Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([O:7][C:8]([C:10]2[CH:15]=[C:14]([N+:16]([O-])=O)[CH:13]=[C:12]([C:19]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:20])[C:11]=2[C:28]([O:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:29])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>CN(C)C=O.[Pd]>[C:1]1([O:7][C:8]([C:10]2[CH:15]=[C:14]([NH2:16])[CH:13]=[C:12]([C:19]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:20])[C:11]=2[C:28]([O:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:29])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(Oc1ccccc1)c1cc([N+](=O)[O-])cc(C(=O)Oc2ccccc2)c1C(=O)Oc1ccccc1
Agent: [Pd]
Solvent: CN(C)C=O
Product: Nc1cc(C(=O)Oc2ccccc2)c(C(=O)Oc2ccccc2)c(C(=O)Oc2ccccc2)c1

Procedure:
A solution of 29.0 g. of 5-nitro-1,2,3-benzenetricarboxylic acid triphenyl ester in dimethylformamide is hydrogenated on a Parr shaker in the presence of 10% palladium-on-carbon catalyst. The mixture is filtered through diatomaceous earth and the filtrate is diluted with water and extracted with methylene chloride. The extract is dried over anhydrous sodium sulfate and evaporated to give an oil. The oil is crystallized from ether, and the solid is recrystallized from benzene and twice from ethanol to provide 15.0 g of the product of the Example.
Reaction SMILES: [CH3:1][N:2]([CH3:8])[CH:3]=[CH:4][N+:5]([O-:7])=[O:6].C(O)(C(F)(F)F)=O.[C:16]1([S:22]([C:25]2[CH:33]=C3[C:28]([CH:29]=CN3)=[CH:27][CH:26]=2)(=[O:24])=[O:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[N+:5]([CH:4]=[CH:3][N:2]1[C:8]2[C:28](=[CH:27][CH:26]=[C:25]([S:22]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)(=[O:23])=[O:24])[CH:33]=2)[CH:29]=[CH:1]1)([O-:7])=[O:6]
Reactant: CN(C)C=C[N+](=O)[O-]
Reactant: O=S(=O)(c1ccccc1)c1ccc2cc[nH]c2c1
Solvent: O=C(O)C(F)(F)F
Product: O=[N+]([O-])C=Cn1ccc2ccc(S(=O)(=O)c3ccccc3)cc21
Temperature: 0 °C
Reaction time: 24 h

Procedure:
Combine 1-dimethylamino-2-nitroethylene (676.9 mg, 5.83 mmol) and TFA (9.0 ml) and stir until dissolved. Add 6-benzenesulfonyl-1H-indole (1.5 g, 5.83 mmol) and stir at ambient temperature. After 24 hours, pour the reaction mixture into ice/water and adjust to pH 8. After stirring, filter the precipitate, wash with water, and dry to give the title compound as a yellow powder: mp 110° C., dec. MS (ACPI): m/e 329.0 (M+1). Analysis for C16H12N2O4S: Calcd: C, 58.53; H, 3.68; N, 8.53; found: C, 58.54; H, 3.83; N, 7.85.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[CH2:13][NH:14][C@H:15]1[CH2:20][CH2:19][CH2:18][NH:17][C@H:16]1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[N:9]([CH3:27])[C:8](=[O:28])[CH2:7][CH2:6]2.[CH3:29][C:30]1[N:31]=[CH:32][NH:33][C:34]=1[CH:35]=O.C([BH3-])#N.[Na+]>C(O)(=O)C.CO.C1COCC1.C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[CH2:13][NH:14][C@H:15]1[CH2:20][CH2:19][CH2:18][N:17]([CH2:29][C:30]3[NH:31][CH:32]=[N:33][C:34]=3[CH3:35])[C@H:16]1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[N:9]([CH3:27])[C:8](=[O:28])[CH2:7][CH2:6]2
Reactant: Cc1nc[nH]c1C=O
Reactant: COc1cc2c(cc1CN[C@H]1CCCN[C@H]1c1ccccc1)N(C)C(=O)CC2
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CO
Product: COc1cc2c(cc1CN[C@H]1CCCN(Cc3[nH]cnc3C)[C@H]1c1ccccc1)N(C)C(=O)CC2
Reaction time: 72 h
Yield: 67.4 %

Procedure:
To 6-Methoxy-1-methyl-7-[(2S,3S)-(2-phenyl-piperidin-3-ylamino)-methyl]-3,4-dihydro-1H-quinolin-2-one (100 mg, 0.26 mmol), 4-methyl-5-imidazolecarboxaldehyde (116 mg, 1.06 mmol), and 5 drops acetic acid in 2 mL of methanol at room temperature was added 1.58 mL (1.58 mmol) of 1.0 M sodium cyanoborohydride in THF. The resultant mixture was stirred for 1 hour at room temperature and then at 50° C. for 3 days. The reaction was then diluted with methylene chloride and washed 1× with sat'd. NaHCO3, dried over MgSO4, filtered, and concentrated. Silica gel chroatography (9:1 ethyl acetate/methanol) gave 83 mg (66%) of the title compound, a white foam. Rf=0.05 (9:1 ethyl acetate/methanol). MS (M+H)+=474.2; 1H NMR (400 MHz, CDCl3): δ 1.35–1.45 (m, 2H), 1.85–1.95 (bd, 1H), 1.99 (s, 3H), 1.99–2.15 (m, 2H), 2.45–2.55 (t, J=7.4 Hz, 2H), 2.62–2.65 (bs, 1H), 2.70–2.80 (t, J=7.4 Hz, 2H), 2.90–2.95 (d, J=13.9 Hz, 1H), 3.00–3.05 (d, J=10.7 Hz, 1H), 3.10 (s, 3H), 3.35–3.40 (m, 2H), 3.47 (s, 3H), 3.60–3.65 (d, J=14.3 Hz, 2H), 6.46 (s, 1H), 6.60 (s, 1H), 7.15–7.30 (m, 3H), 7.35–7.45 (m, 2H); 13C NMR (100 MHz, CDCl3): δ 11.4, 20.1, 25.5, 27.4, 29.6, 31.8, 45.3, 50.3, 53.7, 55.5, 56.2, 71.8, 109.8, 116.1, 125.2, 127.1, 128.2, 128.8, 133.2, 133.4, 141.2, 152.9, 170.0. The dihydrochloride salt was prepared by the addition of 2 M HCl in ether to a solution of the product in ethyl acetate. Concentration gave a white solid (Mp=225–229° C.).
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=O)[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[CH2:12]([NH2:30])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]>>[CH2:12]([N:30]1[C:1](=[O:11])[C:2]2[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4]1=[O:6])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: CCCCCCCCCCCCCCCCCCN
Reactant: O=C1OC(=O)c2ccccc21
Product: CCCCCCCCCCCCCCCCCCN1C(=O)c2ccccc2C1=O
Yield: 89 %

Procedure:
Phthalic anhydride (1.00 g) and octadecylamine (1.82 g) were stirred for 1 hour at 110° C. The reaction mixture was purified by silica gel column chromatography (silica gel 34 g, chloroform:methanol=20:1), thereby yielding 2.40 g of the aimed compound as white crystals.
Reaction SMILES: [CH3:1][N:2]1[C:11](/[CH:12]=[CH:13]/[C:14]([O:16]CC)=[O:15])=[C:10]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:25].C(O)(=O)C.Cl>O>[CH3:1][N:2]1[C:11](/[CH:12]=[CH:13]/[C:14]([OH:16])=[O:15])=[C:10]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:25]
Reactant: CCOC(=O)/C=C/c1c(-c2ccccc2)c2ccccc2c(=O)n1C
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: Cn1c(/C=C/C(=O)O)c(-c2ccccc2)c2ccccc2c1=O
Yield: 76.4 %

Procedure:
A solution of ethyl (E)-3-(2-methyl-1-oxo-4-phenyl-1,2-dihydroisoquinolin-3-yl)propenoate (4.0 g) in a mixture of glacial acetic acid (50 ml) and concentrated hydrochloric acid (50 ml) was heated at reflux for 2 hours and then poured onto a mixture of ice and water (100 g). The resulting white solid was filtered off and crystallised from ethanol, to give (E)-3-(2-methyl-1-oxo-4-phenyl-1,2-dihydroisoquinolin-3-yl)propenoic acid (2.8 g) in the form of white crystals, m.p.266°-268° C. [Elemental analysis: C,74.3; H,5.0; N,4.2%; calculated: C,74.7; H,4.95; N,4.59%].
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4](Cl)=[O:5].[CH3:12][OH:13]>>[Cl:1][C:2]1[N:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([O:13][CH3:12])=[O:5]
Reactant: O=C(Cl)c1cc(Cl)cnc1Cl
Reactant: CO
Product: COC(=O)c1cc(Cl)cnc1Cl
Yield: 86 %

Procedure:
2,5-dichloronicotinic acid chloride (5.0 g) was dissolved in methanol (30 ml) with stirring under ice cooling and then stirred at room temperature for 30 minutes. The solvent was evaporated under reduced pressure and the residue was dissolved in ether and washed with saturated sodium hydrogen carbonate water solution and brine. The extract was dried over anhydrous magnesium sulphate and filtered. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography with cyclohexane/ethyl acetate (30/1), to give the title compound (4.2 g, 86%).
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([F:17])=[C:5]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[CH:6]=[C:7]([F:10])[C:8]=1[F:9].[Cl:18][C:19]1[N:24]=[C:23]2[NH:25][N:26]=[CH:27][C:22]2=[CH:21][N:20]=1>>[Cl:18][C:19]1[N:24]=[C:23]2[N:25]([CH2:2][C:3]3[C:4]([F:17])=[C:5]([N:11]4[CH2:16][CH2:15][O:14][CH2:13][CH2:12]4)[CH:6]=[C:7]([F:10])[C:8]=3[F:9])[N:26]=[CH:27][C:22]2=[CH:21][N:20]=1
Reactant: Clc1ncc2cn[nH]c2n1
Reactant: Fc1cc(N2CCOCC2)c(F)c(CBr)c1F
Product: Fc1cc(N2CCOCC2)c(F)c(Cn2ncc3cnc(Cl)nc32)c1F

Procedure:
4-(3-(bromo methyl)-2,4,5-trifluorophenyl)morpholine and 6-chloro-1H-pyrazolo[3,4-d]pyrimidine were coupled as in Example 1 (Step ii) to afford 4-(3-((6-chloro-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-2,4,5-trifluorophenyl)morpholine followed by Example 1 (Step i) using tert-butyl 4-amino-1H-pyrazole-1-carboxylate to afford the title product. 1H NMR (d6-DMSO) δ 12.55 (s, 1H), 9.87 (br s, 1H), 8.89 (s, 1H), 8.15 (br s, 1H), 8.00 (s, 1H), 7.70 (s, 1H), 7.21-7.14 (m, 1H), 5.58 (s, 2H), 3.68 (t, 4H), 2.93 (t, 4H); LC-MS method B, (ES+) 431.1, RT=7.59 min.
Reaction SMILES: C([O:5][C:6]([C@@H:8]1[NH:12][C@@H:11]([CH2:13][C:14]([CH3:17])([CH3:16])[CH3:15])[C@:10]2([C:25]3[C:20](=[CH:21][C:22]([Cl:26])=[CH:23][CH:24]=3)[NH:19][C:18]2=[O:27])[C@H:9]1[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[C:29]=1[F:35])=[O:7])(C)(C)C.[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39]>ClCCl>[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39].[Cl:26][C:22]1[CH:21]=[C:20]2[NH:19][C:18](=[O:27])[C@:10]3([C@@H:9]([C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[C:29]=4[F:35])[C@H:8]([C:6]([OH:7])=[O:5])[NH:12][C@H:11]3[CH2:13][C:14]([CH3:16])([CH3:15])[CH3:17])[C:25]2=[CH:24][CH:23]=1
Reactant: CC(C)(C)C[C@@H]1N[C@@H](C(=O)OC(C)(C)C)[C@H](c2cccc(Cl)c2F)[C@]12C(=O)Nc1cc(Cl)ccc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)C[C@@H]1N[C@@H](C(=O)O)[C@H](c2cccc(Cl)c2F)[C@]12C(=O)Nc1cc(Cl)ccc12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of chiral (2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid tert-butyl ester (2.7 g, 5.2 mmol) in dichloromethane (15 mL) was added trifluoroacetic acid (15 mL). The reaction mixture was stirred at room temperature for 18 h, then concentrated. The residue was then triturated with ethyl ether hexanes, concentrated, dried in vacuo to give chiral (2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid trifluoroacetic acid as a off white solid (3 g, 100%).
Reaction SMILES: [CH:1]([NH:4][C:5](=[O:14])[CH2:6][C:7]1[CH:12]=[CH:11][C:10](Br)=[CH:9][CH:8]=1)([CH3:3])[CH3:2].[CH:15]([Sn](CCCC)(CCCC)CCCC)=[CH2:16]>C1(C)C=CC=CC=1.C(OCC)(=O)C.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>[CH:1]([NH:4][C:5](=[O:14])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH:15]=[CH2:16])=[CH:9][CH:8]=1)([CH3:3])[CH3:2]
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: CC(C)NC(=O)Cc1ccc(Br)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: C=Cc1ccc(CC(=O)NC(C)C)cc1
Yield: 72.8 %

Procedure:
N-Isopropyl-4-bromophenylacetamide (1.0 g) and vinyltributyltin (1.4 ml) were dissolved in toluene (12 ml). After adding tetrakistriphenylphosphinepalladium (0.5 g) thereto, the resultant mixture was heated under reflux for 4 hr. Then it was allowed to cool and diluted with ethyl acetate. The resulting solid was filtered off and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate system) to give colorless crystals (0.578 g) of the title compound (yield: 72.8%).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:22]2[CH:27]=[CH:26][C:25]([S:28]([CH:31]([CH3:35])[CH2:32]CO)(=[O:30])=[O:29])=[CH:24][CH:23]=2)=[N:6][C:7]=1[C:8]1[O:9][C:10](C2C=CC(CNC)=CC=2)=[N:11][N:12]=1.[NH2:36][CH2:37][C:38]1[CH:39]=[C:40](C2OC(C3C(N)=NC=C(C4C=CC=CC=4S(C)=O)N=3)=NN=2)[CH:41]=[CH:42][CH:43]=1.FC1C=C(C2N=C(C3OC(C4C=CC(CNC)=CC=4F)=NN=3)C(N)=NC=2)C=CC=1S(C(C)C)(=O)=O.ClC1C=C(C2N=C(C3OC(C4C=CC(CNC)=CC=4F)=NN=3)C(N)=NC=2)C=CC=1S(C(C)C)(=O)=O.NC1N=CC(C2C=CC(S(C(C)CCO)(=O)=O)=CC=2)=NC=1C1OC(C2C=CC(CNC)=CC=2F)=NN=1>>[NH2:36][CH2:37][C:38]1[CH:43]=[C:42]([C:10]2[O:9][C:8]([C:7]3[C:2]([NH2:1])=[N:3][CH:4]=[C:5]([C:22]4[CH:23]=[CH:24][C:25]([S:28]([CH:31]([CH3:32])[CH3:35])(=[O:30])=[O:29])=[CH:26][CH:27]=4)[N:6]=3)=[N:12][N:11]=2)[CH:41]=[CH:40][CH:39]=1
Reactant: CS(=O)c1ccccc1-c1cnc(N)c(-c2nnc(-c3cccc(CN)c3)o2)n1
Reactant: CNCc1ccc(-c2nnc(-c3nc(-c4ccc(S(=O)(=O)C(C)CCO)cc4)cnc3N)o2)cc1
Agent: CNCc1ccc(-c2nnc(-c3nc(-c4ccc(S(=O)(=O)C(C)C)c(Cl)c4)cnc3N)o2)c(F)c1
Agent: CNCc1ccc(-c2nnc(-c3nc(-c4ccc(S(=O)(=O)C(C)C)c(F)c4)cnc3N)o2)c(F)c1
Agent: CNCc1ccc(-c2nnc(-c3nc(-c4ccc(S(=O)(=O)C(C)CCO)cc4)cnc3N)o2)c(F)c1
Product: CC(C)S(=O)(=O)c1ccc(-c2cnc(N)c(-c3nnc(-c4cccc(CN)c4)o3)n2)cc1

Procedure:
Compound IA-88 3-[4-[5-amino-6-[5-[4-(methylaminomethyl)phenyl]-1,3,4-oxadiazol-2-yl]pyrazin-2-yl]phenyl]sulfonylbutan-1-ol 1H NMR (400 MHz, DMSO) d 1.21 (d, 3H), 1.38-1.47 (m, 1H), 1.97-2.05 (m, 1H), 2.64 (t, 3H), 3.38-3.46 (m, 2H), 3.51-3.56 (m, 1H), 4.29 (t, 2H), 7.77 (d, 2H), 7.97-8.01 (m, 2H), 8.26 (d, 2H), 8.40-8.44 (m, 2H), 8.97 (s, 2H) and 9.09 (d, 1H) ppm; MS (ES+) 495.0 Compound IA-257 3-[5-[3-(aminomethyl)phenyl]-1,3,4-oxadiazol-2-yl]-5-(2-methylsulfinylphenyl)pyrazin-2-amine 1H NMR (400 MHz, DMSO) d 3.1 (s, 3H), 4.3 (s, 2H), 7.6-7.75 (m, 4H), 8.05 (d, 1H), 8.15 (d, 1H), 8.35-8.5 (m, 4H) and 8.9 (s, 1H) ppm; MS (ES+) 407.1 Compound IA-321 5-(3-fluoro-4-isopropylsulfonyl-phenyl)-3-[5-[2-fluoro-4-(methylaminomethyl)phenyl]-1,3,4-oxadiazol-2-yl]pyrazin-2-amine 1H NMR (400 MHz, DMSO) d 1.25 (d, 6H), 2.7 (s, 3H), 3.5-3.6 (m, 1H), 4.4 (s, 2H), 7.6 (d, 1H), 7.7 (d, 1H), 7.9 (t, 1H), 8.2-8.3 (m, 2H), 8.35 (t, 1H), 8.9-9.0 (br s, 2H) and 9.1 (s, 1H) ppm; MS (ES+) 501.3 Compound IA-329 5-(3-chloro-4-isopropylsulfonyl-phenyl)-3-[5-[2-fluoro-4-(methylaminomethyl)phenyl]-1,3,4-oxadiazol-2-yl]pyrazin-2-amine 1H NMR (400 MHz, DMSO) d 1.25 (d, 6H), 2.7 (s, 3H), 3.7-3.8 (m, 1H), 4.4 (s, 2H), 7.6 (d, 1H), 7.7 (d, 1H), 8.1 (d, 1H), 8.25-8.35 (m, 2H), 8.4 (s, 1H), 8.9-9.0 (br s, 2H) and 9.1 (s, 1H) ppm; MS (ES+) 517.2 Compound IA-342 3-[4-[5-amino-6-[5-[2-fluoro-4-(methylaminomethyl)phenyl]-1,3,4-oxadiazol-2-yl]pyrazin-2-yl]phenyl]sulfonylbutan-1-ol 1H NMR (400 MHz, DMSO) d 1.25 (d, 3H), 1.4-1.5 (m, 1H), 1.95-2.03 (m, 1H), 2.7 (s, 3H), 3.4-3.5 (m, 1H), 3.5-3.6 (m, 1H), 4.45 (s, 2H), 4.6-4.7 (m, 1H), 7.6 (d, 1H), 7.7 (d, 1H), 8.0 (d, 2H), 8.3 (t, 1H), 8.4 (d, 2H), 9.0 (br s, 2H) and 9.1 (s, 1H) ppm; MS (ES+) 513.2
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([CH3:15])=[CH:10][C:9]=1[NH:16][C:17](=[O:33])[CH2:18][C:19](=O)[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]2[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=2)[CH:21]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:14][C:12]1[C:11]([CH3:15])=[CH:10][C:9]2[NH:16][C:17](=[O:33])[CH2:18][C:19]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]4[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=4)[CH:21]=3)=[N:7][C:8]=2[CH:13]=1
Reactant: Cc1cc(NC(=O)CC(=O)c2cccc(-c3ccncc3)c2)c(NC(=O)OC(C)(C)C)cc1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc2c(cc1Cl)N=C(c1cccc(-c3ccncc3)c1)CC(=O)N2

Procedure:
The title compound was prepared from {5-chloro-4-methyl-2-[3-oxo-3-(3-pyridin-4-yl-phenyl)-propionylamino]-phenyl}-carbamic acid tert-butyl ester (Example M63) (0.36 g, 0.75 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as an off-white light solid (269 mg, 99%).
Reaction SMILES: Cl.[CH3:2][NH:3][O:4][CH3:5].C[Al](C)C.[O:10]1[CH2:15][CH2:14][CH2:13][CH2:12][C:11]1=[O:16].Cl>ClCCl>[OH:10][CH2:15][CH2:14][CH2:13][CH2:12][C:11]([N:3]([O:4][CH3:5])[CH3:2])=[O:16]
Reactant: O=C1CCCCO1
Reactant: CNOC
Agent: C[Al](C)C
Agent: Cl
Solvent: ClCCl
Product: CON(C)C(=O)CCCCO
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 60.2 %

Procedure:
To a stirred suspension of N,O-dimethylhydroxyamine hydrochloride (14.6 g, 150 mmol) in dry dichloromethane (150 mL) was added a solution of trimethylaluminum (2.0 M solution in toluene, 75 mL, 150 mmol) drop wise at room temperature. After stirring for 30 min, tetrahydropyran-2-one (10 g, 100 mmol) in dry dichloromethane (50 mL) was added drop wise. The reaction mixture was stirred over night. After cooling to 0° C., 1N HCl (80 mL, 80 mmol) was added slowly (exothermic reaction), diluted with dichloromethane (200 mL). The two layers were separated and the aqueous layer was extracted with dichloromethane twice. The combined organic phases were dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel (120 g column, 0% methanol in dichloromethane to 20% methanol in dichloromethane) to give product (9.7 g, 60%). 1H NMR (CDCl3) δ 3.68 (s, 3H), 3.63 (t, J=6.1 Hz, 2H), 3.17 (s, 3H), 2.46 (t, J=7.0 Hz, 2H), 1.69-1.74 (m, 2H), 1.58-1.64 (m, 2H). MS EI m/z 162 (M+H)+.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([OH:14])[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH:22]([O:28][C:29]1[N:34]=[C:33]([CH3:35])[CH:32]=[C:31]([CH3:36])[N:30]=1)[C:23]([O:25][CH2:26]C)=[O:24].O>C(#N)C>[O:1]([C:8]1[CH:9]=[C:10]([CH:11]=[CH:12][CH:13]=1)[O:14][CH:22]([O:28][C:29]1[N:30]=[C:31]([CH3:36])[CH:32]=[C:33]([CH3:35])[N:34]=1)[C:23]([O:25][CH3:26])=[O:24])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1cccc(Oc2ccccc2)c1
Reactant: CCOC(=O)C(Cl)Oc1nc(C)cc(C)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: COC(=O)C(Oc1cccc(Oc2ccccc2)c1)Oc1nc(C)cc(C)n1
Temperature: 25 °C
Yield: 48.7 %

Procedure:
3-Phenoxyphenol (1.0 g, 5.4 mmol) was placed in a flask with potassium carbonate (0.90 g, 6.5 mmol) and 20 mL of acetonitrile and to this was added dropwise with stirring at ambient temperature, a solution of ethyl 2-chloro-2-(4,6-dimethyl-2-pyrimidinyloxy)acetate (1.40 g, 5.7 mmol) in 5 mL of acetonitrile. The mixture was allowed to stir overnight and was then added to water and the resulting mixture was extracted 3 times with ether. The ethereal solution was extracted 2 times with 1N aqueous sodium hydroxide, dried over magnesium sulfate, filtered, and concentrated by evaporation under reduced pressure to obtain about 1 g of the title compound as a crude yellow oil. This oil, which solidified on standing, was chromatographed on silica eluting with an 85:15 mixture of hexane and ethyl acetate to obtain 0.60 g (28 percent of theory) of the title compound as a white solid melting at 111°-112° C.
Reaction SMILES: [NH2:1][C:2]1[O:6][C:5]([C:7]([O:9][CH3:10])=[O:8])=[CH:4][CH:3]=1.N1C=CC=CC=1.Cl[C:18]([O:20][CH2:21][C:22]([Cl:25])([Cl:24])[Cl:23])=[O:19].O>O1CCCC1>[Cl:23][C:22]([Cl:25])([Cl:24])[CH2:21][O:20][C:18]([NH:1][C:2]1[O:6][C:5]([C:7]([O:9][CH3:10])=[O:8])=[CH:4][CH:3]=1)=[O:19]
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: COC(=O)c1ccc(N)o1
Solvent: C1CCOC1
Solvent: O
Solvent: c1ccncc1
Product: COC(=O)c1ccc(NC(=O)OCC(Cl)(Cl)Cl)o1

Procedure:
To a solution of methyl 5-amino-2-furancarboxylate (1.00 g, 7.09 mmol) and pyridine (1.72 ml, 21.3 mmol) in tetrahydrofuran (24 ml) was added, under ice-cooling, 2,2,2-trichloroethyl chloroformate (1.96 ml, 14.2 mmol), and the mixture was stirred at room temperature for 1 hour and half. Water was poured to the reaction mixture, and the resulting solution was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Hexane was poured to the residue, and 662 mg (29.6%) of the desired product as a solid was separated by filtration.
Reaction SMILES: [NH2:1][C:2](=[O:93])[CH2:3][NH:4][C:5](=[O:92])[C@@H:6]([NH:13][C:14](=[O:91])[C@@H:15]([N:17]([CH3:90])[C:18]([C@H:20]([CH2:86][C:87](O)=[O:88])[NH:21][C:22](=[O:85])[C@H:23]([CH2:78][C:79]1[CH:84]=[CH:83][CH:82]=[CH:81][CH:80]=1)[NH:24][C:25](=[O:77])[C@H:26]([CH:74]([CH3:76])[CH3:75])[NH:27][C:28](=[O:73])[C@H:29]([CH3:72])[NH:30][C:31](=[O:71])[C@H:32]([CH2:67][CH:68]([CH3:70])[CH3:69])[N:33]([CH3:66])[C:34](=[O:65])[CH2:35][NH:36][C:37](=[O:64])[C@H:38]([CH2:57][C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1)[N:39]([CH3:56])[C:40](=[O:55])[C@H:41]([CH3:54])[NH:42][C:43](=[O:53])[CH2:44][NH:45][C:46](=[O:52])[O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:19])[CH3:16])[CH2:7][O:8][C:9]([CH3:12])([CH3:11])[CH3:10].[C:94]1([CH2:100][SH:101])[CH:99]=[CH:98][CH:97]=[CH:96][CH:95]=1.CC(C)N=C=NC(C)C>ClCCl.CN(C=O)C.CN(C)C1C=CN=CC=1>[NH2:1][C:2](=[O:93])[CH2:3][NH:4][C:5](=[O:92])[C@@H:6]([NH:13][C:14](=[O:91])[C@@H:15]([N:17]([CH3:90])[C:18]([C@H:20]([CH2:86][C:87](=[O:88])[S:101][CH2:100][C:94]1[CH:99]=[CH:98][CH:97]=[CH:96][CH:95]=1)[NH:21][C:22](=[O:85])[C@H:23]([CH2:78][C:79]1[CH:80]=[CH:81][CH:82]=[CH:83][CH:84]=1)[NH:24][C:25](=[O:77])[C@H:26]([CH:74]([CH3:75])[CH3:76])[NH:27][C:28](=[O:73])[C@H:29]([CH3:72])[NH:30][C:31](=[O:71])[C@H:32]([CH2:67][CH:68]([CH3:69])[CH3:70])[N:33]([CH3:66])[C:34](=[O:65])[CH2:35][NH:36][C:37](=[O:64])[C@H:38]([CH2:57][C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1)[N:39]([CH3:56])[C:40](=[O:55])[C@H:41]([CH3:54])[NH:42][C:43](=[O:53])[CH2:44][NH:45][C:46](=[O:52])[O:47][C:48]([CH3:50])([CH3:51])[CH3:49])=[O:19])[CH3:16])[CH2:7][O:8][C:9]([CH3:12])([CH3:11])[CH3:10]
Reactant: CC(C)C[C@@H](C(=O)N[C@@H](C)C(=O)N[C@H](C(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](CC(=O)O)C(=O)N(C)[C@@H](C)C(=O)N[C@@H](COC(C)(C)C)C(=O)NCC(N)=O)C(C)C)N(C)C(=O)CNC(=O)[C@H](Cc1ccccc1)N(C)C(=O)[C@H](C)NC(=O)CNC(=O)OC(C)(C)C
Reactant: SCc1ccccc1
Agent: CC(C)N=C=NC(C)C
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)C[C@@H](C(=O)N[C@@H](C)C(=O)N[C@H](C(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](CC(=O)SCc1ccccc1)C(=O)N(C)[C@@H](C)C(=O)N[C@@H](COC(C)(C)C)C(=O)NCC(N)=O)C(C)C)N(C)C(=O)CNC(=O)[C@H](Cc1ccccc1)N(C)C(=O)[C@H](C)NC(=O)CNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 21.9 %

Procedure:
(9S,12S,18S,21S,24S,27S,30S)-30-(((S)-1-(((S)-1-((2-Amino-2-oxoethyl)amino)-3-(tert-butoxy)-1-oxopropan-2-yl)amino)-1-oxopropan-2-yl)(methyl)carbamoyl)-12,27-dibenzyl-18-isobutyl-24-isopropyl-2,2,9,11,17,21-hexamethyl-4,7,10,13,16,19,22,25,28-nonaoxo-3-oxa-5,8,11,14,17,20,23,26,29-nonaazadotriacontan-32-oic acid (Compound P-145, (Boc-Gly-Ala-MePhe-Gly-MeLeu-Ala-Val-Phe-Asp-MeAla-Ser(tBu)-Gly-NH2)) (50.0 mg, 0.038 mmol) was dissolved in dichloromethane (320 μL) and DMF (80 μL), phenylmethanethiol (9.49 mg, 0.076 mmol), DIC (9.64 mg, 0.076 mmol) and N,N-dimethylpyridin-4-amine (3.54 mg, 0.029 mmol) were added and the mixture was stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (10 mM aqueous ammonium acetate solution:methanol) to afford the title compound (11.8 mg, 21.8%).
Reaction SMILES: [C:1](O)(=[O:8])[C:2]1C=CC=CC=1.[CH:10]1[CH:11]=[CH:12][C:13]2N(O)N=[N:16][C:14]=2[CH:15]=1.CCN=C=NCCCN(C)C.CN1CCCNCC1.CCN(C(C)C)C(C)C>CN(C=O)C.O>[NH:16]1[C:14]2[C:13](=[CH:12][CH:11]=[CH:10][CH:15]=2)[CH2:2][C:1]1=[O:8]
Reactant: On1nnc2ccccc21
Reactant: O=C(O)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CN1CCCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: O=C1Cc2ccccc2N1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of (E)-3-(5-chloro-2-oxoindolin-3-ylidene)methyl)furan-2-yl)benzoic acid (541 mg, 1.48 mmol) and HOBt (400 mg, 2.96 mmol) in DMF (2 mL) was added EDCI (565 mg, 2.96 mmol). The reaction was stirred at rt for 10 min and then added 1-methyl homopiperazine (0.734 mL, 5.92 mmol) followed by DIEA (1 mL). The reaction mixture was stirred at rt for 1 h and diluted with H2O (10 mL). The mixture was extracted with EtOAc, dried over Na2SO4 and concentrated. The crude was purified by preparative TLC eluting with 2% methanol in dichloromethane to give (E)-5-chloro-3-(5-(3-(4-methyl-1,4-diazepane-1-carbonyl)phenyl)furan-2-yl)methylene)indolin-2-one. LCMS (ES): m/z 462 [M+1]+.