Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:10]([O:11][CH3:12])=[C:9]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH:24]=[CH:23][CH:22]=[N:21]3)=[CH:16][CH:15]=2)[CH:8]=[C:7]2[C:3]=1[CH:4](O)[N:5]([C@@H:26]1[CH2:31][CH2:30][CH2:29][CH2:28][C@H:27]1[OH:32])[C:6]2=[O:25].FC(F)(F)C(O)=O.C([SiH](CC)CC)C.C(=O)(O)[O-].[Na+]>ClCCl>[Cl:1][C:2]1[C:10]([O:11][CH3:12])=[C:9]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH:24]=[CH:23][CH:22]=[N:21]3)=[CH:16][CH:15]=2)[CH:8]=[C:7]2[C:3]=1[CH2:4][N:5]([C@@H:26]1[CH2:31][CH2:30][CH2:29][CH2:28][C@H:27]1[OH:32])[C:6]2=[O:25]
Reactant: COc1c(Cc2ccc(-n3cccn3)cc2)cc2c(c1Cl)C(O)N([C@@H]1CCCC[C@H]1O)C2=O
Agent: CC[SiH](CC)CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1c(Cc2ccc(-n3cccn3)cc2)cc2c(c1Cl)CN([C@@H]1CCCC[C@H]1O)C2=O
Reaction time: 0.25 h
Yield: 29.6 %

Procedure:
To a solution of rac-4-chloro-3-hydroxy-2-(trans-2-hydroxycyclohexyl)-5-methoxy-6-[4-(1H-pyrazol-1-yl)benzyl]-2,3-dihydro-1H-isoindol-1-one (0.07 g) in dichloromethane (2.00 mL) was added trifluoroacetic acid (0.50 mL) under ice-cooling, and the mixture was stirred for 15 min. Then, triethylsilane (0.40 mL) was added thereto, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was poured into saturated aqueous sodium bicarbonate solution, and the mixture was extracted with ethyl acetate (×2). The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by prep-HPLC, then lyophilized to give the title compound (0.02 g).
Reaction SMILES: O[C:2]([CH2:16][CH2:17][CH3:18])=[CH:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]([F:15])([F:14])[F:13])[CH:7]=1)=O.[NH2:19][C:20]([NH2:22])=[O:21].Cl>C(O)C>[CH2:16]([C:2]1[NH:22][C:20](=[O:21])[N:19]=[C:4]([C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([C:12]([F:15])([F:14])[F:13])[CH:7]=2)[CH:3]=1)[CH2:17][CH3:18]
Reactant: NC(N)=O
Reactant: CCCC(O)=CC(=O)c1cccc(C(F)(F)F)c1
Agent: Cl
Solvent: CCO
Product: CCCc1cc(-c2cccc(C(F)(F)F)c2)nc(=O)[nH]1
Yield: 72.1 %

Procedure:
A stirred mixture of 3-hydroxy-1-(3-trifluoromethylphenyl)-hex-2-en-1-one (259 mg), urea (90 mg), HCl (0.15 mL, 5M) and ethanol (5 mL) was heated at reflux for 16 h. Further urea (60 mg) and HCl (0.15 mL, 5M) were added and heating continued at reflux for 24 h. The mixture was allowed to cool and the solvent was evaporated at reduced pressure. The residue was dissolved in a mixture of ethyl acetate (20 mL) and water (20 mL), the organic layer was separated and further washed with a solution of saturated sodium carbonate (20 mL) followed by water (20 mL). The ethyl acetate extract was then dried over sodium sulphate and evaporated at reduced pressure to afford 6-propyl-4-(3-trifluoromethylphenyl)-1H-pyrimidin-2-one as a brown solid (204 mg). MS m/z 283.0 (M+1), 100%.
Reaction SMILES: Br[C:2]1[CH:15]=[CH:14][C:5]([CH2:6][CH2:7][N:8]2[CH2:12][CH2:11][CH2:10][C@H:9]2[CH3:13])=[CH:4][CH:3]=1.C([Li])CCC.[B:21](OC(C)C)([O:26]C(C)C)[O:22]C(C)C>C1COCC1>[CH3:13][C@@H:9]1[CH2:10][CH2:11][CH2:12][N:8]1[CH2:7][CH2:6][C:5]1[CH:14]=[CH:15][C:2]([B:21]([OH:26])[OH:22])=[CH:3][CH:4]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: C[C@@H]1CCCN1CCc1ccc(Br)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C[C@@H]1CCCN1CCc1ccc(B(O)O)cc1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 98.7 %

Procedure:
To a 1 L 3-neck flask equipped with mechanical stirrer, thermometer, and addition funnel under an atmosphere of nitrogen was charged a solution of (R)-1-(4-bromophenethyl)-2-methylpyrrolidine (26.8 g, 100 mmol) in anhydrous THF (250 mL). The reaction mixture was then cooled to an internal temperature of −78° C. A solution of n-butyl lithium (2.5M in hexane, 52 mL, 130 mmol) was added dropwise, maintaining an internal temperature below −70° C. Once addition was complete, stirring was continued an additional 15 min prior to the addition of triisopropyl borate (75 g, 400 mmol), followed by a rinse with 50 mL anhydrous THF, maintaining an internal temperature below −65° C. during addition. The reaction mixture was then allowed to warm to ambient temperature over 1.5 h, and was then quenched by dropwise addition of 2 N HCl (100 mL). The resulting mixture was stirred overnight, and the solvent volume was reduced to about 150 mL. The resulting suspension was cooled in an ice bath and filtered, rinsing sparingly with cold isopropanol. The filtrate volume was again reduced to 50 mL and the process was repeated. The filter cakes were combined, taken up in boiling isopropanol (250 mL), dissolving most, but not all of the solids. The mixture was then cooled in an ice bath and filtered, then the filtrate was concentrated to half volume and the process was repeated to provide two additional crops. A white solid was obtained as the title compound (23 g). LCMS m/z=234.3 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.41 (d, J=6.6 Hz, 3H), 1.59-1.68 (m, 1H), 1.89-2.00 (m, 2H), 2.15-2.22 (m, 1H), 3.00-3.07 (m, 2H), 3.11-3.19 (m, 2H), 3.37-3.50 (m, 2H), 3.57-3.65 (m, 1H), 4.80-6.75 (bs, 3H), 7.27 (d, J=7.6 Hz, 2H), 7.76 (d, J=8.2 Hz, 2H).
Reaction SMILES: [CH3:1][CH:2]([CH2:4][C:5](=O)[CH2:6][CH2:7][CH2:8][CH3:9])[CH3:3].C([BH3-])#[N:12].[Na+].C([O-])(=O)C.[NH4+]>CO>[CH3:1][CH:2]([CH2:4][CH:5]([NH2:12])[CH2:6][CH2:7][CH2:8][CH3:9])[CH3:3]
Reactant: [BH3-]C#N
Reactant: CCCCC(=O)CC(C)C
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: CCCCC(N)CC(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 25.4 %

Procedure:
A mixture of 2-methyloctan-4-one (6.3 g, 44 mmol), sodium cyanoborohydride (3.0 g, 48 mmol), ammonium acetate (33.9 g, 0.44 mol) and 3Å molecular sieves in dry methanol (50 ml) was stirred overnight at room temperature under argon. The solvent was removed under reduced pressure and the residue taken up in chloroform (100 ml), filtered through a pad of celite and concentrated to give 2-methyl-4-aminooctane (1.6 g, 25%) as a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:42]=[CH:43][CH:44]=1)[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[CH:21]=[N:22][C:23]([N:26]5[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]5)=[CH:24][CH:25]=4)[CH:18]=3)[N:13]([S:32]([C:35]3[CH:41]=[CH:40][C:38]([CH3:39])=[CH:37][CH:36]=3)(=[O:34])=[O:33])[CH:12]=2)[CH:8]=[N:7]1.FC1C=C(C=CC=1)CN1C=C(C2C3C(=NC=C(C4C=NC(N5CCN(C)CC5)=CC=4)C=3)NC=2)C=N1.[CH:80]1([CH2:83][C:84](O)=[O:85])[CH2:82][CH2:81]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH:80]1([CH2:83][C:84]([N:29]2[CH2:30][CH2:31][N:26]([C:23]3[CH:24]=[CH:25][C:20]([C:17]4[CH:18]=[C:19]5[C:11]([C:9]6[CH:8]=[N:7][N:6]([CH2:5][C:4]7[CH:42]=[CH:43][CH:44]=[C:2]([F:1])[CH:3]=7)[CH:10]=6)=[CH:12][N:13]([S:32]([C:35]6[CH:41]=[CH:40][C:38]([CH3:39])=[CH:37][CH:36]=6)(=[O:34])=[O:33])[C:14]5=[N:15][CH:16]=4)=[CH:21][N:22]=3)[CH2:27][CH2:28]2)=[O:85])[CH2:82][CH2:81]1
Reactant: O=C(O)CC1CC1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(N5CCNCC5)nc4)cnc32)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN1CCN(c2ccc(-c3cnc4[nH]cc(-c5cnn(Cc6cccc(F)c6)c5)c4c3)cn2)CC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(N5CCN(C(=O)CC6CC6)CC5)nc4)cnc32)cc1

Procedure:
Using similar reaction conditions as described in step-ii of example-124, 3-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)-5-(6-(piperazin-1-yl)pyridin-3-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (step 1 compound of example 137) (75 mg, 0.123 mmol) was coupled with 2-cyclopropylacetic acid (19 mg, 0.185 mmol) using HATU (70 mg, 0.185 mmol), HOBt (25 mg, 0.185 mmol) and DIPEA (48 mg, 0.37 mmol) in DMF (3 mL) to get 80 mg (95.2.0%) yield of the title compound. MS: m/z=690.6 (M+1).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH:6]=[CH:7][C:8]2[CH:24]=[CH:23][C:11]([C:12]([NH:14][C@H:15]([C:20]([OH:22])=[O:21])[CH2:16][CH2:17][S:18][CH3:19])=[O:13])=[C:10]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH:9]=2)[N:3]=[CH:2]1.[H][H]>[Pd].C(OCC)(=O)C>[NH:1]1[CH:5]=[C:4]([CH2:6][CH2:7][C:8]2[CH:24]=[CH:23][C:11]([C:12]([NH:14][C@H:15]([C:20]([OH:22])=[O:21])[CH2:16][CH2:17][S:18][CH3:19])=[O:13])=[C:10]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH:9]=2)[N:3]=[CH:2]1
Reactant: [H][H]
Reactant: CSCC[C@H](NC(=O)c1ccc(C=Cc2c[nH]cn2)cc1-c1ccccc1)C(=O)O
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CSCC[C@H](NC(=O)c1ccc(CCc2c[nH]cn2)cc1-c1ccccc1)C(=O)O

Procedure:
The resultant olefin (1 mmol) from Example 48 is mixed with 5% palladium on carbon (100 mg) in ethyl acetate. The reaction mixture is attached to a hydrogenation apparatus, and then is detached from the apparatus after about 95% of the theoretical hydrogen has been absorbed. The reaction mixture is filtered and concentrated in vacuo. The crude product is purified with a column chromatography on silica gel to give the title compound.
Reaction SMILES: O.[NH2:2][C:3]1[C:4]([CH2:14]SC)=[C:5]([C:10]([F:13])([F:12])[F:11])[CH:6]=[CH:7][C:8]=1Cl>C(O)(=O)C>[NH2:2][C:3]1[C:4]([CH3:14])=[C:5]([C:10]([F:11])([F:12])[F:13])[CH:6]=[CH:7][CH:8]=1
Reactant: CSCc1c(C(F)(F)F)ccc(Cl)c1N
Solvent: O
Solvent: CC(=O)O
Product: Cc1c(N)cccc1C(F)(F)F

Procedure:
Add 70 ml of water, 150 ml of glacial acetic acid and 100 g. of 3-amino-4-chloro-2-methylthiomethylbenzotrifluoride to a three-necked round bottom flask fitted with mechanical stirrer and condenser. Then add 535 g. of washed and neutralized Raney active nickel catalyst (Grace no. 28 in water). Heat to reflux (98° C.-100° C.) for 20 hours. Steam distill to obtain the title compound.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][N:5]2[C:10]([C:11]=1[CH3:12])=[C:9]([CH:13]1[CH2:15][CH2:14]1)[CH:8]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[C:6]2=[O:20].CC1(C)C(C)(C)OB([C:29]2[CH:30]=[N:31][N:32](C(OC(C)(C)C)=O)[CH:33]=2)O1>>[NH:31]1[CH:30]=[C:29]([C:2]2[CH:3]=[CH:4][N:5]3[C:10]([C:11]=2[CH3:12])=[C:9]([CH:13]2[CH2:15][CH2:14]2)[CH:8]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[C:6]3=[O:20])[CH:33]=[N:32]1
Reactant: COC(=O)c1cc(C2CC2)c2c(C)c(Cl)ccn2c1=O
Reactant: CC(C)(C)OC(=O)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Product: COC(=O)c1cc(C2CC2)c2c(C)c(-c3cn[nH]c3)ccn2c1=O
Yield: 49.1 %

Procedure:
Methyl 8-(1H-pyrazol-4-yl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate was prepared according to General Procedure A from methyl 8-chloro-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (100 mg, 0.34 mmol) and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate (120.8 mg, 0.41 mmol). Purification by flash silica column chromatography (DCM:MeOH) (1:0 to 9:1) afforded the title compound as a yellow solid (54 mg, 49%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([C:19]4[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=4)=[CH:15][C:13]=3[N:14]=2)[C:5]([O:8][CH3:9])=[CH:6][CH:7]=1.[CH:29]1[C:34]([C:35]([OH:37])=[O:36])=[CH:33][C:32]2[C:38]([O:40][C:41](=O)[C:31]=2[CH:30]=1)=[O:39]>>[CH3:9][O:8][C:5]1[C:4]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([C:19]4[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=4)=[CH:15][C:13]=3[N:14]=2)=[CH:3][C:2]([N:1]2[C:38](=[O:39])[C:32]3[C:31](=[CH:30][CH:29]=[C:34]([C:35]([OH:37])=[O:36])[CH:33]=3)[C:41]2=[O:40])=[CH:7][CH:6]=1
Reactant: O=C(O)c1ccc2c(c1)C(=O)OC2=O
Reactant: COc1ccc(N)cc1-c1nc2cc(-c3ccc(C(F)(F)F)cc3)ccc2o1
Product: COc1ccc(N2C(=O)c3ccc(C(=O)O)cc3C2=O)cc1-c1nc2cc(-c3ccc(C(F)(F)F)cc3)ccc2o1

Procedure:
Prepared by the method of Example 15f), from 2-(3-amino-6-methoxyphenyl)-5-(4-trifluoromethylphenyl)benzoxazole (90 mg, 0.23 mmol) and 1,2,4-benzenetricarboxylic anhydride (45 mg, 0.23 mmol) the title compound was obtained (102 mg, 79%). 1H NMR (DMSO) δ 13.74(s, 1H), 8.43(d, 1H), 8.33(s, 1H), 8.22(d, 1H), 8.20(d, 1H), 8.10(d, 1H), 7.99(d, 2H), 7.93(d, 1H), 7.83(m, 3H), 7.72(dd, 1H), 7.48(d, 1H), 4.03(s, 3H). MS 559.3 m/z (M+H)+.
Reaction SMILES: [CH2:1]([C:4]1[C:12]([OH:13])=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[CH:7][NH:8]2)[CH:2]=[CH2:3].C([O-])=O.[NH4+]>CCO.[OH-].[Pd+2].[OH-]>[CH2:1]([C:4]1[C:12]([OH:13])=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[CH:7][NH:8]2)[CH2:2][CH3:3]
Reactant: C=CCc1c(O)ccc2[nH]ccc12
Agent: [Pd+2]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: CCCc1c(O)ccc2[nH]ccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75.3 %

Procedure:
4-Allyl-1H-indol-5-ol (Example 54) 120 mg, 0.69 mmol) was dissolved in EtOH (10 mL), and 20% palladium (II) hydroxide on carbon (20 mg) and ammonium formate (349.5 mg, 5.45 mmol) were added. After stirring for 30 min at rt, the mixture was heated to 40° C. for 2 h. After cooling to rt, the catalyst was removed by filtration, and the filtrate concentrated under reduced pressure. The residue was taken up in water, and the aqueous phase was extracted with EtOAc (2×). The combined organic phases were dried over Na2SO4, filtered, and concentrated under reduced pressure to give 91 mg (75%) of the title compound as a white solid. 1H NMR (400 MHz, CDCl3): δ 1.04 (t, 3H), 2.74 (m, 2H), 2.88 (t, 2H), 6.49 (s, 1H), 6.75 (d, 1H), 7.10 (d, 1H), 7.18 (s, 1H), 8.00 (br, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:18][CH3:19])=[C:14]([OH:17])[CH:15]=2)[CH2:10][CH2:9][N:8]1[CH2:20][C:21]([NH:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22].[CH2:36](I)[CH3:37]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:18][CH3:19])=[C:14]([O:17][CH2:36][CH3:37])[CH:15]=2)[CH2:10][CH2:9][N:8]1[CH2:20][C:21]([NH:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22]
Reactant: COc1cc2c(cc1O)C(Cc1ccc(OC)c(OC)c1)N(CC(=O)NCc1ccccc1)CC2
Reactant: CCI
Product: CCOc1cc2c(cc1OC)CCN(CC(=O)NCc1ccccc1)C2Cc1ccc(OC)c(OC)c1

Procedure:
prepared by reaction of 2-[1-(3,4-dimethoxy-benzyl)-7-hydroxy-6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-benzyl-acetamide with ethyl iodide
Reaction SMILES: [CH:1]12[O:9][CH:5]([CH2:6][NH:7][CH2:8]1)[CH2:4][N:3]([CH2:10][CH2:11][O:12][C:13]1[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=1)[CH2:2]2.[C:21]([O:25][C:26](=[O:32])[NH:27][CH2:28][CH2:29][CH2:30]Br)([CH3:24])([CH3:23])[CH3:22].C([O-])([O-])=O.[K+].[K+]>C(#N)C>[C:21]([O:25][C:26](=[O:32])[NH:27][CH2:28][CH2:29][CH2:30][N:7]1[CH2:8][CH:1]2[O:9][CH:5]([CH2:4][N:3]([CH2:10][CH2:11][O:12][C:13]3[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=3)[CH2:2]2)[CH2:6]1)([CH3:24])([CH3:23])[CH3:22]
Reactant: N#Cc1ccc(OCCN2CC3CNCC(C2)O3)cc1
Reactant: CC(C)(C)OC(=O)NCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)NCCCN1CC2CN(CCOc3ccc(C#N)cc3)CC(C1)O2
Temperature: 60 °C
Reaction time: 8 h
Yield: 40.6 %

Procedure:
A suspension of 4-[2-(9-Oxa-3,7-diaza-bicyclo[3.3.1]non-3-yl)-ethoxy]-benzonitrile (6.5 g, 0.02 mol, see WO 01/28992), (3-Bromo-propyl)-carbamic acid tert-butyl ester (6.0 g, 0.025 mol) and dry K2CO3 (13.08 g, 0.0946 mol) in 40 ml of dry acetonitrile was stirred at 60° C. overnight under N2 atmosphere. The reaction mixture was filtered through celite and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography over silica gel using 20% ethyl acetate in petroleum ether as eluent to yield sub-title compound (3.5 g) as a liquid.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[C:11]([Cl:18])=[CH:10][C:9]=1[NH:19][C:20](=[O:36])[CH2:21][C:22](=O)[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]2[CH:30]=[N:31][CH:32]=[N:33][CH:34]=2)[CH:24]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:18][C:11]1[C:12]([C:14]([F:17])([F:16])[F:15])=[CH:13][C:8]2[N:7]=[C:22]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]4[CH:30]=[N:31][CH:32]=[N:33][CH:34]=4)[CH:24]=3)[CH2:21][C:20](=[O:36])[NH:19][C:9]=2[CH:10]=1
Reactant: CC(C)(C)OC(=O)Nc1cc(C(F)(F)F)c(Cl)cc1NC(=O)CC(=O)c1cccc(-c2cncnc2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1CC(c2cccc(-c3cncnc3)c2)=Nc2cc(C(F)(F)F)c(Cl)cc2N1

Procedure:
The title compound was prepared from {4-chloro-2-[3-oxo-3-(3-pyrimidin-5-yl-phenyl)-propionylamino]-5-trifluoromethyl-phenyl}-carbamic acid tert-butyl ester (Example M102) (0.31 g, 0.58 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light brown solid (110 mg, 46%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:13])=[CH:4][C:5]([Br:12])=[C:6]([CH:11]=1)[C:7]([NH:9][CH3:10])=[O:8].CCN(C(C)C)C(C)C.[Cl:23][CH2:24][C:25](Cl)=[O:26].O>CC(C)=O>[Br:12][C:5]1[CH:4]=[C:3]([CH3:13])[C:2]([NH:1][C:25](=[O:26])[CH2:24][Cl:23])=[CH:11][C:6]=1[C:7]([NH:9][CH3:10])=[O:8]
Reactant: O=C(Cl)CCl
Reactant: CNC(=O)c1cc(N)c(C)cc1Br
Solvent: CC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CNC(=O)c1cc(NC(=O)CCl)c(C)cc1Br
Reaction time: 1 h
Yield: 85.6 %

Procedure:
To a solution of 5-amino-2-bromo-N, 4-dimethylbenzamide (3A) (94 mg, 0.38 mmol) in acetone (4 mL) at 0° C. was added DIPEA (68 μL, 0.39 mmol) followed by 2-chloroacetylchloride (31 μL, 0.39 mmol). The solution was stirred for 60 minutes and another aliquot of 2-chloroacetylchloride (4 μL) was added. Water was added (94 mL) and the acetone removed in vacuo. The solids were stirred rapidly for 1 h, filtered and washed with water to give 104 mg (84% yield) of 2-bromo-5-(2-chloroacetamido)-N-methyl-4-methylbenzamide, 1H NMR: (CDCl3, 400 MHz) δ 8.28 (s, 1H), 8.03 (s, 1H), 7.44 (s, 1H), 6.01 (br s, 1H), 4.23 (s, 2H), 3.01 (d, J=5.0 Hz, 3H), 2.17 (s, 3H); LCMS 320.99 (M+H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@H:26]3[CH2:31][CH2:30][C@@H:29]([N:32]4[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]4)[CH2:28][CH2:27]3)[N:9]=[C:10]([C:11]3[CH:25]=[CH:24][C:14]([O:15][C:16]4[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=4)=[CH:13][CH:12]=3)[C:3]=12.[OH-].[Na+].OO.C(O)(=O)CC(CC(O)=O)(C(O)=O)[OH:46]>O1CCOCC1.O>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@H:26]3[CH2:31][CH2:30][C@@H:29]([N:32]4[CH2:33][CH2:34][N:35]([CH3:38])[CH2:36][CH2:37]4)[CH2:28][CH2:27]3)[N:9]=[C:10]([C:11]3[CH:12]=[CH:13][C:14]([O:15][C:16]4[CH:17]=[CH:18][C:19]([C:20]([NH2:21])=[O:46])=[CH:22][CH:23]=4)=[CH:24][CH:25]=3)[C:3]=12
Reactant: CN1CCN([C@H]2CC[C@@H](n3nc(-c4ccc(Oc5ccc(C#N)cc5)cc4)c4c(N)ncnc43)CC2)CC1
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CN1CCN([C@H]2CC[C@@H](n3nc(-c4ccc(Oc5ccc(C(N)=O)cc5)cc4)c4c(N)ncnc43)CC2)CC1

Procedure:
Cis-4-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenoxy)benzonitrile (0.200 g, 0.000394 mol) was dissolved in dioxane (3 mL), the solution of sodium hydroxide (0.15 g, 0.00197 mol) in water (2 mL) was added followed by the addition of 30% hydrogen peroxide solution in water (5 drops). The reaction mixture was heated at reflux under an atmosphere of nitrogen for 1.5 hours, cooled to ambient temperature and neutralized with 5% solution of citric acid in water. The solvents were removed under reduced pressure and the residue purified by preparative HPLC (Hypersil C18, 8 μm, 25 cm; 10-60% acetonitrile-0.1M ammonium acetate over 25 min, 21 mL/min) to yield cis-4-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenoxy)benzamide (0.120 g, 0.000223 mol) as an off-white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:42]=[CH:43][CH:44]=1)[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[CH:21]=[N:22][C:23]([N:26]5[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]5)=[CH:24][CH:25]=4)[CH:18]=3)[N:13]([S:32]([C:35]3[CH:41]=[CH:40][C:38]([CH3:39])=[CH:37][CH:36]=3)(=[O:34])=[O:33])[CH:12]=2)[CH:8]=[N:7]1.FC1C=C(C=CC=1)CN1C=C(C2C3C(=NC=C(C4C=NC(N5CCN(C)CC5)=CC=4)C=3)NC=2)C=N1.Cl.[CH3:81][N:82]([CH3:87])[CH2:83][C:84](O)=[O:85].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:81][N:82]([CH3:87])[CH2:83][C:84]([N:29]1[CH2:30][CH2:31][N:26]([C:23]2[CH:24]=[CH:25][C:20]([C:17]3[CH:18]=[C:19]4[C:11]([C:9]5[CH:8]=[N:7][N:6]([CH2:5][C:4]6[CH:42]=[CH:43][CH:44]=[C:2]([F:1])[CH:3]=6)[CH:10]=5)=[CH:12][N:13]([S:32]([C:35]5[CH:41]=[CH:40][C:38]([CH3:39])=[CH:37][CH:36]=5)(=[O:34])=[O:33])[C:14]4=[N:15][CH:16]=3)=[CH:21][N:22]=2)[CH2:27][CH2:28]1)=[O:85]
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(N5CCNCC5)nc4)cnc32)cc1
Reactant: CN(C)CC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN1CCN(c2ccc(-c3cnc4[nH]cc(-c5cnn(Cc6cccc(F)c6)c5)c4c3)cn2)CC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(N5CCN(C(=O)CN(C)C)CC5)nc4)cnc32)cc1

Procedure:
Using similar reaction conditions as described in step-ii of example-124, 3-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)-5-(6-(piperazin-1-yl)pyridin-3-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (step 1 compound of example 137) (75 mg, 0.124 mmol) was coupled with 2-(dimethylamino)acetic acid hydrochloride (26 mg, 0.186 mmol) using HATU (71 mg, 0.186 mmol), HOBt (26 mg, 0.186 mmol) and DIPEA (87 μL, 0.498 mmol) in DMF (2 mL) to get 80 mg (93.0%) yield of the title compound. MS: m/z=693.3 (M+1).
Reaction SMILES: Cl.CN.C[CH2:5][N:6](C(C)C)C(C)C.[CH3:13][C:14]([C:18]1[N:22]([CH2:23][CH:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[C:21]2[CH:30]=[CH:31][C:32]([S:34]([N:37]3[CH:41]=[C:40]([C:42]([OH:44])=O)[CH:39]=[N:38]3)(=[O:36])=[O:35])=[CH:33][C:20]=2[N:19]=1)([CH3:17])[CH2:15][CH3:16].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH3:17][C:14]([C:18]1[N:22]([CH2:23][CH:24]2[CH2:25][CH2:26][O:27][CH2:28][CH2:29]2)[C:21]2[CH:30]=[CH:31][C:32]([S:34]([N:37]3[CH:41]=[C:40]([C:42]([NH:6][CH3:5])=[O:44])[CH:39]=[N:38]3)(=[O:35])=[O:36])=[CH:33][C:20]=2[N:19]=1)([CH3:13])[CH2:15][CH3:16]
Reactant: CCN(C(C)C)C(C)C
Reactant: CCC(C)(C)c1nc2cc(S(=O)(=O)n3cc(C(=O)O)cn3)ccc2n1CC1CCOCC1
Agent: CN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Solvent: CN(C)C=O
Product: CCC(C)(C)c1nc2cc(S(=O)(=O)n3cc(C(=O)NC)cn3)ccc2n1CC1CCOCC1
Yield: 91.5 %

Procedure:
Following the same procedure in Example 24, Step A, using methylamine hydrochloride (24 mg, 0.36 mmol), DIPEA (104 uL, 77 mg, 0.59 mmol), 1-{[2-(1,1-dimethylpropyl)-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5-yl]sulfonyl}-1H-pyrazole-4-carboxylic acid (0.18 mmol) (see following Steps B and C for preparation) and HATU (109 mg, 0.29 mmol) in DMF (3 mL). The crude product was purified by MPLC using Hex/EtOAc (1:9) on silica gel to give 78 mg (92%) of a white solid as the title compound. 1H NMR (400 MHz, METHANOL-D4) δ 0.78 (t, J=7.52 Hz, 3 H), 1.40-1.57 (m, 4 H), 1.59 (s, 6 H), 1.95 (q, J=7.29 Hz, 2 H), 2.21-2.37 (m, 1 H), 2.82 (s, 3 H), 3.25-3.35 (m, 2 H), 3.85-3.94 (m, 2 H), 4.42 (d, J=7.42 Hz, 2 H), 7.94 (d, J=9.0 Hz, 1 H), 8.00 (dd, J=8.8, 1.7 Hz, 1 H), 8.02 (d, J=0.59 Hz, 1 H), 8.35 (d, J=1.56 Hz, 1 H), 8.72 (d, J=0.59 Hz, 1 H); MS (ESI) (M+H)+=474.0; Anal. Calcd for C23H31N5O4S+1.10 TFA+0.4H2O (606.23): C, 49.93; H, 5.47; N, 11.55. Found: C, 49.95; H, 5.44; N, 11.48.
Reaction SMILES: [CH3:1][C:2]1([N:8]2[CH2:13][CH2:12][CH:11]([N:14]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:15]3[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=3)[CH2:10][CH2:9]2)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[CH3:27][C:28]1[CH:36]=[CH:35][CH:34]=[C:33]([CH3:37])[C:29]=1[C:30](O)=[O:31].C1(NC2CCN(C(OC(C)(C)C)=O)CC2)C=CC=CC=1.Cl.BrC1C=CN=CC=1>>[CH3:27][C:28]1[CH:36]=[CH:35][CH:34]=[C:33]([CH3:37])[C:29]=1[C:30]([N:5]1[CH2:4][CH2:3][C:2]([CH3:1])([N:8]2[CH2:13][CH2:12][CH:11]([N:14]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:15]3[CH:16]=[CH:17][N:18]=[CH:19][CH:20]=3)[CH2:10][CH2:9]2)[CH2:7][CH2:6]1)=[O:31]
Reactant: Cc1cccc(C)c1C(=O)O
Reactant: CC1(N2CCC(N(c3ccccc3)c3ccncc3)CC2)CCNCC1
Agent: Brc1ccncc1
Agent: CC(C)(C)OC(=O)N1CCC(Nc2ccccc2)CC1
Agent: Cl
Product: Cc1cccc(C)c1C(=O)N1CCC(C)(N2CCC(N(c3ccccc3)c3ccncc3)CC2)CC1

Procedure:
It is prepared from (4′-methyl-[1,4′]bipiperidinyl-4-yl)-phenyl-pyridin-4-yl-amine and 2,6-dimethyl-benzoic acid using a procedure as described in above Example 1. MS/ESI 483 [M+H]+. (4′-Methyl-[1,4′]bipiperidinyl-4-yl)-phenyl-pyridin-4-yl-amine used as starting material can be prepared from tert-butyl 4-phenylaminopiperidine-1-carboxylate and 4-bromopyridine hydrochloride using procedures as described in Example 1a-1d of PCT/EP02/03871. MS/ESI 351 [M+H]+