Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.Br[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].[OH-].[Na+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[CH2:8]([N:3]1[CH:4]=[CH:5][N:6]=[C:2]1[CH3:1])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: Cc1ncc[nH]1
Reactant: CCCCCCCCCCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCCCCCCCCCn1ccnc1C
Temperature: 65 °C
Reaction time: 3 h

Procedure:
A mixture of 2-methylimidazole (12.3 g; 0.15 mol), 1-bromodecane (33.15 g; 0.15 mol), sodium hydroxide solution (69.5 ml. of 11.5M solution; 0.8 mol) and tetra-n-butylammonium bromide (1.95 g; 0.006 mol) in toluene (300 ml) was stirred rapidly for 3 hours at 65° C. After cooling to between 20° and 25° C., the toluene layer was separated and extracted with 5M HCl solution (150 ml). The extract was neutralised with sodium bicarbonate and extracted many times into hexane. The hexane solution was dried over magnesium sulphate and evaporated to dryness to give an oil (25 g; 75% theory).
Reaction SMILES: O.O.O.O.O.O.O.[Cl-].[Ce+3].[Cl-].[Cl-].[Si:12]([O:19][CH2:20][C@@H:21]1[CH:26]=[C:25]([C:27](=[O:31])[N:28]([CH3:30])[CH3:29])[C:24](=[O:32])[CH2:23][N:22]1[C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13].[BH4-].[Na+]>CO>[Si:12]([O:19][CH2:20][C@@H:21]1[CH:26]=[C:25]([C:27](=[O:31])[N:28]([CH3:29])[CH3:30])[C@H:24]([OH:32])[CH2:23][N:22]1[C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13]
Reactant: CN(C)C(=O)C1=C[C@@H](CO[Si](C)(C)C(C)(C)C)N(C(=O)OC(C)(C)C)CC1=O
Agent: [BH4-]
Agent: [Ce+3]
Agent: [Cl-]
Solvent: O
Solvent: CO
Product: CN(C)C(=O)C1=C[C@@H](CO[Si](C)(C)C(C)(C)C)N(C(=O)OC(C)(C)C)C[C@H]1O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 98.2 %

Procedure:
To a stirred solution of cerium(III) chloride heptahydrate (0.948 g, 2.54 mmol) and (S)-tert-butyl 2-((tert-butyldimethylsilyloxy)methyl)-4-(dimethylcarbamoyl)-5-oxo-5,6-dihydropyridine-1(2H)-carboxylate (Intermediate 134, 1.05 g, 2.54 mmol) in 1 mL MeOH at 0° C., sodium tetrahydroborate (0.096 g, 2.54 mmol) was added as a solid. The mixture was stirred at ambient temp for 15 minutes. The mixture was concentrated and diluted with NH4Cl (aq), H2O and ether. The ether layer was separated and washed with brine, dried over Na2SO4, filtered and concentrated to give the desired product (1.034 g, 98%) as a beige solid.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([O:12][CH3:13])[CH:8]=[CH:9][C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].[C:14]1(=O)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.C(O)(=O)C.Cl>CCCCCC>[C:1]([C:5]1[CH:6]=[C:7]([O:12][CH3:13])[CH:8]=[C:9]([C:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH:15]=2)[C:10]=1[OH:11])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C1CCCCC1
Reactant: COc1ccc(O)c(C(C)(C)C)c1
Agent: Cl
Solvent: CC(=O)O
Solvent: CCCCCC
Product: COc1cc(C2=CCCCC2)c(O)c(C(C)(C)C)c1
Temperature: 40 °C
Reaction time: 64 h
Yield: 29 %

Procedure:
A mixture consisting of 36.1 g (0.20 mol) of 3-tert-butyl-4-hydroxyanisol, 19.6 g (0.20 mol) of cyclohexanone and 10 ml of acetic acid is placed in a reactor and saturated, with stirring, with hydrochloric acid gas at room temperature. After standing for 64 hours at room temperature, the mixture is again saturated with hydrochloric acid gas and stirred for another 5 hours at 40° C. The reaction mixture is diluted with hexane and washed with water, sodium chloride solution and sodium hydrogencarbonate solution. The organic phase is dried over magnesium sulfate and concentrated on a rotary evaporator. The residue is chromatographed over silica gel using the solvent system ethyl acetate/hexane=1:49, giving 15.1 g (29%) of 2-tert-butyl-6-cyclohexen-1-yl-4-methoxyphenol as a yellowish thick oil, 1H--NMR (CDCl3), δ(ppm): 3.75 (s, 3H, OCH3), 5.87 (m, 1H, cyclohexenyl--H), (compound (111), Table 1).
Reaction SMILES: FC(F)(F)S(OC1C=CC2C(=CC([C:17]3[C:18]4[C:23]([C:24](C5C6C(=CC=CC=6)C=CC=5)=[C:25]5[C:30]=3[CH:29]=[CH:28][CH:27]=[CH:26]5)=[CH:22][CH:21]=[CH:20][CH:19]=4)=CC=2)C=1)(=O)=O.C1(C2C=CC(B(O)O)=CC=2)C2C(=CC=CC=2)C=CC=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C(O)C>C1(C)C=CC=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].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.CO.O>[CH:19]1[C:18]2[C:23](=[CH:24][C:25]3[C:30]([CH:17]=2)=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH:22]=[CH:21][CH:20]=1
Reactant: O=S(=O)(Oc1ccc2ccc(-c3c4ccccc4c(-c4cccc5ccccc45)c4ccccc34)cc2c1)C(F)(F)F
Agent: [Pd]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: CO
Solvent: CCO
Product: c1ccc2cc3ccccc3cc2c1
Temperature: 25 °C
Yield: 281.4 %

Procedure:
Under the nitrogen atmosphere, 7-(10-(naphthalen-1-yl) anthracen-9-yl)naphthalen-2-yl trifluoromethane sulfonate (3.0 g) as the fifth intermediate compound, (4-(naphthalen-1-yl)phenyl)boronic acid (1.9 g), bis(dibenzylideneacetone)palladium (0) (Pd(dba)2) (0.03 g), tricyclohexyl phosphine (0.03 g), potassium phosphate (2.2 g) and a mixture solvent (22 ml) of toluene, ethanol, and water (toluene/ethanol/water=9/1/1 (volume ratio)) were added to a flask and refluxed for 6.5 hours. Once the heating is completed, the reaction solution was cooled to room temperature and added with methanol. The precipitates were collected by suction filtration. The obtained solid was washed with water followed by methanol, and washed further with ethyl acetate. The obtained crude product was dissolved in toluene, and colored components were removed by passing through a silica gel short column. The solvent was distilled off under reduced pressure. The obtained oily phase substance was added with ethyl acetate and the precipitated products were collected by suction filtration to give 9-(naphthalen-1-yl)-10-(7-(naphthalen-1-yl)phenyl)naphthalen-2-yl)anthracene (2.6 g) as the target compound represented by Formula (1-21). The scheme is illustrated in the following “Reaction 9”.
Reaction SMILES: [NH2:1][C@H:2]([C:5]([OH:7])=[O:6])[CH2:3][SH:4].[CH3:8][C:9]1(C)O[C@]2(OC[C@@H]3OC(C)(C)O[C@@H]3C2=O)C[O:10]1>>[C:9]([NH:1][C@H:2]([C:5]([OH:7])=[O:6])[CH2:3][SH:4])(=[O:10])[CH3:8]
Reactant: N[C@@H](CS)C(=O)O
Reactant: CC1(C)O[C@H]2CO[C@@]3(COC(C)(C)O3)C(=O)[C@H]2O1
Product: CC(=O)N[C@@H](CS)C(=O)O

Procedure:
Cysteine is an amino acid with one chiral carbon atom. It exists as an L-enantiomer, a D-enantiomer or a racemic mixture of the L- and D-enantiomers. The L-enantiomer is the naturally occurring configuration.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[CH:9][C:10]([C:19]([O:21][CH2:22]C)=[O:20])=[N:11][C:12]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>OS(O)(=O)=O.CO.O>[C:1]1([C:7]2[CH:8]=[CH:9][C:10]([C:19]([O:21][CH3:22])=[O:20])=[N:11][C:12]=2[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)c1ccc(-c2ccccc2)c(-c2ccccc2)n1
Agent: O=S(=O)(O)O
Solvent: CO
Solvent: O
Product: COC(=O)c1ccc(-c2ccccc2)c(-c2ccccc2)n1

Procedure:
General Procedure E. A solution of ethyl 5,6-diphenylpyridine-2-carboxylate (Compound 21, 30 mg, 0.1 mmol) and conc. H2SO4 (3 drops) in MeOH (5 ml) was heated at 50° C. overnight. The mixture was diluted with water, and the products were extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over Na2SO4. The filtered solvent was concentrated in vacuo and the residue was purified by column chromatography (20% ethyl acetate in hexane) to obtain the title compound as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[CH:5]=[CH:4][C:3]=1C(O)=O.[OH-].[Na+].S(S([O-])=O)([O-])=O.[Na+].[Na+]>O>[NH2:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Nc1c(C(=O)O)ccc2c1C(=O)c1ccccc1C2=O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Nc1cccc2c1C(=O)c1ccccc1C2=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 78 %

Procedure:
The wet cake of 1-aminoanthraquinone-2-carboxylic acid was dissolved in 2000 ml. of water and 50 ml. of 10 M sodium hydroxide solution. The mixture was heated on a steam bath to 90°-100° C. and 40 g (0.23 mole) sodium hydrosulfite was added. Heating was continued with stirring for 2 hours, after which the mixture was cooled to room temperature. The resulting red solid was collected by filtration and washed with water until the filtrate was neutral. The solid was dried at 80° C. to give 19.5 g (78% yield) of 1-aminoanthraquinone. The Thin Layer Chromatogram of the crude product showed the presence of less than 5% of impurity.
Reaction SMILES: Cl[C:2]1[C:7]2[CH:8]=[CH:9][S:10][C:6]=2[CH:5]=[C:4]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[N:3]=1.[CH2:19]([N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)[CH3:20]>>[CH2:19]([N:21]1[CH2:26][CH2:25][N:24]([C:2]2[C:7]3[CH:8]=[CH:9][S:10][C:6]=3[CH:5]=[C:4]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)[N:3]=2)[CH2:23][CH2:22]1)[CH3:20]
Reactant: CCN1CCNCC1
Reactant: COc1ccc(-c2cc3sccc3c(Cl)n2)cc1
Product: CCN1CCN(c2nc(-c3ccc(OC)cc3)cc3sccc23)CC1
Temperature: 130 °C
Yield: 61.5 %

Procedure:
A mixture of 4-chloro-6-(4-methoxyphenyl)thieno[3,2-c]pyridine (6.6 g) and N-ethylpiperazine (30 ml) was heated at 130° C. for 2 hr. The reaction mixture was evaporated, and to the resulting residue were added potassium carbonate and water. The resulting mixture was extracted with ethyl acetate, and the resulting organic layer was washed with water and brine, and dried over magnesium sulfate. The solvent was removed, and the resulting residue was purified by silica gel column chromatography (methylene chloride/methanol system), to give the title compound as a pale brown oil (5.2 g, yield; 61.5%).
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][C:3]=1[O:4][CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][O:7]1>CCOC(C)=O.[Pd]>[Cl:1][C:2]1[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][C:3]=1[O:4][CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][O:7]1
Reactant: O=[N+]([O-])c1ccc(Cl)c(OCC2CCCO2)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Nc1ccc(Cl)c(OCC2CCCO2)c1
Reaction time: 7 h

Procedure:
A solution of 2-(2-chloro-5-nitro-phenoxymethyl)-tetrahydrofuran (0.45 g, 1.75 mmol) in EtOAc (10 mL) was degassed with argon then charged with 10% by weight Pd/C (0.4 g). The mixture was stirred for 7 h under an H2 atmosphere, filtered through Celite® and concentrated in vacuo. A mixture contained the title compound along with starting material in a 7:3 ratio. MS: (MH+)=227.1; Calc'd 227.69 for C11H15ClNO2.
Reaction SMILES: [Li].[Br:2][C:3]1[CH:4]=[C:5]([C:14]([O-])=[CH:15][C:16](=O)[C:17]([O:19]CC)=[O:18])[CH:6]=[C:7]([O:9][C:10]([F:13])([F:12])[F:11])[CH:8]=1.ClC1C=C(C2[N:36]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][N:38]=3)[N:35]=C(C(O)=O)C=2)C=C(F)C=1.Cl.N1C=CC=CC=1NN>>[Br:2][C:3]1[CH:4]=[C:5]([C:14]2[N:36]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][N:38]=3)[N:35]=[C:16]([C:17]([OH:19])=[O:18])[CH:15]=2)[CH:6]=[C:7]([O:9][C:10]([F:11])([F:12])[F:13])[CH:8]=1
Reactant: O=C(O)c1cc(-c2cc(F)cc(Cl)c2)n(-c2ccccn2)n1
Reactant: CCOC(=O)C(=O)C=C([O-])c1cc(Br)cc(OC(F)(F)F)c1
Agent: Cl
Agent: NNc1ccccn1
Agent: [Li]
Product: O=C(O)c1cc(-c2cc(Br)cc(OC(F)(F)F)c2)n(-c2ccccn2)n1

Procedure:
1.10 g (2.40 mmol) of the compound of Example 5A is reacted analogously to the synthesis of the compound of Example 20A with 525 mg (3.61 mmol) of 2-pyridylhydrazine hydrochloride. After hydrolysis, 557 mg (54% of theory) of the title compound is obtained.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.C([Si]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([S:34][CH:35]2[CH2:39][CH2:38][CH2:37][CH2:36]2)[CH:29]=1)(C)C)(C)(C)C>C1COCC1>[CH:35]1([S:34][C:30]2[CH:29]=[C:28]([CH2:27][OH:26])[CH:33]=[CH:32][CH:31]=2)[CH2:39][CH2:38][CH2:37][CH2:36]1
Reactant: CC(C)(C)[Si](C)(C)OCc1cccc(SC2CCCC2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: OCc1cccc(SC2CCCC2)c1
Reaction time: 18 h
Yield: 92.3 %

Procedure:
A solution of tetrabutylammonium fluoride in THF (1 M, 6 ml) was added to a solution of tert-butyl{[3-(cyclopentylthio)benzyl]oxy}dimethylsilane (1.09 g) in dry THF (10 ml). The solution was stirred for 18 h under nitrogen and the solvent was evaporated in vacuo. The residue was partitioned between dichloromethane and water. The organic phase was separated and washed with water. The organic phase was separated and the solvent evaporated in vacuo. The residue was purified on a 10 g silica SPE cartridge, eluting with a stepped gradient of 10% to 100% dichloromethane-cyclohexane to give the title compound (0.65 g). LCMS RT=3.3 min
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[OH:12])([CH3:3])[CH3:2].[C:13]1([CH3:23])[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1.O>C(Cl)Cl>[CH:1]([C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[O:12][S:19]([C:16]1[CH:17]=[CH:18][C:13]([CH3:23])=[CH:14][CH:15]=1)(=[O:21])=[O:20])([CH3:3])[CH3:2]
Reactant: COc1ccc(O)c(C(C)C)c1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: O
Product: COc1ccc(OS(=O)(=O)c2ccc(C)cc2)c(C(C)C)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 74.5 %

Procedure:
To a solution of 2-isopropyl-4-methoxy-phenol (56.91 g, 342 mmol) triethylamine (57.3.0 ml, 411 mmol) in 750 ml CH2Cl2 was cooled to 0° C. p-Toluenesulfonyl chloride (68.54 g, 360 mmol) in 250 ml CH2Cl2 was added drop-wise at a rate that maintained the internal temperature <10° C. The mixture was allowed to warm to rt. After 16 h, H2O was added and the mixture was extracted with CH2Cl2. The combined organics were washed with brine, dried with Na2SO4, filtered and concentrated in vacuo to afford a crude solid. Recrystallization from hexanes afforded toluene-4-sulfonic acid 2-isopropyl-4-methoxy-phenyl ester (81.67 g, 74%) as white needles.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][O:7][C:8]2[CH:20]=[CH:19][C:11]([C:12]([NH:14][CH2:15][CH:16]3[CH2:18][CH2:17]3)=[O:13])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[H-].[Na+].CI.[C:27](OCC)(=O)C.O>CN(C)C=O>[Cl:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][O:7][C:8]2[CH:20]=[CH:19][C:11]([C:12]([N:14]([CH2:15][CH:16]3[CH2:17][CH2:18]3)[CH3:27])=[O:13])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: CCOC(C)=O
Reactant: O=C(NCC1CC1)c1ccc(OCc2ccc(Cl)cc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: O
Product: CN(CC1CC1)C(=O)c1ccc(OCc2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In 30 ml of N,N-dimethylformamide was dissolved 1.5 g of 4-(4-chlorobenzyloxy)-N-cyclopropylmethylbenzamide. To the solution was added 0.25 g of sodium hydride. The mixture was stirred at room temperature for 30 minutes and then at 60° C. for 30 minutes. The reaction mixture was ice-cooled, and 0.5 ml of methyl iodide was added thereto. The mixture was stirred overnight at room temperature. The reaction mixture was treated with ethyl acetate-water. The resulting ethyl acetate layer was separated, washed with water, dried with anhydrous magnesium sulfate, and subjected to distillation to remove the solvent. The resulting residue was purified by column chromatography (eluant: dichloromethane/acetone=50/1) to obtain 1.4 g of 4-(4-chlorobenzyloxy)-N-cyclopropylmethyl-N-methylbenzamide.
Reaction SMILES: Cl[C:2]1[C:3](F)=[CH:4][C:5](F)=[C:6]([CH:14]=1)[C:7](NS(C)(=O)=O)=[O:8].[Cl:17][C:18]1[C:19](F)=[CH:20][C:21]([F:33])=[C:22]([CH:32]=1)[C:23]([NH:25][S:26](=[O:31])(=[O:30])[N:27]([CH3:29])[CH3:28])=[O:24].C12(CO)CC3CC(CC(C3)C1)C2.C1(CO)CCCCC1>>[Cl:17][C:18]1[C:19]([O:8][CH2:7][CH:6]2[CH2:14][CH2:2][CH2:3][CH2:4][CH2:5]2)=[CH:20][C:21]([F:33])=[C:22]([CH:32]=1)[C:23]([NH:25][S:26](=[O:31])(=[O:30])[N:27]([CH3:29])[CH3:28])=[O:24]
Reactant: CS(=O)(=O)NC(=O)c1cc(Cl)c(F)cc1F
Reactant: CN(C)S(=O)(=O)NC(=O)c1cc(Cl)c(F)cc1F
Agent: OCC12CC3CC(CC(C3)C1)C2
Agent: OCC1CCCCC1
Product: CN(C)S(=O)(=O)NC(=O)c1cc(Cl)c(OCC2CCCCC2)cc1F

Procedure:
Following the procedure as described in Example 8 and making variations as required to replace 5-chloro-2,4-difluoro-N-(methylsulfonyl)benzamide with 5-chloro-N—(N,N-dimethylsulfamoyl)-2,4-difluorobenzamide and adamantan-1-ylmethanol with cyclohexylmethanol, the title compound was obtained as a colorless solid (0.11 g, 28%): 1H NMR (300 MHz, DMSO-d6) δ 11.77 (s, 1H), 7.72 (d, J=7.6 Hz, 1H), 7.23 (d, J=12.4 Hz, 1H), 3.96 (d, J=5.8 Hz, 2H), 2.87 (s, 6H), 1.84-1.62 (m, 6H), 1.30-1.04 (m, 5H); MS (ES−) m/z 391.1, 393.1 (M−1).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@:13]([CH2:22][CH2:23][CH2:24][OH:25])([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[O:12][C:11]2=[O:26])[CH3:9])=[CH:4][CH:3]=1.Br[C:28]1[CH:33]=[CH:32][N:31]=[C:30]([OH:34])[CH:29]=1>>[OH:25][CH2:24][CH2:23][CH2:22][C@@:13]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[O:12][C:11](=[O:26])[N:10]([C@H:8]([C:5]2[CH:6]=[CH:7][C:2]([C:28]3[CH:33]=[CH:32][N:31]=[C:30]([OH:34])[CH:29]=3)=[CH:3][CH:4]=2)[CH3:9])[CH2:15][CH2:14]1
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CCCO)(c2ccccc2)OC1=O
Reactant: Oc1cc(Br)ccn1
Product: C[C@@H](c1ccc(-c2ccnc(O)c2)cc1)N1CC[C@](CCCO)(c2ccccc2)OC1=O

Procedure:
The title compound was prepared from (R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(3-hydroxypropyl)-6-phenyl-1,3-oxazinan-2-one following procedures analogous to those described in Example 313 Steps 3 and 4 using 4-bromo-2-hydroxypyridine in Step 4. LC-MS Method 2 tR=1.019, m/z=865.4; 1H NMR (CDCl3) 1.29-1.40 (m, 1H), 1.49 (d, 3H), 1.60-1.72 (m, 1H), 1.83-2.01 (m, 3H), 2.18 (m, 1H), 2.21-2.37 (m, 2H), 2.88 (m, 1H), 3.51 (m, 2H), 5.63 (m, 1H), 6.41 (d, 1H), 6.68 (s, 1H), 6.90 (d, 2H), 7.21-7.33 (m, 7H), 7.39 (d, 1H).
Reaction SMILES: COC1C=CC(CC(Cl)=O)=CC=1.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21]=[C:22]=[C:23]([CH3:29])[C:24]([O:26]CC)=[O:25])=[CH:17][CH:16]=1>>[CH3:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([CH:21]=[C:22]=[C:23]([CH3:29])[C:24]([OH:26])=[O:25])=[CH:19][CH:20]=1
Reactant: CCOC(=O)C(C)=C=Cc1ccc(OC)cc1
Agent: COc1ccc(CC(=O)Cl)cc1
Product: COc1ccc(C=C=C(C)C(=O)O)cc1

Procedure:
Repeating the procedure of Example 1 but replacing the p-thiomethylphenyl acetyl chloride with an equivalent amount of p-methoxyphenyl acetyl chloride, there is similarly obtained ethyl 4-(p-methoxyphenyl)-2-methyl-buta-2,3-dienoate, which when treated according to the procedure of Example 2, yields 4-(p-methoxyphenyl)-2-methyl-buta-2,3-dienoic acid (m.p. 105° - 108°, from ether/pentane).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[C:13]2[NH:15][C:16](=[O:38])[C:17]3([CH:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=4[F:29])[CH:20]([C:30]([OH:32])=O)[NH:19][CH:18]3[CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:12]2=[CH:11][CH:10]=1.C(N(C(C)C)CC)(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[NH2:63][C:64]1[CH:69]=[CH:68][C:67]([CH2:70][CH2:71][C:72]([O:74][CH3:75])=[O:73])=[CH:66][CH:65]=1>>[CH3:75][O:74][C:72](=[O:73])[CH2:71][CH2:70][C:67]1[CH:68]=[CH:69][C:64]([NH:63][C:30]([C@@H:20]2[NH:19][C@@H:18]([CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C@:17]3([C:12]4[C:13](=[CH:14][C:9]([Cl:8])=[CH:10][CH:11]=4)[NH:15][C:16]3=[O:38])[C@H:21]2[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=2[F:29])=[O:32])=[CH:65][CH:66]=1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Reactant: COC(=O)CCc1ccc(N)cc1
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)CCc1ccc(NC(=O)[C@@H]2N[C@@H](CC(C)(C)C)[C@@]3(C(=O)Nc4cc(Cl)ccc43)[C@H]2c2cccc(Cl)c2F)cc1
Yield: 99.6 %

Procedure:
In a manner similar to the method described in Example 5, rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid trifluoroacetic acid prepared in Example 4 (100 mg, 0.173 mmol), was reacted with diisopropylethylamine (112 mg, 0.863 mmol), diphenylphosphinic chloride (106 mg, 0.446 mmol), then reacted with methyl 3-(4-aminophenyl)propanoate (31 mg, 0.173 mmol) to give rac-3-(4-{[(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carbonyl]amino}-phenyl)-propionic acid methyl ester (108 mg, 56%). MS (ES+) m/z [(M+H)+]: 626
Reaction SMILES: [CH2:1]([C:5]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([CH2:10][CH2:11][CH2:12][CH3:13])[C:6]([O:8]C)=[O:7])[CH2:2][CH2:3][CH3:4].C1(C(CCC)(CCC)C(OC)=O)C=CC=CC=1>>[CH2:1]([C:5]([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)([CH2:10][CH2:11][CH2:12][CH3:13])[C:6]([OH:8])=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC(CCCC)(C(=O)OC)c1ccccc1
Agent: CCCC(CCC)(C(=O)OC)c1ccccc1
Product: CCCCC(CCCC)(C(=O)O)c1ccccc1
Yield: 98 %

Procedure:
The title compound (7.05 g, 98%) was prepared following the procedure of Example 1C, substituting the product of Example 4B for the product of Example 1B. 1H NMR (300MHz, CDCl3): δ 7.28 (m, 5 H), 2.01 (m, 4 H), 1.28 (m, 4 H), 1.09 (m, 4 H), 0.87 (t, J=7.35 Hz, 6 H).
Reaction SMILES: I[C:2]1[CH:3]=[C:4](I)[C:5]2[S:9][C:8]([NH:10][C:11]([NH:13][CH2:14][CH3:15])=[O:12])=[N:7][C:6]=2[CH:16]=1.C([Sn](CCCC)(CCCC)[C:23]1[CH:28]=[N:27][CH:26]=[CH:25][N:24]=1)CCC>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N:24]1[CH:25]=[CH:26][N:27]=[CH:28][C:23]=1[C:2]1[CH:3]=[C:4]([C:28]2[CH:23]=[N:24][CH:25]=[CH:26][N:27]=2)[C:5]2[S:9][C:8]([NH:10][C:11]([NH:13][CH2:14][CH3:15])=[O:12])=[N:7][C:6]=2[CH:16]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnccn1
Reactant: CCNC(=O)Nc1nc2cc(I)cc(I)c2s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CCNC(=O)Nc1nc2cc(-c3cnccn3)cc(-c3cnccn3)c2s1
Temperature: 120 °C

Procedure:
To a solution of 1-(5,7-diiodo-benzothiazol-2-yl)-3-ethyl-urea (0.50 g, 1.0 mmol) in DMF (5.0 mL) was added 2-tributylstannyl-pyrazine (0.78 g, 2.0 mmol) under nitrogen atmosphere at room temperature. The reaction mixture was degassed for half an hour followed by the addition of tetrakis(triphenylphosphine)palladium(0) (0.18 g, 0.10 mmol). The reaction mixture was again degassed for half an hour and then heated at 120° C. for 2 h under nitrogen atmosphere. After the completion of the reaction (TLC monitoring), DMF was distilled off, added water and extracted with ethyl acetate (×3). The combined organic layer was dried over anhydrous Na2SO4, and evaporated to dryness under reduced pressure. The compound was purified by chromatography on silica (230-400 M) using ethyl acetate/Methanol) (95:5) to provide the title compound as off white solid (0.025 g, 6.5%).
Reaction SMILES: [H-].[Na+].[CH3:3][OH:4].Br[C:6]1[CH:7]=[C:8]([CH:11]=[C:12]([O:15][CH2:16][CH3:17])[C:13]=1[OH:14])[CH:9]=[O:10]>C1COCC1.CN(C)C=O.C(OCC)(=O)C.[Cu]Cl>[CH2:16]([O:15][C:12]1[CH:11]=[C:8]([CH:7]=[C:6]([O:4][CH3:3])[C:13]=1[OH:14])[CH:9]=[O:10])[CH3:17]
Reactant: CCOc1cc(C=O)cc(Br)c1O
Reactant: CO
Agent: Cl[Cu]
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCOc1cc(C=O)cc(OC)c1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 61 %

Procedure:
To a suspension of sodium hydride (843 mg) in THF (5 mL) was added methanol (675 mg) under ice-cooling, and the mixture was stirred at room temperature for 0.5 hour. 3-Bromo-5-ethoxy-4-hydroxybenzaldehyde (1.29 g) in dimethylformamide (10 mL), and copper(I) chloride (31 mg) were added thereto, and the mixture was stirred at 120° C. for 4 hours under heating. The mixture was allowed to stand for cooling down to room temperature, diluted with ethyl acetate, washed with 1N hydrochloric acid, dried over anhydrous sodium sulfate, and then concentrated. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=2:1, v/v) to give the title compound (630 mg).