz, CDCl3) δ 7.83 (d, J=2.4 Hz, 1H), 7.48 (dd, J=2.4, 8.4 Hz, 1H), 6.93 (d, J=8.4 Hz, 1H), 4.55-4.52 (m, 2H), 3.62 (s, 3H), 2.80 (t, J=6.4 Hz, 2H), 1.62-1.56 (m, 2H), 1.18-1.15 (m, 2H).
Reaction SMILES: [CH3:1][C@@H:2]1[NH:7][CH2:6][CH2:5][N:4]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH2:3]1.C1C=CC2N(O)N=NC=2C=1.O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:56][C:57]1[CH:58]=[C:59]([C:63](O)=[O:64])[CH:60]=[N:61][CH:62]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:1][C@H:2]1[CH2:3][N:4]([S:8]([C:11]2[CH:12]=[CH:13][C:14]([C:17]([F:20])([F:18])[F:19])=[CH:15][CH:16]=2)(=[O:9])=[O:10])[CH2:5][CH2:6][N:7]1[C:63]([C:59]1[CH:60]=[N:61][CH:62]=[C:57]([CH3:56])[CH:58]=1)=[O:64]
Reactant: C[C@H]1CN(S(=O)(=O)c2ccc(C(F)(F)F)cc2)CCN1
Reactant: Cc1cncc(C(=O)O)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Cc1cncc(C(=O)N2CCN(S(=O)(=O)c3ccc(C(F)(F)F)cc3)C[C@@H]2C)c1

Procedure:
To a solution of (3S)-3-methyl-1-{[4-(trifluoromethyl)phenyl]sulfonyl}piperazine (Description 2) (100 mg, 0.324 mmol) in DMF (5 ml) was added HOBT.H2O (49.7 mg, 0.324 mmol), HBTU (123 mg, 0.324 mmol), 5-methyl-3-pyridinecarboxylic acid (44.5 mg, 0.324 mmol) and DIPEA (0.170 ml, 0.973 mmol) and the reaction mixture was stirred for 1 h at room temperature. The reaction mixture was evaporated in vacuo. The residue was dissolved in DCM (50 ml), transferred to a separating funnel and the solution was washed with aqueous NaHCO3 (5 ml), twice. The organic layer was dried with magnesium sulphate which was removed by filtration and the filtrate evaporated to dryness in vacuo. The residual oil was dissolved in 1:1 MeCN/DMSO (1.8 ml) and purified by MDAP in two batches. The fractions containing the desired product were combined and evaporated to dryness in vacuo to the title compound (95 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[CH:7][NH:8]2)([O-:3])=[O:2].[CH2:13]=O.[CH3:15][NH:16][CH3:17]>>[CH3:15][N:16]([CH2:13][C:6]1[C:5]2[C:4]([N+:1]([O-:3])=[O:2])=[CH:12][CH:11]=[CH:10][C:9]=2[NH:8][CH:7]=1)[CH3:17]
Reactant: CNC
Reactant: O=[N+]([O-])c1cccc2[nH]ccc12
Reactant: C=O
Product: CN(C)Cc1c[nH]c2cccc([N+](=O)[O-])c12

Procedure:
Scheme M illustrates a general method of preparing compounds of the invention (for a synthesis of intermediate amine 8, see also J. Hester J. Org. Chem. 1967, 32, 4095). 4-Nitroindole and formaldehyde/dimethylamine were condensed to form 4-nitrogramine (2). Compound 2 underwent nucleophilic substitution with diethyl malonate to afford diester 3, which was then reduced to the amine 4 via hydrogenolysis over palladium-on-carbon. Indole 4 was cyclized thermally to lactam 5, and then underwent decarboxylation by treatment with potassium hydroxide followed by heating neat to give unsubstituted lactam 7. The lactam 7 was reduced with LAH to afford amine 8, which was acylated with acid chloride 9 (prepared by acylation of methyl 4-aminobenzoate with 2-biphenylcarbonyl chloride followed by sodium hydroxide-mediated saponification of the ester to the acid, and then thionyl chloride-mediated conversion to the acid chloride 9) to give the final product compound 10.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][CH:3]=1.Br[C:10]1[CH:20]=[CH:19][C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:12][CH:11]=1>>[CH2:17]([O:16][C:14](=[O:15])[C:13]1[CH:19]=[CH:20][C:10]([C:2]2[CH:7]=[CH:6][C:5]([F:8])=[CH:4][CH:3]=2)=[CH:11][CH:12]=1)[CH3:18]
Reactant: Fc1ccc(Br)cc1
Reactant: CCOC(=O)c1ccc(Br)cc1
Product: CCOC(=O)c1ccc(-c2ccc(F)cc2)cc1

Procedure:
Using the procedure of Example 551, 4-bromofluorobenzene (1.75 g, 10 mmol) was metallated and coupled with ethyl 4-bromobenzoate (2.28 g, 10 mmol) to give the title compound after chromatography (ethyl acetate-hexanes (1:9) (0.7 g)): 1H-NMR (CDCl3, 300 MHz): 8.1 (d, 2H, J=8), 7.65-7.5 (m, 4H), 7.15 (t, 2H, J=8), 4.4 (q, 2H, J=7), 1.4 (t, 3H, J=7); MS:244.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)([OH:10])[C:5]1[S:6][CH:7]=[CH:8][CH:9]=1.O[C@@H:19]1[CH:24]2C[CH2:26][N:21]([CH2:22][CH2:23]2)[CH2:20]1>C1(C)C=CC=CC=1>[N:21]12[CH2:22][CH2:23][CH:24]([CH2:19][CH2:20]1)[C@@H:1]([O:2][C:3](=[O:17])[C:4]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)([OH:10])[C:5]1[S:6][CH:7]=[CH:8][CH:9]=1)[CH2:26]2
Reactant: COC(=O)C(O)(c1cccs1)C1CCCCC1
Reactant: O[C@H]1CN2CCC1CC2
Solvent: Cc1ccccc1
Product: O=C(O[C@H]1CN2CCC1CC2)C(O)(c1cccs1)C1CCCCC1
Yield: 40.1 %

Procedure:
Prepared using the same method as for Intermediate I-1, but from 16.2 g (0.064 mol) of 2-Cyclohexyl-2-hydroxy-2-thien-2-ylacetic acid methyl ester (Intermediate I-12), dissolved in 400 ml of toluene, 9.5 g (0.074 mol) of (3R)-3-hydroxy-1-azabicyclo[2.2.2]octane and 1.51 g (0.038 mol) of HNa (60% dispersion in mineral oil). The oil obtained (10.97 g) was purified by chromatography on silica gel, eluting with chloroform/methanol/ammonia 95:5:0.5, to obtain 8.97 g of a pure product as a mixture of diastereomers, structure confirmed by 1H-RMN. Three crystallisations of this mixture from ethyl ether yield 1.68 g (15.2%) of a pure diastereomer (Intermediate I-6a). The mother liquors of the crystallisations were enriched with the other diastereomer (Intermediate I-6b).
Reaction SMILES: [CH:1]1([CH2:6][C:7]([NH:9][C:10]2[CH:18]=[C:17]3[C:13]([C:14]([OH:32])=[N:15][N:16]3[CH2:19][C:20]3[CH:29]=[CH:28][C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:22][C:21]=3[O:30][CH3:31])=[CH:12][CH:11]=2)=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:33](Br)[CH:34]=[CH2:35].[H-].[Na+].C(N1C(=O)C2C(=CC(NC(=O)CC3CCCC3)=CC=2)N1CC1C=CC(C(OC)=O)=CC=1OC)C=C>CN(C)C=O>[CH2:35]([O:32][C:14]1[C:13]2[C:17](=[CH:18][C:10]([NH:9][C:7](=[O:8])[CH2:6][CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)=[CH:11][CH:12]=2)[N:16]([CH2:19][C:20]2[CH:29]=[CH:28][C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:22][C:21]=2[O:30][CH3:31])[N:15]=1)[CH:34]=[CH2:33]
Reactant: COC(=O)c1ccc(Cn2nc(O)c3ccc(NC(=O)CC4CCCC4)cc32)c(OC)c1
Reactant: C=CCBr
Agent: C=CCn1c(=O)c2ccc(NC(=O)CC3CCCC3)cc2n1Cc1ccc(C(=O)OC)cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCOc1nn(Cc2ccc(C(=O)OC)cc2OC)c2cc(NC(=O)CC3CCCC3)ccc12

Procedure:
The starting ester methyl 4-[2-allyl-6-(2-cyclopentylacetamido)-3-oxo-2H,3H-indazol-1-ylmethyl]-3-methoxybenzoate was itself prepared as follows. Using a similar procedure to that described in Example 42, except starting from methyl 4-[6-(2-cyclopentylacetamido)-3-hydroxyindazol-1-ylmethyl]-3-methoxybenzoate (that is, reaction of this compound with allyl bromide in N,N-dimethylformamide in the presence of sodium hydride), a mixture of methyl 4-[2-allyl-6-(2-cyclopentylacetamido)-3-oxo-2H,3H-indazol-1-ylmethyl]-3-methoxybenzoate, and methyl 4-[3-allyloxy-6-(2-cyclopentylacetamido)indazol-1-ylmethyl]-3-methoxybenzoate was obtained. The mixture of compounds was heated neat at 200° C. for 18 hours, and the product isolated by flash chromatography on silica gel (60 g.), eluting with 1:30:70 v/v/v acetic acid:ethyl acetate:dichloromethane, to give methyl 4-[2-allyl-6-(2-cyclopentylacetamido)-3-oxo-2H,3H-indazol-1-ylmethyl]-3-methoxybenzoate in 81% yield, as an oil with satisfactory NMR spectral data.
Reaction SMILES: C(O)(=O)C.[Cl:5][C:6]1[C:11]([N+:12]([O-])=O)=[CH:10][C:9]([N:15]2[C:23](=[O:24])[C:18]3=[CH:19][CH2:20][CH2:21][CH2:22][N:17]3[C:16]2=[O:25])=[C:8]([F:26])[CH:7]=1>C(OCC)(=O)C>[NH2:12][C:11]1[C:6]([Cl:5])=[CH:7][C:8]([F:26])=[C:9]([N:15]2[C:23](=[O:24])[C:18]3=[CH:19][CH2:20][CH2:21][CH2:22][N:17]3[C:16]2=[O:25])[CH:10]=1
Reactant: O=C1C2=CCCCN2C(=O)N1c1cc([N+](=O)[O-])c(Cl)cc1F
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: Nc1cc(N2C(=O)C3=CCCCN3C2=O)c(F)cc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 59.4 %

Procedure:
After an acetic acid (172 mL) solution of reduced iron (21.0 g) was stirred for one hour under reflux, an ethyl acetate (113 mL) solution of 2-(4-chloro-2-fluoro-5-nitrophenyl)-5,6-dihydroimidazo [1,5-a] pyridine-1,3[2H, 7H]-dione (5.14 g, 0.016 mol) was dropwise added to the mixture at the same temperature. The reaction mixture was stirred for 2 hours under reflux and cooled down to room temperature. After filtration of the resulting mixture, 1N hydrochloric acid (250 mL) was added to the filtrate, and the organic layer was separated and the aqueous layer was extracted with ethyl acetate (100 mL×2 times). The organic layer combined was washed with water (300 mL) and dried over anhydrous magnesium sulfate. After removal of magnesium sulfate by filtration, the filtrate was evaporated to give crude product, which was purified by silica gel column (Wakogel C-200, ethyl acetate/hexane =1/1) to obtain a white solid of 2-(5-amino-4-chloro-2-fluorophenyl)-5,6-dihydroimidazo [1,5-a] pyridine-1,3[2H, 7H]-dione (2.81 g, yield:59.4%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([N:11]=[C:12]=[S:13])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[CH3:14][CH:15]([CH2:18][CH3:19])[CH2:16][NH2:17].Cl[CH2:21][C:22](O)=[O:23]>>[CH3:1][C:2]1[CH:3]=[C:4]([N:11]=[C:12]2[N:17]([CH2:16][CH:15]([CH3:14])[CH2:18][CH3:19])[C:22](=[O:23])[CH2:21][S:13]2)[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: O=C(O)CCl
Reactant: Cc1cc(N=C=S)ccc1[N+](=O)[O-]
Reactant: CCC(C)CN
Product: CCC(C)CN1C(=O)CSC1=Nc1ccc([N+](=O)[O-])c(C)c1

Procedure:
3-Methyl-4-nitrophenyl isothiocyanate was reacted with 2-methyl-1-butylamine followed by chloroacetic acid according to Method C8a to afford 2-(3-methyl-4-nitrophenylimino)-3-(2-methylbutyl)-1,3-thiazolidin-4-one.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[C:7]([O:9][CH3:10])=[O:8].[CH3:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=1)[CH:15]=O.C([BH3-])#N.[Na+].C(=O)(O)[O-].[Na+]>CO.C(OCC)(=O)C.C(O)(=O)C>[CH3:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=1)[CH2:15][NH:1][C@H:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[C:7]([O:9][CH3:10])=[O:8]
Reactant: Cc1cccc(C=O)c1
Reactant: COC(=O)[C@@H]1CCC[C@@H]1N
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)[C@@H]1CCC[C@@H]1NCc1cccc(C)c1
Reaction time: 0.17 h
Yield: 79.8 %

Procedure:
To a stirred solution of methyl (1R,2S)-2-aminocyclopentanecarboxylate (240 mg, 1.68 mmol) in methanol (10 mL) under a nitrogen atmosphere, 3-methyl-benzaldehyde (202 mg, 1.68 mmol) was added. The mixture was stirred for 10 min, and then acetic acid (0.4 mL) was added followed by sodium cyanoborohydride (265 mg, 4.2 mmol). The resulting mixture was stirred at 25° C. for 16 h, and then poured into a mixture of saturated aqueous sodium bicarbonate solution (50 mL) and ethyl acetate (100 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with saturated aqueous brine solution, dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo to afford the desired product, methyl (1R,2S)-2-[(3-methylbenzyl)amino]cyclopentanecarboxylate (330 mg, 1.34 mmol, 80%), as a clear oil. 1H NMR (400 MHz, CDCl3) δ: 1.62 (1H, m), 1.71 (1H, m), 1.91 (3H, m), 2.05 (1H, m), 2.37 (3H, s), 2.99 (1H, m), 3.34 (1H, m), 3.72 (3H, s), 3.77 (1H, d, J=12.8 Hz), 3.82 (1H, d, J=12.8 Hz), 7.24-7.07 (4H, m).
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:8]([CH3:18])=[N:9][C:10]2[C:15]([CH:16]=1)=[CH:14][N:13]=[C:12]([Cl:17])[CH:11]=2)(=O)=O.[F:21][C:22]1[CH:28]=[C:27]([CH3:29])[C:26](B2OC(C)(C)C(C)(C)O2)=[CH:25][C:23]=1[NH2:24].C([O-])([O-])=O.[K+].[K+].CCOC(C)=O>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:17][C:12]1[CH:11]=[C:10]2[C:15]([CH:16]=[C:7]([C:26]3[C:27]([CH3:29])=[CH:28][C:22]([F:21])=[C:23]([CH:25]=3)[NH2:24])[C:8]([CH3:18])=[N:9]2)=[CH:14][N:13]=1
Reactant: Cc1nc2cc(Cl)ncc2cc1OS(=O)(=O)C(F)(F)F
Reactant: Cc1cc(F)c(N)cc1B1OC(C)(C)C(C)(C)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cc1cc(F)c(N)cc1-c1cc2cnc(Cl)cc2nc1C
Temperature: 60 °C
Yield: 61.4 %

Procedure:
Sparge a mixture of 7-chloro-2-methyl-1,6-naphthyridin-3-yl trifluoromethanesulfonate (2.250 g, 6.89 mmol) and 2-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (1.729 g, 6.89 mmol) in dioxane (32 mL) with argon, add a solution of K2CO3 (2.86 g, 20.66 mmol) in H2O (16 mL) followed by Pd(PPh3)4 (252 mg, 0.689 mmol) and heat at 60° C. for 1 h. Cool to RT, add EtOAc, wash successively with H2O, satd. NaHCO3, then brine, dry over Na2SO4, concentrate to dryness and purify via silica gel chromatography (EtOAc/Hex) to afford the title compound (1.277 g, 61%) as a solid. 1H NMR (400 MHz, DMSO-d6): δ 9.21 (d, J=0.8 Hz, 1H), 8.28 (s, 1H), 8.00 (s, 1H), 7.00 (d, J=12.4 Hz, 1H), 6.59 (d, J=9.3 Hz, 1H), 5.08 (s, 2H), 2.42 (s, 3H), 1.85 (s, 3H); MS (ESI) m/z: 302.1 (M+H+).
Reaction SMILES: Cl.[Br:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9]N)=[CH:5][CH:4]=1.[C:11]1(=[O:28])[N:15]([CH:16]2[CH2:21][CH2:20][C:19](=O)[CH2:18][CH2:17]2)[C:14](=[O:23])[C:13]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:12]12>C(O)CCC>[C:14]1(=[O:23])[N:15]([CH:16]2[CH2:17][C:18]3[C:7]4[C:6](=[CH:5][CH:4]=[C:3]([Br:2])[CH:8]=4)[NH:9][C:19]=3[CH2:20][CH2:21]2)[C:11](=[O:28])[C:12]2=[CH:27][CH:26]=[CH:25][CH:24]=[C:13]12
Reactant: NNc1ccc(Br)cc1
Reactant: O=C1CCC(N2C(=O)c3ccccc3C2=O)CC1
Agent: Cl
Solvent: CCCCO
Product: O=C1c2ccccc2C(=O)N1C1CCc2[nH]c3ccc(Br)cc3c2C1
Yield: 104.1 %

Procedure:
Reaction of 4-bromophenylhydrazine hydrochloride (4.0g, 18.1 mmol) with 4-phthalimido-cyclohexanone (4.39g, 18.1 mmol) in refluxing n-butanol for 20 min, followed by cooling, filtration, and evaporation of the filtrate to dryness yielded 3-phthalimido-6-bromo-1,2,3,4-tetrahydrocarbazole as an orange solid (7.45g).
Reaction SMILES: NCC1C=C(N[C:10]2[C:18]3[C:13](=[N:14][CH:15]=[N:16][C:17]=3[NH:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=3)[NH:12][N:11]=2)C=CC=1.C1COCC1>C(OCC)C>[Cl:26][C:22]1[CH:21]=[C:20]([NH:19][C:17]2[N:16]=[CH:15][N:14]=[C:13]3[NH:12][N:11]=[CH:10][C:18]=23)[CH:25]=[CH:24][CH:23]=1
Reactant: NCc1cccc(Nc2n[nH]c3ncnc(Nc4cccc(Cl)c4)c23)c1
Solvent: CCOCC
Solvent: C1CCOC1
Product: Clc1cccc(Nc2ncnc3[nH]ncc23)c1
Temperature: 20 °C
Reaction time: 1.5 h

Procedure:
A mixture of 300 mg (0.805 mmol) of 3-(3aminomethyl-phenylamino)-4-(3chloro-phenylamino)-1H-pyrazoio[3,4-d]pyrimidine (water content: 1.79%; see Step 90.5), 230 mg (0.845 mmol) of Boc-glycine hydroxysuccinimide ester (Fluka) and 5 ml of THF is stirred at 20° C. for 1.5 hours. The addition of 5 ml of diethyl ether to the reaction mixture, filtration and washing the filter residue with diethyl ether yield 3-13-(N-{N-tert-butyloxy-carbonyl-glycyl}aminomethyl)-phenylamino]4-(3-chloro-phenylamino)-1H-pyrazolo[3,4-d]pyrimidine; m.p. 181-183° C.
Reaction SMILES: FC(F)(F)[C:3]([N:5](C)[CH2:6][C:7]1([CH2:11][N:12]2[CH:16]=[C:15]([NH:17][C:18]3[N:23]=[C:22]4[N:24]([CH2:27][C:28]5[CH:33]=[CH:32][CH:31]=[C:30]([N:34]6[CH2:39][CH2:38][O:37][CH2:36][CH2:35]6)[CH:29]=5)[N:25]=[CH:26][C:21]4=[CH:20][N:19]=3)[CH:14]=[N:13]2)[CH2:10][O:9][CH2:8]1)=O.C([O-])([O-])=O.[K+].[K+]>CO.O.CCOC(C)=O>[CH3:3][NH:5][CH2:6][C:7]1([CH2:11][N:12]2[CH:16]=[C:15]([NH:17][C:18]3[N:23]=[C:22]4[N:24]([CH2:27][C:28]5[CH:33]=[CH:32][CH:31]=[C:30]([N:34]6[CH2:39][CH2:38][O:37][CH2:36][CH2:35]6)[CH:29]=5)[N:25]=[CH:26][C:21]4=[CH:20][N:19]=3)[CH:14]=[N:13]2)[CH2:8][O:9][CH2:10]1
Reactant: CN(CC1(Cn2cc(Nc3ncc4cnn(Cc5cccc(N6CCOCC6)c5)c4n3)cn2)COC1)C(=O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Solvent: CCOC(C)=O
Product: CNCC1(Cn2cc(Nc3ncc4cnn(Cc5cccc(N6CCOCC6)c5)c4n3)cn2)COC1
Temperature: 55 °C
Yield: 10.9 %

Procedure:
2,2,2-trifluoro-N-methyl-N-((3-((4-((1-(3-morpholinobenzyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)-1H-pyrazol-1-yl)methyl)oxetan-3-yl)methyl)acetamide (22 mg, 37.5 μmol) was dissolved in MeOH (1 mL) in a small vial. A solution of K2CO3 (26 mg, 187 μmol) in H2O (60 μL) was added to the solution, and the closed vial was heated at 55° C. for 1.5 h. The mixture was then diluted with EtOAc (7 mL) and washed with H2O (5 ml). The aqueous was extracted with a mixture of CHCl3/IPA=2:1 (3 mL×2). The organics were dried on Na2SO4, filtered and the solvent evaporated. The crude (22 mg) was purified by prep HPLC to give the title compound (2 mg). 1H NMR (d6-Acetone) δ 8.93 (s, 1H), 8.85 (s, 1H), 8.26 (s, 1H), 8.14 (s, 1H), 7.95 (s, 1H), 7.71 (s, 1H), 7.17 (t, 1H), 7.05 (s, 1H), 6.85 (dd, J=8.0, 2.2 Hz, 1H), 6.80 (d, J=7.4 Hz, 1H), 5.52 (s, 2H), 4.59 (d, J=6.1 Hz, 2H), 4.50 (s, 2H), 4.34 (d, J=6.1 Hz, 2H), 3.72 (t, 4H), 3.06 (m, 4H), 2.52 (s, 2H), 2.38 (s, 3H); LC-MS method B, (ES+) 490.2, RT=5.08 min.
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([OH:26])=[CH:16][C:17]=3[O:19][CH:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[N:12]=[CH:11][N:10]=2)=[C:6]2[O:27][CH2:28][O:29][C:5]2=[CH:4][CH:3]=1.[C:30](OC([O-])=O)([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31]>CN(C=O)C>[C:33]([O:32][C:30]([N:23]1[CH2:22][CH2:21][CH:20]([O:19][C:17]2[CH:16]=[C:15]([OH:26])[CH:14]=[C:13]3[C:18]=2[C:9]([NH:8][C:7]2[C:2]([Cl:1])=[CH:3][CH:4]=[C:5]4[O:29][CH2:28][O:27][C:6]=24)=[N:10][CH:11]=[N:12]3)[CH2:25][CH2:24]1)=[O:31])([CH3:36])([CH3:35])[CH3:34]
Reactant: Oc1cc(OC2CCNCC2)c2c(Nc3c(Cl)ccc4c3OCO4)ncnc2c1
Reactant: CC(C)(C)OC(=O)OC(=O)[O-]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(Oc2cc(O)cc3ncnc(Nc4c(Cl)ccc5c4OCO5)c23)CC1
Yield: 69.1 %

Procedure:
A mixture of 4-(6-chloro-2,3-methylenedioxyanilino)-7-hydroxy-5-piperidin-4-yloxyquinazoline (1.4 g), di-(tert-butyl dicarbonate (0.737 g) and DMF (14 ml) was stirred at ambient temperature for 2 hours. The mixture was evaporated and the residue was partitioned between ethyl acetate and water. The organic phase was washed with brine, dried over magnesium sulphate and evaporated. The residue was purified by column chromatography on silica using a 24:1 mixture of methylene chloride and methanol as eluent. There was thus obtained the title compound (1.2 g); NMR Spectrum: (CDCl3) 1.5 (s, 9H), 1.7-1.9 (m, 2H), 2.0-2.15 (m, 2H), 3.0-3.15 (m, 2H), 3.8-3.95 (m, 2H), 4.6 (m, 1H), 6.02 (s, 2H), 6.55 (s, 1H), 6.72 (d, 1H), 6.98 (m, 2H), 8.4 (s, 1H), 9.4 (s, 1H); Mass Spectrum: M+H+ 515 and 517.