Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(CC[CH2:9][NH2:10])C=CC=CC=1.[CH2:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][N:12]1[C:20]([NH:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]([OH:30])=O)=[O:21].C1C2C(=CC=CC=2)CN1C(NC1C=CC(C(O)=O)=CC=1)=O>>[CH3:9][NH:10][C:28](=[O:30])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][NH:22][C:20]([N:12]1[CH2:11][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13]1)=[O:21]
Reactant: O=C(O)CCCCCNC(=O)N1Cc2ccccc2C1
Reactant: NCCCc1ccccc1
Agent: O=C(O)c1ccc(NC(=O)N2Cc3ccccc3C2)cc1
Product: CNC(=O)CCCCCNC(=O)N1Cc2ccccc2C1

Procedure:
The title compound was prepared as described in Example 1C, substituting methylamine for 3-phenylpropan-1-amine and 6-[(1,3-dihydro-2H-isoindol-2-ylcarbonyl)amino]hexanoic acid for 4-(isoindoline-2-carboxamido)benzoic acid. 1H NMR (300 MHz, DMSO-d6) δ ppm 7.60-7.72 (m, 1H), 7.25-7.33 (m, 4H), 6.24-6.29 (m, 1H), 4.57 (s, 4H), 2.94-3.09 (m, 2H), 2.54 (d, J=4.6 Hz, 3H), 2.30 (t, J=7.3 Hz, 1H), 2.04 (t, J=7.4 Hz, 1H), 1.37-1.58 (m, 4H), 1.18-1.35 (m, 2H); MS (ESI(+)) m/e 290 (M+H)+.
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=O)[CH2:3][C:4]([OH:6])=[O:5].[NH2:10][CH2:11][C:12]([OH:14])=[O:13].[NH2:15][C@H:16]([C:24]([OH:26])=O)[CH2:17][CH2:18][CH2:19][NH:20][C:21](=[NH:23])[NH2:22]>>[NH2:15][C@H:16]([C:24]([NH:1][CH2:2][C:7]([NH:1][C@H:2]([C:7]([NH:10][CH2:11][C:12]([OH:14])=[O:13])=[O:9])[CH2:3][C:4](=[O:5])[OH:6])=[O:9])=[O:26])[CH2:17][CH2:18][CH2:19][NH:20][C:21](=[NH:23])[NH2:22]
Reactant: N[C@@H](CC(=O)O)C(=O)O
Reactant: NCC(=O)O
Reactant: N=C(N)NCCC[C@H](N)C(=O)O
Product: N=C(N)NCCC[C@H](N)C(=O)NCC(=O)N[C@@H](CC(=O)O)C(=O)NCC(=O)O

Procedure:
Starting with N-FMOC-glycine-p-alkoxy benzyl resin ester, sequentially coupling L-aspartic acid, glycine and arginine, deprotecting and removing the peptide as in the above examples, L-arginylglycyl-L-aspartyl glycine was obtained as the ditrifluoroacetate salt; m.p. 85°-90° C.
Reaction SMILES: [F:1][C:2]1[C:10]([F:11])=[C:9]([C:12]2[CH:13]=[N:14][C:15]3[N:16]([C:18]([C:21]4([C:24]5[CH:25]=[C:26]6[C:31](=[CH:32][CH:33]=5)[N:30]=[CH:29][CH:28]=[CH:27]6)[CH2:23][CH2:22]4)=[CH:19][N:20]=3)[CH:17]=2)[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.CN.F[P-](F)(F)(F)(F)F.[N:43]1(O[P+](N(C)C)(N(C)C)N(C)C)[C:47]2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[F:1][C:2]1[C:10]([F:11])=[C:9]([C:12]2[CH:13]=[N:14][C:15]3[N:16]([C:18]([C:21]4([C:24]5[CH:25]=[C:26]6[C:31](=[CH:32][CH:33]=5)[N:30]=[CH:29][CH:28]=[CH:27]6)[CH2:23][CH2:22]4)=[CH:19][N:20]=3)[CH:17]=2)[CH:8]=[CH:7][C:3]=1[C:4]([NH:43][CH3:47])=[O:6]
Reactant: O=C(O)c1ccc(-c2cnc3ncc(C4(c5ccc6ncccc6c5)CC4)n3c2)c(F)c1F
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CNC(=O)c1ccc(-c2cnc3ncc(C4(c5ccc6ncccc6c5)CC4)n3c2)c(F)c1F
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 2,3-difluoro-4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]benzoic acid (9.0 mg, 0.020 mmol), methylamine (2M in THF, 0.02 mL, 0.041 mmol), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (11 mg, 0.024 mmol) and N,N-diisopropylethylamine (11 μL, 0.061 mmol) in N,N-dimethylformamide (0.5 mL) was stirred at RT for 4 h. The reaction mixture was purified by RP-HPLC (pH 10) to afford the desired product. LCMS: (M+H)=456.0.
Reaction SMILES: C(=O)(OC)OC.[C:7]([O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=[O:9])C.[O-:17][CH2:18][CH2:19][CH2:20][CH3:21].[O-][CH2:23][CH2:24]CC.C([Sn+2]CCCC)CCC>>[C:7](=[O:9])([O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[O:17][C:18]1[CH:24]=[CH:23][CH:21]=[CH:20][CH:19]=1
Reactant: CC(=O)Oc1ccccc1
Reactant: CCCC[O-]
Agent: CCCC[Sn+2]CCCC
Solvent: COC(=O)OC
Product: O=C(Oc1ccccc1)Oc1ccccc1
Reaction time: 1 h

Procedure:
In a stainless steel pressure vessel equipped with a distillation column packed with PRO-PAK protruded 0.16 inch stainless steel packing, air condensor, and receiver, and equipped to maintain pressure from a nitrogen regulator, a quantity of 78 parts dimethyl carbonate, 136 parts phenyl acetate, and 0.5 part dibutyl tin dibutoxide was heated, at 200 psig, to 240° C. for one hour, and then at atmospheric pressure for one hour. A quantity of 89 parts (83% of the theorectical) of diphenyl carbonate was isolated. The pot residue, after removal of the diphenyl carbonate by vacuum distillation, amounting to 3.3 parts, was used as a catalyst in the reaction of 132 parts phenyl acetate and 72 parts dimethyl carbonate. A quantity of 78.1 parts of diphenyl carbonate was recovered, along with 4.4 parts of pot residue for recycle. Analysis indicated less than 1 ppm of tin in the resulting diphenyl carbonate.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([N+:11]([O-])=O)[CH:10]=1)[NH:7][C:6]([C:14]1[S:15][CH:16]([CH2:19][N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[CH2:17][N:18]=1)=[CH:5]2.[Cl-].[Ca+2].[Cl-].C(O)C.O1CCCC1>[Fe].O>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([NH2:11])[CH:10]=1)[NH:7][C:6]([C:14]1[S:15][CH:16]([CH2:19][N:20]3[CH2:21][CH2:22][O:23][CH2:24][CH2:25]3)[CH2:17][N:18]=1)=[CH:5]2
Reactant: O=[N+]([O-])c1cc(Br)cc2cc(C3=NCC(CN4CCOCC4)S3)[nH]c12
Agent: [Fe]
Agent: [Ca+2]
Agent: [Cl-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: Nc1cc(Br)cc2cc(C3=NCC(CN4CCOCC4)S3)[nH]c12
Temperature: 80 °C
Yield: 22.4 %

Procedure:
A mixture of 5-bromo-2-[5-(morpholinomethyl)-4,5-dihydro-1,3-thiazol-2-yl]-7-nitro-1H-indole (2.4 g), iron (1.7 g), calcium chloride (310 mg), ethanol (50 mL), tetrahydrofuran (25 mL) and water (5 mL) was stirred under heating at 80° C. for 18 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried (MgSO4), and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography to give the title compound (500 mg, yield 22%) as yellow crystals from a fraction eluted with ethyl acetate:hexane=50:50. MS: 396 (MH+).
Reaction SMILES: C1(=O)[NH:5][C:4](=O)[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[K].[CH3:13][C:14]1[CH:28]=[CH:27][C:17]([S:18]C2C=CC(CBr)=CC=2)=[CH:16][CH:15]=1.O>CN(C)C=O>[CH3:13][C:14]1[CH:28]=[CH:27][C:17]([S:18][C:9]2[CH:10]=[CH:2][C:3]([CH2:4][NH2:5])=[CH:7][CH:8]=2)=[CH:16][CH:15]=1
Reactant: Cc1ccc(Sc2ccc(CBr)cc2)cc1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(Sc2ccc(CN)cc2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 77.2 %

Procedure:
To a stirred mixture of potassium phthalimide (3.60 g, 19.4 mM) and dry N,N-dimethylformamide (200 ml) was added dropwise a solution of 4-(4-methylthiophenoxy)benzylbromide (5.00 g, 16.2 mM) in dry N,N-dimethylformamide at room temperature, the mixture was stirred for 5 h at the same temperature. The mixture was poured into water, and the mixture was extracted with toluene. The extract was washed with 5N NaOH, water and brine, dried with magnesium sulfate, and concentrated in vacuo. The residue was diluted with methanol (200 ml), and to the mixture was added dropwise hydrazine monohydrate (1.10 g, 21.1 mM). The mixture was stirred for 6 h under reflux, and this was cooled to the room temperature and concentrated in vacuo. The residue was diluted with chloroform and the mixture was filtered through celite. The filtrate was washed with 5N NaOH(x3) and brine(x2), dried with potassium carbonate, and concentrated in vacuo to give 4-(4-methylthiophenoxy)benzylamine (3.02 g, 76%) as colorless crystals, m.p. 61.8° C.
Reaction SMILES: [C:1]1([O:11][CH:12]([Cl:17])[CH:13]([OH:16])[CH2:14][CH3:15])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH2:18]([NH2:26])[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CC(C)=O>[ClH:17].[C:1]1([O:11][CH2:12][CH:13]([OH:16])[CH2:14][CH2:15][NH:26][CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: NCCc1ccccc1
Reactant: CCC(O)C(Cl)Oc1cccc2ccccc12
Solvent: CC(C)=O
Product: Cl
Product: OC(CCNCCc1ccccc1)COc1cccc2ccccc12

Procedure:
A mixture of 12.5 g. (0.05 mole) of 1-(1-naphthyloxy)-2-hydroxybutyl chloride and 14.5 g. (0.1 mole) of phenethylamine was heated at 120° C. for 20 min. on a hot plate. The resulting mixture was mixed with 250 ml. of acetone, heated to boiling and then filtered at room temperature. The filtrate was treated with 50 ml. of ethereal hydrogen chloride. The resulting white precipitate was filtered. The white crystalline solid was recrystallized from acetone and yielded 11.8 g. of the hydrochloride salt which melted at 163°-165° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][C:9]([CH3:12])([CH3:11])[C:8]([CH2:13][NH:14][OH:15])=[C:7]([N:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]3=[O:22])[C:6]=2[CH:23]=1.C[Si]([N:28]=[C:29]=[O:30])(C)C.O.ClCCl>O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][C:9]([CH3:11])([CH3:12])[C:8]([CH2:13][N:14]([OH:15])[C:29]([NH2:28])=[O:30])=[C:7]([N:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]3=[O:22])[C:6]=2[CH:23]=1
Reactant: CC1(C)Oc2ccc(Br)cc2C(n2ccccc2=O)=C1CNO
Reactant: C[Si](C)(C)N=C=O
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: O
Product: CC1(C)Oc2ccc(Br)cc2C(n2ccccc2=O)=C1CN(O)C(N)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 35.7 %

Procedure:
To a solution of 6-bromo-2,2-dimethyl-3-(hydroxyamino)methyl-4-(2-oxo-1,2-dihydropyridin-1-yl)-2H-1-benzopyran (0.300 g, 0.0795 mol) in tetrahydrofuran was added dropwise trimethylsilyl isocyanate (0.22 ml, 0.18 g, 0.0016 mol) at room temperature under nitrogen. The reaction mixture was stirred overnight at room temperature. Water and dichloromethane were added. The organic layer was separated, dried and evaporated to give crude product which was chromatographed on silica gel, eluting with dichloromethane/methanol (90/10) to afford 0.24 g (72%) of 6-bromo-2,2-dimethyl-3-(N-hydroxyureido)methyl-4-(2-oxo-1,2-dihydropyridin-1-yl)-2H-1-benzopyran, m.p. 216° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([N+:13]([O-:15])=[O:14])=[C:4]([CH:9]=[C:10](Cl)[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[NH:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[NH2:1][C:2]1[C:3]([N+:13]([O-:15])=[O:14])=[C:4]([CH:9]=[C:10]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1cc(Cl)cc(N)c1[N+](=O)[O-]
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(N2CCOCC2)cc(N)c1[N+](=O)[O-]
Temperature: 25 °C
Yield: 46.3 %

Procedure:
A mixture of combined batches of methyl 3-amino-5-chloro-2-nitrobenzoate (39 g), morpholine (29.5 g) and K2CO3 (47 g) was stirred in DMF (200 ml) at 110° C. for 5 h. The mixture was cooled to room temperature and poured into water (1 L). It was extracted with EtOAc (500 mL×3). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in-vacuo to afford the desired product as a yellow solid (22 g, yield 46%). 1H NMR (300 MHz, CDCl3): δ ppm 3.31 (t, 4H, J=4.8 Hz), 3.82 (t, 4H, J=4.8 Hz), 3.89 (s, 3H), 6.03 (d, 1H, J=2.4 Hz), 6.34 (d, 1H, J=2.4 Hz); LC-MS: m/e=282 [M+1]+.
Reaction SMILES: [Cl:1][C:2]12[C:14]([Cl:16])([Cl:15])[C:5]([Cl:17])([CH:6]3[CH:11]1[C:10](=[O:12])[CH:9]=[CH:8][C:7]3=[O:13])[C:4]([Cl:18])=[C:3]2[Cl:19].CO>N1C=CC=CC=1>[Cl:1][C:2]12[C:14]([Cl:15])([Cl:16])[C:5]([Cl:17])([C:6]3[C:7]([OH:13])=[CH:8][CH:9]=[C:10]([OH:12])[C:11]=31)[C:4]([Cl:18])=[C:3]2[Cl:19]
Reactant: O=C1C=CC(=O)C2C1C1(Cl)C(Cl)=C(Cl)C2(Cl)C1(Cl)Cl
Solvent: c1ccncc1
Solvent: CO
Product: Oc1ccc(O)c2c1C1(Cl)C(Cl)=C(Cl)C2(Cl)C1(Cl)Cl

Procedure:
50 g. of 1,2,3,4,9,9-hexachloro-1,4,4a,8a-tetrahydro-1,4-methanonaphthalene-5,8-dione were dissolved in 300 ml. of methanol and 3 g. of pyridine were added. The mixture was refluxed until the yellow color disappeared (about 5 hours). Upon cooling to 5°-7°C., white crystals separated. One recrystallization from methanol gave white crystals, m.p. 186°C. The yield was almost quantitative.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C@H:12]([NH2:18])[CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2].C[O:20][C:21](=O)[C:22]1[C:27]([NH:28][C:29]([CH:31]2[CH2:33][CH2:32]2)=[O:30])=[CH:26][CH:25]=[C:24]([Cl:34])[C:23]=1[CH2:35]Br.C(N(CC)CC)C>CN(C=O)C>[Cl:34][C:24]1[CH:25]=[CH:26][C:27]([NH:28][C:29]([CH:31]2[CH2:32][CH2:33]2)=[O:30])=[C:22]2[C:23]=1[CH2:35][N:18]([C@@H:12]([C:6]1[CH:7]=[CH:8][C:9]([O:10][CH3:11])=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=1)[CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])[C:21]2=[O:20]
Reactant: CCOc1cc([C@H](N)CS(C)(=O)=O)ccc1OC
Reactant: COC(=O)c1c(NC(=O)C2CC2)ccc(Cl)c1CBr
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOc1cc([C@@H](CS(C)(=O)=O)N2Cc3c(Cl)ccc(NC(=O)C4CC4)c3C2=O)ccc1OC
Temperature: 90 °C
Yield: 27.9 %

Procedure:
To a solution of (1S)-1-(3-ethoxy-4-methoxy-phenyl)-2-methanesulfonyl-ethylamine (1.4 g, 5.1 mmol) in DMF (20 ml) was added 2-bromomethyl-3-chloro-6-(cyclopropanecarbonyl-amino)-benzoic acid methyl ester (1.6 g, 4.6 mmol) and triethyl amine (2.0 ml, 14 mmol). The mixture was heated at 90° C. overnight. The solvent was removed in vacuo. The resulted oil was extracted with ethyl acetate (50 ml) and water (30 ml). The organic layer was washed with water (30 ml×2), brine (30 ml) and dried over magnesium sulfate. The solvent was removed in vacuo and the resulted oil was purified by silica gel column to give (1S)-cyclopropanecarboxylic acid {7-chloro-2-[1-(3-ethoxy-4-methoxy-phenyl)-2-methanesulfonyl-ethyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide as a white solid (650 mg, 30%): mp, 197-199° C.; 1H NMR (CDCl3) δ 0.89-0.93 (m, 2H, c-CH2), 1.08-1.12 (m, 2H, c-CH2), 1.44 (t, J=7.0 Hz, 3H, OCH2CH3), 1.65-1.69 (m, 1H, c-CH), 2.97 (s, 3H, CH3SO2), 3.70 (dd, J=5, 15 Hz, 1H, CHH), 3.87(s, 3H, OCH3), 4.05-4.23 (m, 4H, NCH+CH+OCH2CH3), 4.41 (d, J=17 Hz, 1H, CHH), 5.75-5.81 (m, 1H, CHN), 6.86-6.96 (m, 3H, Ar), 7.39 (d, J=9.0 Hz, 1H, Ar), 8.45(d, J=9.0 Hz, 1H, Ar), 10.36 (s, 1H, NHCO). 13CNMR (CDCl3): δ 8.5, 14.7, 16.2, 41.6, 46.9, 51.3, 55.5, 56.0, 64.7, 111.7, 112.3, 118.6, 119.3, 119.7, 121.8, 129.1, 133.2, 136.8, 139.0, 149.0, 149.9, 169.2, 172.6; Anal Calcd for C24H27ClN2O6S: C, 56.86; H, 5.37; N, 5.53; Found: C, 56.81; H, 5.26; N, 5.56.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[N:11]([CH3:12])[CH2:10][CH2:9][N:5]2[C:6](=[O:8])[N:7]=1.[H-].[Na+].[F:15][C:16]1[CH:17]=[C:18]([CH2:34][OH:35])[CH:19]=[C:20]([F:33])[C:21]=1[O:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=1>CN(C=O)C>[F:15][C:16]1[CH:17]=[C:18]([CH:19]=[C:20]([F:33])[C:21]=1[O:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:30])([F:31])[F:32])[CH:24]=1)[CH2:34][O:35][C:2]1[CH:3]=[C:4]2[N:11]([CH3:12])[CH2:10][CH2:9][N:5]2[C:6](=[O:8])[N:7]=1
Reactant: CN1CCn2c1cc(Cl)nc2=O
Reactant: OCc1cc(F)c(Oc2cccc(C(F)(F)F)c2)c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CCn2c1cc(OCc1cc(F)c(Oc3cccc(C(F)(F)F)c3)c(F)c1)nc2=O

Procedure:
Prepared in a manner similar to that described for E1 using 7-chloro-1-methyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one (60 mg, 0.323 mmol), sodium hydride (25.9 mg, 0.647 mmol) and (3,5-difluoro-4-(3-(trifluoromethyl)phenoxy)phenyl)methanol (98 mg, 0.323 mmol) in DMF (2 mL).
Reaction SMILES: [C:1]([O:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(N(CC)CC)C.[Br:23][C:24]1[C:25]([N:39]2[CH2:44][CH2:43][CH2:42][C@@H:41]([NH:45][C:46](=[O:52])[O:47][C:48]([CH3:51])([CH3:50])[CH3:49])[CH2:40]2)=[C:26]2[C:32]([NH:33][C:34]([CH:36]3[CH2:38][CH2:37]3)=[O:35])=[CH:31][NH:30][C:27]2=[N:28][CH:29]=1.O>CN(C1C=CN=CC=1)C.ClCCl>[C:9]([O:8][C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])([O:11][C:12]([CH3:14])([CH3:15])[CH3:13])=[O:10].[Br:23][C:24]1[C:25]([N:39]2[CH2:44][CH2:43][CH2:42][C@@H:41]([NH:45][C:46]([O:47][C:48]([CH3:49])([CH3:51])[CH3:50])=[O:52])[CH2:40]2)=[C:26]2[C:32]([NH:33][C:34]([CH:36]3[CH2:38][CH2:37]3)=[O:35])=[CH:31][N:30]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[C:27]2=[N:28][CH:29]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCN(c2c(Br)cnc3[nH]cc(NC(=O)C4CC4)c23)C1
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@@H]1CCCN(c2c(Br)cnc3c2c(NC(=O)C2CC2)cn3C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 71 %

Procedure:
di-tert-Butyl dicarbonate (150 mg, 0.687 mmol), DMAP (21 mg, 0.172 mmol) and triethylamine (174 mg, 0.239 mL, 1.72 mmol) were added to a solution of (R)-tert-butyl 1-(5-bromo-3-(cyclopropanecarboxamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate (274 mg, 0.573 mmol; Example 29, Step B) in anhydrous dichloromethane (6 mL). The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 2 hours. The mixture was concentrated. The residue was taken up in EtOAc, washed with water (3×10 mL) and brine (3×10 mL), dried over MgSO4 and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by reverse phase chromatography (Biotage SP4, C-18 25M+, 20-95% CH di-tert-butyl dicarbonate (150 mg, 0.687 mmol), DMAP (21 mg, 0.172 mmol) and triethylamine (174 mg, 0.239 mL, 1.72 mmol) CN/water, 25CV) to give (R)-tert-butyl 5-bromo-4-(3-(tert-butoxycarbonylamino)piperidin-1-yl)-3-(cyclopropanecarboxamido)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (237 mg, 71% yield) as a solid. 1H NMR (400 MHz, CDCl3) δ 10.03 (br s, 1H), 8.48 (s, 1H), 8.19 (s, 1H), 3.93-3.73 (m, 1H), 3.67-3.45 (m, 1H), 3.41-3.30 (m, 1H), 3.06-2.99 (m, 1H), 2.27-2.17 (m, 1H), 2.06-1.95 (m, 1H), 1.90-1.77 (m, 1H), 1.63 (s, 9H), 1.60 (s, 1H), 1.42 (s, 9H), 1.22-1.05 (m, 2H), 1.03-0.85 (m, 2H). LCMS (APCI+) m/z 580 (M+2H)+, Retention time=4.53 minutes.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[C:4](F)[CH:3]=1.[Li]CCCC.FC(F)(F)C[I:21].[ClH:24]>C1COCC1>[Cl:24][C:6]1[C:7]([I:21])=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=1[NH:8][C:9](=[O:11])[CH3:10]
Reactant: FC(F)(F)CI
Reactant: Cl
Reactant: CC(=O)Nc1ccc(Cl)cc1F
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(=O)Nc1ccc(Cl)c(I)c1Cl
Temperature: -65 °C
Reaction time: 2 h

Procedure:
To a solution of N-(4-chloro-2-fluorophenyl)acetamide (30.0 g, 147 mmol) in THF (300 mL) at −70° C. is added dropwise (keeping the reaction temperature below −60° C.) n-BuLi (2.0 M in cyclohexane, 147 mL, 294 mmol). The reaction is stirred between −60 to −70° C. for 2 hours and 1,1,1-trifluoro-2-iodoethane (46.2 g, 220 mmol) is added dropwise at −70° C. The reaction mixture is stirred at this temperature for additional 1.5 hours before 3N HCl (108 mL) solution is added slowly. The mixture is allowed to warm up to room temperature and extracted with EtOAc (200 mL×3). The organic layers are combined washed with water, brine and then dried over MgSO4. The solvents are removed and the residue is stirred in ether and hexanes (1:2, 120 mL) for 1 hour. A solid precipitate is filtered to give N-(2,4-dichloro-3-iodophenyl)acetamide.
Reaction SMILES: [C:1]([NH:4][NH:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:8][CH:7]=1)(=[O:3])[CH3:2].[C:20]1([N:26]=[C:27]=[S:28])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.O>C(O)C>[C:1]([NH:4][NH:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:27]([NH:26][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[S:28])=[CH:8][CH:7]=1)(=[O:3])[CH3:2]
Reactant: S=C=Nc1ccccc1
Reactant: CC(=O)NNc1ccc(NCc2ccccc2)cc1
Solvent: O
Solvent: CCO
Product: CC(=O)NNc1ccc(N(Cc2ccccc2)C(=S)Nc2ccccc2)cc1

Procedure:
1-Acetyl-2-(4-benzylaminophenyl)hydrazine (2.80 g, 0.011 mole) and phenylisothiocyanate (1.35 g, 0.01mole) were mixed in ethanol (25 ml) and the resulting mixture was refluxed for 5 minutes. The mixture was chilled in ice and water was added to precipitate the product. The product oiled out of solution, but became crystalline upon standing and scratching. The solid was filtered off and washed with water, then ether. After drying the product was a pale yellow crystalline powder. Yield 3.0 g (77%), m.p. 114°-117° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[OH:13])[CH:5]=[CH:6][C:7]([OH:9])=[O:8].[OH-].[Na+].CN(C)C=O.[CH:21]1[C:26](=[O:27])[C:25]([OH:28])=[CH:24][O:23][C:22]=1[CH2:29]Cl>CO.C(OCC)(=O)C>[OH:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[OH:13])[CH:5]=[CH:6][C:7]([O:9][CH2:29][C:22]1[O:23][CH:24]=[C:25]([OH:28])[C:26](=[O:27])[CH:21]=1)=[O:8]
Reactant: O=C(O)C=Cc1ccc(O)c(O)c1
Reactant: O=c1cc(CCl)occ1O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(C=Cc1ccc(O)c(O)c1)OCc1cc(=O)c(O)co1
Temperature: 110 °C
Reaction time: 2 h
Yield: 53.6 %

Procedure:
0.81 g(4.5 mmol) of 3,4-dihydroxycinnamic acid and 0.18 g (4.5 mmol) of sodium hydroxide were dissolved into 40 ml of methanol. Residues obtained after distillating in methanol dissolved into 70 ml of N,N-dimethylformamide and 0.65 g (4.05 mmol) of chlorokojic acid prepared in the Reference Example was added thereto. The resulting mixture was heated with stirring for 2 hours in an oil bath of 110° C. After distillating the solvent, the residue was dissolved in 300 ml of ethyl acetate. The ethyl acetate solution was washed with 5% hydrochloric acid and distilled water, dried over magnesium sulfate, decolored with active charcoal and filtered. The filtrate was concentrated to give 0.66 g(48.8%) of 2-(3,4-dihydroxycinnamoyl) oxymethyl-5-hydroxy-4H-pyran-4-one as a solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][C@H:10]2[CH2:14][CH2:13][CH2:12][N:11]2[CH2:15][CH:16]([CH3:18])[CH3:17])[C:5](=[O:19])[N:4]([CH2:20][C:21]([O:23]CC2C=CC=CC=2)=[O:22])[C:3]=1[CH3:31]>[OH-].[Pd+2].[OH-]>[ClH:1].[CH2:15]([N:11]1[CH2:12][CH2:13][CH2:14][C@@H:10]1[CH2:9][NH:8][C:6]1[C:5](=[O:19])[N:4]([CH2:20][C:21]([OH:23])=[O:22])[C:3]([CH3:31])=[CH:2][N:7]=1)[CH:16]([CH3:17])[CH3:18]
Reactant: Cc1c(Cl)nc(NC[C@H]2CCCN2CC(C)C)c(=O)n1CC(=O)OCc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Product: Cc1cnc(NC[C@H]2CCCN2CC(C)C)c(=O)n1CC(=O)O
Product: Cl

Procedure:
The title compound was prepared by a similar method to preparation 44 from benzyl 2-[3-chloro-5-({[(2R)-1-isobutylpyrrolidinyl]methyl}amino)-2-methyl-6-oxo-1(6H)-pyrazinyl]acetate [see preparation 61] and palladium hydroxide, to afford the product as a oil. LRMS: 323 (MH+).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:26])[C@@H:10]([NH2:25])[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=2)=[CH:14][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.FC(F)(F)S(O[C@H:40]([CH3:46])[C:41]([O:43][CH2:44][CH3:45])=[O:42])(=O)=O>ClCCl>[CH2:1]([O:8][C:9](=[O:26])[C@@H:10]([NH:25][C@H:40]([C:41]([O:43][CH2:44][CH3:45])=[O:42])[CH3:46])[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=2)=[CH:14][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N[C@@H](Cc1ccc(-c2cccc(Cl)c2)cc1)C(=O)OCc1ccccc1
Reactant: CCOC(=O)[C@@H](C)OS(=O)(=O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)[C@H](C)N[C@@H](Cc1ccc(-c2cccc(Cl)c2)cc1)C(=O)OCc1ccccc1
Reaction time: 0.17 h
Yield: 91.4 %

Procedure:
To a solution of (S)-2-amino-3-(3′-chloro-biphenyl-4-yl)-propionic acid benzyl ester (10.0 g, 24.9 mmol) in dichloromethane (100 mL) was added triethylamine (10.4 mL, 74.6 mmol) at 0° C. After stirred for 10 min, ethyl (R)-2-(trifluoromethylsulfonyloxy)propionate (9.3 mL, 49.5 mmol) was added at room temperature and stirred for 1 hour. Additional triethylamine (10.4 mL, 74.6 mmol) and ethyl (R)-2-(trifluoromethylsulfonyloxy)propionate (9.3 mL, 49.5 mmol) were added at room temperature and stirred for additional 2 hours. The reaction mixture was washed with H2O and the organic layer was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (EtOAc/heptane) to give (S)-3-(3′-chloro-biphenyl-4-yl)-2-((S)-1-ethoxycarbonyl-ethylamino)-propionic acid benzyl ester (10.6 g). 1H NMR (400 MHz, CDCl3) δ 1.21 (t, 3H, J=7.3 Hz), 1.27 (d, 3H, J=6.8 Hz), 1.89 (bs, 1H), 2.95-3.07 (m, 2H), 3.38 (dd, 1H, J=6.8, 14.8 Hz), 3.69 (dd, 1H, J=7.1, 7.1 Hz), 4.06-4.17 (m, 2H), 5.06 (d, 1H, J=12.1 Hz), 5.12 (d, 1H, J=12.1 Hz), 7.20-7.25 (m, 4H), 7.28-7.34 (m, 4H), 7.35 (dd, 1H, J=7.6, 7.6 Hz), 7.41-7.46 (m, 3H), 7.53 (dd, 1H, J=1.5, 1.5 Hz); MS: m/z (MH+) 466.