Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:7][CH2:6][CH:5]([NH:8][C:9]([C:11]2[CH:31]=[CH:30][C:14]3[N:15]([CH3:29])[C:16]([NH:18][C:19]4[S:20][C:21]5[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:22]=5[N:23]=4)=[N:17][C:13]=3[CH:12]=2)=[O:10])[CH2:4]1.[C:32]([O:36][C:37](=[O:42])[NH:38][CH2:39][CH:40]=O)([CH3:35])([CH3:34])[CH3:33].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[C:32]([O:36][C:37](=[O:42])[NH:38][CH2:39][CH2:40][N:3]1[CH2:7][CH2:6][CH:5]([NH:8][C:9]([C:11]2[CH:31]=[CH:30][C:14]3[N:15]([CH3:29])[C:16]([NH:18][C:19]4[S:20][C:21]5[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:22]=5[N:23]=4)=[N:17][C:13]=3[CH:12]=2)=[O:10])[CH2:4]1)([CH3:35])([CH3:34])[CH3:33]
Reactant: Cn1c(Nc2nc3ccc(Cl)cc3s2)nc2cc(C(=O)NC3CCNC3)ccc21
Reactant: CC(C)(C)OC(=O)NCC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Product: Cn1c(Nc2nc3ccc(Cl)cc3s2)nc2cc(C(=O)NC3CCN(CCNC(=O)OC(C)(C)C)C3)ccc21
Yield: 58.5 %

Procedure:
[2-(3-{[2-(6-Chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carbonyl]amino}-pyrrolidin-1-yl)-ethyl]-carbamic acid tert-butyl ester (56 mg) was prepared by following General Procedure P starting from 2-(6-chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylic acid pyrrolidin-3-ylamide dihydrochloride (84 mg), (2-oxo-ethyl)-carbamic acid tert-butyl ester (40 mg), and Na(OAc)3BH (65 mg) in DCM (2 mL).
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:12]=[CH:11][C:3]=1[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[C:62]1[CH:63]=[CH:64][C:65]2[O:69][CH:68]=[CH:67][C:66]=2[CH:70]=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[O:69]1[C:65]2[CH:64]=[CH:63][C:62]([NH:1][C:2]3[CH:14]=[C:13]([C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=4)[CH:12]=[CH:11][C:3]=3[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5])=[CH:70][C:66]=2[CH:67]=[CH:68]1
Reactant: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1N
Reactant: Brc1ccc2occc2c1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1Nc1ccc2occc2c1
Temperature: 25 °C

Procedure:
To toluene 3.0 mL suspension of tert-butyl 2-amino-4-phenylbenzoate 0.10 g, 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl 9 mg, tris(dibenzylideneacetone)dipalladium(0) 3 mg and cesium carbonate 0.24 g was added 5-bromobenzofuran 0.18 g, and it was heated and refluxed for 24 hours. After the reaction mixture was cooled to room temperature, 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl 9 mg and tris(dibenzylideneacetone)dipalladium(0) 3 mg were added to it, and it was heated and refluxed for 24 hours. After the reaction mixture was cooled to room temperature, 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl 9 mg and tris(dibenzylideneacetone)dipalladium(0) 3 mg were added to it, and it was heated and refluxed for 24 hours. After the reaction mixture was cooled to room temperature, insoluble matter was filtrated, and ethyl acetate and 10% citric acid aqueous solution were added to it. The organic layer was separated and collected, dried over anhydrous magnesium sulfate after washing with saturated sodium chloride aqueous solution, and the solvent was removed under reduced pressure. The obtained residue was refined by silica gel column chromatography [Trikonex company, Flash Tube 2008, eluent; hexane:ethyl acetate=30:1] to give tert-butyl 2-((benzofuran-5-yl)amino)-4-phenylbenzoate. Trifluoroacetic acid 3.0 mL solution of the obtained tert-butyl 2-((benzofuran-5-yl)amino)-4-phenylbenzoate was stirred at room temperature for 3 hours. The solvent of reaction mixture was removed under reduced pressure, and the obtained residue was refined by silica gel column chromatography [Trikonex company, Flash Tube 2008, eluent; hexane:ethyl acetate:acetic acid=30:10:1] to give 2-((benzofuran-5-yl)amino)-4-phenylbenzoic acid 42 mg.
Reaction SMILES: Cl[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:5].[OH-].[NH4+:15].Cl>O.[Cu]Cl>[NH2:15][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:5]
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1Cl
Reactant: [NH4+]
Agent: Cl[Cu]
Agent: Cl
Agent: [OH-]
Solvent: O
Product: Nc1c(C(=O)O)cccc1[N+](=O)[O-]

Procedure:
A solution of 2-chloro-3-nitrobenzoic acid (5.00 g, 24.8 mmol), ammonium hydroxide (25.0 ml) and copper (1) chloride (50 mg) is heated in a bomb at 125° for 20 hr and is then allowed to cool to 20°-25°. The solid residue is dissolved in water and the solution acidified with 3N hydrochloric acid. The resultant mixture is filtered, washed, and dried to provide the 2-amino-3-nitrobenzoic acid, mp 201-203; IR (mineral oil) 3478, 3345, 2954, 2925, 2855, 1692, 1677, 1571, 1559, 1520, 1512, 1442, 1271, 1259, 1130 cm-1 ; NMR (300 MHz, CDCl3 -MeOD) 8.38, 8.30, 6.66; MS (EI) m/e 182, 164.
Reaction SMILES: [O:1]([CH2:8][CH2:9][CH2:10][C:11]#[C:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=[O:18])=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>C(O)C>[O:1]([CH2:8][CH2:9][CH2:10][C:11]#[C:12][C:13]1[CH:14]=[CH:15][C:16]([CH2:17][OH:18])=[CH:19][CH:20]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1ccc(C#CCCCOc2ccccc2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: OCc1ccc(C#CCCCOc2ccccc2)cc1
Reaction time: 0.92 h
Yield: 101.2 %

Procedure:
A solution of 2.02 g of 4-(5-phenoxy-1-pentyn-1-yl)benzaldehyde in 5 ml of absolute ethanol was stirred with 0° C. bath cooling and 640 mg of sodium borohydride was added in portions. After stirring for 55 minutes the reaction mixture was quenched by the addition of water and then evaporated in vacuo. The residue was mixed cautiously with 2% sulfuric acid and extracted twice with ethyl acetate. The combined extracts were washed with saturated sodium chloride and then a sodium hydrogen carbonate solution. They were dried over magnesium-sulfate and evaporated in vacuo to yield 2.06 g of the 4-(Phenoxy-1-pentyn-1-yl)-benzyl alcohol which was sufficiently pure to use without purification.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.CC([O-])(C)C.[K+].[C:23]([O:27][C:28]([N:30]1[CH2:34][CH2:33]OS1(=O)=O)=[O:29])([CH3:26])([CH3:25])[CH3:24].COC(C)(C)C>CN(C)C=O>[C:23]([O:27][C:28](=[O:29])[NH:30][CH2:34][CH2:33][N:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([Cl:1])[CH:10]=2)[C:6]([C:11](=[O:16])[C:12]([F:13])([F:14])[F:15])=[CH:7]1)([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)OC(=O)N1CCOS1(=O)=O
Reactant: O=C(c1c[nH]c2cc(Cl)ccc12)C(F)(F)F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: COC(C)(C)C
Product: CC(C)(C)OC(=O)NCCn1cc(C(=O)C(F)(F)F)c2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 61.2 %

Procedure:
To a solution of 11.5 g (46.4 mmol) 1-(6-chloro-1H-indol-3-yl)-2,2,2-trifluoro-ethanone in 150 ml N,N-dimethylformamide were slowly added 6.25 g (55.7 mmol) potassium tert-butylate. The temperature was kept below 32° C. The reaction mixture was allowed to cool to room temperature and stirred for 20 min. To the resulting brown suspension were added slowly 12.4 g (55.7 mmol) 2,2-dioxo-2λ6-[1,2,3]oxathiazolidine-3-carboxylic acid tert-butyl ester. The reaction mixture was stirred at room temperature until complete consumption of 1-(6-chloro-1H-indol-3-yl)-2,2,2-trifluoro-ethanone, which was monitored by thin layer chromatography. Dilution with 300 ml tert-butyl methyl ether was followed by washing with 250 ml of a 0.2 M aqueous solution of hydrochloric acid. The aqueous layer was extracted with two 200-ml portions of tert-butyl methyl ether. The combined organic layers were washed with water and brine, dried over sodium sulfate and concentrated in vacuo. The residue, 19.5 g of a light brown solid, was triturated with 300 ml of warm tert-butyl methyl ether. After cooling to room temperature the precipitate was collected by filtration, washed with cold tert-butyl methyl ether and dried in vacuo to give 11.1 g (61%) of the title compound as an off-white solid. The filtrate was concentrated to dryness. The residue was triturated with 50 ml warm tert-butyl methyl ether. After cooling to room temperature the precipitate was collected by filtration, washed with cold tert-butyl methyl ether and dried in vacuo to give another 3.5 g (19%) of the title compound as an off-white solid.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[NH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[S:14][CH2:15][C:16]1[N:20]=[CH:19][O:18][N:17]=1>C1C=CC=CC=1>[CH2:5]([O:4][C:2]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[S:14][CH2:15][C:16]1[N:20]=[CH:19][O:18][N:17]=1)=[O:3])[CH3:6]
Reactant: Nc1ccccc1SCc1ncon1
Reactant: CCOC(=O)Cl
Solvent: c1ccccc1
Product: CCOC(=O)Nc1ccccc1SCc1ncon1
Reaction time: 48 h

Procedure:
A solution of ethyl chloroformate (0.55 g) in benzene (10 ml) was added dropwise to a solution of 3-(2-aminophenylthiomethyl)-1,2,4-oxadiazole (2.07 g) in benzene (10 ml). The reaction mixture was then stirred for 2 days, filtered and the filtrate evaporated under reduced pressure to give an oil which crystallised on standing. Re-crystallisation from isopropanol gave 3-(2-ethoxycarbonylaminophenylthiomethyl)-1,2,4-oxadiazole, m.p. 55°.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[NH2:4].[C:10]([O:14][C:15](=[O:25])[NH:16][C:17]1[S:18][C:19]([C:22](Cl)=[O:23])=[CH:20][N:21]=1)([CH3:13])([CH3:12])[CH3:11].C(NC(C)C)(C)C>ClCCl>[C:10]([O:14][C:15](=[O:25])[NH:16][C:17]1[S:18][C:19]([C:22](=[O:23])[NH:4][C:3]2[C:5]([CH3:9])=[CH:6][CH:7]=[CH:8][C:2]=2[Cl:1])=[CH:20][N:21]=1)([CH3:13])([CH3:11])[CH3:12]
Reactant: CC(C)(C)OC(=O)Nc1ncc(C(=O)Cl)s1
Reactant: Cc1cccc(Cl)c1N
Solvent: ClCCl
Solvent: CC(C)NC(C)C
Product: Cc1cccc(Cl)c1NC(=O)c1cnc(NC(=O)OC(C)(C)C)s1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
The fourth step involves adding 2-chloro-6-methylaniline to a stirred solution of tert-butyl[5-(chlorocarbonyl)-1,3-thiazol-2-yl]carbamate in dichloromethane at 0° C. Diisopropylamine was added to the reaction mixture, warmed to room temperature, stirred for 24 hours, diluted with dichloromethane, and washed with 2N hydrochloric acid. The organic extract thus obtained was dried, filtered, and concentrated to obtain a residue. The residue was diluted with ethyl acetate-ether, filtered, washed with ether, and dried in vacuo to obtain tert-butyl{5-[(2-chloro-6-methylphenyl)carbamoyl]-1,3-thiazol-2-yl}carbamate (Formula 1b) in an overall yield of 48%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:12]=[C:13]([Br:17])[C:14]=1[O:15][CH3:16])[CH:6]=[C:7]([C:10]#[N:11])[C:8]#[N:9].[C:18]1([CH:25]=[CH:24][CH:23]=[C:21]([OH:22])[CH:20]=1)[OH:19].N1CCCCC1>C(O)C>[NH2:9][C:8]1[O:19][C:18]2[C:25]([CH:6]([C:5]3[CH:4]=[C:3]([O:2][CH3:1])[C:14]([O:15][CH3:16])=[C:13]([Br:17])[CH:12]=3)[C:7]=1[C:10]#[N:11])=[CH:24][CH:23]=[C:21]([OH:22])[CH:20]=2
Reactant: Oc1cccc(O)c1
Reactant: COc1cc(C=C(C#N)C#N)cc(Br)c1OC
Solvent: C1CCNCC1
Solvent: CCO
Product: COc1cc(C2C(C#N)=C(N)Oc3cc(O)ccc32)cc(Br)c1OC
Yield: 59.5 %

Procedure:
To a mixture of 3,4-dimethoxy-5-bromobenzylidenemalononitrile (293 mg, 1 mmol) and resorcinol (110 mg, 1 mmol) in ethanol (2 mL) was added piperidine (0.1 mL, 1 mmol). The mixture was refluxed for 2 h. The solvent was evaporated, the residue was purified by chromatography on silica gel with EtOAc and hexane (1:2) as eluant, yielding 240 mg (59.5%) of the title compound. 1H NMR (DMSO-d6): 9.77 (brs, 1H), 6.96–6.86 (m, 5H), 6.52 (d, J=8.1, 1H), 6.41 (s, 1H), 4.65 (s, 1H), 3.80 (s, 3H), 3.70 (s, 3H).
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[CH:6]=[N:7][N:8]([C:10]2[N:18]=[C:17]3[C:13]([N:14]=[CH:15][N:16]3[C@@H:19]3[CH2:23][C@H:22]([NH:24][C:25](=[O:28])[CH2:26][CH3:27])[C@@H:21]([OH:29])[C@H:20]3[OH:30])=[C:12]([NH:31]C(C3C=CC(OC)=CC=3)C3C=CC(OC)=CC=3)[N:11]=2)[CH:9]=1)=[O:4].FC(F)(F)C(O)=O>ClCCl>[CH3:1][NH:2][C:3]([C:5]1[CH:6]=[N:7][N:8]([C:10]2[N:18]=[C:17]3[C:13]([N:14]=[CH:15][N:16]3[C@@H:19]3[CH2:23][C@H:22]([NH:24][C:25](=[O:28])[CH2:26][CH3:27])[C@@H:21]([OH:29])[C@H:20]3[OH:30])=[C:12]([NH2:31])[N:11]=2)[CH:9]=1)=[O:4]
Reactant: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NC(c4ccc(OC)cc4)c4ccc(OC)cc4)nc(-n4cc(C(=O)NC)cn4)nc32)[C@H](O)[C@@H]1O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(N)nc(-n4cc(C(=O)NC)cn4)nc32)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A cooled (0° C.) solution of 1-[6-{[Bis-(4-methoxy-phenyl)-methyl]-amino}-9-((1R,2S,3R,4S)-2,3-dihydroxy-4-propionylamino-cyclopentyl)-9H-purin-2-yl]-1H-pyrazole-4-carboxylic acid methylamide (0.08 g, 0.122 mmol) in dry dichloromethane (4 ml) is treated slowly with trifluoroacetic acid (2 ml). The reaction mixture is stirred at room temperature for 48 h and then concentrated in vacuo. The residue was co-evaporated with chloroform three times to remove excess trifluoro acetic acid and purification of the crude product by preparative HPLC affords the title compound. LC-MS (0.1% formic acid, acetonitrile): (MH+ 430.28)
Reaction SMILES: [OH:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([O:9][CH3:10])=[O:8].Br[CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O>[O:14]([CH2:13][CH2:12][O:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([O:9][CH3:10])=[O:8])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: COC(=O)c1sccc1O
Reactant: BrCCOc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1sccc1OCCOc1ccccc1
Temperature: 80 °C
Reaction time: 4.5 h
Yield: 93 %

Procedure:
To a solution of methyl 3-hydroxythiophene-2-carboxylate (0.992 g, 6.27 mmol) in N,N-dimethylformamide (12 ml) were added β-bromophenetole (1.268 g, 6.31 mmol) and potassium carbonate (1.059 g, 7.66 mmol), and the mixture was stirred at 80° C. for 4.5 hr. Ethyl acetate was added to the reaction mixture, the mixture was washed with water, and the organic layer was dried over sodium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate) to give methyl 3-(2-phenoxyethoxy)thiophene-2-carboxylate (1.624 g, 5.83 mmol, yield 93%). This was dissolved in methanol (12 ml), 1N-aqueous sodium hydroxide solution (12 ml) was added at room temperature, and the mixture was stirred at 60° C. for 2 hr. The reaction mixture was concentrated under reduced pressure and neutralized with 1N-aqueous hydrochloric acid solution, and the mixture was extracted with ethyl acetate. The extract was dried over sodium sulfate, and the solvent was evaporated under reduced pressure to give a carboxylic acid compound 3-(2-phenoxyethoxy)thiophene-2-carboxylic acid (1.491 g, 5.64 mmol, yield 97%).
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]([C:12]1[S:13][C:14]2[CH:21]=[CH:20][C:19]([NH:22]N)=[CH:18][C:15]=2[C:16]=1[CH3:17])=[O:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(O)(=O)C.[CH3:28][N:29]1[CH2:34][CH2:33][C:32](=O)[CH2:31][CH2:30]1>Cl>[CH3:17][C:16]1[C:15]2=[C:18]3[C:19](=[CH:20][CH:21]=[C:14]2[S:13][C:12]=1[C:10]([O:9][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)=[O:11])[NH:22][C:32]1[CH2:33][CH2:34][N:29]([CH3:28])[CH2:30][C:31]3=1
Reactant: CN1CCC(=O)CC1
Reactant: Cc1c(C(=O)OCc2ccccc2)sc2ccc(NN)cc12
Agent: Cl
Solvent: CC(=O)O
Product: Cc1c(C(=O)OCc2ccccc2)sc2ccc3[nH]c4c(c3c12)CN(C)CC4
Reaction time: 3 h

Procedure:
4.5 g of 5-hydrazino-3-methylbenzothiophene-2-carboxylic acid benzyl ester hydrochloride are suspended in a mixture of HCl and glacial acetic acid; after adding 3 ml of 1-methyl-4-piperidone, the reaction mixture is boiled for 3 hours. The solvent is then evaporated off and the residue is adjusted to pH 7.5, and worked up as described under Example 11. Melting point: 174° C.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][N:5]1[C:9](=[O:10])[C:8]2=[CH:11][CH:12]=[CH:13][CH:14]=[C:7]2[C:6]1=[O:15].C(=O)([O-])[O-].[K+].[K+].[OH:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[CH:33][C:32]([C:35]([O:37][CH2:38][CH3:39])=[O:36])=[CH:31][CH:30]=2)=[CH:25][C:24]=1[C:40]1[CH:49]=[CH:48][C:47]2[C:46]([CH3:51])([CH3:50])[CH2:45][CH2:44][C:43]([CH3:53])([CH3:52])[C:42]=2[CH:41]=1.O>CC(C)=O>[O:15]=[C:6]1[C:7]2[C:8](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9](=[O:10])[N:5]1[CH2:4][CH2:3][CH2:2][O:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:30]=[CH:31][C:32]([C:35]([O:37][CH2:38][CH3:39])=[O:36])=[CH:33][CH:34]=2)=[CH:25][C:24]=1[C:40]1[CH:49]=[CH:48][C:47]2[C:46]([CH3:51])([CH3:50])[CH2:45][CH2:44][C:43]([CH3:52])([CH3:53])[C:42]=2[CH:41]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Reactant: CCOC(=O)c1ccc(-c2ccc(O)c(-c3ccc4c(c3)C(C)(C)CCC4(C)C)c2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CCOC(=O)c1ccc(-c2ccc(OCCCN3C(=O)c4ccccc4C3=O)c(-c3ccc4c(c3)C(C)(C)CCC4(C)C)c2)cc1
Reaction time: 8 h
Yield: 61.1 %

Procedure:
600 mg (2.24 mmol) of N-(3-bromopropyl)phthalimide and 310 mg (2.24 mmol) of potassium carbonate are added to a solution of 800 mg (1.86 mmol) of ethyl 4′-hydroxy-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)biphenyl-4-carboxylate in 50 ml of acetone. The reaction mixture is stirred overnight at reflux. The reaction is stopped by adding water, and is then extracted with ethyl acetate. The organic phases are combined and dried over sodium sulfate. The solvents are evaporated off. The residue is precipitated from a small amount of ethyl acetate. It is filtered off and 700 mg of ethyl 4′-[3-(1,3-dioxo-1,3-dihydroisoindol-2-yl)propoxy]-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)biphenyl-4-carboxylate are obtained in the form of a white solid (yield=61%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][C:12]([OH:14])=O.[NH2:15][CH:16]1[C:29](=[O:30])[N:18]2[CH:19]([C:24]3[NH:28][N:27]=[N:26][N:25]=3)[C:20]([CH3:23])([CH3:22])[S:21][C@H:17]12.[K+].[Br-]>C(N(CC)CC)C>[NH2:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][C:12]([NH:15][CH:16]1[C:29](=[O:30])[N:18]2[CH:19]([C:24]3[NH:25][N:26]=[N:27][N:28]=3)[C:20]([CH3:22])([CH3:23])[S:21][C@H:17]12)=[O:14]
Reactant: CC1(C)S[C@@H]2C(N)C(=O)N2C1c1nnn[nH]1
Reactant: NCCOc1ccccc1CC(=O)O
Agent: [Br-]
Agent: [K+]
Solvent: CCN(CC)CC
Product: CC1(C)S[C@@H]2C(NC(=O)Cc3ccccc3OCCN)C(=O)N2C1c1nnn[nH]1
Yield: 64 %

Procedure:
The title compound is prepared in 64% yield from 2-(2-[2-aminoethoxy]phenyl)acetic acid (U.S. Pat No. 3,759,905) and 6-amino-2,2-dimethyl-3-(5-tetrazolyl)penam, by a procedure analogous to that of Example LXXXV. IR (KBr disc): 1780 cm-1 (β-lactam) and 1667 cm-1 (amide I). NMR (in D2O: 7.1 ppm (m,4H), 5.7 ppm (d,1H), 5.5 ppm (d,1H), 5.2 ppm (s,1H), 3.7-3.3 ppm (m,4H), 3.1 ppm (q,12H), 1.6 ppm (s,3H), 1.2 ppm (t,18H), 1.0 ppm (s,3H). The product is a 1:2 complex of the title compound and triethylamine.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[C:15]1([S:21]Cl)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C1(SSC2C=CC=CC=2)C=CC=CC=1>[Fe].C(Cl)(Cl)(Cl)Cl>[CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[S:11][C:12]([S:21][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: ClSc1ccccc1
Reactant: CC(C)c1ccc(-c2cccs2)cc1
Agent: [Fe]
Agent: c1ccc(SSc2ccccc2)cc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)c1ccc(-c2ccc(Sc3ccccc3)s2)cc1

Procedure:
Into 150 ml of reagent carbon tetrachloride were added 29 g (0.143 mole) 2-(p-isopropylphenyl)thiophene, 17 ml (21 g, 0.145 mole) of benzenesulfenyl chloride and 0.05 g of iron powder. At the end of four days a vapor phase chromatogram of the reaction mixture showed the presence of diphenyl disulfide, unreacted 2-(p-isopropylphenyl)thiophene and the desired product. An additional 4 ml (5 g, 0.035 mole) of benzenesulfenyl chloride and 0.05 g of iron powder was added and the mixture allowed to stand another four days at room temperature. Evaporation of the carbon tetrachloride gave a residue which was twice recrystallized from 250-ml portions of petroleum ether. There was obtained 16 g (36%) of 2-(p-isopropylphenyl)-5-(phenylthio)thiophene, m.p. 61°-63° C.
Reaction SMILES: C([O:8][C:9]1[CH:29]=[CH:28][C:12]([O:13][CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][N:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:18][CH2:17]2)=[CH:11][CH:10]=1)C1C=CC=CC=1.[ClH:30]>CCO>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([O:13][CH2:14][CH2:15][N:16]2[CH2:17][CH2:18][N:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:20][CH2:21]2)=[CH:28][CH:29]=1.[ClH:30]
Reactant: c1ccc(COc2ccc(OCCN3CCN(c4ccccc4)CC3)cc2)cc1
Agent: Cl
Solvent: CCO
Product: Oc1ccc(OCCN2CCN(c3ccccc3)CC2)cc1

Procedure:
35.75 g of 1-[2-(-4-benzyloxyphenoxy)ethyl]-4-phenylpiperazine was added rapidly with stirring to 75 ml concentrated HCl and the mixture was heated on a steam bath for 15 minutes. During this time starting material dissolved and then a white crystalline solid began to form and eventually the reaction mixture almost solidified. The reaction was cooled to ~5° and then was diluted with 100 ml EtOH. The solids were filtered off and were washed in EtOH and ether to give 1-[2-(4-hydroxyphenoxy)ethyl]-4-phenylpiperazine as its monohydrochloride. The salt was dissolved in 150 ml hot MeOH and 50 ml H2O and was then treated with 25 ml triethylamine. Water was then added to the refluxing mixture just to the cloud point whereupon the product began to crystallize from solution. The mixture was chilled and the solids were collected by filtration to give the end product, mp 142°-143°.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](OC)=[O:10])=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][OH:10])=[CH:4][CH:3]=1
Reactant: COC(=O)Cc1ccc(O)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCCc1ccc(O)cc1
Reaction time: 4 h
Yield: 44.1 %

Procedure:
A solution of methyl 2-(4-hydroxyphenyl)acetate (3.0 g, 18.07 mmol), in THF (20 mL) was added to a stirred suspension of LAH (0.89 g, 23.49 mmol) in THF (20 mL) at 0° C. The stirring was continued at RT for 4 h. Excess of LAH was quenched with saturated Na2SO4 solution and the precipitate formed was filtered off. The filtrated was extracted with ethyl acetate and the organic extract was washed with brine, dried (Na2SO4) and evaporated to dryness. Column purification with 50% ethyl acetate-pet ether yielded the title compound (1.1 g, 44%) as a white solid.
Reaction SMILES: [CH:1]1([N:6]2[C:11]3[N:12]=[C:13]([NH:17][CH2:18][CH3:19])[N:14]=[C:15]([CH3:16])[C:10]=3[CH:9]=[C:8]([CH2:20][CH2:21][C:22]([O:24]CC)=[O:23])[C:7]2=[O:27])[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Li+].Cl>C1COCC1.O>[CH:1]1([N:6]2[C:11]3[N:12]=[C:13]([NH:17][CH2:18][CH3:19])[N:14]=[C:15]([CH3:16])[C:10]=3[CH:9]=[C:8]([CH2:20][CH2:21][C:22]([OH:24])=[O:23])[C:7]2=[O:27])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CCNc1nc(C)c2cc(CCC(=O)OCC)c(=O)n(C3CCCC3)c2n1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCNc1nc(C)c2cc(CCC(=O)O)c(=O)n(C3CCCC3)c2n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 80.7 %

Procedure:
Ethyl 3-(8-cyclopentyl-2-(ethylamino)-4-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)propanoate (167 mg, 0.45 mmole) was dissolved in THF (5 ml) in a reaction vial equipped with a stir bar. Lithium hydroxide (35 mg, 1.46 mmole) was dissolved in water (5 ml) and then added to the reaction vial. The reaction mixture was stirred at ambient temperature for 3 h. The volatiles were removed under reduced pressure to a white solid residue. Aqueous hydrochloric acid (3.26 mmole, 3.26 ml of 1.0 M solution) was added. The white solid was collected by filtration as the title compound (125 mg, 81% yield).