Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([N+:32]([O-])=O)[C:18]([NH:19][C@H:20]4[CH2:25][CH2:24][C@H:23]([CH2:26][CH2:27][S:28]([CH3:31])(=[O:30])=[O:29])[CH2:22][CH2:21]4)=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl-].[NH4+]>C(O)C.O.C(Cl)Cl.[Fe]>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([NH2:32])[C:18]([NH:19][C@H:20]4[CH2:25][CH2:24][C@H:23]([CH2:26][CH2:27][S:28]([CH3:31])(=[O:30])=[O:29])[CH2:22][CH2:21]4)=[C:13]3[CH:12]=[CH:11]2)(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CS(=O)(=O)CC[C@H]1CC[C@H](Nc2c([N+](=O)[O-])cnc3c2ccn3S(=O)(=O)c2ccccc2)CC1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: O
Solvent: CCO
Product: CS(=O)(=O)CC[C@H]1CC[C@H](Nc2c(N)cnc3c2ccn3S(=O)(=O)c2ccccc2)CC1
Temperature: 100 °C

Procedure:
Trans (1-benzenesulfonyl-5-nitro-1H-pyrrolo[2,3-b]pyridin-4-yl)-[4-(2-methanesulfonyl-ethyl)-cyclohexyl]-amine (1.04 g, 2.05 mmol) was suspended in a mixture of ethanol (10 mL, IMS grade) and water (3.3 mL). Ammonium chloride (658 mg, 12.3 mmol) was added, followed by iron (dust, 460 mg, 8.20 mmol), and the mixture was heated at 100° C. for 2 h. The mixture was cooled to room temperature, then diluted with a 4:1 mixture of DCM: 2 M ammonia in methanol and filtered through Celite®. The filter cake was washed with further 4:1 DCM: 2 M ammonia in methanol and the combined filtrate was concentrated under vacuum. The residue was suspended in water and extracted with DCM (×3). The combined organic extracts were washed with brine then dried (Na2SO4) and concentrated to give 1.04 g (quant) of crude trans 1-benzenesulfonyl-N*4*-[4-(2-methanesulfonyl-ethyl)-cyclohexyl]-1H-pyrrolo[2,3-b]pyridine-4,5-diamine, which was used directly without further purification. LCMS (Method Q, ESI): RT=2.62 min, m+H=477.1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:4][CH:3]=1.C(O[CH:20](N(C)C)[N:21]([CH3:23])[CH3:22])(C)(C)C>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:9](=[O:14])[C:10]([CH3:11])([CH3:13])[CH3:12])=[CH:20][N:21]([CH3:23])[CH3:22])=[CH:6][CH:7]=1
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Reactant: CC(C)(C)C(=O)Cc1ccc(Cl)cc1
Product: CN(C)C=C(C(=O)C(C)(C)C)c1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
1-(4-Chlorophenyl)-3,3-dimethyl-butan-2-one (30 mmol) and tert-butoxybis-(dimethylamino)methane (31.5 mmol) are heated together at reflux overnight. The reaction mixture is then cooled to RT and the excess tert-butoxybis(dimethylamino)methane removed under reduced pressure to give 2-(4-chlorophenyl)-1-dimethylamino-4,4-dimethyl-pent-1-en-3-one.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:10](=[O:13])[CH2:11][Cl:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(O)=O.C(N(CC)CC)C>C(OCC)(=O)C.Cl[Rh+]C1(C)C(C)=C(C)C(C)=C1C.C1(C)C(S(C2C=CC(C(N)C(C3C=CC=CC=3)N)=CC=2)(=O)=O)=CC=CC=1>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[C@@H:10]([OH:13])[CH2:11][Cl:12])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)CCl
Agent: CC1=C(C)C(C)([Rh+]Cl)C(C)=C1C
Agent: Cc1ccccc1S(=O)(=O)c1ccc(C(N)C(N)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: O=CO
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@@H](O)CCl
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.1 %

Procedure:
(3S)-3-tert-Butoxycarbonylamino-1-chloro-4-phenyl-2-butanone (1.49 g, 5.0 mmol), 90% formic acid (0.224 ml, 5.25 mmol), and triethylamine (0.730 ml, 5.25 mmol) were added to a solution of chloro(pentamethylcyclopentadienyl)rhodium (III) (1R,2R)-N-(p-toluenesulfonyl-1,2-diphenylethylenediamine (3.4 mg, 0.005 mmol, s/c=1000) in ethyl acetate (7.0 ml), followed by stirring at room temperature for 2 hours. After completion of the reaction, the reaction mixture was quantitatively analyzed by HPLC to confirm production of a desired compound, (2R, 3S)-3-tert-butoxycarbonylamino-1-chloro-2-hydroxy-4phenylbutane (1.50 g; yield: 99.9%). The production ratio of the desired (2R,3S)-form to the isomeric (2S,3S)-form, (2R,3S):(2S,3S), was found to be 9.0:1.
Reaction SMILES: C([O:8][C:9](=[O:50])[C@@H:10]([NH:35][C:36](=[O:49])[C@@H:37]([NH:45][C:46](=[O:48])[CH3:47])[CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH2:22][C:21](=[O:23])[N:20]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=3)[S:19]2(=[O:34])=[O:33])=[CH:14][CH:13]=1)C1C=CC=CC=1>CCOC(C)=O.CCO.[Pd]>[C:46]([NH:45][C@@H:37]([CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:36]([NH:35][C@@H:10]([CH2:11][C:12]1[CH:13]=[CH:14][C:15]([N:18]2[CH2:22][C:21](=[O:23])[N:20]([CH2:24][C:25]3[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=3)[S:19]2(=[O:34])=[O:33])=[CH:16][CH:17]=1)[C:9]([OH:50])=[O:8])=[O:49])(=[O:48])[CH3:47]
Reactant: COc1ccc(CN2C(=O)CN(c3ccc(C[C@H](NC(=O)[C@H](Cc4ccccc4)NC(C)=O)C(=O)OCc4ccccc4)cc3)S2(=O)=O)cc1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: COc1ccc(CN2C(=O)CN(c3ccc(C[C@H](NC(=O)[C@H](Cc4ccccc4)NC(C)=O)C(=O)O)cc3)S2(=O)=O)cc1
Reaction time: 1.5 h

Procedure:
The title B compound, (S)-2-((S)-2-acetylamino-3-phenyl-propionylamino)-3-{4-[5-(4-methoxy-benzyl)-1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl]-phenyl}-propionic acid benzyl ester (104.3 mg, 0.149 mmol) is dissolved in EtOAc:EtOH (50:50; 250 mL) and put in a Parr Shaker bottle along with 10% Palladium on carbon (30 mg). This gas in the bottle is evacuated and replaced with hydrogen at 45 psi and shaken for 1.5 h. The reaction mixture is filtered through celite and concentrated to yield (S)-2-((S)-2-acetylamino-3-phenyl-propionylamino)-3-{4-[5-(4-methoxy-benzyl)-1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl]-phenyl}-propionic acid as a light yellow foam.
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]2[C:4](=[C:5]([O:13][CH3:14])[C:6]([CH3:12])=[CH:7][CH:8]=2)[N:3]=1.[NH2:15][C@H:16]1[CH2:21][CH2:20][C@H:19]([OH:22])[CH2:18][CH2:17]1.C1CCN2C(=NCCC2)CC1>CC#N>[CH3:14][O:13][C:5]1[C:6]([CH3:12])=[CH:7][CH:8]=[C:9]2[C:4]=1[N:3]=[C:2]([NH:15][C@H:16]1[CH2:21][CH2:20][C@H:19]([OH:22])[CH2:18][CH2:17]1)[N:11]=[CH:10]2
Reactant: N[C@H]1CC[C@H](O)CC1
Reactant: COc1c(C)ccc2cnc(Cl)nc12
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: COc1c(C)ccc2cnc(N[C@H]3CC[C@H](O)CC3)nc12
Reaction time: 8 h

Procedure:
To a solution of 2-chloro-8-methoxy-7-methylquinazoline (20.4 g, 0.098 mol) in CH3CN (800 mL) were added trans-4-amino-cyclohexanol (22.5 g, 0.195 mol) and DBU (29.7 g, 0.195 mol) in one portion. The reaction mixture was refluxed with stirring overnight. TLC (ethyl acetate/petroleum ether=1:1) indicated the reaction was complete. The solvent was removed in vacuo. The residue was taken up with CHCl3 (550 mL), the solution was washed with water (150 mL×2). The aqueous layer was re-extracted with CHCl3 (150 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and concentrated in vacuo to give the crude product. The crude product was re-crystallized from EtOH (130 mL)/water (200 mL) to give the title compound (17 g, 60.5%) as an off-white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[C:19]([C:25]4[CH:26]=[CH:27][C:28]([O:35][CH3:36])=[C:29]([CH:34]=4)[C:30]([O:32]C)=[O:31])=[CH:18][C:11]=3[C:12]=2[C:13]2[NH:14][CH:15]=[CH:16][N:17]=2)=[CH:4][CH:3]=1.O.[OH-].[Na+]>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[C:19]([C:25]4[CH:26]=[CH:27][C:28]([O:35][CH3:36])=[C:29]([CH:34]=4)[C:30]([OH:32])=[O:31])=[CH:18][C:11]=3[C:12]=2[C:13]2[NH:17][CH:16]=[CH:15][N:14]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)c1cc(-c2cc3c(-c4ncc[nH]4)c(-c4ccc(F)cc4)oc3cc2[N+](=O)[O-])ccc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(-c2cc3c(-c4ncc[nH]4)c(-c4ccc(F)cc4)oc3cc2[N+](=O)[O-])cc1C(=O)O
Temperature: 50 °C

Procedure:
To a mixture of methyl 5-(2-(4-fluorophenyl)-3-(1H-imidazol-2-yl)-6-nitrobenzofuran-5-yl)-2-methoxybenzoate (370 mg, 0.759 mmol) in a mixture of THF (40 mL)/water (4 mL) at room temperature was added a 2.0 M aqueous sodium hydroxide solution (1.518 mL, 3.04 mmol). The reaction mixture was heated to 50° C. and maintained at the same temperature overnight. The reaction mixture was concentrated to remove the solvent. The residue was diluted with water, acidified by using 1.5 N HCl, filtered and dried under suction to give the title compound as a yellow solid. Yield: 320 mg (89%). 1H NMR (400 MHz, DMSO-d6) δ ppm: 13.11-13.73 (m, 1H) 12.66-12.97 (m, 1H) 8.53 (s, 1H) 7.94-8.09 (m, 2H) 7.63-7.82 (m, 1H) 7.34-7.51 (m, 5H) 7.23 (d, J=8.78 Hz, 2H) 3.88 (s, 3H). LCMS: (ES+) m/z=474.23 (M+H)+; Column—ACQUITY UPLC BEH C8 (50×2.1 mm; 1.7 nm); Mphase A: 5 mM Ammonium Acetate:MeCN (95:5); Mphase B: 5 mM Ammonium Acetate:MeCN (5:95)
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:17])[CH:5]=[CH:6][C:7]=1[CH2:8][CH2:9][CH2:10][CH2:11][N:12]1[CH:16]=[CH:15][N:14]=[N:13]1.[H-].[Na+].Cl[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[CH:29]=2)[N:23]=1.O>CN(C)C=O>[Cl:34][C:30]1[CH:29]=[C:28]([C:24]2[CH:25]=[CH:26][CH:27]=[C:22]([CH2:21][O:17][C:4]3[CH:5]=[CH:6][C:7]([CH2:8][CH2:9][CH2:10][CH2:11][N:12]4[CH:16]=[CH:15][N:14]=[N:13]4)=[C:2]([CH3:1])[CH:3]=3)[N:23]=2)[CH:33]=[CH:32][CH:31]=1
Reactant: ClCc1cccc(-c2cccc(Cl)c2)n1
Reactant: Cc1cc(O)ccc1CCCCn1ccnn1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(OCc2cccc(-c3cccc(Cl)c3)n2)ccc1CCCCn1ccnn1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 83 %

Procedure:
A solution of 97 mg (0.42 mmol) 3-methyl-4-(4-[1,2,3]triazol-1-yl-butyl)phenol in 4.0 ml N,N-dimethylformamide was treated at 0° C. with 17 mg (0.42 mmol) of 60% sodium hydride and stirred at 0° C. for 30 min. Then 100 mg (0.42 mmol) 2-Chloromethyl-6-(3-chloro-phenyl)-pyridine were added and stirred continued at r. t. over night. After addition of 8 ml water, the mixture was extracted with ethyl acetate tree times. The combined organic phases were dried (sodium sulphate) and evaporated. Chromatography on silica (eluent: ethyl acetate/n-heptane 2:1) gave 0.151 g (83%) the title compound as white powder.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:20][CH:19]([OH:21])[CH2:18]3)=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[C:22]([O:25][CH2:26][C:27]1[C:32](B2OC(C)(C)C(C)(C)O2)=[CH:31][CH:30]=[CH:29][C:28]=1[N:42]1[CH2:54][CH2:53][N:45]2[C:46]3[CH2:47][CH2:48][CH2:49][CH2:50][C:51]=3[CH:52]=[C:44]2[C:43]1=[O:55])(=[O:24])[CH3:23].COCCOC.C(=O)([O-])[O-].[Na+].[Na+]>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.CO.C(OCC)C.O.C(OCC)(=O)C>[C:22]([O:25][CH2:26][C:27]1[C:28]([N:42]2[CH2:54][CH2:53][N:45]3[C:46]4[CH2:47][CH2:48][CH2:49][CH2:50][C:51]=4[CH:52]=[C:44]3[C:43]2=[O:55])=[CH:29][CH:30]=[CH:31][C:32]=1[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:20][CH:19]([OH:21])[CH2:18]3)=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1)(=[O:24])[CH3:23]
Reactant: Cn1cc(Br)cc(Nc2ccc(N3CC(O)C3)cn2)c1=O
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cccc1N1CCn2c(cc3c2CCCC3)C1=O
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: CCOCC
Solvent: CO
Solvent: O
Product: CC(=O)OCc1c(-c2cc(Nc3ccc(N4CC(O)C4)cn3)c(=O)n(C)c2)cccc1N1CCn2c(cc3c2CCCC3)C1=O
Temperature: 135 °C
Yield: 30.1 %

Procedure:
A microwave tube equipped with a magnetic stirrer was charged with 128c (220 mg, 0.6 mmol), 2-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl acetate 114a (350 mg, 0.8 mmol), DME (7 mL) and 1M aqueous sodium carbonate (1.9 mL). After bubbling N2 for 15 min, Pd(PPh3)4 (36 mg, 0.03 mmol) was added. The mixture was heated in microwave to 135° C. for 15 min. After this time, ethyl acetate (10 mL) and water (10 mL) were added. The separated aqueous layer was extracted with ethyl acetate (2×10 mL). The combined organics were washed with brine (20 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography eluting with a gradient of CH2Cl2-60:35:5 CH2Cl2:diethyl ether:MeOH to afford a 30% yield (110 mg) of 128d.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH:10]([OH:12])[CH3:11])[CH:8]=2)[CH:3]=[N:2]1.C1C=C[NH+]=CC=1.C1C=C[NH+]=CC=1.[O-][Cr](O[Cr]([O-])(=O)=O)(=O)=O>CC(C)=O>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10](=[O:12])[CH3:11])[CH:8]=2)[CH:3]=[N:2]1
Reactant: CC(O)c1ccc2cn[nH]c2c1
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: CC(C)=O
Product: CC(=O)c1ccc2cn[nH]c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.8 %

Procedure:
To a solution of 1-(1H-indazol-6-yl)ethanol (100 mg, 0.6 mmol) in acetone (50 mL) was added PDC (1.11 g, 3 mmol). The mixture was stirred overnight at rt. The mixture was filtered through silica gel and purified by silica gel chromatography (4:1 EtOAc/Hex) to give the title compound as a brown solid (70 mg, 72%). 1H NMR (400 MHz, CDCl3) δ 8.45 (s, 1H), 8.23 (s, 1H), 8.09-8.08 (m, 1H), 7.56-7.54 (m, 1H), 2.72 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10](B3OC(C)(C)C(C)(C)O3)=[CH:9][N:8]([S:20]([C:23]3[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=3)(=[O:22])=[O:21])[C:5]2=[N:6][CH:7]=1.Cl[C:31]1[N:36]=[C:35]([NH:37][C@H:38]2[CH2:43][CH2:42][CH2:41][C:40]([CH3:45])([OH:44])[CH2:39]2)[C:34]([F:46])=[CH:33][N:32]=1.C([O-])([O-])=O.[Na+].[Na+]>C(COC)OC>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:31]3[N:36]=[C:35]([NH:37][C@H:38]4[CH2:43][CH2:42][CH2:41][C:40]([CH3:45])([OH:44])[CH2:39]4)[C:34]([F:46])=[CH:33][N:32]=3)=[CH:9][N:8]([S:20]([C:23]3[CH:24]=[CH:25][C:26]([CH3:29])=[CH:27][CH:28]=3)(=[O:21])=[O:22])[C:5]2=[N:6][CH:7]=1
Reactant: CC1(O)CCC[C@H](Nc2nc(Cl)ncc2F)C1
Reactant: Cc1ccc(S(=O)(=O)n2cc(B3OC(C)(C)C(C)(C)O3)c3cc(Cl)cnc32)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(N[C@H]4CCCC(C)(O)C4)n3)c3cc(Cl)cnc32)cc1
Temperature: 130 °C

Procedure:
Degassed a solution of 5-chloro-1-(p-tolylsulfonyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,3-b]pyridine (1.46 g, 3.37 mmol), (3S)-3-[(2-chloro-5-fluoro-pyrimidin-4-yl)amino]-1-methyl-cyclohexanol, 29c, (0.72 g, 2.81 mmol) and Na2CO3 (4.21 mL of 2M solution, 8.433 mmol) in dimethoxyethane (15 mL) for 30 min with nitrogen. To the reaction mixture was added palladium tetrakis-triphenylphosphane (0.16 g, 0.14 mmol). The reaction mixture was heated at 130° C. in Q-tube apparatus for 45 minutes. The reaction mixture was filtered through a pad of 1 cm of silica gel and 2 cm celite. The product was purified by silica gel chromatography (hexanes/EtOAc) to afford the desired product, 29e (63% yield).
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]1([C:14]2[CH:26]=[CH:25][C:17]([C:18]([O:20]C(C)(C)C)=[O:19])=[C:16]([NH:27][C:28]([C:30]3[CH:31]=[N:32][C:33]([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)=[CH:34][CH:35]=3)=[O:29])[CH:15]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>>[C:8]1([C:14]2[CH:26]=[CH:25][C:17]([C:18]([OH:20])=[O:19])=[C:16]([NH:27][C:28]([C:30]3[CH:31]=[N:32][C:33]([C:36]4[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=4)=[CH:34][CH:35]=3)=[O:29])[CH:15]=2)[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1ccc(-c2ccccc2)nc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1cc(-c2ccccc2)ccc1C(=O)O)c1ccc(-c2ccccc2)nc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Trifluoroacetic acid (5 mL) was added to the obtained tert-butyl 4-phenyl-2-(6-phenylpyridine-3-carboxamido)benzoate, followed by stirring at room temperature for 3 hours. The solvent was evaporated under reduced pressure, and methanol was added to the obtained residue. The solid substance was collected by filtration to obtain 53 mg of 4-phenyl-2-(6-phenylpyridine-3-carboxamido)benzoic acid as a light yellow solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10](=[O:12])[CH3:11].[H-].[Na+].Br[CH2:16][CH:17]([CH3:19])[CH3:18]>CN(C)C=O>[CH2:16]([O:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10](=[O:12])[CH3:11])[CH:17]([CH3:19])[CH3:18]
Reactant: CC(C)CBr
Reactant: COc1ccc(O)c(C(C)=O)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(OCC(C)C)c(C(C)=O)c1
Temperature: 80 °C

Procedure:
A mixture of 10 g (0.06 mol) of 2′-hydroxy-5′-methoxyacetophenone, 2.6 g (0.066 mol) of 60% sodium hydride and 150 ml of dimethylformamide is heated for one hour at 80° C. 7.2 ml (0.066 mol) of 1-bromo-2-methylpropane are added dropwise. The mixture is heated for ten hours at 80° C. and is then poured into ice-water and extracted with ether. The ether solution is washed with normal sodium hydroxide solution. The dried (Na2SO4) organic phase is evaporated under reduced pressure (8.2 g; 62%).
Reaction SMILES: [N+](C1C=CC=CC=1O[C:11](=[O:35])[C@@H:12]([CH2:21][CH2:22][CH2:23][NH:24][C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26])[NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])([O-])=O.Cl.[C:37]1([C@H:47]([NH2:49])[CH3:48])[C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[CH:40]=[CH:39][CH:38]=1>C(Cl)Cl>[C:14]([NH:13][C@@H:12]([C:11]([NH:49][C@@H:47]([C:37]1[C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[CH:40]=[CH:39][CH:38]=1)[CH3:48])=[O:35])[CH2:21][CH2:22][CH2:23][NH:24][C:25]([O:27][CH2:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)=[O:26])([O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:15]
Reactant: C[C@@H](N)c1cccc2ccccc12
Reactant: CC(C)(C)OC(=O)N[C@H](CCCNC(=O)OCc1ccccc1)C(=O)Oc1ccccc1[N+](=O)[O-]
Agent: Cl
Solvent: ClCCl
Product: C[C@@H](NC(=O)[C@@H](CCCNC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C)c1cccc2ccccc12
Yield: 136.2 %

Procedure:
Prepared according to the method described in Example 4(b) above from Nα -Boc-Nδ -Cbz-(R)-ornithine-o-nitrophenyl ester (5.2 g; 10.6 mmol; see Example 4(a) above), (R)-1-(1-naphthyl)ethylamine hydrochloride (2.0 g; 11.7 mmol), and CH2Cl2 (150 mL), 48 hours reaction time. The resultant yellow solution was concentrated to afford the crude sub-title compound as a solid (7.5 g) which was used directly in the next step.
Reaction SMILES: [OH:1][CH:2]([C:5]1[C:14]([C:15]([NH:17][C:18]2[S:19][CH:20]=[CH:21][N:22]=2)=[O:16])=[C:13]([OH:23])[C:12]2[C:7](=[C:8]([C:24]([F:27])([F:26])[F:25])[CH:9]=[CH:10][CH:11]=2)[N:6]=1)[CH2:3][OH:4].[C:28]1(C)[CH:33]=CC(S(O)(=O)=O)=C[CH:29]=1>CC(C)=O>[CH3:29][C:28]1([CH3:33])[O:1][CH:2]([C:5]2[C:14]([C:15]([NH:17][C:18]3[S:19][CH:20]=[CH:21][N:22]=3)=[O:16])=[C:13]([OH:23])[C:12]3[C:7](=[C:8]([C:24]([F:26])([F:25])[F:27])[CH:9]=[CH:10][CH:11]=3)[N:6]=2)[CH2:3][O:4]1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=C(Nc1nccs1)c1c(C(O)CO)nc2c(C(F)(F)F)cccc2c1O
Solvent: CC(C)=O
Product: CC1(C)OCC(c2nc3c(C(F)(F)F)cccc3c(O)c2C(=O)Nc2nccs2)O1
Temperature: 20 °C
Yield: 156.8 %

Procedure:
A suspension of 3 g of the product of Example 2 in 80 ml of acetone was heated to reflux and 0.3 g of p-toluene sulfonic acid were added. The mixture was refluxed for 5 hours, was cooled to 20° C. and was vacuum filtered. The crystals were dried under reduced pressure and dissolved in 100 ml of tetrahydrofuran warmed to 40° C. The mixture was filtered and was concentrated to one half volume. The mixture was cooled to 20° C. and ether was added. The mixture was vacuum filtered and the crystals were washed with ether and dried to obtain 1.2 g of 2-(2,2-dimethyl-1,3-dioxolan-4-yl)-4-hydroxy-N-(2-thiazolyl)-8-trifluoromethyl-3-quinoline-carboxamide melting at 250° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1.Cl.[NH2:11][C:12]1[C:13]([Cl:19])=[N:14][CH:15]=[N:16][C:17]=1[Cl:18].C(O)C>O>[ClH:18].[CH3:9][O:8][C:5]1[N:6]=[CH:7][C:2]([NH:1][C:17]2[C:12]([NH2:11])=[C:13]([Cl:19])[N:14]=[CH:15][N:16]=2)=[CH:3][CH:4]=1
Reactant: Nc1c(Cl)ncnc1Cl
Reactant: COc1ccc(N)cn1
Agent: Cl
Solvent: CCO
Solvent: O
Product: COc1ccc(Nc2ncnc(Cl)c2N)cn1
Yield: 50.7 %

Procedure:
5-Amino-2-methoxypyridine (8.7 g, 70.1 mmol) and conc. hydrochloric acid (1.5 ml) were added successively to a suspension of 5-amino-4,6-dichloropyrimidine (10.0 g, 45.2 mmol, produced by Tokyo Kasei Co., Ltd.) in water (100 ml)/ethanol (15 ml) at room temperature, and the mixture was heated under reflux for 3 hours. After cooling as it was, the resulting solid was collected by filtration, washed with water and air-dried at 50° C., to give the title compound (6.6 g, 72%) as a reddish brown solid.
Reaction SMILES: C[Si]([C:5]#[C:6][C:7]1[N:15]=[CH:14][C:13]2[NH:12][C:11]3[N:16]=[CH:17][C:18]([C:20]4[CH:25]=[CH:24][C:23]([CH2:26][N:27]5[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]5)=[CH:22][CH:21]=4)=[CH:19][C:10]=3[C:9]=2[CH:8]=1)(C)C.C(=O)([O-])[O-].[K+].[K+]>CO.C(Cl)Cl>[C:6]([C:7]1[N:15]=[CH:14][C:13]2[NH:12][C:11]3[N:16]=[CH:17][C:18]([C:20]4[CH:21]=[CH:22][C:23]([CH2:26][N:27]5[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]5)=[CH:24][CH:25]=4)=[CH:19][C:10]=3[C:9]=2[CH:8]=1)#[CH:5]
Reactant: C[Si](C)(C)C#Cc1cc2c(cn1)[nH]c1ncc(-c3ccc(CN4CCCCC4)cc3)cc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: ClCCl
Product: C#Cc1cc2c(cn1)[nH]c1ncc(-c3ccc(CN4CCCCC4)cc3)cc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 6-((trimethylsilyl)ethynyl)-3-(4-piperidin-1-ylmethylphenyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole (120 mg, 0.3 mmol) and potassium carbonate (170 mg, 1.2 mmol) in methanol (2 mL) was stirred at ambient temperature for 1 h. The reaction mixture was diluted with DCM (20 mL) and methanol (2 mL) and washed with water (15 mL). The organic phase was separated, dried over sodium sulfate, filtered and evaporated in vacuo to afford a brown residue that was taken to the next step without purification.
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[K+].[Br-]>>[F:24][C:21]([F:22])([F:23])[C:17]1[CH:16]=[C:15]([N:11]2[CH2:12][CH2:13][CH2:14][NH:8][CH2:9][CH2:10]2)[CH:20]=[CH:19][CH:18]=1
Reactant: CC(C)(C)OC(=O)N1CCCN(c2cccc(C(F)(F)F)c2)CC1
Agent: [Br-]
Agent: [K+]
Product: FC(F)(F)c1cccc(N2CCCNCC2)c1
Yield: 91 %

Procedure:
The title compound was prepared according to the procedure of Example 1, Step 6 except that 4-(3-trifluoromethyl-phenyl)-[1,4]diazepane-1-carboxylic acid tert-butyl ester was used in place of 4-(2-methoxy-phenyl)-[1,4]diazepane-1-carboxylic acid tert-butyl ester. Yield: 91%; 1H NMR (300 MHz, CDCl3): δ1.77 (brs, 1H), 1.92 (pent, J=5.9 Hz, 2H), 2.84 (t, J=5.8 Hz, 2H), 3.04 (t, J=5.4 Hz, 2H), 3.56-3.62 (m, 4H), 6.77-6.88 (m, 3H), 7.29 (d, J=7.7 Hz, 1H); IR (KBr, cm−1): 3286w; MS (ES) m/z (relative intensity): 245 (M++H, 60). Anal. Calcd. for C12H15F3N2: C, 59.01; H, 6.19; N, 11.47. Found: C, 58.56; H, 6.03; N, 10.98.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:21])=[C:6]([C@:8]2([CH3:20])[C:14]([F:16])([F:15])[C:13]([CH3:18])([CH3:17])[O:12][CH2:11][C:10](=[O:19])[NH:9]2)[CH:7]=1.[NH2:22][C:23]1[CH:24]=[N:25][CH:26]=[C:27]([F:29])[CH:28]=1>>[F:15][C:14]1([F:16])[C:13]([CH3:18])([CH3:17])[O:12][CH2:11][C:10](=[O:19])[NH:9][C@@:8]1([C:6]1[CH:7]=[C:2]([NH:22][C:23]2[CH:24]=[N:25][CH:26]=[C:27]([F:29])[CH:28]=2)[CH:3]=[CH:4][C:5]=1[F:21])[CH3:20]
Reactant: CC1(C)OCC(=O)N[C@](C)(c2cc(Br)ccc2F)C1(F)F
Reactant: Nc1cncc(F)c1
Product: CC1(C)OCC(=O)N[C@](C)(c2cc(Nc3cncc(F)c3)ccc2F)C1(F)F
Yield: 26 %

Procedure:
Prepared in an analogous manner as described for intermediate A9A or A13A from (R)-5-(5-bromo-2-fluorophenyl)-6,6-difluoro-5,7,7-trimethyl-1,4-oxazepan-3-one (intermediate A16B) (200 mg, 546 μmol) and commercially available 3-amino-5-fluoropyridine [CAS no 210169-05-4] (122 mg, 1.09 mmol). The (R)-6,6-difluoro-5-(2-fluoro-5-(5-fluoropyridin-3-ylamino)phenyl)-5,7,7-trimethyl-1,4-oxazepan-3-one (56 mg, 26%) was obtained as an off-white foam. MS (ISP): m/z=398.2 [(M+H)+].