Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:28])=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH2:13][CH2:14][CH:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH:29](=O)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl.C(=O)([O-])O.[Na+]>O1CCCC1>[CH3:28][C:3]1[C:2]2[N:1]=[C:29]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[N:12]([CH2:13][CH2:14][CH:15]3[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:25])([CH3:27])[CH3:26])=[O:22])[CH2:17][CH2:16]3)[C:11]=2[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[N:4]=1
Reactant: Cc1nc2ccccc2c(NCCC2CCN(C(=O)OC(C)(C)C)CC2)c1N
Reactant: O=Cc1ccccc1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1nc2ccccc2c2c1nc(-c1ccccc1)n2CCC1CCN(C(=O)OC(C)(C)C)CC1
Yield: 69.1 %

Procedure:
A solution of 0.65 g of tert-butyl 4-[2-[(3-amino-2-methylquinolin-4-yl)amino]-ethyl]-1-piperidinecarboxylate, 0.29 g of benzaldehyde and 0.08 g of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone in 5 ml of tetrahydrofuran was stirred at room temperature for 3 days. The reaction mixture was added with saturated aqueous sodium hydrogencarbonate solution and extracted with ethyl acetate. The extract was washed successively with saturated aqueous sodium hydrogencarbonate solution and saturated brine, and dried, and the solvent was evaporated to give a reddish brown liquid. The resulting liquid was purified by silica gel column chromatography using ethyl acetate—n-heptane (1:1) as an eluting solvent, and washed with diisopropyl ether to give 0.55 g of a colorless solid. Recrystallization from diisopropyl ether gave colorless crystals having the melting point of from 146 to 146.5° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[C:5]([C:10]2[CH:11]=[C:12]([NH2:21])[C:13]([NH:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:14][CH:15]=2)=[CH:4][N:3]=1.[N:22]1([C:27]2[CH:34]=[CH:33][CH:32]=[CH:31][C:28]=2[CH:29]=O)[CH:26]=[N:25][CH:24]=[N:23]1.OOS([O-])=O.[K+].S([O-])([O-])(=O)=S.[Na+].[Na+]>CN(C=O)C.O.CCOC(C)=O>[C:17]([N:16]1[C:13]2[CH:14]=[CH:15][C:10]([C:5]3[C:6]([O:8][CH3:9])=[N:7][C:2]([NH2:1])=[N:3][CH:4]=3)=[CH:11][C:12]=2[N:21]=[C:29]1[C:28]1[CH:31]=[CH:32][CH:33]=[CH:34][C:27]=1[N:22]1[CH:26]=[N:25][CH:24]=[N:23]1)([CH3:18])([CH3:20])[CH3:19]
Reactant: COc1nc(N)ncc1-c1ccc(NC(C)(C)C)c(N)c1
Reactant: O=Cc1ccccc1-n1cncn1
Agent: O=S([O-])([O-])=S
Agent: O=S([O-])OO
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: COc1nc(N)ncc1-c1ccc2c(c1)nc(-c1ccccc1-n1cncn1)n2C(C)(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 37 %

Procedure:
To a round bottom flask is added 4-(2-amino-4-methoxy-pyrimidin-5-yl)-N1-tert-butyl-benzene-1,2-diamine (118 mg, 0.411 mmol) in DMF (4 mL) and water (1 mL), followed by the addition of 2-1,2,4-triazol-1-yl-benzaldehyde (78 mg, 0.45 mmol) and oxone (51 mg, 0.443 mmol). The reaction mixture is stirred at room temperature for 4 hours. Sat. sodium thiosulfate (10 mL) is added. The reaction mixture is diluted with EtOAc. The organic layer is separated, washed with water then brine, dried with Na2SO4, filtered and concentrated. The residue is loaded into a silica gel column. The column is eluted with 0-4% 7M NH3 in MeOH/CH2Cl2. The product fractions are collected and concentrated to afford the title compound (67 mg, 37%) as a light brown solid. LCMS (ESMS): m/z 441.73 (M++1)
Reaction SMILES: C([O:8][C:9]([C@@H:11]([N:16]1[CH:19]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:18]([N:26]=[N+]=[N-])[C:17]1=[O:29])[CH2:12][CH:13]([CH3:15])[CH3:14])=[O:10])C1C=CC=CC=1>[Pd].C(O)C>[NH2:26][C@H:18]([C:17]([NH:16][C@H:11]([C:9]([OH:10])=[O:8])[CH2:12][CH:13]([CH3:14])[CH3:15])=[O:29])[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC(C)C[C@@H](C(=O)OCc1ccccc1)N1C(=O)C(N=[N+]=[N-])C1c1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CC(C)C[C@H](NC(=O)[C@@H](N)Cc1ccccc1)C(=O)O

Procedure:
1-(1(S)-Benzyloxycarbonyl-3-methylbutyl)-3-azido-4-phenylazetidin-2-one (200 mg., 0.51 mmol) was hydrogenated in 10 ml. of ethanol at 50° C. for 19 hours under ambient pressure using a 10% Pd-C (270 mg.) as a catalyst to give D/L-phenylalanyl-L-leucine quantitatively.
Reaction SMILES: [C:1]1([CH2:11][N:12]2[CH2:17][CH2:16][CH:15]([CH2:18][N:19](COCC[Si](C)(C)C)[C:20]3[N:24](COCC[Si](C)(C)C)[C:23]4[CH:33]=[CH:34][C:35]([C:37](=[O:40])[CH2:38][CH3:39])=[CH:36][C:22]=4[N:21]=3)[CH2:14][CH2:13]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C(OCC)(=O)C>CN(C)C=O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[C:1]1([CH2:11][N:12]2[CH2:17][CH2:16][CH:15]([CH2:18][NH:19][C:20]3[NH:24][C:23]4[CH:33]=[CH:34][C:35]([C:37](=[O:40])[CH2:38][CH3:39])=[CH:36][C:22]=4[N:21]=3)[CH2:14][CH2:13]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: CCC(=O)c1ccc2c(c1)nc(N(COCC[Si](C)(C)C)CC1CCN(Cc3cccc4ccccc34)CC1)n2COCC[Si](C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CCC(=O)c1ccc2[nH]c(NCC3CCN(Cc4cccc5ccccc45)CC3)nc2c1
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
After dissolving 1-[2-[(1-naphthalen-1-ylmethyl-piperidin-4-ylmethyl)-(2-trimethylsilanyl-ethoxymethyl)-amino]-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzimidazol-5-yl]-propan-1-one (32 mg, 0.047 mmol) in anhydrous dimethylformamide (1 ml), tetrabutylammonium fluoride (0.8 ml, 1.0 M tetrahydrofuran solution) and water (5 μl) were added, and the mixture was stirred at 100° C. for 2 hours and 30 minutes. Water and ethyl acetate were added, and extraction was performed with ethyl acetate. The organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the obtained residue was purified by thin-layer silica gel chromatography (dichloromethane/methanol/TEA=85/10/1). The purified product was further purified by preparative HPLC and thin-layer silica gel chromatography (dichloromethane/methanol=8/2) to obtain 1-{2-[(1-naphthalen-1-ylmethyl-piperidin-4-ylmethyl)-amino]-1H-benzimidazol-5-yl}-propan-1-one.
Reaction SMILES: [S:1]([N:11]1[C:15]2[N:16]=[CH:17][C:18]3[N:19]([CH:20]=[N:21][C:22]=3[C:23]3[CH:28]=[CH:27][C:26]([C:29]([OH:32])([CH3:31])[CH3:30])=[CH:25][CH:24]=3)[C:14]=2[CH:13]=[CH:12]1)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].C1C(=O)N([Br:40])C(=O)C1>CN(C=O)C.O>[Br:40][C:20]1[N:19]2[C:14]3[CH:13]=[CH:12][N:11]([S:1]([C:4]4[CH:5]=[CH:6][C:7]([CH3:8])=[CH:9][CH:10]=4)(=[O:2])=[O:3])[C:15]=3[N:16]=[CH:17][C:18]2=[C:22]([C:23]2[CH:28]=[CH:27][C:26]([C:29]([OH:32])([CH3:30])[CH3:31])=[CH:25][CH:24]=2)[N:21]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c2ncc2c(-c4ccc(C(C)(C)O)cc4)ncn23)cc1
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2ccc3c2ncc2c(-c4ccc(C(C)(C)O)cc4)nc(Br)n23)cc1
Reaction time: 0.25 h
Yield: 85 %

Procedure:
2-(4-(6-Tosyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-3-yl)phenyl)propan-2-ol (0.285 g, 0.638 mmol, prepared using J.3 from Example #2, Step B with ethyl formate, L.2 with POCl3, AB and D with Preparation #H.1) was dissolved in DMF (3 mL) then treated with NBS (0.114 g, 0.638 mmol). The mixture was stirred for about 15 min then diluted with water (20 mL). The solid was collected by filtration then washed with water (5 mL). The material was dried under vacuum at about 70° C. to a constant weight to give 2-(4-(1-bromo-6-tosyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-3-yl)phenyl)propan-2-ol (0.285 g, 85%): LC/MS (Table 2, Method b) Rt=2.58 min; MS m/z 527 (M+H)+.
Reaction SMILES: C([N:8]1[CH2:31][CH2:30][C:11]2([C:15](=[O:16])[N:14]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH:24]([CH3:29])[C:25]([F:28])([F:27])[F:26])=[CH:19][CH:18]=3)[CH2:13][CH2:12]2)[CH:10]([OH:32])[CH2:9]1)C1C=CC=CC=1>[OH-].[OH-].[Pd+2]>[OH:32][CH:10]1[CH2:9][NH:8][CH2:31][CH2:30][C:11]21[C:15](=[O:16])[N:14]([C:17]1[CH:22]=[CH:21][C:20]([O:23][CH:24]([CH3:29])[C:25]([F:28])([F:26])[F:27])=[CH:19][CH:18]=1)[CH2:13][CH2:12]2
Reactant: CC(Oc1ccc(N2CCC3(CCN(Cc4ccccc4)CC3O)C2=O)cc1)C(F)(F)F
Agent: [Pd+2]
Agent: [OH-]
Product: CC(Oc1ccc(N2CCC3(CCNCC3O)C2=O)cc1)C(F)(F)F

Procedure:
The title compound was prepared in analogy to example 2 step A from a mixture of (5 SR,6RS)-8-benzyl-6-hydroxy-2-[4-((rac)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-2,8-diaza-spiro[4.5]decan-1-one and Pearlman's catalyst under an atmosphere of hydrogen. Light brown solid. MS (ESI): 359.1 (MH+)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:5]([O:10][CH3:11])=[C:6]([CH2:8]Br)[CH:7]=1.[N+:16]([C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=1)([O-:18])=[O:17].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[CH:7]=[C:6]([CH2:8][O:25][C:22]2[CH:23]=[CH:24][C:19]([N+:16]([O-:18])=[O:17])=[CH:20][CH:21]=2)[C:5]([O:10][CH3:11])=[C:4]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH:3]=1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: COc1c(CBr)cc(Br)cc1C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1c(COc2ccc([N+](=O)[O-])cc2)cc(Br)cc1C(C)(C)C
Temperature: 50 °C
Reaction time: 2 h
Yield: 81.7 %

Procedure:
step 2—A mixture of 114 (0.20 g, 0.59 mmol), 4-nitrophenol (0.082 g, 0.59 mmol) and K2CO3 (0.12 g, 0.89 mmol) in DMF was stirred at 50° C. for 2 h. The mixture was cooled to RT and partitioned between water and Et2O. The ether layer was concentrated, and the crude residue was purified by SiO2 chromatography eluting with EtOAc/hexane to afford 0.19 g (83%) of 5-bromo-1-tert-butyl-2-methoxy-3-(4-nitro-phenoxymethyl)benzene (116) as a white solid.
Reaction SMILES: [NH2:1][N:2]1[CH:6]=[CH:5][C:4]([Br:7])=[C:3]1[C:8]([O:10][CH3:11])=[O:9].[C:12]([O:16][C:17]([NH:19][C@@H:20]([CH3:24])[C:21](O)=[O:22])=[O:18])([CH3:15])([CH3:14])[CH3:13]>>[Br:7][C:4]1[CH:5]=[CH:6][N:2]([NH:1][C:21](=[O:22])[C@@H:20]([NH:19][C:17]([O:16][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:18])[CH3:24])[C:3]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: COC(=O)c1c(Br)ccn1N
Product: COC(=O)c1c(Br)ccn1NC(=O)[C@H](C)NC(=O)OC(C)(C)C
Yield: 60.5 %

Procedure:
The title compound was prepared following the experimental procedure described in preparation 20a from 6.1 g (18.38 mmol) of methyl 1-amino-3-bromo-1H-pyrrole-2-carboxylate and 3.5 g (28.50 mmol) of (S)-2-(tert-butoxycarbonylamino)propanoic acid (purchased from Aldrich). The crude product was purified by flash chromatography in hexane/ethyl acetate (0 to 25%) to afford 4.34 g (61% yield) of the title compound.
Reaction SMILES: [NH2:1][CH:2]1[C:8](=[O:9])[N:7]([CH3:10])[C:6]2[CH:11]=[CH:12][C:13]([Cl:15])=[CH:14][C:5]=2[N:4]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:3]1=[O:22].[NH:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[C:24]1[C:32](O)=[O:33].ON1C2C=CC=CC=2N=N1>ClCCl>[Cl:15][C:13]1[CH:12]=[CH:11][C:6]2[N:7]([CH3:10])[C:8](=[O:9])[CH:2]([NH:1][C:32]([C:24]3[NH:23][C:31]4[C:26]([CH:25]=3)=[CH:27][CH:28]=[CH:29][CH:30]=4)=[O:33])[C:3](=[O:22])[N:4]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:5]=2[CH:14]=1
Reactant: O=C(O)c1cc2ccccc2[nH]1
Reactant: CN1C(=O)C(N)C(=O)N(c2ccccc2)c2cc(Cl)ccc21
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CN1C(=O)C(NC(=O)c2cc3ccccc3[nH]2)C(=O)N(c2ccccc2)c2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 59.3 %

Procedure:
A mixture of 1.58 g (5 mmoles) of 3-amino-2,4-dioxo-7-chloro-1-methyl-5-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine, 0.89 g of 2-indol carboxylic acid, 1.05 g of 1-ethyl-3-(3-dimethylamino)-propyl carbodiimide, 1.02 g of 1-hydroxy benzotriazole and 50 ml of dichloromethane was stirred at ambient temperature for 18 hours and the precipitate formed was separated and washed with dichloromethane to obtain 1.36 g of the expected product melting at about 280° C. (yield 59%)
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([N:14]1[CH2:19][CH2:18][CH:17]([CH3:20])[CH2:16][CH2:15]1)=[O:13])[CH:6]=[CH:5]2.[CH3:21][C:22]([CH3:32])([CH2:25][N:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)[CH2:23]O>>[CH3:23][C:22]([CH3:32])([CH2:25][N:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)[CH2:21][O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([N:14]1[CH2:15][CH2:16][CH:17]([CH3:20])[CH2:18][CH2:19]1)=[O:13])[CH:6]=[CH:5]2
Reactant: CC(C)(CO)CN1CCCCC1
Reactant: CC1CCN(C(=O)c2ccc3cc(O)ccc3c2)CC1
Product: CC1CCN(C(=O)c2ccc3cc(OCC(C)(C)CN4CCCCC4)ccc3c2)CC1

Procedure:
The title compound was synthesised from (6-hydroxy-naphthalen-2-yl)-(4-methyl-piperidin-1-yl)-methanone (intermediate B) and 2,2-dimethyl-3-piperidin-1-yl-propan-1-ol (commercially available) according to the procedure described for the synthesis of Example 1. MS (m/e): 423.1 (MH+, 100%)
Reaction SMILES: [CH:1]1([CH2:7][N:8]2[CH2:12][CH2:11][CH2:10][C@H:9]2[CH2:13][NH2:14])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[C:17]([CH:25]=O)[CH:16]=1.[Na]>ClCCl>[CH:1]1([CH2:7][N:8]2[CH2:12][CH2:11][CH2:10][C@H:9]2[CH2:13][NH:14][CH2:25][C:17]2[CH:16]=[N:15][C:24]3[C:19]([CH:18]=2)=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: NC[C@@H]1CCCN1CC1CCCCC1
Reactant: O=Cc1cnc2ccccc2c1
Agent: [Na]
Solvent: ClCCl
Product: c1ccc2ncc(CNC[C@@H]3CCCN3CC3CCCCC3)cc2c1
Yield: 9.1 %

Procedure:
Experimental condition analogous to Example 1, from (S)—C-(1-cyclohexylmethyl-pyrrolidin-2-yl)-methylamine 0.25 g (1.3 mmol), quinoline-3-carbaldehyde 0.2 g (1.3 mmol), sodium triacethoxyborohydride 0.53 g (2.6 mmol), and molecular sieve in 8 mL dichloromethane. Yield to 40 mg of compound.
Reaction SMILES: [ClH:1].Cl.[CH:3]1([NH:6][C:7]([C:9]2[C:17]3[CH:16]=[C:15]([C:18]4[C:23](F)=[CH:22][N:21]=[C:20]([NH:25][CH2:26][CH2:27][CH2:28][CH:29]5[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]5)[N:19]=4)[S:14][C:13]=3[CH:12]=[CH:11][CH:10]=2)=[O:8])CC1.[CH3:36]NC(C1C2C=C(C3C(C)=CN=C(NCCCC4CCNCC4)N=3)SC=2C=CC=1)=O>>[ClH:1].[ClH:1].[CH3:3][NH:6][C:7]([C:9]1[C:17]2[CH:16]=[C:15]([C:18]3[C:23]([CH3:36])=[CH:22][N:21]=[C:20]([NH:25][CH2:26][CH2:27][CH2:28][CH:29]4[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]4)[N:19]=3)[S:14][C:13]=2[CH:12]=[CH:11][CH:10]=1)=[O:8]
Reactant: CNC(=O)c1cccc2sc(-c3nc(NCCCC4CCNCC4)ncc3C)cc12
Reactant: CN1CCC(CCCNc2ncc(F)c(-c3cc4c(C(=O)NC5CC5)cccc4s3)n2)CC1
Agent: Cl
Product: CNC(=O)c1cccc2sc(-c3nc(NCCCC4CCN(C)CC4)ncc3C)cc12

Procedure:
Using the method of 2-{5-fluoro-2-[3-(1-methylpiperidin-4-yl)-propylamino]-pyrimidin-4-yl}-benzo[b]thiophene-4-carboxylic acid cyclopropylamide di-hydrochloride, the title compound is synthesized from 2-[5-methyl-2-(3-piperidin-4-yl-propylamino)-pyrimidin-4-yl]-benzo[b]thiophene-4-carboxylic acid methylamide and isolated as a yellow solid. ES+(m/z) 438 [M(free base)+H].
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10](=[O:17])[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].Br[CH2:25][C:26]([C:28]1[CH:37]=[CH:36][CH:35]=[C:34]2[C:29]=1[N:30]=[C:31]([NH:39][C:40]1([CH3:43])[CH2:42][CH2:41]1)[C:32]([CH3:38])=[N:33]2)=[O:27].C1COCC1>[NH4+].[Cl-].CCO>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10](=[O:17])[CH:11]([CH2:25][C:26]([C:28]1[CH:37]=[CH:36][CH:35]=[C:34]2[C:29]=1[N:30]=[C:31]([NH:39][C:40]1([CH3:43])[CH2:42][CH2:41]1)[C:32]([CH3:38])=[N:33]2)=[O:27])[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CCOC(=O)CC(=O)CNC(=O)OC(C)(C)C
Reactant: Cc1nc2cccc(C(=O)CBr)c2nc1NC1(C)CC1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)C(CC(=O)c1cccc2nc(C)c(NC3(C)CC3)nc12)C(=O)CNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a 25-mL round-bottomed flask was added ethyl 4-((tert-butoxycarbonyl)amino)-3-oxobutanoate (601) (0.60 g, 2.44 mmol), K2CO3 (0.56 g, 4.07 mmol), 2-bromo-1-(2-methyl-3-((1-methylcyclopropyl)amino)quinoxalin-5-yl)ethanone (611) (0.54 g, 1.63 mmol), THF (6 mL), and EtOH (6 mL). The reaction mixture was stirred at RT for 16 h and diluted with sat NH4Cl (5 mL) and extracted with EtOAc (10 mL). The organic extract was washed with water (5 mL), dried over Na2SO4 and concentrated. Ethyl 4-((tert-butoxycarbonyl)amino)-2-(2-(2-methyl-3-((1-methylcyclopropyl)amino)quinoxalin-5-yl)-2-oxoethyl)-3-oxobutanoate (357a) was obtained as a light yellow oil and used without further purification. m/z (ESI, +ve) 499.2 (M+H)+. To a 15-mL glass tube was added ethyl 4-((tert-butoxycarbonyl)amino)-2-(2-(2-methyl-3-((1-methylcyclopropyl)amino)quinoxalin-5-yl)-2-oxoethyl)-3-oxobutanoate (357a), crude from previous step, NH4OAc (0.50 g, 6.51 mmol), EtOH (3 mL), and AcOH (1 mL). The tube was sealed and heated at 50° C. for 3 h. The reaction mixture was cooled to RT and was concentrated to half of its volume. The mixture was diluted with EtOAc (10 mL) and water (5 mL). The organic extract was washed with NaOH (1 N, 5 mL), water (5 mL), brine (5 mL), dried over Na2SO4, and concentrated. The crude material was absorbed onto a plug of silica gel and purified by chromatography through a Redi-Sep pre-packed silica gel column (24 g), eluting with a gradient of 10% to 30% EtOAc in hexanes to give ethyl 2-4(tert-butoxycarbonyl)amino)methyl)-5-(2-methyl-3-((1-methylcyclopropyl)amino)quinoxalin-5-yl)-1H-pyrrole-3-carboxylate (357b) (0.25 g, 32% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 12.24 (br. s., 1H), 7.97 (dd, J=1.17, 7.63 Hz, 1H), 7.54-7.63 (m, 3H), 7.34 (t, J=7.82 Hz, 1H), 6.94 (br. s., 1H), 4.51 (d, J=5.28 Hz, 2H), 4.22 (q, J=7.17 Hz, 2H), 2.48 (s, 3H), 1.56 (s, 3H), 1.38 (s, 9H), 1.29 (t, J=7.00 Hz, 3H), 0.91-0.94 (m, 2H), 0.84-0.89 (m, 2H). m/z (ESI, +ve) 480.4 (M+H)+.
Reaction SMILES: C([O:5][C:6]([NH:8][C@H:9]([C:18]([NH:20][C@H:21]([C:31]([NH:33][C@H:34]([C:43]([NH:45][C@H:46]([C:51]([NH:53][C@H:54]([C:59]([NH:61][CH:62]([B:67]1[O:71]C(C)(C)C(C)(C)[O:68]1)[CH2:63][CH2:64][CH2:65][F:66])=[O:60])[CH2:55][CH:56]([CH3:58])[CH3:57])=[O:52])[C:47]([CH3:50])([CH3:49])[CH3:48])=[O:44])[CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[CH3:42])=[O:32])[CH2:22][CH2:23][C:24](=[O:30])[O:25]C(C)(C)C)=[O:19])[CH2:10][C:11](=[O:17])[O:12]C(C)(C)C)=O)(C)(C)C.ClCCl>FC(F)(F)C(O)=O.O.C1(C)C=CC=CC=1>[F:66][CH2:65][CH2:64][CH2:63][CH:62]([B:67]([OH:68])[OH:71])[NH:61][C:59](=[O:60])[C@H:54]([CH2:55][CH:56]([CH3:57])[CH3:58])[NH:53][C:51](=[O:52])[C@H:46]([C:47]([CH3:48])([CH3:50])[CH3:49])[NH:45][C:43](=[O:44])[C@H:34]([CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[CH3:42])[NH:33][C:31](=[O:32])[C@H:21]([CH2:22][CH2:23][C:24](=[O:30])[OH:25])[NH:20][C:18](=[O:19])[C@H:9]([CH2:10][C:11](=[O:17])[OH:12])[NH:8][C:6](=[O:5])[CH2:9][CH2:10][C:11]([OH:17])=[O:12]
Reactant: Cc1ccccc1C[C@H](NC(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)[C@H](CC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)C(=O)N[C@H](C(=O)N[C@@H](CC(C)C)C(=O)NC(CCCF)B1OC(C)(C)C(C)(C)O1)C(C)(C)C
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: O
Product: Cc1ccccc1C[C@H](NC(=O)[C@H](CCC(=O)O)NC(=O)[C@H](CC(=O)O)NC(=O)CCC(=O)O)C(=O)N[C@H](C(=O)N[C@@H](CC(C)C)C(=O)NC(CCCF)B(O)O)C(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 121.8 %

Procedure:
200 mg (0.18 mmol) of N2-[N-[N-[N-[N-(tert-butoxycarbonyl)-O-tert-butyl-L-α-aspartyl]-O-tert-butyl-L-α-glutamyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-N1-[4-fluoro-1(RS)-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)butyl]-L-leucinamide were dissolved in 4.75 ml of trifluoroacetic acid and 0.25 ml of water. 2 ml of dichloromethane were added and the solution was stirred at room temperature for 3 hours. The solution was diluted with toluene and evaporated. The residue was triturated with diethyl ether and the resulting solid was filtered off and dried to give 95 mg of 4-fluoro-1(RS)-[[N-[N-[N-[N-[N-(3-carboxypropionyl)-L-α-aspartyl]-L-α-glutamyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-L-leucyl]amino]butylboronic acid; MS: m/e 849.4 [M+H-H2O]+.
Reaction SMILES: [Br:1]/[C:2](/[CH:27]=C/C1C(C)(C)C2C(N=1)=[N+](CCCS([O-])(=O)=O)C=C(Cl)C=2)=[CH:3]\[CH:4]=[C:5]1\[N:6]([CH2:20][CH2:21][CH2:22][S:23]([O-:26])(=[O:25])=[O:24])[C:7]2[C:12]([C:13]\1([CH3:15])[CH3:14])=[CH:11][C:10](S([O-])(=O)=O)=[CH:9][CH:8]=2.[Na+:48].[Na+].[CH3:50][C:51]1([CH3:80])[C:59]2[C:58]3[CH:60]=[C:61]([S:68]([O-:71])(=[O:70])=[O:69])[CH:62]=[C:63]([S:64]([O-:67])(=[O:66])=[O:65])[C:57]=3[CH:56]=[CH:55][C:54]=2[N+:53]([CH2:72][CH2:73][CH2:74][S:75]([O-:78])(=[O:77])=[O:76])=[C:52]1[CH3:79].[Na+].[Na+]>>[Br:1]/[C:2](=[CH:3]\[CH:4]=[C:5]1\[N:6]([CH2:20][CH2:21][CH2:22][S:23]([O-:26])(=[O:24])=[O:25])[C:7]2[CH:8]=[CH:9][C:10]3[C:61]([S:68]([O-:71])(=[O:69])=[O:70])=[CH:62][C:63]([S:64]([O-:67])(=[O:66])=[O:65])=[CH:57][C:11]=3[C:12]=2[C:13]\1([CH3:15])[CH3:14])/[CH:27]=[CH:79]/[C:52]1[C:51]([CH3:80])([CH3:50])[C:59]2[C:58]3[CH:60]=[C:61]([S:68]([O-:71])(=[O:69])=[O:70])[CH:62]=[C:63]([S:64]([O-:67])(=[O:65])=[O:66])[C:57]=3[CH:56]=[CH:55][C:54]=2[N+:53]=1[CH2:72][CH2:73][CH2:74][S:75]([O-:78])(=[O:77])=[O:76].[Na+:48].[Na+:48].[Na+:48].[Na+:48].[Na+:48]
Reactant: CC1=[N+](CCCS(=O)(=O)[O-])c2ccc3c(S(=O)(=O)[O-])cc(S(=O)(=O)[O-])cc3c2C1(C)C
Reactant: CC1(C)C(/C=C/C(Br)=C/C=C2/N(CCCS(=O)(=O)[O-])c3ccc(S(=O)(=O)[O-])cc3C2(C)C)=Nc2c1cc(Cl)c[n+]2CCCS(=O)(=O)[O-]
Agent: [Na+]
Product: CC1(C)C(/C=C/C(Br)=C/C=C2/N(CCCS(=O)(=O)[O-])c3ccc4c(S(=O)(=O)[O-])cc(S(=O)(=O)[O-])cc4c3C2(C)C)=[N+](CCCS(=O)(=O)[O-])c2ccc3c(S(=O)(=O)[O-])cc(S(=O)(=O)[O-])cc3c21

Procedure:
Compound 25 is prepared analogously to compound 9 (Example 9), except that compound 23 is used as a starting material.
Reaction SMILES: [CH3:1][C:2]([CH3:35])([CH3:34])[C:3]([C:5]1[C:13]2[C:8](=[N:9][CH:10]=[C:11]([C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)=[CH:16][CH:15]=3)[N:12]=2)[N:7]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[CH:6]=1)=[O:4].C(N(C(C)C)CC)(C)C.[CH3:45][S:46](Cl)(=[O:48])=[O:47]>ClCCl>[CH3:45][S:46]([N:23]1[CH2:24][CH2:25][N:20]([C:17]2[CH:16]=[CH:15][C:14]([C:11]3[N:12]=[C:13]4[C:5]([C:3](=[O:4])[C:2]([CH3:35])([CH3:34])[CH3:1])=[CH:6][N:7]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:31])([CH3:33])[CH3:32])[C:8]4=[N:9][CH:10]=3)=[CH:19][CH:18]=2)[CH2:21][CH2:22]1)(=[O:48])=[O:47]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)C(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3ccc(N4CCNCC4)cc3)nc12
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)C(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3ccc(N4CCN(S(C)(=O)=O)CC4)cc3)nc12
Temperature: 0 °C
Reaction time: 8 h
Yield: 87.4 %

Procedure:
To a solution of 2,2-Dimethyl-1-[2-(4-piperazin-1-yl-phenyl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-propan-1-one (0.10 g, 0.203 mmol) in dichloromethane was added 0.042 mL of diisopropylethylamine (0.031 g, 0.244 mmol) and the reaction mixture was subsequently cooled to 0° C. Methane sulfonyl chloride (0.019 mL; 0.028 g, 0.244 mmol) was added via syringe and the reaction was slowly warmed to room temperature and stirred overnight. The reaction was quenched with water and extracted 3 times with dichloromethane. Combined organics were dried over MgSO4, filtered and conc in vacuo. Silica gel chromatography (15→65% EtOAc/hexanes over 30 minutes) afforded 0.1014 g (87% yield) of 1-[2-[4-(4-Methanesulfonyl-piperazin-1-yl)-phenyl]-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-2,2-dimethyl-propan-1-one as a yellow oil. MS (E/I): 572 (M+H).