Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:10]=[C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH:12]=1)[CH:8]=[O:9])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[CH3:26][C:27](=[O:30])[CH:28]=[CH2:29]>CCO.[Br-].C([N+]1C(C)=C(CCO)SC=1)C>[C:13]([C:11]1[CH:10]=[C:7]([C:8](=[O:9])[CH2:29][CH2:28][C:27](=[O:30])[CH3:26])[CH:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:12]=1)([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)c1cc(C=O)cc(C(C)(C)C)c1
Reactant: C=CC(C)=O
Agent: CC[n+]1csc(CCO)c1C
Agent: [Br-]
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)CCC(=O)c1cc(C(C)(C)C)cc(C(C)(C)C)c1
Temperature: 77.5 °C
Yield: 44.4 %

Procedure:
To a solution of 3,5-di-tert-butylbenzaldehyde (10.9 g, 50 mmol) in EtOH (200 mL) was added DIPEA (12.9 g, 100 mmol), but-3-en-2-one (3.5 g, 50 mmol) and 3-ethyl-5-(2-hydroxyethyl)-4-methylthiazolium bromide (2.5 g, 10 mmol). This mixture was heated to 75-80° C. overnight, evaporated, diluted with water (50 mL) and extracted with EA. The organic layer was washed with brine, dried, concentrated and purified by CC (EA/PE=1/100) to afford compound 5a (6.4 g, 44%) as colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:12]=[C:11]([I:13])[CH:10]=[C:6]([C:7](O)=[O:8])[CH:5]=1.[CH3:15][NH:16][CH3:17].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:12]=[C:11]([I:13])[CH:10]=[C:6]([C:7]([N:16]([CH3:17])[CH3:15])=[O:8])[CH:5]=1
Reactant: CNC
Reactant: COC(=O)c1cc(I)cc(C(=O)O)c1
Agent: CN(C)C(On1nnc2cccnc21)=[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: COC(=O)c1cc(I)cc(C(=O)N(C)C)c1
Temperature: 25 °C
Yield: 75.4 %

Procedure:
To a solution of 5-iodo-isophthalic acid monomethyl ester (3.00 g, 9.8 mmol) in N,N-Dimethylformamide (80 ml) was added dimethyl amine(2M solution in Tetrahydrofuran, 9.8 m, 79.61 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate 3.72 g, 9.8 mmol), and finally di-iso-propyl ethyl amine (5.1 ml, 29.41 mmol), this mixture was stirred at room temperature over night. The solvent was stripped under reduced pressure and the crude purifies by silica gel chromatography to give afford 5-Iodo-N,N-dimethyl-isophthalamic acid methyl ester (2.46 g, 75%). MS: m/z 333.1 (M+H+).
Reaction SMILES: C[Si]([N:5]=[N+:6]=[N-:7])(C)C.C([Sn](=O)CCCC)CCC.[C:18]([C:20]1[CH:27]=[CH:26][C:23]([CH:24]=[O:25])=[CH:22][CH:21]=1)#[N:19].C(OCC)(=O)C>C1(C)C=CC=CC=1>[NH:5]1[C:18]([C:20]2[CH:27]=[CH:26][C:23]([CH:24]=[O:25])=[CH:22][CH:21]=2)=[N:19][N:7]=[N:6]1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: N#Cc1ccc(C=O)cc1
Agent: CCCC[Sn](=O)CCCC
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: O=Cc1ccc(-c2nnn[nH]2)cc1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
Trimethylsilyl azide (25 g) and dibutyltin oxide (8.8 g) were added to a solution of 4-cyanobenzaldehyde (13 g) in toluene (200 ml). The reaction was stirred with warming to 50° C. over 1 hr, and then warmed to 96° C. over 30 minutes and maintained at that temperature for 3 hours. The solvent was evaporated in vacuo to afford an orange oil which was purified by column chromatography over silica gel (ethyl acetate). The crude product was dissolved in refluxing toluene and allowed to cool with stirring overnight. The resulting slurry was granulated in an ice-bath for 1 hour, filtered and washed with cold toluene. The filtrate was evaporated in vacuo to afford a solid. The solid was dissolved in refluxing ethyl acetate (250 ml) and concentrated to 60 ml by rotary evaporation. The solution was cooled to room temperature and then granulated in an ice bath. The thick slurry was collected by filtration, washed and dried, with warming, in a vacuum oven to afford the title compound, 12 g.
Reaction SMILES: O[Li].O.[Si]([O:11][C@H:12]1[CH2:16][N:15]([C:17]2[CH:22]=[CH:21][N:20]3[N:23]=[CH:24][C:25]([C:26]([O:28]CC)=[O:27])=[C:19]3[CH:18]=2)[C@@H:14]([C:31]2[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:32]=2[F:38])[CH2:13]1)(C(C)(C)C)(C)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CCO.O>[F:38][C:32]1[CH:33]=[CH:34][C:35]([F:37])=[CH:36][C:31]=1[C@H:14]1[CH2:13][C@@H:12]([OH:11])[CH2:16][N:15]1[C:17]1[CH:22]=[CH:21][N:20]2[N:23]=[CH:24][C:25]([C:26]([OH:28])=[O:27])=[C:19]2[CH:18]=1
Reactant: CCOC(=O)c1cnn2ccc(N3C[C@H](O[Si](C)(C)C(C)(C)C)C[C@@H]3c3cc(F)ccc3F)cc12
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li]O
Solvent: CCO
Solvent: O
Product: O=C(O)c1cnn2ccc(N3C[C@H](O)C[C@@H]3c3cc(F)ccc3F)cc12
Reaction time: 8 h

Procedure:
1M aq. solution of LiOH.H2O (0.4 mL) was added to a stirred solution of ethyl 5-((2R,4R)-4-((tert-butyldimethylsilyl)oxy)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyridine-3-carboxylate (Isomer-I) (Int-60) (0.07 g, 0.14 mmol) in EtOH (5 mL) and the stirring was continued at 90° C. for 8 h. The reaction mixture was concentrated under reduced pressure to afford the crude product. The crude product thus obtained was diluted with cold water, acidified with citric acid solution, filtered the solid precipitated to afford 5-((2R,4R)-2-(2,5-difluorophenyl)-4-hydroxypyrrolidin-1-yl)pyrazolo[1,5-a]pyridine-3-carboxylic acid (Int-62) as yellow solid. MS (ESI): m/z 360 (M+H).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]([O:23][CH2:24][CH2:25]OS(C)(=O)=O)[C@@H:10]1[CH2:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11]1.[N-:31]=[N+:32]=[N-:33].[Na+]>CN(C=O)C.C(OCC)(=O)C>[N:31]([CH2:25][CH2:24][O:23][CH:9]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([F:8])[C:2]=1[F:1])[C@@H:10]1[CH2:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11]1)=[N+:32]=[N-:33]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](C(OCCOS(C)(=O)=O)c2cccc(F)c2F)C1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC[C@@H](C(OCCN=[N+]=[N-])c2cccc(F)c2F)C1
Temperature: 25 °C
Yield: 91.2 %

Procedure:
A solution of (3R)-tert-butyl 3-((2,3-difluorophenyl)(2-(methylsulfonyloxy)ethoxy)methyl)piperidine-1-carboxylate (4.2 g, 9.4 mmol) and solid NaN3 (0.92 g, 14.1 mmol) in anhydrous DMF (30 mL) was heated to 80° C. overnight. The reaction mixture was cooled to rt and diluted with ethyl acetate (80 mL), the organic phase was washed with water (30 mL×3), dried over Na2SO4 and evaporated. The residue was separated on a silica column to give (3R)-tert-butyl 3-((2-azidoethoxy)(2,3-difluorophenyl)methyl)piperidine-1-carboxylate (3.4 g, 92%). 1H NMR (CDCl3, 400 MHz) δ 7.14 (m, 3H), 4.50 (q, 1H), 4.10 (m, 1H), 3.40 (m, 4H), 2.70 (m, 2H), 1.90 (m, 2H), 1.65 (m, 1H), 1.41 (d, 9H).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:29])[C@@H:10]1[CH2:14][CH2:13][CH2:12][N:11]1[C:15](=[O:28])[C@@H:16]1[CH2:20][CH2:19][CH2:18][N:17]1C(OC(C)(C)C)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.O1CCOCC1.[CH2:37]([N:44]=[C:45]=[O:46])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>>[CH2:1]([O:8][C:9](=[O:29])[C@@H:10]1[CH2:14][CH2:13][CH2:12][N:11]1[C:15](=[O:28])[C@@H:16]1[CH2:20][CH2:19][CH2:18][N:17]1[C:45]([NH:44][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:46])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C=NCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(OCc1ccccc1)[C@@H]1CCCN1C(=O)[C@@H]1CCCN1C(=O)NCc1ccccc1

Procedure:
N-(t-Butoxycarbonyl)-L-prolyl-L-proline benzyl ester (3.60 g) was treated with 4N hydrochloric acid/1,4-dioxane and then reacted with benzylisocyanate (1.2 ml) as in Example 21-B) to give 2.98 g of the title compound as crystals.
Reaction SMILES: C([O:8][N:9]1[C:18](=[O:19])[C:17]2[CH:20]=[C:21]([C:28]#[N:29])[C:22]([N:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)=[C:15]3[C:16]=2[C:11](=[CH:12][CH:13]=[CH:14]3)[C:10]1=[O:30])C1C=CC=CC=1.FC(F)(F)C([O-])=O.FC(F)(F)C([O-])=O.FC(F)(F)C([O-])=O.[B+3]>C(O)(C(F)(F)F)=O>[C:28]([C:21]1[C:22]([N:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)=[C:15]2[CH:14]=[CH:13][CH:12]=[C:11]3[C:16]2=[C:17]([CH:20]=1)[C:18](=[O:19])[N:9]([OH:8])[C:10]3=[O:30])#[N:29]
Reactant: N#Cc1cc2c3c(cccc3c1N1CCCC1)C(=O)N(OCc1ccccc1)C2=O
Agent: O=C([O-])C(F)(F)F
Agent: [B+3]
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cc2c3c(cccc3c1N1CCCC1)C(=O)N(O)C2=O
Yield: 69 %

Procedure:
Following the procedure of Example 52, 2-benzyloxy-5-cyano-6-(pyrrolidin-1-yl)-benzo[de]isoquinoline-1,3-dione (0.15 g, 0.33 mmol, from Example B2) and a 1.0 M solution of boron tris(trifluoroacetate) in TFA (2 mL) was reacted to give 0.070 g of the title compound, mp 247-248° C.
Reaction SMILES: [N:1]#[N:2].O.Cl.Cl.C[O:7][C:8](=[O:34])[C@H:9]([CH2:27][CH2:28][CH2:29][NH:30][C:31](=[NH:33])[NH2:32])[NH:10][S:11]([C:14]1[C:26]2[CH:25]=[CH:24][CH:23]=[C:19]([N:20]([CH3:22])[CH3:21])[C:18]=2[CH:17]=[CH:16][CH:15]=1)(=[O:13])=[O:12].[CH2:35]([NH2:37])[CH3:36]>O1CCCC1>[N:1]#[N:2].[OH2:7].[S:11]([NH:10][C@H:9]([C:8]([NH:37][CH2:35][CH3:36])=[O:34])[CH2:27][CH2:28][CH2:29][NH:30][C:31](=[NH:33])[NH2:32])([C:14]1[C:26]2[CH:25]=[CH:24][CH:23]=[C:19]([N:20]([CH3:21])[CH3:22])[C:18]=2[CH:17]=[CH:16][CH:15]=1)(=[O:12])=[O:13]
Reactant: CCN
Reactant: COC(=O)[C@H](CCCNC(=N)N)NS(=O)(=O)c1cccc2c(N(C)C)cccc12
Agent: Cl
Agent: N#N
Solvent: C1CCOC1
Solvent: O
Product: CCNC(=O)[C@H](CCCNC(=N)N)NS(=O)(=O)c1cccc2c(N(C)C)cccc12
Reaction time: 72 h
Yield: 93 %

Procedure:
To a suspension of 1.0 gram of N2 -dansyl-L-arginine methyl ester dihydrochloride monohydrate in 1 ml of tetrahydrofuran was added 3 ml of ethylamine with cooling. The mixture was allowed to stand in a sealed tube at room temperature for three days. After the excess amine was removed by evaporation, the residue was poured into 50 ml of water to give a precipitate. Recrystallization from 50% aqueous methanol afforded N2 -dansyl-N-ethyl-L-argininamide monohydrate in 93% yield; mp. 220°-222° C.
Reaction SMILES: C([Li])CCC.[O:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[CH:8]=[CH:7]1.[CH3:15][N:16]1[CH2:21][CH2:20][C:19](=[O:22])[CH:18]([CH3:23])[CH2:17]1>CCCCCC.C(OCC)C>[O:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[CH:8]=[C:7]1[C:19]1([OH:22])[CH2:20][CH2:21][N:16]([CH3:15])[CH2:17][CH:18]1[CH3:23]
Reactant: CC1CN(C)CCC1=O
Reactant: c1ccc2occc2c1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: CC1CN(C)CCC1(O)c1cc2ccccc2o1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
50 ml of a bimolar solution of n-butyl lithium in hexane is added dropwise within 30 minutes, at a reaction temperature of -5°, to a solution of 11.8 g of benzofuran in 100 ml of diethyl ether. The solution is then stirred for a further hour at 0°. There is thereupon made within 15 minutes a dropwise addition of a solution of 1,3-dimethyl-4-piperidone in 50 ml of abs. diethyl ether. The reaction temperature is maintained at 0° by external cooling. The reaction solution is subsequently stirred for a further 15 hours at room temperature. It is then poured, with stirring, onto 200 g of ice, and the aqueous phase extracted three times with 500 ml of ethyl acetate each time. The combined organic extracts are dried over sodium sulphate, filtered, and concentrated by evaporation. The residue is dissolved in 500 ml of 2 N hydrochloric acid and the acid solution washed with ether. The aqueous solution is thereupon adjusted by addition of 10% sodium hydroxide solution to pH 12, and extracted with 1 liter of chloroform. The chloroform solution is dried with sodium sulphate, filtered off under suction, and concentrated by evaporation to obtain 4-(2-benzofuranyl)-1,3-dimethyl-4-piperidinol, which melts at 128°-130° after recrystallisation from hexane.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.Cl[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[N:13]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.O.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>[Cl:18][C:14]1[CH:15]=[CH:16][CH:17]=[C:12]([C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=2)[N:13]=1
Reactant: Cc1ccc(B(O)O)cc1
Reactant: Clc1cccc(Cl)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1ccc(-c2cccc(Cl)n2)cc1
Temperature: 80 °C
Reaction time: 15 h
Yield: 268.4 %

Procedure:
4-Methylphenylboronic acid (1.00 g), 2,6-dichloropyridine (3.27 g), tetrakis(triphenylphosphine)palladium(0) (0.255 g) and potassium phosphate (3.12 g) were dissolved in toluene (35 ml) and water (6.0 ml). The mixture was stirred at 80° C. for 15 hours under a nitrogen atmosphere. The organic layer was separated, washed with a saturated aqueous sodium hydrogen carbonate solution, and dried with anhydrous magnesium sulfate and the solvent was distilled off. The resultant was crudely purified through silica gel column chromatography (chloroform), thereby obtaining a mixture (4.02 g) containing the subject compound.
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][CH2:9][OH:10])=[C:6]([Cl:11])[N:5]=[CH:4][N:3]=1.C(N(CC)C(C)C)(C)C.[NH2:21][C@@H:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:24][CH2:23]1>C(O)CCC>[Cl:11][C:6]1[C:7]([CH2:8][CH2:9][OH:10])=[C:2]([NH:21][C@@H:22]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH2:24][CH2:23]2)[N:3]=[CH:4][N:5]=1
Reactant: OCCc1c(Cl)ncnc1Cl
Reactant: N[C@H]1CCc2ccccc21
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: OCCc1c(Cl)ncnc1N[C@H]1CCc2ccccc21
Temperature: 130 °C
Yield: 98.2 %

Procedure:
2-(4,6-dichloropyrimidin-5-yl)ethanol (1.90 g, 9.84 mmol) was dissolved in 1-butanol (97 mL) and N,N-Diisopropylethylamine (3.43 mL, 19.7 mmol) and (S)-1-Aminoindane (1.26 mL, 9.84 mmol) were added. The solution was heated at 130° C. for 3 days. Solvent was removed in vacuo and the residue was purified using chromatography on silica gel using gradient 0 to 100% ethyl acetate in methylene chloride to afford the title compound (2.80 g, 98%). LC/MS: Rt=1.63 min, ES+ 290 (AA standard).
Reaction SMILES: [SH:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[H-].[Na+].[CH3:13][N:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][C:22]=2[CH2:24]Cl)[C:17]([CH3:26])=[CH:16][CH2:15]1>CN(C)C=O>[CH3:13][N:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][C:22]=2[CH2:24][S:1][C:2]2[NH:3][C:4]3[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=3[N:6]=2)[C:17]([CH3:26])=[CH:16][CH2:15]1
Reactant: CC1=CCN(C)c2c(CCl)cccc21
Reactant: Sc1nc2ccccc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1=CCN(C)c2c(CSc3nc4ccccc4[nH]3)cccc21
Reaction time: 0.5 h
Yield: 32.3 %

Procedure:
2-Mercaptobenzimidazole (0.7 g) was dissolved in dimethyl formamide (30 ml). Sodium hydride (60% in oil, 0.19 g) was added thereto under ice-cooling and the mixture was stirred for 30 minutes. Sequentially, a solution of 1,4-dimethyl-8-chloromethyl-1,2-dihydroquinoline (0.8 g) in dimethyl formamide(5 ml) was added dropwise to the reaction mixture and the mixture was stirred for 1 hour under ice-cooling. After distilling off dimethyl formamide, the resulting residue was poured into an ice-cold water and the mixture was extracted with chloroform. The extract was dried over anhydrous magnesium sulfate, then chloroform was distilled off. The resulting residue was purified by silica gel column chromatography [eluent : dichloromethane-methanol (200:1)] to give 1,4-dimethyl-8-(2-benzimidazolyl)thiomethyl-1,2-dihydroquinoline (0.4 g).
Reaction SMILES: [CH2:1]([O:4][C@H:5]1[O:34][C@H:33]([CH2:35][OH:36])[C@@H:24]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C@H:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@H:6]1[O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH:2]=[CH2:3].[C:37]1([CH3:47])[CH:42]=[CH:41][C:40]([S:43](Cl)(=[O:45])=[O:44])=[CH:39][CH:38]=1.O>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[CH2:1]([O:4][C@H:5]1[O:34][C@H:33]([CH2:35][O:36][S:43]([C:40]2[CH:41]=[CH:42][C:37]([CH3:47])=[CH:38][CH:39]=2)(=[O:45])=[O:44])[C@@H:24]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C@H:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@H:6]1[O:7][CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[CH:2]=[CH2:3]
Reactant: C=CCO[C@H]1O[C@H](CO)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: O
Product: C=CCO[C@H]1O[C@H](COS(=O)(=O)c2ccc(C)cc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of the compound (4) (25.1 g, 51.2 mmol) in anhydrous pyridine (250 ml) were added p-toluenesulfonyl chloride (14.6 g, 1.5 equivalents) and 4-dimethylaminopyridine (626 mg, 0.1 equivalents), and the reaction liquid was stirred at room temperature for 16 hours. After the sufficient progress of the reaction was confirmed, water (10 ml) was added to stop the reaction, and the reaction liquid was concentrated under reduced pressure. The residue was suspended in a minor amount of ethyl acetate, poured to 0.5 M hydrochloric acid (200 ml), and extracted with ethyl acetate (3×200 ml). The organic layers were combined, washed with a saturated sodium hydrogen carbonate solution (2×100 ml) and saturated saline (2×100 ml), dried with sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was crystallized twice from heated ethanol to obtain the title compound (5) in the form of colorless needle crystals (25.0 g). The filtrate was concentrated, purified with silica gel chromatography (hexane-ethyl acetate, 5:1→4:1→3:1) to obtain the compound (5) (4.00 g). {29.0 g (45.0 mmol) in total, 87.9%}.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](=[O:8])[NH:6][CH:7]=1.[H-].[Na+].Br[CH2:12][CH2:13][OH:14]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5](=[O:8])[N:6]([CH2:12][CH2:13][OH:14])[CH:7]=1
Reactant: OCCBr
Reactant: O=c1ccc(Br)c[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=c1ccc(Br)cn1CCO
Temperature: 23 °C
Reaction time: 0.33 h

Procedure:
To a stirring solution of 5-bromo-2(1H)-pyridone (1000 mg, 5.74 mmol) in dry DMF (10 mL) under nitrogen was added sodium hydride (60% dispersion in mineral oil, 264 mg, 11.5 mmol). After 20 min at 23° C., 2-bromoethyl alcohol (448 μl, 6.32 mmol) was added and the reaction mixture was stirred at 23° C. for 3 days. The reaction was quenched with NH4Cl (sat., 20 mL) and extracted with 9:1 CH2Cl2/iPrOH (50 mL; 25 mL×6). The combined organics were dried over MgSO4, and concentrated to an oil under reduced pressure from toluene. iPrOH (0.5 mL) was added, and the solution was seeded with crystals of the product. The resulting solids were washed with iPrOH (0.5 mL) and ether (2×2 mL). The mother liquor was then purified on silica (12 g) eluting with 0-3% MeOH/CH2Cl2. MS (ESI pos. ion) m/z (MH+): 217/219. Calc'd exact mass for C7H8BrNO2: 216. 1HNMR (400 MHz, CDCl3): δ 3.34 (br. s., 1H) 3.90-3.94 (m, 2H) 4.02-4.10 (m, 2H) 6.49 (d, J=9.59 Hz, 1H) 7.39 (dd, J=9.68, 2.64 Hz, 1H) 7.49-7.53 (m, 1H). 13C NMR (101 MHz, CDCl3) δ ppm 53.11, 61.04, 98.15, 121.80, 138.62, 143.04, 161.89
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:20]=[C:19]([OH:21])[C:18]([OH:22])=[CH:17][C:4]=2[S:5][C:6]=1[C:7]([N:9]1[CH2:14][CH:13]([CH3:15])[O:12][CH:11]([CH3:16])[CH2:10]1)=[O:8].[N+:23]([O-])([OH:25])=[O:24]>C(OCC)(=O)C.ClCCl>[Cl:1][C:2]1[C:3]2[CH:20]=[C:19]([OH:21])[C:18]([OH:22])=[C:17]([N+:23]([O-:25])=[O:24])[C:4]=2[S:5][C:6]=1[C:7]([N:9]1[CH2:10][CH:11]([CH3:16])[O:12][CH:13]([CH3:15])[CH2:14]1)=[O:8]
Reactant: O=[N+]([O-])O
Reactant: CC1CN(C(=O)c2sc3cc(O)c(O)cc3c2Cl)CC(C)O1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC1CN(C(=O)c2sc3c([N+](=O)[O-])c(O)c(O)cc3c2Cl)CC(C)O1
Reaction time: 4 h

Procedure:
(3-Chloro-5,6-dihydroxy-benzo[b]thiophen-2-yl)-(2,6-dimethyl-morpholin-4-yl)-methanone (0.20 g) was dissolved in ethyl acetate and 1 N HNO3 solution in dichloromethane (0.64 ml) was added. Stirring was continued for 4 hours. The mixture was concentrated to smaller volume and the precipitate filtered and washed with water. The crude product was recrystallized from N,N-dimethylformamide/ethanol (25:75).
Reaction SMILES: C([O:3][C:4]([C@@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([CH2:12][CH2:13][O:14][CH2:15][CH:16]=[C:17]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH3:30])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:7]1)=[O:5])C.[OH-].[Na+].Cl.[Cl:34]CCl>C(O)C>[ClH:34].[CH3:30][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[C:17]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)=[CH:16][CH2:15][O:14][CH2:13][CH2:12][N:8]1[CH2:9][CH2:10][CH2:11][C@@H:6]([C:4]([OH:5])=[O:3])[CH2:7]1
Reactant: ClCCl
Reactant: CCOC(=O)[C@@H]1CCCN(CCOCC=C(c2ccccc2)c2ccccc2C)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1ccccc1C(=CCOCCN1CCC[C@@H](C(=O)O)C1)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
(R)-N-(2-(3-(2-Methylphenyl)-3-phenyl-2-propen-1-yloxy)ethyl)-3-piperidinecarboxylic acid ethyl ester (2.3 g, 5.6 mmol) was dissolved in ethanol (10 ml) and a 12 N sodium hydroxide solution (1.4 ml) was added. The reaction mixture was stirred at room temperature for 4 h. A concentrated hydrochloric acid solution was added with cooling of the reaction vessel in an ice-bath until pH 1 and dichloromethane (250 ml) was added. The resulting emulsion was dried (Na2SO4) and the solvent was evaporated in vacuo to give a residue which was crystallised from acetone. This afforded 1.75 g (76%) of the title compound.
Reaction SMILES: [C:1]1(=[O:10])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[S:11]1[CH:15]=[CH:14][C:13]([CH:16]=O)=[CH:12]1.N1CCCCC1>C(O)(=O)C>[S:11]1[CH:15]=[CH:14][C:13]([CH:16]=[C:2]2[CH2:3][C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[C:1]2=[O:10])=[CH:12]1
Reactant: O=C1CCc2ccccc21
Reactant: O=Cc1ccsc1
Solvent: CC(=O)O
Solvent: C1CCNCC1
Product: O=C1C(=Cc2ccsc2)Cc2ccccc21

Procedure:
Indan-1-one (3.30 g), thiophene-3-carboxaldehyde (2.60 ml), acetic acid (0.47 ml) and piperidine (0.57 ml) were heated together on a steam-bath for 16 hours. The mixture was cooled to give a solid mass which was boiled with IMS (120 ml) and hot filtered to remove insoluble material. The filtrate was cooled in ice to precipitate a brown solid which was collected by filtration and dried to give 2-(3-thienyl)methyleneindan-1-one, m.p. 137-13 8° C.
Reaction SMILES: [OH:1][C@@H:2]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])/[CH:3]=[CH:4]/[C@H:5]1[C@H:12]([O:13][C:14](=[O:27])[C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:17][CH:16]=2)[CH2:11][C@H:10]2[C@@H:6]1[CH2:7][C:8](=[O:28])[O:9]2.[O:36]1[CH:41]=[CH:40][CH2:39][CH2:38][CH2:37]1>C(Cl)Cl>[C:21]1([C:18]2[CH:17]=[CH:16][C:15]([C:14]([O:13][C@@H:12]3[CH2:11][C@H:10]4[C@H:6]([CH2:7][C:8](=[O:28])[O:9]4)[C@H:5]3/[CH:4]=[CH:3]/[C@@H:2]([O:1][CH:37]3[CH2:38][CH2:39][CH2:40][CH2:41][O:36]3)[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])=[O:27])=[CH:20][CH:19]=2)[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CCCCCCC[C@H](O)/C=C/[C@@H]1[C@H]2CC(=O)O[C@H]2C[C@H]1OC(=O)c1ccc(-c2ccccc2)cc1
Reactant: C1=COCCC1
Solvent: ClCCl
Product: CCCCCCC[C@@H](/C=C/[C@@H]1[C@H]2CC(=O)O[C@H]2C[C@H]1OC(=O)c1ccc(-c2ccccc2)cc1)OC1CCCCO1

Procedure:
The 3S-hydroxy compound (4a) (4.58 g) was dissolved into methylene chloride (100 ml), and reacted with dihydropyran in the presence of a catalytic amount of p-toluenesulfonic acid-1H2O. After a usual work-up, the reaction mixture was column-chormatographed to give the title compound (5). Yield: 5.03 g