Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][NH:7][CH2:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH2:15][N:14]([CH2:19][CH2:20][CH2:21][CH2:22][N:23]([CH2:27][CH2:28][CH3:29])[CH2:24][CH2:25][CH3:26])[CH2:13][CH2:12]2.[CH3:30][N:31]1[CH:35]=[CH:34][N:33]=[C:32]1[CH:36]=O.C([BH3-])#N.[Na+].C(O)(=O)C>CO>[NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][N:7]([CH2:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH2:15][N:14]([CH2:19][CH2:20][CH2:21][CH2:22][N:23]([CH2:24][CH2:25][CH3:26])[CH2:27][CH2:28][CH3:29])[CH2:13][CH2:12]2)[CH2:36][C:32]1[N:31]([CH3:30])[CH:35]=[CH:34][N:33]=1
Reactant: Cn1ccnc1C=O
Reactant: CCCN(CCC)CCCCN1CCc2cc(CNCc3ncc[nH]3)ccc2C1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCCN(CCC)CCCCN1CCc2cc(CN(Cc3ncc[nH]3)Cc3nccn3C)ccc2C1
Temperature: 25 °C
Reaction time: 16.5 h
Yield: 89.4 %

Procedure:
The compound (104 mg) obtained in Example 17-7 was dissolved in anhydrous methanol (4.0 ml) and added with 1-methyl-2-imidazole carboxaldehyde (42.9 mg) and sodium cyanoborohydride (49.0 mg). The solution was adjusted to pH 5 with acetic acid and stirred at room temperature for 16.5 hours. After completion of the reaction, the solvent was distilled off. The resultant was added with a 1 mol/l sodium hydroxide aqueous solution, subjected to extraction with chloroform, and dried with magnesium sulfate. The solvent was distilled off. The residue was purified through silica gel column chromatography (chloroform/ethyl acetate) and treated with hydrochloric acid, thereby obtaining a hydrochloride (115 mg) of the subject compound as a white solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[CH3:9].[CH3:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1B(O)O.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCCCO1>[CH3:9][C:3]1[CH:4]=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=1[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[CH3:10]
Reactant: Cc1ccccc1B(O)O
Reactant: Cc1ccc(C)c(Cl)c1
Agent: C1CCOOC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: Cc1ccc(C)c(-c2ccccc2C)c1
Yield: 80.2 %

Procedure:
2-Chloro-p-xylene (56 mg, 0.40 mmol) reacted with 2-methylphenylboronic acid (82 mg, 0.60 mmol) using 2.5/5.0 mol % of Pd(dba)2/Ph5FcP(t-Bu)2 and Cs2CO3 (391 mg, 1.20 mmol) in 1,2-dioxane at 100° C. to give the title compound (63 mg, 80%): 1H-NMR (300 MHz, CDCl3): δ 7.12-7.18 (m, 6H), 6.97 (s, 1H), 2.37 (s, 3H), 2.10 (s, 3H), 2.05 (s, 3H). 13C{1H}-NMR (125 MHz, CDCl3): δ 141.74, 141.45, 135.77, 134.86, 132.60, 129.94, 129.72, 129.65, 129.26, 127.81, 127.02, 125.47, 20.92, 19.81, 19.28. GC/MS(EI): m/z 196 (M+).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:16][CH2:15][N:14]([C@H:17]2[CH2:22][CH2:21][C@@H:20]([NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:19][C@H:18]2[C:31]([OH:33])=O)[C:13]1=[O:34])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)CCl.O[N:40]1C2C=CC=CC=2N=N1>ClCCl>[CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:16][CH2:15][N:14]([C@H:17]2[CH2:22][CH2:21][C@@H:20]([NH:23][C:24]([O:26][C:27]([CH3:28])([CH3:30])[CH3:29])=[O:25])[CH2:19][C@H:18]2[C:31]([NH2:40])=[O:33])[C:13]1=[O:34])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: On1nnc2ccccc21
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@H](N2CC[C@H](NC(=O)OCc3ccccc3)C2=O)[C@H](C(=O)O)C1
Solvent: ClCCl
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N[C@@H]1CC[C@H](N2CC[C@H](NC(=O)OCc3ccccc3)C2=O)[C@H](C(N)=O)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 101.2 %

Procedure:
A 3 L round bottom flask was charged with (1R,2S,5R)-2-((S)-3-(benzyloxycarbonylamino)-2-oxopyrrolidin-1-yl)-5-(tert-butoxycarbonylamino)cyclohexanecarboxylic acid (75.5 g, 0.158 mol), EDC*HCl (33.5 g, 0.175 mol), 1-hydroxybenzotriazole (23.6 g, 0.175 mol), and dichloromethane (1 L). The reaction was stirred at room temperature for 2 h, during which time it changed from a white suspension to a clear solution. Ammonia (gas) was bubbled into the solution until the pH was strongly basic (paper) and the reaction was stirred for 10 min; this ammonia addition was repeated and the reaction was stirred for an additional 10 min. Water was added. The organic phase was washed with sat. NaHCO3, NaH2PO4, and brine before being concentrated in vacuo. The residue was slurried with acetonitrile (0.5 L) and then concentrated in to give (1R,2S,5R)-2-((S)-3-(benzyloxycarbonylamino)-2-oxopyrrolidin-1-yl)-5-(tert-butoxycarbonylamino)cyclohexanecarboxamide as a white solid (75.9 g, ˜100%), which was used in the next step without further purification. LC/MS for primary peak: [M-Boc+H]+=375.3; [M±H]+=475.4; [M-tBu+H]+=419.3. 1H-NMR (400 MHz, d4-MeOH): δ 7.35 (m, 5H), 5.11 (s, 2H), 4.25 (m, 2H), 3.70 (m, 1H), 3.6 (m, 1H), 3.45 (m, 1H), 2.91 (m, 1H), 2.38 (m, 1H), 2.12 (m, 1H), 1.9-2.05 (m, 2H), 1.65-1.9 (m, 4H), 1.46 (s, 9H).
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[CH:18]=[N:17][CH:16]=[CH:15]2.N1C=CC=CC=1>C(Cl)Cl>[C:1]1([S:7]([NH:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[N:17][CH:16]=[CH:15]3)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Nc1ccc2cnccc2c1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=S(=O)(Nc1ccc2cnccc2c1)c1ccccc1
Yield: 28.9 %

Procedure:
Benzenesulphonyl chloride (4.9 g, 0.028M) in CH2Cl2 (15 ml) was added dropwise over 10 minutes to a cooled stirred mixture of 6-aminoisoquinoline (4.0 g, 0.028M) and pyridine (2.37 g, 0.03M) in CH2Cl2 (150 ml). The reaction mixture was stirred overnight at room temperature and was then washed with H2O. The CH2Cl2 solution was dried over MgSO4 and was then chromatographed on a silica gel column. After evaporation the residue was recrystallised from isopropanol to yield 6-phenylsulphonamidoisoquinoline (2.28 g, 33%), m.p. 204°-6° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:14]=[CH:13][C:6]([O:7][CH2:8][C:9]([O:11]C)=[O:10])=[C:5]([NH:15][C:16](=[O:34])[C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:19][CH:18]=2)[CH:4]=1.[OH-].[Na+].Cl>CO.O>[CH3:1][O:2][C:3]1[CH:14]=[CH:13][C:6]([O:7][CH2:8][C:9]([OH:11])=[O:10])=[C:5]([NH:15][C:16](=[O:34])[C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:19][CH:18]=2)[CH:4]=1
Reactant: COC(=O)COc1ccc(OC)cc1NC(=O)c1ccc(OCCCCc2ccccc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1ccc(OCC(=O)O)c(NC(=O)c2ccc(OCCCCc3ccccc3)cc2)c1
Temperature: 60 °C
Reaction time: 2 h
Yield: 76.4 %

Procedure:
In 25 ml of 90% methanol was suspended 0.54 g of methyl 4-methoxy-2-[p-(4-phenylbutoxy)benzamido]phenoxyacetate obtained in Example 95. To the suspension wad added 10 ml of a 1N sodium hydroxide aqueous solution followed by stirring at 60° C. for 2 hours. The reaction mixture was diluted with 50 ml of water and the system was rendered acidic with 7 ml of 2N hydrochloric acid. Extraction was performed with ethyl acetate. After the organic layer was washed water and dried over anhydrous magnesium sulfate, the solvent was distilled off. The obtained solid was recrystallized from isopropyl alcohol to obtain 0.4 g of 4-methoxy-2-[p-(4-phenylbutoxy)benzamido]phenoxyacetic acid.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:9]=2)=[CH:6][N:7]=1.Cl[CH:19]([CH:22]([C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][CH:33]=1)[N:30]=[CH:29][CH:28]=[CH:27]2)[CH3:23])[CH:20]=O.C(N(CC)CC)C>C(O)(C)C>[N:30]1[C:31]2[C:26](=[CH:25][C:24]([CH:22]([C:19]3[N:3]4[N:4]=[C:5]([C:8]5[CH:9]=[CH:10][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:16][CH:17]=5)[CH:6]=[N:7][C:2]4=[N:1][CH:20]=3)[CH3:23])=[CH:33][CH:32]=2)[CH:27]=[CH:28][CH:29]=1
Reactant: CC(c1ccc2ncccc2c1)C(Cl)C=O
Reactant: COC(=O)c1ccc(-c2cnc(N)nn2)cc1
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(-c2cnc3ncc(C(C)c4ccc5ncccc5c4)n3n2)cc1
Temperature: 110 °C
Yield: 22.5 %

Procedure:
A mixture of methyl 4-(3-amino-1,2,4-triazin-6-yl)benzoate (50 mg, 0.217 mmol) and 2-chloro-3-quinolin-6-ylbutanal (61 mg, 0.26 mmol) in isopropyl alcohol (3.0 mL) was heated at 110° C. for 48 h. The mixture was adjusted to pH 9 by adding triethylamine. The volatiles were removed under reduced pressure and the residue was purified by chromatography on silica gel with EtOAc in methylene chloride (0-60%) to afford the desired product (0.020 g, 22%). LCMS: (M+H)=410.0.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.[OH-].[Na+].[N+:12]([C:15]1[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=[CH:17][C:16]=1Cl)([O-:14])=[O:13]>S1(CCCC1)(=O)=O>[CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][C:16]2[CH:17]=[CH:18][C:19]([N+:21]([O-:23])=[O:22])=[CH:20][C:15]=2[N+:12]([O-:14])=[O:13])=[CH:5][CH:4]=1
Reactant: O=[N+]([O-])c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: CSc1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O=S1(=O)CCCC1
Product: CSc1ccc(Oc2ccc([N+](=O)[O-])cc2[N+](=O)[O-])cc1
Temperature: 65 °C
Yield: 97.4 %

Procedure:
To a solution of 15.4 g (0.110 mole) of 4-(methylthio)phenol dissolved in 150 ml of sulfolane was added 4.40 g (0.110 mole) of NaOH. The mixture was heated to 65° C. and 20.25 g (0.100 mole) of 2,4-dinitrochlorobenzene added and the reaction mixture heated at 65° C. for 3.25 hrs. The product was recovered (29.8 g, 97.4% yield) as described in Example 1 and recrystallized from ethanol, which gave purified 1-(4-(methylthio)phenoxy)-2,4-dinitrobenzene, mp 119°-120.5° C.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[N:3]=1.C([O-])([O-])=O.[Na+].[Na+].[CH3:18][NH2:19].O>CCO>[Cl:11][C:4]1[N:3]=[C:2]([NH:19][CH3:18])[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=1
Reactant: CN
Reactant: O=[N+]([O-])c1ccc(Cl)nc1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CNc1nc(Cl)ccc1[N+](=O)[O-]
Temperature: 18 °C
Reaction time: 16 h
Yield: 55.7 %

Procedure:
To a solution of 2,6-dichloro-3-nitropyridine (1 g, 7.3 mmol) in EtOH (10 mL) was added Na2CO3 (1.3 g, 12.3 mmol) and MeNH2 at 18° C. The mixture was stirred for 16 hours at 18° C. after which TLC analysis showed the reaction was complete. The reaction mixture was then concentrated to get the crude material which was treated with water (50 mL) and extracted with ethyl acetate. The combined organic layers were washed with brine (30 mL), dried over Na2SO4 and concentrated to get yield the crude product which was purified by crystallized with ethanol to give the desired product (780 mg, 55.7%) as a yellow solid. LCMS (m/z): 188.1 [M+H]+.
Reaction SMILES: [N:1]1([C:7]2[N:16]=[C:15]([NH2:17])[C:14]3[C:9](=[CH:10][C:11]([O:20][CH3:21])=[C:12]([O:18][CH3:19])[CH:13]=3)[N:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[C:23]1[S:24][C:25]2[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=2[N:27]=1.C(N(CC)CC)C>C(O)CCC>[S:24]1[C:25]2[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=2[N:27]=[C:23]1[N:4]1[CH2:5][CH2:6][N:1]([C:7]2[N:16]=[C:15]([NH2:17])[C:14]3[C:9](=[CH:10][C:11]([O:20][CH3:21])=[C:12]([O:18][CH3:19])[CH:13]=3)[N:8]=2)[CH2:2][CH2:3]1
Reactant: COc1cc2nc(N3CCNCC3)nc(N)c2cc1OC
Reactant: Clc1nc2ccccc2s1
Solvent: CCN(CC)CC
Solvent: CCCCO
Product: COc1cc2nc(N3CCN(c4nc5ccccc5s4)CC3)nc(N)c2cc1OC

Procedure:
A suspension of 2-(1-piperazinyl)-4-amino-6,7-dimethoxyquinazoline (1.96 g), 2-chlorobenzthiazole (1.02 g), triethylamine (1.82 g) in butanol (100 ml) was refluxed for 72 hr and filtered. The precipitate was taken up in a solution of methanol and dimethyl sulfoxide, and 1 N sodium hydroxide was added until the mixture was alkaline. The precipitate was collected, washed with water, dried (1.3 g) and crystallized from methanol to give the title compound: mp 242°-245° C.; ir (nujol) 3460 and 3370 cm-1 : uv max (MeOH) 227 (ε=4130), 250 (ε=5280), 276 (ε=3649) and 340 nm (ε=690); nmr (DMSO-d6) δ 3.65 (m, 4H), 3.9 (m, 4H), 3.85 (s, 3H), 3.93 (s, 3H), 5.2 (s, 2H) and 7.2 (m, 6H); and Anal. Calcd for C21H22N6O2S.CH3OH: C, 58.14% H, 5.72% N, 18.50% and Found: C, 57.88% H, 5.90% N, 18.47%.
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]=[CH:17][N:18]([C:20]3[N:25]=[C:24]([CH3:26])[CH:23]=[C:22]([C:27]4[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=4)[N:21]=3)[CH:19]=2)=[CH:11][CH:10]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[CH3:26][C:24]1[CH:23]=[C:22]([C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:34])[F:35])=[CH:29][CH:28]=2)[N:21]=[C:20]([N:18]2[CH:19]=[C:15]([C:12]3[CH:13]=[CH:14][C:9]([S:6]([NH2:5])(=[O:8])=[O:7])=[CH:10][CH:11]=3)[N:16]=[CH:17]2)[N:25]=1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(-n2cnc(-c3ccc(S(=O)(=O)NC(C)(C)C)cc3)c2)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(-n2cnc(-c3ccc(S(N)(=O)=O)cc3)c2)n1
Temperature: 25 °C
Reaction time: 15 h
Yield: 42.1 %

Procedure:
To a cooled and stirred solution of N-tert-butyl-4-{1-[4-methyl-6-(4-trifluoromethylphenyl)-pyrimidin-2-yl]-1H-imidazol-4-yl}-benzenesulfonamide (0.2 g) in dichloromethane (4 mL) was added TFA (4 mL) and the reaction mixture was allowed to stir at room temperature for 15 h. The mixture was evaporated to dryness and saturated NaHCO3 solution (2 mL), diethyl ether and heptane were added. The mixture was stirred at room temperature for 1 h, the precipitate was collected by filtration, washed with water and heptane and dried to yield the title compound as an off-white solid (0.075 g, 16%). MS (ISP) 460.1 [(M+H)+]; mp 323° C.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:12][O:13][C:14](=[O:31])[C:15]1[C:16](=[C:21]([NH:25]CCCCC)[CH:22]=[CH:23][CH:24]=1)[C:17]([O:19][CH3:20])=[O:18]>>[CH3:12][O:13][C:14](=[O:31])[C:15]1[C:16](=[C:21]([NH:25][CH2:10][CH2:9][O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:22]=[CH:23][CH:24]=1)[C:17]([O:19][CH3:20])=[O:18]
Reactant: CCCCCNc1cccc(C(=O)OC)c1C(=O)OC
Reactant: O=CCOCc1ccccc1
Product: COC(=O)c1cccc(NCCOCc2ccccc2)c1C(=O)OC
Yield: 78 %

Procedure:
Benzyloxyacetaldehyde (5.27 ml, 37.5 mmol) was treated in the same manner as described above for the synthesis of 3-pentylamino-phthalic acid dimethyl ester. The residue (oil) was purified by chromatography (6:3:1 methylene chloride/hexane/ethyl acetate) to give 7.98 g (78%) of yellow oil: 1H NMR (DMSO-d6) d 7.38–7.26 (m, 5H), 6.89–6.77 (m, 3H), 4.57 (s, 2H), 3.85 (s, 3H), 3.82 (s, 3H), 3.69 (t, J=5.5 Hz, 2H), 3.38 (q, J=5.4 Hz, 2H).
Reaction SMILES: [CH:1]([O-:3])=O.[Na+].C(O)=O.[O:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[C:13]([N:15]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([C:25]3[CH:30]=[CH:29][C:28]([S:31]([CH3:34])(=[O:33])=[O:32])=[CH:27][CH:26]=3)[CH:23]=2)[NH:18][C@@H:17]([CH3:35])[CH2:16]1)=[O:14]>>[O:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[C:13]([N:15]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([C:25]3[CH:30]=[CH:29][C:28]([S:31]([CH3:34])(=[O:32])=[O:33])=[CH:27][CH:26]=3)[CH:23]=2)[N:18]([CH:1]=[O:3])[C@@H:17]([CH3:35])[CH2:16]1)=[O:14]
Reactant: C[C@H]1CN(C(=O)c2ccco2)c2cc(-c3ccc(S(C)(=O)=O)cc3)ccc2N1
Reactant: O=C[O-]
Agent: [Na+]
Solvent: O=CO
Product: C[C@H]1CN(C(=O)c2ccco2)c2cc(-c3ccc(S(C)(=O)=O)cc3)ccc2N1C=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 71.9 %

Procedure:
Sodium formate (14 mg, 0.200 mmol) and formic acid (46 mg, 1.0 mmol) were added to (S)-furan-2-yl(3-methyl-7-(4-(methylsulfonyl)phenyl)-3,4-dihydroquinoxaline-1(2H)-yl)methanone (0.2 M in 1,2-dichloroethane, 0.1 mL, 0.02 mmol) and shaken at room temperature for 5 h. The reaction was concentrated and the crude product was purified by mass-triggered preparatory HPLC. The product-containing fractions were combined and concentrated to afford (S)-4-(furan-2-carbonyl)-2-methyl-6-(4-(methylsulfonyl)phenyl)-3,4-dihydroquinoxaline-1(2H)-carbaldehyde (0.0061 g, 72%). MS (ESI, pos. ion) m/z 425.
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[Cl:9][C:10]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:11]=1[CH:12]=O.CC(O)=O.CNC>CC(O)C>[Cl:9][C:10]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:11]=1[CH:12]=[C:2]([C:3](=[O:4])[CH3:5])[C:1]([O:7][CH3:8])=[O:6]
Reactant: O=Cc1ccc(Cl)cc1Cl
Reactant: COC(=O)CC(C)=O
Agent: CNC
Solvent: CC(C)O
Solvent: CC(=O)O
Product: COC(=O)C(=Cc1ccc(Cl)cc1Cl)C(C)=O
Temperature: 40 °C

Procedure:
To a stirred solution of methyl acetoacetate (345 mg, 2.97 mmol) and 2,4-dichlorobenzaldehyde (500 mg, 2.86 mmol) in 2-propanol (5 mL) was added AcOH (7 mg, 0.11 mmol) and dimethylamine (0.06 mL, 2M in THF, 0.11 mmol). The reaction was heated to 40° C. for 4 hrs followed by cooling to ambient temperature for 15 hrs. The reaction was concentrated and purified by flash chromatography (silica gel, 30% EtOAc/hexane) to give methyl 2-(2,4-dichlorobenzylidene)-3-oxobutanoate as a mixture of two isomers (colorless oil, 610 mg, 78%).
Reaction SMILES: [CH2:1]1[CH2:10][N:9]([C:11]2[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=2)[C:14]([OH:16])=O)[CH2:8][C:7]2[CH:6]=[N:5][C:4]3[CH:20]=[CH:21][CH:22]=[CH:23][C:3]=3[C:2]1=2.C(N(CC)CC)C.CCCP(=O)=O.[F:37][C:38]([F:47])([F:46])[C:39]1[CH:40]=[C:41]([CH:43]=[CH:44][CH:45]=1)[NH2:42]>CN(C1C=CN=CC=1)C.ClCCCl>[CH2:1]1[CH2:10][N:9]([C:11]2[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=2)[C:14]([NH:42][C:41]2[CH:43]=[CH:44][CH:45]=[C:39]([C:38]([F:37])([F:46])[F:47])[CH:40]=2)=[O:16])[CH2:8][C:7]2[CH:6]=[N:5][C:4]3[CH:20]=[CH:21][CH:22]=[CH:23][C:3]=3[C:2]1=2
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: O=C(O)c1cccc(N2CCc3c(cnc4ccccc34)C2)c1
Agent: CCCP(=O)=O
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1cccc(C(F)(F)F)c1)c1cccc(N2CCc3c(cnc4ccccc34)C2)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 65.9 %

Procedure:
To a mixture of 3-(1,4-dihydrobenzo[c]-2,7-naphthyridin-3(2H)-yl)benzoic acid (0.20 mmol, 61 mg), triethylamine (0.40 mmol, 0.056 mL), and catalytic DMAP in 2.0 mL 1,2-dichloroethane at rt was added propylphosphonic anhydride solution (50 wt % in EtOAc, 0.24 mmol, 0.143 mL). After 10 min at rt, 3-(trifluoromethyl)aniline (0.30 mmol, 0.037 mL) was added and the reaction stirred at rt for 24 hours. The reaction was quenched into dilute aqueous Na2CO3 solution, extracted into EtOAc, the EtOAc layer washed with H2O, dilute aqueous Na2CO3 solution, brine, dried with anhydrous Na2SO4 and rotary evaporated. The resulting solid was recrystallized from EtOAc/hexane to give the title compound as a light yellow solid (59 mg, 66%).
Reaction SMILES: [C:1]([N:4]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:5][C:6](O)=[O:7])(=[O:3])[CH3:2].C1(N=C=NC2CCCCC2)CCCCC1.[CH3:30][O:31][C:32](=[O:41])[CH2:33][NH:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>C(Cl)(Cl)Cl>[CH3:30][O:31][C:32](=[O:41])[CH2:33][N:34]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:6](=[O:7])[CH2:5][N:4]([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[C:1](=[O:3])[CH3:2]
Reactant: COC(=O)CNc1ccccc1
Reactant: CC(=O)N(CC(=O)O)c1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClC(Cl)Cl
Product: COC(=O)CN(C(=O)CN(C(C)=O)c1ccccc1)c1ccccc1

Procedure:
To 20 parts by volume of chloroform was added 0.96 part by weight of N-acetylphenylglycine. With ice cooling, 1.03 parts by weight of dicyclohexylcarbodiimide was added, and the mixture was stirred. Furthermore, 0.83 part by weight of phenylglycine methyl ester was added, and about 3 hours later, the temperature was returned to room temperature. The mixture was then stirred overnight. After the reaction, the precipitate was collected by filtration, and washed with chloroform. The filtrate was concentrated to dryness. The resulting solid was washed with ethyl acetate, and extracted with a mixture of chloroform and petroleum ether to give 1.2 parts by weight of the captioned compound having a melting point of 198° to 200°C.
Reaction SMILES: CCN(C(C)C)C(C)C.Cl.Cl.[N:12]1([C:18]2[C:23]([C:24]#[N:25])=[CH:22][N:21]=[C:20]3[NH:26][N:27]=[CH:28][C:19]=23)[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.[C:29]([O:33][C:34]([N:36]([CH:49]([CH3:51])[CH3:50])[CH2:37][C@H:38]([C:42]1[CH:47]=[CH:46][C:45]([Cl:48])=[CH:44][CH:43]=1)[C:39](O)=[O:40])=[O:35])([CH3:32])([CH3:31])[CH3:30].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C(Cl)Cl>[Cl:48][C:45]1[CH:46]=[CH:47][C:42]([C@H:38]([C:39]([N:15]2[CH2:16][CH2:17][N:12]([C:18]3[C:23]([C:24]#[N:25])=[CH:22][N:21]=[C:20]4[NH:26][N:27]=[CH:28][C:19]=34)[CH2:13][CH2:14]2)=[O:40])[CH2:37][N:36]([CH:49]([CH3:50])[CH3:51])[C:34](=[O:35])[O:33][C:29]([CH3:31])([CH3:30])[CH3:32])=[CH:43][CH:44]=1
Reactant: N#Cc1cnc2[nH]ncc2c1N1CCNCC1
Reactant: CC(C)N(C[C@@H](C(=O)O)c1ccc(Cl)cc1)C(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)N(C[C@@H](C(=O)N1CCN(c2c(C#N)cnc3[nH]ncc23)CC1)c1ccc(Cl)cc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
DIEA (d 0.742; 0.102 mL, 0.585 mmol) was added to a solution of 4-(piperazin-1-yl)-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile dihydrochloride (0.0661 g, 0.219 mmol), (S)-3-(tert-butoxycarbonyl(isopropyl)amino)-2-(4-chlorophenyl)propanoic acid (0.050 g, 0.146 mmol, see Example B) and TBTU (0.0564 g, 0.176 mmol) in DCM (1 mL) and stirred at room temperature for 18 hours. The mixture was directly loaded onto a silica column and purified by chromatography (hexane:ethyl acetate, 1:1) to give (S)-tert-butyl 2-(4-chlorophenyl)-3-(4-(5-cyano-1H-pyrazolo[3,4-b]pyridin-4-yl)piperazin-1-yl)-3-oxopropyl(isopropyl)carbamate as a solid. The solid was dissolved in DCM (1 mL), and TFA (0.2 mL) was added. The mixture was stirred at room temperature for 1 hour and concentrated to dryness. The resulting residue was dissolved in DCM (0.5 mL), and HCl in ether (1 mL, 2N) was added. The resulting solid was collected by filtration to give (S)-4-(4-(2-(4-chlorophenyl)-3-(isopropylamino)propanoyl)piperazin-1-yl)-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile dihydrochloride (0.043 g, 56%). MS APCI (+) m/z 452.1 detected.
Reaction SMILES: C(O)(=O)C.CO[C:7](=[O:36])[CH2:8][CH2:9][NH:10][C:11](=[O:35])[C@@H:12]1[CH2:16][CH2:15][CH2:14][N:13]1[C:17](=[O:34])[C@H:18]([CH2:28][C:29]1[N:33]=[CH:32][NH:31][CH:30]=1)[NH:19][C:20](=[O:27])[C@@H:21]1[CH2:25][CH2:24][C:23](=[O:26])[NH:22]1.[NH3:37]>CO>[NH:22]1[C:23](=[O:26])[CH2:24][CH2:25][C@H:21]1[C:20]([NH:19][C@H:18]([C:17]([N:13]1[CH2:14][CH2:15][CH2:16][C@H:12]1[C:11]([NH:10][CH2:9][CH2:8][C:7]([NH2:37])=[O:36])=[O:35])=[O:34])[CH2:28][C:29]1[N:33]=[CH:32][NH:31][CH:30]=1)=[O:27]
Reactant: COC(=O)CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@@H]1CCC(=O)N1
Reactant: N
Solvent: CO
Solvent: CC(=O)O
Product: NC(=O)CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@@H]1CCC(=O)N1
Reaction time: 72 h

Procedure:
1.0 g of L-pyroglutamyl-L-histidyl-L-prolyl-β-alanine methyl ester acetate was dissolved in 100 ml of methanol. The resulting solution was saturated with ammonia at 0° C, the vessel was made gas-tight and stored at room temperature for 3 days. The solution was then concentrated in vacuo, the residue dissolved in 50 ml of water and lyophilised. Yield: 900 mg. [α]D25 = -94.9° (c = 1 in 1 N acetic acid).
Reaction SMILES: [Br:1][C:2]1[CH:18]=[CH:17][C:5]2[N:6]([C:10]3[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=3)[C:7](=[O:9])[NH:8][C:4]=2[CH:3]=1.[CH3:19][Si]([N-][Si](C)(C)C)(C)C.[Li+].CI.S(=O)(=O)(O)O>COCCOCCOC>[Br:1][C:2]1[CH:18]=[CH:17][C:5]2[N:6]([C:10]3[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=3)[C:7](=[O:9])[N:8]([CH3:19])[C:4]=2[CH:3]=1
Reactant: O=c1[nH]c2cc(Br)ccc2n1-c1ccc(F)cc1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=S(=O)(O)O
Agent: [Li+]
Solvent: COCCOCCOC
Solvent: CI
Product: Cn1c(=O)n(-c2ccc(F)cc2)c2ccc(Br)cc21
Reaction time: 0.5 h
Yield: 95.8 %

Procedure:
To a stirred room temperature suspension of 5-bromo-1-(4-fluorophenyl)-1,3-dihydro-benzimidazol-2-one (160 mg, 0.52 mmol) in anhydrous bis(2-methoxyethyl)ether (5 mL) was added lithium bis(trimethylsilyl)amide (0.55 mL of 1.06 M solution in THF, 0.58 mmol). After 30 minutes, methyl iodide (125 μL, 2 mmol) was added. After 2 hours, the mixture was poured into 1 N sulfuric acid containing ice. The resulting precipitate was filtered, washed with water, and dried to afford 160 mg of 5-bromo-1-(4-fluorophenyl)-3-methyl-1,3-dihydro-benzimidazol-2-one as an off-white solid. MS m/z 321/323 (MH+).