Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([OH:13])[NH:10][N:9]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].CS(O[CH2:25][C:26](=[O:28])[CH3:27])(=O)=O>CN(C=O)C.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:12]=[C:11]([O:13][CH2:25][C:26]([CH3:27])=[O:28])[NH:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: CC(=O)COS(C)(=O)=O
Reactant: Oc1cc(-c2ccc(F)cc2)n[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)COc1cc(-c2ccc(F)cc2)n[nH]1
Temperature: 30 °C
Reaction time: 0.5 h
Yield: 38.1 %

Procedure:
To a solution of 3-(4-fluorophenyl)-1H-pyrazol-5-ol (5 g, 28 mmol) in DMF (50 ml), potassium carbonate (7.7 g, 56 mmol) was added and the mixture was stirred for 30 min at 30° C. Thereafter, 2-oxopropyl methanesulfonate (4.7 g 30 mmol) was added drop wise and the reaction mixture was heated at 60° C. for 16 h. After completion, the crude was diluted with ethyl acetate (200 ml) and washed with water (3×500 ml). The organic layer was washed with brine, dried over sodium sulphate and evaporated under reduced pressure to get the crude which was then purified by column chromatography with silica gel (100-200 mesh) eluted with 10-25% ethyl acetate in hexane as eluent to get compound 1-{[3-(4-fluorophenyl)-1H-pyrazol-5-yl]oxy}acetone (2.5 g, yield 38%). MS (ESI): 231.0 ([M+H]+)
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]([C:43]1[S:44][CH:45]=[CH:46][N:47]=1)[S:7]([C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[C:16]([C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][C:21]=1[C:30]1[CH2:35][CH2:34][N:33](C(OC(C)(C)C)=O)[CH2:32][CH:31]=1)=[N:15][CH:14]=[CH:13]2)(=[O:9])=[O:8].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:33]1[CH2:32][CH:31]=[C:30]([C:21]2[CH:22]=[C:23]([C:26]([F:29])([F:28])[F:27])[CH:24]=[CH:25][C:20]=2[C:16]2[C:17]3[C:12](=[CH:11][C:10]([S:7]([NH:6][C:43]4[S:44][CH:45]=[CH:46][N:47]=4)(=[O:9])=[O:8])=[CH:19][CH:18]=3)[CH:13]=[CH:14][N:15]=2)[CH2:35][CH2:34]1
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(-c4ccc(C(F)(F)F)cc4C4=CCN(C(=O)OC(C)(C)C)CC4)nccc3c2)c(OC)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=S(=O)(Nc1nccs1)c1ccc2c(-c3ccc(C(F)(F)F)cc3C3=CCNCC3)nccc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Tert-butyl 4-(2-(6-(N-(2,4-dimethoxybenzyl)-N-(thiazol-2-yl)sulfamoyl)isoquinolin-1-yl)-5-(trifluoromethyl)phenyl)-5,6-dihydropyridine-1(2H)-carboxylate (0.073 g, 0.095 mmol) was dissolved in 1 mL of DCM and TFA (0.073 ml, 0.948 mmol) was added. The reaction was stirred overnight at room temperature. The solution was concentrated and concentrated from DCM two more times. The resulting yellow solid was triturated with diethyl ether and stirred for 15 minutes. The solution was filtered and the solids were washed with diethyl ether. The material was dissolved in methanol and loaded onto an SCX ion exchange column (pre-wetted with methanol) (Biotage AB, Uppsala, SE). The column was washed several times with methanol, then the product was liberated with 2.0 M ammonia/methanol solution. The filtrate was concentrated to afford 1-(2-(1,2,3,6-tetrahydropyridin-4-yl)-4-(trifluoromethyl)phenyl)-N-(thiazol-2-yl)isoquinoline-6-sulfonamide as a light yellow solid. 1H NMR (400 MHz, DMSO-d6) δ=8.60 (d, J=5.7 Hz, 1H), 8.44 (d, J=1.5 Hz, 1H), 8.05 (d, J=5.4 Hz, 1H), 7.93-7.79 (m, 2H), 7.72 (s, 1H), 7.61 (dd, J=8.4, 16.3 Hz, 2H), 6.96 (d, J=3.9 Hz, 1H), 6.52 (d, J=3.9 Hz, 1H), 5.49 (br. s., 1H), 3.24 (br. s., 2H), 2.72 (t, J=5.8 Hz, 2H), 2.04 (br. s., 2H). m/z (ESI) 517.2 (M+H)+.
Reaction SMILES: S([O-])([O-])=O.[Na+].[Na+].[C:7](=O)(O)[O-].[Na+].[Cl:12][C:13]1[CH:21]=[C:20]([S:22](Cl)(=[O:24])=[O:23])[CH:19]=[CH:18][C:14]=1[C:15]([OH:17])=[O:16].ClCC(O)=O.[OH-].[Na+].ClC1CC(=S=O)C=CC=1C(O)=O.Cl>O>[Cl:12][C:13]1[CH:21]=[C:20]([S:22]([CH3:7])(=[O:24])=[O:23])[CH:19]=[CH:18][C:14]=1[C:15]([OH:17])=[O:16]
Reactant: O=C([O-])O
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1Cl
Agent: Cl
Agent: O=C(O)CCl
Agent: O=S([O-])[O-]
Solvent: O
Product: CS(=O)(=O)c1ccc(C(=O)O)c(Cl)c1
Temperature: 50 °C
Yield: 105.9 %

Procedure:
A 250 mL round bottom flask equipped with a reflux condenser, thermometer, and magnetic stirrer was charged with 9.2 g (73 mmol) of sodium sulfite, 24.6 g (292 mmol) of sodium bicarbonate and 80 mL of water. The resulting slurry was heated to 50° C., and 20.0 g (70 mmol) of 2-chloro-4-(chlorosulfonyl)benzoic acid was added over 15 minutes. After heating at 50° C. for three hours, chloroacetic acid (10.4 g, 110 mmol) and 5.7 mL (110 mmol) of 50% aqueous sodium hydroxide were added sequentially to the aqueous solution of 2-chloro-4-sulfinylbenzoic acid, and the reaction mixture heated to reflux. After heating for 19 hours, the reaction mixture was allowed to cool to ambient temperature and acidified with dilute HCl. The precipitated solids were collected by filtration, washed with dilute HCl and dried to give 17.4 g of 2-chloro-4-(methylsulfonyl)benzoic acid as a white solid. The solid was assayed at 85% purity, corresponding to an overall yield of 89%.
Reaction SMILES: Cl[C:2]1[NH:6][C:5]2[CH:7]=[C:8]([CH3:12])[C:9]([Cl:11])=[CH:10][C:4]=2[N:3]=1.[Cl:13][C:14]1[CH:15]=[N:16][CH:17]=[C:18]([Cl:26])[C:19]=1[N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>>[Cl:11][C:9]1[C:8]([CH3:12])=[CH:7][C:5]2[N:6]=[C:2]([N:23]3[CH2:24][CH2:25][N:20]([C:19]4[C:18]([Cl:26])=[CH:17][N:16]=[CH:15][C:14]=4[Cl:13])[CH2:21][CH2:22]3)[NH:3][C:4]=2[CH:10]=1
Reactant: Clc1cncc(Cl)c1N1CCNCC1
Reactant: Cc1cc2[nH]c(Cl)nc2cc1Cl
Product: Cc1cc2nc(N3CCN(c4c(Cl)cncc4Cl)CC3)[nH]c2cc1Cl

Procedure:
The benzoimidazole from step (b) above (0.201 g, 1 mmol) and 1-(3,5-dichloropyridin-4-yl)piperazine (0.462 g, 2 mmol, Maybridge) reacted under the conditions of Example 1d to give the title compound as a white amorphous solid. MS (ESI, pos. ion) m/z: 396 (M+1).
Reaction SMILES: [CH3:1][C:2]([CH3:6])=[CH:3][CH2:4][OH:5].[C:7]1([CH3:17])[CH:12]=CC(S(O)(=O)=O)=[CH:9][CH:8]=1>>[CH2:4]([O:5][CH2:9][CH:8]=[C:7]([CH3:17])[CH3:12])[CH:3]=[C:2]([CH3:6])[CH3:1]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CC(C)=CCO
Product: CC(C)=CCOCC=C(C)C
Yield: 50 %

Procedure:
To 30 g of 3-methyl-2-buten-1-ol [prenol] was added 0.74 g of p-toluenesulfonic acid, and the mixture was stirred under reflux (at 130°-140° C.) for 3 hours. The reaction solution separated into two layers. The lower layer comprised water and the upper layer was subjected to gas chromatographic analysis revealing that about 4% of the starting prenol remained and that diprenyl ether was formed in a yield of about 50% based on the starting prenol together with unknown products. After distillation under reduced pressure was isolated diprenyl ether having the following properties.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([OH:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[OH:13].[C:14](Cl)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>N1C=CC=CC=1>[C:14]([O:12][C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([OH:13])=[C:2]([CH3:1])[CH:11]=1)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Cc1cc(O)c2ccccc2c1O
Solvent: c1ccncc1
Product: Cc1cc(OC(=O)c2ccccc2)c2ccccc2c1O
Reaction time: 1 h
Yield: 69.3 %

Procedure:
9.7 g (0.056 mol) of 2-methyl-1,4-dihydroxynaphthalene was dissolved in 60 ml of pyridine, and, while stirring under ice-cooling, 8.4 g (0.06 mol) of benzoyl chloride was added dropwise. Following completion of the addition, stirring was continued under ice-cooling for 30 minutes, and for further one hour at room temperature. The reaction mixture was concentrated under reduced pressure, the residual oil extracted with ethyl acetate, washed with 1N HCl and then water, and the organic layer concentrated under reduced pressure. Methanol was added to the residue, the precipitated crystals collected by filtration and recrystallized from methanol to give 10.8 g of white crystals, m.p. 172-174° C.
Reaction SMILES: [F:1][C:2]1[C:7]([NH:8][CH2:9][C:10]2[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[C:12]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=3)[C:11]=2[F:25])=[C:6]([F:26])[CH:5]=[CH:4][C:3]=1[OH:27].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37].O>CN(C=O)C>[F:1][C:2]1[C:7]([NH:8][CH2:9][C:10]2[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[C:12]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=3)[C:11]=2[F:25])=[C:6]([F:26])[CH:5]=[CH:4][C:3]=1[O:27][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37]
Reactant: COc1cc(CNc2c(F)ccc(O)c2F)c(F)c(-c2cccc(F)c2)c1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc(F)c(NCc2cc(OC)cc(-c3cccc(F)c3)c2F)c1F
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 67.4 %

Procedure:
To a stirred solution of 2,4-difluoro-3-[[2-fluoro-3-(3-fluorophenyl)-5-methoxy-phenyl]methylamino]phenol (180 mg, 0.48 mmol, 1.0 eq) in DMF (4 mL) was added Cs2CO3 (233 mg, 0.72 mmol, 1.5 eq). The resulting mixture was stirred for 40 min at room temperature then ethyl bromoacetate (96 mg, 0.57 mmol, 1.2 eq) was added. The resulting mixture was stirred at room temperature for 2 h then water added and the aqueous layer extracted with EtOAc. The combined organic extracts were washed with brine, dried (Na2SO4), filtered and evaporated in vacuo. The crude residue was purified by chromatography (EtOAc:petroleum ether, 0:1 to 1:10) to give the title compound as an oil (150 mg, 68%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]([O:12][CH3:13])=[O:11])[CH:8]=2)[CH:3]=[N:2]1.[I:14]I.[OH-].[K+]>CC(N(C)C)=O>[I:14][C:3]1[C:4]2[C:9](=[CH:8][C:7]([C:10]([O:12][CH3:13])=[O:11])=[CH:6][CH:5]=2)[NH:1][N:2]=1
Reactant: II
Reactant: COC(=O)c1ccc2cn[nH]c2c1
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)N(C)C
Product: COC(=O)c1ccc2c(I)n[nH]c2c1
Reaction time: 1 h

Procedure:
To a solution of methyl 1H-indazole-6-carboxylate D-2 (5.0 g, 28 mmol) in DMAC (50 mL) at 0° C. was added iodine (14.4 g, 56.7 mmol) and potassium hydroxide (6.3 g, 114 mmol) portionwise. After addition, the mixture was kept stirring for 1 h, then quenched with aq. Na2S2O3 and extracted with EtOAc. The combined organics were concentrated and trituated with hexane. The precipitate was collected by filtration to afford the title compound as a brown solid. LCMS (ESI) calc'd for C9H8IN2O2 [M+H]+: 302.9. found: 302.9.
Reaction SMILES: FC(F)(F)C(O)=O.FC(F)(F)C(O)=O.[O:15]([C:22]1[C:27]2[C:28]([NH:31][CH2:32][CH:33]3[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]3)=[N:29][NH:30][C:26]=2[CH:25]=[CH:24][N:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.Cl.Cl.Cl.[N:42]1[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=1[C:48]1[S:49][C:50]([CH2:53]N2CCC(CN)CC2)=[CH:51][N:52]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.C[N+](C)(C)C>C(#N)C>[O:15]([C:22]1[C:27]2[C:28]([NH:31][CH2:32][CH:33]3[CH2:38][CH2:37][N:36]([CH2:53][C:50]4[S:49][C:48]([C:43]5[CH:44]=[CH:45][CH:46]=[CH:47][N:42]=5)=[N:52][CH:51]=4)[CH2:35][CH2:34]3)=[N:29][NH:30][C:26]=2[CH:25]=[CH:24][N:23]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: NCC1CCN(Cc2cnc(-c3ccccn3)s2)CC1
Reactant: c1ccc(Oc2nccc3[nH]nc(NCC4CCNCC4)c23)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C[N+](C)(C)C
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: c1ccc(Oc2nccc3[nH]nc(NCC4CCN(Cc5cnc(-c6ccccn6)s5)CC4)c23)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 16.7 %

Procedure:
A solution of the compound prepared in Example 436 (0.053 g) and the compound prepared in Example 214 (0.039 g) in acetonitrile (1 mL) was stirred at room temperature for 30 minutes. Tetramethylammoniumtriacetoxy borohydride (0.094 g) was added and stirring at room temperature continued for 1 hour. The reaction mixture was quenched with aqueous saturated sodium bicarbonate. After stirring at room temperature for 20 minutes, hopeful product was extracted with ethyl acetate, washed with aqueous saturated sodium bicarbonate, dried, evaporated in vacuo to an oil that was purified by column chromatography on silica gel (1-5% methanol in dichloromethane) to provide the title compound (0.008 g) with the following physical data.
Reaction SMILES: [C:1]12([C:8]3[CH:13]=[C:12]([CH3:14])[C:11]([CH3:15])=[CH:10][C:9]=3[OH:16])[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.C1(C)C=CC=CC=1.[Na].[CH2:25]([CH:27]1[O:29][CH2:28]1)Cl>O.CCOCC>[C:1]12([C:8]3[CH:13]=[C:12]([CH3:14])[C:11]([CH3:15])=[CH:10][C:9]=3[O:16][CH2:25][CH:27]3[O:29][CH2:28]3)[CH2:7][CH:4]([CH2:3][CH2:2]1)[CH2:5][CH2:6]2
Reactant: Cc1cc(O)c(C23CCC(CC2)C3)cc1C
Reactant: ClCC1CO1
Agent: [Na]
Solvent: O
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: Cc1cc(OCC2CO2)c(C23CCC(CC2)C3)cc1C

Procedure:
108g (0.5 mole) of 2-norbornyl-4,5-dimethyl phenol, 600 cm3 anhydrous toluene and 11.5g (0.5 mole) sodium are introduced into a three-necked flask supplied with a nitrogen stream. The reaction mixture is refluxed for 4 hours, the solvent is then removed and the residue taken up in 500 cm3 tetrahydrofuran. 39.4 cm3 (0.5 mole) epichlorohydrin are added and the mixture is heated under reflux for 8 hours. One extracts with ether, washes the ethereal phase with water, dries and evaporates the solvent. 123.6g of 1-(2'-norbornyl-4',5'-dimethyl phenoxy) 2,3-epoxypropane are obtained in the form of oil. 27.2g (0.1 mole) of the preceding product are dissolved in 100 cm3 isopropylamine. After 5 days contact, the excess amine is evaporated under reduced pressure and extracted with ether. After washing with water and drying, the ether is evaporated and the residue taken up in chloroform. One precipitates by adding gaseous hydrochloric acid. By crystallisation in methylethyl ketone, 20g of pure product are obtained. M.Pt. 183°-185° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:20][CH3:21])=[C:6]([C:8]([CH3:19])([CH3:18])[CH2:9][C:10]([C:14]([F:17])([F:16])[F:15])([OH:13])[CH2:11][OH:12])[CH:7]=1.C(N(CC)CC)C.[NH4+].[Cl-]>CS(C)=O.C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:20][CH3:21])=[C:6]([C:8]([CH3:19])([CH3:18])[CH2:9][C:10]([OH:13])([C:14]([F:17])([F:16])[F:15])[CH:11]=[O:12])[CH:7]=1
Reactant: COc1ccc(F)cc1C(C)(C)CC(O)(CO)C(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: COc1ccc(F)cc1C(C)(C)CC(O)(C=O)C(F)(F)F
Reaction time: 3 h

Procedure:
1.5 g (4.8 mmol) of 4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-trifluoromethylpentane-1,2-diol and 3.4 ml (24.4 mmol) of triethylamine in 17 ml of DMSO and 53 ml of CH2Cl2 are mixed at 10° C. in portions with 3 g (18.9 mmol) of pyridine-sulfur trioxide complex. After 3 hours at 12-18° C., it is hydrolyzed while being cooled with ice with saturated NH4Cl solution, and it is extracted with ethyl acetate. The combined extracts are dried (Na2SO4) and concentrated by evaporation: 1.57 g of the product as a light yellow oil.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][N:10]1[C:22]2[CH:21]=[CH:20][CH:19]=[C:18]([OH:23])[C:17]=2[C:16]2[C:11]1=[CH:12][CH:13]=[CH:14][C:15]=2[C:24](OC)=[O:25].Cl.[OH-].[NH4+:32]>C1COCC1.C(OCC)(=O)C>[F:1][C:2]([F:29])([F:28])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][N:10]1[C:22]2[CH:21]=[CH:20][CH:19]=[C:18]([OH:23])[C:17]=2[C:16]2[C:11]1=[CH:12][CH:13]=[CH:14][C:15]=2[C:24](=[O:25])[NH2:32]
Reactant: [NH4+]
Reactant: COC(=O)c1cccc2c1c1c(O)cccc1n2Cc1ccccc1C(F)(F)F
Agent: Cl
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: NC(=O)c1cccc2c1c1c(O)cccc1n2Cc1ccccc1C(F)(F)F
Yield: 49 %

Procedure:
A solution of the 9-[(2-trifluoromethylphenyl)methyl]-4-hydroxy-5-carbomethoxy carbazole (310 mg, 0.77 mM) in 5 mL THF and 20 mL concentrated aqueous ammonium hydroxide was sonicated for 25 hours at 40-50° C. The mixture was diluted with ethyl acetate and acidified to pH 1 with 5 N HCl. The aqueous layer was extracted twice with ethyl acetate. The combined organic extracts were washed with saturated brine, dried over magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel (elution with gradient methylene chloride/ethyl acetate) to afford 145 mg (49%) of the 9-[(2-trifluoromethylphenyl)methyl]-4-hydroxy-5-carbamoyl carbazole as a white solid. 1H NMR (DMSO-d6) δ10.5 (s, 1H), 8.8 (br s, 1H), 8.4 (br s, 1H), 7.8 (d, 1H, J=8 Hz), 7.6-7.2 (m, 6H), 6.85 (d, 1H, J=8 Hz), 6.6 (d, 1H, J=8 Hz), 6.25 (d, 1H, J=8 Hz), and 5.8 (s, 2H). IR (KBr, cm−1) 3460, 3360, and 1589. MS (ES) m/e 383, 385.
Reaction SMILES: Br.Br.[CH:3]1([C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)=[CH:11][CH:10]=2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.C(=O)(O)[O-].[K+].O.[C:27]([O:30][CH2:31]C)(=[O:29])[CH3:28]>CN(C)C=O>[CH:3]1([C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:16][CH2:17][N:18]([CH2:10][CH2:9][C:3]4[CH:8]=[CH:7][C:28]([C:27]([O:30][CH3:31])=[O:29])=[CH:5][CH:4]=4)[CH2:19][CH2:20]3)=[CH:11][CH:10]=2)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]1
Reactant: CCOC(C)=O
Reactant: c1cc(N2CCNCC2)ccc1C1CCCCC1
Agent: Br
Agent: O=C([O-])O
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(CCN2CCN(c3ccc(C4CCCCC4)cc3)CC2)cc1
Temperature: 120 °C
Reaction time: 24 h

Procedure:
To a suspension of 1-(4-cyclohexylphenyl)piperazine dihydrobromide (2.5 g) and potassium bicarbonate (2.125 g) in N,N-dimethylformamide (6 ml) was added methyl 4-(2-chloroethylphenyl) benzoate (1.22 g) and stirred for 24 hours at 120° C. The reaction mixture was added to a mixture of water and ethyl acetate. The organic layer was taken and dried over magnesium sulfate. The magnesium sulfate was filtered off, and the filtrate was evaporated under reduced pressure to give methyl 4-[2-[4-(4-cyclohexylphenyl)-piperazin-1-yl]ethyl]benzoate (1.247 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[CH2:7][NH:8][CH:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2].[C:15]([S:18][C:19]1[C:27]([CH3:28])=[CH:26][CH:25]=[CH:24][C:20]=1[C:21](O)=[O:22])(=[O:17])[CH3:16]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:14])[CH2:7][N:8]([C:21](=[O:22])[C:20]1[CH:24]=[CH:25][CH:26]=[C:27]([CH3:28])[C:19]=1[S:18][C:15](=[O:17])[CH3:16])[CH:9]1[CH2:10][CH2:11][CH2:12][CH2:13]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CNC1CCCC1
Reactant: CC(=O)Sc1c(C)cccc1C(=O)O
Solvent: ClCCl
Product: CC(=O)Sc1c(C)cccc1C(=O)N(CC(=O)OC(C)(C)C)C1CCCC1
Temperature: 0 °C

Procedure:
N-Cyclopentylglycine t-butyl ester (8.3 g, 0.042 mole) and 2-acetylthio-3-methylbenzoic acid (8.9 g, 0.042 mole) were combined in 90 ml CH2Cl2. This solution was cooled to 0° C. before adding to it a solution of N,N-dicyclohexylcarbodiimide (8.6 g, 0.042 mole) in 30 ml CH2Cl2 dropwise over 15 minutes. The reaction was allowed to warm slowly to room temperature overnight.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][C:10]=1[C:17]#[C:18][C:19]1[CH:20]=[C:21]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH:22]=[N:23][CH:24]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>[Pd].CO>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][C:10]=1[CH2:17][CH2:18][C:19]1[CH:20]=[C:21]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH:22]=[N:23][CH:24]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)Nc1cncc(C#Cc2cc(C#N)ccc2NC(=O)OC(C)(C)C)c1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)Nc1cncc(CCc2cc(C#N)ccc2NC(=O)OC(C)(C)C)c1
Reaction time: 6 h
Yield: 97.4 %

Procedure:
Into a reaction flask were added tert-butyl [5-({2-[(tert-butoxycarbonyl)amino]-5-cyanophenyl}ethynyl)pyridin-3-yl]carbamate (0.94 g, 2.2 mmol), methanol (50 mL), and 10% palladium on carbon (0.40 g, 0.38 mmol). The mixture was hydrogenated at 60 psi for 6 hours. After filtration to remove the catalyst, the mixture was concentrated under vacuum to give the desired product as an off-white powder (0.94 g, 99%). LCMS for C24H31N4O4 (M+H)+: m/z=439.2.
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5](/[CH:6]=[CH:7]/[C:8]([OH:10])=[O:9])=[CH:4][CH:3]=1.Cl[C:14]1[C:15](=[O:27])[NH:16][C:17](=[O:26])[C:18]=1[C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1.CN1CCCC1=O>Cl>[C:8](/[CH:7]=[CH:6]/[C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:14]2[C:15](=[O:27])[NH:16][C:17](=[O:26])[C:18]=2[C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)=[CH:12][CH:11]=1)([OH:10])=[O:9]
Reactant: Nc1ccc(/C=C/C(=O)O)cc1
Reactant: O=C1NC(=O)C(c2ccc(Cl)cc2)=C1Cl
Agent: Cl
Solvent: CN1CCCC1=O
Product: O=C(O)/C=C/c1ccc(NC2=C(c3ccc(Cl)cc3)C(=O)NC2=O)cc1
Reaction time: 28.5 h

Procedure:
A mixture of trans-4-aminocinnamic acid (0.205 g, 1.26 mmol), 3-chloro-4-(4-chlorophenyl)-1H-pyrrole-2,5-dione (0.123 g, 0.51 mmol) and 1-methyl-2-pyrrolidinone (1.0 mL) was heated in a sealed tube in a hotblock set at 69° C., for 28.5 hours. The mixture was diluted with aqueous hydrochloric acid (10 mL) and extracted with ethyl acetate (2×20 mL). The combined organics were washed with brine (2×10 mL), dried over anhydrous magnesium sulphate and evaporated to dryness. The residue was triturated with a mixture of dichloromethane and ethyl acetate to afford the title compound as a solid.
Reaction SMILES: [CH2:1]([N:4]([CH2:15][CH:16]([OH:20])[CH2:17][CH:18]=[CH2:19])[C:5](=[O:14])[O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)C=C>C(Cl)Cl>[OH:20][CH:16]1[CH2:17][CH:18]=[CH:19][CH2:1][N:4]([C:5]([O:6][CH2:7][C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[O:14])[CH2:15]1
Reactant: C=CCC(O)CN(CC=C)C(=O)OCc1ccccc1
Solvent: ClCCl
Product: O=C(OCc1ccccc1)N1CC=CCC(O)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 47.4 %

Procedure:
To a solution of benzyl N-allyl-N-(2-hydroxypent-4-enyl)carbamate (6.10 g, 22.15 mmol, 1.00 Eq) in DCM (400 mL) was added Zhan catalyst 1B (812.63 mg, 1.11 mmol, 0.05 Eq) under N2 protection. The mixture was stirred at 25° C. for 16 hr under N2 protection. Then TLC detected the reaction was completed, the solvent was evaporated, the residue was purified by chromatography (silica gel, eluting with PE:EA=2:1) to afford benzyl 3-hydroxy-2,3,4,7-tetrahydroazepine-1-carboxylate (2.60 g, 10.51 mmol, 47.47% yield) as yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.30-7.46 (m, 5H), 5.63-5.89 (m, 2H), 5.19 (s, 2H), 3.96-4.13 (m, 2H), 3.74-3.90 (m, 2H), 3.54-3.70 (m, 1H), 2.43 (m, 2H).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9]C)=[O:8])=[CH:5][N:4]=1.[H-].[Na+].FC(F)(F)S(O[CH2:21][C:22]([F:25])([F:24])[F:23])(=O)=O.O.[OH-].[Li+]>O1CCCC1.O>[F:23][C:22]([F:25])([F:24])[CH2:21][O:1][CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([OH:9])=[O:8])=[CH:5][N:4]=1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: COC(=O)c1ccc(CO)nc1
Agent: [H-]
Agent: [Li+]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccc(COCC(F)(F)F)nc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 24.3 %

Procedure:
To a solution of methyl 6-(hydroxymethyl)nicotinate (500 mg, 2.99 mmol) in tetrahydrofuran (30 mL) was added sodium hydride 60% dispersion in mineral oil (126 mg, 3.14 mmol) and the reaction mixture was stirred at ambient temperature for 5 min. 2,2,2-trifluoroethyl trifluoromethanesulphonate (729 mg, 3.14 mmol) was added and the reaction mixture was stirred at ambient temperature for 4 h. Additional sodium hydride (42 mg, 1.05 mmol) was added followed by 2,2,2-Trifluoroethyl trifluoromethanesulphonate (243 mg, 1.45 mmol) after 5 min. Water (20 mL) was added carefully followed by lithium hydroxide monohydrate (0.376 g, 8.97 mmol) and the formed reaction mixture was stirred at ambient temperature for 5.5 h. The solvent was partially removed in vacuo and 1M hydrochloric acid added until an acidic pH was reached. The mixture was extracted with ethyl acetate (3×25 mL) and the combined organic layer was dried over magnesium sulfate and concentrated in vacuo. Purification by column chromatography using a gradient of methanol in dichloromethane yielded 171 mg (24%) of the title compound; 1H NMR (400 MHz, DMSO-d6) δ ppm 9.02 (dd, 1 H), 8.32 (dd, 1 H), 7.56 (dd, 1 H), 4.84 (s, 2 H), 4.26 (q, 2 H); MS (ESI) m/z 236[M+H+].