Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:24])[C:14]=1[NH:15][C:16]1[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][C:17]=1[F:23])[N:11]=[N:10][CH:9]=[C:8]2O)=[O:4].O=P(Cl)(Cl)[Cl:28]>>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:24])[C:14]=1[NH:15][C:16]1[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][C:17]=1[F:23])[N:11]=[N:10][CH:9]=[C:8]2[Cl:28])=[O:4]
Reactant: O=P(Cl)(Cl)Cl
Reactant: COC(=O)c1cc2c(O)cnnc2c(F)c1Nc1ccc(Br)cc1F
Product: COC(=O)c1cc2c(Cl)cnnc2c(F)c1Nc1ccc(Br)cc1F
Temperature: 80 °C
Reaction time: 1.5 h

Procedure:
A mixture of 7-(4-bromo-2-fluorophenylamino)-8-fluoro-4-hydroxy-cinnoline-6-carboxylic acid methyl ester (1.00 equiv.) and POCl3 (excess) is stirred for 1.5 hours at 80° C. After evaporation of POCl3 under reduced pressure, the crude material is poured into ice and neutralized to pH 7 to 8 with saturated aqueous NaHCO3. The aqueous layer is extracted with EtOAc. The organic layers is dried over MgSO4, filtered, and concentrated under reduced pressure to give the crude product that is purified by trituration or flash column chromatography to afford the desired product as necessary.
Reaction SMILES: [NH2:1][C@@H:2]([C@@H:11]([OH:28])[C@@H:12]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:3]([NH:5][CH:6]([CH3:10])[CH2:7][CH2:8][CH3:9])=[O:4].[C:29]1([CH3:39])[CH:34]=CC(S(O)(=O)=O)=C[CH:30]=1.[O-]S([O-])(=O)=O.[Na+].[Na+]>CO>[CH2:13]([C@H:12]([NH:20][C:21](=[O:22])[O:23][C:24]([CH3:26])([CH3:25])[CH3:27])[C@H:11]([OH:28])[C@H:2]1[C:3](=[O:4])[N:5]([CH:6]([CH3:10])[CH2:7][CH2:8][CH3:9])[CH:30]([CH:29]([CH3:39])[CH3:34])[NH:1]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CCCC(C)NC(=O)[C@@H](N)[C@@H](O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: CCCC(C)N1C(=O)[C@H]([C@@H](O)[C@H](Cc2ccccc2)NC(=O)OC(C)(C)C)NC1C(C)C
Temperature: 65 °C

Procedure:
To a solution of (2S,3R,4S)-2-amino-4-[(tert-butoxycarbonyl)amino]-3-hydroxy-N-(1-methylbutyl)-5-phenylpentanamide (46 mg, 0.117 mmol) in MeOH (500 mL) was added isobutylaldehyde (100 mL), a small amount of p-toluene sulfonic acid, and Na2SO4 (10 mg). The mixture was capped and heated to 65° C. overnight. The reaction was filtered and the resulting filtrate purified by reverse phase chromatography on a C-18 column using a gradient elution of 95-5% H2O (0.1% TFA)/CH3CN (0.1% TFA). Collection and concentration of the appropriate fractions separately afforded the earlier and later eluting diastereomer products as the trifluoroacetate salts. Earlier eluting diastereomer: 1H NMR (400 MHz, CD3OD) δ 7.29-7.25 (m, 4H), 7.19-7.18 (m, 1H), 4.23 (br s, 1H), 4.05-3.88 (m, 2H), 3.75-3.63 (m, 1H), 3.15-3.05 (m, 1H), 2.80-2.74 (m, 1H), 2.33-2.27 (m, 1H), 1.98 -1.89 (m, 1H), 1.76-1.70 (m, 1H), 1.60-1.51 (m, 1H), 1.48-1.24 (m, 11H), 1.22-1.20 (m, 2H), 1.13 -1.08 (m, 4H), 0.99-0.87 (m, 6H); HRMS (FT-ICR) C25H41N3O4+H=448.3195; calculated 448.3170; Later eluting diastereomer: 1H NMR (400 MHz, CD3OD) δ 7.28-7.25 (m, 4H), 7.19-7.18 (m, 1H), 4.26-4.24 (m, 1H), 4.08-3.99 (m, 2H), 3.77-3.70 (m, 1H), 3.10-3.07 (m, 1H), 2.83 -2.77 (m, 1H), 2.38-2.37 (m, 1H), 1.85-1.77 (m, 2H), 1.62-1.56 (m, 1H), 1.42-1.27 (m, 11H), 1.24 (m, 3H), 1.11 (t, J=5.6 Hz, 3H), 1.02 (d, J=6.8 Hz, 3H), 0.99-0.93 (m, 3H); HRMS (FT-ICR) C25H41N3O4+H=448.3168; calculated 448.3170.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([CH:16]=[CH:17][O:18]C)=[C:12]([F:20])[C:11]=2[F:21])=[C:6]([F:22])[C:5]=1[F:23])[CH3:2].Cl.O>CC(C)=O>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH:17]=[O:18])=[C:12]([F:20])[C:11]=2[F:21])=[C:6]([F:22])[C:5]=1[F:23])[CH3:2]
Reactant: CCOc1ccc(-c2ccc(C=COC)c(F)c2F)c(F)c1F
Agent: Cl
Solvent: CC(C)=O
Solvent: O
Product: CCOc1ccc(-c2ccc(CC=O)c(F)c2F)c(F)c1F
Reaction time: 1 h
Yield: 97.1 %

Procedure:
4-Ethoxy-2,2′,3,3′-tetrafluoro-4′-(2-methoxyvinyl)biphenyl (8) (18.5 g) prepared in the sixth step was dissolved in acetone (200 ml) and hydrochloric acid (6M; 200 ml) was added, and the stirring was continued at room temperature for 1 hour. Water (200 ml) was added, and the water layer was extracted with toluene (100 ml) three times. The combined organic layer was washed with water and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to leave 2-(4′-ethoxy-2,2′,3,3′-tetrafluorobiphenyl-4-yl)acetoaldehyde (9) (17.2 g) in 97.2% yield.
Reaction SMILES: [CH3:1][N:2]([CH3:17])[CH2:3][CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([N+:14]([O-])=O)=[CH:11][CH:12]=2)[CH:7]=[CH:6]1.O.NN>CO.[Ni]>[CH3:1][N:2]([CH3:17])[CH2:3][CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([NH2:14])=[CH:11][CH:12]=2)[CH:7]=[CH:6]1
Reactant: CN(C)CCn1ccc2cc([N+](=O)[O-])ccc21
Agent: [Ni]
Agent: NN
Solvent: CO
Solvent: O
Product: CN(C)CCn1ccc2cc(N)ccc21
Temperature: 25 °C
Yield: 54.7 %

Procedure:
A suspension of compound 91 (250 mg, 1.07 mmol) in dry methanol (10 mL) was treated with Ra—Ni (˜0.05 g) followed by hydrazine hydrate (0.33 mL, 10.7 mmol) and the resulting mixture was refluxed for 20 min. The dark green reaction was cooled to room temperature, filtered through a celite pad, washed with methanol (2×10 mL). The combined methanol layer was evaporated and crude was purified by column chromatography (2 M NH3 in MeOH:CH2Cl2, 5:95) to obtain compound 92(119 mg, 55%) as a yellow oil. 1H NMR (CDCl3) δ 7.16 (d, J=8.7 Hz, 1H), 7.05 (d, J=3.0 Hz, 1H), 6.92 (d, J=2.1 Hz, 1H), 6.67 (dd, J=2.1, 8.7 Hz, 1H), 6.30 (d, J=3.0 Hz, 1H), 4.17 (t, J=7.2 Hz, 2H), 2.68 (t, J=7.5 Hz, 2H), 2.29 (s, 6H); ESI-MS (m/z, %): 204 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8]Br.[O-:10][S:11]([O-:13])=[O:12].[Na+:14].[Na+]>CO.O>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][S:11]([O-:13])(=[O:12])=[O:10].[Na+:14]
Reactant: O=S([O-])[O-]
Reactant: BrCc1ccccc1Br
Agent: [Na+]
Solvent: O
Solvent: CO
Product: O=S(=O)([O-])Cc1ccccc1Br
Temperature: 85 °C
Reaction time: 2.5 h
Yield: 155.6 %

Procedure:
A mixture of 1-bromo-2-(bromomethyl)benzene (20 g, 0.08 mol) and Na2SO3 (15 g, 0.12 mol) in methanol/H2O (100 mL/100 mL) was stirred at 85° Celsius for 2.5 hours, concentrated to dryness and dried to give sodium (2-bromophenyl)methanesulfonate (34 g, crude). 1H NMR (300 MHz, DMSO-d6) δ 7.54 (m, 2H), 7.27 (m, 1H), 7.12 (m, 1H), 3.91 (s, 2H).
Reaction SMILES: [CH2:1]([C:3]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:16]([C:21]([O:23]C(C)(C)C)=[O:22])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:11][CH:10]=2)[C:6]2[CH:28]=[C:29]([C:32]3[N:36]([CH3:37])[C:35]4[CH:38]=[CH:39][CH:40]=[CH:41][C:34]=4[N:33]=3)[CH:30]=[CH:31][C:5]=2[N:4]=1)[CH3:2].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([C:3]1[N:7]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([C:15]3[C:16]([C:21]([OH:23])=[O:22])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:13][CH:14]=2)[C:6]2[CH:28]=[C:29]([C:32]3[N:36]([CH3:37])[C:35]4[CH:38]=[CH:39][CH:40]=[CH:41][C:34]=4[N:33]=3)[CH:30]=[CH:31][C:5]=2[N:4]=1)[CH3:2]
Reactant: CCc1nc2ccc(-c3nc4ccccc4n3C)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCc1nc2ccc(-c3nc4ccccc4n3C)cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared analogously to Example 1 from tert.-butyl 4'-[[2-ethyl-6-(1-methyl-benzimidazol-2-yl)-benzimidazol-1-yl]methyl]biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][C:9]([OH:11])=O.C1N=CN(C(N2C=NC=C2)=O)C=1.CCN(C(C)C)C(C)C.Cl.[F:34][C:35]([F:55])([F:54])[C:36]1[CH:41]=[CH:40][C:39]([C@@H:42]([C:44]2[C:49]([C:50]([F:53])([F:52])[F:51])=[CH:48][CH:47]=[CH:46][N:45]=2)[NH2:43])=[CH:38][CH:37]=1>C(Cl)Cl>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][C:9]([NH:43][C@@H:42]([C:39]1[CH:40]=[CH:41][C:36]([C:35]([F:55])([F:34])[F:54])=[CH:37][CH:38]=1)[C:44]1[C:49]([C:50]([F:51])([F:52])[F:53])=[CH:48][CH:47]=[CH:46][N:45]=1)=[O:11]
Reactant: O=C(O)CCc1ccccn1
Reactant: N[C@@H](c1ccc(C(F)(F)F)cc1)c1ncccc1C(F)(F)F
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(CCc1ccccn1)N[C@@H](c1ccc(C(F)(F)F)cc1)c1ncccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-(pyridin-2-yl)propanoic acid (89 mg, 0.586 mmol, Oakwood) and DCM (4 mL) were added CDI (95 mg, 0.586 mmol) and DIPEA (0.20 mL, 1.148 mmol). After 0.5 hours, the reaction was treated with a solution of (S)-(4-(trifluoromethyl)phenyl)(3-(trifluoromethyl)pyridin-2-yl)methanamine hydrochloride (Intermediate 1) (125 mg, 0.390 mmol) in DCM (1.5 mL). The solution was stirred at rt. After 4 days, the resulting product was adsorbed onto a plug of silica gel and chromatographed through a Redi-Sep® pre-packed silica gel column (4 g), eluting with 0% to 60% EtOAc in hexane, to provide the title compound as a colorless oil. 1H NMR (CDCl3, 300 MHz) δ ppm 8.79 (d, J=3.8 Hz, 1H), 8.45 (d, J=4.8 Hz, 1H), 7.96 (d, J=7.9 Hz, 1H), 7.78 (d, J=7.9 Hz, 1H), 7.44-7.52 (m, 3H), 7.34-7.43 (m, 3H), 7.03-7.12 (m, 2H), 6.63 (d, J=8.0 Hz, 1H), 3.11 (td, J=6.7 & 2.5 Hz, 2H), 2.74 (td, J=7.2 & 2.5 Hz, 2H). MS (ESI pos. ion) m/z: 454.0 (M+H).
Reaction SMILES: [SH:1][C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.Br[CH2:12][CH2:13][CH2:14][N:15]1[C:19](=[O:20])[C:18]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:17]2[C:16]1=[O:25].C(N(CC)CC)C>C(O)C>[C:16]1(=[O:25])[N:15]([CH2:14][CH2:13][CH2:12][S:1][C:2]2[N:7]3[CH:8]=[CH:9][N:10]=[C:6]3[CH:5]=[CH:4][CH:3]=2)[C:19](=[O:20])[C:18]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:17]12
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Reactant: Sc1cccc2nccn12
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=C1c2ccccc2C(=O)N1CCCSc1cccc2nccn12
Temperature: 25 °C
Reaction time: 1 h
Yield: 71 %

Procedure:
To a suspension of 5-mercaptoimidazo[1,2-a]pyridine (3.00 g, 20 mmoles) and N-[3-(bromo)propyl]phthalimide (5.90 g, 22 mmoles) in ethanol (200 ml) was added triethylamine (4.2 ml, 30 mmoles) and the mixture was stirred at room temperature for 1 hour and heated at reflux for 1 hour. After the solvent was distilled off, chloroform was added to the residue, which was washed with water, dried over anhydrous magnesium sulfate and the solvent was distilled off. Then, the residue was purified by column chromatography (eluent: ethyl acetate) to obtain 4.79 g of the desired product (71.1%, colorless crystals).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([CH:12]([CH3:14])[CH3:13])[CH:9]=[C:8]2[C:3]=1[C:4](=[O:17])[CH2:5][C:6]([CH3:16])([CH3:15])[O:7]2.[CH3:18][O:19]C(Cl)Cl>ClCCl.C(OCC)(=O)C.Cl.[Ti](Cl)(Cl)(Cl)Cl>[OH:1][C:2]1[C:11]([CH:18]=[O:19])=[C:10]([CH:12]([CH3:13])[CH3:14])[CH:9]=[C:8]2[C:3]=1[C:4](=[O:17])[CH2:5][C:6]([CH3:15])([CH3:16])[O:7]2
Reactant: CC(C)c1cc(O)c2c(c1)OC(C)(C)CC2=O
Reactant: COC(Cl)Cl
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)c1cc2c(c(O)c1C=O)C(=O)CC(C)(C)O2
Reaction time: 0.08 h

Procedure:
At −50° C., 13.19 ml (13.19 mmol) of a 1 M solution of titanium(IV) chloride in dichloromethane are added dropwise to a solution of 1.03 g (4.40 mmol) of 5-hydroxy-7-isopropyl-2,2-dimethyl-2,3-dihydro-4H-chromen-4-one (Example 17A) in 50 ml of dichloromethane, and the mixture is stirred at this temperature for 5 min. 437 μl (4.84 mmol) of dichloromethyl methyl ether are then slowly added dropwise. Over a period of 2.5 h, the mixture is allowed to thaw to −25° C. The mixture is then diluted with ethyl acetate and 1 M hydrochloric acid, the aqueous phase is extracted with ethyl acetate and the combined organic phases are dried over sodium sulfate. The solvent is removed under reduced pressure and the residue is purified by column chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 16:1).
Reaction SMILES: [N:1]1([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:31][CH2:30][CH2:29][C@H:2]1[C:3]([NH:5][C@H:6]([C:14]([NH:16][C@@H:17]([C:25]([NH:27]N)=[O:26])[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:15])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4].N[CH2:40][C:41]([NH:43][C@H:44]([C:49]([NH:51][C@H:52]([C:57]([NH2:59])=[O:58])[CH2:53][CH2:54][S:55][CH3:56])=[O:50])[CH2:45][CH:46]([CH3:48])[CH3:47])=[O:42].Cl>>[N:1]1([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:31][CH2:30][CH2:29][C@H:2]1[C:3]([NH:5][C@H:6]([C:14]([NH:16][C@H:17]([C:25]([NH:27][CH2:40][C:41]([NH:43][C@H:44]([C:49]([NH:51][C@H:52]([C:57]([NH2:59])=[O:58])[CH2:53][CH2:54][S:55][CH3:56])=[O:50])[CH2:45][CH:46]([CH3:48])[CH3:47])=[O:42])=[O:26])[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:15])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@H](Cc1ccccc1)C(=O)NN
Reactant: CSCC[C@H](NC(=O)[C@H](CC(C)C)NC(=O)CN)C(N)=O
Agent: Cl
Product: CSCC[C@H](NC(=O)[C@H](CC(C)C)NC(=O)CNC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C)C(N)=O
Yield: 79 %

Procedure:
Condensation of BocPro-Phe-DPheNHNH2 (2.44 g.) and HGly-Leu-MetNH2 hydrochloride salt (1.6 g.) by the acyl azide method (Yajima et al., Chem. Pharm. Bull., vol. 19, p. 1900, 1971) gave BocPro-Phe-Phe-Gly-Leu-MetNH2 in 79% yield. De-t-butoxycarbonylation of BocPro-Phe-Phe-Gly-Leu-MetNH2 using hydrogen chloride in acetic acid gave HPro-Phe-Phe-Gly-Leu-MetNH2, which was isolated as the amorphous white solid hydrochloride salt monohydrate in 31% yield.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[C:4]([Cl:9])[N:3]=1.[NH2:10][CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])[CH2:13]1>O1CCOCC1.C(N(C(C)C)CC)(C)C>[Cl:9][C:4]1[N:3]=[C:2]([NH:10][CH2:11][CH:12]2[CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][CH2:21][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)=[O:19])[CH2:13]2)[CH:7]=[C:6]([I:8])[CH:5]=1
Reactant: Clc1cc(I)cc(Cl)n1
Reactant: NCC1CCCN(C(=O)OCc2ccccc2)C1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(OCc1ccccc1)N1CCCC(CNc2cc(I)cc(Cl)n2)C1
Temperature: 150 °C

Procedure:
To a mixture of 2,6-dichloro-4-iodopyridine (1.5 g, 5.5 mmol) and benzyl 3-(aminomethyl)piperidine-1-carboxylate (2.7 g, 11 mmol) in dioxane (10 mL) in a microwave tube was added ten drops of diisopropylethyl amine and sealed. The tube was heated at 150° C. for 72 hours. The reaction mixture was cooled to room temperature and concentrated, the residue was purified by flash chromatography eluting with EtOAc/hexane=1:3 to 1:2 to give the title compound. Yield: 1.0 g (38%). MS (DCI/NH3) m/z 486 (M+H)+.
Reaction SMILES: [C:1]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:2]([C:7]([N:9]2[CH2:13][C@H:12](O)[CH2:11][C@H:10]2[CH2:15][NH:16][C:17]([C:19]2[CH:20]=[CH:21][CH:22]=[C:23]3[C:28]=2[N:27]=[CH:26][CH:25]=[CH:24]3)=[O:18])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1.COCCN(S(F)(F)[F:45])CCOC>C(Cl)Cl>[C:1]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:2]([C:7]([N:9]2[CH2:13][C@@H:12]([F:45])[CH2:11][C@H:10]2[CH2:15][NH:16][C:17]([C:19]2[CH:20]=[CH:21][CH:22]=[C:23]3[C:28]=2[N:27]=[CH:26][CH:25]=[CH:24]3)=[O:18])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COCCN(CCOC)S(F)(F)F
Reactant: O=C(NC[C@@H]1C[C@@H](O)CN1C(=O)c1ccccc1-c1ccccc1)c1cccc2cccnc12
Solvent: ClCCl
Product: O=C(NC[C@@H]1C[C@H](F)CN1C(=O)c1ccccc1-c1ccccc1)c1cccc2cccnc12
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A mixture of N-(((2S,4R)-1-(biphenylcarbonyl)-4-hydroxypyrrolidin-2-yl)methyl)quinoline-8-carboxamide (0.045 g, 0.10 mmol) in DCM was cooled to −78° C., added with bis(2-methoxyethyl)aminosulfur trifluoride (Aldrich) (41 μL, 0.22 mmol) dropwise. The resulting solution was stirred at −78° C. for 0.5 h, allowed to warm to rt gradually over 1.5 h and stirred at rt for 0.5 h, which was quenched by slow addition of MeOH and purified by preparative HPLC using acetonitrile and water (0.1% TFA) as eluent to provide N-(((2S,4S)-1-(biphenylcarbonyl)-4-fluoropyrrolidin-2-yl)methyl)quinoline-8-carboxamide as a white solid. MS (ESI) 454.14 (M+H).
Reaction SMILES: CO[C:3](=[O:21])[CH:4]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][C:8]([F:12])([F:11])[CH2:7]1.[NH2:22][C:23]1[S:24][CH:25]=[CH:26][N:27]=1.C[O-].[Mg+2].C[O-].CO>>[Cl:20][C:15]1[CH:14]=[C:13]([CH:4]([CH2:5][CH:6]2[CH2:10][CH2:9][C:8]([F:11])([F:12])[CH2:7]2)[C:3]([NH:22][C:23]2[S:24][CH:25]=[CH:26][N:27]=2)=[O:21])[CH:18]=[CH:17][C:16]=1[Cl:19]
Reactant: Nc1nccs1
Reactant: COC(=O)C(CC1CCC(F)(F)C1)c1ccc(Cl)c(Cl)c1
Agent: C[O-]
Agent: [Mg+2]
Solvent: CO
Product: O=C(Nc1nccs1)C(CC1CCC(F)(F)C1)c1ccc(Cl)c(Cl)c1
Temperature: 110 °C
Yield: 49.6 %

Procedure:
A mixture of 2-(3,4-dichloro-phenyl)-3-(3,3-difluoro-cyclopentyl)-propionic acid methyl ester (75 mg, 0.22 mmol) and 2-aminothiazole (27 mg, 0.26 mmol) in a solution of magnesium methoxide in methanol (7.4 wt. %, 0.63 mL, 0.44 mmol) was heated to 110° C. for 18 h. At this time, the reaction mixture was cooled to 25° C. and then concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 70/30 hexanes/ethyl acetate) afforded 2-(3,4-dichloro-phenyl)-3-(3,3-difluoro-cyclopentyl)-N-thiazol-2-yl-propionamide (44.2 mg, 49%) as an off-white solid: mp 154–156° C.; FAB-HRMS m/e calcd for C17H16F2Cl2N2OS (M+H)+ 405.0402, found 405.0404.
Reaction SMILES: [Br:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([C:10]2[O:11][CH:12]=[CH:13][CH:14]=2)=[CH:4][C:3]=1[O:15][CH3:16].[CH:17]1([CH2:20][O:21][CH:22]([C:29]2[CH:34]=[CH:33][C:32]([N:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)=[CH:31][CH:30]=2)[C:23](N(OC)C)=[O:24])[CH2:19][CH2:18]1>>[Br:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([C:10]2[O:11][C:12]([C:23](=[O:24])[CH:22]([O:21][CH2:20][CH:17]3[CH2:18][CH2:19]3)[C:29]3[CH:30]=[CH:31][C:32]([N:35]4[CH2:36][CH2:37][O:38][CH2:39][CH2:40]4)=[CH:33][CH:34]=3)=[CH:13][CH:14]=2)=[CH:4][C:3]=1[O:15][CH3:16]
Reactant: CON(C)C(=O)C(OCC1CC1)c1ccc(N2CCOCC2)cc1
Reactant: COc1cc(-c2ccco2)cc(OC)c1Br
Product: COc1cc(-c2ccc(C(=O)C(OCC3CC3)c3ccc(N4CCOCC4)cc3)o2)cc(OC)c1Br

Procedure:
1-(5-(4-Bromo-3,5-dimethoxyphenyl)furan-2-yl)-2-(cyclopropylmethoxy)-2-(4-morpholinophenyl)ethanone was prepared from 2-(4-bromo-3,5-dimethoxyphenyl)furan and 2-(cyclopropylmethoxy)-N-methoxy-N-methyl-2-(4-morpholinophenyl)acetamide according to the procedure used in Example 30. Purification by chromatography (40% EtOAc/hexanes) gave the product as a pale yellow solid (0.092 g, 23% yield). MS: m/z 556.3 [M+H]+.
Reaction SMILES: Br[C:2]1[C:3](=[O:16])[N:4]([CH3:15])[C:5](=[O:14])[C:6]=1[N:7]1[CH2:12][CH2:11][C:10](=[O:13])[CH2:9][CH2:8]1.CC1(C)C(C)(C)OB([C:25]2[CH:42]=[CH:41][C:28]([O:29][CH2:30][C:31]3[CH:40]=[CH:39][C:38]4[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=4)[N:32]=3)=[CH:27][CH:26]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:15][N:4]1[C:3](=[O:16])[C:2]([C:25]2[CH:26]=[CH:27][C:28]([O:29][CH2:30][C:31]3[CH:40]=[CH:39][C:38]4[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=4)[N:32]=3)=[CH:41][CH:42]=2)=[C:6]([N:7]2[CH2:12][CH2:11][C:10](=[O:13])[CH2:9][CH2:8]2)[C:5]1=[O:14]
Reactant: CN1C(=O)C(Br)=C(N2CCC(=O)CC2)C1=O
Reactant: CC1(C)OB(c2ccc(OCc3ccc4ccccc4n3)cc2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CN1C(=O)C(c2ccc(OCc3ccc4ccccc4n3)cc2)=C(N2CCC(=O)CC2)C1=O
Reaction time: 0.5 h
Yield: 53.3 %

Procedure:
To a room temperature, stirred solution of 3-bromo-1-methyl-4-(4-oxopiperidin-1-yl)-1H-pyrrole-2,5-dione (100 mg, 0.34 mmol) in 1,4-dioxane (10 mL) was added 2-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)methyl)quinoline (151 mg, 0.41 mol) under a N2 atmosphere. The reaction mixture was stirred for 30 minutes and then Na2CO3 (87 mg, 1.04 mmol), water (4 mL) and Pd(PPh3)4 (40 mg, 0.03 mmol) were added also under a N2 atmosphere. The resulting mixture was then refluxed for 16 h, diluted with water and extracted with EtOAc (2×20 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The crude material was purified via silica gel column chromatography eluting with 60% EtOAc in hexanes to afford 1-methyl-3-(4-oxopiperidin-1-yl)-4-(4-(quinolin-2-ylmethoxy)phenyl)-1H-pyrrole-2,5-dione (80 mg, 52%) as a solid. 1H NMR (500 MHz, d6-DMSO): δ 8.45 (d, J=7.4 Hz, 1H), 8.12 (t, J=7.2 Hz, 2H) 7.79 (t, J=7.2 Hz, 1H), 7.72 (d, J=7.8 Hz, 1H), 7.64 (t, J=7.6 Hz, 1H), 7.18 (d, J=7.2 Hz, 2H), 7.12 (d, J=7.2 Hz, 2H), 5.38 (s, 2H), 3.62-3.58 (m, 4H), 2.96-2.85 (m, 4H), 2.56 (s, 4H). MS: M+: m/z=441.6; M+H: m/z=442.7. HPLC: 97%, (Condition-B).
Reaction SMILES: [C:1]([OH:5])(=O)[CH2:2][OH:3].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[Cl:30][C:31]1[CH:32]=[C:33]([NH:38][C:39]2[C:48]3[C:43](=[CH:44][C:45]([O:56][CH3:57])=[CH:46][C:47]=3[O:49][CH2:50][C@@H:51]3[CH2:55][CH2:54][CH2:53][NH:52]3)[N:42]=[CH:41][N:40]=2)[CH:34]=[CH:35][C:36]=1[F:37].C(N(CC)C(C)C)(C)C>C(Cl)Cl>[Cl:30][C:31]1[CH:32]=[C:33]([CH:34]=[CH:35][C:36]=1[F:37])[NH:38][C:39]1[C:48]2[C:43](=[CH:44][C:45]([O:56][CH3:57])=[CH:46][C:47]=2[O:49][CH2:50][C@@H:51]2[CH2:55][CH2:54][CH2:53][N:52]2[C:1](=[O:5])[CH2:2][OH:3])[N:42]=[CH:41][N:40]=1
Reactant: O=C(O)CO
Reactant: COc1cc(OC[C@@H]2CCCN2)c2c(Nc3ccc(F)c(Cl)c3)ncnc2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cc(OC[C@@H]2CCCN2C(=O)CO)c2c(Nc3ccc(F)c(Cl)c3)ncnc2c1
Reaction time: 0.5 h
Yield: 50.1 %

Procedure:
Glycolic acid (20 mg) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU, 109 mg) were added sequentially, each in one portion, to a stirred solution of N-(3-chloro-4-fluorophenyl)-7-methoxy-5-[(2S)-pyrrolidin-2-ylmethoxy]-quinazolin-4-amine (96 mg) and N,N-diisopropylethylamine (83 μl) in DCM (3 ml) at room temperature under a nitrogen atmosphere. The reaction mixture was stirred for 16 hours 30 minutes and then diluted with DCM (10 ml) and washed with saturated aqueous sodium hydrogen carbonate and water. The organic layer was dried (MgSO4) and concentrated in vacuo to leave a yellow oil, which was purified by column chromatography using 0-10% methanol in dichloromethane as eluent to give the title compound as a white solid (55 mg, 50%); NMR Spectrum (DMSO-d6) 9.90 (s, 1H), 8.42 (s, 1H), 8.15 (dd, 1H), 7.70-7.60 (m, 1H), 7.40 (t, 1H), 6.88 (d, 1H), 6.78 (d, 1H), 4.65-4.53 (m, 2H), 4.40 (dd, 1H), 4.17 (dd, 1H), 4.03 (d, 1H), 3.90 (s, 3H), 3.45-3.35 (m, 3H), 2.10-1.82 (m, 4H); Mass spectrum MH+ 461.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:15][C:16]2[N:17]=[C:18]([CH2:26][CH2:27][CH:28]3[CH2:32][CH2:31][CH2:30][O:29]3)[C:19]3[CH2:25][NH:24][CH2:23][CH2:22][C:20]=3[N:21]=2)[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1.[C:33](OC(=O)C)(=[O:35])[CH3:34]>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:15][C:16]2[N:17]=[C:18]([CH2:26][CH2:27][CH:28]3[CH2:32][CH2:31][CH2:30][O:29]3)[C:19]3[CH2:25][N:24]([C:33](=[O:35])[CH3:34])[CH2:23][CH2:22][C:20]=3[N:21]=2)[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1
Reactant: COc1cc(Nc2nc3c(c(CCC4CCCO4)n2)CNCC3)ccc1-n1cnc(C)c1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Product: COc1cc(Nc2nc(CCC3CCCO3)c3c(n2)CCN(C(C)=O)C3)ccc1-n1cnc(C)c1
Reaction time: 0.75 h
Yield: 50 %

Procedure:
To a solution of N -(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)-4-(2-(tetrahydrofuran-2-yl)ethyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine (0.114 g, 0.26 mmol) in dichloromethane (2 mL) was added acetic anhydride (0.027 mL, 0.29 mmol) at rt. The reaction mixture was stirred for 45 minutes. The solvent was concentrated; the residue was suspended with methanol and purified by prepHPLC. Fractions were pooled and the solvent was evaporated. The residue was dissolved in water/acetonitrile-mixture (50:50) and freezedried giving 1-(2-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenylamino)-4-(2-(tetrahydrofuran-2-yl)ethyl)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)ethanone (0.062 g, 49.6%).