Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]([C:15]3[C:23]4[C:18](=[CH:19][C:20]([C:24](O)=[O:25])=[CH:21][CH:22]=4)[NH:17][CH:16]=3)=[O:14])=[C:11]([CH3:27])[O:10][N:9]=2)=[CH:4][CH:3]=1.CN(C)CCCN=C=NCC.O[N:40]1[C:44]2[CH:45]=[CH:46][CH:47]=CC=2N=N1.CCN(CC)CC.C1(N)CC1>CN(C=O)C>[CH:45]1([CH2:44][NH:40][C:24]([C:20]2[CH:19]=[C:18]3[C:23]([C:15]([C:13]([C:12]4[C:8]([C:5]5[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=5)=[N:9][O:10][C:11]=4[CH3:27])=[O:14])=[CH:16][NH:17]3)=[CH:22][CH:21]=2)=[O:25])[CH2:47][CH2:46]1
Reactant: Cc1onc(-c2ccc(F)cc2)c1C(=O)c1c[nH]c2cc(C(=O)O)ccc12
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: NC1CC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1onc(-c2ccc(F)cc2)c1C(=O)c1c[nH]c2cc(C(=O)NCC3CC3)ccc12
Yield: 71.9 %

Procedure:
A solution of 62 mg (0.17 mmol) 3-[3-(4-fluoro-phenyl)-5-methyl-isoxazole-4-carbonyl]-1H-indole-6-carboxylic acid, 41 mg (0.21 mmol) N-(3-dimethylaminopropyl)-N′-ethyl carbodiimide, 23 mg (0.17 mmol) 1-hydroxy benzotriazole, 59 uL (0.43 mmol) Et3N and 0.26 mmol cyclopropylamine in DMF (1 mL) was reacted at room temperature overnight. After evaporation the mixture was subjected to preparative HPLC purification on reversed phase eluting with an acetonitrile/water (0.05% NEt3) gradient to afford 51 mg of the title compound in 72% yield as a white solid. (m/e): 418.1 (MH+; 100%).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[N+:6]([C:9]1[CH:27]=[CH:26][C:12]([CH2:13][O:14][C:15]([N:17]2[CH2:24][C@H:23]([OH:25])[CH2:22][C@H:18]2[C:19]([NH2:21])=[O:20])=[O:16])=[CH:11][CH:10]=1)([O-:8])=[O:7].C(N(CC)CC)C>O1CCCC1>[N+:6]([C:9]1[CH:27]=[CH:26][C:12]([CH2:13][O:14][C:15]([N:17]2[CH2:24][C@H:23]([O:25][S:2]([CH3:1])(=[O:4])=[O:3])[CH2:22][C@H:18]2[C:19]([NH2:21])=[O:20])=[O:16])=[CH:11][CH:10]=1)([O-:8])=[O:7]
Reactant: CS(=O)(=O)Cl
Reactant: NC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)O[C@@H]1C[C@@H](C(N)=O)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Reaction time: 1 h

Procedure:
A solution of 1.89 g of methanesulfonyl chloride in 10 ml of dried tetrahydrofuran was added dropwise to a suspension of 2.32 g of trans-1-(p-nitrobenzyloxycarbonyl)-4-hydroxy-L-prolineamide and 1.67 g of triethylamine in 40 ml of dried tetrahydrofuran at room temperature. After stirring for 1 hour, the reaction mixture was concentrated under reduced pressure, and to the residue were added 30 ml of water and 30 ml of diethyl ether. After cooling, the resulting white crystals were separated by filtration, washed successively with cool water and cool diethyl ether and dried under reduced pressure to obtain trans-1-(p-nitrobenzyloxycarbonyl)-4-methanesulfonyloxy-L-prolineamide.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[O:16][C:15]([CH:17]([NH:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]([N:30]([CH3:38])[CH2:31][CH2:32][C:33]([O:35]CC)=[O:34])=[O:29])=[CH:24][CH:23]=3)[CH:18]([CH3:20])[CH3:19])=[C:14]([CH3:39])[C:13]=2[CH:40]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[O:16][C:15]([CH:17]([NH:21][C:22]3[CH:23]=[CH:24][C:25]([C:28]([N:30]([CH3:38])[CH2:31][CH2:32][C:33]([OH:35])=[O:34])=[O:29])=[CH:26][CH:27]=3)[CH:18]([CH3:19])[CH3:20])=[C:14]([CH3:39])[C:13]=2[CH:40]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(NC(c2oc3ccc(OCc4ccccc4)cc3c2C)C(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1c(C(Nc2ccc(C(=O)N(C)CCC(=O)O)cc2)C(C)C)oc2ccc(OCc3ccccc3)cc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77.7 %

Procedure:
Ethyl 3-[{[4-({1-[5-(benzyloxy)-3-methyl-1-benzofuran-2-yl]-2-methylpropyl}amino)phenyl]carbonyl}(methyl)amino]propanoate (0.38 g) synthesized in the above-mentioned (3) was dissolved in ethanol (5 mL), 1N aqueous sodium hydroxide solution (1.5 mL) was added at room temperature, and the mixture was stirred at room temperature for 0.5 hr. Ethanol was evaporated under reduced pressure, 1N hydrochloric acid (1.5 mL) was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was washed with ethanol-water to give the title object compound (0.28 g, 79%) as a colorless solid.
Reaction SMILES: [OH:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+].[N+:14]([C:17]1[CH:18]=[N:19][CH:20]=[CH:21][C:22]=1Cl)([O-:16])=[O:15]>C(O)C>[N+:14]([C:17]1[CH:18]=[N:19][CH:20]=[CH:21][C:22]=1[NH:6][C:5]1[CH:7]=[CH:8][C:2]([OH:1])=[CH:3][CH:4]=1)([O-:16])=[O:15]
Reactant: Nc1ccc(O)cc1
Reactant: O=[N+]([O-])c1cnccc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: O=[N+]([O-])c1cnccc1Nc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred mixture of 50.2 g of p-hydroxyaniline and 38.7 g of sodium bicarbonate in 1.5 1 of ethanol was added dropwise 73 g of 3-nitro-4-chloropyridine in 2.0 l of ethanol. After stirring overnight at room temperature, the resulting solids were filtered, washed with water (2 l) and dried, 85.4 g.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[C:13](=[O:14])[C:12]2[C:7](=[N:8][C:9]([C:15]([F:18])([F:17])[F:16])=[CH:10][CH:11]=2)[N:6]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:5]=1[C:25]([O:27][CH3:28])=[O:26].[S:29]([C:33]1[CH:41]=[CH:40][C:36]([C:37](O)=[O:38])=[CH:35][CH:34]=1)(=[O:32])(=[O:31])[NH2:30]>>[CH3:28][O:27][C:25]([C:5]1[N:6]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:7]2[C:12]([C:13](=[O:14])[C:4]=1[CH2:3][NH:2][C:37](=[O:38])[C:36]1[CH:40]=[CH:41][C:33]([S:29](=[O:32])(=[O:31])[NH2:30])=[CH:34][CH:35]=1)=[CH:11][CH:10]=[C:9]([C:15]([F:16])([F:17])[F:18])[N:8]=2)=[O:26]
Reactant: NS(=O)(=O)c1ccc(C(=O)O)cc1
Reactant: COC(=O)c1c(CN)c(=O)c2ccc(C(F)(F)F)nc2n1-c1ccccc1
Agent: Cl
Product: COC(=O)c1c(CNC(=O)c2ccc(S(N)(=O)=O)cc2)c(=O)c2ccc(C(F)(F)F)nc2n1-c1ccccc1

Procedure:
4-Oxo-1-phenyl-3-[(4-sulfamoyl-benzoylamino)-methyl]-7-trifluoromethyl-1,4-dihydro-[1,8]naphthyridine-2-carboxylic acid methyl ester was prepared starting from intermediate J and 4-sulfamoyl-benzoic acid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.90 (d, J=8.06 Hz, 1H) 8.77 (t, J=4.63 Hz, 1H) 7.91-8.00 (m, 3H) 7.83-7.89 (m, 2H) 7.52-7.59 (m, 3H) 7.47 (s, 2H) 7.43 (dd, J=6.75, 2.72 Hz, 2H) 4.46 (d, J=4.83 Hz, 2H) 3.40 (s, 3H). MS calcd. for C25H19F3N4O6S [(M+H)+] 561.1, obsd. 561.1.
Reaction SMILES: [ClH:1].[CH2:2]([C:6]1([N:23]([CH3:25])[CH3:24])[CH2:11][CH2:10][N:9]([CH2:12][CH2:13][N:14](C)[C:15](=O)OC(C)(C)C)[CH2:8][CH2:7]1)[CH2:3][CH2:4][CH3:5].CO.C(Cl)(Cl)[Cl:29]>C(Cl)(Cl)Cl>[ClH:29].[ClH:1].[ClH:29].[CH2:2]([C:6]1([N:23]([CH3:24])[CH3:25])[CH2:7][CH2:8][N:9]([CH2:12][CH2:13][NH:14][CH3:15])[CH2:10][CH2:11]1)[CH2:3][CH2:4][CH3:5]
Reactant: CCCCC1(N(C)C)CCN(CCN(C)C(=O)OC(C)(C)C)CC1
Reactant: ClC(Cl)Cl
Agent: Cl
Solvent: CO
Product: CCCCC1(N(C)C)CCN(CCNC)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 87 %

Procedure:
HCl gas was passed for approximately 1 hour through a solution at 0° C. of 10.5 g (1 equiv.) of tert-butyl 2-(4-butyl-4-(dimethylamino)piperidin-1-yl)ethyl(methyl)-carbamate in 1000 ml of chloroform. The reaction mixture was then stirred for 12 hours at room temperature. The progress of the reaction was monitored by thin-layer chromatography (20% MeOH/CHCl3). When the reaction was complete, the solvent was removed under reduced pressure and the residue was washed with hexane (3×50 ml) and ethyl acetate (3×50 ml) and dried. 9 g (87%) of product were obtained in the form of a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:24][C:25](=O)[C@@H:26]([NH:28][C:29]2[N:37]=[CH:36][N:35]=[C:34]3[C:30]=2[N:31]=[CH:32][N:33]3C2CCCCO2)[CH3:27])=[C:6]([NH:8][C@@H:9]2[CH2:14][CH2:13][CH2:12][N:11]([CH2:15][CH2:16][O:17]C(=O)C(C)(C)C)[CH2:10]2)[CH:7]=1>Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:24]=[C:25]([C@@H:26]([NH:28][C:29]3[N:37]=[CH:36][N:35]=[C:34]4[C:30]=3[N:31]=[CH:32][NH:33]4)[CH3:27])[N:8]([C@@H:9]3[CH2:14][CH2:13][CH2:12][N:11]([CH2:15][CH2:16][OH:17])[CH2:10]3)[C:6]=2[CH:7]=1
Reactant: C[C@H](Nc1ncnc2c1ncn2C1CCCCO1)C(=O)Nc1ccc(F)cc1N[C@@H]1CCCN(CCOC(=O)C(C)(C)C)C1
Agent: Cl
Product: C[C@H](Nc1ncnc2[nH]cnc12)c1nc2ccc(F)cc2n1[C@@H]1CCCN(CCO)C1
Temperature: 25 °C
Yield: 26.9 %

Procedure:
A solution of 2,2-dimethylpropionic acid 2-[(R)-3-(5-fluoro-2-{(S)-2-[9-(tetrahydropyran-2-yl)-9H-purin-6-ylamino]propionylamino}phenylamino)piperidin-1-yl]ethyl ester (213 mg, 0.35 mmol), in aqueous 6M HCl (10 mL) was refluxed for 40 min. After cooling to RT, volatiles were removed under reduced pressure and the resulting residue was purified by column chromatography (C18, gradient 2-35% MeOH in 0.5% TFA/H2O) then loaded in dioxane/water (1:1) onto an Isolute® SCX-2 cartridge. The cartridge was washed with dioxane/water (1:1), then dioxane and the product eluted with 10% 880 NH3 in dioxane, then 2M NH3/MeOH. Further purification by column chromatography (Si—PCC, gradient 3-21% 2M NH3/MeOH in DCM) afforded 256 as a pale yellow solid (40 mg, 27%). LCMS (Method K): RT 1.94 min [M+H]+ 425.1. 1H NMR (CD3OD, 400 MHz): δ 8.30 (1H, s), 8.08 (1H, s), 7.59 (1H, dd, J=8.9, 5.0 Hz), 7.49 (1H, dd, J=9.5, 2.3 Hz), 7.01 (1H, dt, J=9.2, 2.4 Hz), 6.03 (1H, bs), 3.67 (2H, t, J=5.8 Hz), 3.13-3.09 (1H, m), 2.98-2.92 (2H, m), 2.69-2.55 (2H, m), 2.28-2.14 (2H, m), 1.93-1.88 (1H, m), 1.82 (3H, d, J=7.0 Hz), 1.77-1.74 (1H, m), 1.51-1.41 (1H, m)
Reaction SMILES: [CH2:1]([C:3]1[N:13]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH2:22])=[CH:16][CH:15]=2)[C:6]2=[N:7][C:8]([CH3:12])=[CH:9][C:10]([CH3:11])=[C:5]2[N:4]=1)[CH3:2].[C:23]1([CH3:35])[CH:28]=[CH:27][C:26]([S:29]([N:32]=[C:33]=[O:34])(=[O:31])=[O:30])=[CH:25][CH:24]=1>ClCCl>[CH2:1]([C:3]1[N:13]([C:14]2[CH:15]=[CH:16][C:17]([CH2:20][CH2:21][NH:22][C:33]([NH:32][S:29]([C:26]3[CH:27]=[CH:28][C:23]([CH3:35])=[CH:24][CH:25]=3)(=[O:31])=[O:30])=[O:34])=[CH:18][CH:19]=2)[C:6]2=[N:7][C:8]([CH3:12])=[CH:9][C:10]([CH3:11])=[C:5]2[N:4]=1)[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)N=C=O)cc1
Reactant: CCc1nc2c(C)cc(C)nc2n1-c1ccc(CCN)cc1
Solvent: ClCCl
Product: CCc1nc2c(C)cc(C)nc2n1-c1ccc(CCNC(=O)NS(=O)(=O)c2ccc(C)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 55.9 %

Procedure:
To a solution of 2-[4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethylamine (step 9, 1.2 g, 4.0 mmol) in dichloromethane (15 mL) was added p-toluenesulfonyl isocyanate (805 mg, 4.0 mmol). The resulting mixture was stirred at room temperature for 3 h. After removal of solvent, the residue was purified by flash column chromatography on silica gel eluting with dichloromethane/methanol (20:1) to afford 1.10 g (56%) of the title compound as white solids: 1H-NMR (CDCl3) δ 7.85 (2H, d, J=8.2 Hz), 7.32 (2H, d, J=8.2 Hz), 7.23 (2H, d, J=8.4 Hz), 7.16 (2H, d, J=8.4 Hz), 6.91 (1H, s), 6.12 (1H, br.s), 3.55–3.46 (2H, m), 2.85 (2H, t, J=6.3 Hz), 2.74–2.64 (5H, m), 2.42 (3H, s), 2.41 (3H, s), 1.21 (3H, t, J=7.6 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([C@H:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]([C:22](=[O:30])[C:23]3[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=3)[C@@H:14]([CH3:31])[CH2:13]2)[C:9](=[O:11])[CH3:10])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:38]([O:40][C:41]([C:43]1([CH2:47][CH2:48]Br)[CH2:46][CH2:45][CH2:44]1)=[O:42])[CH3:39]>CN(C=O)C>[CH2:38]([O:40][C:41]([C:43]1([CH2:47][CH2:48][O:29][C:26]2[CH:25]=[CH:24][C:23]([C:22]([N:15]3[C:16]4[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH:12]([N:8]([C:9](=[O:11])[CH3:10])[C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=4)[CH2:13][CH:14]3[CH3:31])=[O:30])=[CH:28][CH:27]=2)[CH2:46][CH2:45][CH2:44]1)=[O:42])[CH3:39]
Reactant: CCOC(=O)C1(CCBr)CCC1
Reactant: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(O)cc2)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1(CCOc2ccc(C(=O)N3c4ccccc4C(N(C(C)=O)c4ccc(Cl)cc4)CC3C)cc2)CCC1
Temperature: 80 °C
Yield: 67.5 %

Procedure:
(2S,4R)-N-(4-Chloro-phenyl)-N-[1-(4-hydroxy-benzoyl)-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl]-acetamide (0.17 g, 0.39 mmol) was dissolved in 5 ml DMF at room temperature and K2CO3 (0.323 g, 2.34 mmol) was added. 1-(2-Bromo-ethyl)-cyclobutanecarboxylic acid ethyl ester (0.184 g, 0.78 mmol) prepared according to the procedure from Tetrahedron 1994, 50(32), 9825-30 was added and the reaction was allowed to heat to 80° C. overnight. The reaction mixture was concentrated in vacuo. The residue was partitioned between ethyl acetate and water, then extracted three times with ethyl acetate, dried over MgSO4, filtered and concentrated down. The crude residue was purified by silica gel chromatography (50% EtOAc/50% Hexane) to afford the 1-[2-(4-{4-[acetyl(4-chloro-phenyl)-amino]-2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl}-phenoxy)-ethyl]-cyclobutanecarboxylic acid ethyl ester (0.155 g, 67%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][CH:25]=1)[CH:5]=[CH:6][C:7]([NH:9][C:10]1[CH:22]=[CH:21][C:13]([CH2:14][N:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)=[CH:12][CH:11]=1)=[O:8].B([O-])([O-])O[C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=1.C(=O)([O-])[O-].[K+].[K+].C(O)C>C1(C)C=CC=CC=1.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>[CH3:35][O:34][C:31]1[CH:32]=[CH:33][C:28]([C:2]2[CH:3]=[C:4]([CH:23]=[CH:24][CH:25]=2)[CH:5]=[CH:6][C:7]([NH:9][C:10]2[CH:22]=[CH:21][C:13]([CH2:14][N:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)=[CH:12][CH:11]=2)=[O:8])=[CH:29][CH:30]=1
Reactant: O=C(C=Cc1cccc(Br)c1)Nc1ccc(CN2CCCCC2)cc1
Reactant: COc1ccc(OB([O-])[O-])cc1
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: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1ccc(-c2cccc(C=CC(=O)Nc3ccc(CN4CCCCC4)cc3)c2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 105.6 %

Procedure:
A suspension of 1-(4-(3-bromocinnamoyl amino)benzyl)piperidine (0.4 g), 4-methoxyphenyl borate (0.14 g), 1M potassium carbonate (2 ml) and ethanol (1 ml) in toluene (5 ml) was stirred under argon atmosphere at room temperature for 30 minutes. To the suspension was added tetrakistriphenylphosphinepalladium (0.05 g), and the mixture was refluxed over night. The mixture was extracted with ethyl acetate, and the organic layer was washed with water and saturated sodium chloride solution, and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column (methanol/triethylamine/ethyl acetate) to give crude crystals, which were recrystallized from ethyl acetate-hexane to give 1-(4-(3-(4-methoxyphenyl)-cinnamoylamino)benzyl)piperidine (Compound 84) (0.38 g) as colorless crystals.
Reaction SMILES: [NH2:1][N:2]1[CH:6]=[C:5]([F:7])[CH:4]=[C:3]1[C:8]([NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:9].[C:17]([O:21][C:22]([NH:24][C@@H:25]([CH3:29])[C:26](O)=[O:27])=[O:23])([CH3:20])([CH3:19])[CH3:18]>>[F:7][C:5]1[CH:4]=[C:3]([C:8](=[O:9])[NH:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:2]([NH:1][C:26](=[O:27])[C@@H:25]([NH:24][C:22](=[O:23])[O:21][C:17]([CH3:19])([CH3:18])[CH3:20])[CH3:29])[CH:6]=1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: Nn1cc(F)cc1C(=O)Nc1ccccc1
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)Nn1cc(F)cc1C(=O)Nc1ccccc1
Yield: 91 %

Procedure:
The title compound was prepared from 1-amino-4-fluoro-N-phenyl-1H-pyrrole-2-carboxamide (0.95 g, 3.6 mmol) and (S)-2-(tert-butoxycarbonylamino)propanoic acid following the experimental procedure described in Preparation 47b. 1.28 g (91% yield) of the desired compound were obtained.
Reaction SMILES: [N+:1]([C:4]1[C:5]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[N:6][CH:7]=[CH:8][CH:9]=1)([O-])=O.[H][H]>CO.[C].[Pd]>[NH2:1][C:4]1[C:5]([N:10]2[CH2:11][CH2:12][NH:13][CH2:14][CH2:15]2)=[N:6][CH:7]=[CH:8][CH:9]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1cccnc1N1CCNCC1
Agent: [Pd]
Solvent: CO
Product: Nc1cccnc1N1CCNCC1
Temperature: 25 °C
Yield: 95.8 %

Procedure:
In 30 ml of methanol was dissolved 3.13 g (0.015 mole) of 1-(3-nitro-2-pyridyl)piperazine, and 2 g of 5% palladium carbon was added thereto. While stirring the mixture at room temperature, hydrogen gas was passed through for one hour. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain 2.56 g of 1-(3-amino-2-pyridyl)piperazine as pale yellow liquid.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([NH:20][CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)[C:5]2[C:10](I)=[CH:9][N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:6]=2[N:7]=1.[OH:26][C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1.C(=O)([O-])[O-].[K+].[K+]>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>[Cl:1][C:2]1[N:3]=[C:4]([NH:20][CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)[C:5]2[C:10]([C:30]3[CH:31]=[CH:32][C:27]([OH:26])=[CH:28][CH:29]=3)=[CH:9][N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:6]=2[N:7]=1
Reactant: C[Si](C)(C)CCOCn1cc(I)c2c(NC3CCCC3)nc(Cl)nc21
Reactant: OB(O)c1ccc(O)cc1
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: [K+]
Solvent: O
Solvent: C1COCCO1
Product: C[Si](C)(C)CCOCn1cc(-c2ccc(O)cc2)c2c(NC3CCCC3)nc(Cl)nc21
Temperature: 100 °C
Reaction time: 16 h
Yield: 32.2 %

Procedure:
2-Chloro-N-cyclopentyl-5-iodo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (1 equiv), 4-hydroxyphenylboronic acid (1 equiv), potassium carbonate (2.5 equiv) and tetrakis(triphenylphosphine)palladium(0) (0.2 equiv), suspended in 1,4-dioxane/water, and flushed with nitrogen, were stirred at 100° C. for 16 h. The reaction mixture was loaded directly onto a silica gel column and purified using 5-100% ethyl acetate in hexanes. Fractions containing desired product were combined and volatile organics were removed under reduced pressure to give 4-(2-chloro-4-(cyclopentylamino)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenol (32.2% yield) as a yellow solid. MS (ESI) m/z 459.3 [M+1]+.
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([CH2:11][N:12]2[C:16]3[C:17](=[O:22])[CH2:18][CH2:19][CH2:20][CH2:21][C:15]=3[N:14]=[C:13]2[CH:23]([CH3:25])[CH3:24])[CH:7]=[CH:8][C:9]=1[Cl:10]>ClCCl.CO>[Cl:3][C:4]1[CH:5]=[C:6]([CH2:11][N:12]2[C:16]3[CH:17]([OH:22])[CH2:18][CH2:19][CH2:20][CH2:21][C:15]=3[N:14]=[C:13]2[CH:23]([CH3:25])[CH3:24])[CH:7]=[CH:8][C:9]=1[Cl:10]
Reactant: CC(C)c1nc2c(n1Cc1ccc(Cl)c(Cl)c1)C(=O)CCCC2
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CC(C)c1nc2c(n1Cc1ccc(Cl)c(Cl)c1)C(O)CCCC2
Reaction time: 3 h
Yield: 94.7 %

Procedure:
Sodium borohydride (204 mg) was added to a stirred solution of Intermediate 7 (630 mg) in dichloromethane (2 mL) and methanol (2 mL). The reaction mixture was stirred for 3 hours. The reaction mixture was partitioned between EtOAc (50 ml) and water (30 ml). The two phases were separated and the aqueous phase was extracted again with EtOAc (30 ml). The phases were separated; the organic extracts were combined, dried (hydrophobic frit) and concentrated under vacuum to give the title compound (600 mg). LC/MS MH+ 353/355, Rt 1.13 min (2 minute run).
Reaction SMILES: O1CCCCC1[O:7][NH:8][C:9]([C@H:11]([C@@H:21]([CH2:30][CH:31]([CH3:33])[CH3:32])[C:22]([NH:24][NH:25][S:26]([CH3:29])(=[O:28])=[O:27])=[O:23])[CH2:12]/[CH:13]=[CH:14]/[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:10].[CH3:34][O:35][CH2:36][CH2:37]Br>>[OH:7][NH:8][C:9]([C@H:11]([C@@H:21]([CH2:30][CH:31]([CH3:32])[CH3:33])[C:22]([NH:24][N:25]([S:26]([CH3:29])(=[O:27])=[O:28])[CH2:37][CH2:36][O:35][CH3:34])=[O:23])[CH2:12]/[CH:13]=[CH:14]/[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:10]
Reactant: COCCBr
Reactant: CC(C)C[C@@H](C(=O)NNS(C)(=O)=O)[C@H](C/C=C/c1ccccc1)C(=O)NOC1CCCCO1
Product: COCCN(NC(=O)[C@H](CC(C)C)[C@H](C/C=C/c1ccccc1)C(=O)NO)S(C)(=O)=O

Procedure:
The starting material was prepared in an analogous manner to that described in Example 15, part (iii), starting from (E)-2(R)-[1(S)-[(tetrahydro-2(RS)-pyranyloxy)carbamoyl]-4-phenyl-3-butenyl]-2′-(methanesulphonyl)-4-methylvalerohydrazide and 2-bromoethyl methyl ether.
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[C:18]([N+:19]([O-:21])=[O:20])=[C:17](Cl)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1.[NH2:23][CH2:24][C:25]1([OH:31])[CH2:30][CH2:29][S:28][CH2:27][CH2:26]1>ClCCl>[Cl:8][C:9]1[C:18]([N+:19]([O-:21])=[O:20])=[C:17]([NH:23][CH2:24][C:25]2([OH:31])[CH2:30][CH2:29][S:28][CH2:27][CH2:26]2)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1
Reactant: NCC1(O)CCSCC1
Reactant: O=[N+]([O-])c1c(Cl)nc2ccccc2c1Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1c(Cl)nc2ccccc2c1NCC1(O)CCSCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.6 %

Procedure:
Under a nitrogen atmosphere triethylamine (3.91 mL, 28.0 mmol) was added to a chilled (0° C.) solution of 2,4-dichloro-3-nitroquinoline (7.22 g, 26.7 mmol) in dichloromethane (100 mL). A solution of 4-(aminomethyl)tetrahydro-2H-thiopyran-4-ol (4.12 g, 28.0 mmol) in dichloromethane (30 mL) was added dropwise. The reaction mixture was stirred at ambient temperature overnight and then concentrated under reduced pressure. The orange residue was combined with saturated aqueous sodium bicarbonate (50 mL) and ethyl acetate (40 mL), sonicated for 10 minutes, and then filtered. The isolated solid was washed extensively with water and then dried to provide 5.63 g of 4-{[(2-chloro-3-nitroquinolin-4-yl)amino]methyl}tetrahydro-2H-thiopyran-4-ol as a yellow solid.
Reaction SMILES: O=[CH:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:6]([O:7][CH3:8])[C:4]=1[OH:5].C(=O)([O-])[O-].[K+].[K+].Br[CH:19](C(OCC)=O)[C:20]([O:22]CC)=[O:21].Cl>CC(=O)CC>[CH3:8][O:7][C:6]1[C:4]2[O:5][C:19]([C:20]([OH:22])=[O:21])=[CH:2][C:3]=2[CH:11]=[CH:10][CH:9]=1
Reactant: COc1cccc(C=O)c1O
Reactant: CCOC(=O)C(Br)C(=O)OCC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: COc1cccc2cc(C(=O)O)oc12
Yield: 37.4 %

Procedure:
To a suspension of o-vanillin (25.0 g) and potassium carbonate (28.4 g) in 2-butanone (10 ml) was added diethyl bromomalonate (49.1 g), and the mixture was refluxed under nitrogen atmosphere for 7 hours and cooled. To the mixture was added 1N hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the resulting red oil was suspended in a solution of potassium hydroxide (17.5 g) in ethanol (175 ml). The suspension was refluxed for 2 hours and cooled, and to the mixture was added water. The mixture was made acidic with 1N hydrochloric acid and extracted with ethyl acetate (twice). The organic layer was washed with water and saturated brine, and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated to give yellow solid of 7-methoxybenzofuran-2-carboxylic acid (11.8 g).