Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([C:8]#N)=[C:6]([C:12]([F:15])([F:14])[F:13])[CH:5]=1)([O-:3])=[O:2].CC(C[AlH]CC(C)C)C.CO.S(=O)(=O)(O)[OH:28]>C1(C)C=CC=CC=1>[N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:28])=[C:6]([C:12]([F:15])([F:14])[F:13])[CH:5]=1)([O-:3])=[O:2]
Reactant: N#Cc1ccc([N+](=O)[O-])cc1C(F)(F)F
Reactant: O=S(=O)(O)O
Agent: CC(C)C[AlH]CC(C)C
Solvent: Cc1ccccc1
Solvent: CO
Product: O=Cc1ccc([N+](=O)[O-])cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 3.75 h

Procedure:
To 4-nitro-2-(trifluoromethyl)benzonitrile (100 mg, 0.463 mmol) in toluene (3 mL) at 0° C. under argon was added DIBAL-H (0.51 mL, 1M in toluene, 0.51 mmol) and the reaction stirred for 3.75 h. MeOH and sulphuric acid were added and the reaction mixture was warmed to room temperature and stirred for 1 h. The mixture was concentrated and the residue was portioned between EtOAc (10 mL) and water (10 mL). The organic phase was dried and concentrated to give the crude product which was purified by column chromatography eluting with 0-15% EtOAc/petroleum ether to give the title compound as a yellow oil (91 mg), δH (CDCl3, 400 MHz) 10.47 (1H, s), 8.66 (1H, d), 8.56 (1H, dd), 8.33 (1H, d).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][CH:10]([NH2:13])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:14](#[N:17])[CH:15]=[CH2:16]>CO>[CH2:1]([N:8]1[CH2:12][CH2:11][CH:10]([NH:13][CH2:16][CH2:15][C:14]#[N:17])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC1CCN(Cc2ccccc2)C1
Reactant: C=CC#N
Solvent: CO
Product: N#CCCNC1CCN(Cc2ccccc2)C1
Temperature: 70 °C
Yield: 88.5 %

Procedure:
4.00 g (22.7 mmol) of 1-benzyl-3-aminopyrrolidine was dissolved in 70 ml of methanol, 1.49 ml (22.7 mmol) of acrylonitrile was added thereto, and the mixture was heated to 70° C. After completion of the reaction, the reaction solution was evaporated, and the resulting crude product was subjected to 100 g of Cromatorex NH silica gel (ethyl acetate 100%), to give 4.60 g (20.1 mmol, 88.4%) of the title compound as a yellow oil.
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:14]([O:16][CH3:17])=[O:15])[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1.C(N(CC)CC)C.[C:25](O)(=[O:30])/[C:26](=[CH:28]/[CH3:29])/[CH3:27].CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[C:25]([NH:2][C@H:3]([C:14]([O:16][CH3:17])=[O:15])[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1)(=[O:30])/[C:26](=[CH:28]/[CH3:29])/[CH3:27]
Reactant: C/C=C(\C)C(=O)O
Reactant: COC(=O)[C@@H](N)Cc1c[nH]c2ccccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C/C=C(\C)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)OC
Yield: 98.9 %

Procedure:
The same procedures as in Example 146 were carried out from methyl L-tryptophanate hydrochloride (3.0 g), triethylamine (2.0 mL), tiglic acid (1.4 g), WSC.HCl (2.7 g), and methylene chloride (80 mL), to give the captioned compound (3.5 g, 99%) as an oily product.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:11]=[C:10]([NH2:12])[N:9]=[C:8]2[NH:13][N:14]=[CH:15][C:7]=12.[H-].[Na+].[F:18][C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[CH2:21]Br>CN(C=O)C>[F:18][C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[CH2:21][N:13]1[C:8]2=[N:9][C:10]([NH2:12])=[N:11][C:6]([C:2]3[O:1][CH:5]=[CH:4][CH:3]=3)=[C:7]2[CH:15]=[N:14]1
Reactant: Fc1ccccc1CBr
Reactant: Nc1nc(-c2ccco2)c2cn[nH]c2n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Nc1nc(-c2ccco2)c2cnn(Cc3ccccc3F)c2n1
Reaction time: 0.33 h
Yield: 80.8 %

Procedure:
A solution of 4-(2-furyl)-1H-pyrazolo[3,4-d]pyrimidine-6-amine (219 mg, 1 mmol) in DMF (2 mL) at 0° C. was treated with NaH (40 mg, 60%, 1 mmol), stirred for 20 min, treated with 2-fluorobenzyl bromide (120 μL, 1 mmol), stirred at room temperature for 1 h, quenched with water, extracted with EtOAc, dried (MgSO4), concentrated in vacuo and purified by chromatography (EtOAc:Heptane, 1:4) to give the title compound (250 mg, 76%) as a cream solid.
Reaction SMILES: [CH2:1]([C:5]1[N:21]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[C:35]3[N:39]([CH:40]([O:42][CH2:43][CH3:44])[CH3:41])[N:38]=[N:37][N:36]=3)=[CH:25][CH:24]=2)[C:8]2=[N:9][C:10]([CH2:19][OH:20])=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:12]=[C:7]2[N:6]=1)[CH2:2][CH2:3][CH3:4]>C(Cl)Cl.O=[Mn]=O>[CH2:1]([C:5]1[N:21]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[C:35]3[N:39]([CH:40]([O:42][CH2:43][CH3:44])[CH3:41])[N:38]=[N:37][N:36]=3)=[CH:25][CH:24]=2)[C:8]2=[N:9][C:10]([CH:19]=[O:20])=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:12]=[C:7]2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2cc(-c3ccccc3)c(CO)nc2n1Cc1ccc(-c2ccccc2-c2nnnn2C(C)OCC)cc1
Agent: O=[Mn]=O
Solvent: ClCCl
Product: CCCCc1nc2cc(-c3ccccc3)c(C=O)nc2n1Cc1ccc(-c2ccccc2-c2nnnn2C(C)OCC)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 88.8 %

Procedure:
0.6 g(0.001 mole) of the compound obtained in step 10 was dissolved in 10 ml of CH2Cl2 and to the resulting solution was added 1.76 g(0.02 mole) of activated MnO2. The resultant was stirred for 16 hours at room temperature and filtered through Cellite with washing with 5% MeOH/CH2Cl2 (10 ml×4). The filtrate was concentrated under reduced pressure to obtain 0.52 g of the title compound(yield 87%).
Reaction SMILES: [C:1]12([C:11]([OH:13])=O)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.C(N(C(F)(F)C(F)C(F)(F)F)CC)C.[CH3:28][O:29][C:30]1[CH:35]=[CH:34][C:33]([NH2:36])=[CH:32][CH:31]=1>C(OCC)C>[CH3:28][O:29][C:30]1[CH:35]=[CH:34][C:33]([NH:36][C:11]([C:1]23[CH2:10][CH:5]4[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]4)[CH2:2]2)[CH2:8]3)=[O:13])=[CH:32][CH:31]=1
Reactant: O=C(O)C12CC3CC(CC(C3)C1)C2
Reactant: COc1ccc(N)cc1
Agent: CCN(CC)C(F)(F)C(F)C(F)(F)F
Solvent: CCOCC
Product: COc1ccc(NC(=O)C23CC4CC(CC(C4)C2)C3)cc1
Temperature: 25 °C

Procedure:
1-Adamantanecarboxylic acid (10.8 g, 0.06 mole) was dissolved in N,N-diethyl-1,1,2,3,3,3-hexafluoropropylamine (13.4 g, 0.06 mole) as described in example 1. After the reaction mixture cooled to room temperature, a solution of p-anisidine (18.5 g, 0. 15 mole) in ethyl ether (minimum amount) was added and the reaction mixture was stirred for about an hour. The ethyl ether was removed at the rotary evaporator and the N-p-methoxyphenyl-1-adamantanecarboxamide was isolated as described in example 1 to give 15.8 g, 92%; mp 186-187° C. The analytical sample was recrystallized from cyclohexane and sublimed. Anal. Calcd. for C18H23NO2: C, 75.80; H, 8.07; N, 4.91. Found: C, 75.69; H, 8.17; N, 4.92.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:5]=[C:6](B(O)O)[CH:7]=[CH:8][CH:9]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].O.[F:24][C:25]([F:38])([F:37])[C:26]1[CH:31]=[CH:30][C:29]([CH2:32][CH2:33][C:34](Cl)=[O:35])=[CH:28][CH:27]=1.C(OCC)(=O)C>C1(C)C=CC=CC=1>[F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:5]=[C:6]([C:34](=[O:35])[CH2:33][CH2:32][C:29]2[CH:28]=[CH:27][C:26]([C:25]([F:37])([F:38])[F:24])=[CH:31][CH:30]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: OB(O)c1cccc(OC(F)(F)F)c1
Reactant: O=C(Cl)CCc1ccc(C(F)(F)F)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(CCc1ccc(C(F)(F)F)cc1)c1cccc(OC(F)(F)F)c1
Temperature: 110 °C
Yield: 57.8 %

Procedure:
To a solution of 522 mg (2.5 mmol) 3-(trifluoromethoxy)phenylboronic acid in 10 ml toluene under argon at RT, was added successively 29.7 mg (0.04 mmol) Pd(PPh3)2Cl, 776.5 mg (3.2 mmol) K3PO4.H2O and 500 mg (2.1 mmol) 3-(4-Trifluoromethyl-phenyl)-propionyl chloride (CAS: 539855-79-3). The reaction mixture was heated at 110° C. for 3 h, cooled to RT and ethyl acetate was added. The solution was washed successively with NaHCO3 sat., water and brine. The organic phase was dried over Na2SO4 and evaporated. The crude oil was purified with flash column chromatography on silica eluting with a gradient formed from heptane and ethylacetate to provide 0.44 g (58%) of the title compound as colorless oil. MS (m/e): 363.0 (MH+).
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([F:11])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][NH:6]2.[NH2:12][CH2:13][C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1>C(Cl)(Cl)Cl.CO>[F:11][C:9]1[N:8]=[C:7]2[C:3]([N:4]=[CH:5][NH:6]2)=[C:2]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)[N:10]=1
Reactant: NCc1ccncc1
Reactant: Fc1nc(Cl)c2nc[nH]c2n1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: Fc1nc(NCc2ccncc2)c2nc[nH]c2n1
Temperature: 20 °C
Reaction time: 3 h
Yield: 54.1 %

Procedure:
To a stirred solution of 6-chloro-2-fluoro-9H-purine (0.9 g, 5.22 mmol) in BunOH (60 mL) under Ar, cooled to −20° C., was added Pri2NEt (2.5 mL, 14.35 mmol) followed by 4-(aminomethyl)pyridine (0.58 mL, 5.69 mmol). The reaction mixture was stirred at-20° C. for 3 h, and then allowed to return to RT over 2 h and stirred at RT for a further 48 h, when TLC (9:1 CHCl3/MeOH) indicated that the reaction had gone to completion. The solvent was evaporated in vacuo and the residue was purified by gradient column chromatography on silica gel, eluted with CHCl3/MeOH (100:0→90:10), to afford the title compound as a white solid (0.69 g, 54%). Mp>340° C. 1H-NMR (d6-DMSO, 250 ME): δ 4.67 (d, 2H, J=6.35 Hz, —HNCH2-Pyr), 7.34, 8.50 (2×m, 4H, Pyr), 8.14 (s, 1H, —N═CH—NH—), 8.84 (bs, 1H, —HNCH2-Pyr), 13.13 (bs, 1H, —N═CH—NH—). FAB-MS m/z (relative intensity): 245 ([M+H]+, 27), 176 (15), 154 (100), 136 (77). Accurate Mass (M+H): Actual: 245.0951, Measured: 245.0942. Microanalysis (Expected:Measured) C11H9N6F.0.6H2O: C, 51.80:52.08; H, 4.03:3.84; N, 32.95:31.29.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5]([N:9]=[C:10]=[O:11])[CH:6]=[CH:7][CH:8]=1.[NH:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]([CH2:23][NH:24][C@@H:25]([CH2:36][CH2:37][C:38]2[NH:39][CH:40]=[C:41]([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[N:42]=2)[C:26](OCC2C=CC=CC=2)=[O:27])=[CH:15]1.C(N(CC)CC)C>C1COCC1>[NH:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]([CH2:23][N:24]2[C@@H:25]([CH2:36][CH2:37][C:38]3[NH:39][CH:40]=[C:41]([C:43]4[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=4)[N:42]=3)[C:26](=[O:27])[N:9]([C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:12])([F:13])[F:1])[CH:4]=3)[C:10]2=[O:11])=[CH:15]1
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Reactant: O=C(OCc1ccccc1)[C@H](CCc1nc(-c2ccccc2)c[nH]1)NCc1c[nH]c2ccccc12
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C1[C@H](CCc2nc(-c3ccccc3)c[nH]2)N(Cc2c[nH]c3ccccc23)C(=O)N1c1cccc(C(F)(F)F)c1
Temperature: 20 °C
Reaction time: 2 h
Yield: 92.9 %

Procedure:
3-trifluoromethyl-phenylisocyanate (11 mg, 1.2 eq.) is added to a solution of benzyl (2S)-2-[(1H-indol-3-ylmethyl)amino]-4-(4-phenyl-1H-imidazol-2-yl)butanoate (23 mg, 1 eq.) in 2 ml of THF. The mixture is stirred for 2 hours at approximately 20° C. then diluted with 2 ml of THF. Aminomethylpolystyrene resin (acquired from Novabiochem, load 3.2 mmol/g, 125 mg, 2 eq.) is added, then triethylamine (200 μl). The mixture is stirred for 15 hours at approximately 20° C. then filtered on frit. The filtrate is then concentrated to dryness under reduced pressure at 40° C. (a co-evaporation with dichloromethane is necessary to eliminate the excess triethylamine) in order to produce the expected compound (25 mg, 92% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]([NH:12][C:13]1[CH:33]=[CH:32][C:16]([O:17][C:18]2[CH:23]=[CH:22][N:21]=[C:20]([C:24]3[CH:25]=[C:26]([C:29](O)=[O:30])[S:27][CH:28]=3)[CH:19]=2)=[CH:15][CH:14]=1)=[O:11].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.Cl.[CH3:68][O:69][C:70](=[O:73])[CH2:71][NH2:72].Cl>CN(C=O)C.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]([NH:12][C:13]1[CH:33]=[CH:32][C:16]([O:17][C:18]2[CH:23]=[CH:22][N:21]=[C:20]([C:24]3[CH:25]=[C:26]([C:29]([NH:72][CH2:71][C:70]([O:69][CH3:68])=[O:73])=[O:30])[S:27][CH:28]=3)[CH:19]=2)=[CH:15][CH:14]=1)=[O:11]
Reactant: COC(=O)CN
Reactant: Cc1ccc(F)c(NC(=O)Nc2ccc(Oc3ccnc(-c4csc(C(=O)O)c4)c3)cc2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CNC(=O)c1cc(-c2cc(Oc3ccc(NC(=O)Nc4cc(C)ccc4F)cc3)ccn2)cs1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of 4-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}thiophene-2-carboxylic acid (100 mg, 0.22 mmol), HATU (100 mg, 0.26 mmol) and N,N-diisopropylethylamine (85 mg, 0.66 mmol) in anhydrous DMF (10 ml) was stirred at room temperature for 10 minutes, followed by addition of glycine methyl ester hydrochloride (41 mg, 0.33 mmol). The mixture was stirred for another 10 minutes and poured into 100 ml of water. 2M HCl was added dropwise until pH=4˜5. The precipitates were filtered, washed with water and dried in vacuo to give methyl {[(4-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-2-thienyl)carbonyl]amino}acetate as white solid. Yield: 90 mg, 78%.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[CH3:14][C:15]1[N:16]=[C:17]([NH2:26])[S:18][C:19]=1[CH2:20][CH2:21][O:22][N+:23]([O-:25])=[O:24]>>[C:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]([C:9]([NH:26][C:17]2[S:18][C:19]([CH2:20][CH2:21][O:22][N+:23]([O-:25])=[O:24])=[C:15]([CH3:14])[N:16]=2)=[O:11])=[CH:12][CH:13]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(C(=O)O)cc1
Reactant: Cc1nc(N)sc1CCO[N+](=O)[O-]
Product: CC(=O)Nc1ccc(C(=O)Nc2nc(C)c(CCO[N+](=O)[O-])s2)cc1
Yield: 44 %

Procedure:
Pet-157 was prepared according to the general procedure described hereinabove and the procedure described above for the preparation of Pet-154, using 4-acetylamino-benzoic acid and 4-methyl-5-(2-nitrooxy-ethyl)-thiazol-2-ylamine (Pet-10) as the starting materials, in an overall yield of 44%.
Reaction SMILES: [C:1]([C:5]1[C:13]2[C:8](=[CH:9][C:10]([N+:14]([O-])=O)=[CH:11][CH:12]=2)[NH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]>C(O)C.[Ni]>[C:1]([C:5]1[C:13]2[C:8](=[CH:9][C:10]([NH2:14])=[CH:11][CH:12]=2)[NH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1c[nH]c2cc([N+](=O)[O-])ccc12
Agent: [Ni]
Solvent: CCO
Product: CC(C)(C)c1c[nH]c2cc(N)ccc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 77.5 %

Procedure:
A suspension of 3-tert-butyl-6-nitro-1H-indole (3.0 g, 13.7 mmol) and Raney Ni (0.5 g) in ethanol was stirred at room temperature under H2 (1 atm) for 3 h. The catalyst was filtered off and the filtrate was concentrated to dryness. The residue was purified by column chromatography on silica gel (Pet.Ether./EtOAc 4:1) to give 3-tert-butyl-1H-indol-6-ylamine (B-11) (2.0 g, 77.3%) as a gray solid. 1H NMR (CDCl3): δ 7.58 (m, 2H), 6.73 (d, J=1.2 Hz, 1H), 6.66 (s, 1H), 6.57 (dd, J=0.8, 8.6 Hz, 1H), 3.60 (br s, 2H), 1.42 (s, 9H).
Reaction SMILES: [CH:1]([CH:3]1[CH2:8][C:7](=[O:9])[CH:6]([C:10](=[O:12])[CH3:11])[C:5](=[O:13])[CH2:4]1)=O.[NH2:14]OS(O)(=O)=O>O>[O:13]=[C:5]1[CH:6]([C:10](=[O:12])[CH3:11])[C:7](=[O:9])[CH2:8][CH:3]([C:1]#[N:14])[CH2:4]1
Reactant: NOS(=O)(=O)O
Reactant: CC(=O)C1C(=O)CC(C=O)CC1=O
Solvent: O
Product: CC(=O)C1C(=O)CC(C#N)CC1=O
Temperature: 25 °C
Reaction time: 17 h
Yield: 58.3 %

Procedure:
19.3 g (0.11 mol) of 5-formyl-2-acetylcyclohexane-1,3-dione in 200 ml of distilled water were initially taken, and 14.7 g (0.13 mol) of hydroxylamine-O-sulfonic acid were added at room temperature. The mixture was then stirred for 17 hours at room temperature. The precipitate was filtered off under suction, washed with water and dried. 11.5 g (61% of theory) of 3,5-dioxo-4-acetylcyclohexanenitrile of melting point 66-69° C. were obtained.
Reaction SMILES: [OH-].[Na+].CC1(C)C(C)(C)OB([C:11]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:12]=2[CH:13]=[CH:14][NH:15]3)O1.Br[C:22]1[CH:23]=[N:24][CH:25]=[N:26][CH:27]=1>[Pd].C1COCC1>[N:24]1[CH:23]=[C:22]([C:11]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:12]=2[CH:13]=[CH:14][NH:15]3)[CH:27]=[N:26][CH:25]=1
Reactant: Brc1cncnc1
Reactant: CC1(C)OB(c2cccc3[nH]ccc23)OC1(C)C
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: c1cc(-c2cncnc2)c2cc[nH]c2c1
Temperature: 70 °C
Reaction time: 4 h
Yield: 71 %

Procedure:
Palladium catalyst Pd(PPh3)4 (142 mg, 0.12 mmol) and freshly prepared aqueous sodium hydroxide (493 mg, 12.33 mmol, in 6 mL of water) were added to a mixture of 4-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)-1H-indole (1 g, 4.11 mmol) and 5-bromopyrimidine (784 mg, 4.93 mmol) in THF (20 mL). The system was degassed and then purged three times with nitrogen. The mixture was stirred under nitrogen at 70° C. in an oil bath for 4 hours. It was then cooled to room temperature and ethyl acetate (300 mL) was added. The organic layer was isolated, washed by brine, dried over anhydrous Na2SO4 and concentrated. The residue was triturated with dichloromethane to give 570 mg (71%) of 4-pyrimidin-5-yl-1H-indole as a pale green solid.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[C:9]([Cl:15])=[N:10][CH:11]=[CH:12][C:13]=1I)(C)(C)C.[C:17]1(B(O)O)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>>[Cl:15][C:9]1[C:8]([NH2:7])=[C:13]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:12]=[CH:11][N:10]=1
Reactant: CC(C)(C)OC(=O)Nc1c(I)ccnc1Cl
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Nc1c(-c2ccccc2)ccnc1Cl

Procedure:
(2-chloro-4-iodo-pyridin-3-yl)-carbamic acid tert-butyl ester a (4.20 g, 11.8 mmol), phenyl boronic acid (1.90 g, 15.6 mmol), potassium carbonate (2.42 g, 17.5 mmol) and tetrakistriphenylphosphine palladium(0) (0.68 g, 0.59 mmol) were weighed into a 20 ml microwave vial. The vial was evacuated, then purged with nitrogen gas 3 times. 16.7 ml dry DMF was added, then 3.3 ml of water, which had been degassed by bubbling nitrogen through it overnight. The vial was then capped and microwaved at 130° C. for 40 minutes. The resulting solution was poured into 250 ml water and extracted with EtOAc (3×50 ml). The combined organics were dried with MgSO4, filtered and concentrated. The resulting oil was adsorbed onto silica gel and purified by flash chromatography (150 g SiO2, 0% to 40% EtOAc in hexanes) to give 2-chloro-3-amino-4-phenyl pyridine b (0.84 g, 4.1 mmol, 35%) and the Boc-protected 2-chloro-3-amino-4-phenyl pyridine c (1.74 g, 5.7 mmol, 48%) as yellow and white solids, respectively.
Reaction SMILES: [CH:1]1([NH2:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.C([O:11][C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20]1[CH:25]=[CH:24][C:23]([CH2:26][N:27]2[C:35]3[C:30](=[CH:31][C:32]([C:36](O)=[O:37])=[CH:33][CH:34]=3)[C:29]([CH3:39])=[C:28]2[CH3:40])=[CH:22][CH:21]=1)=[O:13])(C)(C)C>>[CH:1]1([NH:6][C:36]([C:32]2[CH:31]=[C:30]3[C:35](=[CH:34][CH:33]=2)[N:27]([CH2:26][C:23]2[CH:22]=[CH:21][C:20]([C:15]4[C:14]([C:12]([OH:13])=[O:11])=[CH:19][CH:18]=[CH:17][CH:16]=4)=[CH:25][CH:24]=2)[C:28]([CH3:40])=[C:29]3[CH3:39])=[O:37])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC1CCCC1
Reactant: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c2ccc(C(=O)O)cc12
Product: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)O)cc2)c2ccc(C(=O)NC3CCCC3)cc12

Procedure:
The title compound was prepared following the same general protocol as described in Steps 8-9, Example 1, using cyclopentylamine and 1-((2′-(tert-butoxycarbonyl)biphenyl-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:24])[C:10]2[CH:15]=[CH:14][C:13]([CH2:16][N:17]3[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]3)=[CH:12][CH:11]=2)=[CH:4][C:3]=1[NH:25][C:26]([N:28]1[C:32]2[N:33]=[CH:34][N:35]=[C:36](Cl)[C:31]=2[CH:30]=[CH:29]1)=[O:27].C(Cl)(=O)C.[NH2:42][C:43]1[CH:44]=[C:45]([CH:49]=[CH:50][CH:51]=1)[C:46]([NH2:48])=[O:47]>C(O)CCC>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:24])[C:10]2[CH:15]=[CH:14][C:13]([CH2:16][N:17]3[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]3)=[CH:12][CH:11]=2)=[CH:4][C:3]=1[NH:25][C:26]([N:28]1[C:32]2[N:33]=[CH:34][N:35]=[C:36]([NH:42][C:43]3[CH:51]=[CH:50][CH:49]=[C:45]([C:46](=[O:47])[NH2:48])[CH:44]=3)[C:31]=2[CH:30]=[CH:29]1)=[O:27]
Reactant: NC(=O)c1cccc(N)c1
Reactant: Cc1ccc(NC(=O)c2ccc(CN3CCN(C)CC3)cc2)cc1NC(=O)n1ccc2c(Cl)ncnc21
Solvent: CC(=O)Cl
Solvent: CCCCO
Product: Cc1ccc(NC(=O)c2ccc(CN3CCN(C)CC3)cc2)cc1NC(=O)n1ccc2c(Nc3cccc(C(N)=O)c3)ncnc21
Temperature: 80 °C
Reaction time: 24 h
Yield: 59.9 %

Procedure:
4-Chloro-pyrrolo[2,3-d]pyrimidine-7-carboxylic acid {2-methyl-5-[4-(4-methyl-piperazin-1-ylmethyl)-benzoylamino]-phenyl}-amide resin (50 mg, 0.05 mmol), prepared as in reference 2, in n-butanol (2 mL) is mixed with acetyl chloride (17.8 μL, 0.25 mmol) and 3-aminobenzamide (34 mg, 0.25 mmol), and shaken at 80° C. for 24 hours. The resulting mixture is filtered and the resin is treated with TFA/CH2Cl2/H2O (45/50/5) (600 μL) for 30 minutes before filtering and washing with CH2Cl2 (3×2 mL), MeOH (3×2 mL). The washes are then combined together and concentrated. The residue is purified by preparative HPLC-MS to give 4-(3-carbamoyl-phenylamino)-pyrrolo[2,3-d]pyrimidine-7-carboxylic acid {2-methyl-5-[4-(4-methyl-piperazin-1-ylmethyl)-benzoylamino]-phenyl}-amide (18.5 mg, yield, 60%); 1H NMR (400 MHz, DMSO-d6) δ 11.52 (s, 1H), 10.31 (s, 1H), 9.99 (s, 1H), 8.60 (s, 1H), 8.52 (d, J=1.71 Hz, 1H), 8.23 (s, 1H), 8.12 (d, J=7.59 Hz, 1H), 8.00 (s, 1H), 7.98 (d, J=8.02 Hz, 2H), 7.87 (d, J=3.89 Hz, 1H), 7.59 (dd, J=17.87, 9.00 Hz, 2H), 7.49 (d, J=7.98 Hz, 2H), 7.47 (s, 1H), 7.38 (s, 1H), 7.29 (d, J=8.48 Hz, 1H), 7.11 (d, J=3.89 Hz, 1H), 3.75 (s, 2H), 3.43-2.79 (m, 8H), 2.50 (s, 3H), 2.49 (s, 3H); ESIMS m/z 618.20 (M++1).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][CH2:5][C@H:6]1[CH2:11][CH2:10][C@H:9]([C@H:12]2[CH2:17][CH2:16][C@H:15]([CH2:18][OH:19])[CH2:14][CH2:13]2)[CH2:8][CH2:7]1.[CH2:20](Br)[CH:21]=[CH2:22]>O1CCCC1>[CH2:20]([O:19][CH2:18][C@H:15]1[CH2:14][CH2:13][C@H:12]([C@H:9]2[CH2:10][CH2:11][C@H:6]([CH2:5][O:4][CH3:3])[CH2:7][CH2:8]2)[CH2:17][CH2:16]1)[CH:21]=[CH2:22]
Reactant: COC[C@H]1CC[C@H]([C@H]2CC[C@H](CO)CC2)CC1
Reactant: C=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCOC[C@H]1CC[C@H]([C@H]2CC[C@H](COC)CC2)CC1
Temperature: 70 °C
Reaction time: 0.08 h

Procedure:
150 mg of sodium hydride (as a 50 percent suspension in oil) is suspended in 10 ml of absolute tetrahydrofuran and then treated dropwise at room temperature within 3 minutes with a solution of 0.5 g of [trans-4-[trans-4-(methoxymethyl)cyclohexyl]cyclohexyl]methanol in 8 ml of absolute tetrahydrofuran. The mixture is stirred for a further 5 minutes, then treated with 0.755 g of allyl bromide and stirred under reflux (bath temperature 70° C.) for 16 hours. Thereafter, the reaction mixture is partitioned in diethyl ether/water and extracted three times with diethyl ether. The organic phases are washed twice with water, dried over magnesium sulphate, filtered and evaporated. Chromatographic purification of the resulting crude product on silica gel with ethyl acetate/petroleum ether (vol. 3:97) gives [trans-4-[trans-4-(methoxymethyl)cyclohexyl]cyclohexyl]methyl allyl ether.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[N:9]1[C:14](=[O:15])[CH2:13][CH2:12][C:11]([C:16]([O:18]CC2C=CC=CC=2)=[O:17])=[CH:10]1>C(O)C.[Pd]>[CH3:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[C:3]=1[N:9]1[C:14](=[O:15])[CH2:13][CH2:12][C:11]([C:16]([OH:18])=[O:17])=[CH:10]1
Reactant: Cc1cccc(C)c1N1C=C(C(=O)OCc2ccccc2)CCC1=O
Agent: [Pd]
Solvent: CCO
Product: Cc1cccc(C)c1N1C=C(C(=O)O)CCC1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of the compound prepared in Example 46 (4.77 g) in ethanol (140 mL) was added 5% palladium/carbon (0.5 g) and the mixture was stirred at room temperature for 2 hours under an atmosphere of hydrogen. The reaction mixture was filtrated with Celite (proprietary name) and the filtrate was concentrated to give the compound of the present invention (2.93 g) having the following physical data.