Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[CH:11](O)[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:13]([F:16])([F:15])[F:14])[CH:9]=2)[NH:4][CH:3]1[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[CH:18]=1.FC(F)(F)C(O)=O>C([SiH](CC)CC)C>[CH3:1][C:2]1([CH3:26])[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:13]([F:15])([F:14])[F:16])[CH:9]=2)[NH:4][CH:3]1[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[CH:18]=1
Reactant: CC1(C)C(O)c2cc(C(F)(F)F)ccc2NC1c1cccc([N+](=O)[O-])c1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)Cc2cc(C(F)(F)F)ccc2NC1c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 36.1 %

Procedure:
To a mixture of 3,3-dimethyl-2-(3-nitro-phenyl)-6-trifluoromethyl-1,2,3,4-tetrahydro-quinolin-4-ol (7.1 g, 19 mmol) and triethylsilane (20 mL) at 25° C. was added trifluoroacetic acid (5 mL) dropwise. The resulting mixture was stirred at 25° C. for 1 h. Then the reaction mixture was concentrated in vacuo and the residue was extracted with ethyl acetate (2×200 mL), washed with saturated aqueous sodium bicarbonate solution (2×100 mL), dried over anhydrous sodium sulfate and concentrated in vacuo. Purification on flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company) (10% ethyl acetate/hexanes) to afford 3,3-dimethyl-2-(3-nitro-phenyl)-6-trifluoromethyl-1,2,3,4-tetrahydro-quinoline (2.4 g, 36%) as a white solid: LC/MS m/e calcd for C18H17F3N2O2 (M+H)+: 351.34, observed: 351.1.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([O:18]C(C)(C)C)=[O:17])=[C:11]([C:23]#[N:24])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([OH:18])=[O:17])=[C:11]([C:23]#[N:24])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)Cc1ccc(OCc2ccccc2)cc1C#N
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1cc(OCc2ccccc2)ccc1CC(=O)O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of tert-butyl [4-(benzyloxy)-2-cyanophenyl]acetate (0.48 g, 1.48 mmol) in DCM (7 ml) was treated with TFA (3.43 ml, 44.5 mmol) and the mixture stirred at RT for 30 min. The volatiles were removed in vacuo to afford the title compound. LC/MS (m/z): 268 (M+H)+.
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O.[CH3:32][O:33][C:34]1[CH:35]=[CH:36][C:37]([CH2:40]O)=[CH:38][CH:39]=1.[C:42]1(=[O:48])[NH:46][C:45](=[O:47])[CH:44]=[CH:43]1>>[CH3:32][O:33][C:34]1[CH:39]=[CH:38][C:37]([CH2:40][N:46]2[C:42](=[O:48])[CH:43]=[CH:44][C:45]2=[O:47])=[CH:36][CH:35]=1
Reactant: O=C1C=CC(=O)N1
Reactant: COc1ccc(CO)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: COc1ccc(CN2C(=O)C=CC2=O)cc1

Procedure:
Reagents: Ph3P (1.31 g, 5 mmol), DEAD (0.8 ml, 5 mmol), p-methoxybenzyl alcohol (0.93 ml, 7.5 mmol) and maleimide (0.48 g, 5 mmol).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:3]=1.O.[NH2:15][NH2:16]>C(O)C>[NH:15]([C:2]1[N:7]=[CH:6][N:5]=[C:4]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:3]=1)[NH2:16]
Reactant: Clc1cc(N2CCOCC2)ncn1
Reactant: NN
Solvent: CCO
Solvent: O
Product: NNc1cc(N2CCOCC2)ncn1
Temperature: 25 °C

Procedure:
53.0 g (2.7 mmol) 4-(6-chloropyrimidin-4-yl)morpholine are initially introduced into 260 ml ethanol. 132.9 g (2.7 mol) hydrazine hydrate are added and the mixture is stirred under reflux for 16 h. Thereafter, it is cooled to RT and approx. half of the solvent is removed by distillation. The mixture is cooled to 0° C. and the solid formed is filtered off. It is rinsed with cold ethanol and the solid is dried first in air and then in vacuo.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([NH2:8])=[N:6][CH:7]=1.[C:10](O)(=O)[CH2:11][CH3:12]>>[Br:1][C:2]1[CH:3]=[C:4]2[N:9]=[C:10]([CH2:11][CH3:12])[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Nc1cc(Br)cnc1N
Reactant: CCC(=O)O
Product: CCc1nc2cc(Br)cnc2[nH]1
Yield: 45 %

Procedure:
4 g of 5-bromopyridine-2,3-diamine in 40 ml of propionic acid is heated at 140° C. in a flask until the diamine has reacted completely (HPLC check, about 24 hours). The cooled reaction solution is evaporated to dryness. The residue is suspended in water, filtered off with suction and purified by means of column chromatography (gradient EA: methanol 5-40% in 30 min), giving 2.25 g of 6-bromo-2-ethyl-3H-imidazo[4,5-b]pyridine as yellowish solid (yield 45%, content 98%); MS-FAB (M+H+)=228.0; Rf (polar method): 1.27 min.
Reaction SMILES: [H-].[Na+].[CH3:3][NH:4][CH2:5][CH2:6][OH:7].F[C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[C:11](=[O:19])[NH:12][CH:13]=[N:14]2.CO>CC(N(C)C)=O>[CH3:3][NH:4][CH2:5][CH2:6][O:7][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[C:11](=[O:19])[NH:12][CH:13]=[N:14]2
Reactant: CNCCO
Reactant: O=c1[nH]cnc2cccc(F)c12
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)N(C)C
Product: CNCCOc1cccc2nc[nH]c(=O)c12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (60% dispersion in mineral oil, 732 mg, 18.3 mmol) was suspended in DMA (50 ml) and N-methylethanolamine (734 μl, 9.15 mmol) was added under an atmosphere of nitrogen. The mixture was stirred for 30 minutes at ambient temperature, and 5-fluoroquinazolin-4(3H)-one (1.0 g, 6.10 mmol) was added. The mixture was heated under an atmosphere of nitrogen at 85° C. for 90 minutes. The mixture was cooled to ambient temperature, and the resulting slurry poured into methanol (100 ml). Dowex resin (50WX4-400, 25 g) was added, and the mixture stirred for 1 hour at ambient temperature. The resin was collected by filtration, and washed with methanol (100 ml). The resin was suspended in a solution of ammonia in methanol (2.3 N, 150 ml), and the mixture stirred for 30 minutes. The mixture was filtered and the residue washed with ammonia in methanol (2.3 N, 100 ml). The combined filtrates were concentrated in vacuo, and dried in vacuo (1 mbar, 60° C.) for 16 hours to give 5-[2-(methylamino)ethoxy]quinazolin-4(3H)-one as an off white solid (1.09 g, 82%); NMR Spectrum (DMSO-d6, 400) 2.36 (s, 3H), 2.85 (t, 2H), 5.11 (t, 2H), 6.97 (d, 1H), 7.14 (d, 1H), 7.61 (dd, 1H), 7.97 (s, 1H); Mass spectrum MH+ 220.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.Cl[CH2:7][C:8]([C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:12][CH:11]=1)=[O:9].O>CN(C)C=O>[N:1]1([CH2:7][C:8]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:12][CH:11]=2)=[O:9])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: c1c[nH]cn1
Reactant: O=C(CCl)c1ccc(CCc2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Cn1ccnc1)c1ccc(CCc2ccccc2)cc1
Yield: 77.4 %

Procedure:
To a solution containing 3.4 g of imidazole in 5 ml of dimethylformamide, stirred at 0/+5° C., 2.58 g of 4-chloroacetyl-bibenzyl were slowly added. The reaction mixture was stirred for few minutes, then allowed to stand and then poured into water. The product thus formed was filtered off, purified by silica gel column chromatography (eluant: benzene/acetone) and then crystallized from ethyl acetate to give 2.24 g of the title compound melting at 134°-6° C. Yield 77%.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.[C:9]1([NH:15][C:16]2[N:20]=[CH:19][NH:18][N:17]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(NC(C)C)(C)C>C(#N)C>[Cl:8][C:6]1[N:5]=[CH:4][N:3]=[C:2]([N:18]2[CH:19]=[N:20][C:16]([NH:15][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[N:17]2)[CH:7]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: c1ccc(Nc2nc[nH]n2)cc1
Solvent: CC#N
Solvent: CC(C)NC(C)C
Product: Clc1cc(-n2cnc(Nc3ccccc3)n2)ncn1
Temperature: 25 °C

Procedure:
To a suspension of 4,6-dichloro-pyrimidine (292 mg, 1.96 mmol ) in 5 ml anhydrous acetonitrile was added phenyl-(1H-[1,2,4]triazol-3-yl)-amine together with diisopropylamine (0.4 ml, 4.0 mmol). The mixture was heated at reflux in a sealed tube overnight. The reaction was cooled to room temperature and the solid was collected by filtration. The solid was washed with cold ether and dried under vacuum. Analytical data: LC/MS showed M+1=273.1, and M−1+271.2, retention time is 3.5 min. NMR in DMSO-d6: 9.78 (s, 1H); 9.28 (s, 1H); 8.90 (s, 1H); 7.90 (s, 1H); 7.65 (d, 2H); 7.28 (dd, 2H); 6.90 (dd, 1H).
Reaction SMILES: [NH2:1][N:2]1[C:6]([NH:7][CH3:8])=[N:5][NH:4][C:3]1=[O:9].C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH:21](OCC)(OCC)[O:22][CH2:23][CH3:24]>>[CH2:23]([O:22][CH:21]=[N:1][N:2]1[C:6]([NH:7][CH3:8])=[N:5][NH:4][C:3]1=[O:9])[CH3:24]
Reactant: CCOC(OCC)OCC
Reactant: CNc1n[nH]c(=O)n1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CCOC=Nn1c(NC)n[nH]c1=O
Yield: 54 %

Procedure:
12.9 g (0.1 mol) of 4-amino-5-methylamino-2,4-dihydro-3H-1,2,4-triazol-3-one are refluxed for 4 hours with 100 ml of triethyl orthoformate and 100 mg of p-toluenesulphonic acid. The mixture is then concentrated and crystallized with diethyl ether. Recrystallization from ethanol gives 10.0 g (54% of theory) of 4-ethoxymethyleneamino-5-methylamino-2,4-dihydro-3H-1,2,4-triazol-3-one of melting point 169° C.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.C(N(CC)C(C)C)(C)C.Cl[C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26].C(=O)(O)[O-].[Na+]>ClCCl>[CH2:28]([O:27][C:25]([NH:1][CH:2]1[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]1)=[O:26])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC(NC(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.5 %

Procedure:
tert-Butyl 4-aminopiperidine-1-carboxylate (10 g, 49.9 mmol), N,N-diisopropylethylamine (26 ml, 149 mmol), benzyl chloroformate (8.5 ml, 59.5 mmol) and dichloromethane (dehydrated) (300 ml) were mixed under ice-cooling. The resulting mixture was stirred at room temperature for one hour. An aqueous saturated sodium bicarbonate solution was added to the reaction mixture, which was extracted with dichloromethane three times. The organic layer was washed with brine and dried over anhydrous sodium sulfate, and the solvent was distilled off. The residue was purified by silica gel column chromatography (silica gel, elution solvent: ethyl acetate/heptane) to give the title compound (13.1 g, yield 78.5%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]([OH:24])([C@H:16]([S:18][CH:19]([CH2:22][OH:23])[CH2:20][OH:21])[CH3:17])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1.[F:25][C:26]([F:40])([F:39])[C:27]1[CH:32]=[CH:31][C:30]([C:33]#[C:34]/[CH:35]=[CH:36]/[CH:37]=O)=[CH:29][CH:28]=1>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]([OH:24])([C@H:16]([S:18][C@@H:19]1[CH2:20][O:21][C@@H:37](/[CH:36]=[CH:35]/[C:34]#[C:33][C:30]2[CH:29]=[CH:28][C:27]([C:26]([F:25])([F:39])[F:40])=[CH:32][CH:31]=2)[O:23][CH2:22]1)[CH3:17])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1
Reactant: C[C@@H](SC(CO)CO)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Reactant: O=C/C=C/C#Cc1ccc(C(F)(F)F)cc1
Product: C[C@@H](S[C@H]1CO[C@H](/C=C/C#Cc2ccc(C(F)(F)F)cc2)OC1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Yield: 70 %

Procedure:
Reaction was carried out in the same manner as in Example 4 using (2R,3R)-2-(2,4-difluorophenyl)-3-[(1,3-dihydroxy-2-propyl)thio]-1-(1H-1,2,4-triazol-1-yl)-2-butanol and (E)-5-[4-(trifluoromethyl)phenyl]-2-penten-4-ynal as described in Reference example 48 to obtain the title compound, a major product as an oil in a yield of 70%.
Reaction SMILES: [CH2:1]([C:3]1[C:4]([CH:12](O)[CH2:13][CH3:14])=[CH:5][C:6]2[O:10][CH2:9][O:8][C:7]=2[CH:11]=1)[CH3:2].[SH:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19].O>C1C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:21]([O:20][C:18](=[O:19])[CH2:17][S:16][CH:12]([C:4]1[C:3]([CH2:1][CH3:2])=[CH:11][C:7]2[O:8][CH2:9][O:10][C:6]=2[CH:5]=1)[CH2:13][CH3:14])[CH3:22]
Reactant: CCOC(=O)CS
Reactant: CCc1cc2c(cc1C(O)CC)OCO2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: CCOC(=O)CSC(CC)c1cc2c(cc1CC)OCO2
Yield: 68.8 %

Procedure:
3.9 g of 1-(6-ethyl-1,3-benzodioxol-5-yl)-1-propanol, 0.1 g of p-toluenesulfonic acid and 3.35 g of ethyl mercaptoacetate were dissolved in 80 ml of benzene. The solution was heated under reflux for 12 h while water was removed. Water was added thereto. After extraction with benzene followed by drying over magnesium sulfate and concentration under reduced pressure, the product was purified according to silica gel column chromatography (ethyl acetate/hexane =1:9) to obtain 4.0 g of the intended compound in the form of a colorless, transparent oil.
Reaction SMILES: [N:1]1[CH:2]=[C:3]2[N:12]3[C:7](=[CH:8][CH:9]=[CH:10][C:11]=13)[S:6][C:5]([C:13]([OH:15])=O)=[CH:4]2.ON1C(=O)CCC1=O.Cl.C(N=C=NCCCN(C)C)C.[NH2:36][CH2:37][CH2:38][CH2:39][CH2:40][N:41]1[CH2:46][CH2:45][CH:44]([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[CH2:43][CH2:42]1>C(#N)C.C(N(CC)CC)C>[C:47]1([CH:44]2[CH2:43][CH2:42][N:41]([CH2:40][CH2:39][CH2:38][CH2:37][NH:36][C:13]([C:5]3[S:6][C:7]4[N:12]5[C:3](=[CH:2][N:1]=[C:11]5[CH:10]=[CH:9][CH:8]=4)[CH:4]=3)=[O:15])[CH2:46][CH2:45]2)[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=1
Reactant: O=C(O)C1=Cc2cnc3cccc(n23)S1
Reactant: NCCCCN1CCC(c2ccccc2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C1CCC(=O)N1O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C(NCCCCN1CCC(c2ccccc2)CC1)C1=Cc2cnc3cccc(n23)S1
Reaction time: 2 h

Procedure:
To a suspension of 1.0 g (4.58 mM) of 5-thia-1,8b-diazaacenaphthylene-4-carboxylic acid and 1.05 g (9.12 mM) of N-hydroxysuccinimide in acetonitrile (10 ml) was added 1.76 g (9.18 mM) of N-ethyl-N′-3-(N,N-dimethylamino)propylcarbodiimide hydrochloride at room temperature and the mixture was stirred at the prevailing temperature for 2 hours. To this reaction mixture was added a solution of 1.60 g (6.89 mM) of 1-(4-aminobutan-1-yl)-4-phenylpiperidine and 1.3 ml (9.33 mM) of triethylamine in acetonitrile (5 ml) and the mixture was further stirred for one hour. The solvent was then distilled off under reduced pressure and the residue was diluted with water and extracted with chloroform. The organic layer was washed with saturated aqueous solution of sodium chloride and dried over MgSO4. This crude product was purified by column chromatography (methanol/ethyl acetate 20-50-80%) to provide the title compound as red-purple solid.
Reaction SMILES: [CH3:1][N:2]([CH3:34])[CH:3]1[CH2:6][N:5]([C:7]2[C:12]([N+:13]([O-])=O)=[CH:11][C:10]([NH:16][C:17]3[N:22]=[C:21]([C:23]4[CH:24]=[N:25][N:26]5[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=45)[CH:20]=[CH:19][N:18]=3)=[C:9]([O:32][CH3:33])[CH:8]=2)[CH2:4]1.[NH4+].[Cl-].C(O)C>[Fe].O>[CH3:34][N:2]([CH3:1])[CH:3]1[CH2:4][N:5]([C:7]2[CH:8]=[C:9]([O:32][CH3:33])[C:10]([NH:16][C:17]3[N:22]=[C:21]([C:23]4[CH:24]=[N:25][N:26]5[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=45)[CH:20]=[CH:19][N:18]=3)=[CH:11][C:12]=2[NH2:13])[CH2:6]1
Reactant: COc1cc(N2CC(N(C)C)C2)c([N+](=O)[O-])cc1Nc1nccc(-c2cnn3ccccc23)n1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: COc1cc(N2CC(N(C)C)C2)c(N)cc1Nc1nccc(-c2cnn3ccccc23)n1
Yield: 75.1 %

Procedure:
A mixture of N-[4-(3-dimethylaminoazetidin-1-yl)-2-methoxy-5-nitrophenyl]-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-amine (Intermediate 157, 355 mg, 0.77 mmol), iron (258 mg, 4.63 mmol), NH4Cl (30.9 mg, 0.58 mmol), ethanol (12.6 mL) and water (4.2 mL) was heated at reflux for 1.5 h. After cooling the mixture was concentrated in vacuo. The resulting residue was triturated in 10% CH3OH in CH2Cl2 (20 mL) for 15 minutes and the mixture was then filtered. The residues were triturated again with 10% CH3OH in CH2Cl2 (20 mL) and then filtered. The combined filtrates were washed with brine, dried (MgSO4) and concentrated in vacuo. Purification by FCC, eluting with 0-10% methanolic ammonia in CH2Cl2 gave the title compound (249 mg, 75%) as a brown solid after trituration with diethyl ether; 1H NMR: 2.12 (6H, s), 3.02-3.09 (1H, m), 3.47 (2H, t), 3.71 (3H, s), 3.98 (2H, t), 4.04 (2H, br s), 6.28 (1H, s), 7.05 (1H, td), 7.09 (1H, s), 7.16 (1H, d), 7.36-7.41 (1H, m), 7.93 (1H, s), 8.27 (1H, d), 8.48 (1H, d), 8.74 (1H, s), 8.77 (1H, d); m/z: ES+ MH+ 431.35.
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][N:7]([CH2:9][C:10]([OH:12])=O)[CH3:8])=[O:5])[CH3:2].[NH2:13][C@@H:14]([CH2:37][C:38]1[CH:43]=[CH:42][C:41]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[CH:40][CH:39]=1)[C:15]([N:17]([CH2:27][C:28]1[C:29]2[CH:36]=[CH:35][CH:34]=[CH:33][C:30]=2[S:31][CH:32]=1)[C@@H:18]([CH3:26])[CH:19]([O:23][CH2:24][CH3:25])[O:20][CH2:21][CH3:22])=[O:16]>>[S:31]1[CH:32]=[C:28]([CH2:27][N:17]([C@@H:18]([CH3:26])[CH:19]([O:20][CH2:21][CH3:22])[O:23][CH2:24][CH3:25])[C:15](=[O:16])[C@@H:14]([NH:13][C:10](=[O:12])[CH2:9][N:7]([CH3:8])[NH:6][C:4]([NH:3][CH2:1][CH3:2])=[O:5])[CH2:37][C:38]2[CH:39]=[CH:40][C:41]([O:44][C:45]([CH3:46])([CH3:48])[CH3:47])=[CH:42][CH:43]=2)[C:29]2[CH:36]=[CH:35][CH:34]=[CH:33][C:30]1=2
Reactant: CCOC(OCC)[C@H](C)N(Cc1csc2ccccc12)C(=O)[C@@H](N)Cc1ccc(OC(C)(C)C)cc1
Reactant: CCNC(=O)NN(C)CC(=O)O
Product: CCNC(=O)NN(C)CC(=O)N[C@@H](Cc1ccc(OC(C)(C)C)cc1)C(=O)N(Cc1csc2ccccc12)[C@@H](C)C(OCC)OCC

Procedure:
According to the procedure described in the synthesis method of Compound II-15, 2-(2-(ethylcarbamoyl)-1-methylhydrazinyl)acetic acid (Compound VI-9) 51 mg (0.29 mmol) was coupled with (S)-2-amino-N-(benzo[b]thiophen-3-ylmethyl)-3-(4-tert-butoxyphenyl)-N—((S)-1,1-diethoxypropan-2-yl)propanamide (Compound IV-6) 100 mg (0.20 mmol) to obtain the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([C:9]2[CH:10]=[C:11]([CH:13]=[CH:14][CH:15]=2)[NH2:12])=[N:5][CH:6]=[CH:7][CH:8]=1.[C:16]([O:20][C:21]([NH:23][C:24]([NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])=S)=[O:22])([CH3:19])([CH3:18])[CH3:17].C(N(C(C)C)CC)(C)C.[I-].C[N+]1C=CC=CC=1Cl>ClCCl>[C:30]([O:29][C:27]([NH:26][C:24]([NH:23][C:21]([O:20][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:22])=[N:12][C:11]1[CH:13]=[CH:14][CH:15]=[C:9]([C:4]2[C:3]([O:2][CH3:1])=[CH:8][CH:7]=[CH:6][N:5]=2)[CH:10]=1)=[O:28])([CH3:33])([CH3:32])[CH3:31]
Reactant: COc1cccnc1-c1cccc(N)c1
Reactant: CC(C)(C)OC(=O)NC(=S)NC(=O)OC(C)(C)C
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cccnc1-c1cccc(N=C(NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)c1
Reaction time: 18 h
Yield: 68.1 %

Procedure:
To a suspension of 3-(3-methoxypyridin-2-yl)aniline (0.34 g), N,N′-bis(tert-butoxycarbonyl)thiourea (563 mg) and diisopropylethyl-amine (0.681 ml) in dichloromethane (15 ml) was added 1-methyl-2-chloropyridinium iodide (565 mg), and the mixture was stirred for 18 hours. The mixture was diluted with dichloromethane, washed with water and brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was crystallized from methanol. The precipitate was collected by filtration, washed with methanol and dried to give N,N′-bis(tert-butoxycarbonyl)-N″-(3-(3-methoxypyridin-2-yl)phenyl)guanidine (512 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH2:8][CH:9]([CH3:11])[CH3:10])[CH:5]=[CH:4][C:3]=1[C:12]1[C:13]([S:18]([NH:21][C:22]2[O:26][N:25]=[C:24]([CH3:27])[C:23]=2[CH3:28])(=[O:20])=[O:19])=[CH:14][CH:15]=[CH:16][CH:17]=1.[C:29](O)(=O)[CH3:30].C(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C.C(OCC)(=O)C>[CH3:27][C:24]1[C:23]([CH3:28])=[C:22]([NH:21][S:18]([C:13]2[C:12]([C:3]3[CH:4]=[CH:5][C:6]([CH2:8][CH:9]([CH3:11])[CH3:10])=[CH:7][C:2]=3[NH:1][CH2:29][CH3:30])=[CH:17][CH:16]=[CH:15][CH:14]=2)(=[O:20])=[O:19])[O:26][N:25]=1
Reactant: Cc1noc(NS(=O)(=O)c2ccccc2-c2ccc(CC(C)C)cc2N)c1C
Reactant: CC(=O)O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(Cl)Cl
Product: CCNc1cc(CC(C)C)ccc1-c1ccccc1S(=O)(=O)Nc1onc(C)c1C
Temperature: 7.5 °C
Reaction time: 2 h
Yield: 52.6 %

Procedure:
To a solution of the compound of Example 32 (0.16 g, 0.4 mmol) and acetic acid (0.06 g, 1 mmol) in dichloroethane (2.5 mL) at 0° C., acetaldehyde (24 mg, 0.55 mmol) and sodium triacetoxyborohydride (212 mg, 1 mmol) were added. The mixture was stirred at 0-15° C. for 2 hours, diluted with ethyl acetate, extracted with water and brine, dried and concentrated. The residue was chromatographed on silica gel with 4:1 hexanes/ethyl acetate to afford the title compound (90 mg, 53%) as a light yellow gum.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:15][CH3:16])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[C:17]1([CH2:23][CH2:24][C:25]([NH:27][CH2:28][C:29]([OH:31])=O)=[O:26])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([N:15]([CH3:16])[C:29]([CH2:28][NH:27][C:25](=[O:26])[CH2:24][CH2:23][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[O:31])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)CNC(=O)CCc1ccccc1
Reactant: CNC(c1ccccc1)c1ccc(Cl)cc1
Product: CN(C(=O)CNC(=O)CCc1ccccc1)C(c1ccccc1)c1ccc(Cl)cc1

Procedure:
Prepared in analogy to example 1.1 from rac-[(4-chloro-phenyl)-phenyl-methyl]-methylamine (CA [118762-04-2]) and (3-phenyl-propionylamino)-acetic acid (CA [56613-60-6]).
Reaction SMILES: [CH3:1][N:2]([CH3:7])[S:3]([NH2:6])(=[O:5])=[O:4].Cl.CN(C)CCCN=C=NCC.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:33]=[CH:32][C:31]([O:34][CH2:35][C:36]3[CH:37]=[C:38]([C:42](O)=[O:43])[O:39][C:40]=3[CH3:41])=[CH:30][CH:29]=2)=[CH:24][CH:23]=1>CN(C)C1C=CN=CC=1.ClCCl>[CH3:20][O:21][C:22]1[CH:23]=[CH:24][C:25]([C:28]2[CH:29]=[CH:30][C:31]([O:34][CH2:35][C:36]3[CH:37]=[C:38]([C:42]([NH:6][S:3]([N:2]([CH3:7])[CH3:1])(=[O:5])=[O:4])=[O:43])[O:39][C:40]=3[CH3:41])=[CH:32][CH:33]=2)=[CH:26][CH:27]=1
Reactant: COc1ccc(-c2ccc(OCc3cc(C(=O)O)oc3C)cc2)cc1
Reactant: CN(C)S(N)(=O)=O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: COc1ccc(-c2ccc(OCc3cc(C(=O)NS(=O)(=O)N(C)C)oc3C)cc2)cc1
Reaction time: 18 h
Yield: 35.7 %

Procedure:
N,N-Dimethylsulphamide (73 mg, 0.59 mmoles), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (31 mg, 0.162 mmoles) and dimethyl-pyridin-4-yl-amine (1 mg) were added to a stirred solution of 4-(4′-methoxy-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carboxylic acid (4) (50 mg, 0.148 mmoles) in dichloromethane (20 ml). The mixture was stirred under an argon atmosphere for 18 hours. After evaporation of the solvent, the residue was partitioned between dichloromethane and water. The aqueous phase was separated and extracted with dichloromethane. The combined extracts were washed with 1M aqueous hydrochloric acid, saturated aqueous sodium bicarbonate, brine and dried (MgSO4). Evaporation of the solvent afforded the crude product, which was purified by HPLC (gradient: 30% acetonitrile/70% water containing 0.1% trifluoroacetic acid to 98% acetonitrile/2% water at a rate of 1%/min) to afford compound 122 (23.5 mg) as a white solid. LC/MS System C: Rt=3.67 mins, m/z (ES−)=443 ((M−H) for C22H24N2O6S).
Reaction SMILES: CN(C)C=O.[CH2:6]([C:9]1[C:17]([OH:18])=[CH:16][CH:15]=[C:14]2[C:10]=1[CH2:11][O:12][C:13]2([C:23]([F:26])([F:25])[F:24])[C:19]([F:22])([F:21])[F:20])[CH2:7][CH3:8].[Br:27][CH2:28][CH2:29][CH2:30][CH2:31]Br.C(=O)([O-])[O-].[K+].[K+]>O>[Br:27][CH2:28][CH2:29][CH2:30][CH2:31][O:18][C:17]1[C:9]([CH2:6][CH2:7][CH3:8])=[C:10]2[C:14](=[CH:15][CH:16]=1)[C:13]([C:23]([F:26])([F:24])[F:25])([C:19]([F:20])([F:21])[F:22])[O:12][CH2:11]2
Reactant: CCCc1c(O)ccc2c1COC2(C(F)(F)F)C(F)(F)F
Reactant: BrCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCc1c(OCCCCBr)ccc2c1COC2(C(F)(F)F)C(F)(F)F
Yield: 19.9 %

Procedure:
A N,N-Dimethylformamide (10 mL) solution of 4-propyl-1,1-bis(trifluoromethyl)-1,3-dihydroisobenzofuran-5-ol (800 mg, 2.55 mol), 1,4-dibromobutane (2.75 mL, 12.73 mmol) and potassium carbonate (528 mg, 3.82 mmol) was stirred at room temperature overnight. The reaction solution was added with water and extracted with ethyl acetate. Subsequently, the organic layer was washed with saturated saline, dried using anhydrous sodium sulfate, and concentrated in vacuum. The obtained residue was purified by silica-gel column chromatography (hexane:ethyl acetate=50:1) and the title compound (1.136 g, 99%) was obtained as colorless oil.