Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:11][C:12]([OH:14])=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:27]([O:29][C:30](=[O:41])[CH:31]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[CH2:32][NH2:33])[CH3:28]>ClCCl>[CH2:27]([O:29][C:30](=[O:41])[CH:31]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[CH2:32][NH:33][C:12](=[O:14])[CH2:11][C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1)[CH3:28]
Reactant: O=C(O)Cc1cccc2ccccc12
Reactant: CCOC(=O)C(CN)Cc1ccccc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: CCOC(=O)C(CNC(=O)Cc1cccc2ccccc12)Cc1ccccc1
Yield: 41.1 %

Procedure:
A solution of 173 g of 1-naphthylacetic acid and 151 mg of 1,1'-carbonyldiimidazole in dry dichloromethane was stirred for 1 hour at room temperature. To the mixture was added 227 mg of 3-amino-2-benzylpropionic acid ethyl ester obtained, and the mixture was heated under reflux for 16 hours. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate, and then the organic layer was washed successively with a 1N-hydrochloric acid, a 5% aqueous sodium bicarbonate solution and water. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by preparative silica gel thin layer chromatography (developing solvent: chloroform/ethanol=5/1 by volume) to obtain 169 mg of 2-benzyl-3-(1-naphthylacetamido)propionic acid ethyl ester as colorless crystals.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([NH2:12])[N:8]=[CH:9]2)=[CH:4][CH:3]=1.[CH3:13][C:14]1[CH:19]=[CH:18][N:17]=[CH:16][C:15]=1B(O)O.C(=O)([O-])[O-].[Cs+].[Cs+].COCCOC.O>ClCCl.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.Cl[Pd]Cl>[CH3:13][C:14]1[CH:19]=[CH:18][N:17]=[CH:16][C:15]=1[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([NH2:12])[N:8]=[CH:9]2)=[CH:4][CH:3]=1
Reactant: Nc1cc2ccc(Br)cc2cn1
Reactant: Cc1ccncc1B(O)O
Agent: Cl[Pd]Cl
Agent: CN(C)c1ccc(P(C(C)(C)C)C(C)(C)C)cc1
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: ClCCl
Solvent: O
Product: Cc1ccncc1-c1ccc2cc(N)ncc2c1
Yield: 41.6 %

Procedure:
To a mixture of 7-bromoisoquinolin-3-amine (253.2 mg, 1.135 mmol), 4-methylpyridine-3-boronic acid (188.8 mg, 1.379 mmol), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (81.0 mg, 0.114 mmol), and cesium carbonate (0.7432 g, 2.281 mmol) was added 1,2-dimethoxyethane (5 mL, 50 mmol) and water (0.5 mL, 30 mmol). The reaction mixture was subjected to microwave irradiation at 130° C. for 30 minutes. 4-Methylpyridine-3-boronic acid (197.2 mg, 1.440 mmol) was added and the reaction mixture was subjected to microwave irradiation at 130° C. for 45 min. The reaction mixture was diluted with dichloromethane, washed with saturated aqueous NaHCO3, dried over MgSO4, and evaporated in vacuo. The crude material was purified via flash chromatography on silica gel (25 g silica, solvent gradient: 0-10% methanol in dichloromethane) to yield 111.1 mg (42%) of 7-(4-methylpyridin-3-yl)isoquinolin-3-amine. LCMS (ESI): M+H=236.2; 1H NMR (400 MHz, DMSO-d6) δ 8.87 (s, 1H), 8.43 (d, J=6.4 Hz, 2H), 7.81 (s, 1H), 7.60 (d, J=8.5 Hz, 1H), 7.49 (dd, J=8.6, 1.7 Hz, 1H), 7.35 (d, J=5.0 Hz, 1H), 6.67 (s, 1H), 5.99 (s, 2H), 2.31 (s, 3H).
Reaction SMILES: [CH:1]1([N:6]=[C:7]=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[ClH:16].Cl.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][C:28]([NH:31][C:32]([C@@H:34]3[CH:39]4[CH2:40][CH2:41][N:36]([CH2:37][CH2:38]4)[CH2:35]3)=[O:33])=[CH:27][CH:26]=2)=[CH:21][CH:20]=1.O>CN(C=O)C>[ClH:16].[CH:1]1([NH:6][C:7]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:26]=[CH:27][C:28]([NH:31][C:32]([C@@H:34]4[CH:39]5[CH2:38][CH2:37][N:36]([CH2:41][CH2:40]5)[CH2:35]4)=[O:33])=[CH:29][CH:30]=3)=[CH:21][CH:20]=2)=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C=NC1CCCC1
Reactant: Nc1ccc(-c2ccc(NC(=O)[C@H]3CN4CCC3CC4)cc2)cc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(-c2ccc(NC(=O)[C@H]3CN4CCC3CC4)cc2)cc1)NC1CCCC1
Reaction time: 18 h

Procedure:
33.8 mg (0.30 mmol) of cyclopentyl isocyanate and 84.8 μl (0.61 mmol) of triethylamine are added to a solution of 60 mg (0.15 mmol) of ((3R)—N-(4′-aminobiphenyl-4-yl)quinuclidine-3-carboxamide dihydrochloride (Example 7A) in 0.5 ml of DMF. After 18 h at room temperature, 5 ml of water are added to the reaction mixture. The resulting precipitate is filtered off with suction, washed with water and dried under high vacuum. A preparative HPLC is carried out for further purification. The product fractions are concentrated, mixed with 3 ml of 1 N hydrochloric acid, again concentrated and dried under high vacuum. 28 mg (39.2% of theory) of the title compound are obtained.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][OH:9])=[CH:4][C:3]=1[Cl:10].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[O:9])=[CH:4][C:3]=1[Cl:10]
Reactant: OCc1ccc(Br)c(Cl)c1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: O=Cc1ccc(Br)c(Cl)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of (4-bromo-3-chlorophenyl)methanol (2.0 g, 9.0 mmol), pyridinium chlorochromate (2912 mg, 13.5 mmol) in dichloromethane (50 mL0 was stirred at 25° C. for 3 hours. The mixture was concentrated to give a residue. The residue was purified by column chromatography (silica gel, petroleum ethe/ethyl acetate=1:1) to give 4-bromo-3-chlorobenzaldehyde as a white solid (1.6 g g, 81%). 1H NMR (300 MHz, d6-DMSO): δ 9.96 (s, 1H), 7.69 (d, J=8.1, 1H), δ 7.53 (d, J=0.9, 1H), 7.19 (dd, J=8.1, 1H J2=0.9, 1H)
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[CH3:11])[C:7](=[O:12])[N:6]([C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)[CH:5]2[CH2:19][CH2:20]OS(C)(=O)=O>C(N)CC>[CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[CH3:11])[C:7](=[O:12])[N:6]([C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)[CH:5]2[CH2:19][CH2:20][NH:6][CH2:5][CH2:4][CH3:3]
Reactant: Cc1cc2c(cc1C)C(CCOS(C)(=O)=O)N(c1cccnc1)C2=O
Solvent: CCCN
Product: CCCNCCC1c2cc(C)c(C)cc2C(=O)N1c1cccnc1
Yield: 169.6 %

Procedure:
5,6-Dimethyl-2-(3-pyridyl)-3-mesyloxyethylisoindolin-1-one (0.11 g, 0.31 mmol) was stirred in n-propylamine (3 ml) at 25° C. for 6 hrs. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (chloroform:methanol=15:1) to give 85 mg of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[C:14]([F:16])[C:13]([N:17]2[C:22](=[O:23])[CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[NH:19][C:18]2=[O:28])=[CH:12][C:3]=1[C:4]([O:6][CH:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1)=[O:5].C(=O)(O)[O-].[K+].S(OCC)(O[CH2:38][CH3:39])(=O)=O>CC(C)=O>[Cl:1][C:2]1[CH:15]=[C:14]([F:16])[C:13]([N:17]2[C:22](=[O:23])[CH:21]=[C:20]([C:24]([F:25])([F:26])[F:27])[N:19]([CH2:38][CH3:39])[C:18]2=[O:28])=[CH:12][C:3]=1[C:4]([O:6][CH:7]1[CH2:8][CH2:9][CH2:10][CH2:11]1)=[O:5]
Reactant: CCOS(=O)(=O)OCC
Reactant: O=C(OC1CCCC1)c1cc(-n2c(=O)cc(C(F)(F)F)[nH]c2=O)c(F)cc1Cl
Agent: O=C([O-])O
Agent: [K+]
Solvent: CC(C)=O
Product: CCn1c(C(F)(F)F)cc(=O)n(-c2cc(C(=O)OC3CCCC3)c(Cl)cc2F)c1=O

Procedure:
4.5 g of cyclopentyl 2-chloro-5-[3.6-dihydro-2,6-dioxo-4-trifluoromethyl-1(2H)-pyrimidinyl]-4-fluorobenzoate, 2.1 g of potassium bicarbonate and 1.5 ml of diethyl sulphate are heated at reflux temperature in 50 ml of acetone for 4 hours. Subsequently. the solvent is distilled off and the residue is partitioned in 150 ml of diethyl ether and 150 ml of water. The aqueous phase is extracted with a further 150 ml of diethyl ether and the combined organic phases are washed twice with 150 ml of water each time, dried over anhydrous magnesium sulphate and concentrated. The residue is purified by chromatography on a silica gel column using ethyl acetate/n-hexane (1:4) as the eluent. In this manner there are obtained cyclopentyl 2-chloro-5-[3-ethyl-3,6-dihydro-2,6-dioxo-4-trifluoromethyl-1(2H)-pyrimidinyl]-4-fluorobenzoate as a colourless oil, 1H-NMR (CDCl 3, 400 MHz : 1 36 (t3H), 1.56-2.04 (m,8H), 4.02 (q,2H), 5.36-5.45 (m,1H), 6.35 (s,1H), 7.36 (d,1H), 7.82 (d,1H); mass spectrum (m/e): M+ 448 (1), as well as cyclopentyl 2-chloro- 5-[2-ethoxy-6-oxo-4-trifluoromethyl-1(6H)-pyrimidinyl]-4-fluorobenzoate, m.p. 90°-91° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]([N+:9]([O-])=O)[CH:3]=1.[CH:12]([Mg]Br)=[CH2:13]>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]2[C:3]=1[CH:12]=[CH:13][NH:9]2
Reactant: Cc1ccc(Br)cc1[N+](=O)[O-]
Reactant: C=C[Mg]Br
Solvent: C1CCOC1
Product: Cc1ccc(Br)c2cc[nH]c12
Temperature: -40 °C
Reaction time: 1.5 h
Yield: 35.3 %

Procedure:
To a solution of 4-bromo-2-nitrotoluene (3.0 g, 13.9 mmol) in THF (40 mL) at −40° C. was added vinyl magnesium bromide (48.6 mmol, 48.6 mL; 1.0 M in THF) dropwise over 15 minutes and the mixture stirred at −40° C. for 1.5 hours. The reaction was quenched by the addition of saturated aqueous ammonium chloride and extracted with ethyl acetate. The combined organic layers were washed with brine, separated and dried (MgSO4). The residue was evaporated and purified by column chromatography to yield 4-bromo-7-methylindole (1.03 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:10])[CH:9]=1)[CH:5]=O.[CH3:11][N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.CC(O)=O.[BH3-]C#N.[Na+]>CO>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:10])[CH:9]=1)[CH2:5][N:15]1[CH2:16][CH2:17][N:12]([CH3:11])[CH2:13][CH2:14]1
Reactant: CN1CCNCC1
Reactant: O=Cc1cc(F)cc(Br)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CN1CCN(Cc2cc(F)cc(Br)c2)CC1
Reaction time: 1 h
Yield: 51 %

Procedure:
A solution of 3-bromo-5-fluorobenzaldehyde (CI) (2.12 g, 10.42 mmol) in MeOH (200 mL) was added 1-methylpiperazine (2.3 mL, 20.84 mL). The pH was adjusted to 6 using HOAc and stirred for 1 h. NaCNBH3 (917 mg, 14.59 mmol) was added and stirred at room temperature overnight. The MeOH was removed under vacuum and the residue was partitioned between CHCl3 and saturated aqueous NaHCO3. The organic layer was dried over MgSO4 and evaporated under vacuum. The crude product was purified on a silica gel column (100% CHCl3→3:97 MeOH[7N NH3]:CHCl3) to produce 1-(3-bromo-5-fluorobenzyl)-4-methylpiperazine (CII) as a yellow oil (1.52 g, 5.29 mmol, 51% yield). 1H NMR (DMSO-d6, 500 MHz) δ ppm 2.14 (s, 3H), 2.28-2.40 (m, 8H), 3.46 (s, 2H), 7.15-7.17 (m, 1H), 7.35 (s, 1H), 7.40-7.42 (m, 1H); ESIMS found C12H16BrFN2 m/z 287 (M+H).
Reaction SMILES: [C:1]([C:11]1[CH:31]=[CH:30][C:14]([CH2:15][NH:16][C:17]2[CH:22]=[CH:21][C:20](/[CH:23]=[CH:24]/[C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:19][CH:18]=2)=[CH:13][CH:12]=1)#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[C:32]1([CH2:38][CH2:39][C:40](Cl)=[O:41])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[C:1]([C:11]1[CH:31]=[CH:30][C:14]([CH2:15][N:16]([C:40](=[O:41])[CH2:39][CH2:38][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:17]2[CH:18]=[CH:19][C:20](/[CH:23]=[CH:24]/[C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:21][CH:22]=2)=[CH:13][CH:12]=1)#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: O=C(Cl)CCc1ccccc1
Reactant: CCCCCCCCC#Cc1ccc(CNc2ccc(/C=C/C(=O)OCC)cc2)cc1
Product: CCCCCCCCC#Cc1ccc(CN(C(=O)CCc2ccccc2)c2ccc(/C=C/C(=O)OCC)cc2)cc1

Procedure:
The title compound was prepared following the procedure E using of ethyl (2E)-3-{4-[(4-dec-1-ynylbenzyl)amino]phenyl}acrylate and 3-phenylpropanoyl chloride (58%). M+ (ESI): 560.6. HPLC, Rt: 6.4 min (purity: 98.7%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:25][C@@H:26]3[CH2:30][CH2:29][CH2:28][N:27]3[C:31](=[O:49])[C:32]([C:47]#[N:48])=[CH:33][C:34]([N:37]([CH2:45][CH3:46])C(=O)OC(C)(C)C)([CH3:36])[CH3:35])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][C:12]=3[F:24])[C:3]=12.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:25][C@@H:26]3[CH2:30][CH2:29][CH2:28][N:27]3[C:31]([C:32](=[CH:33][C:34]([NH:37][CH2:45][CH3:46])([CH3:35])[CH3:36])[C:47]#[N:48])=[O:49])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)=[CH:13][C:12]=3[F:24])[C:3]=12
Reactant: CCN(C(=O)OC(C)(C)C)C(C)(C)C=C(C#N)C(=O)N1CCC[C@H]1Cn1nc(-c2ccc(Oc3ccccc3)cc2F)c2c(N)ncnc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCNC(C)(C)C=C(C#N)C(=O)N1CCC[C@H]1Cn1nc(-c2ccc(Oc3ccccc3)cc2F)c2c(N)ncnc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 23.7 %

Procedure:
To a solution of tert-butyl 5-((S)-2-((4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidin-1-yl)-4-cyano-2-methyl-5-oxopent-3-en-2-yl(ethyl)carbamate (60 mg, 0.089 mmol) in DCM (8 mL) was added 2 mL of CF3COOH. The mixture was stirred for 2 h at room temperature, then concentrated and purified by Prep-HPLC. Conditions: (1#-Pre-HPLC-001(SHIMADZU)): Column, SunFire Prep C18, 19*150 mm 5 um; mobile phase, water with 0.05% TFA and CH3CN (40% CH3CN up to 100% in 20 min); Detector, 254 nm. This resulted in 12 mg (16%) of the title compound as a white solid and bis TFA salt. LC-MS: m/z 569 (M+H+). H1-NMR (400 MHz, CDCl3+D2O, ppm): 8.31 (s, 1H), 7.51-7.44 (m, 3H), 7.37 (s, 1H), 7.28-7.25 (m, 1H), 7.13 (d, J=7.6 Hz, 2H), 6.95 (dd, J=8.4, 2.0 Hz, 1H), 6.85 (q, J=11.6 Hz, 2.0 Hz, 1H), 4.89-4.65 (m, 3H), 3.76-3.57 (m, 4H), 2.14-1.83 (m, 4H), 1.50-1.49 (d, 6H), 1.31 (t, q=6.8 Hz, 3H).
Reaction SMILES: [O:1]=[C:2]1[NH:7][CH:6]=[N:5][C:4]([CH2:8][CH2:9][CH3:10])=[C:3]1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1.[CH:26]([O:29][C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1)([CH3:28])[CH3:27].C(N(CC)CC)C.N1C=CC=CC=1>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.C(OCC)(=O)C.C(Cl)Cl>[CH:26]([O:29][C:30]1[CH:35]=[CH:34][C:33]([N:7]2[C:2](=[O:1])[C:3]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([C:18]4[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=4)=[CH:14][CH:13]=3)=[C:4]([CH2:8][CH2:9][CH3:10])[N:5]=[CH:6]2)=[CH:32][CH:31]=1)([CH3:28])[CH3:27]
Reactant: CCCc1nc[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: CC(C)Oc1ccc(B(O)O)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCCc1ncn(-c2ccc(OC(C)C)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 43.2 %

Procedure:
A mixture of 4′-[(6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (1.02 g), (4-isopropoxyphenyl)boronic acid (0.65 g), molecular sieves 4 A (1.98 g), triethylamine (1.7 mL), pyridine (1.0 mL), copper(II) acetate (0.65 g) and methylene chloride (15 mL) was stirred at room temperature for 24 hr. Ethyl acetate was added to the reaction mixture, and the insoluble solid was filtered off. The solvent of the filtrate was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.62 g, 44%).
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:31]=[CH:30][C:6]([CH2:7][N:8]2[C@@H:14]([C:15]([NH:17][C@H:18]([C:20]3[CH:29]=[CH:28][C:23]([C:24]([O:26]C)=[O:25])=[CH:22][CH:21]=3)[CH3:19])=[O:16])[CH2:13][CH2:12][CH:11]3[CH:9]2[CH2:10]3)=[CH:5][CH:4]=1.O[Li].O>>[F:32][C:2]([F:1])([F:33])[C:3]1[CH:31]=[CH:30][C:6]([CH2:7][N:8]2[C@@H:14]([C:15]([NH:17][C@H:18]([C:20]3[CH:21]=[CH:22][C:23]([C:24]([OH:26])=[O:25])=[CH:28][CH:29]=3)[CH3:19])=[O:16])[CH2:13][CH2:12][CH:11]3[CH:9]2[CH2:10]3)=[CH:5][CH:4]=1
Reactant: COC(=O)c1ccc([C@H](C)NC(=O)[C@H]2CCC3CC3N2Cc2ccc(C(F)(F)F)cc2)cc1
Agent: [Li]O
Solvent: O
Product: C[C@H](NC(=O)[C@H]1CCC2CC2N1Cc1ccc(C(F)(F)F)cc1)c1ccc(C(=O)O)cc1
Yield: 74.3 %

Procedure:
The title compound (E26) (7.2 mg) was prepared according to the general procedure for esters hydrolysis (Method D) starting from methyl 4-((1S)-1-((3R)-2-(4-(trifluoromethyl)benzyl)-2-azabicyclo[4.1.0]heptane-3-carboxamido)ethyl)benzoate (diastereoisomers mixture) (D143) (10 mg). (LiOH H2O: 4 eq; reaction time: 10 hrs)
Reaction SMILES: [CH:1]1[C:6]([N+:7]([O-:9])=[O:8])=[CH:5][CH:4]=[C:3]([OH:10])[CH:2]=1.[CH2:11](I)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH2:11]([O:10][C:3]1[CH:4]=[CH:5][C:6]([N+:7]([O-:9])=[O:8])=[CH:1][CH:2]=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: CCCCCCCCCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCCCCCOc1ccc([N+](=O)[O-])cc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 108.8 %

Procedure:
At the outset, p-nitrophenol 1 (13.4 g, 96 mmol) and n-decyl iodide (25 g, 93 mmol) were dissolved in DMF (100 ml) to prepare a solution. Potassium carbonate (12.9 g) was added to the solution, and the mixture was stirred at 100° C. for about 2 hr. After the disappearance of the starting material was confirmed by TLC, the reaction mixture was allowed to cool to room temperature. Upon the addition of water and salt in an ice bath, solid matter was precipitated, and the solid was collected by filtration to give 4-decyloxynitrobenzene 2 (28.28 g, 110%) as a light yellow liquid.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[NH:12][CH:13]=[C:14]([CH2:16][OH:17])[N:15]=1)[CH2:2][CH3:3]>[O-2].[O-2].[Mn+4].C(Cl)(Cl)Cl>[CH2:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[NH:12][CH:13]=[C:14]([CH:16]=[O:17])[N:15]=1)[CH2:2][CH3:3]
Reactant: CCCOc1ccccc1-c1nc(CO)c[nH]1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: CCCOc1ccccc1-c1nc(C=O)c[nH]1

Procedure:
A 44 gm. portion of 2-(o-propoxyphenyl)-4-imidazolemethanol is placed in a 2 liter round bottom flask together with 500 ml. of chloroform and 100 gm. of manganese dioxide. The mixture is stirred and refluxed for 51/2 hours. The reaction mixture is filtered while hot. The manganese dioxide is triturated with 500 ml. of hot chloroform and filtered. The two filtrates are combined and evaporated. The solid residue is recrystallized from 200 ml. of hot ethyl acetate and charcoal giving the desired product, m.p. 104°-105° C.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[O:11]1[C:15]2([CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)[O:14][CH2:13][CH2:12]1>N1C=CC=CC=1.O>[N+:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[N:18]1[CH2:19][CH2:20][C:15]2([O:14][CH2:13][CH2:12][O:11]2)[CH2:16][CH2:17]1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: C1CC2(CCN1)OCCO2
Solvent: O
Solvent: c1ccncc1
Product: O=[N+]([O-])c1ccccc1N1CCC2(CC1)OCCO2
Yield: 81.3 %

Procedure:
A solution of 2-fluoronitrobenzene (10 g, 70.9 mmol) and 1,4-dioxa-8-aza-spiro[4.5]decane (10 g, 69.8 mmol) in pyridine (70 mL) was heated at 70° C. for 1 day, diluted with water, and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried with sodium sulfate, and filtered. The solvent was removed under reduced pressure to give the title compound (15 g) as a red oil; 1H NMR (300 MHz, CDCl3) δ 1.88 (t, J=5.6 Hz, 4H), 3.16 (t, J=5.6 Hz, 4H), 4.00 (s, 4H), 7.03 (dd, J=8.2, 8.2 Hz, 2H), 7.17 (d, J=8.2 Hz, 2H), 7.40 (ddd, J=8.2, 8.2, 1.7 Hz, 1H), 7.77 (dd, J=8.4, 1.7Hz, 1H); MS (ES) m/z: 265.1 (MH+); HRMS Calcd. for C13H17N2O4 (MH+): 265.1188. Found: 265.1164.
Reaction SMILES: [CH:1]([N:3]([CH2:6][CH2:7][C:8]([O:10]CC)=O)[CH:4]=[O:5])=[CH2:2].[CH2:13]([NH2:16])[CH:14]=[CH2:15].C[O-].[Na+]>CO>[CH2:13]([NH:16][C:8](=[O:10])[CH2:7][CH2:6][N:3]([CH:1]=[CH2:2])[CH:4]=[O:5])[CH:14]=[CH2:15]
Reactant: C=CN(C=O)CCC(=O)OCC
Reactant: C=CCN
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: C=CCNC(=O)CCN(C=C)C=O
Temperature: 90 °C

Procedure:
A 100mL stainless steel high pressure reactor was charged with 17.1 grams (0.1 mol) of ethyl 3-(N-vinylformamido)propionate, 5.7 grams (0.1 mol) of allylamine and 0.15 gram of 25% sodium methoxide in methanol solution. The mixture was heated at 90° C. for 3 hours. Subsequent NMR analysis of the reaction mixture showed no conversion of the starting materials.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]([NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C:4]([O:6][CH3:7])=[O:5].CCN(C(C)C)C(C)C.[N+:25]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[S:34](Cl)(=[O:36])=[O:35])([O-:27])=[O:26]>C(Cl)Cl>[C:12]([O:11][C:9]([NH:8][C@@H:3]([CH2:2][NH:1][S:34]([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=1[N+:25]([O-:27])=[O:26])(=[O:35])=[O:36])[C:4]([O:6][CH3:7])=[O:5])=[O:10])([CH3:15])([CH3:14])[CH3:13]
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Reactant: COC(=O)[C@H](CN)NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@H](CNS(=O)(=O)c1ccccc1[N+](=O)[O-])NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.3 %

Procedure:
To a mixture of methyl 3-amino-2(S)-(tert-butoxycarbonylamino)propanoate ii (1.6 g, 7.3 mmoL) in DCM (50 mL) was added DIPEA (1.64 mL, 9.4 mmoL) and 2-nitrobenzene sulfonyl chloride (1.62 g, 7.3 mmoL). The mixture was stirred at rt for 2 h. It was then concentrated, dissolved in ethyl acetate, which was then washed with sat. sodium bicarbonate, brine and dried over magnesium sulfate. It was then filtered, concentrated to yield 2.9 g (98%) of methyl 2(S)-(tert-butoxycarbonylamino)-3-(2-nitrophenylsulfonamido)propanoate iii as a yellow foam. 1H NMR (CD3OD, 300 MHz) δ 1.41 (s, 9H), 3.36-3.51 (m, 2H), 3.71 (s, 3H), 4.22 (m, 1H), 7.80-7.90 (m, 3H), 8.07-8.10 (m, 1H).
Reaction SMILES: [OH:1][NH2:2].C[O:4][C:5](=O)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1.CCOC(C)=O>CN(C=O)C.C1COCC1.[Cl-].[Na+].O>[OH:1][NH:2][C:5](=[O:4])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1
Reactant: NO
Reactant: COC(=O)CCCCCN(c1ccccn1)c1ccccn1
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(CCCCCN(c1ccccn1)c1ccccn1)NO
Temperature: 25 °C
Reaction time: 17 h
Yield: 30 %

Procedure:
HONH2 (50% aqueous, 0.3 mL) was added to II (32 mg, 0.1 mmol) in DMF (0.3 mL) and THF (0.3 mL) at 0° C. The reaction mixture was agitated at rt for 17 h. Brine (3 mL) and EtOAc (3 mL) were added, the phases were separated, and the aqueous phase was extracted with EtOAc (2×3 mL). The organic phases were combined, dried over MgSO4, filtered then evaporated under reduced pressure. The residue was purified by silica gel column chromatography with CH2Cl2/MeOH (100:3 to 100:10) to furnish IV as a colourless oil (9.6 mg, 30%).
Reaction SMILES: [N:1]([O-:3])=O.[Na+].[CH2:5]([N:9]([CH2:16][CH2:17][CH2:18][CH3:19])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:6][CH2:7][CH3:8].Cl.[OH-].[Na+]>O>[CH2:5]([N:9]([CH2:16][CH2:17][CH2:18][CH3:19])[C:10]1[CH:15]=[CH:14][C:13]([N:1]=[O:3])=[CH:12][CH:11]=1)[CH2:6][CH2:7][CH3:8]
Reactant: CCCCN(CCCC)c1ccccc1
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCCN(CCCC)c1ccc(N=O)cc1
Yield: 48 %

Procedure:
A solution was prepared by dissolving 18.5 g (0.26 mol) of sodium nitrite, of a purity of 97%, in 30 ml of water. This solution was added dropwise to a solution composed of 51.3 g (0.25 mol) of N,N-dibutylaniline, 200 g of water and 105 ml of conc HCl (35 to 38%) at a temperature between 10° and 20° C. for one-half hour. After stirring the solution obtained for one hour, the solution was neutralized to pH 8 with a 15% aqueous solution of sodium hydroxide. The crystals obtained were filtered, washed sufficiently on filter paper and thereafter dried with hot-air at 50° C. for 48 hours. 28.1 g of N,N-dibutyl-p-nitrosoaniline with a melting point of 122°~124° C. was obtained. The yield was 48.0%.