Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: SC1C(=O)C=CC=CC=1.SC1C2C=CC=CC=2C=CC(=O)C=1.[NH2:23][C:24]1[C:30]2[CH:31]=[N:32][CH:33]=[CH:34][C:29]=2[CH:28]=[CH:27][C:26](=[O:35])[CH:25]=1.[CH2:36]([O:38][C:39](=[O:42])[CH:40]=[O:41])[CH3:37]>>[CH2:36]([O:38][C:39](=[O:42])[C:40]([NH:23][C:24]1[C:30]2[CH:31]=[N:32][CH:33]=[CH:34][C:29]=2[CH:28]=[CH:27][C:26](=[O:35])[CH:25]=1)=[O:41])[CH3:37]
Reactant: CCOC(=O)C=O
Reactant: Nc1cc(=O)ccc2ccncc12
Agent: O=c1ccc2ccccc2c(S)c1
Agent: O=c1cccccc1S
Product: CCOC(=O)C(=O)Nc1cc(=O)ccc2ccncc12

Procedure:
By following serially the procedures of Examples 1 and 2 but replacing 2-mercapto-2,4,6-cycloheptatrien-1-one with an equivalent amount of 5-mercapto-7H-benzocyclohepten-7-one, 9-amino-7H-cyclohepta[c]pyridin-7-one, 5-mercapto-3H-6,7-dihydrocyclobutacyclohepten-3-one, 1-ethylamino-3H-6,7,8,9,10,11-hexahydrocycloheptacycloocten-3-one and 5-mercapto-3H-6,7,8,9,10,11,12,13-octahydrocycloheptacyclodecen-3-one, the following compounds are obtained respectively: ](7-oxo-7H-benzocyclohepten-5-yl)thio]oxoacetic acid ethyl ester (I; R1, R5, and R6 =H; R2 =S--CO--COOC2H5 ; and R3 and R4 together form a --CH=CH--CH=CH-- chain), [(7-oxo-7H-cyclohepta[c]pyridin-9-yl)-amino]oxo-acetic acid ethyl ester (I; R1, R5 and R6 =H; R2 =NC2H5 --CO--COOC2H5 ; and R3 and R4 together form a --CH=CH--N=CH-- chain). [(3-oxo-3H-6,7-dihydrocyclobutacyclohepten-5-yl)thio]oxo-acetic acid ethyl ester (I; R1, R5 and R6 =H; R2 =S--CO--COOC2H5 ; and R3 and R4 together form a --CH2CH2 -- chain), [N-(3-oxo-3H-6,7,8,9,10,11-hexahydrocycloheptacycloocten-1-yl)ethylamino]oxo-acetic acid ethyl ester (I; R1, R2 and R6 =H; R3 and R4 together form a --(CH2)6 chain; and R5 =NC2H5 --CO--COOC2H5) and [(3-oxo-3H-6,7,8,9,10,11,12,13-octahydrocycloheptacyclodecen-5 -yl)thio]oxoacetic acid ethyl ester (I; R1, R5 and R6 =H; R2 =S--CO--COOC2H5 ; and R3 and R4 together form a --(CH2)8 -- chain).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:15][C:16]([NH2:18])=S)[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1.IC.[C:21]1([CH2:27][C:28]([NH:30][NH2:31])=O)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[OH-].[Na+].Cl>CC(C)=O.C(OCC)C>[CH2:27]([C:28]1[NH:18][C:16]([NH:15][C:5]2[CH:6]=[CH:7][C:8]([N:9]3[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]3)=[C:3]([O:2][CH3:1])[CH:4]=2)=[N:31][N:30]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COc1cc(NC(N)=S)ccc1-n1cnc(C)c1
Reactant: NNC(=O)Cc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: CI
Solvent: CCOCC
Product: COc1cc(Nc2nnc(Cc3ccccc3)[nH]2)ccc1-n1cnc(C)c1
Temperature: 20 °C
Reaction time: 16 h
Yield: 26.7 %

Procedure:
A solution of [3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-thiourea (400 mg, 1.52 mmol) in acetone (25 ml) was treated with iodomethane (0.14 ml, 2.29 mmol) and stirred at 20° C. for 16 h. The reaction mixture was concentrated and the crude S-methyl-isothiourea redissolved in ethanol (25 ml). Phenylacetic acid hydrazide (252 mg, 1.52 mmol) was added and the mixture was refluxed for 16 h under argon. After cooling to 20° C., 2 N sodium hydroxide solution (5 ml) was added and the mixture was refluxed for 2 h. After cooling to 20° C., the mixture was brought to pH 7 by careful addition of 1 N aqueous hydrochloric acid and then extracted with ethyl acetate. The organic phase was dried over sodium sulfate and evaporation under reduced pressure to afford a sticky semisolid which was triturared in diethyl ether (3 mL). Filtration yielded the title compound (146 mg, 27%) as greyish solid.
Reaction SMILES: [CH3:1][SnH:2]([CH3:4])[CH3:3].[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:7]=1[S:13]([OH:15])=[O:14].[H][H]>C1(C)C(C)=CC=CC=1.C(OCC)C>[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:7]=1[S:13]([O-:15])=[O:14].[CH3:1][Sn+:2]([CH3:4])[CH3:3]
Reactant: [H][H]
Reactant: O=S(O)c1cc(Cl)ccc1Cl
Reactant: C[SnH](C)C
Solvent: Cc1ccccc1C
Solvent: CCOCC
Product: C[Sn+](C)C
Product: O=S([O-])c1cc(Cl)ccc1Cl
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A 100 ml three-necked flask, fitted with a reflux condenser and addition funnel, was flushed thoroughly with nitrogen and charged with 4.5 ml (29.4 mmoles) of a solution of trimethyltin hydride in xylene (78 volume/volume %). To this solution was added dropwise with stirring at room temperature 70 ml of a solution of 6.0 g (28.5 mmoles) of 2,5-dichlorobenzenesulfinic acid in diethyl ether. Evolution of hydrogen occurred immediately and throughout the addition which lasted one hour. The flask was cooled in ice-water, and 9.38 g of solid was collected on a filter. The solid was recrystallized from cyclohexaneligroin giving 9.28 g of trimethyltin 2,5-dichlorobenzenesulfinate, m.p. 126.3°-128.8° C. The presence of strong absorption bands at 950 and 980 cm-1, characteristic of the ##STR19## in organotin sulfinates, was observed in the infrared spectrum (KBr). The NMR spectrum showed the following characteristics: The aromatic proton ortho to the sulfinato group appeared as a multiplet centered at 765 Hz (1 proton); the remaining aromatic protons appeared as a multiplet centered at 727 Hz (2 protons); the protons of the trimethyltin group appeared as a singlet at 62 Hz flanked on either side by two satellite bands (9 protons).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:24]=[C:11]3[N:12]=[C:13]([CH3:23])[C:14]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:15](Cl)[N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH2:25]([O:28][C:29]1([CH3:35])[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)[CH:26]=[CH2:27].Cl.CCN(C(C)C)C(C)C>CN(C=O)C.CCOCC>[CH2:25]([O:28][C:29]1([CH3:35])[CH2:30][CH2:31][N:32]([C:15]2[N:10]3[N:9]=[C:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=4)[CH:24]=[C:11]3[N:12]=[C:13]([CH3:23])[C:14]=2[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:33][CH2:34]1)[CH:26]=[CH2:27]
Reactant: C=CCOC1(C)CCNCC1
Reactant: CCOC(=O)Cc1c(C)nc2cc(-c3cccc(Br)c3)nn2c1Cl
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Product: C=CCOC1(C)CCN(c2c(CC(=O)OCC)c(C)nc3cc(-c4cccc(Br)c4)nn23)CC1
Yield: 90 %

Procedure:
A mixture of ethyl 2-(2-(3-bromophenyl)-7-chloro-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)acetate (28 g, 68.5 mmol) in DMF (150 ml) was treated with 4-(allyloxy)-4-methylpiperidine.HCl (14.3 g, 74.6 mmol) and Hunig's Base (35.9 ml, 206 mmol), and the mixture was heated (60° C. oil bath) for 16 h. At this point LCMS indicates completion of reaction. Mixture was then cooled, diluted with Et2O and washed with water (3×100 mL) and brine (100 mL), then dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was then purified by Biotage (5-50% EtOAc/hexane) to afford ethyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(3-bromophenyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)acetate (32.6 g, 61.8 mmol, 90% yield) as viscous oil. 1H NMR (500 MHz, CDCl3) δ 8.16 (t, J=1.7 Hz, 1H), 7.94 (dt, J=7.8, 1.3 Hz, 1H), 7.54-7.49 (m, 1H), 7.37-7.30 (m, 1H), 6.79 (s, 1H), 6.13-5.99 (m, 1H), 5.51-5.40 (m, 1H), 5.26 (dd, J=10.4, 1.4 Hz, 1H), 4.24 (q, J=7.1 Hz, 2H), 4.03 (dt, J=5.2, 1.6 Hz, 2H), 3.82 (br. s, 4H), 3.32 (br. s., 2H), 2.54 (s, 3H), 1.99 (d, J=13.2 Hz, 2H), 1.86 (br. s., 2H), 1.36 (s, 3H), 1.31 (t, J=7.1 Hz, 3H). LCMS (M+H)=528.8.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:9])[CH:5]=[C:6]([O-:8])[CH3:7])[CH3:2].[Na+].Br[CH2:12][C:13](=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15].C(OCC)(=O)C.O>CN(C)C=O>[C:6]([CH:5]([CH2:12][C:13](=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15])[C:4]([O:3][CH2:1][CH3:2])=[O:9])(=[O:8])[CH3:7]
Reactant: CC(C)(C)C(=O)CBr
Reactant: CCOC(=O)C=C(C)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)C(CC(=O)C(C)(C)C)C(C)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of sodium 4-ethoxy-4-oxobut-2-en-2-olate (1.50 g) in N,N-dimethylformamide (50 mL) was added 1-bromo-3,3-dimethylbutan-2-one (2.0 mL), and the mixture was stirred at room temperature for 1 hr. Ethyl acetate and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified by silica gel column chromatography to give the title compound as a pale-yellow viscous substance (1.51 g, 53%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:12][CH:11]=[C:10]([CH:13]=[O:14])[CH:9]=1.[H-].[Na+].C1O[CH2:30][CH2:29]OCCOCCOCCOC1.[S:32](Cl)(Cl)(=[O:34])=[O:33]>O1CCCC1.[Cl-].[Na+].O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:12]([S:32]([C:30]2[CH:29]=[CH:3][CH:8]=[CH:9][C:10]=2[C:11]#[N:12])(=[O:34])=[O:33])[CH:11]=[C:10]([CH:13]=[O:14])[CH:9]=1
Reactant: O=S(=O)(Cl)Cl
Reactant: C1COCCOCCOCCOCCO1
Reactant: O=Cc1c[nH]c(-c2ccccc2F)c1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1ccccc1S(=O)(=O)n1cc(C=O)cc1-c1ccccc1F
Reaction time: 0.5 h
Yield: 154.2 %

Procedure:
To a solution (28 mL) of 5-(2-fluorophenyl)-1H-pyrrole-3-carbaldehyde (284 mg) in tetrahydrofuran was added sodium hydride (60% in oil, 181 mg) at room temperature and the mixture was stirred for 30 min. 15-Crown-5 (992 mg) was added dropwise and the mixture was stirred for 30 min, (2-cyanobenzene) sulfonyl chloride (606 mg) was added, and the mixture was further stirred for 1 hr. Saturated brine was added to the reaction mixture, and the mixture was 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=4:1→2:3) to give the title compound as colorless crystals (yield 410 mg, 77%).
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[C:11](OC(=O)C)(=[O:13])[CH3:12]>COC1C=CC(C2OC(C3C=CC(OC)=C(OC)C=3)CCC2)=CC=1OC>[C:11]([O:4][C:3]1[C:2](=[CH:8][CH:7]=[CH:6][CH:5]=1)[C:1]([OH:10])=[O:9])(=[O:13])[CH3:12]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(O)c1ccccc1O
Agent: COc1ccc(C2CCCC(c3ccc(OC)c(OC)c3)O2)cc1OC
Product: CC(=O)Oc1ccccc1C(=O)O
Temperature: 120 °C

Procedure:
0.0072 moles of salicylic acid and 0.029 moles acetic anhydride (molar ratio=1:4) were taken in a 20 ml reaction vessel of reaction station. Nano-crystalline sulfated zirconia catalyst (SZ-1), activated at 450° C. in static air with salicylic acid to catalyst weight ratio 10:1, was added and the mixture was heated at 120° C. for 30 minutes. The reaction mixture was filtered to separate the catalyst. The acetyl salicylic acid was crystallized from the reaction mixture. The crude yield of acetyl salicylic acid was 92-95%. It was further re-crystallized with ethanol-water to obtain pure crystals of acetyl salicylic acid.
Reaction SMILES: C1COCC1.[Si]([O:13][CH2:14][CH2:15][CH2:16][O:17][C:18]1[C:27](=[O:28])[C:26]2[C:21](=[CH:22][C:23]([NH:30][CH:31]3[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]3)=[C:24]([F:29])[CH:25]=2)[N:20]([CH:37]2[CH2:41][CH2:40][CH2:39][CH2:38]2)[CH:19]=1)(C(C)(C)C)(C)C>O>[CH:31]1([NH:30][C:23]2[CH:22]=[C:21]3[C:26]([C:27](=[O:28])[C:18]([O:17][CH2:16][CH2:15][CH2:14][OH:13])=[CH:19][N:20]3[CH:37]3[CH2:41][CH2:40][CH2:39][CH2:38]3)=[CH:25][C:24]=2[F:29])[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36]1
Reactant: CC(C)(C)[Si](C)(C)OCCCOc1cn(C2CCCC2)c2cc(NC3CCCCC3)c(F)cc2c1=O
Solvent: C1CCOC1
Solvent: O
Product: O=c1c(OCCCO)cn(C2CCCC2)c2cc(NC3CCCCC3)c(F)cc12
Reaction time: 2 h
Yield: 46 %

Procedure:
To a 15 ml THF solution of 762 mg of 3-(3-{[tert-butyl(dimethyl)silyl]oxy}propoxy)-7-(cyclohexylamino)-1-cyclopentyl-6-fluoroquinolin-4(1H)-one was added 1.5 ml of a 1 M tetrabutylammonium fluoride THF solution at room temperature, followed by stirring for 2 hours. Water was added to the reaction mixture, followed by extraction with ethyl acetate and washing with aqueous saturated sodium chloride. After drying over anhydrous sodium sulfate, evaporation was carried out under a reduced pressure. By purifying the residue by silica gel column chromatography, 273 mg of 7-(cyclohexylamino)-1-cyclopentyl-6-fluoro-3-(3-hydroxypropoxy)quinolin-4(1H)-one was obtained.
Reaction SMILES: [C:1]1([C@@H:7]2[CH2:12][CH2:11][CH2:10][NH:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)(=O)C.[CH:17](=O)[CH2:18][CH3:19].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.O>[C:1]1([C@@H:7]2[CH2:12][CH2:11][CH2:10][N:9]([CH2:17][CH2:18][CH3:19])[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc([C@@H]2CCCNC2)cc1
Reactant: CCC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: O
Product: CCCN1CCC[C@@H](c2ccccc2)C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
1 g (6.2 mmol) of commercially available (S)-3-phenylpiperidine was dissolved in dichloromethane and 0.37 ml acetic acid (6.51 mmol). After addition of 0.5 ml of propanal (6.93 mmol) and 1.97 g of sodium triacetoxyborohydride (9.3 mmol), the reaction mixture was stirred at room temperature for 18 h. Water was added, the layers separated, and the aqueous phase extracted with dichloromethane. The combined organic layers were dried over magnesium sulfate, filtered, and evaporated to dryness to yield 1.1 g of (S)-3-phenyl-1-propyl-piperidine.
Reaction SMILES: [N+:1]([O-:4])([OH:3])=O.[N+:5]([C:8]1[CH:25]=[CH:24][C:11]2[O:12][C:13]([CH2:19][C:20]([F:23])([F:22])[F:21])([C:15]([F:18])([F:17])[F:16])[O:14][C:10]=2[CH:9]=1)([O-:7])=[O:6]>S(=O)(=O)(O)O>[N+:1]([C:25]1[C:8]([N+:5]([O-:7])=[O:6])=[CH:9][C:10]2[O:14][C:13]([CH2:19][C:20]([F:23])([F:21])[F:22])([C:15]([F:17])([F:16])[F:18])[O:12][C:11]=2[CH:24]=1)([O-:4])=[O:3]
Reactant: O=[N+]([O-])c1ccc2c(c1)OC(CC(F)(F)F)(C(F)(F)F)O2
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1cc2c(cc1[N+](=O)[O-])OC(CC(F)(F)F)(C(F)(F)F)O2
Temperature: 55 °C
Reaction time: 2 h

Procedure:
A mixture of 250 ml of 100% strength by weight nitric acid and 350 ml of concentrated sulphuric acid was added dropwise to an initial charge of 317 g of the product from Example 15a. The mixture was stirred at 55° C. for 2 hours. The mixture was then cooled and poured into ice-water. The product was extracted with methylene chloride, washed until neutral with sodium hydrogen carbonate solution, dried, and freed on a rotary evaporator from readily volatile constituents. The yield was 339 g (=94% of theory) and the melting point was 101° to 103° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([C@H:13]([OH:23])[CH2:14][O:15]CC2C=CC=CC=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].F[C:25]1[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=1.CN(C=O)C.[H-].[Na+]>[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([C@H:13]([O:23][C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=2)[CH2:14][OH:15])[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CC[C@H]([C@H](O)COCc2ccccc2)C1
Reactant: Fc1ccc(C(F)(F)F)cc1
Agent: [Pd]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC[C@H]([C@@H](CO)Oc2ccc(C(F)(F)F)cc2)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 62.8 %

Procedure:
(S)-3-((S)-2-Benzyloxy-1-hydroxyethyl)-pyrrolidine-1-carboxylic acid t-butyl ester (4.6 g, 14 mmol, 10. eq.) was combined with 4-fluorobenzotrifluoride (5.5 mL, 42.9 mmol, 3.0 eq.) in DMF (30 mL, 400 mmol). The mixture was degassed under nitrogen, and NaH (481 mg, 20.0 mmol) was added in small portions. The resulting mixture was stirred for 10 minutes at room temperature, followed by stirring at 90° C. for 3 hours. The mixture was then cooled to room temperature, extracted with hexanes (50 mL), and washed with water (50 mL) then 2M aqueous NaCl (50 mL). The organic layer was collected, stirred in activated carbon (460 mg) for 5 minutes, dried over Na2SO4, filtered, and concentrated. The resulting crude oil was dissolved in MeOH (50 mL), and 10% Pd/C (0.1:0.9, Palladium:carbon black, 670 mg, 630 mol) was added under nitrogen. The mixture was stirred under hydrogen (1 atm) overnight. The mixture was filtered and the filtrate was concentrated. The resulting crude oil was dissolved in hexanes (˜30 mL) and EtOAc (˜15 ml), then concentrated until precipitate formed. Additional hexanes was added and the precipitate was stirred for 15 minutes. The precipitate was filtered and dried to give the title compound as a white solid (3.3 g).
Reaction SMILES: [C:1](Cl)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:21][CH2:22][C:23]1[CH2:28][C:27](=[O:29])[C:26]([O:30][CH3:31])=[CH:25][N:24]=1>CN(C)C1C=CN=CC=1.CN(C)C=O.O>[CH3:31][O:30][C:26]1[C:27](=[O:29])[CH2:28][C:23]([CH2:22][O:21][C:1]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[N:24][CH:25]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COC1=CN=C(CO)CC1=O
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: CN(C)C=O
Product: COC1=CN=C(COC(c2ccccc2)(c2ccccc2)c2ccccc2)CC1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 58.6 %

Procedure:
Trityl chloride (9.43 g) is added in one portion to a solution of 2-hydroxymethyl-5-methoxy-4-pyridone (5 g) and 4-dimethylaminopyridine (4.2 g) in dry dimethylformamide (80 mL) and the solution stirred at room temperature for 12 hours. The mixture is then heated on a steam bath for 3 hours and diluted with iced water (300 mL) to give a light brown solid. The solid is collected, washed with water and sucked dry. The solid is dissolved in hot ethyl acetate to give a clear solution which immediately deposits a granular off-white solid. The solid does not redissolve on further heating. After cooling the solid is collected, washed with ethyl acetate and diethyl ether and dried to give 5-methoxy-2-trityloxymethyl-4-pyridone (7.5 g) as an off-white solid, m.p. 185-7° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([O:13][CH3:14])=[CH:5][CH:4]=1.[Br:15]Br>C(O)(=O)C>[Br:15][C:4]1[CH:5]=[C:6]([O:13][CH3:14])[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[O:2][CH3:1]
Reactant: BrBr
Reactant: COc1ccc(OC)c2ccccc12
Solvent: CC(=O)O
Product: COc1cc(Br)c(OC)c2ccccc12
Reaction time: 1 h

Procedure:
To a solution of 50 grams (0.26 mol) of 1,4-dimethoxynaphthalene, prepared according to the procedure of L. Fieser, in the Journal of the American Chemical Society, Volume 70, page 3165 (1948), in 500 ml glacial acetic acid is added 13.7 ml (0.26 mol) of bromine at room temperature. The mixture is stirred for 1 hour, and the solvent is removed under reduced pressure and the residue dissolved in ether. The resulting solution is carefully washed twice with sodium bicarbonate, the organic layer separated, dried over sodium sulfate and the solvent removed. Distillation of the residue gave 63.4 grams (81% of theoretical yield) of liquid 2-bromo-1,4-dimethoxy-naphthalene (boiling 200°-210° at 0.1 mm Hg). The product has a nuclear magnetic resonance spectrum consistant with the expected structure and has peaks expressed in parts per million relative to tetramethylsilane at 8.0 (m,2H), 7.4(m,2H), 6.9(s,1H), 3.9(d,6H).
Reaction SMILES: Cl[O-:2].[Na+].P([O-])([O-])(O)=O.[Na+].[Na+].[CH2:11]([O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[O:22][C:21]([CH3:27])([CH3:26])[CH:20]=[CH:19]2)[CH2:12][CH2:13][CH3:14]>C(Cl)Cl>[CH2:11]([O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[O:22][C:21]([CH3:26])([CH3:27])[C@H:20]1[O:2][C@@H:19]21)[CH2:12][CH2:13][CH3:14]
Reactant: CCCCOc1ccc2c(c1)C=CC(C)(C)O2
Reactant: [O-]Cl
Agent: O=P([O-])([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCCCOc1ccc2c(c1)[C@@H]1O[C@@H]1C(C)(C)O2
Reaction time: 3 h

Procedure:
(3S, 4S)-(-)-6-Butoxy-2,2-dimethyl-3,4-epoxychroman At 0° C., 76 ml (42 mmol) of a 0.55 M sodium hypochlorite solution which had been adjusted to pH 11.3 using disodium hydrogen phosphate were added to a solution of 4.6 g (20 mmol) of 6-butoxy-2,2-dimethyl-2H-chromen (Example 5b) and 0.5 g (0.8 mmol) of (S,S)-(+)-N,N'-bis-(3,5-di-tert-butylsalicylidene)-1,2-diaminocyclohexanemanganese(III) chloride (Jacobsen's catalyst) in 20 ml of methylene chloride. The reaction mixture was stirred vigorously for 3 h and the organic phase was then separated off and the aqueous phase was extracted twice with methylene chloride. Silica gel chromatography of the crude product using cyclohexane/EA 9:1 gave 1.6 g of (3S, 4S)-(-)-6-butoxy-2,2-dimethyl-3,4-epoxychroman; optical rotation -14.9° (c=0.6; methanol).
Reaction SMILES: [CH2:1]([O:8][CH:9]([CH3:15])[CH2:10][CH2:11][C:12]([OH:14])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.CN(C)C=O.Cl.[NH2:28][C:29]1[C:37]([OH:38])=[C:36]2[C:32]([CH2:33][CH2:34][CH:35]2[CH2:39][CH2:40][NH:41][C:42](=[O:44])[CH3:43])=[CH:31][CH:30]=1>O1CCCC1.N1C=CC=CC=1>[C:42]([NH:41][CH2:40][CH2:39][CH:35]1[C:36]2[C:32](=[CH:31][CH:30]=[C:29]([NH:28][C:12](=[O:14])[CH2:11][CH2:10][CH:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH3:15])[C:37]=2[OH:38])[CH2:33][CH2:34]1)(=[O:44])[CH3:43]
Reactant: CC(=O)NCCC1CCc2ccc(N)c(O)c21
Reactant: CC(CCC(=O)O)OCc1ccccc1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CC(=O)NCCC1CCc2ccc(NC(=O)CCC(C)OCc3ccccc3)c(O)c21
Reaction time: 0.5 h
Yield: 57.4 %

Procedure:
4-(Benzyloxy)pentanoic acid (230 mg, 1.10 mmol) was dissolved in tetrahydrofuran (10 mL), oxalyl chloride (90 μL, 1.05 mmol) and dimethylformamide (10 μL) were added under ice-cooling, and the mixture was stirred for 30 min. The solvent was evaporated under reduced pressure, and the residue was diluted with dichloromethane (1 mL). This was added to a solution of N-[2-(6-amino-7-hydroxy-2,3-dihydro-1H-inden-1-yl)ethyl]acetamide hydrochloride (244 mg, 0.903 mmol) in pyridine (10 mL) under ice-cooling, and the mixture was stirred at room temperature for 15 min. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=80/20→100/0) to give the title compound (220 mg, yield 57%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:13]=[C:12]([CH:14]([CH3:16])[CH3:15])[S:11][C:10]=1[C:17](N(OC)C)=[O:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([Mg]Br)=[CH:27][CH:26]=1>O1CCCC1>[CH2:1]([O:8][C:9]1[CH:13]=[C:12]([CH:14]([CH3:15])[CH3:16])[S:11][C:10]=1[C:17]([C:28]1[CH:29]=[CH:30][C:25]([O:24][CH3:23])=[CH:26][CH:27]=1)=[O:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CON(C)C(=O)c1sc(C(C)C)cc1OCc1ccccc1
Reactant: COc1ccc([Mg]Br)cc1
Solvent: C1CCOC1
Product: COc1ccc(C(=O)c2sc(C(C)C)cc2OCc2ccccc2)cc1
Temperature: 22 °C
Reaction time: 0.5 h

Procedure:
860 mg of 3-benzyloxy-5-isopropyl-N-methoxy-N-methylthiophene-2-carboxamide were dissolved in 50 ml of tetrahydrofuran (THF) and cooled to 0> C. in an ice bath, and 31.3 ml of 0.5 molar 4-methoxyphenymagnesium bromide solution in tetrahydrofuran were added. After 30 min, the ice bath was removed and the reaction mixture was warmed to 22° C. After one hour, 70 ml of saturated sodium bicarbonate solution were added to the reaction mixture, and it was extracted twice with 100 ml of methyl acetate each time. The combined organic phases were washed with 70 ml of saturated sodium chloride solution, dried over sodium sulfate and concentrated. The crude product was purified by column chromatography (SiO2, ethyl acetate/n-heptane=1:3).