Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:43])([F:42])[C:3]1[CH:4]=[C:5]([CH:39]=[CH:40][CH:41]=1)[CH2:6][NH:7][C:8](=[O:38])[C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C:15]2[CH:20]=[C:19]([N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[CH:18]=[CH:17][C:16]=2[NH:27][C:28](=[O:37])[C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([CH2:35]Cl)[CH:30]=2)[CH:10]=1.[CH3:44][NH:45][CH2:46][CH2:47][N:48]1[CH2:53][CH2:52][N:51]([C:54]([O:56][C:57]([CH3:60])([CH3:59])[CH3:58])=[O:55])[CH2:50][CH2:49]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C)C=O.CC(C)=O>[CH3:44][N:45]([CH2:35][C:31]1[CH:32]=[CH:33][CH:34]=[C:29]([C:28](=[O:37])[NH:27][C:16]2[CH:17]=[CH:18][C:19]([N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:20][C:15]=2[C:11]2[CH:10]=[C:9]([C:8](=[O:38])[NH:7][CH2:6][C:5]3[CH:39]=[CH:40][CH:41]=[C:3]([C:2]([F:43])([F:42])[F:1])[CH:4]=3)[CH:14]=[CH:13][N:12]=2)[CH:30]=1)[CH2:46][CH2:47][N:48]1[CH2:53][CH2:52][N:51]([C:54]([O:56][C:57]([CH3:60])([CH3:59])[CH3:58])=[O:55])[CH2:50][CH2:49]1
Reactant: CNCCN1CCN(C(=O)OC(C)(C)C)CC1
Reactant: O=C(NCc1cccc(C(F)(F)F)c1)c1ccnc(-c2cc(N3CCCCC3)ccc2NC(=O)c2cccc(CCl)c2)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: CN(CCN1CCN(C(=O)OC(C)(C)C)CC1)Cc1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Temperature: 70 °C
Reaction time: 2.5 h
Yield: 54.6 %

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of N-(3-(trifluoromethyl)benzyl)-2-(2-(3-(chloromethyl)benzamido)-5-(piperidin-1-yl)phenyl)-isonicotinamide (100 mg, 0.17 mmol, 1.00 equiv) in N,N-dimethylformamide (2.5 mL), acetone (2.5 mL), tert-butyl 4-(2-(methylamino)ethyl)piperazine-1-carboxylate (48 mg, 0.20 mmol, 1.20 equiv), potassium carbonate (68 mg, 0.49 mmol, 3.00 equiv), and potassium iodide (6 mg, 0.04 mmol, 0.20 equiv). The resulting solution was stirred for 2.5 h at 70° C. in an oil bath. The resulting mixture was concentrated under vacuum. The crude product (100 mg) was purified by reverse phase HPLC eluting with a water/CH3CN gradient containing 0.05% TFA. The product was obtained as 75.5 mg (49%) of a yellow solid. 1H-NMR (300 MHz, DMSO-d6, ppm): δ 12.28 (s, 1H), 9.58-9.54 (m, 1H), 8.94-8.92 (d, J=5.1 Hz, 1H), 8.33-8.27 (m, 2H), 8.04 (s, 1H), 7.96-7.93 (d, J=7.8 Hz, 1H), 7.85-7.84 (d, J=4.2 Hz, 1H), 7.71-7.55 (m, 7H), 7.31-7.28 (d, J=8.1 Hz, 1H), 4.64-4.62 (d, J=5.7 Hz, 2H), 4.29 (s, 2H), 3.44-3.31 (m, 8H), 3.20 (s, 2H), 3.06 (s, 2H), 3.27-3.26 (m, 6H), 1.73 (s, 4H), 1.60 (s, 2H), 1.39 (s, 9H). MS (ES, m/z): 814 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][C:9]=1[N:14]([CH2:31][C:32]([O:34][CH3:35])=[O:33])[C:15](=[O:30])[C:16]1[CH:21]=[C:20]([C:22](F)(F)F)N=[C:18]([C:26]([F:29])([F:28])[F:27])[CH:17]=1.[CH3:36][S:37](C1C=C(C=C(C(F)(F)F)C=1)C(O)=O)(=[O:39])=[O:38].F[B-](F)(F)F.BrC1C=CC=C[N+]=1CC.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[CH3:35][O:34][C:32](=[O:33])[CH2:31][N:14]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][C:8]=1[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[F:1])[C:15](=[O:30])[C:16]1[CH:17]=[C:18]([C:26]([F:27])([F:29])[F:28])[CH:22]=[C:20]([S:37]([CH3:36])(=[O:39])=[O:38])[CH:21]=1
Reactant: CS(=O)(=O)c1cc(C(=O)O)cc(C(F)(F)F)c1
Reactant: COC(=O)CN(C(=O)c1cc(C(F)(F)F)nc(C(F)(F)F)c1)c1cnccc1-c1ccccc1F
Agent: CC[n+]1ccccc1Br
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CN(C(=O)c1cc(C(F)(F)F)cc(S(C)(=O)=O)c1)c1cnccc1-c1ccccc1F
Temperature: 25 °C
Reaction time: 22 h

Procedure:
To a solution of methyl 2-(4-(2-fluorophenyl)pyridin-3-ylamino)acetate (272 mg, 1.05 mmol; example 196, intermediate) in CH2Cl2 (3 mL) was added 3-(methylsulfonyl)-5-(trifluoromethyl)benzoic acid (280 mg, 1.05 mmol, example 114, intermediate a) and 2-bromo-1-ethylpyridinium tetrafluoroborate (343 mg, 1.25 mmol) and N,N-diisopropylethylamine (270 mg, 365 μL, 2.09 mmol). The reaction mixture was stirred at room temperature for 22 hours and then concentrated under vacuum. The residue was dissolved in 30 mL 1M aqueous HCl and 30 mL EtOAc and the layers were separated. The aqueous layer was extracted a second time with 30 mL EtOAc. The organic layers were washed with 30 mL 1M aqueous HCl and 30 mL 10% aqueous NaHCO3 and 30 mL brine, dried over MgSO4, filtered and concentrated under vacuum. The residue was purified by silica gel chromatography on a 20 g column using an MPLC (Flashmaster) system eluting with a gradient of n-heptane:EtOAc (100:0 to 0:100). Light brown foam (323 mg, 61%). MS (ESI): m/z=511.094 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[CH:5](Br)[C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1)[CH3:2].[C:14]([NH2:18])([CH3:17])([CH3:16])[CH3:15].CCN(CC)CC>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:13])[CH:5]([NH:18][C:14]([CH3:17])([CH3:16])[CH3:15])[C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1)[CH3:2]
Reactant: CCOC(=O)C(Br)c1cccnc1
Reactant: CC(C)(C)N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C(NC(C)(C)C)c1cccnc1
Yield: 41.2 %

Procedure:
Bromo-pyridin-3-yl-acetic acid ethyl ester (2.4 g; 9.8 mmol) was reacted in refluxing CH2Cl2, overnight with tert-butylamine (6.2 mL; 55.8 mmol; 6 equiv) and Et3N (2.8 mL; 19.6 mmol; 2 equiv). The reaction solution was evaporated to dryness, dissolved in CH2Cl2, washed six times with saturated NaHCO3 (aq), washed once with saturated NaCl (aq), dried with Na2SO4, filtered, and concentrated in vacuo. The resulting brown oil was purified with silica gel chromatography in a 6×8 cm glass column using a 30% EtOAc/hexanes (v/v) mobile phase. A total of 955 mg desired product was isolated (41% yield). MS(ES) calc'd: [M+H]+=237.1 m/z. Found: 237.1 m/z.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[NH:6][C:5](=[O:7])[C:4]([CH3:9])([CH3:8])[NH:3]1.[H-].[Na+].[CH3:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22]OC1C=C(S([O-])(=O)=O)C=CC=1C>CN(C)C=O>[CH3:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][N:6]1[C:5](=[O:7])[C:4]([CH3:9])([CH3:8])[NH:3][C:2]1([CH3:10])[CH3:1]
Reactant: COCCOCCOCCOc1cc(S(=O)(=O)[O-])ccc1C
Reactant: CC1(C)NC(=O)C(C)(C)N1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCOCCOCCN1C(=O)C(C)(C)NC1(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 42.7 %

Procedure:
2,2,5,5-Tetramethylimidazolidin-4-one (20.00 g, 140.6 mmol), prepared as described in U.S. Pat. No. 5,126,057 (Worely et al., Jun. 30, 1992), was dissolved in N,N-dimethylformamide (300 ml). To the stirring room temperature solution was added sodium hydride (60%, 5.06 g, 126.5 mmol), in 8 portions over 30 minutes. After an additional one hour of stirring at room temperature, [2-[2-(2-methoxyethoxy)ethoxy]ethoxy]p-toluenesulfonate (40.15 g, 126.1 mmol) was slowly added to the basic solution over a 20 minute period. The reaction mixture was stirred for an additional 18 hours at room temperature. The reaction mixture was concentrated under high vacuum. The solid material was dissolved in dichloromethane and the solution was filtered to remove any solid material. The organic layer was concentrated in vacuo, and crude material was purified by silica gel column chromatography (0 to 10% methanol in dichloromethane) to give 15.51 g (38%) of the title compound. 1H NMR (D2O, 400 MHz) δ 3.70-3.46 (m, 12H), 3.64-3.59 (m, 2H), 3.46 (t, J=6.2 Hz, 2H), 3.26 (s, 3H), 1.31 (s, 6H), 13C NMR (D2O, 100 MHz) δ 179.48, 76.22, 70.99, 69.59, 69.56, 69.39, 67.71, 58.90, 58.00, 39.70, 27.28, 25.67; LRMS (ESI/APCI) m/z 289 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][CH2:7][O:8][Si:9]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10])=[C:4]([CH2:18]C)[CH:3]=1.Br[C:21]1C=C(C)C(CCO)=C(C)C=1.C([Si](Cl)(C)C)(C)(C)C>>[Br:1][C:2]1[CH:3]=[C:4]([CH3:18])[C:5]([CH2:6][CH2:7][O:8][Si:9]([C:12]([CH3:13])([CH3:14])[CH3:15])([CH3:10])[CH3:11])=[C:16]([CH3:21])[CH:17]=1
Reactant: CCc1cc(Br)ccc1CCO[Si](C)(C)C(C)(C)C
Reactant: Cc1cc(Br)cc(C)c1CCO
Agent: CC(C)(C)[Si](C)(C)Cl
Product: Cc1cc(Br)cc(C)c1CCO[Si](C)(C)C(C)(C)C
Yield: 80 %

Procedure:
Using a procedure analogous to that used to prepare 46A, 32B (3.0 g, 13.1 mmol) was reacted tert-butylchlorodimethylsilane to afford 50A (3.58 g, 80%) as a clear oil. 1H NMR (400 MHz, CDCl3) δ ppm −0.01 (s, 9 H) 2.30 (s, 6 H) 2.84 (t, J=7.70 Hz, 2 H) 3.66 (t, J=7.70 Hz, 2 H) 7.13 (s, 2 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][CH2:29][N:28]([C:32](=[O:36])[CH2:33][C:34]#[N:35])[CH2:27]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[C:22]([F:24])[CH:21]=[C:20]([F:25])[CH:19]=4)=[CH:13][CH:12]=3)[C:3]=12.[CH:37]1([CH:40]=O)[CH2:39][CH2:38]1.N1CCCCC1.ClCCl>CO>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@@H:26]3[CH2:31][CH2:30][CH2:29][N:28]([C:32]([C:33](=[CH:40][CH:37]4[CH2:39][CH2:38]4)[C:34]#[N:35])=[O:36])[CH2:27]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:19]=[C:20]([F:25])[CH:21]=[C:22]([F:24])[CH:23]=4)=[CH:13][CH:12]=3)[C:3]=12
Reactant: N#CCC(=O)N1CCC[C@@H](n2nc(-c3ccc(Oc4cc(F)cc(F)c4)cc3)c3c(N)ncnc32)C1
Reactant: O=CC1CC1
Solvent: C1CCNCC1
Solvent: ClCCl
Solvent: CO
Product: N#CC(=CC1CC1)C(=O)N1CCC[C@@H](n2nc(-c3ccc(Oc4cc(F)cc(F)c4)cc3)c3c(N)ncnc32)C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 41.7 %

Procedure:
Into a 50 mL round-bottom flask, was placed a solution of 3-[(3R)-3-[4-amino-3-[4-(3,5-difluorophenoxy)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidin-1-yl]-3-oxopropanenitrile (150 mg, 0.31 mmol, 1.00 equiv) in methanol (20 mL), cyclopropanecarbaldehyde (64 mg, 0.91 mmol, 3.00 equiv), piperidine (13 mg, 0.15 mmol, 0.50 equiv), and dichloromethane (5 mL). The resulting solution was stirred for 12 h at room temperature and then concentrated under vacuum. The residue was loaded onto a silica gel column and eluted with dichloromethane/methanol (100:1) to give 70 mg (42%) of the title compound as a white solid. LC-MS: (ES, m/z): 542 [M+H]+. 1HNMR (300MHz,CDCl3, ppm) 8.405 (1H, s), 7.762˜7.715 (2H, m), 7.282˜7.223 (2H, m), 6.656˜6.575 (4H, m), 6.696 (2H,s),5.022˜4.924 (1H,m),4.8˜2.9 (4H,m), 2.424˜2.301 (2H,m),2.271˜2.259 (3H,d),1.295˜1.228 (2H,t),0.903˜0.892 (2H,d).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:28])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:10][NH:9]2)[CH:5]=[CH:6][CH:7]=1.[C:29](Cl)(Cl)=[O:30].C(N(CC)CC)C.[C:40]([O:44][C:45]([N:47]1[CH2:52][CH2:51][CH:50]([CH2:53][NH2:54])[CH2:49][CH2:48]1)=[O:46])([CH3:43])([CH3:42])[CH3:41]>C(Cl)Cl>[C:40]([O:44][C:45]([N:47]1[CH2:52][CH2:51][CH:50]([CH2:53][NH:54][C:29]([N:9]2[CH2:10][C@@H:11]([CH2:23][C:24]([CH3:25])([CH3:27])[CH3:26])[C@@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:8]2[C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=2[F:28])=[O:30])[CH2:49][CH2:48]1)=[O:46])([CH3:43])([CH3:42])[CH3:41]
Reactant: CC(C)(C)OC(=O)N1CCC(CN)CC1
Reactant: CC(C)(C)CC1CNC(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Reactant: O=C(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)C[C@@H]1CN(C(=O)NCC2CCN(C(=O)OC(C)(C)C)CC2)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Yield: 73.1 %

Procedure:
In a manner similar to the method described in Example 4, rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-4-(2,2-dimethyl-propyl)-pyrrolidine-3-carbonitrile (42.3 mg, 0.10 mmol) was reacted with phosgene solution (Aldrich, 20% in toluene, 0.12 mL, 0.12 mmol), in the presence of triethylamine (TEA, 30.0 mg, 0.30 mmol) in CH2Cl2 (2 mL) followed by reacting with 4-aminomethyl-piperidine-1-carboxylic acid tert-butyl ester (66.3 mg, 0.30 mmol) at rt for 30 min to give rac-4-({[(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidine-1-carbonyl]-amino}-methyl)-piperidine-1-carboxylic acid tert-butyl ester (48.5 mg, 73.0%) as a white amorphous.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:7][CH2:8][CH2:9]Cl>>[Cl-:7].[Cl:7][CH2:8][CH2:9][N+:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccncc1
Reactant: ClCCCl
Product: ClCC[n+]1ccccc1
Product: [Cl-]

Procedure:
A solution of pyridine (100 g, 1.25 mole) in 800 ml. of 1,2-dichloroethane was refluxed for 72 hours. The white crystalline material which formed was filtered, washed repeatedly with fresh 1,2-dichloroethane and dried. Collected 200 g (89 per cent yield), nmr (D2O) ppm (δ), 4.3 (t, 3), 5.6 (t, 3), 8.1 - 9.3 (m, 5).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:11])[C:5]([OH:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].[C:12](=O)([O-])[O-].[K+].[K+].ICI>CN(C)C=O>[Br:1][C:2]1[CH:9]=[C:6]([CH:7]=[O:8])[C:5]2[O:10][CH2:12][O:11][C:4]=2[CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: O=Cc1cc(Br)cc(O)c1O
Agent: [K+]
Solvent: ICI
Solvent: CN(C)C=O
Product: O=Cc1cc(Br)cc2c1OCO2
Temperature: 85 °C
Yield: 79.4 %

Procedure:
Dimethylformamide, 750 mL, was purged with dry nitrogen gas and 5-bromo-2,3-dihydroxy-benzaldehyde (83 g, 382 mmol) was added. To the solution was added potassium carbonate (158 g, 1.14 mol) followed by diiodomethane (306 g, 1.14 mol). The mixture was warmed to 85° C. for 2.5 hours, and evaporated in vacuo to an oil. The mixture was partitioned between ethyl acetate and water and filtered through celite. The phases were separated, and the organic phase was washed with brine, dried over anhydrous magnesium sulfate, filtered, and evaporated to a small volume causing a solid to precipitate. The solid was filtered, washed with 50:50 hexane/ethyl acetate, and set aside. Three more crops of solid were subsequently isolated in this manner from the filtrate. The solids were combined and dried in vacuo giving a beige solid, 69.45 g, 79.4% yield. NMR spectra and elemental analysis were consistent with the structure.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([C:12]([O:14][CH3:15])=[O:13])[N:6]=[CH:7]2.C1(C)C=CC=CC=1.[Cl:23][C:24]1[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:25]=1[CH2:31][N:32]=[C:33]=[O:34]>C1COCC1>[Cl:23][C:24]1[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:25]=1[CH2:31][NH:32][C:33]([NH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([C:12]([O:14][CH3:15])=[O:13])[N:6]=[CH:7]2)=[O:34]
Reactant: COC(=O)c1cc2c(N)cccc2cn1
Reactant: O=C=NCc1ccc(Cl)cc1Cl
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COC(=O)c1cc2c(NC(=O)NCc3ccc(Cl)cc3Cl)cccc2cn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 72.6 %

Procedure:
The product of Example 71B (0.156 g, 0.77 mmol) in THF:toluene (10 mL, 1:1) was treated with a solution of 2,4-dichloro-1-(isocyanatomethyl)benzene (0.195 g, 0.97 mmol) in THF (1.0 mL). After stirring for 16 hours at room temperature, the reaction mixture was concentrated under reduced pressure and the residue was triturated with diethyl ether to provide the title compound as a tan solid (0.226 g, 73%). MS (ESI+) m/z 404 (M+H)+; MS (ESI−) m/z 402 (M−H)−; 1H NMR (DMSO-d6, 300 MHz) δ 3.96 (s, 3H), 4.44 (d, J 6.0, 2H), 7.29 (m, 1H), 7.48 (m, 1H), 7.65 (d, J 1.7, 1H), 7.76 (t, J 7.8, 1H), 7.86 (d, J 7.8, 1H), 8.41 (dd, J 1.0, 7.8, 1H), 8.84 (s, 1H), 9.15 (s, 1H), 9.35 (s, 1H); Anal. Calcd for C19H15Cl2N3O3: C, 56.45; H, 3.74; N, 10.39. Found: C, 56.08; H, 3.67; N, 10.03.
Reaction SMILES: [Mg].Br[CH:3]([CH3:5])[CH3:4].[Br:6][C:7]1[S:8][C:9]([Br:12])=[CH:10][CH:11]=1.Cl.[CH2:14]1[CH2:18]OC[CH2:15]1>>[Br:6][C:7]1[S:8][C:9]([Br:12])=[CH:10][C:11]=1[CH2:4][CH2:3][CH2:5][CH2:15][CH2:14][CH3:18]
Reactant: C1CCOC1
Reactant: Brc1ccc(Br)s1
Reactant: CC(C)Br
Agent: Cl
Agent: [Mg]
Product: CCCCCCc1cc(Br)sc1Br
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a dry 3-necked flask under nitrogen is added magnesium filings (354 mg, 14.6 mmol). A solution of 2,5-dibromo-3-hexylthiophene (4.41 g, 13.5 mmol) in anhydrous THF (45 ml) is prepared and 5 ml of this solution is added to the magnesium at 5° C. The reaction is initated by the addition of 2-bromopropane (80 mg, 0.65 mmol). After 5 min, the remaining solution of 2,5-dibromothiophene is added dropwise, keeping the temperature below 10° C. The resulting yellow solution is warmed to room temperature and stirred for 4 h at that temperature. An aliquot is taken, hydrolysed with dilute hydrochloric acid and analysed by GCMS to reveal 98% formation of monogrignard reagent and 2% formation of a digrignard reagent. No starting material remained. The solution is transferred, via cannula, to a new reaction vessel and heated to reflux. 1,2-bis{diphenylphosphinopropane)dichloronickel (II) (72 mg, 1 mol %) is added as a solid and the reaction refluxed for 4 h. The reaction is cooled to room temperature and precipitated into methanol. The resulting polymer is filtered, and washed with additional methanol (soxhlet) and heptane (soxhlet). The resulting polymer is dissolved in chloroform and precipitated into methanol to afford 0.6 g of polymer.
Reaction SMILES: [CH2:1]([Mg]Br)[CH3:2].[Cl:5][C:6]1[CH:37]=[CH:36][C:9]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][N:15]([C:18]3[CH:19]=[CH:20][C:21]4[N:25]=[C:24]([CH:26]5[CH2:28][CH:27]5[C:29]([O:31]C)=O)[N:23]([CH3:33])[C:22]=4[CH:34]=3)[C:14](=[O:35])[CH:13]=2)=[CH:8][CH:7]=1.[CH2:38]1COC[CH2:39]1>>[Cl:5][C:6]1[CH:37]=[CH:36][C:9]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][N:15]([C:18]3[CH:19]=[CH:20][C:21]4[N:25]=[C:24]([CH:26]5[CH2:28][CH:27]5[C:29]([OH:31])([CH2:1][CH3:2])[CH2:38][CH3:39])[N:23]([CH3:33])[C:22]=4[CH:34]=3)[C:14](=[O:35])[CH:13]=2)=[CH:8][CH:7]=1
Reactant: CC[Mg]Br
Reactant: C1CCOC1
Reactant: COC(=O)C1CC1c1nc2ccc(-n3ccc(OCc4ccc(Cl)cc4)cc3=O)cc2n1C
Product: CCC(O)(CC)C1CC1c1nc2ccc(-n3ccc(OCc4ccc(Cl)cc4)cc3=O)cc2n1C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Ethylmagnesium bromide (1.0 M solution in THF, 1.29 ml) was added to a solution of methyl(1RS,2RS)-2-(6-(4-((4-chlorobenzyl)oxy)-2-oxopyridin-1(2H)-yl)-1-methyl-1H-benzimidazol-2-yl)cyclopropanecarboxylate (150 mg) in THF (5 ml) at 0° C., and the mixture was stirred at room temperature for 3 h. The mixture was quenched with saturated NH4Cl solution, and extracted with EtOAc. The organic layer was separated, washed with water and brine successively, dried over MgSO4, and concentrated in vacuo. The residue was purified by NH silica gel column chromatography (EtOAc/MeOH), and the resulting solid was crystallized from EtOH to give the title compound (48 mg) as a white solid.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[O:16][CH2:17][CH2:18][O:19][CH3:20])[NH:12][C:11](=O)[N:10]=[CH:9]2.C(Cl)(Cl)[Cl:23].C(Cl)(=O)C(Cl)=O>CN(C)C=O>[Cl:23][C:9]1[C:8]2[C:13](=[CH:14][C:15]([O:16][CH2:17][CH2:18][O:19][CH3:20])=[C:6]([O:5][CH2:4][CH2:3][O:2][CH3:1])[CH:7]=2)[N:12]=[CH:11][N:10]=1
Reactant: ClC(Cl)Cl
Reactant: COCCOc1cc2cnc(=O)[nH]c2cc1OCCOC
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Product: COCCOc1cc2ncnc(Cl)c2cc1OCCOC
Temperature: 27.5 °C

Procedure:
6,7-Bis(2-methoxy-ethoxy)-quinazolone (68 gm), chloroform (1360 ml) and dimethylformamide (7.5 ml) are taken in a reaction flask at 25-30° C. and stirring begun. To the contents is added oxalyl chloride (120 ml) at 25-30° C. slowly for 30 minutes, which is then heated to reflux for 1 hour 30 minutes. The solvent is distilled at 55-60° C. under vacuum, diisopropyl ether (560 ml) is added, cooled to 25-30° C. and then stirred for 30 minutes. The compound is filtered and washed with diisopropyl ether (100 ml). The compound is added to chloroform (1000 ml), the chloroform is washed two times with 8% NaHCO3 solution (each time 680 ml) and the resulting organic layer is washed with water (500 ml), the organic layer is dried over sodium sulfate and the solvent is distilled under a vacuum at 55-60° C. To the residue is added n-heptane and stirred for 1 hour at 25-30° C. The material, is filtered washed with n-heptane (100 ml) and then the material is dried at 50° C. under vacuum to obtain 65 gm of 4-Chloro-6,7-bis-(2-methoxyethoxy)-quinazoline.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3([CH2:22][NH2:23])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:24]1([CH:27]=O)[CH2:26][CH2:25]1>>[CH:24]1([CH2:27][N:23]([CH2:27][CH:24]2[CH2:26][CH2:25]2)[CH2:22][C:16]2([C:13]3[CH:14]=[CH:15][C:10]([O:9][CH2:8][CH2:7][CH2:6][N:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)=[CH:11][CH:12]=3)[CH2:17][CH2:18][O:19][CH2:20][CH2:21]2)[CH2:26][CH2:25]1
Reactant: O=CC1CC1
Reactant: NCC1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Product: c1cc(C2(CN(CC3CC3)CC3CC3)CCOCC2)ccc1OCCCN1CCCC1
Yield: 51 %

Procedure:
The title compound (169 mg, 51%) was prepared from {4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydropyran-4-yl}methylamine free base and cyclopropane carboxaldehyde similarly to the procedure used for example 54. 3 equivalents of cyclopropane carboxaldehyde were required for the synthesis of this Example. 1H NMR (400 MHz, CDCl3) δ −0.04 (q, 4H), 0.39 (q, 4H), 0.71-0.76 (m, 2H), 1.80-1.86 (m, 4H), 1.94-2.12 (m, 6H), 2.16 (d, 4H), 2.55-2.72 (m, 8H), 3.51 (t, 2H), 3.75-3.79 (m, 2H), 4.04 (t, 2H), 6.88 (d, 2H), 7.21 (d, 2H). HRMS ESI+ m/z 427.3306 [MH]+.
Reaction SMILES: N1C=CC=CC=1[CH:7]=[CH:8][C:9]1[C:17]2[C:12](=[CH:13][C:14]([NH:18][C:19]3[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=3[C:21]([OH:23])=O)=[CH:15][CH:16]=2)[NH:11][N:10]=1.[CH3:28][N:29]1[CH:33]=[CH:32][CH:31]=[C:30]1[C:34]([NH:36][NH2:37])=[O:35].C(N(CC)CC)C.CN(C(ON1N=N[C:55]2[CH:56]=[CH:57][CH:58]=[N:59][C:54]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[N:59]1[CH:58]=[CH:57][CH:56]=[CH:55][C:54]=1/[CH:7]=[CH:8]/[C:9]1[C:13]2[C:12](=[CH:17][CH:16]=[CH:15][C:14]=2[NH:18][C:19]2[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=2[C:21]([NH:37][NH:36][C:34]([C:30]2[N:29]([CH3:28])[CH:33]=[CH:32][CH:31]=2)=[O:35])=[O:23])[NH:11][N:10]=1
Reactant: Cn1cccc1C(=O)NN
Reactant: O=C(O)c1ccccc1Nc1ccc2c(C=Cc3ccccn3)n[nH]c2c1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cn1cccc1C(=O)NNC(=O)c1ccccc1Nc1cccc2[nH]nc(/C=C/c3ccccn3)c12
Reaction time: 8 h
Yield: 40.1 %

Procedure:
A solution of 2-[3-(2-Pyridin-2-yl-vinyl)-1H-indazol-6-ylamino]-benzoic acid (50.0 mg, 0.084 mmol), 1-methyl-1H-pyrrole-2-carboxylic acid hydrazide (23.3 mg, 0.17 mmol), triethylamine(58 μl, 0.42 mmol), dissolved in DMF (0.8 mL), was treated with HATU (48 mg, 0.13 mmol). The mixture was stirred overnight, then purified by reverse phase HPLC yielding 16.1 mg (40%) of the title compound as a yellow solid. 1H NMR (DMSO-d6): δ 10.39 (1H, s), 10.00 (1H, s), 9.52 (1H, s), 8.67 (1H, d, J=2.4), 8.07 (4H, m), 7.77 (1H, d, J=5.2), 7.51 (4H, m), 7.32 (1H, s), 7.09 (1H, d, J=6.3), 6.98 (3H, m), 6.13 (1H, m), 3.87 (3H, s). ESIMS (M+H+):478.1.
Reaction SMILES: [Br:1][C:2]1[C:3](F)=[C:4]2[C:10]([NH:11][C:12](=[O:18])[CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[NH:20]1[CH2:25][CH2:24][CH2:23][C@@H:22]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:21]1>C(O)(CC)C>[Br:1][C:2]1[C:3]([N:20]2[CH2:25][CH2:24][CH2:23][C@@H:22]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:31])([CH3:30])[CH3:32])[CH2:21]2)=[C:4]2[C:10]([NH:11][C:12](=[O:18])[CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CS(=O)(=O)CC(=O)Nc1c[nH]c2ncc(Br)c(F)c12
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCNC1
Solvent: CCC(C)O
Product: CC(C)(C)OC(=O)N[C@@H]1CCCN(c2c(Br)cnc3[nH]cc(NC(=O)CS(C)(=O)=O)c23)C1
Yield: 67.3 %

Procedure:
N-(5-Bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-(methylsulfonyl) acetamide (300 mg, 0.857 mmol) and (R)-tert-butyl piperidin-3-ylcarbamate (515 mg, 2.57 mmol) in s-BuOH (5 mL) were heated to 135° C. in a sealed tube for 24 hours. After cooling down, the residue was concentrated and purified by reverse phase chromatography (SP4, 25M, water/ACN 80/20→0/100, 30 CV) to yield (R)-tert-butyl 1-(5-bromo-3-(2-(methylsulfonyl)acetamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate (306 mg, 67.3% yield) as a solid.