Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:10]2[N:9]=[N:8][NH:7][C:6]=2[CH:5]=[CH:4][C:3]=1[N+:11]([O-])=O>C(O)C.Cl.[Pd]>[NH2:1][C:2]1[C:10]2[N:9]=[N:8][NH:7][C:6]=2[CH:5]=[CH:4][C:3]=1[NH2:11]
Reactant: Nc1c([N+](=O)[O-])ccc2[nH]nnc12
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: Nc1ccc2[nH]nnc2c1N
Yield: 117.3 %

Procedure:
A suspension of 4-amino-5-nitrobenzotriazole (0.72 g, 4 mmol) in 100 ml of ethanol and 1 ml of conc. hydrochloric acid was hydrogenated at atmospheric pressure and room temperature for 6 h in the presence of 100 mg of 5% palladium-on-charcoal. The mixture was filtered and the catalyst was washed with about 50 ml of water. The combined filtrate was evaporated to dryness giving 0.70 g of the 4,5-diamino-benzotriazole as an hydrochloride. A solution of the crude diamino compound in 40 ml of 4M hydrochloric acid was refluxed with oxalic acid dihydrate (0.50 g, 4 mmol) for 3 h. The mixture was cooled on ice, and pH was adjusted to 5-6 with 2N sodium hydroxide. The precipitate was filtered off and washed with water and ethanol. It was then dissolved in 10 ml of 2N sodium hydroxide, treated with decolourising charcoal, and filtered. After adjustment to pH 6-7 with 4M hydrochloric acid the reprecipitated product was isolated, washed with water and ethanol, and dried at 100 ° C. affording 0.12 g (15%) of pure title compound; m.p. >300° C.; IR (KBr): 3200-2000, 1670 cm-1 ; 1H-NMR (DMSO-d6): 6.9 (broad s, 3H, NH+2OH); 7.03 (d,J=8 Hz, 1H, ArH); 7.43 (d,J=8 Hz,1H, ArH).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]([F:11])([F:10])[F:9])=[N:6][CH:7]=1.[CH:12]([Sn](CCCC)(CCCC)CCCC)=[CH2:13]>CN(C=O)C.C1COCC1.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>[F:9][C:8]([F:11])([F:10])[C:5]1[CH:4]=[CH:3][C:2]([CH:12]=[CH2:13])=[CH:7][N:6]=1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: FC(F)(F)c1ccc(Br)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: C=Cc1ccc(C(F)(F)F)nc1
Temperature: 100 °C
Yield: 1324.9 %

Procedure:
2 g of 5-bromo-2-(trifluoromethyl)pyridine was dissolved in DMF:THF (3:1, 12 mL). vinyltributyltin (3 g) and tetrakis(triphenylphosphine)palladium (135 mg) were added to this solution. The reaction mixture was degassed and purged with nitrogen for 5 min and then heated at 100° C. for 2 h. at which point the reaction was found complete (monitored by TLC). The reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure (Caution: product may be volatile) and the residue was purified by SiO2 chromatography (100-200 mesh, eluent: hexane-ethyl acetate gradient). The requisite fractions were concentrated below 40° C. under reduced pressure to obtain 20.3 g of 2-(trifluoromethyl)-5-vinylpyridine as oil.
Reaction SMILES: [CH3:1][O:2][C:3]([O:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=1)=[O:4].[CH3:14][O:15]C(Cl)Cl>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[CH3:13][O:12][C:9]1[CH:10]=[CH:11][C:6]([O:5][C:3]([O:2][CH3:1])=[O:4])=[CH:7][C:8]=1[CH:14]=[O:15]
Reactant: COC(Cl)Cl
Reactant: COC(=O)Oc1ccc(OC)cc1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: COC(=O)Oc1ccc(OC)c(C=O)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.6 %

Procedure:
To a stirred solution of 5 (20 g, 0.11 mol) in CH2Cl2 (250 mL) at 0° C. was added TiCl4 (49.2 g, 28.5 mL, 0.26 mol) in CH2Cl2 (50 mL). Stirring was continued at 0° C. while a solution of MeOCHCl2 (14.6 g, 11.5 mL, 0.127 mol) was added dropwise over 30 min. When the addition was complete, the solution was warmed to room temperature, left to stand for 30 min, and concentrated to half-volume by rotary evaporation. The resulting solution, containing the α-chloro ether 6, was poured into a mixture of ice (250 g) and 12 N HCl (10 mL), and then EtOAc (200 mL) was added. The two-phase mixture was stirred vigorously for 30 min, the layers were separated, the aqueous layer was back-extracted with EtOAc, and the combined EtOAc extracts were evaporated to dryness. Recrystallization of the crude solid (24.2 g) from a mixture of isooctane and absolute EtOH afforded 2-methoxy-5-(methoxycarbonyloxy) benzaldehyde (7) as white needles (17.7 g, 77%); mp 88–89° C. (lit. mp 88–90° C. 1H NMR (CDCl3) δ 3.90 (s, 3H, MeO), 3.92 (s, 3H, MeO), 6.99 (d, J=9 Hz, 1H, aryl 3-H), 7.38 (dd, J=9 Hz, J=3 Hz, 1H aryl 4-H), 7.63 (d, J=3 Hz, 1H, aryl 6-H), 10.45 (s, 1H, CH═O). Evaporation of the supernatant from the first crop afforded an additional 5.3 g (23%), bringing the total to 23 g (100%). The two fractions were combined and used without further purification.
Reaction SMILES: N1C=CN=C1.[Si:6](Cl)([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7].[Cl:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][OH:20].[Na+].[Cl-]>CN(C)C=O>[Cl:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][Si:6]([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCCOCCCl
Agent: [Cl-]
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCOCCCl
Reaction time: 8 h
Yield: 100.1 %

Procedure:
Imidazole (17.8 g, 261 mmol) was dissolved in dimethylformamide (100 ml) and t-butyldimethylsilyl chloride (36.3 g, 241 mmol) was added and stirred. 2-(2-chloroethoxy)ethanol (25.0 g, 200 mmol) was added dropwise over 1 hour under cooling with ice, and the mixture was stirred for 1 further hour, left standing overnight at room temperature, and then poured into saturated aqueous NaCl (500 ml). The resulting mixture was extracted twice with ether. The extract was washed twice with saturated aqueous NaCl, and dried over MgSO4. Then the solvent was removed in vacuo, giving 1-chloro-2-(2-t-butyldimethylsilyloxyethoxy)ethane (47.8 g, yield).
Reaction SMILES: C[O:2][C:3](=[O:31])[C@H:4]([CH2:25][C:26]1[N:30]=[CH:29][NH:28][CH:27]=1)[NH:5][C:6]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[OH-].[K+].Cl.C(OCC)(=O)C>C(OCC)(=O)C.C(O)C>[C:7]1([C:6]([NH:5][C@H:4]([C:3]([OH:31])=[O:2])[CH2:25][C:26]2[N:30]=[CH:29][NH:28][CH:27]=2)([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: COC(=O)[C@H](Cc1c[nH]cn1)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: O=C(O)[C@H](Cc1c[nH]cn1)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.83 h

Procedure:
53 mg of L-Nα -[(2RS)-3-ethylsulfonyl-2-(1-naphthylmethyl)propionyl]-Nim -triphenylmethylhistidine methyl ester was dissolved in 0.8 ml of methanol/water (10/1), and 0.387 ml of a solution of 1N potassium hydroxide in methanol/water (10/1) was added thereto. The mixture was stirred at room temperature for 50 minutes. The mixture was neutralized with 1N hydrochloric acid under cooling with ice, and 20 ml of ethyl acetate was added thereto. The ethyl acetate layer was washed with water and with a saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue thereby obtained was purified by silica gel column chromatography (chloroform/methanol/acetic acid=15/1/0.15). The fractions containing the desired product were collected, and the organic layer was washed with a 4% sodium hydrogencarbonate aqueous solution and with a saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. Then, the solvent was distilled off to obtain 49 mg of L-Nα -[(2RS)-3-ethylsulfonyl--2-(1-naphthylmethyl)propionyl]-Nim -triphenylmethylhistidine as colorless solid.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[NH:7]1[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1>O>[S:3]1[CH:4]=[CH:5][N:6]=[C:2]1[N:7]1[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1
Reactant: Brc1nccs1
Reactant: C1COCCN1
Solvent: O
Product: c1csc(N2CCOCC2)n1
Temperature: 25 °C
Reaction time: 61 h
Yield: 75.3 %

Procedure:
A solution of 2-bromothiazole (356 μL, 4.00 mmol) in morpholine (2.09 mL, 24.0 mmol) was warmed at 100° C. in a sealed tube. After 61 hours, the mixture was cooled to room temperature, diluted with 20 mL of water, and extracted with three 30 mL portions of diethyl ether. The combined organic layers were washed with five 30 mL portions of water, 30 mL of brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was chromatographed over SiO2 (20-100% ethyl acetate in hexanes, gradient) to afford 513 mg (75%) of 4-thiazol-2-yl-morpholine.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[C:7]([CH3:12])[CH:6]=1)[CH3:2].[Br:14]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>>[CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[C:7]([CH2:12][Br:14])[CH:6]=1)[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1ccc(Br)c(C)c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Product: CCOC(=O)c1ccc(Br)c(CBr)c1
Temperature: 80 °C
Reaction time: 6 h

Procedure:
4-Bromo-3-methyl-benzoic acid ethyl ester (18.24 g, 75.4 mmol), N-bromosuccinimide (14.1 g, 79.2 mmol), and benzoyl peroxide (0.9 g, 3.77 mmol) were combined in CC14, and the reaction was heated to 80° C. and stirred with a halogen desk lamp shining on it for 6 hours. The mixture was concentrated and partitioned between CH2Cl2 and H2O. The organic layer was separated and washed with H2O and brine, and then dried and concentrated. The residue was triturated with hexane (3×50 mL) and dried to give the title compound.
Reaction SMILES: C([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH:20]=[CH:21][C@H:22]1[CH2:27][CH2:26][C@H:25]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[C:29]=2[F:35])[CH2:24][CH2:23]1)C1C=CC=CC=1.C(O)C>C(OCC)(=O)C>[OH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C@H:22]1[CH2:23][CH2:24][C@H:25]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[C:29]=2[F:35])[CH2:26][CH2:27]1
Reactant: Fc1cccc([C@H]2CC[C@H](C=CCCCCCCCCCCCOCc3ccccc3)CC2)c1F
Solvent: CCO
Solvent: CCOC(C)=O
Product: OCCCCCCCCCCCCC[C@H]1CC[C@H](c2cccc(F)c2F)CC1
Temperature: 25 °C
Reaction time: 120 h

Procedure:
First, 10.9 g of 1-[trans-4-{13-benzyloxy-1-tridecenyl}cyclohexyl]-2,3-difluorobenzene, 1 g of 10% Pd--C, 50 ml of ethanol, and 50 ml of ethyl acetate were placed in a 500 ml autoclave. The mixture was stirred at room temperature for 5 days under a hydrogen pressure of 8 kg/cm2. A catalyst was filtered away and a filtrate was concentrated. Thereafter, the residue was purified by silica gel column chromatography (eluent: toluene/ethyl acetate=4/1) and recrystallized from acetone to obtain 5.7 g of 1-[trans-4-(13-hydroxytridecyl)cyclohexyl]-2,3-difluorobenzene (Y: 64%). The compound thus obtained had a purity of 97.2% by GC and 99.8% by HPLC.
Reaction SMILES: [C:1]([OH:12])(=[O:11])[C:2]1[CH:10]=[CH:9][C:7]([OH:8])=[C:4]([O:5][CH3:6])[CH:3]=1.[N+:13]([O-])([OH:15])=[O:14]>C(O)(=O)C>[OH:8][C:7]1[C:4]([O:5][CH3:6])=[CH:3][C:2]([C:1]([OH:12])=[O:11])=[CH:10][C:9]=1[N+:13]([O-:15])=[O:14]
Reactant: O=[N+]([O-])O
Reactant: COc1cc(C(=O)O)ccc1O
Solvent: CC(=O)O
Product: COc1cc(C(=O)O)cc([N+](=O)[O-])c1O

Procedure:
A suspension of vanillic acid (68.8 kg) in acetic acid (720 kg) is cooled to 17° C. before an excess of a 65% nitric acid (44.0 kg) is added. After complete dosage of nitric acid the suspension is stirred for 2 hours. The suspension is filtered off and the wet cake is successively washed with acetic acid (80.0 kg), acetic acid/water (1:2 w/w—105 kg) and finally water (80 kg—if necessary repeat). The solid is dried at 52° C. for NMT 12 hours prior going to next step.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][N:5]2[N:4]=1.C([Li])CCC.[Br:17]C(Cl)(Cl)C(Br)(Cl)Cl.O>O1CCCC1>[Br:17][C:10]1[N:5]2[N:4]=[C:3]([O:2][CH3:1])[CH:11]=[C:6]2[CH:7]=[CH:8][CH:9]=1
Reactant: ClC(Cl)(Br)C(Cl)(Cl)Br
Reactant: COc1cc2ccccn2n1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: COc1cc2cccc(Br)n2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64.8 %

Procedure:
A solution of 2-methoxypyrazolo[1,5-a]pyridine (Reference; Bull. Chem. Soc. Japan, vol. 49(7), 1980–1984(1976)) (7.15 g) in tetrahydrofuran (140 mL) was cooled to −78° C. under a nitrogen stream, and after adding n-butyllithium (1.6M hexane solution: 46 mL) dropwise thereto, the reaction mixture was stirred for 30 minutes. A solution of 1,2-dibromo-1,1,2,2-tetrachloroethane (18.9 g) in tetrahydrofuran (30 mL) was added dropwise to the reaction mixture at −78° C., and stirring was continued for 1 hour. The reaction mixture was raised to room temperature, water was added, and then extraction was performed with ethyl acetate. The organic extract was washed with brine, dried over anhydrous magnesium sulfate and filtered, the solvent was evaporated under reduced pressure, the residue was purified by silica gel column chromatography and the title compound (7.1 g) was obtained as a yellow oil from the n-hexane:ethyl acetate (50:1) fraction.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([N:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)=[N:7][NH:8]2)=[CH:4][CH:3]=1.C([O-])(O)=O.[Na+].[CH3:22][C:23]#[N:24]>O>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([N:11]3[CH2:12][CH2:13][N:14]([CH2:22][C:23]#[N:24])[CH2:15][CH2:16]3)=[N:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: Fc1ccc2c(N3CCNCC3)n[nH]c2c1
Reactant: CC#N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: N#CCN1CCN(c2n[nH]c3cc(F)ccc23)CC1
Yield: 999.9 %

Procedure:
A mixture of 6-fluoro-3-(4-piperazinyl)-1H-indazole (6.0 g, 2.7 mmol), NaHCO3 (2.5 g, 3.0 mmol) chloroacetonitrile (2.5 g, 3.3 mmol) and CH3CN (150 mol) was stirred at reflux under N2 for 18 hours. The cooled reaction was poured into H2O and the aqueous solution was extracted with EtOAc. The EtOAc extract was washed with H2O, washed with brine, dried with MgSO4 and concentrated to yield 7.0 g of a tan solid. A 1.3 g sample was recrystallized from EtOAc to yield 0.65 g of a beige solid, m.p. 154°-156° C.
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].C(O)CCCC>[Cu]>[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([NH:19][C:2]2[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4]([OH:6])=[O:5])=[CH:15][CH:14]=1
Reactant: COc1ccc(N)cc1
Reactant: O=C(O)c1ccccc1Cl
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCO
Product: COc1ccc(Nc2ccccc2C(=O)O)cc1
Reaction time: 4 h

Procedure:
A mixture of 80 g. 2-chlorobenzoic acid, 80 g. 4-anisidine, 80 g. potassium carbonate, 4 g. activated copper powder, and 800 ml. amyl alcohol was heated under reflux with efficient stirring for four hours. The amyl alcohol was removed by steam distillation and the remaining aqueous phase was filtered and made neutral by addition of 1:1 concentrated hydrochloric acid-water. The resulting solid (102 g.) was collected by filtration to give after recrystallization from isopropyl alcohol N-(4-methoxyphenyl)anthranilic acid; m.p. 183°-184°C.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C:2]1=[O:6].[CH3:7][O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13](Cl)=[O:14])=[CH:11][CH:10]=1>>[CH3:7][O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([N:1]2[CH2:5][CH2:4][CH2:3][C:2]2=[O:6])=[O:14])=[CH:11][CH:10]=1
Reactant: O=C1CCCN1
Reactant: COc1ccc(C(=O)Cl)cc1
Product: COc1ccc(C(=O)N2CCCC2=O)cc1

Procedure:
10 g. of 2-pyrrolidinone and 10 g. of p-methoxybenzoyl chloride are heated at 80°-90° C. (internal temperature) in the absence of a solvent for 1 hour. The mixture is then left to cool down and is worked-up as described in Example 3. After recrystallization from alcohol, there is obtained 1-(p-methoxybenzoyl)-2-pyrrolidinone having a melting point of 120°-121° C.
Reaction SMILES: BrBr.[CH3:3][O:4][C:5](=[O:16])[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([NH:12][C:13]([NH2:15])=[S:14])[CH:7]=1.CCOCC>C(O)(=O)C>[CH3:3][O:4][C:5]([C:6]1[C:7]2[S:14][C:13]([NH2:15])=[N:12][C:8]=2[CH:9]=[CH:10][CH:11]=1)=[O:16]
Reactant: COC(=O)c1cccc(NC(N)=S)c1
Agent: BrBr
Solvent: CCOCC
Solvent: CC(=O)O
Product: COC(=O)c1cccc2nc(N)sc12
Temperature: 70 °C
Reaction time: 4 h

Procedure:
At 0° C. a solution of bromine (13.4 mmol) in acetic acid (9.4 mL) is added dropwise to a vigorously stirred solution of 3-thioureido-benzoic acid methyl ester (12.5 ml) in acetic acid (37 mL). The mixture is allowed to reach RT, stirred at 70° C. for 4 h and cooled to RT. Ether is added and the precipitate is filtered off. The residue is stirred vigorously in a sat aq. NaHCO3 solution, filtered off and washed with water. The obtained solid is dried in vacuo to give the desired product which is used without further purification. LC-MS: tR=0.62 min; [M+H]+=209.0.
Reaction SMILES: C[O-].[Na+].[C:4](=[O:9])(OC)[O:5]C.[CH3:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:26]=[C:25]3[C:20]([CH2:21][CH2:22][CH2:23][C:24]3=O)=[CH:19][CH:18]=2)=[CH:13][CH:12]=1>Cl>[CH3:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]2[CH:26]=[C:25]3[C:20]([CH2:21][CH2:22][C:23]([C:4]([OH:5])=[O:9])=[CH:24]3)=[CH:19][CH:18]=2)=[CH:15][CH:16]=1
Reactant: Cc1ccc(-c2ccc3c(c2)C(=O)CCC3)cc1
Reactant: COC(=O)OC
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Product: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CC3)cc1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
A mixture of sodium methoxide (5.63 g), dimethyl carbonate (33 ml) and 7-(4-methylphenyl)-1-tetralone (4.93 g) was refluxed for 30 minutes. The reaction mixture was cooled to 0° C. and to the mixture was gradually added 3N hydrochloric acid (80 ml). The mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was dissolved in THF (30 ml), and to the mixture was added sodium boron hydride (494 mg) at 0° C. and then was dropwise added methanol (3 ml) for 30 minutes. The reaction mixture was stirred at 0° C. for 4 hours, and to the mixture was added water (500 ml). The mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was dissolved in methanol (20 ml), and to the mixture was added 1N sodium hydroxide (20 ml). The mixture was refluxed for 4 hours, cooled, acidified with concentrated hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was dissolved in Diglyme (20 ml), and to the mixture was added concentrated hydrochloric acid (4 ml). The mixture was stirred at 100° C. for 2 hours, and to the mixture was added water (500 ml). The mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, and concentrated under reduced pressure. The residue was dissolved in 0.5N sodium hydroxide (400 ml), and the mixture was washed with diethylether. The aqueous layer was separated and acidified with concentrated hydrochloric acid. The mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-diisopropylether to give 7-(4-methyl-phenyl)-3,4-dihydronaphthalene-2-carboxylic acid (1.96 g) as pale brown crystals.
Reaction SMILES: Br[C:2]1[O:6][C:5]([CH3:7])=[C:4]([C:8]([O:10][CH3:11])=[O:9])[CH:3]=1.[F:12][C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[C:15]([CH3:22])[CH:14]=1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>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.O>[F:12][C:13]1[CH:18]=[CH:17][C:16]([C:2]2[O:6][C:5]([CH3:7])=[C:4]([C:8]([O:10][CH3:11])=[O:9])[CH:3]=2)=[C:15]([CH3:22])[CH:14]=1
Reactant: COC(=O)c1cc(Br)oc1C
Reactant: Cc1cc(F)ccc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COC(=O)c1cc(-c2ccc(F)cc2C)oc1C
Yield: 92.2 %

Procedure:
A mixture of methyl 5-bromo-2-methyl-3-furancarboxylate (2.2 g), 4-fluoro-2-methylphenylboronic acid (1.9 g), tetrakis(triphenylphosphine)palladium(0) (0.6 g), 2N aqueous sodium carbonate solution (12 mL) and 1,2-dimethoxyethane (20 mL) was stirred under reflux overnight under an argon atmosphere. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (0% ethyl acetate/hexane to 20% ethyl acetate/hexane), and crystallized from ethyl acetate/hexane to give the title compound (2.3 g, 91%) as a white solid.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C([O:9][C:10]([C:12]1[S:16][C:15]([C:17]2[S:18][CH:19]=[CH:20][CH:21]=2)=[N:14][CH:13]=1)=O)C.C(OCC)(=O)C>C(OCC)C>[S:18]1[CH:19]=[CH:20][CH:21]=[C:17]1[C:15]1[S:16][C:12]([CH2:10][OH:9])=[CH:13][N:14]=1
Reactant: CCOC(=O)c1cnc(-c2cccs2)s1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: OCc1cnc(-c2cccs2)s1
Temperature: 0 °C
Reaction time: 24 h
Yield: 72.6 %

Procedure:
To a suspension of lithium aluminum hydride (52 mg, 1.25 mmol) in diethyl ether (2 mL) under argon was added 2-(2-thienyl)thiazole-5-carboxylic acid ethyl ester (lit: Robba, M., LeGuen, Y., Bull. Soc. Chim. Fr., 1969(5)1762; 0.3 g, 1.25 mmol) at 0° C. The reaction mixture was allowed to equilibrate to room temperature and was stirred for 24 h. The reaction was re-cooled to 0° C. and was quenched by the careful addition of saturated aqueous ammonium chloride solution dropwise until no further reaction was apparent. The resulting solids were recovered by filtration, washed with diethyl ether and retained for further processing (vide infra). The filtrate was washed with brine, dried (MgSO4), filtered and concentrated under reduced pressure. The solids that were recovered from the ammonium chloride quench were then slurried in ethyl acetate, filtered and washed with ethyl acetate. The resulting filtrate was washed with brine, dried (MgSO4), filtered and evaporated reduced pressure. The solid residues obtained from the work up of both the diethyl ether filtrate and the ethyl acetate filtrate were combined to yield 179 mg (72% yield) of 2-(2-thienyl)thiazole-5-methanol as a yellow solid.
Reaction SMILES: [NH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1)[NH2:2].[C:12]([CH2:15][C:16](=O)[CH3:17])(=O)[CH3:13]>C(O)C>[CH3:13][C:12]1[CH:15]=[C:16]([CH3:17])[N:1]([C:3]2[CH:4]=[CH:5][C:6]([C:7]([OH:9])=[O:8])=[CH:10][CH:11]=2)[N:2]=1
Reactant: CC(=O)CC(C)=O
Reactant: NNc1ccc(C(=O)O)cc1
Solvent: CCO
Product: Cc1cc(C)n(-c2ccc(C(=O)O)cc2)n1
Yield: 0.1 %

Procedure:
A solution of 4-hydrazino-benzoic acid (0.60 g, 3.95 mmol) and acetyl acetone (0.405 ml, 3.95 mmol) in ethanol (20 ml) refluxed for 1 hour. Ethanol was removed in vacuum and the remaining solid was triturated with water and collected by filtration to produce 285 (0.71 mg, 83% yield). [M−1]− 215.1.