Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(#N)C.[OH:4][C:5]1[CH:20]=[CH:19][C:8]([CH2:9][CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:7][C:6]=1[O:21][CH3:22].Br[CH:24]([CH3:26])[CH3:25].C(=O)([O-])[O-].[K+].[K+]>CCOC(C)=O>[CH:24]([O:4][C:5]1[CH:20]=[CH:19][C:8]([CH2:9][CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:15])[CH3:16])=[CH:7][C:6]=1[O:21][CH3:22])([CH3:26])[CH3:25]
Reactant: CC(C)Br
Reactant: COc1cc(CCNC(=O)OC(C)(C)C)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COc1cc(CCNC(=O)OC(C)(C)C)ccc1OC(C)C
Temperature: 65 °C
Reaction time: 18 h
Yield: 70 %

Procedure:
To a 250 mL round bottom flask containing acetonitrile (18.7 mL) was added tert-butyl 4-hydroxy-3-methoxyphenethylcarbamate (1.0 g, 3.74 mmol), 2-bromopropane (0.51 g, 4.11 mmol), and potassium carbonate (1.5 g, 11.22 mmol). The resulting suspension was stirred at 65° C. for 18 hours. A second addition of 2-bromopropane (0.51 g, 4.11 mmol) was performed and heating was continued for another 18 hours. The reaction mixture was concentrated reaction in vacuo. The resulting oil was dissolved in EtOAc and washed with H2O, aqeuous saturated sodium bicarbonate and brine, then dried with sodium sulfate and concentrated in vacuo. The crude product was purified by silica gel chromatography (0-100% EtOAc in Heptane) to afford tert-butyl 4-isopropoxy-3-methoxyphenethylcarbamate (0.81 g). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 6.84 (d, J=8.03 Hz, 1H), 6.67-6.75 (m, 2H), 4.37-4.70 (m, 2H), 3.86 (s, 3H), 3.27-3.46 (m, 2H), 2.68-2.81 (m, 2H), 1.45 (s, 9H), 1.37 (d, J=6.02 Hz, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][N:8](CC3C=CC(OC)=CC=3)[C:9]2=[O:12])=[CH:5][CH:4]=1.[N+]([O-])(O)=O.[N+]([O-])(O)=O.[N+]([O-])(O)=O.[N+]([O-])(O)=O.[N+]([O-])(O)=O.[N+]([O-])(O)=O.[Ce].O>C(#N)C>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][NH:8][C:9]2=[O:12])=[CH:5][CH:4]=1
Reactant: COc1ccc(CN2Cc3ccc(OC)cc3C2=O)cc1
Agent: [Ce]
Solvent: CC#N
Solvent: O
Solvent: O=[N+]([O-])O
Product: COc1ccc2c(c1)C(=O)NC2
Yield: 41.8 %

Procedure:
A mixture of 6-methoxy-2-(4-methoxy-benzyl)-2,3-dihydro-isoindol-1-one (300 mg, 1.1 mmol) and ammonium ceric nitrate (2.2 g, 4.0 mmol) in acetonitrile:water (12 mL, 2:1) was stirred at RT for 1 h. Then the mixture was poured into water and extracted with ethyl acetate. The combined extracts were then washed with sodium hydrogen carbonate and water. The organic layer was then dried over sodium sulphate, filtered and evaporated. The residue was then purified by chromatography (SiO2, dichloromethane:MeOH 20:1) to afford the title product (75 mg, 43%) as a light yellow solid. MS m/e=164.2 (M).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH2:17][CH2:18][CH2:19][NH:20]CC3C=CC=CC=3)[C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2].[H][H]>C1COCC1.[OH-].[OH-].[Pd+2]>[CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH2:17][CH2:18][CH2:19][NH2:20])[C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1oc2cccc(OCCCNCc3ccccc3)c2c1C
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCOC(=O)c1oc2cccc(OCCCN)c2c1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-(3-benzylamino-propoxy)-3-methyl-benzofuran-2-carboxylic acid ethyl ester (the compound in Example 98: 180 mg) in THF (10 ml) was added 20% Pd(OH)2 on charcoal catalyst (40 mg) under N2. The nitrogen atmosphere was replaced by hydrogen (1 atom) and the resulting mixture was stirred overnight at room temperature. The reaction mixture was filtered through a pad of celite and the pad of celite was rinsed with methanol and dichloromethane. The filtrate combined was concentrated in vacuo. The residue was purified by silica gel column chromatography (dichloromethane-MeOH) to give 4-(3-amino-propoxy)-3-methyl-benzofuran-2-carboxylic acid ethyl ester (125 mg) as a colorless oil. FAB-MS: m/z 278 (MH+).
Reaction SMILES: Cl[C:2]1[S:10][C:9]2[C:8]([C:11]([C:13]3[S:14][CH:15]=[CH:16][CH:17]=3)=[O:12])=[N:7][C:6]([NH:18][CH2:19][C:20]3[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=3)=[N:5][C:4]=2[CH:3]=1.[CH2:26]([NH2:28])[CH3:27].Cl>CC(N(C)C)=O>[CH2:26]([NH:28][C:2]1[S:10][C:9]2[C:8]([C:11]([C:13]3[S:14][CH:15]=[CH:16][CH:17]=3)=[O:12])=[N:7][C:6]([NH:18][CH2:19][C:20]3[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=3)=[N:5][C:4]=2[CH:3]=1)[CH3:27]
Reactant: O=C(c1cccs1)c1nc(NCc2cccnc2)nc2cc(Cl)sc12
Reactant: CCN
Agent: Cl
Solvent: CC(=O)N(C)C
Product: CCNc1cc2nc(NCc3cccnc3)nc(C(=O)c3cccs3)c2s1
Temperature: 170 °C
Yield: 40 %

Procedure:
A stirred solution of Example 5 (0.025 g, 0.065 mmol) in dimethyl acetamide (1.5 ml) was treated with ethylamine (2.0M in THF, 0.65 mmol). The solution was heated to 170° C. for 30 min in a microwave reactor. The cooled solution was poured on to aqueous HCl solution (2.5M, 25 ml). The aqueous solution was washed with ethylacetate (50 ml) and basified (pH 9) using aqueous sodium hydroxide solution (5M). The title compound was filtered as an orange solid in 40% yield, >90% purity. LC-MS m/z=396.0 [M+H]+; RT=2.78; LC-MS method 1. 1H NMR: δH (400 MHz, D6-DMSO) 1.21 (3H, t, J 7.0 Hz), 3.22-3.33 (2H, m), 4.68 (2H, bd), 5.82 (1H, s), 7.23-8.63 (11H, m).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)=O.C([O-])(O)=O.[Na+].[CH2:17]([C:24]1[NH:25][CH2:26][CH2:27][CH:28]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(O)C>[F:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]2[C:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[C:24]3[N:25]([CH2:26][CH2:27][CH2:28]3)[CH:2]=2)=[CH:6][CH:7]=1
Reactant: O=C(CBr)c1ccc(F)cc1
Reactant: C1=C(Cc2ccccc2)NCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Fc1ccc(-c2cn3c(c2-c2ccccc2)CCC3)cc1
Reaction time: 42 h

Procedure:
According to the procedure of Laufer et al. (J. Med. Chem. 1994, 37, 1894-1897), first 2-bromo-1-(4-fluorophenyl)ethanone (10.8 g, 0.05 mol) in portions and then NaHCO3 (5.0 g, 0.06 mol) are added to a solution of 2-benzylpyrroline (Example 1a, 15 g, 80%, 0.075 mol) in ethanol (150 ml) in a round-bottomed flask. The reaction mixture is stirred for 24-60 h with exclusion of light; during this time the temperature of the solution is kept between 30-40° C.
Reaction SMILES: Cl.[CH3:2][NH:3][CH3:4].[C-]#N.[K+].[CH3:8][NH:9]C.[CH2:11]([N:18]1[CH2:23][CH2:22][C:21](=O)[CH2:20][CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.Cl>O.CO.C(OCC)(=O)C.CCOC(C)=O.CCCCCC>[CH2:11]([N:18]1[CH2:23][CH2:22][C:21]([N:3]([CH3:4])[CH3:2])([C:8]#[N:9])[CH2:20][CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CNC
Reactant: O=C1CCN(Cc2ccccc2)CC1
Agent: Cl
Agent: [C-]#N
Agent: [K+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: O
Product: CN(C)C1(C#N)CCN(Cc2ccccc2)CC1
Temperature: 0 °C
Reaction time: 24 h
Yield: 85 %

Procedure:
208 g (3 eq) N,N-dimethylamine hydrochloride, 154 g (3 eq) potassium cyanide in 154 ml water and 1050 ml (7 eq) of a 40% dimethylamine solution were added to a solution of 150 g (1 eq) 1-benzylpiperidin-4-one in 300 ml methanol and the mixture was cooled to 0° C. 75 ml (0.5 eq) concentrated hydrochloric acid were then added at 0° C. and the reaction mixture was stirred for 24 h at room temperature. The reaction course was monitored by thin-layer chromatography (20% EtOAc/hexane). Once the conversion was complete, the solid that had formed was filtered off and washed with iced water (4 I). The solid obtained was then dissolved in ethyl acetate and dried with Na2SO4. Following removal of the solvent under reduced pressure, 165 g (85%) of crude product were obtained in the form of a solid.
Reaction SMILES: C(O)C.[OH-].[Na+].[Br:6][C:7]1[N:8]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:36]([O:38]CC)=[O:37])[N:9]=[C:10]2[C:15]=1[CH:14]=[C:13]([CH2:16][N:17]1[C:21]3=[N:22][CH:23]=[CH:24][C:25]([CH3:26])=[C:20]3[N:19]=[C:18]1[CH2:27][CH2:28][CH3:29])[CH:12]=[CH:11]2>O>[Br:6][C:7]1[N:8]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:36]([OH:38])=[O:37])[N:9]=[C:10]2[C:15]=1[CH:14]=[C:13]([CH2:16][N:17]1[C:21]3=[N:22][CH:23]=[CH:24][C:25]([CH3:26])=[C:20]3[N:19]=[C:18]1[CH2:27][CH2:28][CH3:29])[CH:12]=[CH:11]2
Reactant: CCCc1nc2c(C)ccnc2n1Cc1ccc2nn(-c3ccccc3C(=O)OCC)c(Br)c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCc1nc2c(C)ccnc2n1Cc1ccc2nn(-c3ccccc3C(=O)O)c(Br)c2c1
Temperature: 25 °C
Reaction time: 15.5 h
Yield: 59.5 %

Procedure:
Ethanol (1.2 ml), water (0.3 ml), and sodium hydroxide (34 mg, 0.840 mmol) were added to 3-[3-bromo-2-(2-ethoxycarbonylphenyl)-2H-indazol-5-yl]methyl-7-methyl-2-propyl-3H-imidazo[4,5-b]pyridine (0.149 mg, 0.280 mmol) obtained from two batches of Example 19, and the mixture was stirred at room temperature for 15.5 hours. After concentration, it was partitioned by water (2.5 ml) and ether (5 ml). Conc. hydrochloric acid was dropwise added to the water layer while stirring so as to adjust its pH to 5. The resultant solid was filtered off, washed twice with water (1 ml), and dried overnight at 37° C. to give 84 mg of 3-[3-bromo-2-(2-carboxyphenyl)-2H-indazol-5-yl]methyl-7-methyl-2-propyl-3H-imidazo[4,5-b]pyridine.
Reaction SMILES: [CH3:1][C:2]1[CH2:7][CH2:6][CH2:5][C:4]([CH3:9])([CH3:8])[C:3]=1/[CH:10]=[CH:11]/[C:12](/[CH3:22])=[CH:13]/[CH:14]=[CH:15]/[C:16](/[CH3:21])=[CH:17]/[C:18]([OH:20])=[O:19]>C(O)(C)C>[CH3:1][C:2]1[CH2:7][CH2:6][CH2:5][C:4]([CH3:8])([CH3:9])[C:3]=1/[CH:10]=[CH:11]/[C:12](/[CH3:22])=[CH:13]\[CH:14]=[CH:15]\[C:16](\[CH3:21])=[CH:17]\[C:18]([OH:20])=[O:19]
Reactant: CC1=C(/C=C/C(C)=C/C=C/C(C)=C/C(=O)O)C(C)(C)CCC1
Solvent: CC(C)O
Product: CC1=C(/C=C/C(C)=C\C=C\C(C)=C\C(=O)O)C(C)(C)CCC1

Procedure:
The raw retinoic acid thus obtained was suspended in 235.5 g (300 ml) isopropanol (w=1.0) and refluxed.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]([CH2:19][CH2:20][CH:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[NH:23][C:22]1=[O:30])[CH2:12][CH2:13]OS(C)(=O)=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].O>CN(C)C=O>[CH2:1]([O:8][C:9]([N:11]1[CH2:12][CH2:13][C:21]2([C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[NH:23][C:22]2=[O:30])[CH2:20][CH2:19]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)OCCN(CCC1C(=O)Nc2ccccc21)C(=O)OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(OCc1ccccc1)N1CCC2(CC1)C(=O)Nc1ccccc12
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 60.7 %

Procedure:
3-[2-[N-(Benzyloxycarbonyl)-N-(2-methanesulfonyloxyethyl)amino]ethyl]-2,3-dihydro-1H-indol-2-one (158 mg) was dissolved in N,N-dimethylformamide (3 ml), added with sodium hydride (60%, in oil, 29.2 mg) and stirred at room temperature for 1.5 hours. The reaction mixture was added with water (10 ml) and extracted twice with dichloromethane (10 ml). The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: hexane:ethyl acetate=2:1) to obtain 74.6 mg of the title compound. Yield: 61%.
Reaction SMILES: [N+:1]([CH2:4][CH3:5])([O-:3])=[O:2].C(N)CCC.[Br:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][C:19]=1[O:20][CH3:21])[CH:15]=O>C(O)C>[Br:11][C:12]1[CH:13]=[C:14]([CH:15]=[C:4]([N+:1]([O-:3])=[O:2])[CH3:5])[CH:17]=[CH:18][C:19]=1[O:20][CH3:21]
Reactant: CC[N+](=O)[O-]
Reactant: COc1ccc(C=O)cc1Br
Solvent: CCCCN
Solvent: CCO
Product: COc1ccc(C=C(C)[N+](=O)[O-])cc1Br
Temperature: 95 °C
Reaction time: 8 h

Procedure:
Nitroethane (0.800 mL, 836 mg, 11.1 mmol) and n-butylamine (0.050 mL, 37 mg, 0.51 mmol) were added to a solution of 3-bromo-4-methoxybenzaldehyde (2.00 g, 9.30 mmol) in 2.0 mL of absolute ethanol. The solution was heated in a 95° C. oil bath for 8 h and then stirred overnight at room temperature. The ethanol was evaporated, the residue was stirred with 12 mL of 8% ether in hexane, and the supernatant was decanted. The undissolved material was stirred with 12 mL of 8% ether in hexane, and sufficient toluene was added to bring it into solution at 60° C. The crystals which separated at room temperature were recrystallized again from a solution of hexane (7 mL) and toluene (1.8 mL) at 55° C. cooled to room temperature to give 1-(3-bromo-4-methoxyphenyl)-2-nitropropene as 598 mg of yellow needles. All of the mother liquors were combined and evaporated, and the residue was purified by flash column chromatography on 85 g of silica gel eluting with 25% dichloromethane in hexane to give an additional 791 mg of 1-(3-bromo-4-methoxyphenyl)-2-nitropropene (total isolated yield of 55%). 1H NMR (400 MHz, CDCl3): δ 8.00 (s, 1H), 7.68 (d, 1H, J=2 Hz),7.40 (dd, 1H, J=9, 2 Hz),6.97(d, 1H, J=9Hz), 3.96 (s, 3H), 2.47 (s, 3H). Mass spectrum (NH3CI): m/e=272 (M+1).
Reaction SMILES: O=P(Cl)(Cl)[Cl:3].[Cl:6][C:7]1[C:16]2[C:11](=[CH:12][C:13]([S:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:14][CH:15]=2)[C:10](=O)[NH:9][CH:8]=1.O>CC#N>[Cl:3][C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[C:13]([S:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:12]=2)[C:7]([Cl:6])=[CH:8][N:9]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]cc(Cl)c2ccc(Sc3ccccc3)cc12
Solvent: CC#N
Solvent: O
Product: Clc1cnc(Cl)c2cc(Sc3ccccc3)ccc12
Yield: 71.4 %

Procedure:
POCl3 (46 μL, 0.50 mmol) was added to a stirred suspension of 4-chloro-7-(phenylsulfanyl)-1-(2H)-isoquinolone (120 mg, 0.42 mmol) in MeCN (2 mL) at 23° C., and the mixture was heated at reflux for 1.5 h which gave a clear solution. This cooled solution was poured into water (20 mL) and the mixture was extracted with EtOAc (×3). The combined organic extracts were washed with brine, dried (Na2SO4) and evaporated in vacuo. The residue was purified by column chromatography upon silica gel using hexanes-EtOAc (90:10) as eluant to give 1,4-dichloro-7-(phenylsulfanyl)isoquinoline (92 mg, 0.30 mmol) as an oil which solidified on standing.
Reaction SMILES: [CH3:1][C@@:2]1([CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][C:24]([N:27]4[CH2:32][CH2:31][N:30]([C:33](OC(C)(C)C)=O)[CH2:29][CH2:28]4)=[CH:23][CH:22]=3)=[CH:17][CH:16]=2)[O:6][C:5]2=[N:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][N:4]2[CH2:3]1.Cl[CH2:41][Cl:42]>FC(F)(F)C(O)=O>[Cl:42][C:41]1[CH:19]=[CH:20][C:15]([CH2:33][N:30]2[CH2:31][CH2:32][N:27]([C:24]3[CH:23]=[CH:22][C:21]([C:18]4[CH:17]=[CH:16][C:15]([O:14][CH2:13][C@:2]5([CH3:1])[O:6][C:5]6=[N:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][N:4]6[CH2:3]5)=[CH:20][CH:19]=4)=[CH:26][CH:25]=3)[CH2:28][CH2:29]2)=[CH:16][CH:17]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3ccc(OC[C@@]4(C)Cn5cc([N+](=O)[O-])nc5O4)cc3)cc2)CC1
Reactant: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@]1(COc2ccc(-c3ccc(N4CCN(Cc5ccc(Cl)cc5)CC4)cc3)cc2)Cn2cc([N+](=O)[O-])nc2O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.8 %

Procedure:
850 mg of (R)-2-methyl-2-(4′-(4-tert-butoxycarbonylpiperazin-1-yl)biphenyl-4-yloxymethyl)-6-nitro-2,3-dihydroimidazo[2,1-b]oxazole was dissolved in 10 ml of trifluoroacetic acid and 5 ml of dichloromethane, followed by stirring at room temperature overnight. Thereafter, the reaction solution was concentrated under a reduced pressure, and then, 6 ml of dichloromethane and 6 ml of triethylamine were added thereto. The mixture was stirred at room temperature for 5 minutes, and it was then concentrated under a reduced pressure. The residue was dissolved in 10 ml of DMF, and then, 444.2 mg of 4-chlorobenzaldehyde and 672 mg of triacetoxy sodium borohydride were added thereto while cooled by ice, followed by stirring at room temperature overnight. Thereafter, an aqueous sodium bicarbonate solution and ethyl acetate were added to the reaction solution, the mixture was stirred, and the insoluble precipitate was removed by filtration. The filtrate was washed with water and ethyl acetate, and was then dried to obtain 730 mg (yield: 51.8%) of light yellow powders, (R)-2-(4′-(4-(4-chlorobenzyl)piperazin-1-yl)biphenyl-4-yloxymethyl)-2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazole.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:21][CH3:22])=[C:4]([C:10]([CH2:13][S:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:11][CH:12]=1)[C:5]([O:7][CH2:8]C)=[O:6].BrC1C(OC)=C(C(CBr)=CC=1)C(OC)=O.[Cl:38]C1C=CC=CC=1S>>[Br:1][C:2]1[C:3]([O:21][CH3:22])=[C:4]([C:10]([CH2:13][S:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[Cl:38])=[CH:11][CH:12]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: Sc1ccccc1Cl
Reactant: CCOC(=O)c1c(CSc2ccccc2)ccc(Br)c1OC
Agent: COC(=O)c1c(CBr)ccc(Br)c1OC
Product: COC(=O)c1c(CSc2ccccc2Cl)ccc(Br)c1OC

Procedure:
Prepared by proceeding in a similar manner to Intermediate 73, starting from methyl 3-bromo-6-bromomethyl-2-methoxybenzoate (Intermediate 89) and 2-chlorothiophenol.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:11]1[C:12]([O:29][CH3:30])=[C:13]([C:19]2[N:24]=[C:23]([C:25]([O:27]C)=[O:26])[CH:22]=[CH:21][CH:20]=2)[C:14]([CH3:18])=[C:15]([Cl:17])[CH:16]=1)[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].O.[OH-].[Li+].C(O)(=O)C>CO.O.C(#N)C>[C:1]([O:5][C:6]([NH:8][CH:9]([C:11]1[C:12]([O:29][CH3:30])=[C:13]([C:19]2[N:24]=[C:23]([C:25]([OH:27])=[O:26])[CH:22]=[CH:21][CH:20]=2)[C:14]([CH3:18])=[C:15]([Cl:17])[CH:16]=1)[CH3:10])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1cccc(-c2c(C)c(Cl)cc(C(C)NC(=O)OC(C)(C)C)c2OC)n1
Agent: [Li+]
Agent: [OH-]
Solvent: CC#N
Solvent: CC(=O)O
Solvent: CO
Product: COc1c(C(C)NC(=O)OC(C)(C)C)cc(Cl)c(C)c1-c1cccc(C(=O)O)n1
Temperature: 25 °C

Procedure:
The methyl 6-(3-{1-[(tert-butoxycarbonyl)amino]ethyl}-5-chloro-2-methoxy-6-methylphenyl)pyridine-2-carboxylate (0.075 g, 0.17 mmol) was dissolved in methanol (5.0 mL) and the lithium hydroxide-monohydrate (0.022 g, 0.52 mmol) dissolved in water (0.5 mL) was added. The reaction was stirred at room temperature and monitored by LC/MS. After stirring for 18 h the reaction was complete. Acetic acid was added to adjust the pH 5 and the reaction was concentrated to give a semisolid residue. The crude was diluted with acetonitrile and concentrated 3× to remove residual water and finally give 6-(3-{1-[(tert-butoxycarbonyl)amino]ethyl}-5-chloro-2-methoxy-6-methylphenyl)pyridine-2-carboxylic acid as a crude solid residue. LCMS calculated for C17H18ClN2O5(M+H)+: m/z=365.1. found: 365.0.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[NH:6]1[CH2:11][CH2:10][S:9][CH2:8][CH2:7]1.C(N(CC)CC)C>C(Cl)Cl>[Cl:1][CH2:2][C:3]([N:6]1[CH2:11][CH2:10][S:9][CH2:8][CH2:7]1)=[O:4]
Reactant: O=C(Cl)CCl
Reactant: C1CSCCN1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CCl)N1CCSCC1
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 42.4 %

Procedure:
To an ice-cold solution of chloroacetyl chloride (2.87 g, 25 mmol) in 15 mL of methylene chloride was added thiomorpholine (2.50 g, 24 mmol) and triethylamine (4.9 g, 48 mmol) slowly. The reaction mixture was stirred at 5° C. for 30 minutes, then warmed to room temperature and stirred for 18 hours. After quenching with water (20 mL) at 5° C., additional methylene chloride (200 mL) was added. The organic layer was separated, washed with saturated aqueous NaHCO3 (2×100 mL), brine (2×100 mL), dried over MgSO4, filtered, and the filtrate was concentrated at reduced pressure. The concentrated residue was dried in vacuo to give 1.83 g (42.0%) of 4-(2-chloroacetyl) thiomorpholine as a brown liquid. 1HNMR (300 MHz / CDCl3):δ 2.62 (t, 2H, J=5.03 Hz), 2.68 (t, 2H, J=4.93Hz), 3.75 (t, 2H, J=5.04 Hz), 3.85 (t, 2H, J=5.04 Hz), 4.04 (s, 2H); mass spectrum, m/z =180.2 (M+H).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]([NH:11][C:12](=[O:14])[CH3:13])[CH3:10])=[CH:5][CH:4]=1.Cl.Cl.[F:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[CH:20][CH:19]=1>>[F:17][C:18]1[CH:19]=[CH:20][C:21]([N:24]2[CH2:29][CH2:28][N:27]([CH2:2][C:3]3[CH:8]=[CH:7][C:6]([C@@H:9]([NH:11][C:12](=[O:14])[CH3:13])[CH3:10])=[CH:5][CH:4]=3)[CH2:26][CH2:25]2)=[CH:22][CH:23]=1
Reactant: CC(=O)N[C@@H](C)c1ccc(CCl)cc1
Reactant: Fc1ccc(N2CCNCC2)cc1
Agent: Cl
Product: CC(=O)N[C@@H](C)c1ccc(CN2CCN(c3ccc(F)cc3)CC2)cc1

Procedure:
By similar reaction and treatment to that in Example 1(5) using (S)-N-(1-(4-chloromethylphenyl)ethyl)acetamide instead of N-(4-chloromethylphenylmethyl)acetamide and 1-(4-fluorophenyl)piperazine dihydrochloride instead of phenylpiperazine, the title compound was obtained as white crystals, m.p.=114-115° C.
Reaction SMILES: [NH2:1][NH2:2].[C:3]1(=O)[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[C:5](=[O:12])[O:4]1>O.CC(O)=O>[C:5]1(=[O:12])[C:6]2[CH2:7][CH2:8][CH2:9][CH2:10][C:11]=2[C:3](=[O:4])[NH:2][NH:1]1
Reactant: O=C1OC(=O)C2=C1CCCC2
Reactant: NN
Solvent: O
Solvent: CC(=O)O
Product: O=c1[nH][nH]c(=O)c2c1CCCC2
Temperature: 25 °C
Yield: 96 %

Procedure:
To a solution of hydrazine (392 μL, 13.1 mmol) in water (6 mL) and HOAc (2 mL) is added 4,5,6,7-tetrahydro-isobenzofuran-1,3-dione (2 g, 13.1 mmol). The reaction mixture is refluxed for 3 h, then cooled down to room temperature and the precipitate is collected by filtration, washed with water and dried under vacuum to give 2,3,5,6,7,8-hexahydro-phthalazin-1,4-dione (40) (2.09 g, 96%).
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:10][C@H:11]([CH3:16])[C:12]([O:14][CH3:15])=[O:13]>>[CH2:1]([NH:10][C@@H:11]([CH3:16])[C:12]([O:14][CH3:15])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccccc1
Reactant: COC(=O)[C@@H](C)N
Agent: Cl
Product: COC(=O)[C@H](C)NCc1ccccc1
Yield: 95 %

Procedure:
Prepared as in Example 12-1b from benzaldehyde and (R)-methyl 2-aminopropanoate hydrochloride. Yield 95%. MS 194 (MH+).
Reaction SMILES: [C:1]([CH:3]([CH:7]([CH3:12])[C:8]([CH3:11])([CH3:10])[CH3:9])[C:4]([OH:6])=O)#[N:2].[NH2:13][CH:14]([CH3:26])[CH2:15][CH2:16][N:17]1[C:21]([CH3:22])=[C:20]([Cl:23])[CH:19]=[C:18]1[C:24]#[N:25].C(N(CC)CC)C>S(Cl)(Cl)=O.C(OCC)(=O)C>[Cl:23][C:20]1[CH:19]=[C:18]([C:24]#[N:25])[N:17]([CH2:16][CH2:15][CH:14]([NH:13][C:4](=[O:6])[CH:3]([C:1]#[N:2])[CH:7]([CH3:12])[C:8]([CH3:11])([CH3:10])[CH3:9])[CH3:26])[C:21]=1[CH3:22]
Reactant: CC(C(C#N)C(=O)O)C(C)(C)C
Reactant: Cc1c(Cl)cc(C#N)n1CCC(C)N
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: O=S(Cl)Cl
Product: Cc1c(Cl)cc(C#N)n1CCC(C)NC(=O)C(C#N)C(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 0.54 g (3.5 mmol) 2-cyano-3,4,4-trimethylpentanoic acid in 15 mL thionyl chloride was heated at reflux for 30 min. The thionyl chloride was stripped and the residue was dried in vacuo. The residue was then dissolved in 20 mL methylene chloride and a solution of 0.66 g (3.13 mmol) of 1-(3-aminobutyl)-4-chloro-5-methyl-1H-pyrrole-2-carbonitrile and 0.59 mL (4.2 mmol) triethylamine was added dropwise. The mixture was stirred at room temperature overnight. Solvent was stripped and the residue was taken up in ethyl acetate which was washed with water and brine. Drying (MgSO4) and removal of solvent gave an oil which was chromatographed (40% ether in hexanes) on silica gel to give the title compound as a mixture of diastereomers, mp 111–118° C. 1H NMR (CDCl3) δ 1.0 (m, 3H), 1.2–1.3 (2m, 6H), 1.4 (d, 1H), 1.6 (m, 2H), 1.9 (m, 2H), 2.2 (m, 3H), 4.1 (2m, 2H), 5.7 (m, 1H), 6.65 (2s, 1H).
Reaction SMILES: [Br:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[C:14]([NH2:18])([CH3:17])([CH3:16])[CH3:15].CCN(C(C)C)C(C)C.C1CN([P+](ON2N=NC3C2=CC=CC=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:18][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:6]
Reactant: CC(C)(C)N
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1Br
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CC(C)(C)NC(=O)c1cccc([N+](=O)[O-])c1Br
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-bromo-3-nitrobenzoic acid (500 mg, 2.03 mmol) in DMF (3 mL) was added tert-butylamine (0.22 mL, 2.04 mmol), 1,1′-dimethyltriethylamine (0.71 mL, 4.1 mmol) and (1H-benzo[d][1,2,3]triazol-1-yloxy)tripyrrolidin-1-ylphosphonium hexafluorophosphate(V) (1.27 g, 2.44 mmol). The resulting mixture was stirred at rt for 2 h. The reaction mixture was diluted with EtOAc, washed with water, brine, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel using 0 to 100% gradient of EtOAC:DCM (1:1) in DCM as eluent to give 2-bromo-N-tert-butyl-3-nitrobenzamide: 1H NMR (400 MHz, CDCl3) δ 7.74 (1H, dd, J=8.0, 4.0 Hz), 7.62 (1H, d, J=8.0 Hz), 7.51 (1H, t, J=8.0 Hz), 5.62 (1H, br), 1.52 (9H, s); LC-MS (ESI) m/z 301.0 [M+H]+.