Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7](=[O:8])[N:6]([CH2:9][C:10]([NH:12][CH:13]([CH:20]([CH3:22])[CH3:21])[C:14](=[O:19])[C:15]([F:18])([F:17])[F:16])=[O:11])[C:5]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[N:4][CH:3]=1.ClS([N:33]=[C:34]=[O:35])(=O)=O.C(=O)([O-])[O-].[Na+].[Na+]>O1CCCC1.C(OCC)(=O)C>[O:8]=[C:7]1[N:6]([CH2:9][C:10]([NH:12][CH:13]([CH:20]([CH3:22])[CH3:21])[C:14](=[O:19])[C:15]([F:16])([F:18])[F:17])=[O:11])[C:5]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[N:4][CH:3]=[C:2]1[NH:1][C:34]([NH2:33])=[O:35]
Reactant: CC(C)C(NC(=O)Cn1c(-c2ccccc2)ncc(N)c1=O)C(=O)C(F)(F)F
Reactant: O=C=NS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)C(NC(=O)Cn1c(-c2ccccc2)ncc(NC(N)=O)c1=O)C(=O)C(F)(F)F
Reaction time: 0.75 h
Yield: 13.8 %

Procedure:
To a solution of the compound from Example 6 (0.40 g) in tetrahydrofuran (10 mL) cooled to 0° C. was added dropwise chlorosulfonyl isocyanate (0.16 g) and the mixture was stirred for 45 min. The reaction mixture was neutralized with saturated aqueous sodium carbonate solution (3 mL), diluted with ethyl acetate (10 mL), and the separated organic phase was washed (water, brine). TLC examination revealed that the major reaction product was present in the aqueous phase. Following saturation of the aqueous phase with sodium chloride, repeated ethyl acetate extractions (4×25 mL) were performed. The combined organic layers were dried (magnesium sulfate) and evaporated. Chromatography with dichloromethane:tetrahydrofuran (10:1) as the eluent, followed by overnight drying (50° C., 27 Pa) gave the title compound (0.061 g) as an off-white solid; TLC: Rf =0.36, dichloromethane:methanol (10:1); NMR: 8.85 (d,1), 8.69 (s,1), 8.35 (s,1), 7.48 (m,5), 6.47 (broad s, 2), 4.70 (dd,1), 4.55 (dd,2), 2.2 (m,1), 0.89 (dd,6); MS: m/z=440(M+1).
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([OH:13])[CH:10]=[CH:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:15][CH2:16][OH:17].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:1]1([C:7]2[CH:8]=[C:9]([CH:10]=[CH:11][CH:12]=2)[O:13][CH2:15][CH2:16][OH:17])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OCCBr
Reactant: Oc1cccc(-c2ccccc2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: OCCOc1cccc(-c2ccccc2)c1
Temperature: 100 °C
Reaction time: 5 h

Procedure:
In a nitrogen atmosphere, 3-phenylphenol 2.65 g, 2-bromoethanol 2.92 g and potassium carbonate 6.51 g were dissolved in N,N-dimethylformamide 16 ml and stirred at 100° C. After 5 hours, the reaction mixture was cooled to room temperature and partitioned by adding water and diethyl ether. The organic layer was washed with water and then with brine, dried over magnesium sulfate anhydride, and evaporated. The residue was purified by silica gel column chromatography (hexane/ethyl acetate system), whereby the title compound (1.78 g, 53%) was obtained as a colorless crystalline.
Reaction SMILES: [NH2:1][C:2]1[C:11]([NH2:12])=[CH:10][C:9]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[C:19](O)([C:21]([F:24])([F:23])[F:22])=O>>[N:13]1([C:9]2[CH:8]=[C:3]([C:4]([O:6][CH3:7])=[O:5])[C:2]3[NH:1][C:19]([C:21]([F:24])([F:23])[F:22])=[N:12][C:11]=3[CH:10]=2)[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1
Reactant: O=C(O)C(F)(F)F
Reactant: COC(=O)c1cc(N2CCOCC2)cc(N)c1N
Product: COC(=O)c1cc(N2CCOCC2)cc2nc(C(F)(F)F)[nH]c12
Temperature: 25 °C

Procedure:
A mixture of methyl 2,3-diamino-5-(4-morpholinyl)benzoate (4.0 g) in CF3COOH (20 mL) was heated at reflux temperature for 8 h. When TLC analysis indicated consumption of starting material, the mixture was cooled to room temperature and the solvent was removed in-vacuo. The residue was diluted with aqueous NaHCO3 and extracted with EtOAc (250 mL×3). The combined organic layers were washed with brine (250 mL×2), dried over anhydrous Na2SO4. After filtration, the solvent was removed by rotary evaporator. The residue was then purified by silica gel chromatography eluted with EtOAc:petroleum ether=1:4 to afford the desired product as a pale solid. (4.3 g, 82.7%). 1H NMR (300 MHz, DMSO-d6): δ ppm 13.47 (s, 1H), 7.71 (s, 1H), 7.56 (s, 1H), 3.96 (s, 3H), 3.79 (t, 4H, J=4.5 Hz), 3.17 (s, 4H). LC-MS: m/e=330.1 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=2)[C:10](Cl)=[O:11])=[C:4]([N+:18]([O-:20])=[O:19])[CH:3]=1.[C:21]([Si:25]([CH3:35])([CH3:34])[O:26][C:27]1[CH:28]=[C:29]([NH2:33])[CH:30]=[CH:31][CH:32]=1)([CH3:24])([CH3:23])[CH3:22].C(N(CC)C(C)C)(C)C.O>C1COCC1>[C:21]([Si:25]([CH3:35])([CH3:34])[O:26][C:27]1[CH:28]=[C:29]([NH:33][C:10](=[O:11])[C:9]2[CH:13]=[CH:14][CH:15]=[C:7]([O:6][C:5]3[CH:16]=[CH:17][C:2]([Cl:1])=[CH:3][C:4]=3[N+:18]([O-:20])=[O:19])[CH:8]=2)[CH:30]=[CH:31][CH:32]=1)([CH3:24])([CH3:23])[CH3:22]
Reactant: O=C(Cl)c1cccc(Oc2ccc(Cl)cc2[N+](=O)[O-])c1
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc(N)c1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)Oc1cccc(NC(=O)c2cccc(Oc3ccc(Cl)cc3[N+](=O)[O-])c2)c1
Reaction time: 16 h
Yield: 62 %

Procedure:
To the product from Example 168b (1.3 g, 4.2 mmol) in THF (25 mL) was added 3-(tert-Butyl-dimethyl-silanyloxy)-phenylamine (1.0 g, 4.2 mmol), and N,N-diisopropylethylamine (0.67 g, 5.2 mmol). The reaction was stirred for 16 h. The reaction was poured into water and extracted with ethyl acetate. The organic layer washed with 5% HCL, water, brine, and dried over sodium sulfate, filtered and concentrated under vacuum giving the title compound (1.3 g, 85%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]2[CH:19]=[CH:18][C:17](Br)=[C:16]([F:21])[CH:15]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:22][C:23]([F:32])([F:31])[C:24]1[CH:25]=[N:26][C:27]([NH2:30])=[N:28][CH:29]=1>O1CCOCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]2[CH:19]=[CH:18][C:17]([NH:30][C:27]3[N:26]=[CH:25][C:24]([C:23]([F:32])([F:22])[F:31])=[CH:29][N:28]=3)=[C:16]([F:21])[CH:15]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCOC(c2ccc(Br)c(F)c2)C1
Reactant: Nc1ncc(C(F)(F)F)cn1
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCOC(c2ccc(Nc3ncc(C(F)(F)F)cn3)c(F)c2)C1
Temperature: 120 °C
Yield: 46.8 %

Procedure:
To a 20 ml glass vial was added (RS)-2-(4-bromo-3-fluoro-phenyl)-morpholine-4-carboxylic acid tert-butyl ester (200 mg, example 96(e)) and 5-trifluoromethyl-pyrimidin-2-ylamine (145 mg, CAS 69034-08-8) in dioxane (5 ml). The reaction mixture was purged with argon for 5 min. 2-Di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl (38.9 mg), tris(dibenzylideneacetone)dipalladium(0) (20.3 mg) and sodium tert-butoxide (59.9 mg) were then added. The vial was capped and heated at 120° C. for 16 h. The reaction mixture was then filtered through sintered glass and the filtrate was concentrated in vacuo. The residue was purified by flash column chromatography (silica gel; gradient: 0% to 50% EtOAc in heptane) to afford (RS)-2-[3-fluoro-4-(5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-morpholine-4-carboxylic acid tert-butyl ester (115 mg, 47%) as a yellow gum. MS (ISP): 441.4 ([M−H]−).
Reaction SMILES: [C:1]([O:6][CH2:7]Cl)(=[O:5])[CH2:2][CH2:3][CH3:4].[Cl:9][C:10]1[CH:11]=[CH:12][C:13]([F:39])=[C:14]([C:16]2[CH:21]=[CH:20][C:19]([CH2:22][C@@H:23]([NH:30][C:31]([C:33]3[N:34]=[N:35][N:36]([OH:38])[CH:37]=3)=[O:32])[CH2:24][C@@H:25]([OH:29])[C:26]([OH:28])=[O:27])=[CH:18][CH:17]=2)[CH:15]=1.CC(C)=O.CCN(CC)CC>>[C:1]([O:6][CH2:7][O:38][N:36]1[CH:37]=[C:33]([C:31]([NH:30][C@H:23]([CH2:22][C:19]2[CH:20]=[CH:21][C:16]([C:14]3[CH:15]=[C:10]([Cl:9])[CH:11]=[CH:12][C:13]=3[F:39])=[CH:17][CH:18]=2)[CH2:24][C@@H:25]([OH:29])[C:26]([OH:28])=[O:27])=[O:32])[N:34]=[N:35]1)(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: O=C(N[C@H](Cc1ccc(-c2cc(Cl)ccc2F)cc1)C[C@@H](O)C(=O)O)c1cn(O)nn1
Reactant: CCCC(=O)OCCl
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: CCCC(=O)OCOn1cc(C(=O)N[C@H](Cc2ccc(-c3cc(Cl)ccc3F)cc2)C[C@@H](O)C(=O)O)nn1
Temperature: 65 °C
Reaction time: 2 h
Yield: 16.4 %

Procedure:
Chloromethyl butyrate (13.7 mg, 100 μmol) was added to a solution of (2R,4R)-5-(5′-chloro-2′-fluorobiphenyl-4-yl)-2-hydroxy-4-[(1-hydroxy-1H-1,2,3-triazole-4-carbonyl)amino]pentanoic acid (30.0 mg, 66.8 μmol) in acetone (0.5 mL, 6.8 mmol). Et3N (18.6 μL, 134 μmol) was added and the resulting mixture was stirred at 65° C. for 2 hours. The mixture was then concentrated in vacuo to yield a yellow liquid. The crude liquid was purified (preparative scale C18 column chromatography, small column, using 30-90% MeCN in water with 0.05% TFA) to yield the title compound as a white solid (6.0 mg). MS m/z [M+H]+ calc'd for C25H26ClFN4O7, 549.15. found 549.1.
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:11]([NH2:13])=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[OH-].[Na+].O=[CH:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH:24]([CH3:26])[CH3:25])=[O:21]>O>[CH2:4]([C@H:3]1[C:11](=[O:12])[NH:13][CH:17]([CH2:18][CH2:19][C:20]([O:22][CH2:23][CH:24]([CH3:26])[CH3:25])=[O:21])[NH:2]1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: NC(=O)[C@@H](N)Cc1ccccc1
Reactant: CC(C)COC(=O)CCC=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)COC(=O)CCC1NC(=O)[C@H](Cc2ccccc2)N1
Yield: 19.7 %

Procedure:
To a solution of L-phenylalaninamide hydrochloride (20 g, 0.1 mol) in water (200 ml), adjusted to pH 8.2 with 10% sodium hydroxide (about 35 ml), was added isobutyl 4-oxobutanoate (16 g, 0.1 mol). The solution was refluxed for 24 hours. After cooling, the solution was extracted with dichloromethane (4×200 ml). The organic phase was dried and evaporated to dryness under vacuum. The residue was chromatographed over silica gel (dichloromethanemethanol 9:1) to afford 6 g (20%) of the title compound, as an oil, which was characterized as the hydrochloride, m.p. 152°-155° C. (with decomposition) (after crystallization from ethanol-diethyl ether). NMR (DMSO-d6, CDCl3): deltaH =9.25 (b.s., 1H, CONH); 7.6-7.1 (c.a., 5H, PhH), 4.90 (t, J=6.1 Hz, 1H, NHCHNH); 4.17 (t, J=6.1 Hz, 1H, CHCH2Ph); 3.84 (d, J=6.9 Hz, 2H, COOCH2CH); 3.35 (c.a., 2H, CH2Ph); 2.50-1.60 (c.a., 5H, CH2CH2COO, CH2CH(CH3)2. MS (E.I., 70 eV, 1.5 mA) m/z=304 (M+), 213 M-C7H7)+, 84 (C3H4N2O)+.
Reaction SMILES: F[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8]CC)=[O:7])=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14].[NH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.[OH-].[Li+]>CN(C=O)C.O.C1COCC1>[N+:13]([C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:2]=1[N:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)[C:6]([OH:8])=[O:7])([O-:15])=[O:14]
Reactant: C1CCNCC1
Reactant: CCOC(=O)c1ccc(F)c([N+](=O)[O-])c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)c1ccc(N2CCCCC2)c([N+](=O)[O-])c1
Temperature: 50 °C
Reaction time: 3 h
Yield: 95.6 %

Procedure:
A mixture of ethyl 4-fluoro-3-nitrobenzoate (Chontech 01072; 500 mg; 2.35 mmol; 1 eq.) and piperidine (Fluka 80640; 599.18 mg; 7.04 mmol; 3 eq.) in DMF (2 mL) was stirred at 50° C. for 3 hours. The reaction was then allowed to cool to room temperature and diluted with water. Extraction with ethyl acetate, drying over sodium sulfate and concentration in vacuo gave a yellow oil. The oil was taken up in THF (15 mL) and lithium hydroxide (280.86 mg; 11.73 mmol; 5 eq.) was added, followed by water (15 mL). The reaction mixture was then stirred at room temperature for 5 hours. THF was evaporated and the residue diluted with water. The aqueous phase was washed with Et2O and acidified to pH 5 with acetic acid. Extraction with Et2O followed by drying over magnesium sulfate and concentration in vacuo afforded the title compound (562 mg, 96%) as a yellow solid.
Reaction SMILES: CN.[CH2:3]([N:5](CC)CC)C.[Cl:10][C:11]1[N:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:12]=1[C:13](Cl)=[O:14]>CC#N>[Cl:10][C:11]1[N:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:12]=1[C:13]([NH:5][CH3:3])=[O:14]
Reactant: CCN(CC)CC
Reactant: O=C(Cl)c1cc(Cl)cnc1Cl
Agent: CN
Solvent: CC#N
Product: CNC(=O)c1cc(Cl)cnc1Cl
Reaction time: 16 h
Yield: 93.7 %

Procedure:
Methanamine (0.355 mL, 2.85 mmol) and triethylamine (0.662 mL, 4.75 mmol) were dissolved in CH3CN (14.2 mL) at 23° C. 2,5-Dichloronicotinoyl chloride (500 mg, 2.376 mmol) was added and the reaction was stirred for 16 h. The solvent was removed by rotary evaporation and the residue was partitioned between EtOAc (20 mL) and 5% aq. NaHCO3 soln. (20 mL). The aqueous phase was extracted with EtOAc (3×20 mL). The combined organics were washed with brine, dried over MgSO4 and concentrated. The resulting solid was triturated in 5% EtOAc-Hexane to provide the desired product as a cream powder (456.7 mg, 94%). 1H NMR (CD3OD) δ 8.46 (d, 1H, J=2.54 Hz), 7.96 (d, 1H, J=2.54 Hz), 2.90 (s, 3H); MS(ESI+) m/z 205.1 (M+H)+.
Reaction SMILES: [C:1]([O:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][O:20][CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][O:22]2)=[CH:14][CH:13]=1)(=[O:6])[CH2:2][C:3]([CH3:5])=O.[NH2:27]/[C:28](/[CH3:34])=[CH:29]\[C:30]([O:32][CH3:33])=[O:31].[N+:35]([C:38]1[CH:39]=[C:40]([CH:43]=[CH:44][CH:45]=1)[CH:41]=O)([O-:37])=[O:36]>>[CH3:34][C:28]1[NH:27][C:3]([CH3:5])=[C:2]([C:1]([O:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][O:20][CH:21]3[CH2:26][CH2:25][CH2:24][CH2:23][O:22]3)=[CH:14][CH:13]=2)=[O:6])[CH:41]([C:40]2[CH:43]=[CH:44][CH:45]=[C:38]([N+:35]([O-:37])=[O:36])[CH:39]=2)[C:29]=1[C:30]([O:32][CH3:33])=[O:31]
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Reactant: CC(=O)CC(=O)OCCCOc1ccc(CCOC2CCCCO2)cc1
Reactant: COC(=O)/C=C(/C)N
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCCOc2ccc(CCOC3CCCCO3)cc2)C1c1cccc([N+](=O)[O-])c1

Procedure:
An ω-phenylalkylacetoacetate derivative (2) is reacted with an alkyl β-aminoalkenoate (3) (for example, methyl β-aminocrotonate) and a benzaldehyde derivative of formula 4 under Hantzsch dihydropyridine synthesis conditions (see, e.g., Fox, et al., J. Org. Chem., 16, 1259 (1951)) to form a 4-phenyl-2,6-dialkyl-1,4-dihydropyridine dicarboxylate diester derivative (1). For example, 3-(4-[2-(tetrahydropyran-2-yloxy)ethyl]phenoxy)propyl acetoacetate (2) is reacted with methyl β-aminocrotonate and 3-nitrobenzaldehyde to produce 2,6-dimethyl-3-carbomethoxy-4-(3-nitrophenyl)-5-(3-[4-(2-tetrahydropyran-2-yloxyethyl)phenoxy]propoxycarbonyl)-1,4-dihydropyridine (1). (Scheme I)
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[S:11]1[C:15]2[C:16]([CH2:20][OH:21])=[CH:17][CH:18]=[CH:19][C:14]=2[N:13]=[N:12]1.C(N(CC)CC)C.[Cl-].[NH4+]>C(Cl)Cl>[S:11]1[C:15]2[C:16]([CH:20]=[O:21])=[CH:17][CH:18]=[CH:19][C:14]=2[N:13]=[N:12]1
Reactant: OCc1cccc2nnsc12
Agent: O=C(Cl)C(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: O=Cc1cccc2nnsc12
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 91 %

Procedure:
Under nitrogen atmosphere, to a solution of oxalyl chloride (7.03 mL, 83.0 mmol) in methylene chloride (50 mL) was added dimethyl sulfoxide (8.84 mL, 125 mmol) and the mixture was stirred at −78° C. for 30 min. To the reaction mixture was added 1,2,3-benzothiadiazol-7-ylmethanol (6.90 g, 41.5 mmol) at −78° C. and the mixture was stirred for 2 hr. To the reaction mixture was added triethylamine (35.0 mL, 249 mmol) at −78° C. and the mixture was stirred for 30 min. The reaction mixture was warmed to room temperature, and stirred at room temperature for 4 hr. Saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with methylene chloride. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by recrystallization (methylene chloride/hexane) to give the title compound (6.20 g, yield 91%).
Reaction SMILES: [ClH:1].[NH2:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([CH2:13][CH:14]([NH:23][C:24](=[O:45])[CH2:25][NH:26][S:27]([C:30]3[C:31]([CH3:44])=[C:32]([CH3:43])[C:33]4OC(C)(C)CC[C:34]=4[C:41]=3[CH3:42])(=[O:29])=[O:28])[C:15](=[O:22])[N:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)=[CH:10][CH:11]=2)[CH:6]=[CH:5][N:4]=1.NC1C2C(=CC(CC(NC(=O)OC(C)(C)C)[C:59](=[O:66])N3CCCCC3)=CC=2)C=CN=1.[N:75]1([C:81](=[O:102])[CH2:82][C@H](NS(C2C(C)=CC(OC)=C(C)C=2C)(=O)=O)C(O)=O)[CH2:80][CH2:79][O:78][CH2:77][CH2:76]1>>[ClH:1].[NH2:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([CH2:13][CH:14]([NH:23][C:24](=[O:45])[C@@H:25]([NH:26][S:27]([C:30]3[C:41]([CH3:42])=[CH:34][C:33]([O:66][CH3:59])=[C:32]([CH3:43])[C:31]=3[CH3:44])(=[O:28])=[O:29])[CH2:82][C:81]([N:75]3[CH2:80][CH2:79][O:78][CH2:77][CH2:76]3)=[O:102])[C:15](=[O:22])[N:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)=[CH:10][CH:11]=2)[CH:6]=[CH:5][N:4]=1
Reactant: CC(C)(C)OC(=O)NC(Cc1ccc2c(N)nccc2c1)C(=O)N1CCCCC1
Reactant: COc1cc(C)c(S(=O)(=O)N[C@@H](CC(=O)N2CCOCC2)C(=O)O)c(C)c1C
Reactant: Cc1c(C)c(S(=O)(=O)NCC(=O)NC(Cc2ccc3c(N)nccc3c2)C(=O)N2CCCCC2)c(C)c2c1OC(C)(C)CC2
Agent: Cl
Product: COc1cc(C)c(S(=O)(=O)N[C@@H](CC(=O)N2CCOCC2)C(=O)NC(Cc2ccc3c(N)nccc3c2)C(=O)N2CCCCC2)c(C)c1C

Procedure:
The procedure described for 5c was used. Deprotection of 5a and coupling with 51a yielded after purification the title compound (79%) as a mixture of diastereomers (1:1). 1H-NMR 200 MHz (CD3OD) δ: 1.30-1.51 (6H, m), 2.14 (3H, s), 2.51 and 2.53 (3H, 2× s), 2.63 (3H, s), 2.31-3.62 (16H, m), 3.84 and 3.86 (3H, 2× s), 3.99-4.15 (1H, m), 5.08-5.21 (1H, m), 6.75 and 6.76 (1H, 2× s), 7.18-7.25 (1H, m), 7.52-7.81 (3H, m), 8.25-8.37 (1H, m).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=2)[CH2:10][CH2:9][NH:8]1.Br[CH2:27][C:28](Br)=[O:29].[CH3:31][O:32][C:33]1[CH:40]=[CH:39][CH:38]=[CH:37][C:34]=1[CH2:35][NH2:36]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=2)[CH2:10][CH2:9][N:8]1[CH2:27][C:28]([NH:36][CH2:35][C:34]1[CH:37]=[CH:38][CH:39]=[CH:40][C:33]=1[O:32][CH3:31])=[O:29]
Reactant: O=C(Br)CBr
Reactant: COc1ccc(CC2NCCc3cc(OC)c(OC)cc32)cc1OC
Reactant: COc1ccccc1CN
Product: COc1ccccc1CNC(=O)CN1CCc2cc(OC)c(OC)cc2C1Cc1ccc(OC)c(OC)c1

Procedure:
prepared by reaction of 1-(3,4-Dimethoxy-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline and 2-bromoacetyl bromide with 2-methoxybenzylamine
Reaction SMILES: Cl.Cl.[C:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)([CH3:6])([CH3:5])[CH3:4].[C:19]1([N:25]2[CH2:32][CH2:31][CH2:30][C@H:26]2[C:27](O)=[O:28])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(N(CC)CC)C.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C)C=O>[C:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]1[CH2:18][CH2:17][N:16]([C:27](=[O:28])[C@@H:26]2[CH2:30][CH2:31][CH2:32][N:25]2[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:15][CH2:14]1)([CH3:6])([CH3:4])[CH3:5]
Reactant: O=C(O)[C@@H]1CCCN1c1ccccc1
Reactant: CC(C)(C)c1ccccc1N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)c1ccccc1N1CCN(C(=O)[C@@H]2CCCN2c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 25 %

Procedure:
A mixture of 1-(2-tert-butylphenyl)piperazine dihydrochloride obtained in Reference Example 1 (0.30 g, 1.03 mmol), 1-phenylproline (Reference example 7, 0.22 g, 1.13 mmol), triethylamine (0.23 g, 2.26 mmol), EDCI (0.22 g, 1.13 mmol) and HOBt (0.17 g, 1.13 mmol) in N,N-dimethylformamide (10 mL) was stirred at room temperature for 16 h. The reaction mixture was concentrated under reduced pressure and the resulting residue was partitioned between ethyl acetate and 10% sodium hydrogen carbonate solution. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate 90:10 to 50:50) and the resulting yellow solid was triturated with hexane-ethyl acetate to give the title compound (0.10 g, 25%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]2[C:8]([C:11]([OH:13])=O)=[CH:9][NH:10][C:5]2=[N:4][CH:3]=1.[CH3:14][C:15]([NH2:18])([CH3:17])[CH3:16].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>ClCCl>[Br:1][C:2]1[N:7]=[C:6]2[C:8]([C:11]([NH:18][C:15]([CH3:17])([CH3:16])[CH3:14])=[O:13])=[CH:9][NH:10][C:5]2=[N:4][CH:3]=1
Reactant: CC(C)(C)N
Reactant: O=C(O)c1c[nH]c2ncc(Br)nc12
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CC(C)(C)NC(=O)c1c[nH]c2ncc(Br)nc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 41.8 %

Procedure:
A mixture of 2-bromo-5H-pyrrolo[3,2-b]pyrazine-7-carboxylic acid (0.2 g, 0.83 mmol), 2-methylpropan-2-amine (66 mg, 0.91 mmol), EDCI (476 mg, 2.49 mmol) and HOBt (112 mg, 0.83 mmol) in dry dichloromethane (20 mL) was stirred at room temperature for 16 hours. Reaction mixture was concentrated to about half the volume and the formed precipitate was separated by filtration, the filter cake was washed with dichloromethane and dried to afford 2-bromo-N-tert-butyl-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide (103 mg, 42%) as a yellow solid. LCMS: (M+H)+=297.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([NH2:6])=[N:2]1.[C:7](OCC)(=[O:14])[CH2:8][C:9](OCC)=[O:10].CC[O-].[Na+]>CCO>[N:1]1[N:2]2[C:7]([OH:14])=[CH:8][C:9]([OH:10])=[N:6][C:3]2=[CH:4][CH:5]=1
Reactant: Nc1cc[nH]n1
Reactant: CCOC(=O)CC(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: Oc1cc(O)n2nccc2n1
Temperature: 80 °C
Yield: 76.6 %

Procedure:
To 1H-pyrazol-3-amine (12.3 g, 148.0 mmol) in EtOH (50 mL) was added diethyl malonate (25.0 mL, 164.7 mmol), 21 wt % NaOEt in EtOH (110 mL, 294.6 mmol) and additional EtOH (50 mL). The resulting reaction mixture was then heated at 80° C. under an atmosphere of argon for 16 hours, at which time the reaction was allowed to cool to room temperature. The reaction mixture was then concentrated in vacuo until almost dry, before H2O (500 mL) was added. Vigorous stirring aided the dissolution of solids, at which time conc. HCl was added until pH˜2 was attained (precipitate formed). The precipitate was collected and dried by vacuum filtration giving pyrazolo[1,5-a]pyrimidine-5,7-diol as a tan solid (17.13 g, 113.4 mmol, 77%).
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[CH2:11][CH2:10][C:9](=[O:12])[C:8]2[CH:7]=[C:6]([N:13]=[N:14][C:15]3[CH:25]=[CH:24][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:17][CH:16]=3)[CH:5]=[CH:4][C:3]1=2.[BH4-].[Na+]>C1COCC1.CCO>[CH3:26][C:2]1([CH3:1])[CH2:11][CH2:10][CH:9]([OH:12])[C:8]2[CH:7]=[C:6]([N:13]=[N:14][C:15]3[CH:16]=[CH:17][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:24][CH:25]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CCOC(=O)c1ccc(N=Nc2ccc3c(c2)C(=O)CCC3(C)C)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)c1ccc(N=Nc2ccc3c(c2)C(O)CCC3(C)C)cc1
Reaction time: 3 h

Procedure:
To a solution of ethyl 4-[(5,5-dimethyl-5,6-dihydronaphthalen-8(7H)-one-2-yl)azo]benzoate (Compound D10, 60 mg, 0.171 mmol) in 2 ml of THF and 7 ml of EtOH at 0° C. was added NaBH4 (6.5 mg, 0.171 mmol) and the mixture stirred for 3 h. The reaction was quenched by slow addition of cold water. Solvent was removed under reduced pressure and the residue was extracted with ethyl acetate. The organic layer was washed with brine, dried (MgSO4) and solvent removed under reduced pressure. The crude product was purified by flash chromatography (silica, ethyl acetate/hexane, 1:3) to afford the title compound as a red oil.