Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[N:2](C)[CH:3]=[C:4]([C:14]1[CH:19]=[CH:18][N:17]=[C:16]([S:20][CH3:21])[N:15]=1)[C:5]([C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1)=O.C(OC([NH:30]C1C=C(C(=CN(C)C)C(C2C=CC(F)=CC=2)=O)C=CN=1)=O)(C)(C)C>>[F:13][C:10]1[CH:11]=[CH:12][C:7]([C:5]2[C:4]([C:14]3[CH:19]=[CH:18][N:17]=[C:16]([S:20][CH3:21])[N:15]=3)=[CH:3][NH:2][N:30]=2)=[CH:8][CH:9]=1
Reactant: CN(C)C=C(C(=O)c1ccc(F)cc1)c1ccnc(NC(=O)OC(C)(C)C)c1
Reactant: CSc1nccc(C(=CN(C)C)C(=O)c2ccc(F)cc2)n1
Product: CSc1nccc(-c2c[nH]nc2-c2ccc(F)cc2)n1
Yield: 93 %

Procedure:
The reaction was carried out in the same manner as in Example 2-2) except for using 4.13 g (13.0 mmol) of 3-dimethylamino-1-(4-fluorophenyl)-2-(2-methylthiopyrimidin-4-yl)-2-propen-1-one obtained in Example 66-1) in place of 2-(2-t-butoxycarbonylaminopyridin-4-yl)-3-dimethylamino-1-(4-fluorophenyl)-2-propen-1-one to obtain 3.44 g of the title compound as a white powder. (Yield: 93%)
Reaction SMILES: C([O:4][CH2:5][CH2:6][CH2:7][CH2:8][N:9]1[C:17]2[C:16]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=4)=[C:21]([Cl:36])[CH:20]=3)=[N:15][CH:14]=[N:13][C:12]=2[CH:11]=[CH:10]1)(=O)C.[OH-].[Na+].Cl.O>O1CCCC1>[Cl:36][C:21]1[CH:20]=[C:19]([NH:18][C:16]2[C:17]3[N:9]([CH2:8][CH2:7][CH2:6][CH2:5][OH:4])[CH:10]=[CH:11][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:24]=[CH:23][C:22]=1[O:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=1
Reactant: CC(=O)OCCCCn1ccc2ncnc(Nc3ccc(Oc4cccc(C(F)(F)F)c4)c(Cl)c3)c21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: OCCCCn1ccc2ncnc(Nc3ccc(Oc4cccc(C(F)(F)F)c4)c(Cl)c3)c21
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 82.9 %

Procedure:
To a solution of 4-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]butyl acetate (281 mg) in tetrahydrofuran (4.0 mL) was added 1N aqueous sodium hydroxide solution (2.8 mL), and the mixture was stirred at room temperature for 4.5 hrs. 1N Aqueous hydrochloric acid solution (2.8 mL) was added, and the mixture was stirred for 15 min. The reaction mixture was poured into water (50 mL), and the mixture was extracted with ethyl acetate (50 mL×3). The organic layer was washed successively with 5% aqueous sodium hydrogen carbonate solution, water and saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was subjected to basic silica gel chromatography (eluent:hexane/ethyl acetate=95/5→0/100). The object fraction was concentrated under reduced pressure and dried. Ethanol/diisopropyl ether (5/95) was added to the residue, and the mixture was stirred with heating to 80° C., allowed to cool to room temperature, and stood still. The resultant precipitate was collected by filtration. The obtained precipitate was washed with diisopropyl ether and dried under reduced pressure to give the title compound (214 mg) as white powder crystals.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:11][CH2:10][N:9](CC2C=CC=CC=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[H][H]>C(O)C.[Pd]>[CH2:1]([O:3][C:4]([C:6]1([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(C(=O)OCC)CCN(Cc2ccccc2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C1(C(=O)OCC)CCNCC1

Procedure:
To a solution of benzylpiperidine-4,4-dicarboxylic acid diethyl ester (21.5 g, 0.067 mol) in ethanol (300 mL) is added 5% Pd/C (25 g, 50% wet). The reaction mixture is stirred under 40 psi pressure of hydrogen for 3 hrs, then filtered through a celite bed and the filtrate is concentrated to give a crude viscous liquid which is purified by column chromatography (silica gel 230-400 mesh, methanol:dichloromethane 10:90) to furnish piperidine-4,4-dicarboxylic acid diethyl ester as pale yellow liquid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:24]=[CH:23][C:18]([C:19](OC)=[O:20])=[C:17]([O:25][CH3:26])[CH:16]=2)[N:10]=1.[F:27][C:28]1[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][C:29]=1[NH2:30].C[Al](C)C>C1(C)C=CC=CC=1>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:24]=[CH:23][C:18]([C:19]([NH:30][C:29]3[CH:31]=[C:32]([C:35]([F:36])([F:37])[F:38])[CH:33]=[CH:34][C:28]=3[F:27])=[O:20])=[C:17]([O:25][CH3:26])[CH:16]=2)[N:10]=1
Reactant: COC(=O)c1ccc(-n2nc(-c3c(Cl)cccc3Cl)[nH]c2=O)cc1OC
Reactant: Nc1cc(C(F)(F)F)ccc1F
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: COc1cc(-n2nc(-c3c(Cl)cccc3Cl)[nH]c2=O)ccc1C(=O)Nc1cc(C(F)(F)F)ccc1F
Yield: 25.9 %

Procedure:
The title compound was prepared by following the procedure as described for Example-31 by using methyl 4-(3-(2,6-dichlorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-methoxybenzoate (Intermediate-21, 0.100 g, 0.25 mmol), 2-fluoro-5-(trifluoromethyl)aniline (0.069 g, 0.38 mmol), trimethyl aluminium (2M solution in toluene) (0.5 mL) and dry toluene (5.0 mL) to afford 0.035 g of desired product. 1H NMR (DMSO-d6): δ 4.06 (s, 3H), 7.59 (d, J=7.8 Hz, 1H), 7.77-7.68 (m, 5H), 7.84 (s, 1H), 8.09 (d, J=8.7 Hz, 1H), 8.67 (d, J=6.9 Hz, 1H), 10.38 (s, 1H), 12.79 (br s, 1H); MS (m/z): 540.92 [M+H]+.
Reaction SMILES: CN(C)[CH:3]=[CH:4][C:5]([C:7]1[C:12]([O:13][CH3:14])=[CH:11][C:10]([O:15][CH3:16])=[CH:9][C:8]=1[OH:17])=[O:6].CO.[I:21]I.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[CH3:14][O:13][C:12]1[CH:11]=[C:10]([O:15][CH3:16])[CH:9]=[C:8]2[C:7]=1[C:5](=[O:6])[C:4]([I:21])=[CH:3][O:17]2
Reactant: COc1cc(O)c(C(=O)C=CN(C)C)c(OC)c1
Reactant: II
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: COc1cc(OC)c2c(=O)c(I)coc2c1
Temperature: 80 °C
Reaction time: 0.25 h
Yield: 51.6 %

Procedure:
To an eggplant type flask (500 ml), 3-dimethylamino-4',6'-dimethoxy-2'-hydroxyacrylophenone (5.026 g) prepared in Example 15 and methyl alcohol (200 ml) were added. The mixture was dissolvedby heating at 80° C. for 10 minutes with stirring. After the solution was cooled, iodine (10.152 g) was slowly added. After 15 minutes, the disappearance of the starting material was confirmed by thin layer chromatography. To the reaction mixture, methylene chloride (700 ml) and then 5% aqueous solution of sodium thiosulfate (200 ml) were added to reduce iodine. The organic layer was separated, and washed with distilled water (100 ml). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (n-hexane/ethyl acetate=2/1 to 1/2), and recrystallized from ether to give the titled compound (3.43 g; yield=34.5%) as colorless crystals. Melting point: 158°-160° C. 1H-NMR(CDCl3, δ ppm): 3.88 (s, 3H, OMe), 3.93 (s, 3H, OMe), 6.38 (s, 1H, ArH), 6.42 (s, 1H, ArH), 8.06 (s, 1H, H2).
Reaction SMILES: [CH3:1][C:2]1[CH2:6][C:5](=[O:7])[N:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:3]=1.[CH3:14][C:15]1[C:20]([OH:21])=[C:19]([CH:22]=O)[C:18]([CH2:24][OH:25])=[CH:17][N:16]=1.Cl>[OH-].[Na+].O>[OH:7][C:5]1[N:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:3]=[C:2]([CH3:1])[C:6]=1[CH:22]1[C:19]2[C:20]([OH:21])=[C:15]([CH3:14])[N:16]=[CH:17][C:18]=2[CH2:24][O:25]1
Reactant: CC1=NN(c2ccccc2)C(=O)C1
Reactant: Cc1ncc(CO)c(C=O)c1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1ncc2c(c1O)C(c1c(C)nn(-c3ccccc3)c1O)OC2
Temperature: 4 °C
Yield: 733.8 %

Procedure:
To a stirring solution of 3-methyl-1-phenyl-2-pyrazolin-5-one (1.74 g) (hereinafter, referred to edaravone) in 0.1M of NaOH (100 mL) at room temperature, were added dropwise a solution of pyridoxal hydrochloride (2.44 g) in water (100 mL) with stirring and then reacted. After dropwise, the mixture was stirred for 30 minutes and the reaction was stopped when it was appeared to finish deposition of white precipitate. The mixture was cooled to 4° C. in refrigerator to deposit sufficiently the precipitate. The reaction solution was stood to cool overnight, the white precipitate was filtered off to give crude (wet) of 1-(5-hydroxy-3-methyl-1-phenyl-1H-pyrazol-4-yl)-6-methyl-1,3-dihydro-furo[3,4-c]pyridin-7-ol (23.7 g).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([S:21]([CH3:24])(=[O:23])=[O:22])[CH:7]=[C:8]([C:10](=O)[NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[C:13]=2[F:19])[CH:9]=1)=[O:4].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:34])=CC=1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[N:6]([S:21]([CH3:24])(=[O:23])=[O:22])[CH:7]=[C:8]([C:10](=[S:34])[NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[C:13]=2[F:19])[CH:9]=1)=[O:4]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: COC(=O)c1cc(C(=O)Nc2cccc(F)c2F)cn1S(C)(=O)=O
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(C(=S)Nc2cccc(F)c2F)cn1S(C)(=O)=O
Yield: 143.7 %

Procedure:
To a solution of 4-(2,3-difluoro-phenylcarbamoyl)-1-methanesulfonyl-1H-pyrrole-2-carboxylic acid methyl ester (410 mg, 1.14 mmol) in dry toluene (10 mL) was added Lawesson's reagent (320 mg, 0.79 mmol). The suspension was heated at reflux for 2 hours. The solvent was removed by evaporation and the residue was purified by flash column eluting with 30% of EtOAc/hexanes to afford the title compound as a yellow solid (425 mg, 99%). MS (ES+): m/e=375.1 (M+H); LC/Method A/3.61 min.
Reaction SMILES: Cl[CH2:2][CH:3]1[O:8][CH2:7][CH2:6][N:5]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:4]1.[NH2:16][CH3:17]>CCO>[CH3:17][NH:16][CH2:2][CH:3]1[O:8][CH2:7][CH2:6][N:5]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:4]1
Reactant: CN
Reactant: ClCC1CN(Cc2ccccc2)CCO1
Solvent: CCO
Product: CNCC1CN(Cc2ccccc2)CCO1
Temperature: 110 °C

Procedure:
Commercially available 2-chloromethyl-4-benzyl morpholine was dissolved in an 8 M solution of NH2Me in EtOH and heated in a glass pressure vessel at 110° C. overnight. The solvent was removed in vacuo, and the compound was used in the next step without further purification. LC/MS m/z: 221.2 (MH+), Rt 0.55 minutes.
Reaction SMILES: [C:1](O[BH-](OC(=O)C)OC(=O)C)(=O)[CH3:2].[Na+].[NH2:15][C:16]1[CH:17]=[C:18]([CH:25]=[CH:26][C:27]=1[N:28]1[CH2:33][CH2:32][CH:31]([N:34]2[C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=3[CH2:37][O:36][C:35]2=[O:44])[CH2:30][CH2:29]1)[C:19]([NH:21][CH:22]([CH3:24])[CH3:23])=[O:20].C(=O)C>C(O)(=O)C.CN(C)C=O.O>[CH2:1]([NH:15][C:16]1[CH:17]=[C:18]([CH:25]=[CH:26][C:27]=1[N:28]1[CH2:29][CH2:30][CH:31]([N:34]2[C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=3[CH2:37][O:36][C:35]2=[O:44])[CH2:32][CH2:33]1)[C:19]([NH:21][CH:22]([CH3:24])[CH3:23])=[O:20])[CH3:2]
Reactant: CC(C)NC(=O)c1ccc(N2CCC(N3C(=O)OCc4ccccc43)CC2)c(N)c1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC=O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CCNc1cc(C(=O)NC(C)C)ccc1N1CCC(N2C(=O)OCc3ccccc32)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Sodium triacetoxyborohydride (0.1 g) was added to a solution of the product from example 160 (0.1 g), acetaldehyde (0.015 ml), acetic acid (1 drop) in N,N-dimethylformamide (10 ml). The reaction mixture was stirred at room temperature for 16 h. The mixture was diluted with water, extracted with ethyl acetate, dried, and evaporated under reduced pressure. Yield 0.035 g.
Reaction SMILES: [N+:1]([C:4]1[CH:19]=[CH:18][C:7]([O:8][CH2:9][CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[CH:6][CH:5]=1)([O-])=O.[H][H]>CO.[Pd]>[N:12]1([CH2:11][CH2:10][CH2:9][O:8][C:7]2[CH:6]=[CH:5][C:4]([NH2:1])=[CH:19][CH:18]=2)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]1
Reactant: O=[N+]([O-])c1ccc(OCCCN2CCCCC2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Nc1ccc(OCCCN2CCCCC2)cc1

Procedure:
1-[3-(4-nitrophenoxy)propyl]piperidine was dissolved in methanol, and the target compound was obtained by catalytic reduction using a palladium charcoal catalyst in a current of hydrogen.
Reaction SMILES: CON(C)[C:4]([CH:6]([NH:11][C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)=[O:13])[CH2:7][CH:8]([CH3:10])[CH3:9])=[O:5].[H-].[H-].[H-].[H-].[Li+].[Al+3].OS([O-])(=O)=O.[K+]>C1COCC1.O>[CH:4]([CH:6]([NH:11][C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)=[O:13])[CH2:7][CH:8]([CH3:10])[CH3:9])=[O:5]
Reactant: CON(C)C(=O)C(CC(C)C)NC(=O)c1ccccn1
Agent: O=S(=O)([O-])O
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)CC(C=O)NC(=O)c1ccccn1
Temperature: 0 °C
Yield: 86 %

Procedure:
The amide from above (4.7 g, 14.7 mmol) was dissolved in 50 mL THF and added to a slurry of LiAlH4 (558 mg, 14.7 mmol) in 50 mL THF at −78° C. The reaction mixture was allowed to warm to 0° C. and maintained for 15 min, after which time it was cooled to −78° C. and cannulated into an ice-cooled solution of KHSO4 (8.16 g, 60 mmol) in 200 mL H2O. The resulting mixture was extracted with 5×100 mL EtOAc. The combined extracts were washed with 2×100 mL satd.NaHCO3 and 1×100 mL brine, dried with Na2SO4 and evaporated to an oily residue which was flash chromatographed through SiO2 (25% EtOAc/hexane—35% EtOAc/hexane) yielding 2.8 g (86%) of pyridine-2-carboxylic acid (1-formyl-3-methylbutyl)amide as a colorless oil which solidified on standing.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)=[CH:6][C:5]=1[NH:15][C:16](=[O:32])[NH:17][CH2:18][CH:19]1[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH2:20]1)([O-:3])=[O:2].C(O)(C(F)(F)F)=O>ClCCl>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)=[CH:6][C:5]=1[NH:15][C:16]([NH:17][CH2:18][CH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)=[O:32])([O-:3])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCC(CNC(=O)Nc2cc(-c3cccs3)ccc2[N+](=O)[O-])CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(NCC1CCNCC1)Nc1cc(-c2cccs2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.4 %

Procedure:
To a solution of tert-butyl 4-((3-(2-nitro-5-(thiophen-2-yl)phenyl)ureido)methyl)piperidine-1-carboxylate (0.30 g, 0.65 mmol) in dichloromethane (15 mL) was added TFA (3 mL) at 0° C. The reaction was warmed to room temperature and stirred for 2 h. The reaction was concentrated. The crude residue was diluted with a saturated aqueous solution of sodium bicarbonate. The obtained solid was filtered, washed with water then washed with ether and pentane to afford 1-(2-nitro-5-(thiophen-2-yl)phenyl)-3-(piperidin-4-ylmethyl)urea (0.20 g, 85% yield).
Reaction SMILES: C(OCC1C=CC=CC=1)(=O)C.[CH3:12][C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([N:24]=[C:25]=O)([CH3:23])[CH3:22])[CH:16]=1)=[CH2:14].[C:27]1([N:33]=C=O)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.N=C=N.C1(N=C=NC2C=CC=CC=2)C=CC=CC=1>>[C:27]1([N:33]=[C:25]=[N:24][C:21]([C:17]2[CH:18]=[CH:19][CH:20]=[C:15]([C:13]([CH3:12])=[CH2:14])[CH:16]=2)([CH3:23])[CH3:22])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=C=Nc1ccccc1
Reactant: C=C(C)c1cccc(C(C)(C)N=C=O)c1
Agent: C(=Nc1ccccc1)=Nc1ccccc1
Agent: N=C=N
Solvent: CC(=O)OCc1ccccc1
Product: C=C(C)c1cccc(C(C)(C)N=C=Nc2ccccc2)c1
Temperature: 150 °C
Reaction time: 6 h

Procedure:
We combined 0.0982 g TPAO, 19.30 g benzyl acetate (internal standard), 60.40 g of m-TMI, and 35.77 g phenyl isocyanate. Heating at 150° C. was carried out for 6 hours; at 2 hours IR showed nearly complete conversion of isocyanates to carbodiimides. GC-FID showed that product was predominantly the title carbodiimide (89.3%), unreacted TMI (4.2%), 1,3-bis[2-(3-isopropenylphenyl-2-propyl]carbodiimide (4.2%) and 1,3-diphenylcarbodiimide (2.9%) versus internal standard. Material from this Example was distilled to obtain in 71% recovery on products of a purified sample (92% pure) of the title product and in 6% recovery on products of a crude (66% purity) sample of the same product.
Reaction SMILES: [C:1]([O-])(=[O:3])[CH3:2].[Na+].BrCCO.[CH2:10]1[O:19][C:18]2[CH:17]=[CH:16][C:14]([NH2:15])=[CH:13][C:12]=2[O:11]1.O>C(O)C>[CH2:10]1[O:19][C:18]2[CH:17]=[CH:16][C:14]([NH:15][CH2:2][CH2:1][OH:3])=[CH:13][C:12]=2[O:11]1
Reactant: CC(=O)[O-]
Reactant: Nc1ccc2c(c1)OCO2
Agent: OCCBr
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: OCCNc1ccc2c(c1)OCO2

Procedure:
27 mmol of sodium acetate and 15 mmol of 2-bromoethanol are added to 10 mmol of 3,4-methylenedioxyaniline dissolved in ethanol. After 24 hours of heating at reflux, the reaction mixture is brought to ambient temperature, water is added, and then the aqueous phase is extracted with dichloromethane. The organic phases are combined, the solvent is evaporated off and the crude residue is purified by chromatography on silica, using a 10:90 dichloromethane/ethyl acetate mixture as eluant, to yield the expected product in the form of an oil.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([I:12])[C:10]=1[OH:11])[C:5]([OH:7])=[O:6].[I:13][C:14]1[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=1[CH2:16]Cl.C(=O)([O-])[O-].[Cs+].[Cs+].Cl>CN(C=O)C>[I:13][C:14]1[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=1[CH2:16][O:6][C:5](=[O:7])[C:4]1[CH:3]=[C:2]([I:1])[C:10]([OH:11])=[C:9]([I:12])[CH:8]=1
Reactant: O=C(O)c1cc(I)c(O)c(I)c1
Reactant: ClCc1ccccc1I
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1I)c1cc(I)c(O)c(I)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 61 %

Procedure:
A suspension of 3,5-diiodo-4-hydroxybenzoic acid (1 95 mg, 0.5 mmol, 2-iodo benzyl chloride (320 mg, 1.25 mmol), and cesium carbonate (490 mg, 1.5 mmol) in 5 mL DMF was stirred for 15 hours at room temperature. The mixture was then poured into 1 M HCl (100 mL) and a white precipitate formed. The precipitate was isolated filtration and was recrystallized from hot isopropanol/chloroform, yielding the title compound as bright white crystals (140 mg, 61%). 1H NMR (400 MHz, CDC13): δ 8.40 (s, 2H), 7.90 (dd, J=8.0, 1.2 Hz, 1H), 7.44-7.36 (m, 2H), 7.06 (td, J=8.0, 2.0 Hz, 1H), 6.14 (s, 1H), 5.35 (s, 2H).
Reaction SMILES: [C:1]([C:4]1([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].C1C(=O)N([Br:19])C(=O)C1.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[Br:19][CH2:2][C:1]([C:4]1([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:6][CH2:5]1)=[O:3]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)C1(C(C)=O)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CCOC(=O)C1(C(=O)CBr)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71 %

Procedure:
To a 100 mL of round-bottomed flask was added ethyl 1-acetylcyclo-propanecarboxylate (15.6 g, 100 mmol) and NBS solid (21.36 g, 120 mmol), followed by p-toluene sulfonic acid (1.9 g, 10 mmol). After stirring at rt for 8 hrs, the reaction mixture was extracted with diethyl ether (200 mL) and washed with 80 mL of water. The organic phase was then dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (1:30(v/v)EtOAc/n-hexane) to give the title compound as colorless oil (16.68 g, 71%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6](=[O:17])[S:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10](Br)[CH:9]=2)=[O:4].[C:18]1(B(O)O)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH3:1][O:2][C:3]([C:5]1[C:6](=[O:17])[S:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH:9]=2)=[O:4]
Reactant: OB(O)c1ccccc1
Reactant: COC(=O)c1c(O)c2ccc(Br)cc2sc1=O
Product: COC(=O)c1c(O)c2ccc(-c3ccccc3)cc2sc1=O

Procedure:
4-Hydroxy-2-oxo-7-phenyl-2H-thiochromene-3-carboxylic acid methyl ester was prepared from 7-bromo-4-hydroxy-2-oxo-2H-thiochromene-3-carboxylic acid methyl ester (Example 5 e) and phenylboronic acid under conditions analogous to Example 7(a). 1H NMR (200 MHz, CDCl3): δ (ppm)=15.26 (s, 1H), 8.40 (d, J=9.1 Hz, 1H), 7.65-7.45 (m, 7H), 4.02 (s, 3H).
Reaction SMILES: [OH:1][C:2]([CH3:16])([CH3:15])[CH2:3][O:4][C:5]1[C:12]([CH3:13])=[CH:11][C:8]([C:9]#[N:10])=[CH:7][C:6]=1[CH3:14].N1C=CN=C1.[Si:22](Cl)([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23].O>CN(C=O)C>[Si:22]([O:1][C:2]([CH3:16])([CH3:15])[CH2:3][O:4][C:5]1[C:12]([CH3:13])=[CH:11][C:8]([C:9]#[N:10])=[CH:7][C:6]=1[CH3:14])([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Cc1cc(C#N)cc(C)c1OCC(C)(C)O
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(C#N)cc(C)c1OCC(C)(C)O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 72 h
Yield: 50.9 %

Procedure:
To a solution of 4-(2-hydroxy-2-methylpropoxy)-3,5-dimethyl benzonitrile (2.90 g, 13.2 mmol) in anhydrous DMF (20 mL) was added imidazole (2.7 g, 40 mmol) and tert-butyldimethylsilylchloride (2.19 g, 14.6 mmol). The reaction mixture was stirred at room temperature under nitrogen for 3 d. Water (200 mL) was added and the mixture was extracted with ethyl acetate (200 mL). The organic layer was washed with water (2×100 mL) and brine (100 mL), and dried over anhydrous Na2SO4. The solvent was removed under reduced pressure and the crude compound was purified by column chromatography to give 4-[2-(tert-butyldimethylsilanyloxy)-2-methylpropoxy]-3,5-dimethylbenzonitrile (2.24 g, 54%). N-Butyl lithium (6.2 mL, 6.6 mmol, 1.6 M solution in hexanes) was added to a solution of 2,4-dimethoxy-6-N-dimethylbenzamide (0.9 g, 4.3 mmol) in anhydrous THF (10 mL) drop-wise at −10° C. over a period of 10 min under nitrogen. The stirring was continued at 0° C. for 1 h. The reaction mixture was cooled to −50° C. A solution of 4-[2-(tert-butyldimethylsilanyloxy)-2-methylpropoxy]-3,5-dimethylbenzonitrile (1.58 g, 4.73 mmol) in anhydrous THF (5 mL) was quickly added. The cooling bath was removed and the reaction mixture was allowed to warm to room temperature. The stirring was continued at room temperature for 1 h. An aqueous ammonium chloride solution (10 mL) was added followed by ethyl acetate (100 mL). The organic layer was separated, washed with water (10 mL) and dried (Na2SO4). The solvent was removed under reduced pressure and the crude compound was purified by column chromatography (silica gel 230-400 mesh; 0-5% methanol in CH2Cl2 as eluent) to give 3-{4-[2-(tert-butyldimethylsilanyloxy)-2-methylpropoxy]-3,5-dimethylphenyl}-6,8-dimethoxy-2H-isoquinolin-1-one (0.82 g, 37%), as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:14]S(C2C=CC=CC=2)(=O)=O)=[C:6]([CH:13]=1)/[CH:7]=[CH:8]/[C:9]([O:11][CH3:12])=[O:10].Br.Br[CH2:26][C:27]([C:29]1[S:30][C:31]([CH3:34])=[CH:32][N:33]=1)=[O:28]>>[CH3:12][O:11][C:9](=[O:10])[CH2:8][C:7]1[C:6]2[C:5](=[CH:4][CH:3]=[C:2]([Cl:1])[CH:13]=2)[NH:14][C:26]=1[C:27]([C:29]1[S:30][C:31]([CH3:34])=[CH:32][N:33]=1)=[O:28]
Reactant: Cc1cnc(C(=O)CBr)s1
Reactant: COC(=O)/C=C/c1cc(Cl)ccc1NS(=O)(=O)c1ccccc1
Agent: Br
Product: COC(=O)Cc1c(C(=O)c2ncc(C)s2)[nH]c2ccc(Cl)cc12

Procedure:
The title compound was prepared according to the procedure described in Example 57 from methyl trans-5-chloro-2-(phenylsulfonylamino)cinnamate (Example 36, step 3) and 2-bromoacetyl-5-methylthiazole hydrobromide*.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[CH2:11]1[CH:19]2[N:14]([CH2:15][CH2:16][C:17](=O)[CH2:18]2)[CH2:13][CH2:12]1>CC(=O)OCC>[CH2:11]1[CH:19]2[N:14]([CH2:15][CH:16]=[C:17]([C:5]3[C:4]4[C:8](=[CH:9][CH:10]=[C:2]([Cl:1])[CH:3]=4)[NH:7][CH:6]=3)[CH2:18]2)[CH2:13][CH2:12]1
Reactant: Clc1ccc2[nH]ccc2c1
Reactant: O=C1CCN2CCCC2C1
Solvent: CCOC(C)=O
Product: Clc1ccc2[nH]cc(C3=CCN4CCCC4C3)c2c1

Procedure:
5-Chloro-1H-indole (1.00 g, 6.63 mmol) and 7-octahydroindolizinone (1.39 g, 9.95 mmol) were converted to product by the procedure of Preparation 17 to give 595 mg. (33.1%). EA calculated for C16H17N2Cl: C, 70.45; H, 6.28; N, 10.27. Found: C, 70.60; H, 6.46; N, 10.28. MS(FD) (m/e): 272.