Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[O-].[Na+].C(N(CC)CC)C.[Br:11][C:12]1[CH:20]=[CH:19][C:15](/[CH:16]=[N:17]/[OH:18])=[C:14]([O:21][CH2:22][C:23]#[C:24][C:25]2[C:29]([C:30]([F:33])([F:32])[F:31])=[C:28]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[O:27][N:26]=2)[CH:13]=1>ClCCl>[Br:11][C:12]1[CH:20]=[CH:19][C:15]2[C:16]3=[N:17][O:18][C:24]([C:25]4[C:29]([C:30]([F:33])([F:31])[F:32])=[C:28]([C:34]5[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=5)[O:27][N:26]=4)=[C:23]3[CH2:22][O:21][C:14]=2[CH:13]=1
Reactant: O/N=C/c1ccc(Br)cc1OCC#Cc1noc(-c2ccccc2)c1C(F)(F)F
Agent: [Na+]
Agent: [O-]Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: FC(F)(F)c1c(-c2onc3c2COc2cc(Br)ccc2-3)noc1-c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 72.7 %

Procedure:
To a mixture of sodium hypochlorite (23 mL), triethylamine (Preparation 62E, 0.021 mL, 0.155 mmol), and dichloromethane (1.0 mL) at 0° C. was added dropwise a solution of (E)-4-bromo-2-(3-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)prop-2-ynyloxy)benzaldehyde oxime (0.036 g, 0.077 mmol) in dichloromethane (3 mL). The reaction mixture was stirred at 0° C. for 30 min. and then at room temperature for 1.5 h. The reaction mixture was diluted with dichloromethane, and the organic layer was collected. The aqueous layer was extracted with dichloromethane (2×), and the combined organic layers were washed with brine and dried over anhydrous sodium sulfate. Concentration under reduced pressure followed by trituration with methanol with sonication afforded 7-bromo-3-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-4H-chromeno[4,3-c]isoxazole (0.026 g, 0.056 mmol, 73% yield) as a white solid. The product had an HPLC ret. time=3.91 min.−Column: Chromolith SpeedROD 4.6×50 mm (4 min.); Solvent A=10% MeOH, 90% H2O, 0.1% TFA; Solvent B=90% MeOH, 10% H2O, 0.1% TFA. LC/MS M+1=464.9. 1H NMR (500 MHz, CDCl3) δ ppm 5.49 (s, 2H), 7.23-7.27 (m, 2H), 7.55-7.59 (m, 2H), 7.60-7.65 (m, 1H), 7.73 (d, J=7.49 Hz, 2H), and 7.78 (d, J=8.05 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[C:18]([F:33])=[CH:19][CH:20]=[C:21]4[C:25]=3[NH:24][CH:23]=[C:22]4[CH2:26][CH2:27][C:28]([O:30]CC)=[O:29])[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].[OH-].[Na+]>C(O)(C)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[C:18]([F:33])=[CH:19][CH:20]=[C:21]4[C:25]=3[NH:24][CH:23]=[C:22]4[CH2:26][CH2:27][C:28]([OH:30])=[O:29])[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10]
Reactant: CCOC(=O)CCc1c[nH]c2c(-c3noc(-c4ccc(OC(C)C)c(Cl)c4)n3)c(F)ccc12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: CC(C)Oc1ccc(-c2nc(-c3c(F)ccc4c(CCC(=O)O)c[nH]c34)no2)cc1Cl
Temperature: 90 °C
Reaction time: 2 h
Yield: 46.5 %

Procedure:
To a solution of ethyl 3-[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-6-fluoro-1H-indol-3-yl]propanoate (D146) (320 mg) in isopropanol (7 mL) and water (7.00 mL) was added NaOH (6.78 mL, 0.5 M aqueous solution) at room temperature. The reaction suspension was stirred at 90° C. for 2 hours, and the solution turned clear. Isopropanol was removed in vacuo and water (8 mL) was added to the residue. The aqueous solution was acidified to pH=1 and extracted with ethyl acetate (3×10 mL). The combined organic phases were dried over sodium sulphate. The organic solution was concentrated and the residue was purified by MDAP to afford 3-[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-6-fluoro-1H-indol-3-yl]propanoic acid (E103) (140 mg) as a white solid. δH (DMSO-d6, 400 MHz): 1.31 (6H, d), 2.56 (2H, t), 2.92 (2H, t), 4.85 (1H, m), 7.03 (1H, m), 7.22 (1H, s), 7.39 (1H, d), 7.74 (1H, m), 8.21 (1H, dd), 8.47 (1H, d), 11.01 (1H, s), 12.07 (1H, s). MS (ES): C22H19ClFN3O4 requires 443; found 444.2 (M+H+).
Reaction SMILES: [C:1]([C:5]1[C:6](Br)=[C:7]([CH:26]=[CH:27][CH:28]=1)[NH:8][C:9]1[CH2:14][CH:13]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH2:12][C:11](=[O:25])[CH:10]=1)([O:3][CH3:4])=[O:2].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:1]([C:5]1[CH:28]=[CH:27][CH:26]=[C:7]2[C:6]=1[C:10]1[C:11](=[O:25])[CH2:12][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)[CH2:14][C:9]=1[NH:8]2)([O:3][CH3:4])=[O:2]
Reactant: COC(=O)c1cccc(NC2=CC(=O)CC(c3ccc(C(F)(F)F)cc3)C2)c1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COC(=O)c1cccc2[nH]c3c(c12)C(=O)CC(c1ccc(C(F)(F)F)cc1)C3
Yield: 87.1 %

Procedure:
A suspension of 3-(3-carbomethoxy-2-bromoanilino)-5-(4-trifluoromethylphenyl)-cyclohex-2-en-1-one (2.18 g, 4.66 mM), palladium acetate (0.10 g, 0.47 mM), tri-o-tolylphosphine (0.28 g, 0.93 mM), and triethylamine (0.8 ml, 5.78 mM) in 12 mL acetonitrile was heated at reflux for 3 hours. The solvent was removed in vacuo. The residue was dissolved in methylene chloride, washed with 1 N HCl, then with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to afford 2.21 g. Purification by HPLC on silica gel (elution with gradient methylene chloride/ethyl acetate) afforded 1.57 g (87%) of the 5-carbomethoxy-1,2-dihydro-2-(4-trifluoromethylphenyl)-9H-carbazol-4(3H)-one. 1H NMR (CDCl3) δ 9.2 (bs, 1H), 7.6 (d, J=8 Hz, 2H), 7.45-7.35 (m, 5H), 7.25 (d, J=8 Hz, 2H), 3.55 (m, 1H), 3.2-3.0 (m, 2H), 2.7 (m, 2H). MS (ES) m/e 356, 388.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[NH2:12][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[C:15]([N+:29]([O-:31])=[O:30])[CH:14]=1.CCN(CC)CC>C(Cl)Cl>[CH2:5]([O:4][C:2]([NH:12][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[C:15]([N+:29]([O-:31])=[O:30])[CH:14]=1)=[O:3])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CCOC(=O)Cc1c([N+](=O)[O-])cc(N)c2ccccc12
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)Cc1c([N+](=O)[O-])cc(NC(=O)OCc2ccccc2)c2ccccc12
Yield: 26.2 %

Procedure:
Benzyl chloroformate (1.56 mL, 10.94 mmol) was added to a solution of ethyl (4-amino-2-nitronaphthalen-1-yl)acetate (1.0 g, 3.65 mmoml) and Et3N (0.56 mL, 4.01 mmol) in dry CH2Cl2 (20 mL) slowly that was at 0° C. under N2 atmosphere. The mixture was heated to reflux for 3 days and concentrated. The residue was dissolved in AcOEt (50 mL), and washed with H2O (10 mL) and saturated aqueous NaCl (25 mL). The organic layer was dried (Na2SO4) and concentrated under reduced pressure. Flash chromatography (20% AcOEt-Petroleum ether to CHCl3) afforded ethyl [4-(N-benzyloxycarbonylamino)-2-nitronaphthalen-1-yl]acetate (0.39 g, 26%) as an orange solid. M.p. 160-164° C.; 1H NMR (CDCl3, 500 MHz) δ 8.09 (d, 8.5, 1H), 7.88 (d, 8.0, 1H), 7.66 (t, 8.0, 1H), 7.60 (t, 7.0, 1H), 7.46 (d, 7.5, 2H), 7.41 (t, 7.5, 2H), 7.35 (t, 7.5, 1H), 7.07 (s, 1H), 4.92 (brs, 1H), 4.52 (d, 4.0, 2H), 4.24 (s, 2H), 4.19 (q, 7.0, 2H), 1.26 (t, 7.5, 3H); IR (neat) 3397, 2927, 1723, 1594, 1537, 1515, 1439, 1333, 1200, 1124, 1027, 823, 752, 703 cm−1.
Reaction SMILES: [C:1]([CH:3]=[C:4]([C:15]1[CH:16]=[CH:17][C:18]([O:25][CH3:26])=[C:19]([NH:21][C:22](=[O:24])[CH3:23])[CH:20]=1)[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([O:13][CH3:14])[CH:6]=1)#[N:2].N[C:28]1C=C(C(C2C=CC(OC)=C(OCC)C=2)=CC#N)C=CC=1OC.C(Cl)(=O)C>CCCCCC>[C:1]([CH:3]=[C:4]([C:15]1[CH:16]=[CH:17][C:18]([O:25][CH3:26])=[C:19]([NH:21][C:22](=[O:24])[CH3:23])[CH:20]=1)[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([O:13][CH2:14][CH3:28])[CH:6]=1)#[N:2]
Reactant: CCOc1cc(C(=CC#N)c2ccc(OC)c(N)c2)ccc1OC
Reactant: COc1ccc(C(=CC#N)c2ccc(OC)c(OC)c2)cc1NC(C)=O
Solvent: CCCCCC
Solvent: CC(=O)Cl
Product: CCOc1cc(C(=CC#N)c2ccc(OC)c(NC(C)=O)c2)ccc1OC
Yield: 41 %

Procedure:
N-{5-[2-Cyano-1-(3-ethoxy-4-methoxy-phenyl)-vinyl]-2-methoxy-phenyl}-acetamide (E and Z isomers) were prepared analogously to N-{5-[2-cyano-1-(3,4-dimethoxy-phenyl)-vinyl]-2-methoxy-phenyl}-acetamide using 3-(3-amino-4-methoxy-phenyl)-3-(3-ethoxy-4-methoxy-phenyl)-acrylonitrile (0.4 g, 1.1 mmol) and acetyl chloride (1.1 mL). The crude product was slurried with hexane to give N-{5-[2-cyano-1-(3-ethoxy-4-methoxy-phenyl)-vinyl]-2-methoxy-phenyl}-acetamide (0.2 g, 41%) as a white solid: mp 155-157° C.; 1H NMR (CDCl3) δ 9.25 (d, J=2 Hz, 1H), 7.90 (d, 13.5 Hz, 1H), 7.17-6.90 (m, 3H), 6.75 (d, J=1 Hz, 1H), 6.13 (s, 1H), 5.97 (s, 1H), 4.02-3.97 (m, 2H), 3.94-3.97 (m, 6H), 2.07 (d, J=7 Hz, 3H), 1.70 (t, 3H); 13C NMR (CDCl3) δ 161.29, 151.18, 150.02, 147.76, 147.32, 130.47, 130.23, 129.18, 128.91, 127.26, 127.22, 122.40, 122.18, 118.77, 118.70, 113.81, 122.20, 111.43, 111.34, 111.04, 110.77, 92.73, 92.45, 63.76, 63.71, 55.87, 55.41, 23.80, 23.68, 14.57; Anal Calcd for C21H22N2O4: C, 68.84; H, 6.05; N, 7.65. Found: C, 68.94, 5.93; N, 7.53.
Reaction SMILES: [CH2:1]([CH2:7][OH:8])[CH2:2][NH:3][CH2:4][CH2:5][NH2:6].CS[C:11](=[C:14]([C:17]#[N:18])[C:15]#[N:16])SC.C(OC(C)C)(C)C>C(Cl)Cl>[CH2:5]1[NH:6][C:11](=[C:14]([C:17]#[N:18])[C:15]#[N:16])[N:3]([CH2:2][CH2:1][CH2:7][OH:8])[CH2:4]1
Reactant: NCCNCCCO
Reactant: CSC(SC)=C(C#N)C#N
Solvent: ClCCl
Solvent: CC(C)OC(C)C
Product: N#CC(C#N)=C1NCCN1CCCO
Reaction time: 1 h
Yield: 88.7 %

Procedure:
In 10 ml of methylene chloride was dissolved 10.4 g of N-(2-aminoethyl)propanolamine, and the solution was added to 15.0 g of [bis(methylthio)methylene]propanedinitrile. The mixture was allowed to stand at room temperature for 1 hour under reduced pressure. Diisopropyl ether was added to the mixture, and the solid was collected by filtration. The crystals were purified by silica gel column chromatography (chloroform:methanol=5:1) to give 15.0 g (87%) of Compound (VIa) as pale yellow crystals.
Reaction SMILES: [CH3:1][C:2]1([CH3:32])[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:12]([O:14]C)=[O:13])[CH:9]=2)[NH:4][CH:3]1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:23](=[O:31])[CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:17]=1.[OH-].[Na+]>CO.O>[CH3:1][C:2]1([CH3:32])[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:12]([OH:14])=[O:13])[CH:9]=2)[NH:4][CH:3]1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:23](=[O:31])[CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:17]=1
Reactant: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(NC(=O)Cc3ccccc3)c1)N2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1cccc(NC(=O)Cc2ccccc2)c1
Yield: 52.2 %

Procedure:
To a mixture of methyl 3,3-dimethyl-2-(3-(2-phenylacetamido)phenyl)-1,2,3,4-tetrahydroquinoline-6-carboxylate (139 mg, 0.32 mmol) in methanol (5 mL) and water (2.5 mL) was added a solution of sodium hydroxide (220 mg, 5.50 mmol) in water (2.5 mL). The resultant mixture was heated for reflux for 1.5 hours. The methanol was removed under vacuum. The residue was acidified with 2 M hydrochloric acid to pH=5. The precipitates were collected by filtration, purified by preparative thin layer chromatography (silica gel, petroleum ether/ethyl acetate=3:1) to afford 3,3-dimethyl-2-(3-(2-phenylacetamido)phenyl)-1,2,3,4-tetrahydroquinoline-6-carboxylic acid as a solid. (70 mg, yield: 52.2%). MS (ESI+APCI) M+1-OH=397.2.
Reaction SMILES: [C:1]([CH:3]([N:5]1[C:9]2=[N:10][C:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:12][CH:13]=[C:8]2[CH:7]=[C:6]1[C:19]([O:21]CC)=O)[CH3:4])#[N:2].[BH4-].[Na+]>CO.C1COCC1>[CH3:4][CH:3]1[N:5]2[C:9]3[N:10]=[C:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:12]=[CH:13][C:8]=3[CH:7]=[C:6]2[C:19](=[O:21])[NH:2][CH2:1]1
Reactant: CCOC(=O)c1ccc2cc(C(=O)OCC)n(C(C)C#N)c2n1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc2cc3n(c2n1)C(C)CNC3=O
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 42.6 %

Procedure:
To a solution of diethyl 1-(1-cyanoethyl)-1H-pyrrolo[2,3-b]pyridine-2,6-dicarboxylate (807 mg, 2.56 mmol) in methanol/THF (14 mL, 1:1 v/v) at 0° C. is added sodium borohydride (968 mg, 25.6 mmol). The cold bath is removed and the reaction mixture is stirred for 30 min, at which point the reaction vessel is sealed and warmed to 60° C. After being stirred for 4 h, the mixture is cooled to room temperature and diluted with EtOAc. The organic phase is washed twice with 1Ma aqueous NaHSO4 and once with brine, is dried (Na2SO4), filtered and concentrated to provide the title compound as a light yellow solid (298 mg, 43%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:10][C:6]([C:7]([NH2:9])=[O:8])=[C:5]([N+:20]([O-])=O)[CH:4]=1>C(O)(=O)C.CO.[Fe]>[CH3:1][O:2][C:3]1[C:11]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:10][C:6]([C:7]([NH2:9])=[O:8])=[C:5]([NH2:20])[CH:4]=1
Reactant: COc1cc([N+](=O)[O-])c(C(N)=O)cc1OCc1ccccc1
Agent: [Fe]
Solvent: CO
Solvent: CC(=O)O
Product: COc1cc(N)c(C(N)=O)cc1OCc1ccccc1
Temperature: 85 °C
Yield: 87.2 %

Procedure:
A mixture of 4-methoxy-5-benzyloxy-2-nitrobenzamide (6.60 g, 21.9 mmol) and iron powder (8.14 g, 0.146 mol) in acetic acid/methanol (80 mL/80 mL) was heated at 85±5° C. for 1.5 h. The reaction mixture was allowed to cool to RT and the iron was removed by filtration, and volatiles were removed in vacuo. The residue was taken up in sat. sodium bicarbonate and the mixture was extracted with ethyl acetate (600 mL×3). The combined organic layers were washed with water (1×150 mL), brine (1×150 mL), dried (Na2SO4), filtered and concentrated in vacuo to give 4-methoxy-5-benzyloxy-2-aminobenzamide (5.2 g, 19.1 mmol, 87%). MS 273.2. (M+). HPLC retention time 4.585 min.
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.[CH3:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH:19]([C:21]1[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=1)[OH:20].C(OCC)C>ClCCl>[CH3:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]([C:21]1[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=1)=[O:20]
Reactant: Cc1ccccc1C(O)c1ccncc1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Solvent: ClCCl
Product: Cc1ccccc1C(=O)c1ccncc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 48.4 %

Procedure:
Pyridinium chlorochromate (9.29 g, 43.1 mmol) was dissolved in dichloromethane (50 ml) and a solution of 2-methylphenyl-(4-pyridyl)methanol (5.72 g, 28.7 mmol) in dichloromethane (30 ml) was added. The reaction mixture became dark immediately, and was stirred for 2 h at room temperature. Diethyl ether (350 ml) was added, and the reaction mixture was filtered through "hyflo" and evaporated to a dark oil (11.26 g). Flash chromatography on silica gel (Merck Art 9385) eluting with heptane/tetrahydrofuran (4:1) provided the title compound (2.74 g, 48%) as an oil. T.l.c. rf=0.45 (SiO2, ethyl acetate).
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][S:23]([CH3:26])(=[O:25])=[O:24])[CH:17]=2)[N:10]=1.[CH3:27][CH:28]([CH3:31])[CH2:29][OH:30]>>[F:8][C:6]1[CH:5]=[CH:4][C:3]([C:9]2[N:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][S:23]([CH3:26])(=[O:25])=[O:24])[CH:17]=3)[N:10]=2)=[C:2]([O:30][CH2:29][CH:28]([CH3:31])[CH3:27])[CH:7]=1
Reactant: CS(=O)(=O)Cc1cccc(Nc2ncnc(-c3ccc(F)cc3F)n2)c1
Reactant: CC(C)CO
Product: CC(C)COc1cc(F)ccc1-c1ncnc(Nc2cccc(CS(C)(=O)=O)c2)n1

Procedure:
Starting with 4-(2,4-difluorophenyl)-N-{3-[(methylsulfonyl)methyl]phenyl}-1,3,5-triazin-2-amine (75 mg; 0.197 mmol), intermediate 42.1, and 2-methylpropan-1-ol (74 μl; 0.789 mmol), example 58 was prepared analogously to the procedure for the preparation of example 42.
Reaction SMILES: [CH2:1]([N:3]1[C:12](=[O:13])[C:11]2[N:10]([CH3:14])[C:9](/[CH:15]=[CH:16]/[C:17]3[CH:22]=[CH:21][C:20]([O:23]COC)=[C:19]([O:27][CH3:28])[CH:18]=3)=[N:8][C:7]=2[N:6]([CH2:29][CH3:30])[C:4]1=[O:5])[CH3:2].Cl.[OH-].[Na+].O>O1CCCC1>[CH2:1]([N:3]1[C:12](=[O:13])[C:11]2[N:10]([CH3:14])[C:9](/[CH:15]=[CH:16]/[C:17]3[CH:22]=[CH:21][C:20]([OH:23])=[C:19]([O:27][CH3:28])[CH:18]=3)=[N:8][C:7]=2[N:6]([CH2:29][CH3:30])[C:4]1=[O:5])[CH3:2]
Reactant: CCn1c(=O)c2c(nc(/C=C/c3ccc(OCOC)c(OC)c3)n2C)n(CC)c1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCn1c(=O)c2c(nc(/C=C/c3ccc(O)c(OC)c3)n2C)n(CC)c1=O
Yield: 80.5 %

Procedure:
Compound o (1.50 g, 3.62 mmol) obtained in Reference Example 14 was suspended in tetrahydrofuran (30 ml), and 2N HCl (9 ml) was added thereto, followed by heating under reflux for one hour. The reaction mixture was neutralized with a 2N aqueous solution of sodium hydroxide under ice-cooling, and water was added thereto. The precipitated crystals were collected by filtration and recrystallized from ethyl acetate to give 1.08 g (yield 81%) of Compound p as yellow plates.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:7]([OH:14])[C:6]([CH3:15])=[C:5]([C:16]([F:19])([F:18])[F:17])[N:4]=1.Br[CH2:23][C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:25].C(=O)([O-])[O-].[K+].[K+]>>[F:21][C:2]([F:20])([F:1])[C:3]1[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:7]([O:14][CH2:23][C:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:25])[C:6]([CH3:15])=[C:5]([C:16]([F:19])([F:18])[F:17])[N:4]=1
Reactant: CCOC(=O)c1c(C(F)(F)F)nc(C(F)(F)F)c(C)c1O
Reactant: O=C(CBr)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOC(=O)c1c(C(F)(F)F)nc(C(F)(F)F)c(C)c1OCC(=O)c1ccccc1
Yield: 65.4 %

Procedure:
Reaction of product of Example 35 with bromoacetophenone and potassium carbonate similar to the above Example 63 gave a crude product which was recrystallized successively from methanol and cyclohexane to give 4.45 g (65.4%) of product as a solid; mp 95°-97° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:12][CH:11]=[C:10]([CH:13]=O)[CH:9]=1.[BH4-].[Na+].O.[CH3:18][NH2:19]>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:12][CH:11]=[C:10]([CH2:13][NH:19][CH3:18])[CH:9]=1
Reactant: CN
Reactant: O=Cc1c[nH]c(-c2ccccc2F)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Product: CNCc1c[nH]c(-c2ccccc2F)c1
Reaction time: 1 h

Procedure:
5-(2-Fluorophenyl)-1H-pyrrol-3-carboxaldehyde 1d (1.89 g, 10 mmol, prepared by a known method disclosed in “Journal of Medicinal Chemistry”, 2012, 55(9), 4446-4456) was dissolved in 20 mL of methylamine, and the reaction solution was stirred for 1 h. Sodium borohydride (1.14 g, 30 mmol) was added and continuously stirred for 1 h. 10 mL of water were added to the reaction solution, and the reaction solution was concentrated under reduced pressure to obtain the title product 1-(5-(2-fluorophenyl)-1H-pyrrol-3-yl)-N-methylmethanamine 1e (2.0 g, a yellow oil), which was used directly in the next step.
Reaction SMILES: [CH2:1]([NH:7][C:8](=[O:11])[CH:9]=[CH2:10])[NH:2][C:3](=[O:6])[CH:4]=[CH2:5].[CH3:12][Si:13]([CH3:16])([CH3:15])Cl.[S]>C(N(CC)CC)C>[CH3:12][Si:13]([CH3:16])([CH3:15])[N:7]([CH2:1][N:2]([Si:13]([CH3:16])([CH3:15])[CH3:12])[C:3](=[O:6])[CH:4]=[CH2:5])[C:8](=[O:11])[CH:9]=[CH2:10]
Reactant: C=CC(=O)NCNC(=O)C=C
Reactant: C[Si](C)(C)Cl
Agent: [S]
Solvent: CCN(CC)CC
Product: C=CC(=O)N(CN(C(=O)C=C)[Si](C)(C)C)[Si](C)(C)C
Temperature: 60 °C
Reaction time: 8 h
Yield: 60.3 %

Procedure:
850 ml of anhydrous triethylamine and 92.5 g (0.6 mol) of N,N'-methylene-bis-acrylamide are initially introduced into a 2.5 liter sulphonation flask equipped with a stirrer, a thermometer, a reflux condenser and a dropping funnel. 220 g (approximately 2 mols) of trimethylchlorosilane are then added dropwise, whilst cooling occasionally with an ice bath, in such a way that the temperature of the reaction mixture does not exceed 15°-25° C. A little sulphur is then added, as a polymerisation inhibitor, to the reaction mixture, which is stirred overnight at 60° C. The following day, the triethylamine hydrochloride which has precipitated is filtered off, the filter cake is washed with approximately 300 ml of triethylamine, and the filtrates are finally combined and distilled in vacuo. 108 g of N,N'-bis-trimethylsilyl-N,N'-methylene-bis-acrylamide are obtained as a fraction distilling at 120° C/0.8 mm Hg.
Reaction SMILES: [C:1]12([C:11](=[O:21])[CH2:12][N:13]3[CH2:20][CH2:19][CH2:18][C@H:14]3[C:15]([OH:17])=O)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.C(N(CC)CC)C.ClC(OCC(C)C)=O.[CH2:37]([NH:44][C:45](=[O:52])[C@H:46]([CH2:48][CH:49]([CH3:51])[CH3:50])[NH2:47])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>C1COCC1>[C:1]12([C:11](=[O:21])[CH2:12][N:13]3[CH2:20][CH2:19][CH2:18][C@H:14]3[C:15]([N:44]([CH2:37][C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=3)[C:45](=[O:52])[C@H:46]([CH2:48][CH:49]([CH3:51])[CH3:50])[NH2:47])=[O:17])[CH2:10][CH:5]3[CH2:4][CH:3]([CH2:9][CH:7]([CH2:6]3)[CH2:8]1)[CH2:2]2
Reactant: CC(C)C[C@H](N)C(=O)NCc1ccccc1
Reactant: O=C(O)[C@@H]1CCCN1CC(=O)C12CC3CC(CC(C3)C1)C2
Agent: CC(C)COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)C[C@H](N)C(=O)N(Cc1ccccc1)C(=O)[C@@H]1CCCN1CC(=O)C12CC3CC(CC(C3)C1)C2
Yield: 67.9 %

Procedure:
Using the procedure described previously, a solution of 1-(2-adamantan-1-yl-2-oxoethyl) L-proline (108 mg, 0.37 mmol, 1.0 eq), triethylamine (156 uL, 1.11 mmol, 3.0 eq), and THF (1.5 mL), was treated with isobutyl chloroformate (53 uL, 0.41 mL, 1.1 eq), then with L-leucine N-benzylamide (123 mg, 570 umol, 1.5 eq). Workup as before provided 124 mg (68%) of L-leucine, N-[1-(2-adamantan-1-yl-2-oxoethyl)-L-prolyl] benzylamide.
Reaction SMILES: [CH2:1]([C:3]1([O:35][C:36](=[O:45])[O:37][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:8]2[CH:9]=[C:10]3[N:18]([C:19](=[O:20])[C:7]=2[CH2:6][O:5][C:4]1=[O:34])[CH2:17][C:16]1[C:15]([CH2:21][CH2:22][Si:23]([CH2:26][CH2:27][CH2:28][OH:29])([CH3:25])[CH3:24])=[C:14]2[CH:30]=[CH:31][CH:32]=[CH:33][C:13]2=[N:12][C:11]3=1)[CH3:2].N1C=CC=CC=1.[C:52](OC(=O)C)(=[O:54])[CH3:53]>ClCCl>[CH2:38]([O:37][C:36]([O:35][C:3]1([CH2:1][CH3:2])[C:8]2[CH:9]=[C:10]3[N:18]([C:19](=[O:20])[C:7]=2[CH2:6][O:5][C:4]1=[O:34])[CH2:17][C:16]1[C:15]([CH2:21][CH2:22][Si:23]([CH3:25])([CH3:24])[CH2:26][CH2:27][CH2:28][O:29][C:52](=[O:54])[CH3:53])=[C:14]2[CH:30]=[CH:31][CH:32]=[CH:33][C:13]2=[N:12][C:11]3=1)=[O:45])[C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1
Reactant: CC(=O)OC(C)=O
Reactant: CCC1(OC(=O)OCc2ccccc2)C(=O)OCc2c1cc1n(c2=O)Cc2c-1nc1ccccc1c2CC[Si](C)(C)CCCO
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCC1(OC(=O)OCc2ccccc2)C(=O)OCc2c1cc1n(c2=O)Cc2c-1nc1ccccc1c2CC[Si](C)(C)CCCOC(C)=O
Temperature: 21 °C
Reaction time: 5 h

Procedure:
A mixture of Compound 53 (200 mg, 0.32 mmol), Pyridine (1.26 mL), and acetic anhydride (0.3 mL, 2.9 mmol) in 6.0 mL of dichloromethane was stirred at 21° C. for 5 hours. The reaction was quenched with saturated sodium bicarbonate solution, and aqueous layer was extracted with dichloromethane. The combined organic layers were dried over sodium sulfate and concentrated to afford a crude product, which was chromatographed to give the desired product.