Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH2:15][CH2:16][NH2:17])[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:18](OC(=O)C)(=[O:20])[CH3:19]>N1C=CC=CC=1>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH2:15][CH2:16][NH:17][C:18](=[O:20])[CH3:19])[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1ccc(CCN)cc1OC1CCCC1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: COc1ccc(CCNC(C)=O)cc1OC1CCCC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of crude 2-(3-cyclopentyloxy-4-methoxyphenyl)ethylamine (0.5 g, 2.1 mmol) in pyridine (1.8 mL) under an argon atmosphere was added acetic anhydride (1.25 mL). The resulting solution was stirred at room temperature for 16 h and then concentrated under reduced pressure. The residue was dissolved in methylene chloride, washed with water and dried (sodium sulfate). The solvent was removed in vacuo, the residue was purified by flash chromatography, eluting with 4% methanol/ether, and then triturated with ether to provide the acetamide: m.p. 87°-88° C.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:17]=[C:16]2[C:8]([C:9]3[C:14]([CH2:18][CH2:19][CH2:20][CH3:21])([CH2:15]2)[CH2:13][CH2:12][C:11](=[O:22])[CH:10]=3)=[CH:7][C:6]=1[F:23])(=[O:3])[CH3:2].[Br:24]N1C(=O)CCC1=O>C(Cl)Cl>[C:1]([NH:4][C:5]1[CH:17]=[C:16]2[C:8]([C:9]3[C:14]([CH2:18][CH2:19][CH2:20][CH3:21])([CH2:15]2)[CH2:13][CH2:12][C:11](=[O:22])[C:10]=3[Br:24])=[CH:7][C:6]=1[F:23])(=[O:3])[CH3:2]
Reactant: CCCCC12CCC(=O)C=C1c1cc(F)c(NC(C)=O)cc1C2
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: CCCCC12CCC(=O)C(Br)=C1c1cc(F)c(NC(C)=O)cc1C2
Reaction time: 1 h
Yield: 122.3 %

Procedure:
The product from step 1 (1.1 g, approx. 3.5 mmol) was dissolved in anhydrous CH2Cl2 (11 mL) and the solution was purged with N2, cooled in an ice bath, and treated with N-bromosuccinimide (0.498 g, 2.8 mmol). After stirring at 0–5° C. for one hour, the reaction mixture was partitioned between water (150 mL) and EtOAc (150 mL). The organic portion was washed with aqueous 5% NaHCO3 and brine, dried over MgSO4, filtered, and evaporated under vacuum to provide crude 7-(acetylamino)-4-bromo-9a-butyl-6-fluoro-1,2,9,9a-tetrahydro-3H-fluoren-3-one (1.35 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[CH2:13])[CH2:9][CH2:10][CH2:11][OH:12])=[CH:4][CH:3]=1.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>ClCCl.C(OCC)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[CH2:13])[CH2:9][CH2:10][CH:11]=[O:12])=[CH:6][CH:7]=1
Reactant: C=C(CCCO)c1ccc(Cl)cc1
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCOCC
Product: C=C(CCC=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 47.8 %

Procedure:
A mixture of 4-(4-chlorophenyl)pent-4-en-1-ol (5.5 g) and pyridinium dichromate (14.62 g) in dichloromethane (50 ml) was stirred at room temperature for 24 hours. The mixture was diluted with diethyl ether and the solid material was filtered off. The filtrate was washed with water, dried over magnesium sulfate, and concentrated under reduced pressure to give 4-(4-chlorophenyl)pent-4-enal (2.6 g, 48%) as a yellow oil, 1H nmr (CDCl3): 9.75 (1H, broad singlet, CHO), 1R (film): 1720 cm-1.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][N:15]([CH3:27])[C:16](=[O:26])[CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH:9]=2)=[CH:4][CH:3]=1.[C:28](O)(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[N:31][CH:30]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.O>[CH3:27][N:15]([CH2:14][C:10]1[CH:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:1][C:28]([C:29]3[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=3)=[O:35])=[CH:3][CH:4]=2)[CH:13]=[CH:12][CH:11]=1)[C:16](=[O:26])[CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:23])([CH3:24])[CH3:22]
Reactant: O=C(O)c1cccnc1
Reactant: CN(Cc1cccc(-c2ccc(N)cc2)c1)C(=O)CNC(=O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CN(Cc1cccc(-c2ccc(NC(=O)c3cccnc3)cc2)c1)C(=O)CNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 20 h
Yield: 85.1 %

Procedure:
tert-Butyl (2-{[(4′-aminobiphenyl-3-yl)methyl](methyl)amino}-2-oxoethyl)carbamate (300 mg) was dissolved in DMF (6 ml), and nicotinic acid (150 mg), WSC hydrochloride (233 mg), and HOBt (165 mg) were added thereto, followed by stirring at room temperature for 20 hours. Water was added thereto, followed by extraction with EtOAc. The organic layer was dried over MgSO4, and then the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (CHCl3/MeOH=20/1) to obtain tert-butyl {2-[methyl({4′-[(pyridin-3-ylcarbonyl)amino]biphenyl-3-yl}methyl)amino]-2-oxoethyl}carbamate (328 mg).
Reaction SMILES: [CH3:1][C:2]1[N:7]([C:8]2[N:9]([CH3:13])[N:10]=[CH:11][CH:12]=2)[CH:6]=[C:5]([C:14]([OH:16])=[O:15])[C:4](=[O:17])[CH:3]=1.S(Cl)(Cl)=O.[CH3:22]O>>[CH3:22][O:15][C:14]([C:5]1[C:4](=[O:17])[CH:3]=[C:2]([CH3:1])[N:7]([C:8]2[N:9]([CH3:13])[N:10]=[CH:11][CH:12]=2)[CH:6]=1)=[O:16]
Reactant: Cc1cc(=O)c(C(=O)O)cn1-c1ccnn1C
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cn(-c2ccnn2C)c(C)cc1=O
Temperature: 70 °C
Reaction time: 1.5 h

Procedure:
To a solution of preparation 4a (1.8 g, 90% purity, 6.95 mmol) in methanol (5 mL) is added slowly thionyl chloride (1.64 g, 13.8 mmol) at 0° C. The reaction mixture is stirred at 70° C. for 1.5 h, concentrated under reduced pressure and purified by reversed-phase HPLC (Gilson: Sunfire, 30° C., gradient of acetonitrile in water+0.1% formic acid). Yield: 199 mg (12% of theory). ESI mass spectrum: [M+H]+=248; r.t. HPLC: 0.56 min (Z018_S04).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[C:7]([O:12][CH3:13])[C:3]=1[C:4](O)=[O:5].CN(C1C=CC=CN=1)C.S(Cl)([Cl:25])=O>C(Cl)Cl>[Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[C:7]([O:12][CH3:13])[C:3]=1[C:4]([Cl:25])=[O:5]
Reactant: COc1cc(Cl)cc(Cl)c1C(=O)O
Reactant: O=S(Cl)Cl
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Product: COc1cc(Cl)cc(Cl)c1C(=O)Cl
Reaction time: 15 h
Yield: 55 %

Procedure:
26.0 g. (0.117 mol) 2,4-Dichloro-6-methoxybenzoic acid were dissolved in 50 ml. anhydrous methylene chloride and, after the addition of 0.1 g. dimethylaminopyridine, 50 ml. thionyl chloride were added dropwise thereto at ambient temperature. After stirring for 15 hours, the reaction mixture was evaporated and the residue distilled. Yield: 55% of theory; b.p. 118-124° C./0.1 mm.Hg.
Reaction SMILES: [CH2:1]([C@@H:8]1[NH:13][CH2:12][CH2:11][N:10]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:15]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O:29][C:30](=O)[CH2:31][C:32]1[O:36][N:35]=[C:34]([CH3:37])[N:33]=1>>[CH2:1]([C@H:8]1[CH2:9][N:10]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:15]=2)[CH2:11][CH2:12][N:13]1[C:30](=[O:29])[CH2:31][C:32]1[O:36][N:35]=[C:34]([CH3:37])[N:33]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)Cc1nc(C)no1
Reactant: COc1ccc(N2CCN[C@@H](Cc3ccccc3)C2)cc1OC1CCCC1
Product: COc1ccc(N2CCN(C(=O)Cc3nc(C)no3)[C@@H](Cc3ccccc3)C2)cc1OC1CCCC1
Yield: 34 %

Procedure:
Prepared using the same procedure described in Example 275 from (S)-3-benzyl-1-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazine and (3-methyl-[1,2,4]oxadiazol-5-yl)-acetic acid methyl ester with heating for 2 days to afford the title compound as tan solid (65 mg, 34%). LC/MS (Method B) 4.05 min, [M+1]+ 491.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:10])[NH2:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:11][C:12]1[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=1B(O)O.C(N(CC)CC)C>ClCCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:1]([O:5][C:6]([N:8]([CH3:10])[NH:9][C:16]1[CH:15]=[CH:14][CH:13]=[C:12]([Cl:11])[C:17]=1[Cl:18])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)c1cccc(Cl)c1Cl
Reactant: CN(N)C(=O)OC(C)(C)C
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: CN(Nc1cccc(Cl)c1Cl)C(=O)OC(C)(C)C
Temperature: 50 °C
Yield: 39.1 %

Procedure:
A mixture of N-methyl-hydrazinecarboxylic acid tert-butyl ester (Intermediate 1; 1.00 g, 6.8 mmol), 2,3-dichlorophenylboronic acid (Lancaster; 1.29 g, 6.8 mmol), copper(II) acetate (1.24 g, 6.8 mmol) and triethylamine (960 μL, 6.8 mmol) in 1,2-dichloroethane (15 mL) was heated in an oil bath at 50° C. for 3 h. The mixture was allowed to cool, and it was then adsorbed onto silica gel and purified by chromatography using an ISCO 40 g column, eluting with 10% ethyl acetate/hexanes, to give N′-(2,3-dichloro-phenyl)-N-methyl-hydrazinecarboxylic acid tert-butyl ester (775 mg, 39%) as a solid.
Reaction SMILES: [O:1]=[C:2]1[C@H:7]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([Si:15]([CH2:20]C)([CH2:18]C)[CH2:16]C)[CH:10]=2)[N:6](C(OC(C)(C)C)=O)[C@@H:5]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C@@H:4]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[O:3]1.C(O)(C(F)(F)F)=O.CCN(CC)CC>C(Cl)Cl>[O:1]=[C:2]1[C@H:7]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([Si:15]([CH3:16])([CH3:18])[CH3:20])[CH:10]=2)[NH:6][C@@H:5]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[C@@H:4]([C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[O:3]1
Reactant: CC[Si](CC)(CC)c1cccc(C[C@H]2C(=O)O[C@H](c3ccccc3)[C@H](c3ccccc3)N2C(=O)OC(C)(C)C)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: C[Si](C)(C)c1cccc(C[C@@H]2N[C@@H](c3ccccc3)[C@@H](c3ccccc3)OC2=O)c1
Yield: 92.4 %

Procedure:
According to example 82, 2.47 g of tert-butyl (2R, 3S, 5S)-6-oxo-2,3-diphenyl-5-(3-(triethylsilyl)benzyl)-4-morpholinecarboxylate was treated with 4.1 mL of TFA in 40 mL of CH2Cl2 for 3 h. Neutralization with 8 mL of Et3N and work-up in the usual manner gave a thick oil. Purification of the crude material by flash chromatography on 80 g of silica gel (85:15 hexane:EtOAc) afforded 1.70 g (83%) of (2R, 3S, 5S)-6-oxo-2,3-diphenyl-5-(3-(trimethylsilyl)benzyl)morpholine as a white crystalline solid, m.p. 94-95° C.
Reaction SMILES: [CH3:1][C:2]([CH3:29])([CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([S:15]([N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)(=[O:17])=[O:16])=[CH:12][CH:13]=2)[C:8]2([O:27][CH2:26][CH2:25][CH2:24][O:23]2)[C:7]1=O)[C:3]#[N:4].N.C1COCC1.[H][H]>[Ni].CCO>[CH3:1][C:2]1([CH3:29])[CH2:5][N:6]2[C:14]3[CH:13]=[CH:12][C:11]([S:15]([N:18]4[CH2:19][CH2:20][CH2:21][CH2:22]4)(=[O:16])=[O:17])=[CH:10][C:9]=3[C:8]3([O:27][CH2:26][CH2:25][CH2:24][O:23]3)[C:7]2=[N:4][CH2:3]1
Reactant: CC(C)(C#N)CN1C(=O)C2(OCCCO2)c2cc(S(=O)(=O)N3CCCC3)ccc21
Reactant: [H][H]
Agent: [Ni]
Agent: N
Solvent: C1CCOC1
Solvent: CCO
Product: CC1(C)CN=C2N(C1)c1ccc(S(=O)(=O)N3CCCC3)cc1C21OCCCO1
Temperature: 135 °C
Yield: 45.1 %

Procedure:
A mixture of 2,2-dimethyl-3-[2′-oxo-5′-(pyrrolidin-1-ylsulfonyl)spiro[1,3-dioxane-2,3′-indol]-1′(2′H)-yl]propanenitrile (0.69 g, 1.64 mmol) and wet Raney Nickel (0.70 g) in 2M EtOH.NH3 (50 mL) and THF (20 mL) was hydrogenated in a Parr hydrogenation bottle (500 mL) at 541 b/in2 hydrogen for 67 hr. The Raney Nickel was removed by filtration through Sulka Floc and the filtrate was poured into a steel pressure vessel, diluted with 2M EtOH.NH3 (50 mL) and THF (20 mL) and heated at 135° C. for 22 hr. The reaction was cooled to room temperature and concentrated. The crude product was purified on Biotage KP silica gel eluting with CH2Cl2/CH3OH/NH4OH (98.5/1/.05) to give the title compound as a white solid (0.300 g, 45% yield). NMR: consistent. MS: (API-ES+) m/z 406 [M+H].
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C@H:10]([CH2:14][C:15]1[CH:24]=[CH:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=1)[C:11](O)=[O:12])[CH3:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].ON1C2N=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[CH2:47]([N:54]([C:56]([NH:58][CH2:59][CH3:60])=[O:57])[NH2:55])[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1.C(N(C(C)C)CC)(C)C>ClCCl>[CH2:47]([N:54]([C:56]([NH:58][CH2:59][CH3:60])=[O:57])[NH:55][C:11](=[O:12])[C@H:10]([N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])[CH3:9])[CH2:14][C:15]1[CH:24]=[CH:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=1)[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1
Reactant: CCNC(=O)N(N)Cc1ccccc1
Reactant: CN(C(=O)OC(C)(C)C)[C@H](Cc1ccc2ccccc2c1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCNC(=O)N(Cc1ccccc1)NC(=O)[C@@H](Cc1ccc2ccccc2c1)N(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90.1 %

Procedure:
##STR188## To a solution of (2R)-2-(N-tert-butoxycarbonyl-N-methylamino)-3-(2-naphthyl)propionic acid (2.6 g, 7.9 mmol) in dichloromethane (20 ml) was added 1-hydroxy-7-azabenzotriazole (1.1 g, 8.0 mmol) and 1-ethyl-3-dimethylaminopropyl carbodiimide hydrochloride (1.6 g, 8.6 mmol) and the mixture was stirred at 30 min at room temperature. Then 2-benzyl-4-ethylsemicarbazide (1.3 g, 6.6 mmol) and diisopropylethylamine (1.5 ml, 8.6 mmol) in dichloromethane (20 ml) were added and the mixture was stirred overnight. The mixture was washed with saturated sodium bicarbonate (2×50 ml), dried (magnesium sulfate) and concentrated in vacuo. The obtained product was chromatographed on silica (100 g) with petrol ether/ethyl acetate 1:1 to give 3.0 g (90%) of 2-benzyl-1-[(2R)-2-(N-(tert-butoxycarbonyl)-N-methylamino)-3-(2-naphtyl)propionyl]-4-ethylsemicarbazide.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:10]=[C:11]([CH2:15][C:16]([NH2:18])=[O:17])[CH:12]=[CH:13][CH:14]=2)[N:3]=1.[Cl:19][C:20]1[NH:21][C:22]2[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=2[N:24]=1.C(=O)([O-])[O-].[K+].[K+]>C(C#N)(C)=O>[Cl:19][C:20]1[N:24]([C:2]2[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]3[CH:10]=[C:11]([CH2:15][C:16]([NH2:18])=[O:17])[CH:12]=[CH:13][CH:14]=3)[N:3]=2)[C:23]2[CH:25]=[CH:26][CH:27]=[CH:28][C:22]=2[N:21]=1
Reactant: Clc1nc2ccccc2[nH]1
Reactant: NC(=O)Cc1cccc(Nc2ncnc(Cl)n2)c1
Agent: CC(=O)C#N
Agent: O=C([O-])[O-]
Agent: [K+]
Product: NC(=O)Cc1cccc(Nc2ncnc(-n3c(Cl)nc4ccccc43)n2)c1
Temperature: 70 °C

Procedure:
2-[3-(4-Chloro-[1,3,5]triazin-2-ylamino)-phenyl]-acetamide (136.5 mg, 0.5177 mmol) is combined with 2-chlorobenzimidazole (86.9 mg, 0.5177 mmol) and potassium carbonate (93 mg, 0.673 mmol) in AcCN (5 ml) and heated at 65-75° C. for 2 to 20 hours. The reaction mix is cooled to RT and the inorganic salts were filtered off. The AcCN solution is concentrated down under reduced pressure. The crude is purified on a silica gel column with an EtOAc/hexane to MeOH/CH2Cl2 elution gradient, giving 2-{3-[4-(2-chloro-benzoimidazol-1-yl)-[1,3,5]triazin-2-ylamino]-phenyl}acetamide.
Reaction SMILES: [CH2:1]([C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:15]([OH:17])=O)[CH:13]=2)[CH:8]=[CH:7][N:6]=1)[CH2:2][CH2:3][CH3:4].C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:51][C@@H:52]([CH2:66][C:67]1[CH:72]=[C:71]([F:73])[CH:70]=[C:69]([F:74])[CH:68]=1)[C@H:53]([OH:65])[CH2:54][NH:55][CH2:56][C:57]1[CH:62]=[CH:61][CH:60]=[C:59]([CH2:63][CH3:64])[CH:58]=1>C(Cl)Cl>[CH2:1]([C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:15]([NH:51][C@@H:52]([CH2:66][C:67]3[CH:68]=[C:69]([F:74])[CH:70]=[C:71]([F:73])[CH:72]=3)[C@H:53]([OH:65])[CH2:54][NH:55][CH2:56][C:57]3[CH:62]=[CH:61][CH:60]=[C:59]([CH2:63][CH3:64])[CH:58]=3)=[O:17])[CH:13]=2)[CH:8]=[CH:7][N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nccc2ccc(C(=O)O)cc12
Reactant: CCc1cccc(CNC[C@@H](O)[C@@H](N)Cc2cc(F)cc(F)c2)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCCc1nccc2ccc(C(=O)N[C@@H](Cc3cc(F)cc(F)c3)[C@H](O)CNCc3cccc(CC)c3)cc12
Reaction time: 0.5 h
Yield: 72.6 %

Procedure:
To a solution of 1-butylisoquinoline-7-carboxylic acid (79 mg, 0.26 mmol) and N,N-diisopropylethylamine (150 μL, 0.86 mmol) in methylene chloride (1.8 mL) was added HBTU (100 mg, 0.264 mmol) and the reaction mixture stirred for 0.5 h. To this was added a solution of (2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-[(3-ethylbenzyl)amino]butan-2-ol (107 mg, 0.264 mmol) in methylene chloride (1.8 mL) containing N,N-diisopropylethylamine (150 μL, 0.86 mmol). The reaction mixture was then stirred at room temperature overnight. The reaction mixture was diluted with methylene chloride, washed with saturated sodium bicarbonate, and saturated sodium chloride. The organic layer was then dried (sodium sulfate), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica, 93:7 chloroform/methanol) gave 1-butyl-N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}isoquinoline-7-carboxamide (103 mg): mp 109-110° C.; ESI MS m/z 546 [M+H]+.
Reaction SMILES: OCC(NC(=O)OC(C)(C)C)(C)C.[CH3:14][O:15][CH2:16][CH2:17][O:18][CH2:19][C:20]([NH:23][C:24](=O)OC(C)(C)C)([CH3:22])[CH3:21].C(O)(C(F)(F)F)=O.NC(C)(C)CO.F[C:45]1[C:46](C)=[N:47][C:48]2[C:53]([N:54]=1)=[C:52]([C:55]1[NH:63][C:62]3[CH2:61][CH2:60][NH:59][C:58](=[O:64])[C:57]=3[CH:56]=1)[CH:51]=[CH:50][CH:49]=2>C(Cl)Cl.CS(C)=O.CCOC(C)=O>[CH3:14][O:15][CH2:16][CH2:17][O:18][CH2:19][C:20]([NH:23][C:24]1[C:46]([CH3:45])=[N:47][C:48]2[C:53]([N:54]=1)=[C:52]([C:55]1[NH:63][C:62]3[CH2:61][CH2:60][NH:59][C:58](=[O:64])[C:57]=3[CH:56]=1)[CH:51]=[CH:50][CH:49]=2)([CH3:21])[CH3:22]
Reactant: COCCOCC(C)(C)NC(=O)OC(C)(C)C
Reactant: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1F
Agent: CC(C)(CO)NC(=O)OC(C)(C)C
Agent: CC(C)(N)CO
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: ClCCl
Product: COCCOCC(C)(C)Nc1nc2c(-c3cc4c([nH]3)CCNC4=O)cccc2nc1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 20 %

Procedure:
A solution of the above obtained 0.53 g of 1:1 mixture of tert-butyl (1-hydroxy-2-methylpropan-2-yl)carbamate and tert-butyl (1-(2-methoxyethoxy)-2-methylpropan-2-yl)carbamate in 10 mL of DCM and TFA (1.4 mL, 19.60 mmol) was stirred at RT for 2 h. It was concentrated under reduced pressure. The residue was treated with 10 mL of 1 N NaOH, and extracted with 3×30 mL of EtOAc. The combined organic layers were washed with 5 mL of brine, dried over Na2SO4 and concentrated to give an off-white amorphous solid containing a 1:1 mixture of tert-butyl (1-(2-methoxyethoxy)-2-methylpropan-2-yl)carbamate (317b) [m/z (ESI, +ve) 148.0 (M+H)+] and 2-amino-2-methylpropan-1-ol [m/z (ESI, +ve) 90.0 (M+H)+]. This material was used without further purification. A solution of the above obtained off-white amorphous solid containing a 1:1 mixture of tert-butyl (1-(2-methoxyethoxy)-2-methylpropan-2-yl)carbamate (317b) [m/z (ESI, +ve) 148.0 (M+H)+] and 2-amino-2-methylpropan-1-ol [m/z (ESI, +ve) 90.0 (M+H)+], and 2-(3-fluoro-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (126) (135 mg, 0.45 mmol), and TEA (0.13 mL, 0.91 mmol) in 1.5 mL of DMSO in a sealed glass tube was heated in a microwave at 150° C. for 0.5 h. The reaction mixture was diluted with 75 mL of EtOAc, washed with 5 mL of water followed by 5 mL of brine. The organic layer was dried over Na2SO4 and concentrated. The residue was purified on a silica gel column (1-5% MeOH in DCM) to give 2-(3-((1-(2-methoxyethoxy)-2-methylpropan-2-yl)amino)-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (40 mg, 20% yield) in 92% pure as a yellow crystalline solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.87 (1H, br.), 7.82 (1H, d, J=7.6 Hz), 7.61 (1H, d, J=8.0 Hz), 7.36 (1H, t, J=7.7 Hz), 7.00 (2H, m), 5.92 (1H, br.), 3.71 (2H, s), 3.59 (2H, m), 3.44 (2H, m), 3.20 (3H, s), 3.18 (2H, m), 2.87 (2H, m), 2.55 (3H, s.), 1.54 (6H, s). m/z (ESI, +ve) 424.0 (M+H)+.
Reaction SMILES: C([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13]1[NH:17][C:16]2[CH:18]=[C:19]([C:22]3[CH:54]=[CH:53][C:25]4[C:26]5[CH:32]=[CH:31][C:30]([C:33]6[NH:37][C:36]([C@@H:38]7[CH2:42][CH2:41][CH2:40][N:39]7[C:43]([O:45][CH2:46][C:47]7[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=7)=[O:44])=[N:35][CH:34]=6)=[CH:29][C:27]=5[S:28][C:24]=4[CH:23]=3)[CH:20]=[CH:21][C:15]=2[N:14]=1)=O)(C)(C)C.Cl.[CH3:56][O:57][C:58]([NH:60][C@@H:61]([CH:65]([CH3:67])[CH3:66])C(O)=O)=[O:59].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C)C=O.C(#N)C.CO.[OH-].[Na+].C(OCC)(=O)C.C(O)C>[CH3:56][O:57][C:58]([NH:60][C@@H:61]([CH:65]([CH3:67])[CH3:66])[C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13]1[NH:17][C:16]2[CH:18]=[C:19]([C:22]3[CH:54]=[CH:53][C:25]4[C:26]5[CH:32]=[CH:31][C:30]([C:33]6[NH:37][C:36]([C@@H:38]7[CH2:42][CH2:41][CH2:40][N:39]7[C:43]([O:45][CH2:46][C:47]7[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=7)=[O:44])=[N:35][CH:34]=6)=[CH:29][C:27]=5[S:28][C:24]=4[CH:23]=3)[CH:20]=[CH:21][C:15]=2[N:14]=1)=[O:5])=[O:59]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1c1nc2ccc(-c3ccc4c(c3)sc3cc(-c5cnc([C@@H]6CCCN6C(=O)OCc6ccccc6)[nH]5)ccc34)cc2[nH]1
Reactant: COC(=O)N[C@H](C(=O)O)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc2ccc(-c3ccc4c(c3)sc3cc(-c5cnc([C@@H]6CCCN6C(=O)OCc6ccccc6)[nH]5)ccc34)cc2[nH]1)C(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 50.8 %

Procedure:
A solution of (S)-benzyl 2-(5-(7-(2-((S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-1H-benzo[d]imidazol-6-yl)dibenzo[b,d]thiophen-3-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (0.75 g, 1.0 mmol), concentrated HCl (2.0 mL) and ethanol (12 mL) was heated to 60° C. for one hour. The reaction was concentrated and redissolved in a minimal amount of methanol. An equal volume of dichloromethane was added and the solution was again concentrated. Dichloromethane was added to the resulting residue and concentrated off three more times, until the crude material was a powder. A portion of the crude amine (0.29 g, ˜0.40 mmol) was dissolved in dimethylformamide (3.9 mL). To this solution was added (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (82 mg, 0.47 mmol), HATU (163 mg, 0.43 mmol) and diisopropylethylamine (0.70 mL, 4.0 mmol). The reaction was stirred at room temperature for one hour, and then diluted with acetonitrile (2 mL) and methanol (2 mL). To this solution was added ten drops of 5M aqueous NaOH solution and stirring was continued for 30 minutes. The reaction was diluted with ethyl acetate and the organic layer was washed with water and brine. The combined aqueous washings were extracted three times with ethyl acetate, and the combined organic layers were dried (MgSO4) and concentrated. The crude material was purified by flash column chromatography to yield (S)-benzyl 2-(5-(7-(2-((S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H-benzo[d]imidazol-6-yl)-dibenzo[b,d]thiophen-3-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (0.19 g, ˜60%). LCMS-ESI+: calculated for C45H45N7O5S: 795.95; observed [M+1]+: 796.73.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[N:11]=[CH:10][N:9]([O:12]CC(O)=O)[C:8]=2[CH:17]=1)([O-:3])=[O:2].C(OC(=O)C)C.C1COCC1.[ClH:29]>O>[ClH:29].[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[N:11]=[CH:10][N:9]([OH:12])[C:8]=2[CH:17]=1)([O-:3])=[O:2]
Reactant: O=C(O)COn1cnc2ccc([N+](=O)[O-])cc21
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: O=[N+]([O-])c1ccc2ncn(O)c2c1
Reaction time: 0.5 h

Procedure:
(6-Nitro-benzoimidazol-1-yloxy)-acetic acid (6) A mixture of 6-nitro-benzoimidazol-1-yloxy)-acetic acid ethyl ester (5) (250 mg, 0.94 mmol), THF (5 mL), water (1 mL) and concentrated HCl (1 mL) was heated to reflux for 2 hours. The reaction mixture was evaporated and the crude residue was purified by HPLC (21.2×250 mm Phenomenex Luna C18(2) column; flow rate=20 mL/min; linear gradient 0-100% B over 30 minutes; A Buffer=water with 0.1% TFA, B Buffer=acetonitrile with 0.1% TFA). HPLC solvents removed in vacuo to yield yellow solid. Yield 65 mg (29%).