Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=O)[C:5]([OH:24])([C:20]([F:23])([F:22])[F:21])[CH2:6][C:7]([C:10]1[C:18]2[O:17][CH2:16][CH2:15][C:14]=2[CH:13]=[C:12](Br)[CH:11]=1)([CH3:9])[CH3:8])C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[CH2:15]([C:14]1[C:18]([OH:17])=[C:10]([C:7]([CH3:9])([CH3:8])[CH2:6][C:5]([C:20]([F:22])([F:23])[F:21])([OH:24])[CH2:4][OH:3])[CH:11]=[CH:12][CH:13]=1)[CH3:16]
Reactant: CCOC(=O)C(O)(CC(C)(C)c1cc(Br)cc2c1OCC2)C(F)(F)F
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CCc1cccc(C(C)(C)CC(O)(CO)C(F)(F)F)c1O
Yield: 7.9 %

Procedure:
Over-reduction of 10 g (23.51 mmol) of 4-(5-bromo-2,3-dihydrobenzofuran-7-yl)-2-hydroxy-4-methyl-2-trifluoromethylpentanoic acid ethyl ester with lithium aluminum hydride for 14 days at reflux gave 570 mg (7.9%) of 4-(3-ethyl-2-hydroxyphenyl)-4-methyl-2-trifluoromethylpentane-1,2-diol which was methylated by methods analogous to those described in Example 8 and oxidized by methods analogous to those described in Example 1 to afford 4-(3-ethyl-2-methoxyphenyl)-1,1,1-trifluoro-4-methylpentan-2-one. The title compound was prepared by methods analogous to those described in Example 5, using 2-chloro-4-cyanobenzyl bromide.
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([CH2:15][N:16]2[C:20]([CH:21]=[O:22])=[C:19]([Cl:23])[N:18]=[C:17]2[CH2:24][CH2:25][CH2:26][CH3:27])=[CH:11][CH:10]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:24]([C:17]1[N:16]([CH2:15][C:12]2[CH:13]=[CH:14][C:9]([S:6]([NH2:5])(=[O:7])=[O:8])=[CH:10][CH:11]=2)[C:20]([CH:21]=[O:22])=[C:19]([Cl:23])[N:18]=1)[CH2:25][CH2:26][CH3:27]
Reactant: CCCCc1nc(Cl)c(C=O)n1Cc1ccc(S(=O)(=O)NC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCc1nc(Cl)c(C=O)n1Cc1ccc(S(N)(=O)=O)cc1

Procedure:
Intermediate (2b) was dissolved into 60 mL of 1:1 DCM:TFA and heated to 40° C. for 16 hours. The mixture was concentrated under reduced pressure to yield intermediate (2c) as a yellow oil in a quantitative yield. MS m/z: [M+H−] calcd for C15H18ClN3O3S 356.1; found 356.3.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH3:19])[N:9]=[C:10]([C:11]3[O:12][C:13]([N+:16]([O-:18])=[O:17])=[CH:14][CH:15]=3)[C:3]=12.[NH3:20]>C(O)C>[NH2:20][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH3:19])[N:9]=[C:10]([C:11]3[O:12][C:13]([N+:16]([O-:18])=[O:17])=[CH:14][CH:15]=3)[C:3]=12
Reactant: Cn1nc(-c2ccc([N+](=O)[O-])o2)c2c(Cl)ncnc21
Reactant: N
Solvent: CCO
Product: Cn1nc(-c2ccc([N+](=O)[O-])o2)c2c(N)ncnc21

Procedure:
A mixture of 1.0 grams of 4-chloro-1-methyl-3-(5-nitro-2-furyl)-1H-pyrazolo[3,4-d]pyrimidine and a solution of 100 milliliters of dry ethanol saturated at room temperature with ammonia gas, was heated in a sealed stainless steel tube at a bath temperature of 130° C. and 7 atmospheres pressure for 3 hours, and cooled. The crystalline product was collected washed with water and dried. Recrystallisation from dimethylformamide gave 4-amino-1-methyl-3-(5-nitro-2-furyl)-1H-pyrazolo [3,4-d]pyrimidine having decomposition point 305° C. identical with the product obtained in Example 1.
Reaction SMILES: [C:1]([CH2:4][C:5](=O)[CH3:6])(=[O:3])[CH3:2].[Na].C([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1)=C>>[N:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[CH2:6][CH2:5][CH2:4][C:1](=[O:3])[CH3:2]
Reactant: C=Cc1ccccn1
Reactant: CC(=O)CC(C)=O
Agent: [Na]
Product: CC(=O)CCCc1ccccn1
Yield: 14.6 %

Procedure:
According to reference F. Noel, Albertson J. Am. Chem. Soc. 1950, 72, 2594-99, a reaction mixture comprising 50 g of acetyl acetone, 1.5 g of sodium and 108 g of 2-vinylpyridine is refluxed for 7 hours. The produced may be distilled as a yellow oil at 1.5. 102 Pa (1.1 Torr) (b.p.: 90-127° C.). Fractional distillation of this oil yields 11.9 g of 5-(2-pyridyl)-2-pentanone (4a) with a boiling point of 88-105° C. and 1.3·102 Pa (1.0 Torr).
Reaction SMILES: C[O:2][C:3](=[O:15])[CH2:4][C:5]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[C:7]([Cl:14])[CH:6]=1.[OH-].[Na+]>CO.O>[Cl:14][C:7]1[CH:6]=[C:5]([CH2:4][C:3]([OH:15])=[O:2])[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=1
Reactant: COC(=O)Cc1cc(Cl)cc([N+](=O)[O-])c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)Cc1cc(Cl)cc([N+](=O)[O-])c1
Reaction time: 2 h
Yield: 93.9 %

Procedure:
To a solution of (3-Chloro-5-nitro-phenyl)-acetic acid methyl ester (327, 920 mg, 4.0 mmol) in 20 mL of MeOH was added a solution of NaOH (EM, 1.6 g, 40 mmol) in 10 mL of H2O. The mixture was stirred for 2 h. MeOH was removed under reduced pressure, and the mixture was diluted with water, brought to pH 2 with con. HCl. The mixture was extracted 3× with EtOAc (50 mL). The organic layers were washed twice with a brine solution (50 mL), dried over Na2SO4. Removal of the solvent gave 810 mg (94%) of product. 1H NMR (400 MHz, DMSO-d6) δ 8.17-8.14 (m, 2H), 7.84 (br s, 1H), 3.77 (s, 3H).
Reaction SMILES: [O:1]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([CH2:11][OH:12])[CH2:2]1.[H][H]>CO.[Pd]>[O:1]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH:3]([CH2:11][OH:12])[CH2:2]1
Reactant: OCC1=Cc2ncccc2OC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: OCC1COc2cccnc2C1
Yield: 78.5 %

Procedure:
A mixture of intermediate (25) (0.0027 mol) in methanol (20 ml) was hydrogenated for 24 hours at room temperature with palladium-on-carbon (0.04 g) as a catalyst. After uptake of hydrogen (1 equivalent), the catalyst was filtered off and the filtrate was evaporated, yielding 0.35 g of 3,4-dihydro-2H-pyrano[3,2-b]pyridine-3-methanol (intermediate 26).
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([N:11]2[CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3[C:20]([F:23])([F:22])[F:21])[C:12]2=[O:24])[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.[Br:31][C:32]1[N:33]=[CH:34][C:35]([NH2:38])=[N:36][CH:37]=1.N1C(C)=CC=CC=1C>C(Cl)Cl.CN(C)C=O>[Br:31][C:32]1[N:33]=[CH:34][C:35]([NH:38][C:8](=[O:10])[C@@H:7]([N:11]2[CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3[C:20]([F:23])([F:22])[F:21])[C:12]2=[O:24])[CH2:6][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)=[N:36][CH:37]=1
Reactant: O=C(O)[C@H](CC1CCCC1)N1Cc2c(cccc2C(F)(F)F)C1=O
Reactant: Nc1cnc(Br)cn1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Solvent: CN(C)C=O
Product: O=C(Nc1cnc(Br)cn1)[C@H](CC1CCCC1)N1Cc2c(cccc2C(F)(F)F)C1=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 51.3 %

Procedure:
A solution of (S)-3-cyclopentyl-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-propionic acid (prepared as in Example 1, 100 mg, 0.29 mmol) in methylene chloride (4 mL) and N,N-dimethylformamide (4 drops) was treated with a solution of oxalyl chloride in methylene chloride (2.0 M, 150 μL, 0.30 mmol) and stirred for 15 min at room temperature. After this time, the reaction mixture was then concentrated in vacuo and the resulting residue was dissolved in methylene chloride (4 mL) and then added dropwise to a separate reaction flask containing a mixture of 5-bromo-pyrazin-2-ylamine (76 mg, 0.44 mmol) and 2,6-lutidine (100 μL, 0.87 mmol) in methylene chloride (3 mL) at room temperature. The resulting reaction mixture was the stirred room temperature for 1.5 h. The reaction mixture was quenched by the addition of methanol and then diluted with methylene chloride and the organic layer was washed with a 1N aqueous hydrochloric acid solution. The organic layer was then dried, filtered and the filtrate concentrated in vacuo. The crude material was purified via Biotage flash column chromatography (40 S silica gel column, 25% ethyl acetate/hexanes) to afford (S)—N-(5-bromo-pyrazin-2-yl)-3-cyclopentyl-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-propionamide (74 mg, 51%) as a white foam: HR-ES(+) m/e calcd for C21H20N4O2F3Br [M+H]+ 497.0795, observed 497.0796; 1H NMR (400 MHz, DMSO-d6) δ ppm 11.50 (s, 1H), 9.09 (d, J=1.07 Hz, 1H), 8.65 (d, J=1.28 Hz, 1H), 8.02 (dd, J=7.88, 10.44 Hz, 2H), 7.77 (t, J=7.67 Hz, 1H), 5.22 (dd, J=4.90, 10.66 Hz, 1H), 5.04 (d, J=18.33 Hz, 1H), 4.76 (d, J=18.11 Hz, 1H), 1.04-2.19 (m, 11H).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH:4](C)[CH:5]=O.[CH:8]([O:15][CH2:16][CH3:17])([O:12][CH2:13][CH3:14])OCC.C([O-])([O-])=O.[Na+].[Na+]>O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(O)C>[CH2:16]([O:15][CH:8]([O:12][CH2:13][CH3:14])[CH:4]([CH3:5])[CH2:3][CH2:2][Cl:1])[CH3:17]
Reactant: CCOC(OCC)OCC
Reactant: CC(C=O)CCCl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOC(OCC)C(C)CCCl
Temperature: 45 °C
Reaction time: 8 h
Yield: 41.1 %

Procedure:
A mixture of 4-chloro-2-methylbutyraldehyde (4.8 g, 0.040 moles), triethyl orthoformate (6.48 g, 0.044 moles), ethyl alcohol (3.0 g), and p-toluenesulfonic acid monohydrate (0.0144 g, 0.000757 moles) was stirred at 45° C. overnight under an argon atmosphere. Next, after cooling to room temperature, Na2CO3 (0.40 g) was added and the mixture was stirred for 15 min. The reaction mixture was filtered and ethyl alcohol and residual triethyl orthoformate were distilled off under reduced pressure. The residue was subjected to fractional vacuum distillation giving 3.2 g of pure 4-chloro-2-methylbutyraldehyde diethyl acetal. NMR (d6-DMSO): 0.85 ppm (d, —CH3, 3H) 1.13 ppm (m, —CH3, 6H), 1.52 ppm (m, —CH—, 1H), 1.87 ppm (m, —CH2CH2Cl, 2H), 3.35-3.75 ppm (bm, —OCH2CH3, 4H, and —CH2Cl, 2H), 4.22 ppm (d, —CH acetal, 1H).
Reaction SMILES: [CH3:1][Si:2]([CH3:35])([CH3:34])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[C:8]1[N:13]2[N:14]=[CH:15][CH:16]=[C:12]2[N:11]=[C:10]([CH:17]2[CH2:22]C[C:20](=[CH:23][C:24]#[N:25])[CH2:19][CH2:18]2)[CH:9]=1.C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)C1N2N=CC=C2N=C(C2CCC(=O)C2)C=1.C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)C1N2N=CC=C2N=C(C2CCC(=O)CC2)C=1>>[CH3:1][Si:2]([CH3:35])([CH3:34])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:31])[CH3:32])[C:8]1[N:13]2[N:14]=[CH:15][CH:16]=[C:12]2[N:11]=[C:10]([CH:17]2[CH2:18][CH2:19][C:20](=[CH:23][C:24]#[N:25])[CH2:22]2)[CH:9]=1
Reactant: C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)c1cc(C2CCC(=CC#N)CC2)nc2ccnn12
Agent: C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)c1cc(C2CCC(=O)C2)nc2ccnn12
Agent: C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)c1cc(C2CCC(=O)CC2)nc2ccnn12
Product: C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)c1cc(C2CCC(=CC#N)C2)nc2ccnn12

Procedure:
2-(3-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)cyclopentylidene)acetonitrile was synthesized in a manner similar to the synthesis of 2-(4-(7-(Bis((2-(trimethylsilyl)ethoxy)methyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)cyclohexylidene)acetonitrile, but with 3-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)cyclopentanone substituted for 4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)cyclohexanone.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[C:15]2([OH:19])[CH2:18][O:17][CH2:16]2)[CH2:3][CH2:2]1.[NH2:20][C@@H:21]([CH2:25][CH:26]([CH3:28])[CH3:27])[C:22]([NH2:24])=[O:23]>>[C:22]([C@@H:21]([NH:20][C:12]([C:10]1[CH:9]=[CH:8][C:7]([C:15]2([OH:19])[CH2:18][O:17][CH2:16]2)=[C:6]([O:5][CH2:4][CH:1]2[CH2:2][CH2:3]2)[N:11]=1)=[O:14])[CH2:25][CH:26]([CH3:28])[CH3:27])(=[O:23])[NH2:24]
Reactant: CC(C)C[C@H](N)C(N)=O
Reactant: O=C(O)c1ccc(C2(O)COC2)c(OCC2CC2)n1
Product: CC(C)C[C@H](NC(=O)c1ccc(C2(O)COC2)c(OCC2CC2)n1)C(N)=O

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-cyclopropylmethoxy-5-(3-hydroxy-oxetan-3-yl)-pyridine-2-carboxylic acid and (2S)-2-amino-4-methyl-pentanamide (CAN 687-51-4) as starting materials, MS (EI): m/e=378.2 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:10][C@H:9]2[NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[F:25][C:26]([F:37])([F:36])[C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[CH:31][CH:32]=1>C(#N)C.O>[F:25][C:26]([F:37])([F:36])[C:27]1[CH:32]=[C:31]([C:2]2[CH:7]=[CH:6][C:5]([C@@H:8]3[CH2:10][C@H:9]3[NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:4][CH:3]=2)[CH:30]=[CH:29][CH:28]=1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)N[C@@H]1C[C@H]1c1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CC(C)(C)OC(=O)N[C@@H]1C[C@H]1c1ccc(-c2cccc(C(F)(F)F)c2)cc1
Yield: 66.2 %

Procedure:
To a solution of tert-butyl (trans)-2-(4-bromophenyl)cyclopropylcarbamate (Intermediate E[a2]) (1 g, 3.2 mmol), potassium carbonate (1.31 g, 9.6 mmol), 3-(trifluoromethyl) phenylboronic acid (0.73 g, 3.8 mmol) in acetonitrile:water (4:1) were degassed for 30 mins, added tetrakis triphenylphosphine palladium (36 mg, 0.032 mmol), degassed again for 10 mins, heated the reaction mixture at reflux temperature for 5 h. After completion, the reaction mixture was poured in ice water (50 mL), extracted with, ethyl acetate (2×50 mL). Combined extracts were washed with water (70 mL), brine (70 mL), dried over anhydrous Na2SO4, filtered and evaporated. The crude residue was purified by column chromatography (SiO2), by using EtOAc:Petroleum ether (2:8) to get tert-butyl (trans)-2-(3′-(trifluoromethyl)biphenyl-4-yl)cyclopropylcarbamate (0.8 g, 66%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[N:5]=[C:4](Cl)[N:3]=1.[CH2:10]([NH2:12])[CH3:11].O1CCOCC1.[OH-].[Na+]>O>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[N:5]=[C:4]([NH:12][CH2:10][CH3:11])[N:3]=1
Reactant: Nc1nc(N)nc(Cl)n1
Reactant: CCN
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CCNc1nc(N)nc(N)n1
Yield: 74.6 %

Procedure:
A mixed solution of 14.5 g (0.1 mol) of 2,4-diamino-6-chloro-1,3,5-triazine prepared in Reference Example 1, 12.8 g (0.2 mol) of aqueous ethylamine solution (70%), 20 mL of water, and 50 mL of 1,4-dioxane was warmed with stirring and allowed to react at a reflux temperature for 4 hours. Thereafter, a solution of 4.0 g (0.1 mol) of sodium hydroxide in 15 mL of water was dropwise added thereto over 1 hour while maintaining the reflux state. After cooling the reaction mixture, the solvent and excess ethylamine were distilled off under reduced pressure, 30 mL each of methanol and acetonitrile were added, and the unnecessary salts were filtered. To the residue obtained by distilling off the solvent from the filtered solution were added 5 mL of methanol and 40 mL of acetone to precipitate crystals, which were collected by filtration, washed with 10 mL of acetone, and dried to obtain 11.5 g (yield 75%) of the titled compound. Melting point: 171° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:19]=[CH:20][C:21]=1[N+:22]([O-])=O)[CH2:7][N:8]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]1=[O:18])([O-])=O.C(O)C.C1COCC1>[Pd].C(O)(=O)C>[NH2:1][C:4]1[CH:5]=[C:6]([CH:19]=[CH:20][C:21]=1[NH2:22])[CH2:7][N:8]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]1=[O:18]
Reactant: O=C1c2ccccc2C(=O)N1Cc1ccc([N+](=O)[O-])c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CCO
Product: Nc1ccc(CN2C(=O)c3ccccc3C2=O)cc1N
Temperature: 25 °C
Reaction time: 15 h
Yield: 92 %

Procedure:
A mixture of 2-(3,4-dinitrobenzyl)isoindole-1,3-dione (8 g, 24.4 mmol), prepared as in Example 1, and 10% palladium on carbon (300 mg) was combined with anhydrous ethanol (200 mL, anhydrous THF (100 mL) and glacial acetic acid (30 mL) under a continuous stream of nitrogen. The mixture then was stirred vigorously 15 hours at room temperature under hydrogen, filtered and concentrated to a volume of approximately 30 mL by rotary evaporation. The mixture was diluted with water (100 mL) and ammonium hydroxide was added to give an orange precipitate. The precipitate was isolated by filtration and washed several times with water to provide 2-(3,4-diaminobenzyl)isoindole-1,3-dione (6 g, 91% yield); 1H-NMR (300 Mhz, DMSO-d6): 7.76-7.85 (m, 4H), 6.31-6.43 (m, 3H), 4.51 (broad s, 4H), 4.47 (s, 2H).
Reaction SMILES: [CH2:1]([C:3]1[C:12]([C:13]([O:15]C)=[O:14])=[C:11]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([O:25][CH3:26])[CH:18]=2)[C:10]2[C:5](=[CH:6][C:7]([O:29][CH3:30])=[C:8]([O:27][CH3:28])[CH:9]=2)[N:4]=1)[CH3:2].[OH-].[Na+].CO>O>[CH3:28][O:27][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][C:7]=1[O:29][CH3:30])[N:4]=[C:3]([CH2:1][CH3:2])[C:12]([C:13]([OH:15])=[O:14])=[C:11]2[C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([O:25][CH3:26])[CH:18]=1
Reactant: CCc1nc2cc(OC)c(OC)cc2c(-c2ccc(OC)c(OC)c2)c1C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCc1nc2cc(OC)c(OC)cc2c(-c2ccc(OC)c(OC)c2)c1C(=O)O
Reaction time: 14 h
Yield: 71 %

Procedure:
A mixture of methyl 2-ethyl-6,7-dimethoxy-4-(3,4-dimethoxyphenyl)quinoline-3-carboxylate (0.5 g), 4N sodium hydroxide (20 ml) and methanol was stirred for 14 hours under reflux, poured into water, made acidic and extracted with chloroform. The chloroform layer was washed with water and dried over magnesium sulfate. Evaporation of the solvent gave 6,7-dimethoxy-4-(3,4-dimethoxyphenyl)-2-ethylquinoline-3-carboxylic acid (0.343 g, 71%) which was then recrystallized from acetone-methanol. mp. 264°-267° C.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:10](=O)[CH2:9][CH:8]([C:13]3[CH:17]=[CH:16][S:15][CH:14]=3)[CH2:7][C:6]=2[N:5]=[CH:4][CH:3]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH2:29][NH:30][C:31]([NH:33][OH:34])=[NH:32].[ClH:35]>C(O)C>[ClH:35].[OH:34][NH:33][C:31]([NH:30][N:29]=[C:10]1[CH2:9][CH:8]([C:13]2[CH:17]=[CH:16][S:15][CH:14]=2)[CH2:7][C:6]2[N:5]=[CH:4][CH:3]=[C:2]([CH3:1])[C:11]1=2)=[NH:32]
Reactant: N=C(NN)NO
Reactant: Cc1ccnc2c1C(=O)CC(c1ccsc1)C2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: CCO
Product: Cc1ccnc2c1C(=NNC(=N)NO)CC(c1ccsc1)C2
Temperature: 90 °C
Reaction time: 2 h

Procedure:
A mixture of 4-methyl-7-(3-thienyl)-5,6,7,8-tetrahydroquinolin-5-one (243 mg), 1-amino-3-hydroxyguanidine p-toluenesulfonate (393 mg) and concentrated hydrochloric acid (0.2 ml) in ethanol (3 ml) was stirred at 90° C. (bath temperature) for 2 hours. The reaction solution was concentrated under reduced pressure, and to the residue were added ethyl acetate (30 ml), tetrahydrofuran (20 ml) and 0.2 N sodium hydroxide (20 ml). The mixture was shaken, and the separated upper layer was washed with 0.2 N sodium hydroxide (10 ml) and water (10 ml, thrice). To the upper layer was added 2 N hydrochloric acid (1 ml), and the mixture was concentrated under reduced pressure. To the residue was added ether (3 ml), and the mixture was stirred at 90° C. (bath temperature) for 2 hours and cooled to give crystals, which were filtered, washed with ethanol and dried to give 5-(1-hydroxyguanidin-3-yl)imino-4-methyl-7-(3-thienyl)-5,6,7,8-tetrahydroquinoline hydrochloride (Compound 103) (233 mg) as pale yellow crystals.
Reaction SMILES: [S:1]1[CH2:6][CH2:5][N:4]([C:7]([CH2:9][O:10][CH:11]2[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[N:15]([C:22](=[O:39])[C:23]3[CH:28]=[CH:27][C:26]([NH:29][C:30](=[O:38])[C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=4[CH3:37])=[CH:25][CH:24]=3)[CH2:14][CH2:13][CH2:12]2)=[O:8])[CH2:3][CH2:2]1.ClC1C=CC=C(C(OO)=[O:48])C=1.S([O-])(O)=O.[Na+]>ClCCl>[O:48]=[S:1]1[CH2:6][CH2:5][N:4]([C:7]([CH2:9][O:10][CH:11]2[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[N:15]([C:22](=[O:39])[C:23]3[CH:28]=[CH:27][C:26]([NH:29][C:30](=[O:38])[C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=4[CH3:37])=[CH:25][CH:24]=3)[CH2:14][CH2:13][CH2:12]2)=[O:8])[CH2:3][CH2:2]1
Reactant: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(OCC(=O)N3CCSCC3)c3ccccc32)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(OCC(=O)N3CCS(=O)CC3)c3ccccc32)cc1
Temperature: -8 °C
Yield: 77.7 %

Procedure:
To a solution of 5-(thiomorpholinocarbonylmethoxy)-1-[4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.40 g) in dichloromethane (40 ml) is added 80% m-chloroperbenzoic acid (175 mg) with stirring at -8° C., and the mixture is stirred at -8° C. for 1 hour. To the reaction solution is added 20% aqueous sodium hydrogensulfite solution (40 ml) and the mixture is stirred at room temperature for 30 minutes. The dichloromethane layer is collected, washed with saturated saline solution and dried over magnesium sulfate. The solvent is distilled off and the resulting residue is purified by silica gel column chromatography (eluent; dichloromethane:methanol=20:1) to give 5-[(1-oxothiomorpholino)carbonylmethoxy]-1-[4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.32 g) as colorless amorphous.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]([NH2:11])[CH3:10])=[C:5]([C:12]([F:15])([F:14])[F:13])[CH:4]=1.C([O:20][C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29]1[CH:34]=[CH:33][C:32]([CH2:35][N:36]2[C:44]3[C:39](=[CH:40][C:41]([C:45](O)=[O:46])=[CH:42][CH:43]=3)[C:38]([CH3:48])=[C:37]2[CH3:49])=[CH:31][CH:30]=1)=[O:22])(C)(C)C>>[F:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]([NH:11][C:45]([C:41]2[CH:40]=[C:39]3[C:44](=[CH:43][CH:42]=2)[N:36]([CH2:35][C:32]2[CH:31]=[CH:30][C:29]([C:24]4[C:23]([C:21]([OH:22])=[O:20])=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:34][CH:33]=2)[C:37]([CH3:49])=[C:38]3[CH3:48])=[O:46])[CH3:10])=[C:5]([C:12]([F:13])([F:14])[F:15])[CH:4]=1
Reactant: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c2ccc(C(=O)O)cc12
Reactant: C[C@H](N)c1ccc(F)cc1C(F)(F)F
Agent: Cl
Product: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)O)cc2)c2ccc(C(=O)N[C@@H](C)c3ccc(F)cc3C(F)(F)F)cc12

Procedure:
The title compound was prepared following the same general protocol as described in Step 8-9, Example 1, using the (S)-1-(4-fluoro-2-(trifluoromethyl)phenyl)ethanamine hydrochloride and the 1-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid. ESI-MS (m/z): 589 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([N:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:22][NH:23][CH2:24][CH2:25][OH:26]>>[CH3:21][O:20][C:17]1[CH:18]=[CH:19][C:14]([N:12]([CH3:13])[C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=[C:2]([N:23]([CH3:22])[CH2:24][CH2:25][OH:26])[N:11]=2)=[CH:15][CH:16]=1
Reactant: CNCCO
Reactant: COc1ccc(N(C)c2nc(Cl)nc3ccccc23)cc1
Product: COc1ccc(N(C)c2nc(N(C)CCO)nc3ccccc23)cc1
Temperature: 130 °C
Reaction time: 0.33 h

Procedure:
A mixture of (2-chloroquinazolin-4-yl)-(4-methoxyphenyl)-methylamine 0.335 g (1.0 mmol), 2-methylamino-ethanol 1.0 mL was stirred at 130° C. for 20 minutes under microwave irradiation. The crude mixture was directly charged to silica-gel, and purified by MPLC (SiO2, EtOAc 0˜100% in hexanes) to give the title compound. 1H NMR (CDCl3, 400 MHz) δ 7.31-7.40 (m, 2H), 7.08-7.11 (m, 2H), 6.87-6.90 (m, 2H), 6.81-6.84 (m, 1H), 6.61-6.65 (m, 1H), 3.94-3.96 (m, 2H), 3.84-3.86 (m, 2H), 3.82 (s, 3H), 3.51 (s, 3H), 3.34 (s, 3H); HRMS (ES) m/z calcd for C19H22N4O2 (M+H) 339.1815, found 339.1830.
Reaction SMILES: [NH:1]1[C:7]2=[C:8]3[C:13](=[N:14][C:15]4[CH2:16][CH2:17][CH2:18][CH:5]([C:6]=42)[O:4][CH2:3][C:2]1=[O:19])[CH:12]=[CH:11][CH:10]=[CH:9]3.[CH3:20]C(C)([O-])C.[K+].CI>O1CCCC1>[CH3:20][N:1]1[C:7]2=[C:8]3[C:13](=[N:14][C:15]4[CH2:16][CH2:17][CH2:18][CH:5]([C:6]=42)[O:4][CH2:3][C:2]1=[O:19])[CH:12]=[CH:11][CH:10]=[CH:9]3
Reactant: CC(C)(C)[O-]
Reactant: O=C1COC2CCCc3nc4ccccc4c(c32)N1
Agent: [K+]
Solvent: CI
Solvent: C1CCOC1
Product: CN1C(=O)COC2CCCc3nc4ccccc4c1c32
Temperature: 25 °C
Reaction time: 2 h
Yield: 46.3 %

Procedure:
To a solution of 1,3,4a,5,6,7-hexahydro-2H-quino[4,3,2-ef][1,4]-benzoxazepin-2-one (4.09 g) in tetrahydrofuran (100 ml) was added potassium t-butoxide (2.17 g) followed by methyl iodide (1.25 ml). The reaction mixture was stirred for 2 hrs at ambient temperature and then concentrated. The residue was stirred in water/ethyl ether, the precipitate was collected and dried to give 2.0 g (46%) of 1,3,4a,5,6,7-hexahydro-1-methyl-2H-quino[4,3,2-ef][1,4]benzoxazepin-2-one.