Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][NH:6][C:7]([C@:9]1([CH3:38])[C@H:14]([NH:15][S:16]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]3[C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[N:30]=[C:29]([CH3:37])[CH:28]=3)=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH2:13][CH2:12][NH:11][CH2:10]1)=[O:8])([CH3:4])([CH3:3])[CH3:2].C(=O)(O)[O-].[Na+].[CH:44]([S:47](Cl)(=[O:49])=[O:48])([CH3:46])[CH3:45]>C(Cl)Cl.C(OCC)(=O)C>[C:1]([O:5][NH:6][C:7]([C@:9]1([CH3:38])[C@H:14]([NH:15][S:16]([C:19]2[CH:20]=[CH:21][C:22]([O:25][CH2:26][C:27]3[C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[N:30]=[C:29]([CH3:37])[CH:28]=3)=[CH:23][CH:24]=2)(=[O:18])=[O:17])[CH2:13][CH2:12][N:11]([S:47]([CH:44]([CH3:46])[CH3:45])(=[O:49])=[O:48])[CH2:10]1)=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)S(=O)(=O)Cl
Reactant: Cc1cc(COc2ccc(S(=O)(=O)N[C@@H]3CCNC[C@]3(C)C(=O)NOC(C)(C)C)cc2)c2ccccc2n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cc1cc(COc2ccc(S(=O)(=O)N[C@@H]3CCN(S(=O)(=O)C(C)C)C[C@]3(C)C(=O)NOC(C)(C)C)cc2)c2ccccc2n1
Reaction time: 8 h
Yield: 66.3 %

Procedure:
To a solution of 0.15 g (0.28 mmol) of (3S,4R)-N-tert-butoxy-3-methyl-4-(4-((2-methylquinolin-4-yl)methoxy)phenylsulfonamido)piperidine-3-carboxamide (Example 47, Step 8) in CH2Cl2 (1.3 mL) was added 3 mL of saturated sodium bicarbonate followed by isopropylsulfonyl chloride (0.1 mL, 0.9 mmol). The reaction mixture was stirred overnight, taken up in ethyl acetate, washed with brine, dried over MgSO4, filtered and concentrated. The residue was purified by silica chromatography (silica pre-washed with methanol) eluting with a gradient of 1-5% MeOH/CH2Cl2 to afford (3S,4R)-N-tert-butoxy-1-(isopropylsulfonyl)-3-methyl-4-[({4-[(2-methylquinolin-4-yl)methoxy]phenyl}sulfonyl)amino]piperidine-3-carboxamide (0.12 g, 66%) as a colorless solid. MS: 647.2 (M+H)+
Reaction SMILES: Cl.COC1C=CC(C[S:9][C@@H:10]2[CH2:14][N:13]([C:15]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=3)=[O:16])[C@H:12]([C:28]([N:30]3[CH2:36][CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)=[O:29])[CH2:11]2)=CC=1.[N+:39]([C:42]1[CH:54]=[CH:53][C:45]([CH2:46][O:47][C:48]([NH:50][CH:51]=N)=[O:49])=[CH:44][CH:43]=1)([O-:41])=[O:40].FC(F)(F)S([O-])(=O)=O>>[SH:9][C@@H:10]1[CH2:14][N:13]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=2)=[O:16])[C@H:12]([C:28]([N:30]2[CH2:36][CH2:35][CH2:34][N:33]([CH:51]=[N:50][C:48]([O:47][CH2:46][C:45]3[CH:53]=[CH:54][C:42]([N+:39]([O-:41])=[O:40])=[CH:43][CH:44]=3)=[O:49])[CH2:32][CH2:31]2)=[O:29])[CH2:11]1
Reactant: N=CNC(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: COc1ccc(CS[C@H]2C[C@@H](C(=O)N3CCCNCC3)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Agent: Cl
Agent: O=S(=O)([O-])C(F)(F)F
Product: O=C(N=CN1CCCN(C(=O)[C@@H]2C[C@H](S)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)CC1)OCc1ccc([N+](=O)[O-])cc1

Procedure:
Following a procedure similar to that described in Preparation 4, but using 2.10 g of (2S,4S)-4-(4-methoxy-benzylthio)-2-(1-homopiperazinylcarbonyl)-1-(4-nitro-benzyloxycarbonyl)pyrrolidine hydrochloride [prepared as described in Preparation 2(i)] and 0.93 g of N-(4-nitrobenzyloxycarbonyl)formamidine, 2.38 g of the trifluoromethanesulfonate of the title compound were obtained. The salt was treated by the same procedure as described in Preparation 4(ii), to give 1.90 g of the title compound.
Reaction SMILES: Br[C:2]1[C:3](=[O:33])[C:4]2[C:9]([C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=1[F:18])=[CH:8][CH:7]=[C:6]([O:19][CH2:20][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][N:26]([S:29]([CH3:32])(=[O:31])=[O:30])[CH2:25][CH2:24]1)[CH:5]=2.O1CCN(CCO[C:43]2[CH:51]=[C:50]3[C:46]([C:47](C4C=CC=CC=4)=C(Br)C3=O)=[CH:45][CH:44]=2)CC1.B(O)(O)C1C=CC(C)=CC=1>>[F:18][C:12]1[CH:13]=[C:14]([F:17])[CH:15]=[CH:16][C:11]=1[C:10]1[C:9]2[C:4](=[CH:5][C:6]([O:19][CH2:20][CH2:21][CH2:22][N:23]3[CH2:28][CH2:27][N:26]([S:29]([CH3:32])(=[O:30])=[O:31])[CH2:25][CH2:24]3)=[CH:7][CH:8]=2)[C:3](=[O:33])[C:2]=1[C:43]1[CH:51]=[CH:50][C:46]([CH3:47])=[CH:45][CH:44]=1
Reactant: CS(=O)(=O)N1CCN(CCCOc2ccc3c(c2)C(=O)C(Br)=C3c2ccc(F)cc2F)CC1
Reactant: O=C1C(Br)=C(c2ccccc2)c2ccc(OCCN3CCOCC3)cc21
Agent: Cc1ccc(B(O)O)cc1
Product: Cc1ccc(C2=C(c3ccc(F)cc3F)c3ccc(OCCCN4CCN(S(C)(=O)=O)CC4)cc3C2=O)cc1
Yield: 76 %

Procedure:
The procedure of Step 7 of Example 1 was repeated except for using 2-bromo-3-(2,4-difluorophenyl)-6-[3-(4-(methylsulfonyl)piperazin-1-yl)propoxy]-1H-inden-1-one obtained in Step 1 as a starting material instead of 6-(2-morpholinoethoxy)-2-bromo-3-phenyl-1H-inden-1-one and p-tolylboronic acid instead of 3-pyridinylboronic acid to obtain the title compound (76%).
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:7]([NH:8][CH2:9][CH2:10][SH:11])=[N:6][S:5](=[O:12])[N:4]=1.[CH3:13][N:14]([CH2:16][C:17]1[O:21][C:20]([CH2:22]O)=[CH:19][CH:18]=1)[CH3:15]>Cl>[CH3:13][N:14]([CH2:16][C:17]1[O:21][C:20]([CH2:22][S:11][CH2:10][CH2:9][NH:8][C:7]2[C:3]([NH:2][CH3:1])=[N:4][S:5](=[O:12])[N:6]=2)=[CH:19][CH:18]=1)[CH3:15]
Reactant: CNC1=NS(=O)N=C1NCCS
Reactant: CN(C)Cc1ccc(CO)o1
Agent: Cl
Product: CNC1=NS(=O)N=C1NCCSCc1ccc(CN(C)C)o1

Procedure:
When 3-methylamino-4-(2p-mercaptoethylamino)-1,2,5-thiadiazole 1-oxide [prepared in Step A] is treated with about one equivalent of 5-dimethylaminomethyl-2-furanmethanol in concentrated hydrochloric acid according to the procedure described in Example 25, Step B, the title compound is thereby produced; identical to the product of Example 18.
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[O-]CC.[Na+].CS(C)=O.[CH2:17](Cl)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(O)C>[Cl:1][C:2]1[C:7]([O:8][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Oc1cccnc1Cl
Reactant: ClCc1ccccc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CS(C)=O
Product: Clc1ncccc1OCc1ccccc1

Procedure:
2-Chloro-3-hydroxypyridine (9.47 g; 0.073 moles) was added to a solution of sodium ethoxide in ethanol (from sodium, 1.67 g; 0.073 g. atom). Sufficient dimethyl sulphoxide was added to dissolve all of the solid, and ethanol was removed in vacuo . To the resulting solution was added benzyl chloride (9.3 g; 0.073 moles) with cooling and stirring, and the reaction mixture was left to stir under reflux for 6 hours. Unreacted benzyl chloride, and solvent, were evaporated off under vacuum on a boiling water bath, and the residue was treated with water to precipitate out an oil which was extracted with chloroform, washed with N sodium hydroxide solution and dried over anhydrous magnesium sulfate. After removing the solvent, 2-chloro-3-benzyloxypyridine was obtained as a solid (11.63 g, mp 36°-8°).
Reaction SMILES: [CH2:1]([C:16]1[CH:25]=[CH:24][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]=1[OH:26])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].C(O)(=[O:29])C>O>[CH2:1]([C:16]1[C:17](=[O:26])[C:18]2[C:23]([C:24](=[O:29])[CH:25]=1)=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCCCCCCCCCCCCCc1ccc2ccccc2c1O
Reactant: CC(=O)O
Solvent: O
Product: CCCCCCCCCCCCCCCC1=CC(=O)c2ccccc2C1=O
Temperature: 25 °C

Procedure:
2-Pentadecyl-1-naphthol (48 , 135 mmol) was dissolved in acetic acid with slight warming. Chromic oxide (55.5 g, 555 mmol) was dissolved in 50 ml water and then 50 ml acetic acid was added. This chromic oxide solution was then added dropwise with stirring to the solution of the pentadecylnaphthol maintaining the temperature between 45°-50° C. The mixture was then stirred for several hours while slowly cooling to room temperature. The pentadecylnaphthoquinone, which had crystallized from solution was filtered off, washed with acetic acid, water, and air dried. Yield: 24 g (48 percent). (Method of L. F. Fieser et al, J. Am. Chem. Soc., 74, 3910 (1952)).
Reaction SMILES: [F-:1].[K+].Cl[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N+:10]([O-:12])=[O:11]>CN(C)C=O>[F:1][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N+:10]([O-:12])=[O:11]
Reactant: [F-]
Reactant: O=[N+]([O-])c1ccccc1Cl
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccccc1F
Yield: 52.4 %

Procedure:
A finely ground mixture of potassium fluoride (11.62 g, 0.2 mole) and CsF-silica (5 g, ca. 5 mmole equiv. F) is dried at 150° C. and then immediately transferred to a three-necked flask containing 2-chloronitrobenzene (7.88 g, 0.05 mole) and dimethylformamide. The flask is connected to a water-condenser and a mechanical stirrer and the reaction mixture is brought to reflux with vigorous stirring. After 24 h. the reaction mixture is cooled and separated into its ether- and water-soluble components. Chloride analysis of the aqueous extracts (AgNO3 titration, K2CrO4 indicator) shows better than 60% conversion of the 2-chloronitrobenzene. The ethereal extracts are washed with water (to remove the D.M.F.), dried over anhydrous Na2SO4, evaporated to dryness on a rotary evaporator and distilled under reduced pressure to give 3.7 g (52%) of 2-fluoronitrobenzene, b.p. 68°-70° C. (4 Torr). When the same reaction is carried out using (i) a dried mixture of KF (11.62 g) and CsF (0.75 g) and (ii) dried KF (11.62 g) alone in place of the KF-CsF-silica mix, chloride analysis of the aqueous extracts shows ca. 60% and ca. 20% conversion of 2-chloronitrobenzene respectively.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2(O)[CH2:15][CH2:14][CH:13]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][CH2:25][CH3:26])=[C:18]([F:27])[C:17]=3[F:28])[CH2:12][CH2:11]2)=[C:6]([F:30])[C:5]=1[F:31])[CH3:2].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH2:15][CH2:14][CH:13]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][CH2:25][CH3:26])=[C:18]([F:27])[C:17]=3[F:28])[CH2:12][CH:11]=2)=[C:6]([F:30])[C:5]=1[F:31])[CH3:2]
Reactant: CCCCOc1ccc(C2CCC(O)(c3ccc(OCC)c(F)c3F)CC2)c(F)c1F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCOc1ccc(C2CC=C(c3ccc(OCC)c(F)c3F)CC2)c(F)c1F
Temperature: 30 °C
Yield: 56.5 %

Procedure:
The compound (29) (19.0 g), p-toluenesulfonic acid (0.57 g) and toluene (200 ml) were mixed, and the mixture was heated under reflux for 2 hours while water being distilled was removed. The obtained reaction mixture was cooled to 30° C., and water (200 ml) and toluene (200 ml) were added thereto, and mixed. The mixture was then allowed to separate into organic and aqueous phases, and the extraction into an organic phase was carried out. The organic phase obtained was washed sequentially with a saturated aqueous solution of sodium hydrogencarbonate and water, and dried over anhydrous magnesium sulfate. The solution obtained was purified by means of column chromatography (silica gel; toluene), and further purified by means of recrystallization (Solmix A-11: ethyl acetate=2:1 by volume), giving 10.3 g of 1-(4-ethoxy-2,3-difluorophenyl)-4-(4-butoxy-2,3-difluorophenyl)cyclohexene (No. 77). The yield based on the compound (27) was 55.0%.
Reaction SMILES: [C:1]1(=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](=[O:10])[CH2:2]1.[Cl:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][C:20]=1[Cl:21])[CH:16]=O>CCO.N1CCCCC1>[Cl:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][C:20]=1[Cl:21])[CH:16]=[C:2]1[C:1](=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:10]
Reactant: O=Cc1ccc(Cl)c(Cl)c1
Reactant: O=C1CC(=O)c2ccccc21
Solvent: C1CCNCC1
Solvent: CCO
Product: O=C1C(=Cc2ccc(Cl)c(Cl)c2)C(=O)c2ccccc21
Yield: 85 %

Procedure:
To a solution of indan-1,3-dione (1a) (960 mg, 6.6 mmol) in EtOH (8.2 mL) was added 3,4-dichlorobenzaldehyde (1b) (1.3 g, 7.2 mmol) followed by piperidine (3 drops). The reaction mixture was heated to reflux for 30 min. After cooling, the reaction was diluted with EtOH (8 mL) and the precipitate was filtered. The resulting solid was triturated twice with EtOH and dried under high vacuum to give 2-(3,4-dichloro-benzylidene)-indane-1,3-dione (1c) (1.7 g, 82% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[C:4]([OH:11])[CH:3]=1.[F:12][CH:13]([F:17])[C:14]([CH3:16])=O.N1CCCC1>CO>[Cl:1][C:2]1[CH:3]=[C:4]2[C:5]([C:8](=[O:10])[CH2:9][C:14]([CH:13]([F:17])[F:12])([CH3:16])[O:11]2)=[CH:6][CH:7]=1
Reactant: CC(=O)c1ccc(Cl)cc1O
Reactant: CC(=O)C(F)F
Solvent: C1CCNC1
Solvent: CO
Product: CC1(C(F)F)CC(=O)c2ccc(Cl)cc2O1
Reaction time: 3 h
Yield: 83.9 %

Procedure:
1-(4-Chloro-2-hydroxyphenyl)ethanone (8.07 g, 47.3 mmol), MeOH (81 mL), 1,1-difluoroacetone (4.89 g, 52.0 mmol), and pyrrolidine (4.30 ml, 52.0 mmol) were stirred at ambient temperature for 45 hours, at 35° C. for 7 hours, then at 50° C. for 3 hours. The reaction mixture was concentrated, diluted with MTBE (75 mL), then washed with water (40 mL), 2N HCl (2×25 mL), brine (20 mL), 2N NaOH (2×20 mL), and brine (2×20 mL). The organic portion was dried (Na2SO4), filtered, and concentrated to give the title compound (9.78 g, 39.7 mmol, 84% yield) as a brown oil. MS (DCI/NH3) m/z 264 (M+NH4)+.
Reaction SMILES: S(OC)(O[CH3:5])(=O)=O.Cl.[C:9]([C@@H:12]1[CH2:16][C@H:15]([S:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[CH2:14][NH:13]1)(=[O:11])[NH2:10].[OH-].[Na+]>O1CCOCC1>[C:9]([C@@H:12]1[CH2:16][C@H:15]([S:17][CH2:18][C:19]2[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=2)[CH2:14][N:13]1[CH3:5])(=[O:11])[NH2:10]
Reactant: COc1ccc(CS[C@@H]2CN[C@H](C(N)=O)C2)cc1
Reactant: COS(=O)(=O)OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: COc1ccc(CS[C@H]2C[C@@H](C(N)=O)N(C)C2)cc1
Reaction time: 1 h

Procedure:
10.86 ml of dimethyl sulfate were added to a solution of 30 g of (2S,4S)-2-carbamoyl-4-(4-methoxybenzylthio)pyrrolidine hydrochloride in a mixture of 36 ml of a 20% w/v aqueous solution of sodium hydroxide and 470 ml of dioxane, and the resulting mixture was stirred at a temperature of between 22° C. and 23° C. for 1 hour. At the end of this time, the reaction mixture was concentrated by evaporation under reduced pressure, and the resulting residue was extracted with 2 liters of ethyl acetate. The extract was washed with an aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The solution was then concentrated by evaporation under reduced pressure, until crystals emerged, and then 400 ml of diisopropyl ether were added to the mixture and the crystals which precipitated were collected by filtration, to give 23 g of the title compound as crystals, melting at 113°-114° C.
Reaction SMILES: [Na][Na].[C:3]([CH2:11][C:12]([C:14]1[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=1[C:16]([OH:18])=[O:17])=O)(=O)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl.O.[NH2:25][NH2:26]>CO.O>[C:16]([C:15]1[CH:19]=[CH:20][CH:21]=[CH:22][C:14]=1[C:12]1[CH:11]=[C:3]([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:26][N:25]=1)([OH:18])=[O:17]
Reactant: NN
Reactant: O=C(CC(=O)c1ccccc1C(=O)O)c1ccccc1
Agent: Cl
Agent: [Na][Na]
Solvent: O
Solvent: CO
Product: O=C(O)c1ccccc1-c1cc(-c2ccccc2)[nH]n1

Procedure:
To a slurry of 100 g of the disodium salt of 2-benzoylacetylbenzoic acid in 400 ml of methanol is added first 12.5 g concentrated hydrochloric acid, followed by 11 g of hydrazine hydrate. This reaction mixture is heated at reflux for 1/2 hour, cooled to 5°-10°, acidified to pH 3 with concentrated hydrochloric acid, and diluted with 300 ml of water. The crystals are filtered off and recrystallized from ethanol-water, yielding 59 g of 3-(2-carboxyphenyl)-5-phenylpyrazole, mp 204°-205.5°.
Reaction SMILES: N(C(C)=O)(CNC(C)=O)CNC(C)=O.C=O.O.[C:18]([OH:21])(=[O:20])[CH3:19].N(CC(O)=O)CC(O)=O.[C:31]([NH:34][CH2:35][C:36]([OH:38])=[O:37])(=[O:33])[CH3:32]>COCCOC>[C:31]([N:34]([CH2:35][C:36]([OH:38])=[O:37])[CH2:19][C:18]([OH:21])=[O:20])(=[O:33])[CH3:32]
Reactant: CC(=O)O
Reactant: CC(=O)NCC(=O)O
Agent: C=O
Agent: CC(=O)NCN(CNC(C)=O)C(C)=O
Agent: O=C(O)CNCC(=O)O
Solvent: O
Solvent: COCCOC
Product: CC(=O)N(CC(=O)O)CC(=O)O
Temperature: 125 °C
Yield: 91 %

Procedure:
A 300 mL autoclave was charged with acetamide (VII)(11.8 g, 0.2 mole), 95% paraformaldehyde (13.6 g, 0.43 mole), water (10.8 g, 0.60 mole), acetic acid (16.8 g, 0.28 mole, 0.19 g/mL of DME), DME (90 mL) and Co2(CO)8 (4.1 g, 0.012 mole) and pressurized to 1500 psi (10,345 kPa) CO:H2 (95:5) at 25° C. This mixture was heated to 125° C. for 30 min. HPLC analysis of this stream indicated a 91% yield of (XVI), 1% (XIV), and 3% (XVIII).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:13])=[C:6](/[CH:8]=[C:9](\[CH3:12])/[CH:10]=O)[CH:7]=1.CC1C=CC(S([NH:24][NH2:25])(=O)=O)=CC=1.[OH-].[Na+]>C(#N)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:13])=[C:6]([C:8]2[NH:25][N:24]=[CH:10][C:9]=2[CH3:12])[CH:7]=1
Reactant: C/C(C=O)=C\c1cc(Cl)ccc1O
Reactant: Cc1ccc(S(=O)(=O)NN)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Product: Cc1cn[nH]c1-c1cc(Cl)ccc1O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of (E)-3-(5-chloro-2-hydroxyphenyl)-2-methylacrylaldehyde (40 mg, 0.203 mmol) and 4-methylbenzenesulfonohydrazide (41.7 mg, 0.224 mmol) in Acetonitrile (3 mL) were stirred at room temperature for 3 h and then acetonitrile (2 mL), Sodiumhydroxide (8.95 mg, 0.224 mmol) were added and the mixture was heated at reflux for 16 h. Product was used for further reaction without purification.
Reaction SMILES: [CH3:1][Li].[CH3:3][CH:4]([CH2:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:5][C:6]([OH:8])=O.[Cl-].[NH4+]>C(OCC)C>[CH3:3][CH:4]([CH2:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:5][C:6](=[O:8])[CH3:1]
Reactant: CC(CC(=O)O)CC(C)(C)C
Reactant: [Li]C
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: CC(=O)CC(C)CC(C)(C)C
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
250 ml. of a ca. 2-M ethereal methyl lithium solution are added dropwise to 39.5 g. of 3,5,5-trimethylhexanoic acid in 250 ml. of absolute diethyl ether at such a rate that a slight reflux is maintained. After completion of the addition, the mixture is stirred at room temperature for 1.5 hours, then cooled in an ice bath and 100 ml. of saturated aqueous ammonium chloride solution are cautiously added dropwise with stirring. The mixture is filtered through diatomaceous earth and the two phases of the filtrate are separated. The aqueous phase is back-extracted once with diethyl ether and the ether solutions are washed successively with ammonium chloride solution, water and saturated aqueous sodium chloride solution, dried over sodium sulfate and evaporated. By distillation there is obtained pure 4,6,6-trimethyl-2-heptanone of boiling point 64°-67° C./12 mmHg; nD20 = 1.4258.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH:5]=[O:6].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[O:6])[CH:7]=[CH:8][C:9]=1[O:10][CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20]
Reactant: O=Cc1ccc(O)c(Br)c1
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)COc1ccc(C=O)cc1Br
Temperature: 25 °C
Reaction time: 18 h
Yield: 98.2 %

Procedure:
To a solution of 3-bromo-4-hydroxybenzaldehyde (5 g, 25 mmol, 1 eq, Aldrich, Milwaukee, Wis., USA) in DMF (200 mL) was added solid cesium carbonate (16.25 g, 50 mmol, 2 eq) followed by dropwise addition of t-butyl 2-bromoacetate (4.4 mL, 30 mmol, 1.2 eq, Aldrich, Milwaukee, Wis., USA). After stirring at room temperature for 18 h, the DMF was removed in vacuo and the resultant residue was extracted between EtOAc (50 mL) and brine (50 mL). The separated organic layer was dried (Na2SO4), and concentrated in vacuo to give 7.74 g (98.4%) of t-butyl 2-(2-bromo-4-formylphenoxy)acetate (1). 1HNMR (CDCl3, 300 MHz): δ 9.83 (s, 1H), 8.08 (d, 1H), 7.76 (dd, 1H), 6.83 (d, 1H), 4.67 (s, 1H).1.44 (s, 9H).
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[O:15][C:6]2=[CH:7][C:8]3[C:9]([CH:14]=[C:5]2[CH:4]2[O:16][CH:3]12)=[N:10][O:11][N+:12]=3[O-].P(OCC)(OCC)OCC>C1C=CC=CC=1>[CH3:1][C:2]1([CH3:17])[O:15][C:6]2=[CH:7][C:8]3[C:9]([CH:14]=[C:5]2[CH:4]2[O:16][CH:3]12)=[N:10][O:11][N:12]=3
Reactant: CC1(C)Oc2cc3c(cc2C2OC21)no[n+]3[O-]
Agent: CCOP(OCC)OCC
Solvent: c1ccccc1
Product: CC1(C)Oc2cc3nonc3cc2C2OC21
Reaction time: 0.25 h

Procedure:
1.00 (4 27 mmol) of 7,8 dihydro-6,6-dimethyl-7,8-epoxy-6H-pyrano[2,3-f]benz-2,1,3-oxadiazole-3-oxide (compound [G]) and 6 ml of benzene were stirred at 60° C., while 0.80 ml (4.70 mmol) of triethyl phosphite was added thereto dropwise within 15 minutes. Next, the obtained mixture was stirred for three hours.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:20]2[CH:25]=[CH:24][C:23]([O:26][C:27](=[O:31])[CH2:28][CH2:29][OH:30])=[CH:22][CH:21]=2)[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15](=[O:19])[CH2:16][CH2:17][OH:18])=[CH:10][CH:9]=2)[CH:7]=1.[C:32]([OH:37])(=O)[C:33]([CH3:35])=[CH2:34]>>[CH3:34][C:33](=[CH2:35])[C:32]([O:30][CH2:29][CH2:28][C:27]([O:26][C:23]1[CH:24]=[CH:25][C:20]([C:4]2[CH:3]=[C:2]([O:1][C:32](=[O:37])[C:33]([CH3:35])=[CH2:34])[CH:7]=[C:6]([C:8]3[CH:9]=[CH:10][C:11]([O:14][C:15](=[O:19])[CH2:16][CH2:17][O:18][C:32](=[O:37])[C:33]([CH3:35])=[CH2:34])=[CH:12][CH:13]=3)[CH:5]=2)=[CH:21][CH:22]=1)=[O:31])=[O:37]
Reactant: C=C(C)C(=O)O
Reactant: O=C(CCO)Oc1ccc(-c2cc(O)cc(-c3ccc(OC(=O)CCO)cc3)c2)cc1
Product: C=C(C)C(=O)OCCC(=O)Oc1ccc(-c2cc(OC(=O)C(=C)C)cc(-c3ccc(OC(=O)CCOC(=O)C(=C)C)cc3)c2)cc1

Procedure:
In analogy to step 2 of Example 1, 3-hydroxy-propionic acid-5′-hydroxy-4″-(3-hydroxy-propionyloxy)-[1,1′;3′,1″]terphenyl-4-yl ester and methacrylic acid are reacted to give 2-methyl-acrylic acid-4,4″-bis-[3-(2-methylacryloyloxy)-propionyloxy]-[1,1′;3′,1″]terphenyl-5′-yl ester as colourless crystals, m.p. 88° C.
Reaction SMILES: [CH3:1][N:2]([CH3:21])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[O:11][CH2:12][C:13](=[O:20])[C:14]=2[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:5][CH:4]=1.[NH:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][N:29]=2)[C:24]([CH:31]=O)=[CH:23]1.[ClH:33]>C(O)C>[ClH:33].[NH:22]1[C:30]2=[N:29][CH:28]=[CH:27][CH:26]=[C:25]2[C:24]([CH:31]=[C:12]2[O:11][C:10]([NH:9][C:6]3[CH:7]=[CH:8][C:3]([N:2]([CH3:1])[CH3:21])=[CH:4][CH:5]=3)=[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:13]2=[O:20])=[CH:23]1
Reactant: O=Cc1c[nH]c2ncccc12
Reactant: CCOC(=O)C1=C(Nc2ccc(N(C)C)cc2)OCC1=O
Agent: Cl
Solvent: CCO
Product: CCOC(=O)C1=C(Nc2ccc(N(C)C)cc2)OC(=Cc2c[nH]c3ncccc23)C1=O
Temperature: 25 °C
Yield: 35 %

Procedure:
To a solution of ethyl 2-{[4-(dimethylamino)phenyl]amino}-4-oxo-4,5-dihydrofuran-3-carboxylate (0.073 g, 0.20 mmol) which similarly prepared according to the procedure described in the Example 2, First step and 7-azaindole-3-carboxaldehyde (0.029 g, 0.20 mmol) in ethanol (1.5 mL), 2M hydrochloric acid in ethanol (0.33 mL, 0.66 mmol) was added at ambient temperature. The mixture was refluxed for 1 h. Cooled to ambient temperature, the precipitate was collected by filtration, washed with ethanol and diisopropyl ether then dried to afford the titled compound (0.034 g, y. 35%).
Reaction SMILES: N1C=CC=CC=1.[C:7](Cl)(=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[O:16]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[CH:18]=[C:17]1[C:25]1[O:30][C:29](=[O:31])[C:28]([CH3:32])=[C:27]([OH:33])[C:26]=1[CH3:34].OS([O-])(=O)=O.[K+]>C(Cl)Cl>[O:16]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[CH:18]=[C:17]1[C:25]1[O:30][C:29](=[O:31])[C:28]([CH3:32])=[C:27]([O:33][C:7](=[O:14])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:26]=1[CH3:34]
Reactant: Cc1c(-c2cc3ccccc3o2)oc(=O)c(C)c1O
Reactant: O=C(Cl)c1ccccc1
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1c(-c2cc3ccccc3o2)oc(=O)c(C)c1OC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.83 h

Procedure:
Pyridine (64 μl) and benzoyl chloride (45 μl) were added to a suspension of 6-(benzofuran-2-yl)-3,5-dimethyl-4-hydroxy-2H-pyran-2-one (40 mg) in CH2Cl2 (5 ml), and the mixture was stirred at room temperature for 50 minutes. The reaction solution was poured into a KHSO4 aqueous solution and extracted with AcOEt, and the organic layer was rinsed with saturated saline and dried with MgSO4, and then filtered and concentrated. The residue was purified by silica gel column chromatography (n-hexane/AcOEt=5/1→4/1) to obtain 6-(benzofuran-2-yl)-4-benzoyloxy-3,5-dimethyl-2H-pyran-2-one.