Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC1C=C2C(C3N=C(N[C@H]4CCC[C@@H](N)C4)C(F)=CN=3)=CN(S(C3C=CC(C)=CC=3)(=O)=O)C2=[N:6]C=1.C(OC([N:43]1[CH2:48][CH2:47][O:46][CH:45]([C:49]([OH:51])=O)[CH2:44]1)=O)(C)(C)C.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[OH-].[Li+]>C(Cl)Cl>[NH:43]1[CH2:48][CH2:47][O:46][CH:45]([C:49]([NH2:6])=[O:51])[CH2:44]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(N[C@H]4CCC[C@@H](N)C4)n3)c3cc(Cl)cnc32)cc1
Reactant: CC(C)(C)OC(=O)N1CCOC(C(=O)O)C1
Agent: On1nnc2ccccc21
Agent: [Li+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: NC(=O)C1CNCCO1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (1S,3R)—N1-[2-[5-chloro-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]-5-fluoro-pyrimidin-4-yl]cyclohexane-1,3-diamine (0.06 g, 0.12 mmol) in CH2Cl2 (3 mL) was added 4-tert-butoxycarbonylmorpholine-2-carboxylic acid (40.4 mg, 0.17 mmol), EDC (0.03 g, 0.14 mmol), HOBt (0.02 g, 0.12 mmol) and iPr2NEt (0.06 g, 0.47 mmol), and the reaction mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure, and the residue was dissolved in CH2Cl2 (2 mL) and TFA (2 mL) and allowed to stir at room temperature for 2 hours. The resulting solution was concentrated in vacuo, dissolved in THF (4 mL) and treated with 1N aqueous lithium hydroxide (3.0 mL, 3.0 mmol). The reaction mixture was heated in the microwave to 130° C. for 20 min. The solvent was evaporated under reduced pressure, and the residue was purified by HPLC, using 5-70% MeOH/H2O with 6 mM HCl over 15 minutes. The purified fractions were concentrated to provide the bis-hydrochloride of N-[(1R,3S)-3-[[2-(5-chloro-1H-pyrrolo[2, 3-1)]pyridin-3-yl)-5-fluoro-pyrimidin-4-yl]amino]cyclohexyl]morpholine-2-carboxamide.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][C@H:10]([OH:13])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:14]([Cl:22])(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(OC)(C)(C)C>ClCCl>[ClH:22].[C:14]([O:13][C@H:10]1[CH2:11][CH2:12][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:9]1)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O[C@H]1CCN(Cc2ccccc2)C1
Reactant: O=C(Cl)c1ccccc1
Solvent: COC(C)(C)C
Solvent: ClCCl
Product: Cl
Product: O=C(O[C@H]1CCN(Cc2ccccc2)C1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.4 %

Procedure:
To an ice cold, stirred solution of (S)-N-benzyl-3-pyrrolidinol (6.90 Kg, 38.9 mole) in dichloromethane (21 L), was slowly added a solution of benzoyl chloride (5.75 Kg, 40.8 mole) in dichloromethane (5 L). The reaction mixture was warmed to room temperature and stirred an additional two hours. Upon confirmation of reaction completion, methyl t-butyl ether (26 L) was added, and the resulting slurry was stirred for two hours at −10° C. The solids were isolated by filtration, washed with methyl t-butyl ether (14 L) and dried under vacuum at 40° C. to provide the title pyrrolidine (11.8 Kg, 96.6%) as a colorless crystalline material. mp 203-204° C.; 1H NMR (400 MHz, CDCl3) (major isomer) δ 8.14-7.90 (m, 2H), 7.70-7.39 (m, 8H), 5.59-5.58 (m, 1H), 4.30 (d, J=5.5 Hz, 2H), 4.14-4.08 (m, 1H), 3.80-3.76 (m, 1H), 3.24-3.17 (m, 2H), 2.66-2.61 (m, 1H), 2.37-2.32 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 166.2, 165.6, 134.0, 133.7, 131.1, 130.9, 130.3, 130.2, 130.1, 130.0, 129.8, 129.6, 129.5, 129.4, 129.1, 129.0, 128.8, 128.6, 73.0, 71.9, 59.1, 58.5, 57.5, 57.2, 52.1, 52.0, 31.3, 30.6; MS [(m+1)/z] 282.2.
Reaction SMILES: [CH:1]([C:4]1[N:5]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[C:6]2[C:11]([C:12]=1[C:13](O)=[O:14])=[CH:10][CH:9]=[C:8](OC)[CH:7]=2)([CH3:3])[CH3:2].[F:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][C:33]=1[F:34])[CH2:29][NH2:30].[N:35]1[CH:40]=[CH:39][C:38](B(O)O)=[CH:37][CH:36]=1>>[F:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][C:33]=1[F:34])[CH2:29][NH:30][C:13]([C:12]1[C:11]2[C:6](=[CH:7][C:8]([C:38]3[CH:39]=[CH:40][N:35]=[CH:36][CH:37]=3)=[CH:9][CH:10]=2)[N:5]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[C:4]=1[CH:1]([CH3:3])[CH3:2])=[O:14]
Reactant: OB(O)c1ccncc1
Reactant: NCc1ccc(F)c(F)c1
Reactant: COc1ccc2c(C(=O)O)c(C(C)C)n(Cc3ccccn3)c2c1
Product: CC(C)c1c(C(=O)NCc2ccc(F)c(F)c2)c2ccc(-c3ccncc3)cc2n1Cc1ccccn1

Procedure:
The title compound was prepared from 2-isopropyl-6-methoxy-1-(pyridin-2-ylmethyl)-1H-indole-3-carboxylic acid (Compound 139), 3,4-difluorobenzylamine, and pyridin-4-ylboronic acid by, in order, General Procedure C, General Procedure L, General Procedure V, and General Procedure W.
Reaction SMILES: [N:1]1([CH2:7][C@@H:8]2[CH2:13][CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9]2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:21]1([N:27]=[C:28]=[O:29])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C1(C)C=CC=CC=1.CO>[NH:27]([C:28]([N:4]1[CH2:5][CH2:6][N:1]([CH2:7][C@@H:8]2[CH2:13][CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9]2)[CH2:2][CH2:3]1)=[O:29])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C=Nc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](CN2CCNCC2)C1
Solvent: CO
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC[C@@H](CN2CCN(C(=O)Nc3ccccc3)CC2)C1
Yield: 80.5 %

Procedure:
tert-Butyl (3S)-3-(piperazin-1-ylmethyl)piperidine-1-carboxylate (3.5 g) and phenyl isocyanate (1.62 g) were stirred in toluene (50 ml) at room temperature for 20 h. The solvent was then concentrated in-vacuo to afford a white solid. The solid was dissolved in methanol and passed through an SCX2 column. The SCX2 column was then flushed with 5% ammonia in methanol solution. The solution was collected and the solvent removed under reduced pressure. The resultant solid was re-crystalised from EtOAc and isoHexane, to afford the desired product as a white solid (4 g).
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[N:4]([C@H:12]2[CH2:17][CH2:16][C@@H:15]([N:18]3[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]3)[CH2:14][CH2:13]2)[N:3]=1.[NH:25]([C:32]([C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=1)=[O:33])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>O>[C:26]1([NH:25][C:32](=[O:33])[C:34]2[CH:39]=[CH:38][C:37]([C:2]3[C:10]4[C:5](=[N:6][CH:7]=[N:8][C:9]=4[NH2:11])[N:4]([C@H:12]4[CH2:17][CH2:16][C@@H:15]([N:18]5[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]5)[CH2:14][CH2:13]4)[N:3]=3)=[CH:36][CH:35]=2)[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CN1CCN([C@H]2CC[C@@H](n3nc(I)c4c(N)ncnc43)CC2)CC1
Reactant: O=C(Nc1ccccc1)c1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CN1CCN([C@H]2CC[C@@H](n3nc(-c4ccc(C(=O)Nc5ccccc5)cc4)c4c(N)ncnc43)CC2)CC1
Yield: 27.7 %

Procedure:
cis-3-Iodo-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (100 mg, 0.226 mmol), 4-(anilinocarbonyl)phenylboronic acid (60 mg, 0.249 mmol), palladium tetrakistriphenyphosphine(16 mg, 0.014 mmol) and sodium carbonate (58 mg, 0.544 mmol) were mixed with ethylene glycol dimethyl ether (3 mL) and water (1.5 mL). The reaction mixture was heated at reflux overnight. Organic solvent was removed under reduced pressure and the aqueous layer was extracted with dichloromethane. The combined organic layer was washed with water then brine, dried over MgSO4, filtered and evaporated. The residue was by preparative thin layer column chromatography using dichloromethane/methanol/ammonium hydroxide (95:5:05) as mobile phase to give cis-N1-phenyl-4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}benzamide (32 mg, 27%). 1H NMR (DMSO-d6) δ 1.60 (m, 4H), 1.73 (m, 2H), 2.08 (m, 2H), 2.19 (s, 3H), 2.28 (m, 11H), 4.84 (m, 1H), 7.12 (m, 1H), 7.38 (m, 2H), 7.81 (m, 4H), 8.16 (d, J=8.30 Hz, 2H), 8.27 (s, 1H), 10.34 (s, 1H). LC/MS (Micromass-Column: Pecosphere, C18, 3 um, 33×4.6 mm. Eluents: 0% B/A to 100% B/A in 4.5 min. (B: acetonitrile, A: 50 mM ammonia acetate buffer, pH 4.5), 3.5 mL/min.): MH+=511.2, Rt=2.41 min.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[CH2:5][NH2:6])[CH3:2].[C:10]([O:14][C:15](=[O:22])[NH:16][CH2:17][CH2:18][N:19]=[C:20]=[O:21])([CH3:13])([CH3:12])[CH3:11]>C1(C)C=CC=CC=1>[C:10]([O:14][C:15](=[O:22])[NH:16][CH2:17][CH2:18][NH:19][C:20]([NH:6][CH2:5][CH:4]([O:7][CH2:8][CH3:9])[O:3][CH2:1][CH3:2])=[O:21])([CH3:13])([CH3:11])[CH3:12]
Reactant: CCOC(CN)OCC
Reactant: CC(C)(C)OC(=O)NCCN=C=O
Solvent: Cc1ccccc1
Product: CCOC(CNC(=O)NCCNC(=O)OC(C)(C)C)OCC
Reaction time: 1 h
Yield: 99.9 %

Procedure:
Add 2,2-diethoxy ethanamine (3.33 g, 25.04 mmol) to a solution of (2-isocyanato-ethyl)-carbamic acid tert-butyl ester (3.73 g, 20.03 mmol) in toluene (50 mL). After 1 hour, concentrate the mixture to afford a white solid (6.39 g). 1H NMR (DMSO-d6) δ 6.74 (t, J=5 Hz, 1H), 6.03 (t, J=5.6 Hz, 1H), 5.85 (t, J=5.8 Hz, 1H), 4.39 (t, J=5.4 Hz, 1H), 3.61-3.55 (m, 2H), 3.48-3.42 (m, 2H), 3.06 (t, J=5.7 Hz, 2H), 3.01 (q, J=6.2 Hz, 2H), 2.92 (q, J=6.2 Hz, 2H), 1.37 (s, 9H), 1.11 (t, J=6.4 Hz, 6H).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][O:9][C:10]1[CH:11]=[C:12]([NH2:22])[CH:13]=[CH:14][C:15]=1[N:16]1[CH:20]=[C:19]([CH3:21])[N:18]=[CH:17]1.[Cl:23][C:24]1[N:29]=[C:28](Cl)[N:27]=[C:26]([O:31][CH3:32])[N:25]=1>CO>[Cl:23][C:24]1[N:25]=[C:26]([O:31][CH3:32])[N:27]=[C:28]([NH:22][C:12]2[CH:13]=[CH:14][C:15]([N:16]3[CH:20]=[C:19]([CH3:21])[N:18]=[CH:17]3)=[C:10]([O:9][CH3:8])[CH:11]=2)[N:29]=1
Reactant: COc1nc(Cl)nc(Cl)n1
Reactant: COc1cc(N)ccc1-n1cnc(C)c1
Solvent: CO
Solvent: CCN(CC)CC
Product: COc1nc(Cl)nc(Nc2ccc(-n3cnc(C)c3)c(OC)c2)n1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Triethylamine (0.23 ml, 1.62 mmol) was added to a solution of 3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamine (300 mg, 1.48 mmol) in 5 ml of methanol. The mixture was cooled in an ice-bath and 2,4-dichloro-6-methoxy-[1,3,5]triazine (266 mg, 1.48 mmol) added portionwise. The mixture was stirred for 1 hour at 0° C. The resulting precipitate was removed by filtration and dried to give the title compound as a slightly brownish solid (317 mg, 62%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=1)[C:5]([NH2:7])=[O:6].[C:14](=O)([O-])[O-].[Cs+].[Cs+].S(OC)(OC)(=O)=O>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=1)[C:5]([NH:7][CH3:14])=[O:6]
Reactant: O=C([O-])[O-]
Reactant: NC(=O)c1cc(F)cc([N+](=O)[O-])c1
Agent: [Cs+]
Solvent: COS(=O)(=O)OC
Solvent: CN(C)C=O
Product: CNC(=O)c1cc(F)cc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 74.3 %

Procedure:
To a solution of 3-fluoro-5-nitrobenzamide (1.0 g, 5.43 mmoL) in DMF (17 mL) was added cesium carbonate (2.6 g, 8.14 mmoL) and dimethyl sulphate (547 mg, 4.34 mmol) and the reaction mixture was stirred at RT for 24 h. The reaction mixture was concentrated under reduced pressure and extracted with EtOAc (2×40 ml). The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. Purification by silica gel column chromatography provided 3-fluoro-N-methyl-5-nitrobenzamide (0.800 g, 80%) as a solid. Observed mass (M−1): 196.9.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH:5]([CH2:10][PH:11]([O:13]CC)=O)[CH2:6][CH:7]([CH3:9])[CH3:8])[CH3:2].C(N(C(C)C)CC)(C)C.C[Si]([CH:30]([Si](C)(C)C)[C:31](N)=[O:32])(C)C.[CH2:38]=[O:39]>C1COCC1.C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:16])[C:5]([CH2:10][PH:11]([CH2:38][OH:39])=[O:13])([O:32][CH2:31][CH3:30])[CH2:6][CH:7]([CH3:8])[CH3:9])[CH3:2]
Reactant: C=O
Reactant: C[Si](C)(C)C(C(N)=O)[Si](C)(C)C
Reactant: CCOC(=O)C(CC(C)C)C[PH](=O)OCC
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C(CC(C)C)(C[PH](=O)CO)OCC
Temperature: 0 °C

Procedure:
Crude 2-(ethoxy)phosphinoylmethyl-4-methylpentanoic acid ethyl ester (26 g) was dissolved in 600 mL THF/CH2Cl2 (50/50) and cooled to 0° C. Diisopropyl-ethylamine (32 mL) and 90.8 mL of bis-(trimethylsilyl) acetamide were then added to the solution and the resulting mixture was stirred for 20 minutes before paraformaldehyde (5.5 g) was added. The solution was brought to room temperature and heated at 37° C. for 18 hours. The solvent was removed by evaporation, and the resulting oil dissolved in 200 mL ethyl acetate. The solution was washed with 50 mL of 1N HCl (2×), 50 mL of brine (2×), dried over MgSO4, filtered and evaporated to yield 19.3 g of 2-(ethoxy)(hydroxymethyl)phosphinoylmethyl-4-methylpentanoic acid ethyl ester as a faintly yellow oil, MS: 281.2 (MH+).
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][CH:10]([NH2:13])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:14]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][CH3:23])[C:17]=1[N:24]=[C:25]=[O:26])[CH3:15].N1C=CC=CC=1.Cl>ClCCl>[CH2:14]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][CH3:23])[C:17]=1[NH:24][C:25]([NH:13][CH:10]1[CH2:9][CH2:8][CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:12][CH2:11]1)=[O:26])[CH3:15]
Reactant: CCc1cccc(CC)c1N=C=O
Reactant: NC1CCC(c2ccccc2)CC1
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCc1cccc(CC)c1NC(=O)NC1CCC(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 1 g of 4-phenylcyclohexylamine in 10 ml of dichloromethane was added 2,6-diethylphenylisocyanate dropwise in the presence of pyridine and the mixture was stirred for 2 hours at room temperature. To the resultant mixture was added 30 ml of diluted hydrochloric acid and the solution was extracted with chloroform. The extract was washed with water, aqueous sodium hydrogencarbonate solution and saturated brine, and then dried over magnesium sulfate. The solvent was distilled away and the residue was crystallized from methanol to give 0.4 g of N-(2,6-diethylphenyl)-N'-(4-phenylcyclohexyl)urea, melting at 247°-249° C.
Reaction SMILES: [CH:1]1([C:7]2[O:11][C:10]([CH2:12][CH3:13])=[C:9]([C:14]([OH:16])=O)[CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N:17]1([C:23]2[N:28]=[CH:27][C:26]([NH2:29])=[CH:25][CH:24]=2)[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C.C(OCC)(=O)C>[N:17]1([C:23]2[N:28]=[CH:27][C:26]([NH:29][C:14]([C:9]3[CH:8]=[C:7]([CH:1]4[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]4)[O:11][C:10]=3[CH2:12][CH3:13])=[O:16])=[CH:25][CH:24]=2)[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1
Reactant: Nc1ccc(N2CCOCC2)nc1
Reactant: CCc1oc(C2CCCCC2)cc1C(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCc1oc(C2CCCCC2)cc1C(=O)Nc1ccc(N2CCOCC2)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 25.9 %

Procedure:
5-Cyclohexyl-2-ethyl-furan-3-carboxylic acid (26 mg, 0.116 mmol), 6-morpholin-4-yl-pyridin-3-ylamine (20 mg, 0.116 mmol), and triethylamine (49 uL, 0.348 mmol) were dissolved in 4 mL of DMF and chilled in an ice bath. To this solution was added BOP (53 mg, 0.121 mmol) in one portion. The mixture was stirred at room temperature, for one hour and then diluted with 30 mL ethyl acetate. The ethyl acetate solution was washed with saturated sodium bicarbonate (2×10 mL) and saturated sodium chloride (10 mL). The organic layer was dried over MgSO4, filtered and evaporated to dryness under vacuum. The crude product was purified by flash chromatography using ethyl acetate/hexane to yield 5-cyclohexyl-2-ethyl-furan-3-carboxylic acid (6-morpholin-4-yl-pyridin-3-yl)-amide as a light grey powder (11.5 mg, 26%). ES-MS calcd for C22H29N3O3 (m/e) 383.5, obsd 384 (M+H).
Reaction SMILES: [N+]([C:4]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[C:5]=1[C:6]#[N:7])([O-])=O.[O:15]1[CH:19]=[CH:18][C:17]([CH2:20][OH:21])=[CH:16]1>>[N+:12]([C:8]1[CH:9]=[CH:10][CH:11]=[C:4]([O:21][CH2:20][C:17]2[CH:18]=[CH:19][O:15][CH:16]=2)[C:5]=1[C:6]#[N:7])([O-:14])=[O:13]
Reactant: OCc1ccoc1
Reactant: N#Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Product: N#Cc1c(OCc2ccoc2)cccc1[N+](=O)[O-]
Yield: 100 %

Procedure:
Prepared as in Example 111c from 2,6-dinitrobenzonitrile and 3-furanmethanol in 100% yield. 1H NMR (400 MHz, d-DMSO) δ 5.27 (s, 2H), 6.59 (s, 1H), 7.69 (s, 1H), 7.91-7.84 (m, 4H).
Reaction SMILES: C([C:3]1[C:11]2[C:6](=[C:7]([C:12]3[N:16]=[C:15]([C:17]4[CH:18]=[CH:19][C:20]([O:25][CH:26]([CH3:28])[CH3:27])=[C:21]([CH:24]=4)[C:22]#[N:23])[O:14][N:13]=3)[CH:8]=[CH:9][CH:10]=2)[NH:5][CH:4]=1)=O.[CH3:29][NH:30][CH2:31][C:32]([OH:34])=[O:33].[C:35](O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[C:22]([C:21]1[CH:24]=[C:17]([C:15]2[O:14][N:13]=[C:12]([C:7]3[CH:8]=[CH:9][CH:10]=[C:11]4[C:6]=3[NH:5][CH:4]=[C:3]4[CH2:29][N:30]([CH3:35])[CH2:31][C:32]([OH:34])=[O:33])[N:16]=2)[CH:18]=[CH:19][C:20]=1[O:25][CH:26]([CH3:28])[CH3:27])#[N:23]
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4c(C=O)c[nH]c34)no2)cc1C#N
Reactant: CNCC(=O)O
Reactant: CC(=O)O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c(CN(C)CC(=O)O)c[nH]c34)no2)cc1C#N
Temperature: 40 °C
Reaction time: 8 h
Yield: 59 %

Procedure:
To a stirred solution of 5-[3-(3-formyl-1H-indol-7-yl)-1,2,4-oxadiazol-5-yl]-2-[(1-methylethyl)oxy]benzonitrile (200 mg), N-methylglycine (96 mg) and acetic acid (32 mg) in DCM (10 mL) was added NaBH(OAc)3 (228 mg). The mixture was stirred at 40° C. overnight. After cooled to room temperature, the reaction mixture was diluted with DCM (10 mL), washed with water (20 mL) and aqueous saturated sodium bicarbonate (20 mL). The organic phase was separated and dried over anhydrous sodium sulphate. After concentration, the residue was purified by Mass Directed Auto Prep to afford N-{[7-(5-{3-cyano-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indol-3-yl]methyl}-N-methylglycine (E55) (140 mg, TFA salt). δH (DMSO-d6, 400 MHz): 1.38 (6H, d), 2.73 (3H, s), 3.80 (2H, s), 4.46 (2H, s), 4.98 (1H, m), 7.31 (1H, t), 7.55 (1H, d), 7.71 (1H, d), 7.98 (1H, d), 8.05 (1H, d), 8.48 (1H, dd), 8.71 (1H, d), 11.41 (1H, br s). MS (ES): C24H23N5O4 requires 445; found 357.2 (M—C3H6NO2+).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]([O:12][CH3:13])=[O:11])#[CH:2].C(N(CC)CC)C.Cl[C:22]1[C:27]([C:28]([F:31])([F:30])[F:29])=[CH:26][N:25]=[C:24]([NH:32][C:33]2[CH:38]=[CH:37][C:36]([CH:39]3[CH2:44][CH2:43][N:42]([C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[CH2:41][CH2:40]3)=[CH:35][CH:34]=2)[N:23]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C)C=O.CCOC(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:13][O:12][C:10](=[O:11])[CH2:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[C:1]#[C:2][C:26]1[C:27]([C:28]([F:29])([F:30])[F:31])=[CH:22][N:23]=[C:24]([NH:32][C:33]2[CH:38]=[CH:37][C:36]([CH:39]3[CH2:40][CH2:41][N:42]([C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[CH2:43][CH2:44]3)=[CH:35][CH:34]=2)[N:25]=1
Reactant: C#Cc1ccccc1CC(=O)OC
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(Nc3ncc(C(F)(F)F)c(Cl)n3)cc2)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)Cc1ccccc1C#Cc1nc(Nc2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)cc2)ncc1C(F)(F)F
Temperature: 120 °C

Procedure:
A solution of methyl 2-(2-ethynylphenyl)acetate (I4) (0.069 g, 0.394 mmol) in dimethylformamide (2 mL) and triethylamine (0.183 mL, 1.31 mmol) was added to a mixture of tert-butyl 4-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylate (I45) (0.150 g, 0.328 mmol), Pd(PPh3)2Cl2 (0.023 g, 0.033 mmol), Cu(I)I (0.0090 g, 0.049 mmol) and triphenylphosphine (0.013 g, 0.049 mmol) in dimethylformamide (2 mL). The reaction mixture was heated under microwave irradiation at 120° C. for 15 minutes. The reaction was cooled and the mixture diluted with EtOAc and passed through a plug of celite and washed through with ethyl acetate (50 mL). Water (50 mL) was added and the layers separated. The aqueous layer was extracted with EtOAc (2×50 mL). The combined organic extracts were washed with water (50 mL) and brine (50 mL) and dried over Na2SO4. After filtration the solvent was removed under reduced pressure to give a dark brown residue. The residue was purified by column chromatography on silica gel (0-20% EtOAc in cyclohexane) to yield the title compound (I46) (0.157 g, 80%) as a brown viscous oil.
Reaction SMILES: [CH:1]1([C:4]2[N:9]=[CH:8][C:7]([OH:10])=[CH:6][C:5]=2[O:11][C:12]([F:15])([F:14])[CH3:13])[CH2:3][CH2:2]1.[Cl:16][C:17]1[C:18](F)=[CH:19][C:20]([F:30])=[C:21]([CH:29]=1)[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.O>[Cl:16][C:17]1[C:18]([O:10][C:7]2[CH:8]=[N:9][C:4]([CH:1]3[CH2:2][CH2:3]3)=[C:5]([O:11][C:12]([F:15])([F:14])[CH3:13])[CH:6]=2)=[CH:19][C:20]([F:30])=[C:21]([CH:29]=1)[C:22]([O:24][C:25]([CH3:26])([CH3:27])[CH3:28])=[O:23]
Reactant: CC(F)(F)Oc1cc(O)cnc1C1CC1
Reactant: CC(C)(C)OC(=O)c1cc(Cl)c(F)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)c1cc(Cl)c(Oc2cnc(C3CC3)c(OC(C)(F)F)c2)cc1F
Temperature: 25 °C
Reaction time: 4 h
Yield: 81.4 %

Procedure:
A suspension of 6-cyclopropyl-5-(1,1-difluoroethoxy)pyridin-3-ol (Preparation 269, 155 mg, 0.72 mmol), tert-butyl 5-chloro-2,4-difluorobenzoate (179 mg, 0.72 mmol) and potassium carbonate (299 mg, 2.16 mmol) in dimethyl sulfoxide (3 mL) was stirred for 4 hours at room temperature. The reaction mixture was diluted with water (40 mL) then extracted with ethyl acetate (3×30 mL). The organic layers were combined, dried over magnesium sulfate, filtered and concentrated in vacuo. The crude material was purified by silica gel column chromatography eluting with 5% diethyl ether in heptane to afford the title compound as a white solid (260 mg, 81%).
Reaction SMILES: [N:1]1([CH2:7][CH2:8]O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=[O:32].[CH3:41][O:42][C:43]1[CH:44]=[C:45]([CH2:51][CH2:52][C:53]2[N:54]=[C:55]3[CH:61]=[C:60]([C:62]4[CH:63]=[N:64][NH:65][CH:66]=4)[N:59](S(C4C=CC=CC=4)(=O)=O)[C:56]3=[N:57][CH:58]=2)[CH:46]=[C:47]([O:49][CH3:50])[CH:48]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1>[CH3:41][O:42][C:43]1[CH:44]=[C:45]([CH2:51][CH2:52][C:53]2[N:54]=[C:55]3[CH:61]=[C:60]([C:62]4[CH:66]=[N:65][N:64]([CH2:8][CH2:7][N:1]5[CH2:2][CH2:3][CH:4]([OH:32])[CH2:5][CH2:6]5)[CH:63]=4)[NH:59][C:56]3=[N:57][CH:58]=2)[CH:46]=[C:47]([O:49][CH3:50])[CH:48]=1
Reactant: COc1cc(CCc2cnc3c(cc(-c4cn[nH]c4)n3S(=O)(=O)c3ccccc3)n2)cc(OC)c1
Reactant: CCOC(=O)N=NC(=O)OCC
Reactant: OCCN1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1cc(CCc2cnc3[nH]c(-c4cnn(CCN5CCC(O)CC5)c4)cc3n2)cc(OC)c1
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 13.2 %

Procedure:
To a stirred solution of 1-piperidineethanol (7.9 mg, 0.0613 mmol) and triphenylphosphine (16.1 mg, 0.0613 mmol) in tetrahydrofuran (1.0 mL), diethyl azodicarboxylate (9.65 μL, 0.0613 mmol) was added at ambient temperature. After 15 minutes, a solution of 2-[2-(3,5-dimethoxyphenyl)ethyl]-5-(phenylsulfonyl)-6-(1H-pyrazol-4-yl)-5H-pyrrolo[2,3-b]pyrazine (from Example 35, Step 1, 25 mg, 0.0510 mmol) in tetrahydrofuran (0.5 mL) was added. After 16 hours, the reaction was quenched with saturated aqueous NaHCO3, extracted with methylene chloride. The combined organic layers were dried over MgSO4, and then concentrated. The residue was dissolved in methanol (2 mL) and potassium carbonate (14.1 mg, 0.102 mmol) was added. The reaction mixture was then warmed up to 60° C. After 30 minutes, the crude mixture was cooled to ambient temperature and purified on RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.05% TFA, at flow rate of 30 mL/min) to give the desired product (3.2 mg) as its TFA salt. LCMS calculated for C26H33N6O3 (M+H)+: m/z=477.3. Found: 477.2.