Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:14](=[CH:15][CH:16]=1)[CH:13]([CH2:17]OS(C1C=CC(C)=CC=1)(=O)=O)[CH:12]([C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=1)[CH:11]1[CH:6]2[CH2:7][CH2:8][CH2:9][CH2:10]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O1CCCC1.[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+]>C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:14](=[CH:15][CH:16]=1)[CH:13]([CH3:17])[CH:12]([C:29]1[CH:30]=[CH:31][C:32]([O:35][CH3:36])=[CH:33][CH:34]=1)[CH:11]1[CH:6]2[CH2:7][CH2:8][CH2:9][CH2:10]1
Reactant: COc1ccc(C2C(COS(=O)(=O)c3ccc(C)cc3)c3ccc(OC)cc3C3CCCCC32)cc1
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc(C2C(C)c3ccc(OC)cc3C3CCCCC32)cc1
Reaction time: 5 h
Yield: 85.3 %

Procedure:
Combine toluene-4-sulfonic acid 6-methoxy-10-(4-methoxy-phenyl)-1,2,3,4,4a,9,10,10a-octahydro-phenanthren-9-ylmethyl ester (0.471 g, 0.93 mmol), lithium aluminum hydride (0.069 g, 1.86 mmol), and tetrahydrofuran (8.0 mL), and reflux under nitrogen atmosphere. After 5 hours, quench reaction by adding reaction to a stirred solution of Rochelle's salt (Na K Tartrate) and ethyl acetate. After several hours, separate the organic phase and wash with brine. Dry the organic phase with anhydrous sodium sulfate and flash chromatograph using 0% to 20% ethyl acetate/hexanes to yield the titled compound (0.267 g, 85%) as a white solid. TLC Rf=0.43 in 3:1 hexanes:ethyl acetate. 1H NMR (CDCl3): 7.35 (d, 1H, J=8.4 Hz), 7.23 (d, 2H, J=8.4 Hz), 6.94 (m, 3H), 6.82 (dd, 1H, J=8.8, 2.6 Hz), 3.86 (s, 6H), 3.31 (m, 2H), 2.82 (dd, 1H, J=11.9, 2.6 Hz), 2.50 (d, 1H, J=13.7 Hz), 1.89 (m, 1H), 1.64 (m, 2H), 1.44 (m, 2H), 1.16 (m, 6H).
Reaction SMILES: C([O-])([O-])=O.[Cs+].[Cs+].[O:7]1[CH2:12][CH2:11][N:10]([CH2:13][C:14]2[CH:15]=[C:16](B(O)O)[CH:17]=[CH:18][CH:19]=2)[CH2:9][CH2:8]1.Br[C:24]1[CH:25]=[C:26]([C:31]2[N:32]=[N:33][N:34]([CH:36]([CH3:38])[CH3:37])[CH:35]=2)[C:27]([NH2:30])=[N:28][CH:29]=1>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:36]([N:34]1[CH:35]=[C:31]([C:26]2[C:27]([NH2:30])=[N:28][CH:29]=[C:24]([C:16]3[CH:17]=[CH:18][CH:19]=[C:14]([CH2:13][N:10]4[CH2:11][CH2:12][O:7][CH2:8][CH2:9]4)[CH:15]=3)[CH:25]=2)[N:32]=[N:33]1)([CH3:38])[CH3:37]
Reactant: OB(O)c1cccc(CN2CCOCC2)c1
Reactant: CC(C)n1cc(-c2cc(Br)cnc2N)nn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)n1cc(-c2cc(-c3cccc(CN4CCOCC4)c3)cnc2N)nn1
Temperature: 120 °C
Yield: 58.5 %

Procedure:
Cs2CO3 (858 mg, 2.64 mmol) was added to a solution of (3-(morpholinomethyl)phenyl)boronic acid (250 mg, 0.88 mmol) and 5-bromo-3-(1-isopropyl-1H-[1,2,3]triazol-4-yl)-pyridin-2-ylamine (215 mg, 0.97 mmol) in dioxane: water (8 mL: 4 mL) degassed the reaction mixture for 10 min with nitrogen. Then added Pd(PPh3)4 (50 mg, 0.044 mmol), degassed the reaction mixture for additional 10 min with nitrogen, the reaction mixture was heated to 120° C. in microwave for 1 h. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (2×30 mL). Combined organic layers was dried over Na2SO4 and concentrated under reduced pressure. Crude product was purified by silica (100-200 mesh) column eluted with 80-90% ethyl acetate in pet-ether to afford 195 mg (Yield: 58.13%) of the title compound as a pale yellow solid. Product was converted to its HCl salt by using HCl in ether (2M) to afford 202 mg as a pale yellow solid.
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])[CH2:2][C:3]([O:5][CH3:6])=[O:4].C([O-])([O-])=O.[K+].[K+].F[C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][C:18]=1[F:26]>CN(C=O)C>[F:26][C:18]1[CH:19]=[C:20]([N+:23]([O-:25])=[O:24])[CH:21]=[CH:22][C:17]=1[CH:2]([C:1]([O:8][CH3:9])=[O:7])[C:3]([O:5][CH3:6])=[O:4]
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Reactant: COC(=O)CC(=O)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C(C(=O)OC)c1ccc([N+](=O)[O-])cc1F
Temperature: 50 °C
Reaction time: 5 h
Yield: 76.3 %

Procedure:
To a stirred solution of dimethyl malonate (6.22 g, 47.1 mmol, 1.5 eq) in DMF (30 mL) was added K2CO3 (8.70 g, 63 mmol, 2.0 eq) and heated to 50° C. for 30 min when 1,2-difluoro-4-nitrobenzene (5.0 g, 31.4 mmol, 1.0 eq) was added and the reaction mixture was stirred for 5 h at 50° C. The reaction mixture was cooled to RT, filtered to remove K2CO3, and the DMF was evaporated under vacuum. The residue was diluted with EtOAc (100 mL), washed with water, brine, dried over Na2SO4 and evaporated to get dimethyl 2-(2-fluoro-4-nitrophenyl)malonate (6.5 g, 76%) as a solid (TLC system: EtOAc/PE (3:7), Rf: 0.50).
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][C:13]2[C:4](=[C:5]([NH2:16])[C:6]3[C:11]([N:12]=2)=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH:3]=1.[C:17](OC(=O)C)(=[O:19])[CH3:18]>C(O)(=O)C>[C:17]([NH:1][C:2]1[CH:15]=[CH:14][C:13]2[C:4](=[C:5]([NH2:16])[C:6]3[C:11]([N:12]=2)=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH:3]=1)(=[O:19])[CH3:18]
Reactant: Nc1ccc2nc3ccccc3c(N)c2c1
Reactant: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CC(=O)Nc1ccc2nc3ccccc3c(N)c2c1

Procedure:
To a 5 mL rbf equipped with condenser and a nitrogen bubbler were charged 2,9-diaminoacridine (100 mg, 0.48 mmol) and acetic acid (300 μL). To the resulting solution was added acetic anhydride (47 μL, 0.50 mmol). The reaction mixture was heated to reflux for 10 min under a nitrogen atmosphere. LCMS showed only formation of expected product and some traces of starting material. The reaction mixture was concentrated to dryness. NMR showed desired product, alkanes impurities coming from starting material sample and acetic acid left. The residue was dissolved in water and washed with DCM to remove the alkanes impurities. The aqueous layer was lyophilised to afford 2-acetamidyl-9-aminoacridine as a brown solid (130 mg, quantitative). Analyses by 1H NMR and LCMS conformed to structure.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[O:14][C@H:15]1[CH2:19][CH2:18][O:17][CH2:16]1)=O.[CH3:20][C:21]([S@@:24]([NH2:26])=[O:25])([CH3:23])[CH3:22]>C1COCC1.[O-]CC.[Ti+4].[O-]CC.[O-]CC.[O-]CC>[Cl:1][CH2:2][CH2:3][CH2:4]/[C:5](=[N:26]/[S@:24]([C:21]([CH3:23])([CH3:22])[CH3:20])=[O:25])/[C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[O:14][C@@H:15]1[CH2:19][CH2:18][O:17][CH2:16]1
Reactant: CC(C)(C)[S@@](N)=O
Reactant: O=C(CCCCl)c1cc(F)ccc1O[C@H]1CCOC1
Agent: [Ti+4]
Agent: CC[O-]
Solvent: C1CCOC1
Product: CC(C)(C)[S@](=O)/N=C(/CCCCl)c1cc(F)ccc1O[C@@H]1CCOC1
Temperature: 27.5 °C
Yield: 296.7 %

Procedure:
Titanium (IV) ethoxide (17.5 g, 76.92 mmol) was added to a solution of (S)-4-chloro-1-(5-fluoro-2-((tetrahydrofuran-3-yl)oxy)phenyl)butan-1-one (11 g, 38.46 mmol) and (S)-2-methylpropane-2-sulfinamide (9.32 g, 76.92 mmol) in THF (170 mL) with stirring. The mixture was stirred continuously at 70° C. for 16 h. Reaction mixture was then cooled to a temperature of 20-35° C., quenched with saturated aqueous NH4Cl solution, diluted with ethyl acetate and filtered. The filtrate was washed with water followed by brine solution. The organic layer was separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford 44.5 g of the title compound as a colorless liquid. MS (ESI): 390.2 (M+H).
Reaction SMILES: C(O)(C(F)(F)F)=O.[N:8]1[CH:9]=[C:10]([C:17]([NH:19][C:20]2[CH:21]=[C:22]([NH:27]C(=O)OC(C)(C)C)[CH:23]=[CH:24][C:25]=2[CH3:26])=[O:18])[N:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=12>S(C)C.ClCCl>[NH2:27][C:22]1[CH:23]=[CH:24][C:25]([CH3:26])=[C:20]([NH:19][C:17]([C:10]2[N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]3=[N:8][CH:9]=2)=[O:18])[CH:21]=1
Reactant: Cc1ccc(NC(=O)OC(C)(C)C)cc1NC(=O)c1cnc2ccccn12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CSC
Product: Cc1ccc(N)cc1NC(=O)c1cnc2ccccn12

Procedure:
TFA (50 mL) was added to a stirred suspension of tert-butyl 3-(imidazo[1,2-a]pyridine-3-carboxamido)-4-methylphenylcarbamate (66) in Me2S (5 mL) and dichloromethane (10 mL). After 2 hours the solution was evaporated and partitioned with dichloromethane and saturated NaHCO3. The aqueous layer was extracted several times with dichloromethane and the combined organic layers were dried over Na2SO4. N-(5-amino-2-methylphenyl)imidazo[1,2-a]pyridine-3-carboxamide (67) was isolated and used without further purification. 1H NMR (400 MHz, CDCl3) δ 9.44 (d, J=6.8 Hz, 1 H), 8.05 (s, 1 H), 7.67 (d, J=8.8 Hz, 1 H), 7.38-7.33 (m, 2 H), 6.98-6.94 (m, 2 H), 2.19 (s, 3 H). MS m/z 267.1 (M+1)+.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[N:26]1[C:35]2[CH:34]=[CH:33][N:32]=[C:31]([C:36](O)=[O:37])[C:30]=2[CH:29]=[CH:28][CH:27]=1>>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][N:20]([C:36]([C:31]4[N:32]=[CH:33][CH:34]=[C:35]5[C:30]=4[CH:29]=[CH:28][CH:27]=[N:26]5)=[O:37])[CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: O=C(O)c1nccc2ncccc12
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)cc1OC
Agent: Cl
Product: COc1ccc(C2=NN(C3CCN(C(=O)c4nccc5ncccc45)CC3)C(=O)C2(C)C)cc1OC

Procedure:
The title compound is prepared analogously as described for GP2-WU2 using 5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2-(piperidin-4-yl)-2,4-dihydro-3H-pyrazol-3-one (compound B1) and 1,6-naphthyridine-5-carboxylic acid as starting compounds. The crude product is purified by chromatography (silica gel and DCM/methanol=95:5) to yield the title compound.
Reaction SMILES: [SH:1][C:2]1[O:3][C:4]([C:7]2[O:11][C:10]([CH3:12])=[N:9][N:8]=2)=[N:5][N:6]=1.O1CCOCC1.Br[CH2:20][CH2:21][C:22]([F:26])=[C:23]([F:25])[F:24]>CN(C)C=O>[F:26][C:22](=[C:23]([F:25])[F:24])[CH2:21][CH2:20][S:1][C:2]1[O:3][C:4]([C:7]2[O:11][C:10]([CH3:12])=[N:9][N:8]=2)=[N:5][N:6]=1
Reactant: FC(F)=C(F)CCBr
Reactant: Cc1nnc(-c2nnc(S)o2)o1
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: Cc1nnc(-c2nnc(SCCC(F)=C(F)F)o2)o1
Yield: 54.5 %

Procedure:
3.7 g of 2-mercapto-5-(2-methyl-1,3,4-oxadiazol-5-yl)-1,3,4-oxadiazole according to Example H1 are initially introduced into a mixture of 36 ml of dioxane and 4 ml of dimethylformamide, and 2.24 g of potassium t-butylate are added, while stirring. 4.2 g of 4-bromo-1,1,2-trifluorobut-1-ene are added dropwise and the mixture is stirred overnight at room temperature. After the salts have been filtered off, the solvents are distilled off in vacuo, the residue is taken up in methylene chloride, the solution is washed with water and 1-normal sodium hydroxide solution in succession and the solvent is evaporated off in vacuo. 3.2 g of the desired compound of melting point 77°-79° C. are obtained as the residue.
Reaction SMILES: [C:1]1(=O)[CH2:5][CH2:4][C:3](=[O:6])[CH2:2]1.[F:8][C:9]([F:36])([F:35])[C:10]1[CH:11]=[C:12]([C@H:20]([O:22][C@@H:23]2[C@@H:27]([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)[CH2:26][NH:25][CH2:24]2)[CH3:21])[CH:13]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:15]=1.CC1C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[F:36][C:9]([F:8])([F:35])[C:10]1[CH:11]=[C:12]([C@H:20]([O:22][C@@H:23]2[C@@H:27]([C:28]3[CH:29]=[CH:30][C:31]([F:34])=[CH:32][CH:33]=3)[CH2:26][N:25]([C:1]3[CH2:5][CH2:4][C:3](=[O:6])[CH:2]=3)[CH2:24]2)[CH3:21])[CH:13]=[C:14]([C:16]([F:18])([F:19])[F:17])[CH:15]=1
Reactant: C[C@@H](O[C@H]1CNC[C@@H]1c1ccc(F)cc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: O=C1CCC(=O)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: C[C@@H](O[C@H]1CN(C2=CC(=O)CC2)C[C@@H]1c1ccc(F)cc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C

Procedure:
In a pressure tube was placed 562 mg cyclopentane-1,3-dione (5.73 mmol) followed by a solution of 2.3 g (3R,4S)-3-({(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}oxy)-4-(4-fluorophenyl)pyrrolidine (5.46 mmol) (step E) in 12.5 mL benzene. To this solution was added 52 mg PTSA (0.027 mmol) and 4 Å bead molecular sieves (1 g). The tube was sealed and heated for 3 hr. The tube was cooled to RT and the resulting solution filtered and the solvent removed under vacuum. The resulting bright yellow oil was purified by column chromatography on silica gel eluting with EtOAc/hexanes (1/1), then EtOAc (100%), then methylene chloride/methanol (9/1). The fractions containing the desired product (as determined by TLC) were combined and the solvent removed under vacuum. The resulting yellow oil was purified by prep HPLC on Chiralcel OD eluting with heptanes/reagent alcohol (87.5/12.5) to afford the title compound as a white solid. 1H-NMR (CD3OD) rotamers: δ: 1.43 (d, 3H, 6.5 Hz), 2.46 (m, 2H), 2.7-2.85 (m, 2H), 3.40-3.65 (m, 3H), 3.78-4.20 (m, 3H), 4.76 (quin., 1H, 6.5 Hz), 4.97, 5.03 (2s 1H), 6.98 (t, 2H), 7.18 (br. s, 2H), 7.72 (s, 2H), 7.83 (s, 1H)ppm. MS: 502.2 (MH+) observed. Crystallization of 3-[(3R,4S)-3-({(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}oxy)-4-(4-fluorophenyl)pyrrolidin-1-yl]cyclopent-2-en-1-one was achieved in aq. methanol (mp 45-46° C.). Alternatively, crystalline solid was obtained by crystallization in ether/hexanes mixture (mp 44-45° C.).
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]=1[CH2:10][NH:11][CH2:12][CH2:13][NH2:14].[C:15]([NH:17][C:18](=[N:21][CH3:22])SC)#[N:16]>>[N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]=1[CH2:10][NH:11][CH2:12][CH2:13][NH:14][C:18]([NH:17][C:15]#[N:16])=[N:21][CH3:22]
Reactant: NCCNCc1nc2ccccc2[nH]1
Reactant: CN=C(NC#N)SC
Product: CN=C(NC#N)NCCNCc1nc2ccccc2[nH]1

Procedure:
Reacting N-(2-benzimidazolylmethyl)ethylenediamine with N-cyano-N',S-dimethylisothiourea by the procedure of Example 36 gives N-[2-(2-benzimidazolylmethylamino)ethyl]-N'-cyano-N"-methylguanidine. Treating with hydrobromic acid gives the hydrobromide salt. Hydrolysis of this compound by the procedure of Example 3(e) gives N-[2-(2-benzimidazolylmethylamino)ethyl]-N'-methylguanidin trihydrochloride.
Reaction SMILES: Cl.[NH2:2][C:3]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH3:14])[N:6]=[C:5]([CH3:15])[CH:4]=1.[C:16]([N:19]1[CH2:23][C:22](=O)[N:21]=[CH:20]1)(=[O:18])[CH3:17]>>[C:16]([N:19]1[CH2:23][CH2:22][N:21]=[C:20]1[NH:2][C:3]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH3:14])[N:6]=[C:5]([CH3:15])[CH:4]=1)(=[O:18])[CH3:17]
Reactant: CC(=O)N1C=NC(=O)C1
Reactant: Cc1cc(N)n(-c2ccccc2C)n1
Agent: Cl
Product: CC(=O)N1CCN=C1Nc1cc(C)nn1-c1ccccc1C

Procedure:
5-Amino-3-methyl-1-(2-methylphenyl)pyrazole HCl (Farmaco, 19, 638, 1964) (26.5 g.) and 1-acetyl-2-imidazolinone (18.2 g.) were reacted as described in Example I to give 12.6 g. product, mp 160°-161°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:16])[C:5](N[C@@H]2CCS(=O)(=O)C2)=[CH:6][CH:7]=1.[F:17][C:18]([F:23])([F:22])[CH2:19][CH2:20][NH2:21]>>[Cl:1][C:2]1[CH:3]=[C:4]([NH2:16])[C:5]([NH:21][CH2:20][CH2:19][C:18]([F:23])([F:22])[F:17])=[CH:6][CH:7]=1
Reactant: NCCC(F)(F)F
Reactant: Nc1cc(Cl)ccc1N[C@@H]1CCS(=O)(=O)C1
Product: Nc1cc(Cl)ccc1NCCC(F)(F)F

Procedure:
4-Chloro-N1-(3,3,3-trifluoropropyl)benzene-1,2-diamine was prepared in analogy to 4-chloro-N—((R)-1,1-dioxo-tetrahydro-1λ6-thiophen-3-yl)-benzene-1,2-diamine in Example 2-1 by using 3,3,3-trifluoropropan-1-amine instead of (R)-1,1-dioxo-tetrahydro-1λ6-thiophen-3-ylamine.
Reaction SMILES: FC1C([O:8][C:9]([C:11]2[C:16]([Cl:17])=[N:15][C:14]3=[N:18][N:19]([CH2:21][C:22]4[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=4)[CH:20]=[C:13]3[C:12]=2[NH2:30])=O)=C(F)C(F)=C(F)C=1F.[NH3:35]>C1COCC1>[NH2:30][C:12]1[C:13]2[C:14](=[N:18][N:19]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=3)[CH:20]=2)[N:15]=[C:16]([Cl:17])[C:11]=1[C:9]([NH2:35])=[O:8]
Reactant: COc1ccc(Cn2cc3c(N)c(C(=O)Oc4c(F)c(F)c(F)c(F)c4F)c(Cl)nc3n2)cc1
Reactant: N
Solvent: C1CCOC1
Product: COc1ccc(Cn2cc3c(N)c(C(N)=O)c(Cl)nc3n2)cc1
Reaction time: 8 h

Procedure:
A solution of 4-amino-6-chloro-2-(4-methoxyphenyl)methyl-2H-pyrazolo[3,4-b]pyridine-5-carboxylic acid pentafluorophenyl ester (374 mg) in anhydrous THF was saturated with NH3 gas and stirred overnight. Removal of the solvent gave the desired product as a white solid (contain some pentafluorophenol). LC: 2.60 (Gradient 1); MH+: 332.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:32]([OH:34])=[O:33])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][CH2:20][N:21]2C(=O)C3=CC=CC=C3C2=O)=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.NN>C(O)C>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:32]([OH:34])=[O:33])[CH2:10][C:11]1[CH:12]=[CH:13][C:14]([O:17][CH2:18][CH2:19][CH2:20][NH2:21])=[CH:15][CH:16]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OCCCN2C(=O)c3ccccc3C2=O)cc1)C(=O)O
Agent: NN
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OCCCN)cc1)C(=O)O
Yield: 78.7 %

Procedure:
A mixture of diphenylmethyl ester of N-tert-butoxycarbonyl-O-(3-phthalimidopropyl)-L-tyrosine (4.4 g) and hydrazine hydrate (0.52 g) in ethanol (50 ml) was heated under reflux for 2.5 hours. After cooling, the resulting precipitates were filtered off and the filtrate was concentrated under reduced pressure. The residue was diluted with water and extracted with ethyl acetate. The extract was washed with water and brine, dried and evaporated to dryness to give diphenylmethyl ester of N-tert-butoxycarbonyl-O-(3-aminopropyl)-L-tyrosine (2.5 g) as oil.
Reaction SMILES: C([O:3][C:4](=[O:31])/[C:5](/[O:28][CH2:29][CH3:30])=[CH:6]/[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]2[N:16]=[C:17]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[O:18][C:19]=2[CH3:20])=[CH:9][C:8]=1[CH3:27])C.[OH-].[Na+]>>[CH2:29]([O:28]/[C:5](=[CH:6]\[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]2[N:16]=[C:17]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[O:18][C:19]=2[CH3:20])=[CH:9][C:8]=1[CH3:27])/[C:4]([OH:31])=[O:3])[CH3:30]
Reactant: CCOC(=O)/C(=C/c1ccc(OCc2nc(-c3ccccc3)oc2C)cc1C)OCC
Agent: [Na+]
Agent: [OH-]
Product: CCO/C(=C\c1ccc(OCc2nc(-c3ccccc3)oc2C)cc1C)C(=O)O

Procedure:
In analogy to the procedure described in example 1a f], (Z)-2-ethoxy-3-[2-methyl-4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-phenyl]-acrylic acid ethyl ester was treated with NaOH to obtain (Z)-2-ethoxy-3-[2-methyl-4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-phenyl]-acrylic acid as colorless solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12]([O:14][CH3:15])=[O:13])[C@@H:7]([CH3:16])[CH2:6][NH:5]2.BrC1C=C2C(N(C(C3CC3)=O)[C@@H](C)CN2[C:28]([O:30][CH:31]([CH3:33])[CH3:32])=[O:29])=CC=1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12]([O:14][CH3:15])=[O:13])[C@@H:7]([CH3:16])[CH2:6][N:5]2[C:28]([O:30][CH:31]([CH3:33])[CH3:32])=[O:29]
Reactant: CC(C)OC(=O)N1C[C@H](C)N(C(=O)C2CC2)c2ccc(Br)cc21
Reactant: COC(=O)N1c2ccc(Br)cc2NC[C@@H]1C
Product: COC(=O)N1c2ccc(Br)cc2N(C(=O)OC(C)C)C[C@@H]1C

Procedure:
4-isopropyl 1-methyl (S)-6-bromo-2-methyl-2,3-dihydroquinoxaline-1,4-dicarboxylate was synthesized from (S)-methyl 6-bromo-2-methyl-3,4-dihydroquinoxaline-1(2H)-carboxylate according to the procedure outlined above for (S)-isopropyl 7-bromo-4-(cyclopropanecarbonyl)-3-methyl-3,4-dihydroquinoxalin-1(2H)carboxylate. MS (ESI, pos. ion) m/z 393, 395 [M+Na]+.
Reaction SMILES: Cl.[CH:2]([C:5]1[CH:6]=[C:7]([C@@H:11]([NH2:13])[CH3:12])[CH:8]=[CH:9][CH:10]=1)([CH3:4])[CH3:3].[Cl:14][C:15]1[CH:35]=[C:34]([O:36][C@@H:37]([CH3:42])[C:38]([O:40][CH3:41])=[O:39])[CH:33]=[CH:32][C:16]=1[CH2:17][N:18]1[C:26]2[C:21](=[CH:22][C:23]([C:27](O)=[O:28])=[CH:24][CH:25]=2)[C:20]([CH3:30])=[C:19]1[CH3:31]>>[Cl:14][C:15]1[CH:35]=[C:34]([CH:33]=[CH:32][C:16]=1[CH2:17][N:18]1[C:26]2[C:21](=[CH:22][C:23]([C:27](=[O:28])[NH:13][C@H:11]([C:7]3[CH:8]=[CH:9][CH:10]=[C:5]([CH:2]([CH3:4])[CH3:3])[CH:6]=3)[CH3:12])=[CH:24][CH:25]=2)[C:20]([CH3:30])=[C:19]1[CH3:31])[O:36][C@@H:37]([CH3:42])[C:38]([O:40][CH3:41])=[O:39]
Reactant: CC(C)c1cccc([C@H](C)N)c1
Reactant: COC(=O)[C@H](C)Oc1ccc(Cn2c(C)c(C)c3cc(C(=O)O)ccc32)c(Cl)c1
Agent: Cl
Product: COC(=O)[C@H](C)Oc1ccc(Cn2c(C)c(C)c3cc(C(=O)N[C@@H](C)c4cccc(C(C)C)c4)ccc32)c(Cl)c1

Procedure:
The title compound was prepared following the same protocol as described in Step 5, Example 36, using the (S)-1-(3-isopropylphenyl)ethanamine hydrochloride instead of the (S)-1-(3-cyclopropylphenyl)ethanamine hydrochloride and the (S)-1-(2-chloro-4-((1-methoxy-1-oxopropan-2-yl)oxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylic acid instead of the 1-(4-(2-methoxy-2-oxoethoxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylic acid.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH:6]([OH:8])[C:5]2[S:9][CH:10]=[CH:11][C:4]=2[CH2:3]1.[Cl:12][C:13]1[CH:14]=[C:15](F)[CH:16]=[CH:17][C:18]=1[Cl:19]>>[Cl:12][C:13]1[CH:14]=[C:15]([O:8][CH:6]2[CH2:7][N:2]([CH3:1])[CH2:3][C:4]3[CH:11]=[CH:10][S:9][C:5]2=3)[CH:16]=[CH:17][C:18]=1[Cl:19]
Reactant: Fc1ccc(Cl)c(Cl)c1
Reactant: CN1Cc2ccsc2C(O)C1
Product: CN1Cc2ccsc2C(Oc2ccc(Cl)c(Cl)c2)C1

Procedure:
The same method as in Example 1 was conducted using 5-methyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-7-ol (Reference Example 14) instead of 6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-4-ol (Reference Example 6) and was conducted using 3,4-dichloro-1-fluorobenzene instead of 1-fluoronaphthalene to give the objective compound.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[C:13]=1[N:19]1[N:23]=[CH:22][CH:21]=[N:20]1)=[O:11].Cl[C:25]1[N:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][N:26]=1>>[F:18][C:14]1[C:13]([N:19]2[N:23]=[CH:22][CH:21]=[N:20]2)=[C:12]([C:10]([N:4]2[CH2:5][CH2:6][CH2:7][C@@H:8]([CH3:9])[C@H:3]2[CH2:2][NH:1][C:25]2[N:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][N:26]=2)=[O:11])[CH:17]=[CH:16][CH:15]=1
Reactant: FC(F)(F)c1cnc(Cl)nc1
Reactant: C[C@@H]1CCCN(C(=O)c2cccc(F)c2-n2nccn2)[C@@H]1CN
Product: C[C@@H]1CCCN(C(=O)c2cccc(F)c2-n2nccn2)[C@@H]1CNc1ncc(C(F)(F)F)cn1

Procedure:
The title compound was prepared following the same general protocol as described for Example A1 using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(3-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone and 2-chloro-5-(trifluoromethyl)pyrimidine. ESI-MS (m/z): 464 [M+1]+. 1H NMR (300 MHz, DMSO-d6) δ 8.75-6.75 (m, 8H), 4.80-2.70 (m, 5H), 1.65-0.70 (m, 8H).
Reaction SMILES: [NH:1]([C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22])[C@H:2]([C:7]([NH:9][C@H:10]([C:18]([OH:20])=[O:19])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].[NH2:31][C@H:32]([CH2:37][OH:38])[CH2:33][CH2:34][S:35][CH3:36]>CS(C)=O>[NH:1]([C:21]([O:23][CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)=[O:22])[C@H:2]([C:7]([NH:9][C@H:10]([C:18]([OH:20])=[O:19])[CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].[NH2:31][C@H:32]([CH:37]=[O:38])[CH2:33][CH2:34][S:35][CH3:36]
Reactant: CSCC[C@H](N)CO
Agent: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](Cc1ccccc1)C(=O)O
Solvent: CS(C)=O
Product: CSCC[C@H](N)C=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
CBZ-L-Leu-L-Phe-L-methioninol (sulfoxide) (1.38 g, 2.53 mmol) was dissolved in DMSO, o-lodoxybenzoic acid (2.12 g, 7.59 mmol) was added, requiring a few minutes of stirring at room temperature to dissolve. After three hours, the DMSO was removed under reduced pressure. The residue was twice diluted with CH2Cl2, and the solvent was evaporated to remove any residual DMSO. The residue was diluted with a minimum of acetone, and the white precipitate was filtered off. The filtrate was concentrated to near dryness and dissolved in EtOAc, which produced more of the white precipitate, which was again filtered off. The filtrate was washed with a 10% Na, S2O3/10% NaHCO, solution, water, and brine before drying over Na3SO4. Upon removal of the organic solvent, the residue was twice taken up in benzene and evaporated to remove any residual water, giving 0.98 g (71%) of a white glassy solid which was used immediately without further purification: 1H NMR (DMSO-d6) δ0.81 (m, 6H), 1.30 (m, 2H), 1.50 (m, 1H), 1.97 (m, 1H), 2.48 (s, 3H), 2.55-3.27 (m, 5H), 3.70 (m, 1), 4.47 (m, 1H), 4.71 (m, 1H), 5.00 (s, 2H), 7.20-7.40 (m, 10H), 7.93 (m, 1H), 8.08 (m, 1H), 8.51 (m, 1H), 9.22 (s, 1H); (M+H) 544.