Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[Cl-].[Al+3].[Cl-].[Cl-].[CH2:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][CH:10]1[NH:18][C:19](=[O:24])[C:20]([F:23])([F:22])[F:21].Cl.C(OC(C)C)(=O)C>CCCCCCC>[C:1]([C:15]1[CH:16]=[C:17]2[C:12](=[CH:13][CH:14]=1)[CH2:11][CH:10]([NH:18][C:19](=[O:24])[C:20]([F:21])([F:23])[F:22])[CH2:9]2)(=[O:3])[CH3:2]
Reactant: O=C(NC1Cc2ccccc2C1)C(F)(F)F
Reactant: CC(=O)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCCCCCC
Solvent: CC(=O)OC(C)C
Product: CC(=O)c1ccc2c(c1)CC(NC(=O)C(F)(F)F)C2
Temperature: 2.5 °C
Reaction time: 0.25 h
Yield: 89.7 %

Procedure:
A 1 L, 3-necked, round-bottomed flask, equipped with a mechanical stirrer, digital thermometer, cooling bath, and nitrogen inlet-outlet, was charged with acetyl chloride (205.5 g, 2.62 mole) and cooled to 0-5° C. Aluminum chloride was added in portions (4×36.4 g [145.5 g, 1.09 mole]) at 0-5° C., while maintaining the internal temperature below 15° C. The slurry was cooled to 0-5° C. and stirred for 15 minutes. N-(2,3-dihydro-1H-inden-2-yl)-2,2,2-trifluoroacetamide (5×20 g, 0.436 mole) was added in portions over 40 minutes at 10-minute intervals, while maintaining temperature at 0-10° C. The resulting tan solution was stirred at 0-5° C. for 1 hour. To the solution was added 400 mL of heptane, while maintaining the temperature at 0-5° C. The resulting bi-phasic mixture was added to a 0° C. to −5° C. mixture of 1 N HCl (650 mL) and isopropyl acetate (125 mL) in a 5 L, 3-necked, round-bottomed flask, equipped with a mechanical stirrer, digital thermometer, and a cooling bath, while maintaining the internal temperature at 0-25° C. over a period of 20 minutes. The 5 L, round-bottomed flask was rinsed with acetyl chloride (20 mL), followed by heptane (110 mL) and added to the batch. The reaction mixture was warmed to 22-24° C. over a period of 30 minutes and then heated to 40-45° C. and stirred at 40-45° C. for 1 hour. The slurry was cooled to 21-25° C. and stirred for 1 hour. The solids were collected by filtration using a Büchner funnel with suction over a polypropylene filter paper. The filter cake was washed with heptane (2×200 mL) followed by 1 N HCl (350 mL), and deionized water (2×200 mL). The solids were dried at 60-65° C. under vacuum (10-30 torr) with nitrogen bleeding to obtain 106.1 g (yield 90%) of N-(5-acetyl-2,3-dihydro-1H-inden-2-yl)-2,2,2-trifluoroacetamide (m.p. 113-115° C.).
Reaction SMILES: [F:1][C:2]1[C:3]([CH2:14][N:15]([CH3:23])[C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:4][NH:5][C:6]=1[C:7]1[C:8]([F:13])=[N:9][CH:10]=[CH:11][CH:12]=1.[H-].[Na+].C1OCCOCCOCCOCCOC1.[N:41]1([S:47](Cl)(=[O:49])=[O:48])[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]1>O1CCCC1.O>[F:1][C:2]1[C:3]([CH2:14][N:15]([CH3:23])[C:16](=[O:22])[O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[CH:4][N:5]([S:47]([N:41]2[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]2)(=[O:49])=[O:48])[C:6]=1[C:7]1[C:8]([F:13])=[N:9][CH:10]=[CH:11][CH:12]=1
Reactant: O=S(=O)(Cl)N1CCCCC1
Reactant: CN(Cc1c[nH]c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CN(Cc1cn(S(=O)(=O)N2CCCCC2)c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Reaction time: 0.25 h
Yield: 44.5 %

Procedure:
To a solution of tert-butyl {[4-fluoro-5-(2-fluoropyridin-3-yl)-1H-pyrrol-3-yl]methyl}methylcarbamate (324 mg) in tetrahydrofuran (20 mL) was added sodium hydride (60% in oil, 121 mg) at room temperature and the mixture was stirred for 15 min. 15-Crown-5 (664 mg) was added dropwise, and the mixture was stirred for 5 min. Piperidine-1-sulfonyl chloride (240 mg) was added, and the mixture was further stirred for 3 hr. The reaction mixture was diluted with water, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=1:4→1:1) to give the title compound as a colorless oil (yield 210 mg, 45%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=O)[CH:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)Cl)=[CH:5][CH:4]=1.[NH2:21][C:22]([NH2:27])=[N:23][C:24]([NH2:26])=[S:25].O>C(O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:26]=[C:24]([NH:23][C:22]([NH2:27])=[NH:21])[S:25][C:10]=2[C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)=[CH:5][CH:4]=1
Reactant: NC(=S)N=C(N)N
Reactant: COc1ccc(C(=O)C(Cl)c2ccc(OC)cc2)cc1
Solvent: CCO
Solvent: O
Product: COc1ccc(-c2nc(NC(=N)N)sc2-c2ccc(OC)cc2)cc1
Temperature: 25 °C
Yield: 53.3 %

Procedure:
A mixture of 1,2-bis(4-methoxyphenyl)-2-chloroethanone (1.00 g) and N-diaminomethylenethiourea (0.65 g) in ethanol (20 ml) was refluxed for 12 hours. After allowing to cool to ambient temperature, then the reaction mixture was poured into water and extracted with ethyl acetate. The separated organic layer was washed with water and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was chromatographed n alumina, eluting with a mixture of chloroform and methanol. The desired fractions were combined and concentrated in vacuo. The residue was washed with isopropy ether to give 4,5-bis(4methoxyphenyl)-2-guanidinothiazole (0.65 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N:7][C:6]([NH:12][C:13](=[O:35])[O:14][CH2:15][C@@H:16]([N:21]([CH3:34])[C:22]([NH:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[C:27]=1[Cl:33])=[O:23])[CH2:17][CH2:18][CH2:19][NH2:20])=[CH:5]2.[C:36]([O:40][C:41]([NH:43][CH2:44][C:45](O)=[O:46])=[O:42])([CH3:39])([CH3:38])[CH3:37].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[C:36]([O:40][C:41]([NH:43][CH2:44][C:45]([NH:20][CH2:19][CH2:18][CH2:17][C@H:16]([N:21]([CH3:34])[C:22]([NH:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[C:27]=1[Cl:33])=[O:23])[CH2:15][O:14][C:13](=[O:35])[NH:12][C:6]1[N:7]=[CH:8][C:9]2[C:4]([CH:5]=1)=[CH:3][C:2]([F:1])=[CH:11][CH:10]=2)=[O:46])=[O:42])([CH3:39])([CH3:38])[CH3:37]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: CN(C(=O)NCc1cccc(F)c1Cl)[C@@H](CCCN)COC(=O)Nc1cc2cc(F)ccc2cn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(C(=O)NCc1cccc(F)c1Cl)[C@@H](CCCNC(=O)CNC(=O)OC(C)(C)C)COC(=O)Nc1cc2cc(F)ccc2cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83.3 %

Procedure:
To a solution of (S)-5-amino-2-(3-(2-chloro-3-fluorobenzyl)-1-methylureido)pentyl 6-fluoroisoquinolin-3-ylcarbamate (96 mg, 0.19 mmol), 2-(tert-butoxycarbonylamino)acetic acid (51 mg, 0.29 mmol) and HBTU (110 mg, 0.29 mmol) in DMF (1.0 mL) was added DIEA (63 □L, 0.38 mmol). The mixture was stirred at RT for 30 min. The mixture was filtered and the filtrate was purified by RP-HPLC using a mixture of acetonitrile and water to give (6-Fluoro-isoquinolin-3-yl)-carbamic acid (S)-5-(2-tert-butoxycarbonylamino-acetylamino)-2-[3-(2-chloro-3-fluoro-benzyl)-1-methyl-ureido]-pentyl ester (105 mg, 83%). LRMS (M+Na+) m/z 663.2.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][C@H:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([Br:17])[CH:14]=2)[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:21](Br)[CH2:22][CH3:23]>CN(C)C=O>[C:1]([O:5][C:6](=[O:18])[N:7]([C@H:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([Br:17])[CH:14]=2)[CH2:9]1)[CH2:21][CH2:22][CH3:23])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCCBr
Reactant: CC(C)(C)OC(=O)N[C@@H]1Cc2ccc(Br)cc2C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCN(C(=O)OC(C)(C)C)[C@@H]1Cc2ccc(Br)cc2C1
Yield: 110.7 %

Procedure:
3 g of ((R)-5-Bromo-indan-2-yl)-carbamic acid tert-butyl ester (9.61 mmol) were dissolved in 20 ml of dimethylformamide and 0.442 g of sodium hydride (60% in mineral oil) (11.05 mmol) added. Stirring continued for 14 minutes before 1.3 g of propylbromide (10.57 mmol) were added. The reaction mixture was stirred at room temperature for 15 h and at 40° C. for 3 h. An additional equivalent of sodium hydride and 0.7 ml propylbromide were added followed by stirring for 2 h at 40° C. and 15 h at room temperature. The solvent was evaporated under reduced pressure, the residue treated with water and extracted three times with diethyl ether. The combined organic layers were washed once with water, dried over magnesium sulfate, filtered, and the solvent evaporated under reduced pressure to yield 3.77 g of crude product which was used in the subsequent reaction without further purification.
Reaction SMILES: [CH:1]1([C:14]2([C:18]([OH:20])=[O:19])[CH2:17][CH2:16][CH2:15]2)[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH2:4][CH2:3][NH:2]1.[C:21](Cl)(=[O:23])[CH3:22]>>[C:21]([N:2]1[CH2:3][CH2:4][C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[NH:12][C:13]=2[CH:1]1[C:14]1([C:18]([OH:20])=[O:19])[CH2:15][CH2:16][CH2:17]1)(=[O:23])[CH3:22]
Reactant: CC(=O)Cl
Reactant: O=C(O)C1(C2NCCc3c2[nH]c2ccccc32)CCC1
Product: CC(=O)N1CCc2c([nH]c3ccccc23)C1C1(C(=O)O)CCC1

Procedure:
The procedure is as in Example 55, using as substrate the compound of Example 35 and as reagent acetyl chloride.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].C(N(C(C)C)C(C)C)C.[CH3:19][O:20][CH2:21]Cl>ClCCl>[CH3:19][O:20][CH2:21][O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6]
Reactant: COCCl
Reactant: O=Cc1cccc(O)c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCOc1cccc(C=O)c1
Reaction time: 1 h

Procedure:
A solution of 100 g of 3-hydroxybenzaldehyde and 214 ml of N-ethyldiisopropylamine in 800 ml of dichloromethane was ice-cooled and a solution of 68.4 ml of chloromethyl methyl ether in 200 ml of dichloromethane was added dropwise. After stirring for one hour, an ice bath was removed and the mixture was continuously stirred at room temperature overnight. The reaction solution was washed in turn with an aqueous 10% sodium hydroxide solution and 10% citric acid and dried over magnesium sulfate, and then the solvent was evaporated under reduced pressure. The residue was distilled off under reduced pressure to obtain 81.3 g of the desired compound as a colorless oily substance. Boiling point: 125 to 127° C./10 mmHg
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:4])([CH3:3])[CH3:2].[Br:17]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[C:12]([C:7]1[CH:8]=[C:9]([CH2:11][Br:17])[CH:10]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:6]=1[OH:16])([CH3:15])([CH3:14])[CH3:13]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)c1cc(CBr)cc(C(C)(C)C)c1O
Reaction time: 1.5 h

Procedure:
A mixture of 1 g of 2,6-di-t-butyl-4-methyl phenol, 0.9 g of N-bromosuccinimide and 40 ml of carbon tetrachloride was boiled for 1.5 hours. Succinimide was removed by filtration, and the resulting organic solution was evaporated to give a viscous liquid with the following 1H NMR spectrum (CDCl3, ppm from TMS): 7.05 ppm (s, ArH, 2), 5,15 ppm (s, OH, 1), 4.35 ppm (s, CH2Br, 2) and 1.3 ppm (s, CH3, 18).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[OH:9])#[N:2].Br[CH2:11][CH2:12][CH2:13][Cl:14].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.C(Cl)(Cl)Cl>[Cl:14][CH2:13][CH2:12][CH2:11][O:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[C:1]#[N:2]
Reactant: ClCCCBr
Reactant: N#Cc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CC(C)=O
Product: N#Cc1ccccc1OCCCCl
Yield: 97.5 %

Procedure:
A mixture of 2-cyanophenol (50.0 g, 0.42 mole), 1-bromo-3-chloropropane (67.7 g, 0.43 mole), and potassium carbonate (58.0 g, 0.42 mole) was heated overnight at gentle reflux in 500 ml of acetone. The reaction mixture was stripped to dryness and the residue was dissolved in chloroform. The chloroform layer was extracted several times with 5% sodium hydroxide. The chloroform layer was dried (anhydrous sodium sulfate), filtered, and the solvent was removed, to give a brown oil (80.09 g). A ten gram portion of this oil was subjected to flash chromatography on silica gel with 10% ethyl acetate-hexanes and 20% ethyl acetate-hexanes used for elution. Fractions were combined and solvent removed in vacuo. The clear oil obtained was dried 18 hrs in vacuo at room temperature and 8 hrs at 80° C. in vacuo. This furnished 5.24 g (50.0% yield--based on aliquot taken) of clear oil. 1H HMR (CDCl3); δ 2.1-2.5 (q, 2, --CH2), 3.8 (t, 2, --ClCH2), 4.2 (t, 2, --OCH2), 6.9 (m, 2, aromatic protons ortho and para to ether), 7.5 (m, 2, aromatic protons ortho and para to CN group).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].C(OC(=O)CC)(=O)CC.C([O:20][C@H:21]1[C@H:25]([O:26][C:27](=[O:29])[CH3:28])[C@@H:24]([CH2:30][O:31][Si](C(C)(C)C)(C)C)[O:23][C@H:22]1[N:39]1[CH:47]=[N:46][C:45]2[C:40]1=[N:41][CH:42]=[N:43][C:44]=2[NH2:48])(=O)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.N1C=CC=CC=1>[C:27]([O:26][C@@H:25]1[C@@H:24]([CH2:30][O:31][C:1](=[O:3])[CH3:2])[O:23][C@@H:22]([N:39]2[CH:47]=[N:46][C:45]3[C:40]2=[N:41][CH:42]=[N:43][C:44]=3[NH2:48])[C@H:21]1[OH:20])(=[O:29])[CH3:28]
Reactant: CC(=O)O[C@H]1[C@H](OC(C)=O)[C@@H](CO[Si](C)(C)C(C)(C)C)O[C@H]1n1cnc2c(N)ncnc21
Reactant: CC(=O)OC(C)=O
Agent: CCC(=O)OC(=O)CC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@@H](O)[C@@H]1OC(C)=O

Procedure:
By substituting 9.5 ml. of acetic anhydride for the propionic anhydride in paragraph 1 (a) and using 200 ml. of dry pyridine, the product obtained by the procedure of paragraph 1 a) is 9-(2,3-di-O-acetyl-5O-(tert-butyldimethylsily)-β-D-arabinofuranosyl)adenine, which, on reaction with 31.3 g. of tetrabutylammonium fluoride in 300 ml. of tetrahydrofuran, following the procedure of paragraph 1 (b), gives 9-(3,5-di-O-acetyl-β-D-arabinofuranosyl)adenine. By substituting 23.4 ml. of butyryl chloride for the propionic anhydride in paragraph 1 (a) and using 17.9 g. of the silyl ether in 250 ml. of pyridine, the product obtained is 9-(2,3-di-O-butyryl-5-O-(tert-butyldimethylsilyl)-β-D-arabinofuranosyl) adenine, which on reaction with 37 g. of tetrabutylammonium fluoride in 350 ml. of tetrahydrofuran following the procedure of paragraph 1 (b) gives 9-(3,5-di-O-butyryl-β-D-arabinofuranosyl)adenine.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][OH:6].[Si:10](Cl)([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11].O>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][O:6][Si:10]([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11]
Reactant: OCc1cccc(Br)c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCc1cccc(Br)c1

Procedure:
A solution 3-bromobenzyl alcohol (7.1 g, 38 mmol) and tert-butyldimethylsilyl chloride (5.7 g, 38 mmol) in N,N-dimethylformamide (40 mL) was stirred at room temperature for 5 h. Water (40 mL) was added and the mixture was extracted with hexanes. The combined extracts were washed with 10% aqueous hydrochloric acid, saturated sodium bicarbonate, saturated sodium chloride, and dried over magnesium sulfate. The desired product was isolated after concentration and purification by silica gel chromatography (hexanes). 1H NMR (CDCl3) 7.48 (s, 1H), 7.34 (m, 1H), 7.24 (m, 2H), 4.72 (s, 2H), 0.95 (s, 9H), 0.11 (s, 6H).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=O)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C1N=CN(C(N2C=NC=C2)=O)C=1.Cl.[CH3:30][NH:31][O:32][CH3:33]>C1COCC1.CCOC(C)=O>[C:4]([O:3][C:1]([N:8]1[CH2:9][CH2:10][CH:11]([C:14](=[O:16])[N:31]([O:32][CH3:33])[CH3:30])[CH2:12][CH2:13]1)=[O:2])([CH3:5])([CH3:6])[CH3:7]
Reactant: CNOC
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CON(C)C(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 2 h

Procedure:
N-BOC-piperidine-4-carboxylic acid (3.00 g, 13.08 mmol) was dissolved in THF and CDI (4.00 g, 24.7 mmol) was added in portions. The mixture was stirred for 2 h and N,O-dimethylhydroxylamine hydrochloride (4.00 g, 41 mmol) was added and stirring continued for 12 hours. The mixture was diluted with EtOAc and extracted 3 times with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified Biotage® to provide the title compound. 1H NMR (CD2Cl2) δ 4.12 (d,2H), 3.71 (s, 3H), 3.15 (s, 3H), 2.83 (m, 1H), 2.76 (t, 2H), 1.70 (dd, 2H), 1.59 (m, 2H), 1.45 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]([OH:11])=[O:10])[C:4]=1[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:13]=1.Cl.[CH3:24][CH2:25]OC(C)=O.CCCCCC>CCO>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]([O:11][CH2:24][CH3:25])=[O:10])[C:4]=1[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:13]=1
Reactant: CCOC(C)=O
Reactant: CCOC(=O)c1cccc(-c2c(OC)cccc2C(=O)O)c1
Agent: Cl
Solvent: CCO
Solvent: CCCCCC
Product: CCOC(=O)c1cccc(-c2c(OC)cccc2C(=O)OCC)c1
Yield: 73 %

Procedure:
Acid 5a (0.583 g., 1.90 mmol, 1 equiv.) is dissolved in 12 mL of absolute EtOH. Concentrated HCl (0.6 mL) is added, and the mixture heated to reflux for 24 hours. The mixture is then partitioned between EtOAc and water. The organic phase is washed with brine, dried (MgSO4), and concentrated in vacuo. Chromatography on silica gel using 5%, then 10% EtOAc/hexane yields 2-methoxy-3'-carboethoxy-[1,1'-biphenyl]-6-carboxylic acid, ethyl ester (6a) (0.432 g., 1.32 mmol, 73%) as a clear oil: UVmax (CHCl3) 242 nm (ε=12036), 296 nm (ε=4724); 1H NMR (300 MHz, CDCl3) δ 8.01 (m, 1H, ArH), 7.92 (m, 1H, ArH), 7.47-7.40 (m, 3H, ArH), 7.39 (dd, J=8, 8 Hz, 1H, ArH), 7.09 (dd, J= 2, 8 Hz, 1H, ArH), 4.34 (q, J=7 Hz, 2H, CO2CH2), 3.98 (q, J=7 Hz, 2H, CO2CH2), 3.73 (s, 3H, OCH3), 1.35 (t, J=7 Hz, 3H, CH2CH3), 0.91 (t, J=7 Hz, 3H, CH2CH3); 13C NMR (75 MHz, CDCl3) δ 168.04 (C=O), 166.65 (C=O), 156.92, 137.28, 134.11, 133.22, 130.73, 130.07, 129.98, 128.78, 128.22, 127.63, 121.63, 113.87, 60.88, 56.02, 14.34, 13.65; IR (film) 2982, 1718, 1466, 1366, 1298, 1260, 1234, 1110, 1060 cm-1 ; MS (DCI) m/e 329 (MH+), 283 (M--C2H5O). Anal. Calcd for C19H20O5 : C, 69.50; H, 6.14. Found: C, 69.44; H, 6.19.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[NH:8][C:7](=[O:14])[CH2:6]2.ClS([N:19]=[C:20]=[O:21])(=O)=O.C(#N)C>C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N:8]([C:20]([NH2:19])=[O:21])[C:7](=[O:14])[CH2:6]2
Reactant: O=C=NS(=O)(=O)Cl
Reactant: COc1cc2c(cc1OC)NC(=O)C2
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COc1cc2c(cc1OC)N(C(N)=O)C(=O)C2

Procedure:
Following the procedure of Example 24, the title compound was prepared from 5,6-dimethoxy-2-oxindole (8.0 g, 0.042 mole), chlorosulfonyl isocyanate (7.08 g, 0.05 mole) and acetonitrile (75 ml). The crude product obtained upon evaporation of the ethyl acetate extract was recrystallized from acetonitrile/acetic acid (1:1). Yield=6.02 g (60%); m.p. 206.5°-209° C.
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]1[CH:4]=[C:5]([CH:22]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:24]=1)[CH2:6][O:7][CH2:8][C:9]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[CH:10][C:11]([O:13][CH2:14][CH3:15])=[O:12].[H][H]>[Pd].[C].C(O)C>[F:1][C:2]([F:29])([F:30])[C:3]1[CH:4]=[C:5]([CH:22]=[C:23]([C:25]([F:27])([F:26])[F:28])[CH:24]=1)[CH2:6][O:7][CH2:8][CH:9]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC(=O)C=C(COCc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CC(COCc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ccccc1
Yield: 100 %

Procedure:
A mixture of ethyl 4-(3,5-bis(trifluoromethyl)benzyloxy)-3-phenyl-2-butenoate (40.00 g, 92.5 mmol), 5% Pd-carbon (1.00 g) and ethanol (250 mL) was stirred for 20 hours at room temperature in a hydrogen atmosphere. After filtering the catalyst, the solvent was evaporated in vacuo to give ethyl 4-(3,5-bis(trifluoromethyl)benzyloxy)-3-phenylbutanoate (40.18 g, 100%) as an oily product. 1H-NMR (DMSO-d6) δ: 1.04 (t, J=7.1 Hz, 3H), 2.60 (dd, J=8.0, 15.5 Hz, 1H), 2.81 (dd, J=6.8, 15.5 Hz, 1H), 3.38-3.45 (m, 1H), 3.65 (d, J=6.9 Hz, 2H), 3.94 (q, J=7.1 Hz, 2H), 4.65 and 4.66 (ABq, J=14.1 Hz, 2H), 7.20-7.24 (m, 1H), 7.28-7.32 (m, 4H), 7.90 (s, 2H), 7.99 (s, 1H).
Reaction SMILES: C(OC([CH:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:13](=[O:31])[CH:14]([NH:16][C:17](=[O:30])[C:18]1[CH:23]=[C:22]([CH3:24])[C:21]([O:25][CH2:26][CH:27]=[CH2:28])=[C:20]([CH3:29])[CH:19]=1)[CH3:15])=O)(C)(C)C.[O:32]=[C:33]1[O:37][CH:36]([O:38][CH2:39][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43]C=2)[CH:35]([NH:47][C:48](C2CCCN2C(=O)C(NC(=O)C2C=CC(N)=C(Cl)C=2)C)=[O:49])[CH2:34]1>>[CH2:39]([O:38][CH:36]1[CH:35]([NH:47][C:48]([CH:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13](=[O:31])[CH:14]([NH:16][C:17](=[O:30])[C:18]2[CH:19]=[C:20]([CH3:29])[C:21]([O:25][CH2:26][CH:27]=[CH2:28])=[C:22]([CH3:24])[CH:23]=2)[CH3:15])=[O:49])[CH2:34][C:33](=[O:32])[O:37]1)[C:40]1[CH:41]=[CH:46][CH:45]=[CH:44][CH:43]=1
Reactant: C=CCOc1c(C)cc(C(=O)NC(C)C(=O)N2CCCC2C(=O)OC(C)(C)C)cc1C
Reactant: CC(NC(=O)c1ccc(N)c(Cl)c1)C(=O)N1CCCC1C(=O)NC1CC(=O)OC1OCCc1ccccc1
Product: C=CCOc1c(C)cc(C(=O)NC(C)C(=O)N2CCCC2C(=O)NC2CC(=O)OC2OCc2ccccc2)cc1C
Yield: 46 %

Procedure:
Prepared from 1-[2-(4-allyloxy-3,5-dimethyl-benzoylamino)-propionyl]-pyrrolidine-2-carboxylic acid tert-butyl ester and 40 according to the procedure used to prepare 98a to afford 264 mg (yield 46%) of the title compound. 1H-NMR (500 MHz, CDCl3): δ 1.09-1.43 (m, 3H), 1.90-2.20 (m, 3H), 2.20-2.38 (m, 7H), 2.38-2.52 (m, H), 2.80-2.95 (m, H), 3.52-3.67 (m, H), 3.70-3.80 (m, H), 4.10-4.40 (m, 2H), 4.40-4.95 (m, 5H), 5.26-5.55 (m, 3H), 6.00-6.14 (m, H), 6.87 (d, H), 7.10-7.70 (m, 8H); retention time on analytical HPLC: 18.56 and 18.92 min1; LC-MS: m/z=564 (M+H+).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.Br[CH2:11][CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[N:1]1([CH2:11][CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: CCOC(=O)CCCBr
Reactant: c1ccc2[nH]ccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCn1ccc2ccccc21
Temperature: 50 °C
Yield: 12.4 %

Procedure:
A mixture of indole (11.7 g), ethyl 4-bromobutyrate (58.5 g) and potassium carbonate (41.5 g) in N,N-dimethylformamide (500 ml) was heated at 50° C. for 10 hours. The mixture was filtered and the filtrate was poured into a mixture of ethyl acetate and ice water. The organic layer was separated, washed with water, and dried over magnesium sulfate. After evaporation of the solvent, the residue was chromatographed on silica gel (1 kg) eluting with a mixture of methanol, chloroform and hexane (1:50:50) to give ethyl 4-(1-indolyl)butyrate (2.86 g) as a blue oil.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11][CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:17]2[CH:18]=[CH:19][C:20]3[NH:25][C:24](=[O:26])[O:23][C:22]([CH:33]4[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]4)([CH:27]4[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]4)[C:21]=3[CH:39]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[OH:40]O>>[C:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]([S:11]([CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:17]2[CH:18]=[CH:19][C:20]3[NH:25][C:24](=[O:26])[O:23][C:22]([CH:33]4[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]4)([CH:27]4[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]4)[C:21]=3[CH:39]=2)=[O:40])=[CH:9][CH:10]=1)(=[O:3])[CH3:2]
Reactant: OO
Reactant: CC(=O)Nc1ccc(SCCCCOc2ccc3c(c2)C(C2CCCCC2)(C2CCCCC2)OC(=O)N3)cc1
Product: CC(=O)Nc1ccc(S(=O)CCCCOc2ccc3c(c2)C(C2CCCCC2)(C2CCCCC2)OC(=O)N3)cc1

Procedure:
Prepared analogously to Example 2 from 6-[4-(4-acetamido-phenylmercapto)-butoxy]-4,4-dicyclohexyl-4H-3,1-benzoxazin-2-one and hydrogen peroxide.