Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][CH2:9][CH2:10][CH:11]([NH:19][C:20]([C:22]1([NH:37]C(=O)OC(C)(C)C)[CH2:27][CH2:26][N:25]([C:28]2[C:29]3[CH:36]=[CH:35][NH:34][C:30]=3[N:31]=[CH:32][N:33]=2)[CH2:24][CH2:23]1)=[O:21])[C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1>C(Cl)Cl>[NH2:37][C:22]1([C:20]([NH:19][CH:11]([C:12]2[CH:13]=[CH:14][C:15]([Cl:18])=[CH:16][CH:17]=2)[CH2:10][CH2:9][NH2:8])=[O:21])[CH2:23][CH2:24][N:25]([C:28]2[C:29]3[CH:36]=[CH:35][NH:34][C:30]=3[N:31]=[CH:32][N:33]=2)[CH2:26][CH2:27]1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)NC(CCN)c2ccc(Cl)cc2)CCN(c2ncnc3[nH]ccc23)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCCC(NC(=O)C1(N)CCN(c2ncnc3[nH]ccc23)CC1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Trifluoroacetic acid (0.05 mL) was added to a stirred suspension of tert-butyl 4-(3-amino-1-(4-chlorophenyl)propylcarbamoyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-ylcarbamate (Intermediate 38) (7.0 mg) in DCM (1 mL) under argon at 25° C. The resulting suspension was stirred at 25° C. for 2 days. The reaction mixture was evaporated to dryness to afford the di-TFA salt of 4-amino-N-(3-amino-1-(4-chlorophenyl)propyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamide as a partially solid oil (13.0 mg).
Reaction SMILES: Cl.Cl[C:3]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[CH:10]=2)[N:6]=[C:5]2[CH2:16][CH2:17][CH2:18][C:4]=12.[NH2:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27]#[N:28])=[CH:22][CH:21]=1>>[Cl:15][C:11]1[CH:10]=[C:9]([C:7]2[N:6]=[C:5]3[CH2:16][CH2:17][CH2:18][C:4]3=[C:3]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([CH2:26][C:27]#[N:28])=[CH:22][CH:21]=3)[CH:8]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: Clc1cccc(-c2cc(Cl)c3c(n2)CCC3)c1
Reactant: N#CCc1ccc(N)cc1
Agent: Cl
Product: N#CCc1ccc(Nc2cc(-c3cccc(Cl)c3)nc3c2CCC3)cc1
Temperature: 150 °C
Yield: 44.5 %

Procedure:
An 18-mL test tube was charged with 4-chloro-2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridine HCl salt (30 mg, 0.1 mmol, 1 eq.) and 2-(4-aminophenyl)acetonitrile (30 mg, 0.23 mmol, 2.3 eq.). The resulting mixture was heated at 150° C. under Ar for 1 hr. After cooling to room temperature, the mixture was partitioned between NaHCO3 aq. (10 ml) and dichloromethane (10 ml). The organic layer was collected and concentrated on a rotary evaporator. The residue was purified by chromatography on silica gel using dichloromethane followed by ethyl acetate as eluent to give 2-[4-[[2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl]amino]phenyl]acetonitrile (16 mg, 44% yield). MW=359.85. 1H NMR (CDCl3, 360 MHz) δ 7.84 (s, 1H), 7.68 (m, 1H), 7.32 (m, 4H), 7.21 (m, 2H), 7.15 (s, 1H), 5.82 (brs, 1H), 3.75 (s, 2H), 3.09 (t, J=7.50 Hz, 2H), 2.83 (t, J=7.20 Hz, 2H), 2.21 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH3:13])=[C:5]([CH3:12])[C:6]=1[C:7]([O:9]CC)=[O:8].[OH-].[Na+]>C(O)C.O.C(O)(=O)C>[NH2:1][C:2]1[S:3][C:4]([CH3:13])=[C:5]([CH3:12])[C:6]=1[C:7]([OH:9])=[O:8]
Reactant: CCOC(=O)c1c(N)sc(C)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: CC(=O)O
Product: Cc1sc(N)c(C(=O)O)c1C

Procedure:
A mixture of 15 parts of ethyl 2-amino-4,5-dimethylthiophene-3-carboxylate and 75 parts by volume of 2N solution of sodium hydroxide in 50% aqueous ethanol is refluxed for 2.5 hours. After cooling the solution is diluted with 75 parts by volume of water and neutralized with acetic acid under cooling with ice. The resulting precipitate in collected by filtration to give 2-amino-4,5-dimethylthiophene-3-carboxylic acid as crystals. Recrystallization from chloroform with charcoal gives colorless needles melting at 136°-138° C (decomposition).
Reaction SMILES: [C:1]1(=O)[NH:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:9]1([NH2:16])[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH2:15].S(=O)(=O)(O)O>>[NH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:1]1[NH:15][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:16]=1
Reactant: O=C1CCCCCN1
Reactant: Nc1ccccc1N
Agent: O=S(=O)(O)O
Product: NCCCCCc1nc2ccccc2[nH]1

Procedure:
339.5 g (3 mols) of caprolactam, 430 g (4 mols) of o-phenylene diamine and 30 g of 50 % by weight sulphuric acid are reacted in the same way as described in Example 3, giving 510 g (83.7 % of the theoretical) of 2-(5'-aminopentyl)-benzimidazole with a boiling point at 0.1 Torr of 210° to 220°C, and a melting point of 101°C.
Reaction SMILES: [CH3:1][S:2]([O:5][C:6]1[C:14]([O:15][CH3:16])=[CH:13][C:12]([C:17]2[N:18]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C:19]3[C:24]([CH:25]=2)=[CH:23][C:22]([CH:26]=O)=[CH:21][CH:20]=3)=[C:11]2[C:7]=1[CH2:8][NH:9][C:10]2=[O:35])(=[O:4])=[O:3].[CH:36]1([NH2:39])[CH2:38][CH2:37]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(#N)C>[CH3:1][S:2]([O:5][C:6]1[C:14]([O:15][CH3:16])=[CH:13][C:12]([C:17]2[N:18]([C:28]([O:30][C:31]([CH3:32])([CH3:33])[CH3:34])=[O:29])[C:19]3[C:24]([CH:25]=2)=[CH:23][C:22]([CH2:26][NH:39][CH:36]2[CH2:38][CH2:37]2)=[CH:21][CH:20]=3)=[C:11]2[C:7]=1[CH2:8][NH:9][C:10]2=[O:35])(=[O:3])=[O:4]
Reactant: COc1cc(-c2cc3cc(C=O)ccc3n2C(=O)OC(C)(C)C)c2c(c1OS(C)(=O)=O)CNC2=O
Reactant: NC1CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC#N
Solvent: CC(=O)O
Product: COc1cc(-c2cc3cc(CNC4CC4)ccc3n2C(=O)OC(C)(C)C)c2c(c1OS(C)(=O)=O)CNC2=O
Yield: 72.2 %

Procedure:
In a similar manner to Step 2 of Example 6, 4-methanesulfonyloxy-5-methoxy-7-[1-(tert-butoxycarbonyl)-5-formylindol-2-yl]isoindolinone (50 mg, 0.100 mmol) was dissolved in acetonitrile (2.9 mL), and the solution was treated with cyclopropylamine (0.069 mL, 1.0 mmol), acetic acid (0.115 mL, 2.00 mmol) and sodium triacetoxyborohydride (64 mg, 0.30 mmol) to obtain 4-methanesulfonyloxy-5-methoxy-7-[1-(tert-butoxycarbonyl)-5-(cyclopropylaminomethyl)indol-2-yl]isoindolinone (39.1 mg, yield 72%).
Reaction SMILES: [C:1]([NH:4][NH:5][C:6](=O)[CH2:7][CH2:8][N:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[N:11]=[C:10]1[C:18]([N:20]([CH2:42][CH:43]([CH3:45])[CH3:44])[C@H:21]1[CH2:26][C@@H:25]([C:27]([N:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)=[O:28])[CH2:24][N:23]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:22]1)=[O:19])(=[O:3])[CH3:2].FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O>N1C=CC=CC=1>[CH3:2][C:1]1[O:3][C:6]([CH2:7][CH2:8][N:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]=[C:10]2[C:18]([N:20]([CH2:42][CH:43]([CH3:44])[CH3:45])[C@H:21]2[CH2:26][C@@H:25]([C:27]([N:29]3[CH2:30][CH2:31][O:32][CH2:33][CH2:34]3)=[O:28])[CH2:24][N:23]([C:35]([O:37][C:38]([CH3:40])([CH3:41])[CH3:39])=[O:36])[CH2:22]2)=[O:19])=[N:5][N:4]=1
Reactant: CC(=O)NNC(=O)CCn1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](C(=O)N3CCOCC3)CN(C(=O)OC(C)(C)C)C2)nc2ccccc21
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Product: Cc1nnc(CCn2c(C(=O)N(CC(C)C)[C@H]3C[C@@H](C(=O)N4CCOCC4)CN(C(=O)OC(C)(C)C)C3)nc3ccccc32)o1
Temperature: 25 °C
Reaction time: 15 h
Yield: 41.2 %

Procedure:
tert-Butyl (3S,5R)-3-[({1-[3-(2-acetylhydrazino)-3-oxopropyl]-1H-benzimidazol-2-yl}carbonyl)(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate (292 mg) was dissolved in pyridine (5 ml), and trifluoromethanesulfonic anhydride (230 μl) was added dropwise at room temperature. The reaction mixture was stirred at room temperature for 15 hr, and concentrated. The residue was diluted with 10% aqueous citric acid solution, and the mixture was extracted with ethyl acetate. The extract was washed with aqueous sodium bicarbonate and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate was concentrated under reduced pressure to give the object product (117 mg).
Reaction SMILES: [C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[C:22](I)[CH:23]=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[CH:12][N:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:26][C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[CH:31][CH:32]=1>>[C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[C:22]([C:31]5[CH:30]=[CH:29][CH:28]=[C:27]([NH2:26])[CH:32]=5)[CH:23]=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[CH:12][N:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C[C@H](Nc1nccc(-n2cnc3ccc(I)cc32)n1)c1ccccc1
Reactant: Nc1cccc(B(O)O)c1
Product: C[C@H](Nc1nccc(-n2cnc3ccc(-c4cccc(N)c4)cc32)n1)c1ccccc1

Procedure:
The title compound was prepared according to the procedure described in EXAMPLE 416, starting from 2-[(S)-1-Phenylethylamino]-4-[6-iodobenzimidazol-1-yl]pyrimidine and 3-aminophenylboronic acid. Mass spectrum (ESI) 407.3 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]=[C:9]2[OH:12])=[CH:4][CH:3]=1.[CH2:13](Br)[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[OH-].[Na+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1.CC(OC)(C)C>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]([CH2:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:9]2=[O:12])=[CH:4][CH:3]=1
Reactant: BrCCc1ccccc1
Reactant: Oc1nccc2ccc(Br)cc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: COC(C)(C)C
Solvent: Cc1ccccc1
Product: O=c1c2cc(Br)ccc2ccn1CCc1ccccc1
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 77.6 %

Procedure:
7-Bromo-1-hydroxyisoquinoline (300 mg, 1.34 mmol, 1.0 equiv), tetrabutylammonium bromide (50 mg, 0.13 mmol, 0.10 equiv), and phenethyl bromide (220 uL, 1.6 mmol, 1.2 equiv) were combined in toluene (14 mL) and treated with 50% aq. NaOH (3 mL), and the resulting mixture stirred rapidly while heating to 80° C. After 1.5 hours, the mixture was diluted with MTBE and washed with water, saturated NaHCO3, and brine. The organic phase was dried over Na2SO4. Addition of silica gel, concentration, and purification of the crude residue using flash silica gel chromatography (gradient of 2-30% ethyl acetates/hexanes) provided 7-bromo-2-phenethyl-isoquinolin-1-one (340 mg, 1.04 mmol, 77%) as a white solid. This isoquinolinone (340 mg, 1.04 mmol) was converted, via Methods 1 and 2, to compound 11 (141 mg, 46%) which was isolated as a white solid. Activity: B
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:12])[C:3]=1[OH:13].Cl[C:15]1[C:24]2[C:19](=[CH:20][C:21]([O:27][CH3:28])=[C:22]([O:25][CH3:26])[CH:23]=2)[N:18]=[CH:17][CH:16]=1>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:12])[C:3]=1[O:13][C:15]1[C:24]2[C:19](=[CH:20][C:21]([O:27][CH3:28])=[C:22]([O:25][CH3:26])[CH:23]=2)[N:18]=[CH:17][CH:16]=1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: Cc1nc2ccccc2c(Br)c1O
Agent: CN(C)c1ccncc1
Solvent: Clc1ccccc1Cl
Product: COc1cc2nccc(Oc3c(C)nc4ccccc4c3Br)c2cc1OC
Temperature: 140 °C
Reaction time: 5 h
Yield: 32 %

Procedure:
4-Bromo-3-hydroxy-2-methyl-quinoline (35 mg), 4-chloro-6,7-dimethoxyquinoline (110 mg), and 4-dimethylaminopyridine (89 mg) were suspended in o-dichlorobenzene (5 ml), and the suspension was stirred at 140° C. for 5 hr. The reaction solution was cooled to room temperature, and the solvent was removed by distillation under the reduced pressure. The residue was purified by thin layer chromatography using acetone-chloroform to give the title compound (20 mg, yield 32%).
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1)[C:6]([N:8]1[CH2:27][CH2:26][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:14][N:13]([CH2:22][CH2:23]O)[C:12]2=[O:25])[CH2:10][CH2:9]1)=[O:7].[CH:37]([NH2:40])([CH3:39])[CH3:38]>>[F:32][C:31]([F:34])([F:33])[C:29]1[CH:28]=[C:5]([CH:4]=[C:3]([C:2]([F:35])([F:1])[F:36])[CH:30]=1)[C:6]([N:8]1[CH2:9][CH2:10][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:14][N:13]([CH2:22][CH2:23][NH:40][CH:37]([CH3:39])[CH3:38])[C:12]2=[O:25])[CH2:26][CH2:27]1)=[O:7]
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCC2(CC1)C(=O)N(CCO)CN2c1ccccc1
Reactant: CC(C)N
Product: CC(C)NCCN1CN(c2ccccc2)C2(CCN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC2)C1=O

Procedure:
The title compound, MS: m/e=557.2 (M+H+), was prepared in accordance with the general method of example 48 from 8-(3,5-bis-trifluoromethyl-benzoyl)-3-(2-hydroxy-ethyl)-1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one and isopropylamine.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=2)[C:6](=[C:17](OCC)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]1=[O:27])(=O)C.[N:28]1[N:29]([CH2:33][C:34]2[CH:40]=[CH:39][C:37]([NH2:38])=[CH:36][CH:35]=2)[N:30]=[CH:31][CH:32]=1>>[N:28]1[N:29]([CH2:33][C:34]2[CH:40]=[CH:39][C:37]([NH:38]/[C:17](=[C:6]3\[C:5](=[O:27])[NH:4][C:12]4[C:7]\3=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=4)/[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:36][CH:35]=2)[N:30]=[CH:31][CH:32]=1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2cc(C(=O)OC)ccc21)c1ccccc1
Reactant: Nc1ccc(Cn2nccn2)cc1
Product: COC(=O)c1ccc2c(c1)NC(=O)/C2=C(\Nc1ccc(Cn2nccn2)cc1)c1ccccc1

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-methoxycarbonyl-2-indolinone and 4-(1,2,3-triazol-2-yl-methyl)-aniline Rf value: 0.5 (silica gel, methylene chloride/methanol=20:1) C26H21N5O3
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([N:5]2[CH2:10][CH2:9][N:8]([C:11]([C:13]3[S:14][CH:15]=[CH:16][N:17]=3)=[O:12])[CH2:7][CH2:6]2)[CH2:2]1.[CH2:18]([N:25]1[C:33]2[C:28](=[CH:29][C:30]([C:34](O)=[O:35])=[CH:31][CH:32]=2)[CH2:27][CH2:26]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(Cl)CCl.CCN(CC)CC.Cl>C(Cl)Cl.O>[CH2:18]([N:25]1[C:33]2[C:28](=[CH:29][C:30]([C:34]([N:1]3[CH2:2][CH:3]([N:5]4[CH2:6][CH2:7][N:8]([C:11]([C:13]5[S:14][CH:15]=[CH:16][N:17]=5)=[O:12])[CH2:9][CH2:10]4)[CH2:4]3)=[O:35])=[CH:31][CH:32]=2)[CH2:27][CH2:26]1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: O=C(O)c1ccc2c(c1)CCN2Cc1ccccc1
Reactant: O=C(c1nccs1)N1CCN(C2CNC2)CC1
Agent: Cl
Solvent: O
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: O=C(c1ccc2c(c1)CCN2Cc1ccccc1)N1CC(N2CCN(C(=O)c3nccs3)CC2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 35 %

Procedure:
To a solution of compound 5e (89.5 mg, 0.261 mmol), compound 55f (60 mg, 0.237 mmol), and EDC (68.1 mg, 0.356 mmol) in CH2Cl2 (5 mL) was added Et3N (0.1 mL, 0.711 mmol). The reaction mixture was stirred at room temperature overnight. The mixture was diluted with CH2Cl2 and H2O and the water layer was acidified to pH ˜6 with 1 N aqueous HCl. The organic solution was dried over Na2SO4 and concentrated. The residue was purified by reverse phase chromatography to give Cpd 994 as a TFA salt (40.4 mg). 1H NMR (400 MHz, CD3OD): δ 7.98 (d, J=3.2 Hz, 1H), 7.89 (d, J=3.2 Hz, 1H), 7.36-7.44 (m, 2H), 7.29-7.36 (m, 4H), 7.22-7.29 (m, 1H), 6.52 (d, J=8.3 Hz, 1H), 4.39-4.91 (m, 6H), 4.38 (s, 2H), 3.99-4.23 (m, 3H), 3.48 (t, J=8.6 Hz, 2H), 3.42 (br. s., 4H), 3.01 (t, J=8.6 Hz, 2H). MS m/z (M+H+) 488.1.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@@H:19]([CH2:23][C:24]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[NH:26][CH:25]=3)[C:20]([OH:22])=[O:21])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.I[C:34]1[CH:39]=[CH:38][C:37]([O:40][CH2:41][CH3:42])=[CH:36][CH:35]=1>>[CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@@H:19]([CH2:23][C:24]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[NH:26][C:25]=3[C:34]3[CH:39]=[CH:38][C:37]([O:40][CH2:41][CH3:42])=[CH:36][CH:35]=3)[C:20]([OH:22])=[O:21])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: CCOc1ccc(I)cc1
Reactant: O=C(N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O)OCC1c2ccccc2-c2ccccc21
Product: CCOc1ccc(-c2[nH]c3ccccc3c2C[C@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)O)cc1
Yield: 66 %

Procedure:
(S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(2-(4-ethoxyphenyl)-1H-indol-3-yl)propanoic acid (1.11 g, 66%) was obtained from (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(1H-indol-3-yl)propanoic acid and 1-iodo-4-ethoxybenzene using the procedure described for (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(2-(3-methoxyphenyl)-1H-indol-3-yl)propanoic acid. 1H NMR (400 MHz, chloroform-d) δ 8.12 (s, 1H), 7.77 (d, J=7.5 Hz, 2H), 7.69 (d, J=7.8 Hz, 1H), 7.54-7.34 (m, 8H), 7.33-7.12 (m, 4H), 6.97-6.90 (m, 2H), 5.16 (d, J=7.8 Hz, 1H), 4.64 (d, J=6.3 Hz, 1H), 4.28-4.06 (m, 4H), 3.62-3.42 (m, 2H), 1.44-1.36 (t, J=8.0 Hz, 3H); [α]20D −10.68° (4.01 mg/mL, MeOH). LCMS retention time=1.898 min., m/z 547=(M+H), 98.2% purity. The LCMS data was obtained on a Shimadzu analytical LC/MICROMASS® Platform LC (ESI+) at 220 nm using The following set of conditions: PHENOMENEX® Luna 3 μm C18, 2×50 mm column, with a gradient of 0-100% B (B=90% HPLC grade acetonitrile/0.1% trifluoroacetic acid/10% HPLC grade water), (A=90% HPLC grade water/0.1% trifluoroacetic acid/10% HPLC grade acetonitrile), in 2 minutes with a 1 minute hold at a flow rate of 1 mL/minute.
Reaction SMILES: [N:1]1([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:8][CH2:7][CH2:6][C@@H:2]1[C:3]([OH:5])=O.[NH2:16][C@H:17]([C:26]([NH:28][C@H:29]([C:37]([O:39][CH3:40])=[O:38])[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:27])[CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22]C=1.ClC(OCC(C)C)=O>>[N:1]1([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:8][CH2:7][CH2:6][C@@H:2]1[C:3]([NH:16][C@H:17]([C:26]([NH:28][C@H:29]([C:37]([O:39][CH3:40])=[O:38])[CH2:30][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)=[O:27])[CH2:18][C:19]1[CH:20]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:5]
Reactant: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N)CCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1C(=O)O
Agent: CC(C)COC(=O)Cl
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H]1CCCN1C(=O)OC(C)(C)C
Yield: 75 %

Procedure:
Condensation of BocDProOH (1.51 g.) and HPhe-PheOMe (2.53 g.) by the mixed anhydride method using isobutyl chloroformate gave BocDPro-Phe-PheOMe in 75% yield. Hydrazinolysis of BocDPro-Phe-PheOMe (2.00 g.) gave BocDPro-Phe-PheNHNH2 in 79% yield.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:10]#[N:11])=[N:4][CH:5]=[C:6]([CH2:8]O)[CH:7]=1.S(Cl)([Cl:14])=O>C(Cl)Cl>[Cl:1][C:2]1[C:3]([C:10]#[N:11])=[N:4][CH:5]=[C:6]([CH2:8][Cl:14])[CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: N#Cc1ncc(CO)cc1Cl
Solvent: ClCCl
Product: N#Cc1ncc(CCl)cc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 3-chloro-5-(hydroxymethyl)picolinonitrile (from the previous step) in CH2Cl2 (0.2 M) at 0° C. was added thionyl chloride (10 eq). After stirring at room temperature overnight the reaction mixture was concentrated under vacuum and the resulting crude was purified by chromatography (silica gel, 20-50% EtOAc in hexanes) to afford 3-chloro-5-(chloromethyl)picolinonitrile as a colorless oil.
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[N:15]2[CH:16]=[N:17][CH:18]=[C:14]2[CH:13]=[CH:12][CH:11]=1)([OH:3])=[O:2].[H][H].[ClH:21]>C(O)C.[Pd]>[ClH:21].[C:1]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]1[N:15]2[CH:16]=[N:17][CH:18]=[C:14]2[CH2:13][CH2:12][CH2:11]1)([OH:3])=[O:2]
Reactant: [H][H]
Reactant: O=C(O)CCCCCCc1cccc2cncn12
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: O=C(O)CCCCCCC1CCCc2cncn21

Procedure:
A solution of 2.7 g of 5-(6-carboxyhexyl)-imidazo[1,5-a]pyridine in a mixture of 120 ml of ethanol and 30 ml of concentrated hydrochloric acid is hydrogenated at 3 atmospheres in the presence of 1 g of 10% palladium on charcoal catalyst until 2 moles of hydrogen are consumed. The mixture is filtered free of catalyst and evaporated to dryness. The residue is recrystallized from isopropanol-ether to yield the 5-(6-carboxyhexyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine hydrochloride melting at 150°-4°.
Reaction SMILES: O[C:2]1[C:6](=[O:7])[N:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH2:4][C:3]=1[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].Cl.[NH2:21][OH:22]>N1C=CC=CC=1>[OH:22][N:21]=[C:2]1[C:6](=[O:7])[N:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH2:4][CH:3]1[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14]
Reactant: NO
Reactant: CCCCCN1CC(C(=O)OC(C)(C)C)=C(O)C1=O
Agent: Cl
Solvent: c1ccncc1
Product: CCCCCN1CC(C(=O)OC(C)(C)C)C(=NO)C1=O
Reaction time: 36 h
Yield: 89.2 %

Procedure:
To a mechanically stirred solution of the title compound of Example F (17.5 g, 0.065 mol) in 60 ml of pyridine was added hydroxylamine hydrochloride (5.41 g, 0.078 mol) and resulting solution was stirred for 36 h. Evaporation of the solvent afforded a light yellow oil which was chromatographed on silica gel eluting with 3% EtOH/CH2Cl2 to give the title compound (16.48 g, 89%) as a white solid: Anal calcd for C14H24N2O4 : C, 59.14, H, 8.51; N, 9.85. Found C, 58.91; H, 8.48; N, 9.71. MS calcd for C14H24N2O4 284, found 284. DSC=131.0°-134.7° C. at 93.1 J/g.
Reaction SMILES: [BrH:1].[CH3:2][C:3]([NH:16][CH2:17][C:18]([C:20]1[CH:25]=[CH:24][C:23]([O:26]CC2C=CC=CC=2)=[C:22]([O:34]CC2C=CC=CC=2)[CH:21]=1)=[O:19])([CH3:15])[CH2:4][NH:5][C:6](=[O:14])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[H][H]>C(O)C.[Pd]>[BrH:1].[CH3:15][C:3]([NH:16][CH2:17][C:18]([C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[C:22]([OH:34])[CH:21]=1)=[O:19])([CH3:2])[CH2:4][NH:5][C:6](=[O:14])[CH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: [H][H]
Reactant: CC(C)(CNC(=O)Cc1ccccc1)NCC(=O)c1ccc(OCc2ccccc2)c(OCc2ccccc2)c1
Agent: [Pd]
Agent: Br
Solvent: CCO
Product: CC(C)(CNC(=O)Cc1ccccc1)NCC(=O)c1ccc(O)c(O)c1

Procedure:
A solution of 2-bromo-3',4'-bis(benzyloxy)acetophenone (5.24 g.) and N-(2-amino-2-methylpropyl)-2-phenylacetamide (5.5 g.) in dioxan (25 ml.) was stirred for 2 hours at room temperature. The reaction mixture was diluted with dry ether (200 ml.) and the precipitate of N-(2-amino-2-methylpropyl)-2-phenylacetamide hydrobromide was separated by filtration. The ethereal filtrate was washed with water (3×50 ml.), brine (100 ml.) dried (MgSO4) and then a fresh solution of saturated ethereal hydrogen bromide was added until the solution was just acid. After 18 hours at 0°-5° C. the precipitate which had formed was collected to give 2-[1,1-dimethyl-2-(2-phenylacetamido)ethyl]amino-3',4'-bis(benzyloxy)acetophenone hydrobromide as a solid (6.85 g.) m.p. 155°-160° C. This hydrobromide (5.0 g.) was dissolved in absolute ethanol (300 ml.) and the solution was hydrogenated at atmospheric pressure using 10% w/w palladium-on-carbon (3.0 g.) as catalyst. When the uptake of hydrogen was complete (about 3 hours), the catalyst was removed by filtration and the ethanolic filtrate was evaporated at a temperature below 30° C. to give 2-[1,1-dimethyl-2-(2-phenylacetamido)ethyl]amino-3',4'-dihydroxyacetophenone hydrobromide as a foam (3.7 g.) which was used directly for further acylation.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([C:11]([F:14])([F:13])[F:12])[CH:3]=1.[C:15](Cl)(=O)C(Cl)=O.CO>ClCCl.CN(C)C=O>[CH3:15][O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([F:1])=[CH:3][C:4]=1[C:11]([F:12])([F:13])[F:14]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1ccc(F)cc1C(F)(F)F
Solvent: CN(C)C=O
Solvent: CO
Solvent: ClCCl
Product: COC(=O)c1ccc(F)cc1C(F)(F)F
Reaction time: 2 h
Yield: 65.9 %

Procedure:
A suspension of 4-fluoro-2-trifluoromethylbenzoic acid (25.6 g, 123.0 mmol) in dichloromethane (250 mL) containing a few drops of dimethylformamide was treated dropwise under nitrogen with oxalyl chloride (11.3 mL, 129.5 mmol). After the gas evolution subsided, the reaction mixture was refluxed for an additional 15 minutes. The mixture was cooled and methanol (50 mL) was added. After stirring for 2 hrs, the reaction was concentrated, and the residue was partitioned between dichloromethane and water. The organic phase was washed with saturated aqueous sodium bicarbonate, dried over sodium sulfate, and evaporated to dryness to give 18.0 g of the title compound as a golden oil.