Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([C@H]1COC(=O)N1[C:14](=[O:43])[CH2:15][C@@H:16]([C:22]1[CH:42]=[CH:41][C:25]([O:26][CH2:27][C:28]2[CH:29]=[C:30]([NH:34][C:35](=[O:40])[C:36]([CH3:39])([CH3:38])[CH3:37])[CH:31]=[CH:32][CH:33]=2)=[CH:24][CH:23]=1)[C:17]1[CH:21]=[CH:20][O:19][N:18]=1)C1C=CC=CC=1.[OH:44]O.[Li+].[OH-].Cl>C1COCC1.O>[C:35]([NH:34][C:30]1[CH:29]=[C:28]([CH:33]=[CH:32][CH:31]=1)[CH2:27][O:26][C:25]1[CH:41]=[CH:42][C:22]([C@@H:16]([C:17]2[CH:21]=[CH:20][O:19][N:18]=2)[CH2:15][C:14]([OH:44])=[O:43])=[CH:23][CH:24]=1)(=[O:40])[C:36]([CH3:39])([CH3:38])[CH3:37]
Reactant: CC(C)(C)C(=O)Nc1cccc(COc2ccc([C@H](CC(=O)N3C(=O)OC[C@@H]3Cc3ccccc3)c3ccon3)cc2)c1
Reactant: OO
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)Nc1cccc(COc2ccc([C@H](CC(=O)O)c3ccon3)cc2)c1
Reaction time: 5 h
Yield: 64.2 %

Procedure:
To a solution of the oxazolidinone 30.1 (62.0 mg, 0.107 mmol) dissolved in THF (10 mL), was added a 30% hydrogen peroxide solution (0.120 mL, 1.07 mmol) followed by a 2M LiOH solution (0.266 mL, 0.533 mmol). The resulting slurry was stirred for five hours. The reaction mixture was diluted with water and acidified with hydrochloric acid to a pH ˜3. The mixture was then extracted with EtOAc (1×50 mL), and the organic layer was washed with acidic sodium sulfite solution (2×30 mL) and brine (1×30 mL), and dried over magnesium sulfate. The filtrate was concentrated under reduced pressure, and the residue was purified by reverse phase HPLC to give 30 (29.0 mg). MS ESI (pos.) m/e: 423.1 (M+H). 1H NMR (400 MHz, CD3CN) δ ppm 8.32 (1H, d, J=1.6 Hz), 7.92 (1H, br. s.), 7.61 (1H, s), 7.42 (1H, d, J=7.8 Hz), 7.22 (1H, t, J=7.8 Hz), 7.12 (2H, d, J=9.0 Hz), 7.05 (1H, d, J=7.4 Hz), 6.84 (2H, d, J=9.0 Hz), 6.15 (1H, d, J=1.6 Hz), 4.95 (2H, s), 4.43 (1H, t, J=7.8 Hz), 3.08 (1H, dd, J=16.6, 8.4 Hz), 2.83 (1H, dd, J=16.4, 7.4 Hz), 1.16 (9H, s).
Reaction SMILES: [CH2:1]([NH:4][CH2:5][C:6]([OH:8])=[O:7])[CH:2]=[CH2:3].O1CCOCC1.[CH3:15][C:16]([O:19][C:20](ON=C(C1C=CC=CC=1)C#N)=[O:21])([CH3:18])[CH3:17]>CCOCC.O.C(N(CC)CC)C>[C:20]([CH:3]=[CH:2][CH2:1][NH:4][CH2:5][C:6]([OH:8])=[O:7])([O:19][C:16]([CH3:18])([CH3:17])[CH3:15])=[O:21]
Reactant: CC(C)(C)OC(=O)ON=C(C#N)c1ccccc1
Reactant: C=CCNCC(=O)O
Solvent: C1COCCO1
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)C=CCNCC(=O)O
Temperature: 25 °C
Reaction time: 3.75 h

Procedure:
A mixture of 884 mg of allylglycine, 4.6 ml of water, 4.6 ml of dioxane, 1.6 ml of triethylamine and 2.08 g BOC-ON is stirred for 3.75 hrs at 25° C. Then 15 ml of water and 20 ml of ether are added. The aqueous layer is separated, washed with ether, acidified to pH 2 with HCl, and filtered to isolate the crystalline product, 1.4. g, m.p. 109° C.
Reaction SMILES: [S:1](=[O:5])(=[O:4])([O-:3])[NH2:2].[NH4+].[N:7]12[CH2:17][CH2:16][CH2:15][N:14]=[C:13]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2>>[S:1](=[O:4])(=[O:3])([O-:5])[NH2:2].[NH+:7]12[CH2:17][CH2:16][CH2:15][N:14]=[C:13]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2
Reactant: C1CCC2=NCCCN2CC1
Agent: NS(=O)(=O)[O-]
Agent: [NH4+]
Product: C1CCC2=NCCC[NH+]2CC1

Procedure:
57.1 g (0.5 mol) of ammonium sulfamate were introduced into a 500 ml stirred reactor fitted with nitrogen inlet and separate feed device and suspended in 200 ml of methanol. Over the course of 30 minutes 76.1 g (0.5 mol) of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) were added, where upon the reaction mixture was solubilized. The mixture was stirred over night at ambient temperature and then the solvent was evaporated and the remaining solid dried in vacuo.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([C:9]2([CH3:15])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:3]=1.Cl[C:17]([O:19][CH3:20])=[O:18]>CN(C1C=CN=CC=1)C>[C:17](=[O:18])([O:19][CH3:20])[O:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=1[C:9]1([CH3:15])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: CC1(c2cc(F)ccc2O)CCCCC1
Reactant: COC(=O)Cl
Agent: CN(C)c1ccncc1
Product: COC(=O)Oc1ccc(F)cc1C1(C)CCCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.1 %

Procedure:
To a solution of 4-fluoro-2-(1-methylcyclohexyl)phenol (23.5 g, 113 mmol), TEA (31 mL, 226 mmol) and DMAP (700 mg, 5.7 mmol) in CH2C1-2 (250 mL) was added methyl chloroformate dropwise at 0° C. The mixture was allowed to warm to room temperature and stirred for 2 hours. The reaction mixture was poured onto crushed ice and extracted with CH2Cl2 (100 mL×3). The organic layer was washed with brine, dried over MgSO4, evaporated under vacuum. The crude product was purified by chromatography on silica gel diluted with (hexane:ethyl acetate=100:1) to give 4-fluoro-2-(1-methylcyclohexyl)phenyl methyl carbonate as red brown oil (43.9 g, 72.1% yield). 1H NMR (400 MHz, CDCl3) δ 7.10 (dd, J=3.2, 11.2 Hz, 1H), 7.05-7.02 (m, 1H), 6.93-6.88 (m, 1H), 3.91 (s, 3H), 2.02-1.96 (m, 2H), 1.66-1.36 (m, 8H), 1.23 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1B(O)O.Br[C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][C:14]=1C.ClC1C=CC(B(O)O)=CC=1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][CH:14]=1
Reactant: OB(O)c1c(Cl)cccc1Cl
Reactant: Cc1cc(N)ccc1Br
Agent: OB(O)c1ccc(Cl)cc1
Product: Nc1ccc(-c2c(Cl)cccc2Cl)cc1
Temperature: 90 °C

Procedure:
The title compound was prepared as described in Example 76, STEP B, but heating at 90° C. for 14 hrs, substituting 4-iodoaniline and 2,6-dichlorophenylboronic acid for 4-bromo-3-methylaniline and 4-chlorophenylboronic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[C:16]([Cl:18])[C:5]2[S:6][C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[CH:9](Cl)[CH2:10][C:4]=2[CH:3]=1.[Br:19][CH2:20][CH2:21][OH:22].C(=O)([O-])[O-].[K+].[K+]>ClCCl>[Br:19][CH2:20][CH2:21][O:22][CH:9]1[C:8]2[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=2[S:6][C:5]2[C:16]([Cl:18])=[CH:17][C:2]([Cl:1])=[CH:3][C:4]=2[CH2:10]1
Reactant: OCCBr
Reactant: Clc1cc(Cl)c2c(c1)CC(Cl)c1ccccc1S2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: Clc1cc(Cl)c2c(c1)CC(OCCBr)c1ccccc1S2
Temperature: 40 °C
Reaction time: 11 h
Yield: 74.8 %

Procedure:
A mixture of 2,4,10-trichloro-10,11-dihydrodibenzo[b,f]thiepine (2.5 g, 8.6 mmol, prepared as described in Coll. Czech. Chem. Commun. 46, 781, 1981), 2-bromoethanol (12.5 g, 100 mmol) and potassium carbonate (4.0 g, 30 mmol) in dichloromethane (20 ml) was stirred at 40° C. for 11 h. The solid was filtered off and the filtrate was evaporated in vacuo. The residue (3.4 g) was dissolved in a mixture of diethyl ether and light petroleum (1:1) (40 ml) and left to stand in a refrigerator for a week, affording after isolation 2.6 g (80%) of 10-(2-bromoethoxy)-2,4-dichloro-10,11-dihydrodibenzo[b,f]thiepine.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([F:9])[C:4]=1[CH:10]([OH:16])[C:11](=[NH:15])[O:12]CC.C(N(CC)CC)C.[O:24]1CCC[CH2:25]1>>[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([F:9])[C:4]=1[CH:10]1[O:16][C:25](=[O:24])[NH:12][C:11]1=[O:15]
Reactant: CCOC(=N)C(O)c1c(F)cccc1Cl
Reactant: C1CCOC1
Agent: Cl
Solvent: CCN(CC)CC
Product: O=C1NC(=O)C(c2c(F)cccc2Cl)O1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
Ethyl 1-(2-chloro-6-fluorophenyl)-1-hydroxymethanecarboximidate hydrochloride (15.0 g., 0.056 mole) and triethylamine (16.8 g., 23.3 ml., 0.167 mole) were taken into 560 ml. of tetrahydrofuran and cooled to 0° C. Phosgene was bubbled through the reaction mixture for 35 minutes. It was then stirred for 2.5 hours at room temperature, poured into 600 cc. of crushed ice and extracted with three portions of ethyl acetate. The combined extracts were washed with water, washed with brine, dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to product (14.4 g.). Recrystallization from toluene afforded purified 5-(2-chloro-6-fluorophenyl)oxazolidine-2,4-dione [10.7 g., 83%; m.p. 153°-155° C.; ir (KBr) 1820, 1740 cm-1 ].
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[O:14][C:13](=O)[NH:12][N:11]=3)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[CH:16]([NH2:19])([CH3:18])[CH3:17].C1(OC2C=CC=CC=2)C=CC=CC=1.CCN(C(C)C)C(C)C.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[O:14][C:13]([NH:19][CH:16]([CH3:18])[CH3:17])=[N:12][N:11]=3)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: O=c1[nH]nc(-c2ccc3[nH]ccc3c2)o1
Reactant: CC(C)N
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC(C)Nc1nnc(-c2ccc3[nH]ccc3c2)o1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 62.2 %

Procedure:
To a solution of 5-(1H-indol-5-yl)-1,3,4-oxadiazol-2(3H)-one (200 mg, 0.995 mmol) in DMF (2 mL) was added isopropyl amine (0.169 mL, 1.99 mmol), diphenyl ether (161 mg, 0.995 mmol), and DIPEA (0.34 mL, 1.99 mmol) and the reaction was stirred at RT for 5 min. To the above mixture at RT was added BOP reagent (461 mg, 1.045 mmol) and the reaction was further stirred for 18 h at RT. The mixture was treated with H2O (10 mL) to get off white precipitate. The precipitate was filtered, washed with H2O (10 mL) and dried. The solid was further triturated with petroleum ether (2×5 mL) to afford 5-(1H-indol-5-yl)-N-isopropyl-1,3,4-oxadiazol-2-amine (150 mg, 62%) as an off white solid. MS (ESI, pos. ion) m/z: 243.1 (M+1); 1H NMR (400 MHz, DMSO-d6): δ 11.40 (brs, 1H), 7.98 (s, 1H), 7.59 (dd, J=6.8, 1.6 Hz, 1H), 7.51 (t, J=7.2 Hz, 2H), 7.44 (m, 1H), 3.70-3.75 (m, 1H), 1.22 (d, J=6.4 Hz, 6H).
Reaction SMILES: Br[CH:2]1[CH2:5][CH2:4][CH2:3]1.[CH3:6][O:7][C:8]1[CH:9]=[C:10]([C:16]2[N:21]=[C:20]([O:22][C@@H:23]([C@H:25]3[CH2:29][NH:28][C:27](=[O:30])[CH2:26]3)[CH3:24])[C:19]3[NH:31][CH:32]=[N:33][C:18]=3[CH:17]=2)[CH:11]=[CH:12][C:13]=1[O:14][CH3:15].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.C(OCC)(=O)C>[CH:2]1([N:31]2[C:19]3[C:20]([O:22][C@@H:23]([C@H:25]4[CH2:29][NH:28][C:27](=[O:30])[CH2:26]4)[CH3:24])=[N:21][C:16]([C:10]4[CH:11]=[CH:12][C:13]([O:14][CH3:15])=[C:8]([O:7][CH3:6])[CH:9]=4)=[CH:17][C:18]=3[N:33]=[CH:32]2)[CH2:5][CH2:4][CH2:3]1
Reactant: COc1ccc(-c2cc3nc[nH]c3c(O[C@H](C)[C@H]3CNC(=O)C3)n2)cc1OC
Reactant: BrC1CCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(-c2cc3ncn(C4CCC4)c3c(O[C@H](C)[C@H]3CNC(=O)C3)n2)cc1OC
Temperature: 80 °C

Procedure:
Bromocyclobutane (18 mg, 0.137 mmol) was added to a mixture of (R)-4-((R)-1-(6-(3,4-dimethoxyphenyl)-3H-imidazo[4,5-c]pyridin-4-yloxy)ethyl)pyrrolidin-2-one 3.09 (50 mg, 0.131 mmol) and cesium carbonate (127 mg, 0.392 mmol) in 5 mL of DMF at room temperature. Reaction mixture was heated at 80° C. in a microwave reactor for one hour. Reaction mixture was taken up in ethyl acetate and washed with saturated NaHCO3 (aq) and brine. The separated organic layers were dried (MgSO4), filtered, and concentrated under reduced pressure. Residues were purified via reverse phase chromatography to yield (R)-4-((R)-1-(3-cyclobutyl-6-(3,4-dimethoxyphenyl)-3H-imidazo[4,5-c]pyridin-4-yloxy)ethyl)pyrrolidin-2-one 3.27.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[C:16]([C:22](O)=[O:23])=[N:17][CH:18]=[C:19]([Cl:21])[CH:20]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[F:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[NH:32][CH3:33].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN1C(=O)CCC1>[F:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[N:32]([CH3:33])[C:22]([C:16]1[C:15]([NH:14][S:11]([C:8]2[CH:7]=[CH:6][C:5]([C:1]([CH3:3])([CH3:4])[CH3:2])=[CH:10][CH:9]=2)(=[O:12])=[O:13])=[CH:20][C:19]([Cl:21])=[CH:18][N:17]=1)=[O:23]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Nc2cc(Cl)cnc2C(=O)O)cc1
Reactant: CNc1ccccc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCCC1=O
Product: CN(C(=O)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(C(C)(C)C)cc1)c1ccccc1F
Temperature: 60 °C
Reaction time: 8 h

Procedure:
3-(4-tert-Butyl-benzenesulfonylamino)-5-chloro-pyridine-2-carboxylic acid (75 mg, 0.20 mmol), (2-fluoro-phenyl)-methyl-amine (23 mg, 0.61 mmol), HATU (193 mg, 0.51 mmol), TEA (114 μL, 0.81 mmol) and 0.5 mL NMP were combined in a 4 mL vial and stirred overnight at 60° C. HPLC purification (10 to 95% gradient of MeCN-water) provided 3-(4-tert-butyl-benzenesulfonylamino)-5-chloro-pyridine-2-carboxylic acid (2-fluoro-phenyl)-methyl-amide: 1H NMR (400 MHz, CDCl3) 9.98 (s, 1H), 8.01 (s, 1H), 7.82 (d, 2H), 7.63 (s, 1H), 7.51 (d, 2H), 7.13 (m, 1H), 6.92 (t, 1H), 6.84 (t, 1H), 6.37 (m, 1H), 3.38 (t, 3H), 1.26 (s, 9H); MS m/z 476.1.
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([C:12](N)=O)[CH:7]=1.[NH2:18]C1C=CC(O)=CC=1.ClC1C=CN=C(C)C=1>>[CH3:12][C:8]1[CH:7]=[C:6]([O:5][C:4]2[CH:3]=[CH:2][C:17]([NH2:18])=[CH:16][CH:15]=2)[CH:11]=[CH:10][N:9]=1
Reactant: NC(=O)c1cc(Oc2cccc(N)c2)ccn1
Reactant: Nc1ccc(O)cc1
Agent: Cc1cc(Cl)ccn1
Product: Cc1cc(Oc2ccc(N)cc2)ccn1

Procedure:
{4-[(2-Methylpyridin-4-yl) oxy]phenyl} amine (2B) was prepared by a method analogous to that described for 4-(3-aminophenoxy) pyridine-2-carboxamide (2C), starting from 4-aminophenol and 4-chloro-2-methylpyridine, MS ES: 201 (M+H)+, calcd 201, RT=1.01 min.
Reaction SMILES: Cl.[NH2:2][OH:3].C([O-])(=O)C.[Na+].O=[C:10]([C:20]1[CH:29]=[CH:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=1)[CH2:11][CH2:12][CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16]>>[OH:3][N:2]=[C:10]([C:20]1[CH:29]=[CH:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=1)[CH2:11][CH2:12][CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCOC(=O)CCCCC(=O)c1ccc2ccccc2c1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Product: CCOC(=O)CCCCC(=NO)c1ccc2ccccc2c1
Yield: 120.3 %

Procedure:
An ethanolic solution (150 ml) of ethyl 6-oxo-6-(2-naphthyl)hexanoate (15 g) was added to an aqueous solution (42 ml) of hydroxylamine hydrochloride (4.8 g) and sodium acetate (5.7 g) and the mixture was refluxed for 2 hours. The ethanol was then distilled off under reduced pressure and the residue was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium chloride solution and dried and the solvent was distilled off. The crude residue was purified by silica gel column chromatography (hexane-ethyl acetate =10:1) to provide ethyl 6-hydroxyimino-6-(2-naphthyl)hexanoate (19 g).
Reaction SMILES: [CH2:1]([N:4]([CH2:11][CH2:12][CH3:13])[CH2:5][C:6]#[C:7][C:8]([OH:10])=O)[CH2:2][CH3:3].CN1CCOCC1.[NH2:21][C:22]1[CH:23]=[C:24]2[C:29](=[CH:30][CH:31]=1)[N:28]=[CH:27][C:26]([C:32]#[N:33])=[C:25]2[NH:34][C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([Br:41])[CH:36]=1>C1COCC1.N1C=CC=CC=1>[Br:41][C:37]1[CH:36]=[C:35]([NH:34][C:25]2[C:24]3[C:29](=[CH:30][CH:31]=[C:22]([NH:21][C:8](=[O:10])[C:7]#[C:6][CH2:5][N:4]([CH2:1][CH2:2][CH3:3])[CH2:11][CH2:12][CH3:13])[CH:23]=3)[N:28]=[CH:27][C:26]=2[C:32]#[N:33])[CH:40]=[CH:39][CH:38]=1
Reactant: N#Cc1cnc2ccc(N)cc2c1Nc1cccc(Br)c1
Reactant: CCCN(CC#CC(=O)O)CCC
Solvent: CN1CCOCC1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CCCN(CC#CC(=O)Nc1ccc2ncc(C#N)c(Nc3cccc(Br)c3)c2c1)CCC
Reaction time: 0.5 h

Procedure:
Partially dissolved 1.28 g (7.0 mmol) 4-dipropylamino-2-butynoic acid in 100 ml THF and chilled to 0° C. under N2. Added 974 μl (8.85 mmol) N-methylmorpholine 768 μl (5.90 mmol) isobutyl chloroformate and stirred for 30 minutes. Added a solution of 1.00 g (2.95 mmol) ) 6-amino-4-[(3-bromophenyl)amino]-3-quinolinecarbonitrile in 8 ml pyridine. At two hours, quenched with ice water and extracted with ethyl acetate. Dried organic layer with magnesium sulfate, reduced solvent to a small volume and loaded onto a column of silica gel. Eluted with ethyl acetate, stripped solvent from desired fractions and dried in vacuo, giving 764 mg of yellow solid: mass spectrum (electrospray m/e): M+H=504, 506.4.
Reaction SMILES: [NH2:1][CH:2]([CH:7]1[CH2:10][CH2:9][CH2:8]1)[CH2:3][C:4]([OH:6])=[O:5].[N+](=[CH:13][Si](C)(C)C)=[N-]>CO.C1C=CC=CC=1.CCOC(C)=O.[Cl-].[Na+].O>[NH2:1][CH:2]([CH:7]1[CH2:10][CH2:9][CH2:8]1)[CH2:3][C:4]([O:6][CH3:13])=[O:5]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: NC(CC(=O)O)C1CCC1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: c1ccccc1
Product: COC(=O)CC(N)C1CCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
To a solution of racemic 3-amino-3-cyclobutyl-propanoic acid, 48a, (0.34 g, 2.38 mmol) in MeOH (10.2 mL) and benzene (10.2 mL) was added diazomethyltrimethyl-silane (3.56 mL of 2 M solution, 7.13 mmol) and the reaction mixture was allowed to stir at room temperature under a nitrogen atmosphere overnight. The mixture was diluted with EtOAc and brine. The layers were separated and the organic phase was dried (MgSO4), filtered and concentrated in vacuo to afford 354 mg (95%) of crude product that was used without further purification: 1H NMR (400 MHz, CDCl3) δ 3.71-3.66 (m, 3H), 3.18-2.98 (m, 1H), 2.46-2.32 (m, 2H), 2.27-1.63 (m, 10H).
Reaction SMILES: [ClH:1].[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:13][CH2:12][N:11](CCCCN2C(=O)C3C=CC=C4C=3C(=CC=C4)C2=O)[CH2:10][CH2:9]1.Br[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][N:40]1[C:49](=[O:50])[C:48]2[CH:51]=[CH:52][CH:53]=[C:46]3[C:47]=2[C:42](=[CH:43][CH:44]=[CH:45]3)[C:41]1=[O:54].BrCCCCN1C(=O)C2C=CC=C3C=2C(=CC=C3)C1=O>>[ClH:1].[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:9][CH2:10][N:11]([CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][N:40]2[C:49](=[O:50])[C:48]3[CH:51]=[CH:52][CH:53]=[C:46]4[C:47]=3[C:42](=[CH:43][CH:44]=[CH:45]4)[C:41]2=[O:54])[CH2:12][CH2:13]1
Reactant: O=C1c2cccc3cccc(c23)C(=O)N1CCCCCCBr
Reactant: O=C1c2cccc3cccc(c23)C(=O)N1CCCCN1CCN(c2ccccn2)CC1
Agent: Cl
Agent: O=C1c2cccc3cccc(c23)C(=O)N1CCCCBr
Product: O=C1c2cccc3cccc(c23)C(=O)N1CCCCCCN1CCN(c2ccccn2)CC1

Procedure:
Following the procedure of part (b) of example 46 but substituting 2-(6-bromohexyl)-1H-benz[de]isoquinoline-1,3(2H)-dione for the 2-(4-bromobutyl)-1H-benz[de]isoquinoline-1,3-(2H)-dione, one obtains 2-[6-[4-(2-pyridinyl)-1-piperazinyl]-hexyl]-1H-benz[de]isoquinoline-1,3(2H)-dione, hydrochloride (1:2).
Reaction SMILES: Cl[C:2]1[CH:34]=[CH:33][C:5]2=[N:6][N:7]([C:9]3[CH:14]=[C:13]([C:15]([CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:17])[CH3:16])[CH:12]=[C:11]([C:23]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)([CH3:25])[CH3:24])[C:10]=3[OH:32])[N:8]=[C:4]2[CH:3]=1.[CH2:35]([SH:39])[CH2:36][CH2:37][CH3:38].[OH-].[K+].CN1CCCC1=O.Cl>>[CH2:35]([S:39][C:2]1[CH:34]=[CH:33][C:5]2=[N:6][N:7]([C:9]3[CH:14]=[C:13]([C:15]([CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:17])[CH3:16])[CH:12]=[C:11]([C:23]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)([CH3:25])[CH3:24])[C:10]=3[OH:32])[N:8]=[C:4]2[CH:3]=1)[CH2:36][CH2:37][CH3:38]
Reactant: CC(C)(C)CC(C)(C)c1cc(-n2nc3ccc(Cl)cc3n2)c(O)c(C(C)(C)c2ccccc2)c1
Reactant: CCCCS
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: CCCCSc1ccc2nn(-c3cc(C(C)(C)CC(C)(C)C)cc(C(C)(C)c4ccccc4)c3O)nc2c1
Temperature: 170 °C
Reaction time: 5 h
Yield: 83 %

Procedure:
5-Chloro-2-(2-hydroxy-3-α-cumyl-5-tert-octylphenyl)-2H-benzotriazole (38.1 g, 0.08 mol), n-butyl mercaptan (9 g, 0.10 mol), potassium hydroxide (10.1 g, 0.18 mol) and N-methylpyrrolidone (99 g, 1.0 mol) are charged to a reactor and heated to 170° C. The reaction mass is held at 170° C. with vigorous stirring for five hours. The reaction is judged as complete using thin layer chromatogrphy. The temperature is reduced to 5° C. and 100 mL of aqueous 2N hydrochloric acid are then added to the reactor. The liquid is decanted and the solids are dissolved in ethyl acetate. The organic layer is washed with aqueous 2N hydrochloric acid followed by water. The ethyl acetate is stripped off and the product is crystallized from ethanol and toluene. The title compound is obtained as a yellow crystalline product in 83% yield. The structure is verified by 1Hnmr.
Reaction SMILES: Br[CH:2](Br)[C:3]1[C:4]([N:9]2[C:13](=[O:14])[C:12]3=[CH:15][CH:16]=[CH:17][CH:18]=[C:11]3[C:10]2=[O:19])=[N:5][CH:6]=[CH:7][CH:8]=1.[NH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1.CC(O)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl.CCOC(C)=O>[C:13]1(=[O:14])[N:9]([C:4]2[C:3]([CH2:2][N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:8][CH:7]=[CH:6][N:5]=2)[C:10](=[O:19])[C:11]2=[CH:18][CH:17]=[CH:16][CH:15]=[C:12]12
Reactant: O=C1c2ccccc2C(=O)N1c1ncccc1C(Br)Br
Reactant: C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: O=C1c2ccccc2C(=O)N1c1ncccc1CN1CCCCC1
Temperature: 23 °C
Reaction time: 2 h

Procedure:
3-(Dibromomethyl)-2-(phthalimidyl)pyridine (185 mg, 0.47 mmol) was dissolved in CH2Cl2 (2 mL) and treated with piperidine (0.460 mL, 4.66 mmol), and glacial AcOH (0.160 mL, 2.80 mmol) in a dropwise fashion. The resulting yellow solution was stirred at 23° C. for 2 h, then treated with solid NaBH(OAc)3 (393 mg, 1.86 mmol) in one portion, and stirring was continued for 14 h. After stirring 14 h at 23° C., the mixture was treated with 2M K2CO3 (6 mL), and stirred for 1 h. After 1 h, the mixture was diluted with EtOAc (50 mL) and washed with H2O (1×50 mL), and saturated NaCl (1×50 mL). The organic phase was then dried (MgSO4) and concentrated in vacuo to provide the title compound as a yellow residue. The crude material was used in subsequent transformations without further purification. MS m/z: 323 (M+H).
Reaction SMILES: C([O:3][C:4](=[O:50])[C@@H:5]([O:47][CH2:48][CH3:49])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14]/[CH:15]=[CH:16]/[C:17]#[C:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]#[C:26]/[CH:27]=[CH:28]/[CH2:29][O:30][C:31]3[CH:36]=[CH:35][C:34]([CH2:37][C@H:38]([O:44][CH2:45][CH3:46])[C:39]([O:41]CC)=[O:40])=[CH:33][CH:32]=3)=[CH:21][CH:20]=2)=[CH:9][CH:8]=1)C.[OH-].[Na+]>C1COCC1.C(O)C>[C:39]([C@@H:38]([O:44][CH2:45][CH3:46])[CH2:37][C:34]1[CH:33]=[CH:32][C:31]([O:30][CH2:29]/[CH:28]=[CH:27]/[C:26]#[C:25][C:22]2[CH:23]=[CH:24][C:19]([C:18]#[C:17]/[CH:16]=[CH:15]/[CH2:14][O:13][C:10]3[CH:9]=[CH:8][C:7]([CH2:6][C@H:5]([O:47][CH2:48][CH3:49])[C:4]([OH:50])=[O:3])=[CH:12][CH:11]=3)=[CH:20][CH:21]=2)=[CH:36][CH:35]=1)([OH:41])=[O:40]
Reactant: CCOC(=O)[C@H](Cc1ccc(OC/C=C/C#Cc2ccc(C#C/C=C/COc3ccc(C[C@H](OCC)C(=O)OCC)cc3)cc2)cc1)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CCO[C@@H](Cc1ccc(OC/C=C/C#Cc2ccc(C#C/C=C/COc3ccc(C[C@H](OCC)C(=O)O)cc3)cc2)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (E)(E)(S)(S) 2-ethoxy-3-{4-[5-(4-{5-[4-(2-ethoxy-2-ethoxycarbonyl-ethyl)-phenoxy]-pent-3-en-1-ynyl}-phenyl)-pent-2-en-4-ynyloxy]-phenyl}-propionic acid ethyl ester (example 1) (88 mg 0.13 mmol) in THF (3 mL) and ethanol (3 mL) was added 1N sodium hydroxide (2 mL). After stirring at room temperature for 1 h, the reaction mixture was concentrated in vacuo, added water and 1N hydrochloride acid to pH 1. The product was extracted with dichloromethane (×3) and the combined organic phases were dried (MgSO4), filtered and concentrated in vacuo to give the title compound as a crystalline product. The product was recrystallised from ethyl acetate and petroleum ether to give 35 mg of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:22])[N:9]2[CH2:14][CH2:13][CH:12]([NH2:15])[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[N:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH:29]=O>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:22])[N:9]2[CH2:10][CH2:11][CH:12]([N:15]=[CH:29][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][N:23]=3)[CH2:13][CH2:14]2)=[CH:6][CH:7]=1
Reactant: NC1CCN(C(c2ccc(Br)cc2)c2ccccc2Cl)CC1
Reactant: O=Cc1ccccn1
Product: Clc1ccccc1C(c1ccc(Br)cc1)N1CCC(N=Cc2ccccn2)CC1

Procedure:
When an equivalent quantities of 1-[(4-bromophenyl)(2-chlorophenyl)methyl]-4-piperidinamine and 2-pyridinecarboxaldehyde are substituted in the procedure of Example 1, there is obtained 1-[(4-bromophenyl)(2-chlorophenyl)methyl]-N-[(2-pyridyl)methylene]-4-piperidinamine having the following structural formula ##STR30##