Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OP([CH2:9][C:10]1[CH:11]=[C:12]([CH:17]=[CH:18][CH:19]=1)[C:13]([O:15][CH3:16])=[O:14])(OCC)=O)C.[H-].[Na+].[CH:22](=O)[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[CH:24]=1>C1COCC1>[CH3:16][O:15][C:13](=[O:14])[C:12]1[CH:17]=[CH:18][CH:19]=[C:10](/[CH:9]=[CH:22]/[C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[CH:24]=2)[CH:11]=1
Reactant: CCOP(=O)(Cc1cccc(C(=O)OC)c1)OCC
Reactant: COc1cccc(C=O)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1cccc(/C=C/c2cccc(OC)c2)c1
Temperature: 0 °C
Yield: 78.2 %

Procedure:
To a solution of methyl 3-[(diethoxyphosphoryl)methyl]benzoate (1.02 g, 3.56 mmol; see step (i) above) in THF (5 mL, dry) under a nitrogen atmosphere was added sodium hydride (0.212 g, 60%, 18.8 mmol). After cooling the reaction mixture to 0° C., m-anisaldehyde (0.485 g, 3.56 mmol) in THF 10 mL, dry) was carefully added dropwise with stirring. The reaction mixture was stirred for 1 h at room temperature and then quenched with water. After neutralisation with dilute HCl, the two layers were separated. The water layer was extracted with ethyl acetate and the organic layers were combined, dried (MgSO4), filtered and the solvent removed under reduced pressure. The product was purified using silica gel column chromatography (RF=0.80 20% ethyl acetate/n-hexane) to give the sub-title compound as a white solid (0.747 g, 78%), m.p.=92-94° C.
Reaction SMILES: [CH3:1][Sn:2]([CH3:26])([CH3:25])[C:3]1[CH:4]=[CH:5][C:6]2[C:10]3[CH:11]=[CH:12][C:13]([CH2:15][O:16][Si](C(C)(C)C)(C)C)=[CH:14][C:9]=3[O:8][C:7]=2[CH:24]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Cl-].[NH4+].CCOC(C)=O>C1COCC1>[CH3:1][Sn:2]([CH3:26])([CH3:25])[C:3]1[CH:4]=[CH:5][C:6]2[C:10]3[CH:11]=[CH:12][C:13]([CH2:15][OH:16])=[CH:14][C:9]=3[O:8][C:7]=2[CH:24]=1
Reactant: CC(C)(C)[Si](C)(C)OCc1ccc2c(c1)oc1cc([Sn](C)(C)C)ccc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C[Sn](C)(C)c1ccc2c(c1)oc1cc(CO)ccc12
Reaction time: 0.5 h
Yield: 71 %

Procedure:
To a solution of the dibenzofuran 23 (339 mg, 0.71 mmol) in anhydrous THF (7 mL) at 0° C. under a nitrogen atmosphere was added dropwise a 1M solution of tetrabutylammonium fluoride in THF (0.92 mL, 0.92 mmol). The reaction solution was stirred for 30 min., then saturated ammonium chloride was added. The mixture was then extracted with EtOAc and the organic solution was washed with brine. The organic solution was then dried with magnesium sulfate and then filtered and concentrated under vacuum. Flash chromatography of the residue (silica gel, 25% EtOAc in hexanes) provided 182 mg of 24 (70% yield) as a white solid.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]([C:9]1[CH:14]=[CH:13][C:12]([CH2:15][N:16]2[CH2:21][CH2:20][N:19]([CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([N+:29]([O-])=O)[CH:24]=3)[CH2:18][CH2:17]2)=[CH:11][CH:10]=1)([OH:8])[C:4]([F:7])([F:6])[F:5].Cl>CC(O)C.ClCCl.C(=O)([O-])[O-].[K+].[K+].[Fe]>[NH2:29][C:25]1[CH:24]=[C:23]([CH:28]=[CH:27][CH:26]=1)[CH2:22][N:19]1[CH2:20][CH2:21][N:16]([CH2:15][C:12]2[CH:11]=[CH:10][C:9]([C:3]([OH:8])([C:2]([F:33])([F:32])[F:1])[C:4]([F:5])([F:6])[F:7])=[CH:14][CH:13]=2)[CH2:17][CH2:18]1
Reactant: O=[N+]([O-])c1cccc(CN2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)c1
Agent: [Fe]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CC(C)O
Solvent: ClCCl
Product: Nc1cccc(CN2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 64 %

Procedure:
To a stirred suspension of 1,1,1,3,3,3-hexafluoro-2-(4-((4-(3-nitrobenzyl)piperazin-1-yl)methyl)phenyl)propan-2-ol (2.095 mmol, 1 g) and iron powder (20.95 mmol, 1.170 g) in 2-propanol was added a small volume of hydrochloric acid (37%). The reaction was refluxed for 2 hours then was allowed to cool to room temperature. The reaction was diluted with dichloromethane and solid potassium carbonate was added. The suspension was stirred for 18 hours then was filtered through celite. The filtrate was concentrated under reduced pressure then was purified by silica chromatography eluting with ethyl acetate to give the title compound (600 mg). MS (ESI) m/z 448.3 [M+H]+
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:14]1[C:15]([CH3:31])=[C:16]([NH:20][C:21](=[O:30])[O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:17]=[CH:18][CH:19]=1)[C:4]1[C:12]2[C:7](=[CH:8][C:9]([Br:13])=[CH:10][CH:11]=2)[NH:6][CH:5]=1.O=[CH:33][C:34]([O:36][CH2:37][CH3:38])=[O:35].C1(C)C=CC=CC=1.Cl.O1CCOCC1>O1CCCC1>[CH2:23]([O:22][C:21]([NH:20][C:16]1[C:15]([CH3:31])=[C:14]([C:3]2[C:4]3[C:12]4[C:7](=[CH:8][C:9]([Br:13])=[CH:10][CH:11]=4)[NH:6][C:5]=3[C:33]([C:34]([O:36][CH2:37][CH3:38])=[O:35])=[N:1][CH:2]=2)[CH:19]=[CH:18][CH:17]=1)=[O:30])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CCOC(=O)C=O
Reactant: Cc1c(NC(=O)OCc2ccccc2)cccc1C(CN)c1c[nH]c2cc(Br)ccc12
Agent: Cl
Solvent: C1CCOC1
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ncc(-c2cccc(NC(=O)OCc3ccccc3)c2C)c2c1[nH]c1cc(Br)ccc12
Temperature: 25 °C
Reaction time: 24 h
Yield: 36 %

Procedure:
To a mixture of benzyl 3-(2-amino-1-(6-bromo-1H-indol-3-yl)ethyl)-2-methylphenylcarbamate (2.320 g, 4.85 mmol) and 4 angstrom molecular sieves (powder, activated, <5 mesh, 1.80 g) in tetrahydrofuran (100 mL) at room temperature was added ethyl 2-oxoacetate in toluene (1.923 mL, 9.70 mmol), followed by hydrogen chloride in 1,4-dioxane (1.334 mL, 5.33 mmol). The mixture was stirred at room temperature for 24 h. The solid phase was removed by suction filtration through CELITE®, and the filtrate was concentrated under vacuum. The residue was diluted with water (60 mL), basified with saturated NaHCO3 solution, and extracted with ethyl acetate (3×80 mL). The combined extract was washed with brine (60 mL) and dried over anhydrous MgSO4. The solvent was removed under vacuum. To the residue was added p-xylene (200 mL) and 10% Pd/C (1.5 g), and the mixture was heated under atmosphere at 125° C. for 16 hr. The solid phase was removed by suction filtration through CELITE®. The filtrate was concentrated under vacuum, and the residue was purified by ISCO (220 g silica gel, solid loading, 20-50% ethyl acetate/hexane) to provide the desired product (0.977 g, 36% yield) as a beige solid.
Reaction SMILES: [NH:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9](O)=[O:10])=[CH:7][CH:6]=1)[C:2]([NH2:4])=[NH:3].S(Cl)([Cl:16])=O>>[NH:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([Cl:16])=[O:10])=[CH:7][CH:6]=1)[C:2]([NH2:4])=[NH:3]
Reactant: N=C(N)Nc1ccc(C(=O)O)cc1
Reactant: O=S(Cl)Cl
Product: N=C(N)Nc1ccc(C(=O)Cl)cc1

Procedure:
The antineoplastic drug shown as Compound 1 may be synthesized as follows: p-guanidinobenzoic acid is refluxed with thionyl chloride to yield the corresponding p-guanidinobenzoic acid chloride. This is then reacted with ethyl p-hydroxybenzoylacetate in the presence of a catalyst such as dimethylaminopyridine (DMAP) to yield Compound 2 of the following structure: ##STR12##
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[O:11][C@@H:10]([CH2:13][O:14][Si](C(C)(C)C)(C)C)[CH2:9][CH2:8]2.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[O:11][C@@H:10]([CH2:13][OH:14])[CH2:9][CH2:8]2
Reactant: COc1cccc2c1O[C@@H](CO[Si](C)(C)C(C)(C)C)CC2
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COc1cccc2c1O[C@@H](CO)CC2
Temperature: 22 °C
Reaction time: 0.5 h
Yield: 87.8 %

Procedure:
To a solution of tert-butyl(dimethyl)silyl [(2R)-8-methoxy-3,4-dihydro-2H-chromen-2-yl]methyl ether (4.50 g, 14.6 mmol) in tetrahydrofuran (150 mL) at 0° C. was added excess tetrabutylammonium fluoride (1.0 M in tetrahydrofuran) and the reaction mixture was allowed to stir at 22° C. for 30 min. The solvent was removed in vacuo and the residue was purified by flash column chromatography (silica, ethyl acetate:hexanes 1:1) to give 2.49 g (88%, 40% ee) of [(2R)-8-methoxy-3,4-dihydro-2H-chromen-2-yl]methanol as a white crystalline solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([S:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[F:16])=[CH:7][CH:6]=[CH:5][C:4]=1[CH:17](O)[CH3:18].S(Cl)([Cl:22])=O>N1C=CC=CC=1.C1C=CC=CC=1>[CH3:1][O:2][C:3]1[C:4]([CH:17]([Cl:22])[CH3:18])=[CH:5][CH:6]=[CH:7][C:8]=1[S:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[F:16]
Reactant: COc1c(Sc2ccccc2F)cccc1C(C)O
Reactant: O=S(Cl)Cl
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: COc1c(Sc2ccccc2F)cccc1C(C)Cl
Yield: 79.7 %

Procedure:
A mixture of 1-[2-methoxy-3-(2-fluorophenylthio)phenyl]ethanol (1 g), thionyl chloride (500 mg) and pyridine (2 drops) in benzene (30 ml) was refluxed under heating for 30 minutes. The reaction mixture was evaporated under reduced pressure. To the residue was added water, and the mixture was extracted with diethyl ether. The extract was washed with dil. hydrochloric acid, saturated aqueous sodium bicarbonate and water in turn, dried and then evaporated under reduced pressure to give oily 2-fluorophenyl 2-methoxy-3-(1-chloroethyl)phenyl thioether (850 mg).
Reaction SMILES: FC(F)(F)C(OC(=O)C(F)(F)F)=O.CS(C)=O.[Cl:18][CH2:19][CH2:20][CH2:21][S:22]([NH:25][CH2:26][CH:27]([CH2:46][CH:47]([OH:49])[CH3:48])[CH2:28][S:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])(=[O:24])=[O:23].ClCCCS(NCC(CC(=O)C)COC(=O)NCCCCCCCCCCCCCCCCCC)(=O)=O>ClCCl.C(N(CC)CC)C>[Cl:18][CH2:19][CH2:20][CH2:21][S:22]([NH:25][CH2:26][CH:27]([CH2:46][C:47](=[O:49])[CH3:48])[CH2:28][S:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])(=[O:23])=[O:24]
Reactant: CCCCCCCCCCCCCCCCSCC(CNS(=O)(=O)CCCCl)CC(C)O
Agent: CCCCCCCCCCCCCCCCCCNC(=O)OCC(CNS(=O)(=O)CCCCl)CC(C)=O
Solvent: ClCCl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCCSCC(CNS(=O)(=O)CCCCl)CC(C)=O
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 50 %

Procedure:
To a cooled solution of 0.19 ml (1.33 mM) of trifluoroacetic anhydride in 20 ml of dichloromethane at -78° C. is added 0.19 ml (2.66 mM) of dimethylsulfoxide and the mixture is stirred at -78° C. for 5 minutes. To the reaction mixture is added a solution of 428 mg (0.83 mM) of 1-(3-chloropropylsulfonylamino)-2-(2-hydroxypropan-1-yl)-3-n-hexadecylthiopropane m15 in 2 ml of dichloromethane with stirring and the mixture is stirred at -70° C. for an additional 15 minutes. 3.50 ml (24.9 mM) of triethylamine is added and the mixture is allowed to react by the same procedure as described in (132) and 213 mg (41.6% yield) of the titled compound IIIm2 is obtained.
Reaction SMILES: [CH3:1][C:2]([CH3:23])([CH3:22])[CH2:3][N:4]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]#[CH:21])=[CH:16][CH:15]=1)[C:5]1[CH:10]=[CH:9][N:8]=[C:7]([C:11]#[N:12])[N:6]=1>CCO.[Pd]>[CH3:1][C:2]([CH3:22])([CH3:23])[CH2:3][N:4]([CH2:13][C:14]1[CH:15]=[CH:16][C:17]([CH2:20][CH3:21])=[CH:18][CH:19]=1)[C:5]1[CH:10]=[CH:9][N:8]=[C:7]([C:11]#[N:12])[N:6]=1
Reactant: C#Cc1ccc(CN(CC(C)(C)C)c2ccnc(C#N)n2)cc1
Agent: [Pd]
Solvent: CCO
Product: CCc1ccc(CN(CC(C)(C)C)c2ccnc(C#N)n2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 112 %

Procedure:
4-[(2,2-Dimethyl-propyl)-(4-ethynyl-benzyl)-amino]-pyrimidine-2-carbonitrile (47 mg, 0.11 mmoles) is dissolved in 5 ml of EtOH and 10% Pd—C (5 mg) is added at rt. The mixture is stirred under hydrogen at rt for overnight and is filtered through a pad of Celite which is washed with EtOH. The filtrate is concentrated and the crude product is purified by silica gel column chromatography to give 38 mg of desired 4-[(2,2-dimethyl-propyl)-(4-ethyl-benzyl)-amino]-pyrimidine-2-carbonitrile in 77% yield.
Reaction SMILES: C([NH:8][C@@H:9]([C:19]([OH:21])=[O:20])[CH2:10][O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(OC(C)(C)C)=O.O=S(Cl)Cl.[CH3:26]O>>[CH3:26][O:21][C:19](=[O:20])[C@@H:9]([CH2:10][O:11][CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[NH2:8]
Reactant: CO
Reactant: CC(C)(C)OC(=O)N[C@H](COCc1ccccc1)C(=O)O
Solvent: O=S(Cl)Cl
Product: COC(=O)[C@H](N)COCc1ccccc1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
To a solution of BOC-O-benzyl-D-serine (5.05 g, 17.12 mmol) in MeOH (100 mL) at −78° C., was added SOCl2 dropwise. The reaction mixture was warmed to 0° C. and stirred for ˜4 hours and then concentrated. The residue was taken up in EtOAc and washed with 10% Na2CO3 (3×80 mL). The organic layer was dried over sodium sulfate, filtered and concentrated. To the crude material in EtOAc (100 mL) at 0° C. was bubbled HCl gas for approximately 10 minutes, and the reaction was capped and the mixture stirred at 0° C. for 30 minutes before it was concentrated in vacuo. The crude material was diluted with 50 mL of a 1:1 solution of saturated NaHCO3/10% Na2CO3 and extracted with EtOAc (4×50 mL). The combined organics were dried over sodium sulfate, filtered, and concentrated to give O-benzyl-D-serine methyl ester (3.13 g, 14.96 mmol) which was used without further purification. LCMS (ES) m/z 210.1 (M+H)+.
Reaction SMILES: [Na].[CH3:2][C:3]1[CH:8]=[CH:7][C:6]([SH:9])=[CH:5][CH:4]=1.Cl[CH:11](Cl)[C:12]([O:14][CH2:15][CH3:16])=[O:13]>CO.C(OCC)C>[CH3:2][C:3]1[CH:8]=[CH:7][C:6]([S:9][CH:11]([S:9][C:6]2[CH:7]=[CH:8][C:3]([CH3:2])=[CH:4][CH:5]=2)[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:5][CH:4]=1
Reactant: CCOC(=O)C(Cl)Cl
Reactant: Cc1ccc(S)cc1
Agent: [Na]
Solvent: CCOCC
Solvent: CO
Product: CCOC(=O)C(Sc1ccc(C)cc1)Sc1ccc(C)cc1
Temperature: 20 °C
Reaction time: 1 h
Yield: 68 %

Procedure:
Sodium (3.54 g) is dissolved in methanol (140 cc) and a solution of 4-methylthiophenol (21.8 g) in methanol (25 cc) is added. The mixture is stirred for 1 hour at 20° C. and a solution of ethyl dichloroacetate (12.5 g) in methanol (30 cc) is then added. The mixture is allowed to cool, the white precipitate obtained is filtered off, and the filtrate is concentrated to dryness under reduced pressure (20 mmHg) at 40° C. The oil obtained is taken up in diethyl ether (250 cc) and washed four times with N sodium hydroxide solution (50 cc each time) and four times with distilled water (50 cc each time). The ethereal phase is dried over anhydrous sodium sulphate, filtered, treated with animal charcoal, filtered and concentrated to dryness under reduced pressure (20 mmHg) at 40° C. Ethyl 2,2-bis(4-methylthiophenoxy)acetate (18 g) is thus obtained as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=CC2C(=O)N3OC(C)CC3O[C:4]=2[CH:3]=1.[Cl:17][C:18]1[CH:27]=[C:22]([C:23]([NH:25][OH:26])=[O:24])[C:21]([OH:28])=[CH:20][CH:19]=1.C(=O)/C=C/C.Cl>C(O)(=O)C>[Cl:17][C:18]1[CH:19]=[CH:20][C:21]2[O:28][CH:4]([CH2:3][CH:2]([Cl:1])[CH3:16])[N:25]([OH:26])[C:23](=[O:24])[C:22]=2[CH:27]=1
Reactant: O=C(NO)c1cc(Cl)ccc1O
Reactant: CC1CC2Oc3cc(Cl)ccc3C(=O)N2O1
Agent: C/C=C/C=O
Agent: Cl
Solvent: CC(=O)O
Product: CC(Cl)CC1Oc2ccc(Cl)cc2C(=O)N1O

Procedure:
Prior to the present invention, 6-chloro-2-methyl-3,3a-dihydro-2H,9H-isoxazolo (3,2-b) (1,3) benzoxazin-9-one has been prepared by the reaction of 5-chlorosalicylhydroxamic acid (made from 5-chlorosalicylate and hydroxylamine) and crotonaldehyde in the presence of hydrogen chloride and glacial acetic acid to obtain 6-chloro-2-(2-chloropropyl)-2,3-dihydro-3-hydroxy-4H-1, 3-benzoxazin-4-one. The latter compound was then cyclized to 7-chloro-2-methyl-3,3a-dihydro-2H,9H-isoxazolo (3,2-b) (1,3) benzoxazin-9-one. Said cyclization can be carried out using organic or inorganic bases in the appropriate solvent. U.S. Pat. No. 3,598,814 discloses and claims 7-chloro-2-methyl-3, 3a-dihydro-2H,9H-isoxazolo (3,2b) (1,3) benzoxazin-9-one and several methods for its manufacture.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]=[C:16]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:17]=1[O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:12]([OH:14])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:34][O:35][C:36]1[CH:47]=[C:46]2[C:39]([NH:40][CH:41]=[C:42]2[CH2:43][CH2:44][NH2:45])=[CH:38][CH:37]=1.C(Cl)CCl.CO>C(Cl)(Cl)Cl>[CH2:27]([O:26][C:16]1[CH:15]=[C:11]([CH:10]=[C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:17]=1[O:18][CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C:12]([NH:45][CH2:44][CH2:43][C:42]1[C:46]2[C:39](=[CH:38][CH:37]=[C:36]([O:35][CH3:34])[CH:47]=2)[NH:40][CH:41]=1)=[O:14])[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: O=C(O)c1cc(OCc2ccccc2)c(OCc2ccccc2)c(OCc2ccccc2)c1
Reactant: COc1ccc2[nH]cc(CCN)c2c1
Solvent: ClCCCl
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COc1ccc2[nH]cc(CCNC(=O)c3cc(OCc4ccccc4)c(OCc4ccccc4)c(OCc4ccccc4)c3)c2c1

Procedure:
2g was synthesized by the condensation of 1b (480 mg, 1.09 mmol) and 5-methoxy tryptamine (248 mg, 1.308 mmol) using standard EDC coupling method and was isolated as white solid (565 mg, 84%) by elution with 0.5% methanol in chloroform. Rf: 0.517 (1.6% methanol in chloroform); mp: 125-128° C.;
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[Cl:13][C:14]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:15]=1[C:16]([OH:18])=O.[Cl:24][C:25]1[N:30]=[CH:29][C:28]([S:31]([NH2:34])(=[O:33])=[O:32])=[CH:27][CH:26]=1.N12CCCN=C1CCCCC2>ClCCl>[Cl:13][C:14]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:15]=1[C:16]([NH:34][S:31]([C:28]1[CH:29]=[N:30][C:25]([Cl:24])=[CH:26][CH:27]=1)(=[O:32])=[O:33])=[O:18]
Reactant: NS(=O)(=O)c1ccc(Cl)nc1
Reactant: O=C(O)c1ccc(Cl)cc1Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: O=C(NS(=O)(=O)c1ccc(Cl)nc1)c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74.1 %

Procedure:
1,1′-Carbonyl-diimidazole (4.22 g, 26 mmol) was added to a solution of 2,4-dichlorobenzoic acid (4.73 g, 24.8 mmol) in 100 ml dichloromethane the mixture was stirred for 30 minutes at room temperature and subsequently refluxed for 30 minutes. Then 6-chloro-pyridine-3-sulfonic acid amide (5.00 g, 26 mmol) and 1,8-diazabicylo[5.4.0]undec-7-en (3.96 g, 26 mmol) were added and the mixture was stirred at room temperature overnight. After evaporation to dryness the residue was taken up with 100 ml ethyl acetate and washed with 1 M HCl and 1 M NaOH and the organic phase was dried over sodium sulphate and concentrated in vacuo. Flash chromatography (SiO2, heptane-ethyl acetate gradient) yielded 6.72 g of the title compound as a white solid, m/z=365 (ES+), 363 (ES−).
Reaction SMILES: C(O[C:9]1[CH:20]=[CH:19][C:12]([C:13]([N:15]([O:17][CH3:18])[CH3:16])=[O:14])=[CH:11][CH:10]=1)C1C=CC=CC=1.[CH:21]([Si:24]([CH:39]([CH3:41])[CH3:40])([CH:36]([CH3:38])[CH3:37])[O:25][CH2:26]C1C=CC(C(O)=O)=CC=1)([CH3:23])[CH3:22]>>[CH3:18][O:17][N:15]([CH3:16])[C:13](=[O:14])[C:12]1[CH:11]=[CH:10][C:9]([CH2:26][O:25][Si:24]([CH:21]([CH3:23])[CH3:22])([CH:39]([CH3:41])[CH3:40])[CH:36]([CH3:38])[CH3:37])=[CH:20][CH:19]=1
Reactant: CON(C)C(=O)c1ccc(OCc2ccccc2)cc1
Reactant: CC(C)[Si](OCc1ccc(C(=O)O)cc1)(C(C)C)C(C)C
Product: CON(C)C(=O)c1ccc(CO[Si](C(C)C)(C(C)C)C(C)C)cc1

Procedure:
Following the procedure for the preparation of 4-benzyloxy-N-methoxy-N-methyl-benzamide but substituting 4-Triisopropylsilanyloxymethyl-benzoic acid provided the title compound. MS: (M+H m/z=352.1).
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[CH:4][C:3]=1[C:10](=[O:18])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[Cl:17].S(Cl)(Cl)=O.Cl.[CH2:24]([O:26][C:27](=[O:30])[CH2:28][NH2:29])[CH3:25].C(N(CC)CC)C>ClCCl>[CH2:24]([O:26][C:27](=[O:30])[CH2:28][NH:29][C:7]([C:5]1[S:6][C:2]([NH2:1])=[C:3]([C:10](=[O:18])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:17])[CH:4]=1)=[O:9])[CH3:25]
Reactant: Nc1sc(C(=O)O)cc1C(=O)c1ccccc1Cl
Reactant: CCOC(=O)CN
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Product: CCOC(=O)CNC(=O)c1cc(C(=O)c2ccccc2Cl)c(N)s1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
14.0 g (50 mmol) of 5-amino-4-(2-chlorobenzoyl)-thiophene-2-carboxylic acid [the synthesis is carried out analogously to Hromatka et al., Monatsh. Chem. 104, 973 (1973)] are suspended in 250 ml of anhydrous dichloromethane, 8 ml of thionyl chloride are added dropwise, and the mixture is stirred at room temperature for 2.5 hours. It is then evaporated in vacuo, the residue is taken up in dichloromethane, and the solution is added dropwise to a mixture of 7 g (50 mmol) of glycine ethyl ester hydrochloride and 16 ml of triethylamine in 100 ml of anhydrous dichloromethane. After 1 our at room temperature the mixture is extracted with water. The residue from the concentrated organic phase is worked up by chromatography on silica gel. 8.1 g (44% of theory) of the title compound of melting point 216°-218° C. are obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][CH2:7][CH:8]2[CH2:13][C:14](OCC)=[O:15].[H-].[Al+3].[Li+].[H-].[H-].[H-].Cl>O1CCCC1>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][CH2:7][CH:8]2[CH2:13][CH2:14][OH:15]
Reactant: CCOC(=O)CC1CCCc2c(OC)cccc21
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: COc1cccc2c1CCCC2CCO
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 100.3 %

Procedure:
A suspension of ethyl (5-methoxy-1,2,3,4-tetrahydro-1-naphthyl)acetate (1.02 g) and lithium aluminum hydride (0.20 g) in tetrahydrofuran (15 ml) was stirred at 0° C. for 2.5 hours. The solution was poured into cold 1N-hydrochloric acid, then the resulting mixture was filtered through the celite, and extracted with ethyl acetate. The extract was washed with brine, dried over sodium sulfate, and evaporated in vacuo to afford 2-(5-methoxy-1,2,3,4-tetrahydro-1-naphthyl)ethanol as a colorless oil (0.85 g).
Reaction SMILES: [CH2:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7](O)=[O:8])=[CH:5][CH:4]=1)[CH3:2].O=S(Cl)[Cl:14]>CN(C=O)C>[CH2:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([Cl:14])=[O:8])=[CH:5][CH:4]=1)[CH3:2]
Reactant: CCc1ccc(C(=O)O)cc1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: CCc1ccc(C(=O)Cl)cc1
Yield: 100 %

Procedure:
A mixture of 4-ethylbenzoic acid (0.50 g, 3.33 mmol) in SOCl2 (1 mL) and DMF(1 drop) was refluxed for 2 h. The reaction mixture was concentrated and then stripped with toluene (2×10 mL) to yield 4-ethylbenzoyl chloride (0.59 g, >100%) as a colorless oil. The crude acid chloride (0.59 g, 3.5 mmol) in toluene (minimum amount) was added dropwise to conc. aq. NH4OH (1.4 mL). After stirring for 1 h, the reaction mixture was concentrated, the residue was dissolved in water and extracted with EtOAc (3×25 mL). The combined organic layers were washed with 1 N aq. NaOH (10 mL) and brine and dried over Na2SO4 prior to removal of the volatiles to yield 4-ethylbenzamide (460 mg, 88%) as a white solid. A suspension of this crude amide (430 mg, 2.87 mmol) and LiAlH4 (180 mg, 4.7 mmol) in dry THF (5 mL) was refluxed at 65° C. for 4.5 h. More LiAlH4 (60 mg, 1.58 mmol) was added, and the reaction mixture was heated at 65° C. for 2 h. The reaction mixture was cooled, and 1 N aq. NaOH (0.4 mL) was added. After stirring for 4 h, the mixture was filtered, and the filtrate was concentrated to give 4-ethylbenzylamine (350 mg, 90w) as a pale yellow oil.