Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][O:7][CH2:8][C@@H:9]2[CH2:11][C@@H:10]2[CH:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]2)=[CH:4][C:3]=1[F:27].[CH:28](OCC)(OCC)OCC.[N-:38]=[N+:39]=[N-:40].[Na+]>C(O)(=O)C>[F:27][C:3]1[CH:4]=[C:5]([CH:25]=[CH:26][C:2]=1[N:1]1[CH:28]=[N:40][N:39]=[N:38]1)[CH2:6][O:7][CH2:8][C@@H:9]1[CH2:11][C@@H:10]1[CH:12]1[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:22])[CH3:23])=[O:19])[CH2:16][CH2:17]1
Reactant: CCOC(OCC)OCC
Reactant: CC(C)(C)OC(=O)N1CCC([C@H]2C[C@H]2COCc2ccc(N)c(F)c2)CC1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC([C@H]2C[C@H]2COCc2ccc(-n3cnnn3)c(F)c2)CC1
Temperature: 100 °C
Yield: 90.7 %

Procedure:
A solution of tert-butyl 4-((1R,2R)-2-((4-amino-3-fluorobenzyloxy)methyl)cyclopropyl)piperidine-1-carboxylate (Step B product, 400 mg, 1.06 mmol), triethyl orthoformate (880 uL, 5.28 mmol), and sodium azide (344 mg, 5.28 mmol) in acetic acid (4.3 mL) that had been placed under an inert atmosphere was heat in a sealed vial at 100° C. for 3 hrs. The reaction mixture was cooled to rt and concentrated under reduced pressure. The resulting crude was partitioned between EtOAc (20 mL) and water (20 mL) and the layers were cut. The aqueous phase was extracted with EtOAc (20 mL×2) and the combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was loaded onto a silica column (KP-Sil 25 g SNAP column, Biotage system) eluting with a range of 20-60% EtOAc/Hex over 12 CV to give the desired compound (415 mg, 91%). LC/MS (m/z): 432 (M+H)+.
Reaction SMILES: [CH2:1]([OH:6])[CH2:2][CH2:3][CH2:4][OH:5].[CH3:7][Si:8]([CH3:11])([CH3:10])Cl>[Br-].C([P+](CCCC)(CCCC)CCCCCCCCCCCCCCCC)CCC>[CH3:7][Si:8]([CH3:11])([CH3:10])[O:5][CH2:4][CH2:3][CH2:2][CH2:1][O:6][Si:8]([CH3:11])([CH3:10])[CH3:7]
Reactant: OCCCCO
Reactant: C[Si](C)(C)Cl
Agent: CCCCCCCCCCCCCCCC[P+](CCCC)(CCCC)CCCC
Agent: [Br-]
Product: C[Si](C)(C)OCCCCO[Si](C)(C)C

Procedure:
1 mole of butane-1,4-diol, 3 moles of trimethylchlorosilane and 0.002 moles of tributyl-hexadecyl phosphonium bromide were reacted at the reflux temperature (56°-96° C.) as in Example 1. The product was worked up by fractional distillation.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([C:16]3[CH:20]=[CH:19][S:18][CH:17]=3)=[C:11]([CH2:13][CH2:14][OH:15])[N:12]=2)=[CH:4][CH:3]=1.[CH3:21][S:22](Cl)(=[O:24])=[O:23].C(N(CC)CC)C.O>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([C:16]3[CH:20]=[CH:19][S:18][CH:17]=3)=[C:11]([CH2:13][CH2:14][O:15][S:22]([CH3:21])(=[O:24])=[O:23])[N:12]=2)=[CH:4][CH:3]=1
Reactant: OCCc1nc(-c2ccc(F)cc2)oc1-c1ccsc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CS(=O)(=O)OCCc1nc(-c2ccc(F)cc2)oc1-c1ccsc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Under argon atmosphere, to a solution of 2-(4-fluoro-phenyl)-4-(2-hydroxyethyl)-5-(3-thienyl)oxazole (300 mg) in methylene chloride (10 ml) were successively added methane-sulfonyl chloride (96 μl) and triethylamine (188 μl) under ice-cooling, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into water and extracted with methylene chloride. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure to obtain a crude product of 2-(4-fluorophenyl)-4-(2-methanesulfonyloxyethyl)-5-(3-thienyl)oxazole.
Reaction SMILES: [C:1]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)(=[O:5])/[CH:2]=[CH:3]/[CH3:4].CO[CH2:16][N:17]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:18][Si](C)(C)C>ClCCl.FC(F)(F)C(O)=O>[CH2:23]([N:17]1[CH2:16][CH:3]([CH3:4])[CH:2]([C:1]([O:6][CH2:7][C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[O:5])[CH2:18]1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: C/C=C/C(=O)OCc1ccccc1
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1CN(Cc2ccccc2)CC1C(=O)OCc1ccccc1
Yield: 105.9 %

Procedure:
Benzyl (2E)-but-2-enoate obtained in Example 1e (20.5 g, 116 mmol) was dissolved in dichloromethane (5 ml), and the mixture was cooled in an ice bath with stirring. Trifluoroacetic acid (257 μl, 3.47 mmol) was added, and N-(methoxymethyl)-N-(trimethylsilylmethyl)benzylamine (33.1 g, 139 mmol) was added dropwise to the reaction liquid over 15 minutes so that the internal temperature did not exceed 62° C., while washing with dichloromethane (25 ml). The reaction liquid was left to stand until it reached mom temperature and was stirred for 15 hours. The reaction liquid was concentrated and purified by silica gel column chromatography (elution solvent: ethyl acetate/heptane) to give the title compound (38 g).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][OH:14])[CH:10]([CH3:12])[CH3:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.CC(C)([O-])C.[K+]>CN(C=O)C.C(OCC)(=O)C>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH:10]([CH3:11])[CH3:12])=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: BrCc1ccccc1
Reactant: CC(C)[C@H](CO)NC(=O)OC(C)(C)C
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)[C@H](COCc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 2 h
Yield: 68.8 %

Procedure:
To a solution of N-tert-butoxycarbonyl-(D)-valinol (10 g, 49.3 mmol) and benzylbromide (5.86 ml, 49.3 mmol) in anhydrous DMF (50 ml) was added at -5° C. and under nitrogen, potassium-tert-butoxide (11.06 g, 98.6 mmol) as a solid, portionwise, and in such a way that the internal temperature does not exceed +5° C. The reaction mixture was stirred for 2 hours at 0° C., diluted with ethyl acetate (2×300 ml), extracted with a 1N solution of potassium hydrogenosulfate (50 ml) and water (250 ml) and washed twice with water (2×200 ml). After drying of the organic phase on sodium sulfate, filtration and concentration in vacuo, the resulting oil was purified by flash chromatography (silica gel, ethyl acetate/petroleum ether: 1/9, Rf.: 0.42) to give the title compound as a colorless oil (9.95 g, 69% yield). MS: MH+ =294.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[C:13]1[NH:14][CH:15]=[CH:16][N:17]=1.[N+:18]([O-])([OH:20])=[O:19].S(=O)(=O)(O)O>O>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:5]=[C:4]([Cl:12])[C:3]=1[C:13]1[NH:17][CH:16]=[C:15]([N+:18]([O-:20])=[O:19])[N:14]=1
Reactant: O=[N+]([O-])O
Reactant: FC(F)(F)c1cc(Cl)c(-c2ncc[nH]2)c(Cl)c1
Agent: O=S(=O)(O)O
Solvent: O
Product: O=[N+]([O-])c1c[nH]c(-c2c(Cl)cc(C(F)(F)F)cc2Cl)n1
Temperature: 70 °C

Procedure:
A mixture of 2-(2,6-dichloro-4-trifluoromethylphenyl)-imidazole (5.62 g, 0.02 mol), nitric acid (70% w/w, 5.6 ml) and sulphuric acid (98% w/w, 5.6 ml) was strirred and heated at 70° C. for a total of 51 hours. After cooling the ceaction mixture was poured into a mixture of ice and water (approximately 75 ml) and the precipitated solid was filtered off. It was purified by mplc on silica eluted with a mixture of ethyl acetate and dichloromethane (1:20) to give 2-(2,6-dichloro-4-trifluoromethylphenyl)-4-nitroimidazole (4.21g), m.p. 254°-255° C., as a cream crystalline solid.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:10]([NH2:11])=[N:9][C:8]([O:12][CH3:13])=[CH:7][N:6]=1)=[O:4].[OH-].[Na+:15].[ClH:16].C1(C)C=CC=CC=1>C1COCC1>[NH2:11][C:10]1[C:5]([C:3]([OH:4])=[O:2])=[N:6][CH:7]=[C:8]([O:12][CH3:13])[N:9]=1.[Cl-:16].[Na+:15]
Reactant: COC(=O)c1ncc(OC)nc1N
Reactant: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COc1cnc(C(=O)O)c(N)n1
Product: [Cl-]
Temperature: 25 °C
Reaction time: 29 h

Procedure:
To a solution of 200 mg (1.092 mmol) 3-amino-5-methoxy-pyrazine-2-carboxylic acid methyl ester in 4 ml THF was added 1.20 ml (1.20 mmol) 1N sodium hydroxide and the mixture was stirred at room temperature for 29 h. To the mixture were added 1.09 ml (1.09 mmol) 1N HCl after stirring for 5 min toluene was added and the solvents were evaporated to provide the title compound together with sodium chloride as colorless solid. The mixture was used for coupling reactions without further purification.
Reaction SMILES: [CH2:1]=[C:2]1[CH2:11][CH2:10][C:5]2([O:9]CCO2)[CH2:4][CH2:3]1.[Cl:12][C:13]1[CH:14]=[C:15]([C:19]#[C:20][C:21]2[CH2:25]C3(CCC(=O)CC3)O[N:22]=2)[CH:16]=[CH:17][CH:18]=1>>[Cl:12][C:13]1[CH:14]=[C:15]([C:19]#[C:20][C:21]2[CH2:25][C:5]3([CH2:4][CH2:3][C:2](=[CH2:1])[CH2:11][CH2:10]3)[O:9][N:22]=2)[CH:16]=[CH:17][CH:18]=1
Reactant: O=C1CCC2(CC1)CC(C#Cc1cccc(Cl)c1)=NO2
Reactant: C=C1CCC2(CC1)OCCO2
Product: C=C1CCC2(CC1)CC(C#Cc1cccc(Cl)c1)=NO2

Procedure:
The title compound was synthesized using the same methodology described for Compound 31a, but starting from the compound of Example 32 instead of 1,4-dioxaspiro[4.5]decan-8-one. After the usual work-up procedure, the residue was purified by means of automated flash chromatography (Horizon®TM-Biotage; gradient Petroleum Ether-Acetone EtOAc from 95:5 to 9:1) to give the title compound as a grey solid. Yield: 67.3%
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl.[CH2:17]([NH:31][C:32]1[CH:40]=[CH:39][C:35]([C:36](Cl)=[O:37])=[CH:34][CH:33]=1)[CH2:18][CH2:19][CH:20]=[CH:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]>C(Cl)Cl>[CH2:17]([NH:31][C:32]1[CH:33]=[CH:34][C:35]([C:36]([O:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)=[O:37])=[CH:39][CH:40]=1)[CH2:18][CH2:19][CH:20]=[CH:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: CCCCCCCCCC=CCCCNc1ccc(C(=O)Cl)cc1
Reactant: Oc1ccc(Cl)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCCC=CCCCNc1ccc(C(=O)Oc2ccc(Cl)cc2)cc1

Procedure:
To a solution of 6.4 g. 4-chlorophenol and 7.6 g. triethylamine in 500 ml. methylene chloride is added 10.4 g. 4(4-tetradecenylamino)benzoyl chloride hydrochloride in 250 ml. methylene chloride. After four hours at reflux, the solution is cooled, washed with water and dilute phosphoric acid, and dried. After passing the solution through a column of alumina, the solvent is evaporated and the residue is crystallized from diisopropyl ether.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[C:11]([Br:18])[CH:12]=[N:13][CH:14]=2)[N:9]=1)(C)(C)C.C([Cl:23])(=O)C.CCOC(C)=O>CO>[ClH:23].[ClH:23].[Br:18][C:11]1[CH:12]=[N:13][CH:14]=[C:15]2[C:10]=1[N:9]=[C:8]([NH2:7])[CH:17]=[CH:16]2
Reactant: CC(=O)Cl
Reactant: CC(C)(C)OC(=O)Nc1ccc2cncc(Br)c2n1
Solvent: CO
Solvent: CCOC(C)=O
Product: Cl
Product: Nc1ccc2cncc(Br)c2n1

Procedure:
(8-Bromo-[1,6]naphthyridin-2-yl)-carbamic acid tert-butyl ester (1 equiv.) is suspended in methanol (10 mL). Acetyl chloride (ca. 1 mL) is added over 1 minute. After the reaction mixture cools to ambient temperature, the solvent is brought briefly to reflux using a heat gun. The heat gun is applied twice more, at which point TLC (1:1 EtOAc:hexanes) indicated complete reaction. Concentration, followed by trituration twice with dry methanol affords the title compound as a white solid, LC/MS (M+H) 224.1.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][CH:7]([C:12]([OH:14])=[O:13])[CH2:6][CH2:5]2.[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[OH-].[K+]>>[CH2:15]([O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][CH:7]([C:12]([OH:14])=[O:13])[CH2:6][CH2:5]2)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(O)C1CCc2cc(O)ccc2C1
Reactant: BrCc1ccccc1
Agent: [K+]
Agent: [OH-]
Product: O=C(O)C1CCc2cc(OCc3ccccc3)ccc2C1

Procedure:
The 1,2,3,4-tetrahydro-6-hydroxynaphthalene-2-carboxylic acid obtained in the above manner is reacted with benzyl bromide in the presence of potassium hydroxide to obtain 1,2,3,4-tetrahydro-6-benzyloxynaphthalene-2-carboxylic acid (11).
Reaction SMILES: Br[CH2:2][C:3]1[O:4][C:5]2[C:11]([Cl:12])=[CH:10][C:9]([F:13])=[C:8]([C:14]3[C:15](=[O:25])[N:16]([CH3:24])[C:17]([C:20]([F:23])([F:22])[F:21])=[CH:18][CH:19]=3)[C:6]=2[CH:7]=1.[CH3:26][SH:27].C(=O)([O-])[O-].[K+].[K+]>C1COCC1>[Cl:12][C:11]1[C:5]2[O:4][C:3]([CH2:2][S:27][CH3:26])=[CH:7][C:6]=2[C:8]([C:14]2[C:15](=[O:25])[N:16]([CH3:24])[C:17]([C:20]([F:21])([F:23])[F:22])=[CH:18][CH:19]=2)=[C:9]([F:13])[CH:10]=1
Reactant: Cn1c(C(F)(F)F)ccc(-c2c(F)cc(Cl)c3oc(CBr)cc23)c1=O
Reactant: CS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CSCc1cc2c(-c3ccc(C(F)(F)F)n(C)c3=O)c(F)cc(Cl)c2o1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.2 %

Procedure:
0.31 g (0.71 mmol) of 3-(2-bromomethyl-7-chloro-5-fluorobenzofuran-4-yl)-1-methyl-6-trifluoromethyl-2-(1H)-pyridone was dissolved in 20 ml of THF, and 0.014 g (0.85 mmol) of a methanethiol 30% methanol solution and 0.12 g (0.85 mmol) of potassium carbonate were added thereto, followed by stirring at room temperature for 8 hours. THF was distilled off under reduced pressure. Then, the obtained residue was poured into water and extracted with ethyl acetate. After washing with water, the organic layer was dried over anhydrous magnesium sulfate. Ethyl acetate was distilled off under reduced pressure. Then, the obtained crude crystals were washed with n-hexane to obtain 0.28 g (yield: 98%) of the desired product. 1H-NMR (300 MHz, CDCl3) δ value: 2.17(3H,s), 3.73(3H,s), 3.79(2H,s), 6.47(1H,s), 6.80(1H,d), 7.14(1H,d), 7.54(1H,d)ppm.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][O:7][C:8]1[CH:12]=[C:11]([NH:13][S:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:19][CH:18]=2)(=[O:16])=[O:15])[O:10][N:9]=1)(=[O:3])[CH3:2].[I:27]N1C(=O)CCC1=O>O1CCCC1>[C:1]([O:4][CH2:5][CH2:6][O:7][C:8]1[C:12]([I:27])=[C:11]([NH:13][S:14]([C:17]2[CH:18]=[CH:19][C:20]([C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:21][CH:22]=2)(=[O:15])=[O:16])[O:10][N:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCCOc1cc(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)on1
Reactant: O=C1CCC(=O)N1I
Solvent: C1CCOC1
Product: CC(=O)OCCOc1noc(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)c1I
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirring solution of 2-{[5-({[4-(tert-butyl)phenyl]sulfonyl}amino)-3-isoxazolyl]oxy}ethyl acetate (Preparation 24) (1.17 g) in tetrahydrofuran (10 ml) was added N-iodosuccinimide (0.76 g). The reaction mixture was left stirring at room temperature overnight. The solvent was removed in vacuo to yield the crude material as a brown oil (1.5 g). The crude material was purified using the Biotage™ Flash 40i system (silica, 90 g) and eluted with hexane:ethyl acetate (1:9) to yield the product as a brown oil.
Reaction SMILES: [C:1]([BH3-])#N.[Na+].[NH:5]1[C:14]2[C:9](=[CH:10][C:11]([C:15]3[CH:16]([CH3:22])[NH:17][C:18](=[O:21])[NH:19][N:20]=3)=[CH:12][CH:13]=2)[CH2:8][CH2:7][CH2:6]1.C=O.C(O)(=O)C>CO>[CH3:1][N:5]1[C:14]2[C:9](=[CH:10][C:11]([C:15]3[CH:16]([CH3:22])[NH:17][C:18](=[O:21])[NH:19][N:20]=3)=[CH:12][CH:13]=2)[CH2:8][CH2:7][CH2:6]1
Reactant: [BH3-]C#N
Reactant: CC1NC(=O)NN=C1c1ccc2c(c1)CCCN2
Agent: C=O
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC1NC(=O)NN=C1c1ccc2c(c1)CCCN2C
Reaction time: 0.5 h
Yield: 84.5 %

Procedure:
Sodium cyanoborohydride (0.19 g) was added portionwise to a suspension of 6-(1,2,3,4-tetrahydroquinolin-6-yl)-5-methyl-4,5-dihydro-1,2,4-triazin-3(2H)-one (0.74 g), 36% aqueous formaldehyde (0.34 ml), acetic acid (1 ml) and methanol (3 ml) at room temperature. After stirring for 0.5 hours at the same temperature, the resultant precipitates were collected by filtration, washed with methanol, dried, and recrystallized from 70% aqueous ethanol to give 0.66 g of 6-(1-methyl-1,2,3,4-tetrahydroquinolin-6-yl)-5-methyl-4,5-dihydro-1,2,4-triazin-3(2H)-one.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][C:2]1=O.[NH:12]1[CH2:17][CH:16]([C:18]([NH2:20])=[O:19])[O:15][CH2:14][CH2:13]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)=O>[C:1]1(=[O:15])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[NH:12]1[CH2:17][CH:16]([C:18]([NH2:20])=[O:19])[O:15][CH2:14][CH2:13]1
Reactant: O=C1CCc2ccccc2C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: NC(=O)C1CNCCO1
Solvent: CC(C)=O
Product: O=C1CCCc2ccccc21

Procedure:
2-Tetralone-6-morpholinamide, ethylene ketal (323 mg, 1.06 mmol) and catalytic p-toluenesulfonic acid were stirred in acetone (50 mL) at ambient temperature for 48 hours. TLC indicated a mixture of 2-tetralone-6-morpholinamide, ethylene ketal and desired product, so the solution was heated to reflux for 16 hours. The volatiles were removed in vacuo and the residue applied to a silica flash chromatography column and eluted with 50-100% EtOAc in hexanes to yield 27 mg (10%) of 2-tetralone-6-morpholinamide a slowly crystallizing solid, pure by NMR, TLC. MS.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([C@@H:11]([OH:21])[C@H:12]([NH:15][C:16]([CH:18]([Cl:20])[Cl:19])=[O:17])[CH2:13][F:14])=[CH:9][CH:10]=1)(=[O:4])=[O:3].[C:22]1(=[O:32])[O:27][C:25](=[O:26])[C:24]2=[CH:28][CH:29]=[CH:30][CH:31]=[C:23]12.C(N(CC)CC)C.[OH2:40]>O1CCOCC1.ClCCl>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([C@@H:11]([OH:21])[C@H:12]([NH:15][C:16]([CH:18]([Cl:20])[Cl:19])=[O:17])[CH2:13][F:14])=[CH:9][CH:10]=1)(=[O:4])=[O:3].[C:25]([O-:27])(=[O:26])[C:24]1[C:23](=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:22]([O-:32])=[O:40]
Reactant: O
Reactant: O=C1OC(=O)c2ccccc21
Agent: CS(=O)(=O)c1ccc([C@@H](O)[C@@H](CF)NC(=O)C(Cl)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: O=C([O-])c1ccccc1C(=O)[O-]
Temperature: 25 °C
Reaction time: 6 h

Procedure:
3.9 g of florfenicol, 3.6 g of phthalic anhydride and 7.2 ml of triethyl amine in 36 ml of dioxane were taken in a 100 ml round bottom flask equipped with a magnetic stir bar and a drying tube. The reaction mixture was stirred at room temperature for 6 hours. After 6 hours, the contents were poured into 300 ml of cold water. The resulting gummy solid was dissolved in dichloromethane and washed thoroughly with saturated bicarbonate several times followed by water. The organic layer was dried over anhydrous sodium sulfate and concentrated over roto-evaporator. The semisolid obtained was recrystallized in a mixture of ethylacetate and hexane to obtain a solid product of 4.2 grams.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([OH:20])=[C:16]([OH:19])[CH:17]=3)[N:12]=[CH:11][C:10]=2[C:21]#[N:22])[CH:5]=[CH:6][CH:7]=1.CN(C1C=CC=CN=1)C.[C:32](OC(=O)C)(=[O:34])[CH3:33].C(=O)(O)[O-].[Na+]>O.CO.N1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([N:8]([C:9]2[C:18]3[C:13](=[CH:14][C:15]([OH:20])=[C:16]([OH:19])[CH:17]=3)[N:12]=[CH:11][C:10]=2[C:21]#[N:22])[C:32](=[O:34])[CH3:33])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)OC(C)=O
Reactant: N#Cc1cnc2cc(O)c(O)cc2c1Nc1cccc(Br)c1
Agent: CN(C)c1ccccn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CO
Solvent: O
Product: CC(=O)N(c1cccc(Br)c1)c1c(C#N)cnc2cc(O)c(O)cc12

Procedure:
A solution of 4-(3-bromophenylamino)-6,7-dihydroxy-3-quinolinecarbonitrile (1.78 g, 5.0 mmol), dimethylaminopyridine (60 mg, 0.50 mmol), 5.0 ml of acetic anhydride, and 10 ml of pyridine was stirred at reflux temperature for 1.5 h and concentrated to dryness. The residue was stirred with 50 ml of methanol, 5 ml of water, and sodium bicarbonate (2.1 g, 25 mmol) at 25° C. for 16 h and concentrated to dryness. The residue was stirred with water containing acetic acid to give pH-4-5, and the resulting solid was filtered off, washed with water, and dried. A solution of the resulting solid in THF was passed through a pad of silica gel; the filtrate was concentrated to give a tan solid; mass spectrum (electrospray, m/e) M-H 396.3, 398.3.
Reaction SMILES: Cl[C:2](OC(Cl)(Cl)Cl)=[O:3].[F:9][C:10]1[CH:16]=[C:15]([Cl:17])[C:14]([O:18][CH:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)=[CH:13][C:11]=1[NH2:12].C(N(CC)CC)C>C1(C)C=CC=CC=1>[F:9][C:10]1[CH:16]=[C:15]([Cl:17])[C:14]([O:18][CH:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)=[CH:13][C:11]=1[N:12]=[C:2]=[O:3]
Reactant: Nc1cc(OC2CCCC2)c(Cl)cc1F
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=C=Nc1cc(OC2CCCC2)c(Cl)cc1F
Temperature: 0 °C

Procedure:
The mixture of trichloromethyl chloroformate (530 ml, 4.4 mol) and toluene (4 liters) were put in a 10-liter three-neck flask as equipped with a stirrer, a dropping funnel, and a reflux condenser, and cooled to 0° C. To the solution was dropwise added a toluene solution (1 liter) containing 2-fluoro-4-chloro-5-cyclopentyloxyaniline (1.0 kg, 2.86 mol) and triethylamine (20 ml) over a period of 8 hours. After addition, the reaction solution was stirred under heat at about 100° C. After reaction, toluene was removed by distillation, and the impurities as precipitated out were removed by filtration. As a result, 2-fluoro-4-chloro-5-cyclopentyloxyphenylisocyanate was obtained almost quantitatively. Spectral data and other data of the product are those as shown in Example 24.
Reaction SMILES: Br[CH2:2][C:3](=O)[CH2:4][CH2:5][C:6]#[C:7][Si:8]([CH3:11])([CH3:10])[CH3:9].[Cl:13][C:14]1[C:15]([NH2:20])=[N:16][CH:17]=[CH:18][CH:19]=1>>[Cl:13][C:14]1[C:15]2[N:16]([CH:2]=[C:3]([CH2:4][CH2:5][C:6]#[C:7][Si:8]([CH3:11])([CH3:10])[CH3:9])[N:20]=2)[CH:17]=[CH:18][CH:19]=1
Reactant: Nc1ncccc1Cl
Reactant: C[Si](C)(C)C#CCCC(=O)CBr
Product: C[Si](C)(C)C#CCCc1cn2cccc(Cl)c2n1
Yield: 72.2 %

Procedure:
The title compound was prepared in accordance with the general method of Example 223(D), from 1-bromo-6-(trimethylsilyl)hex-5-yn-2-one (4.96 g, 20.1 mmol, Example 223(C)) and 3-chloropyridin-2-amine (1.29 g, 10.0 mmol). The crude residue was purified by flash chromatography (cyclohexane/AcOEt 4:1) to yield 2.00 g (7.22 mmol, 72%) of 8-chloro-2-(4-(trimethylsilyl)but-3-ynyl)-imidazo[1,2-a]pyridine as a brown solid.
Reaction SMILES: [OH:1][CH:2]([C:7]1[N:8]=[C:9]([CH2:33][CH2:34][CH3:35])[N:10]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]([C:29]([O:31]C)=[O:30])=[O:28])=[CH:17][CH:16]=2)[C:11]=1[C:12]#[N:13])[C:3]([CH3:6])([CH3:5])[CH3:4].[OH-:36].[Na+]>>[OH:1][CH:2]([C:7]1[N:8]=[C:9]([CH2:33][CH2:34][CH3:35])[N:10]([CH2:14][C:15]2[CH:16]=[CH:17][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]([C:29]([OH:31])=[O:30])=[O:28])=[CH:19][CH:20]=2)[C:11]=1[C:12]([NH2:13])=[O:36])[C:3]([CH3:6])([CH3:4])[CH3:5]
Reactant: CCCc1nc(C(O)C(C)(C)C)c(C#N)n1Cc1ccc(-c2ccccc2C(=O)C(=O)OC)cc1
Reactant: [OH-]
Agent: [Na+]
Product: CCCc1nc(C(O)C(C)(C)C)c(C(N)=O)n1Cc1ccc(-c2ccccc2C(=O)C(=O)O)cc1

Procedure:
246 mg of 4-(1-hydroxy-2,2-dimethylpropyl)-1-[(2'-methoxalylbiphenyl-4-yl)methyl]-2-propylimidazole-5-carbonitrile [prepared as described in step (a) above] were subjected to hydrolysis using 6 ml of a 1N aqueous solution of sodium hydroxide in the same manner as described in Example 10(b), to give 182 mg of the title compound as crystals, melting at 198°-200° C.
Reaction SMILES: O[C:2]1([OH:11])[CH:7]=[C:6]([OH:8])[CH:5]=[C:4]([OH:9])[CH:3]1[OH:10].[C:12](#N)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.CC[O:22]CC>[Cl-].[Zn+2].[Cl-]>[C:13]1([C:12]([C:5]2[C:6]([OH:8])=[CH:7][C:2]([OH:11])=[C:3]([OH:10])[C:4]=2[OH:9])=[O:22])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCOCC
Reactant: N#Cc1ccccc1
Reactant: OC1=CC(O)(O)C(O)C(O)=C1
Agent: [Cl-]
Agent: [Zn+2]
Product: O=C(c1ccccc1)c1c(O)cc(O)c(O)c1O
Temperature: 0 °C
Reaction time: 13 h
Yield: 45.9 %

Procedure:
Under a stream of argon, 1.30 g (9.15 mmol) of 1,2,3,5-tetrahydroxyphenol (3) was suspended in 13 ml of ether and 0.935 ml (9.15 mmol, 1.00 equivalent) of benzonitrile was added to the suspension with stirring. The resultant mixture was cooled with ice water and 0.624 g (4.57 mmol, 0.50 equivalent) of zinc chloride was added and they were stirred at room temperature for 6 hours by bubbling hydrogen chloride gas throughout. The aeration of the mixture with the gas was stopped and the mixture was left standing at 4° C. for 13 hours. From the tarry precipitates consequently formed was removed the ether layer by decantation. The precipitates were stirred in an ice bath and 39 ml of water was added and were then refluxed for 2 hours. The product of reflux was filtered while kept in hot and stand still to form red brown from the filtrate. By dissolving the crystals again in ether, filtering off insolubles from the solution, and concentrating, 0.97 g (yield 45.9%) of the product (10) was obtained in the form of orange powder crystals.