Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:5]([O:7][CH3:8])=[O:6].C(=O)([O-])[O-].[K+].[K+].Cl[CH:21]1[CH2:25][CH2:24][CH2:23][C:22]1=[O:26]>CN(C=O)C>[CH3:13][O:12][C:11]1[CH:10]=[CH:9][C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:3][C:2]=1[O:1][CH:21]1[CH2:25][CH2:24][CH2:23][C:22]1=[O:26]
Reactant: COC(=O)c1ccc(OC)c(O)c1
Reactant: O=C1CCCC1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OC)c(OC2CCCC2=O)c1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
23.8 g of methyl 3-hydroxy-4-methoxybenzoate are dissolved in 200 ml of anhydrous DMF and the solution is treated with 35 g of potassium carbonate (ground) and 13 ml of 2-chlorocyclopentanone. The mixture is stirred at 60° C. for 3 h, then the solid is filtered off and the filtrate is concentrated in vacuo. The residue is chromatographed on a silica gel column using ethyl acetate/petroleum ether (4:6). The chromatographically pure fractions are combined, concentrated and dried in a high vacuum. 24.3 g of the title compound are obtained as a pale yellow oil.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C:14]([CH3:19])([CH3:18])[C:15]([OH:17])=O)[N:5]=[C:4]([CH3:20])[C:3]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22].[CH2:26]([NH2:30])[CH:27]([CH3:29])[CH3:28]>>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C:14]([CH3:18])([CH3:19])[C:15]([NH:30][CH2:26][CH:27]([CH3:29])[CH3:28])=[O:17])[N:5]=[C:4]([CH3:20])[C:3]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: CC(C)CN
Reactant: CCOC(=O)c1c(C)nc2cccc(OCC(C)(C)C(=O)O)c2c1N
Product: CCOC(=O)c1c(C)nc2cccc(OCC(C)(C)C(=O)NCC(C)C)c2c1N

Procedure:
Prepared as in Example Da from 3-((4-amino-3-(ethoxycarbonyl)-2-methylquinolin-5-yl)oxy)-2,2-dimethylpropanoic acid (Example Eb) and isobutylamine as an off-white solid (82%). MS 402 (MH+).
Reaction SMILES: [CH2:1]1[CH2:6][CH2:5][C:4]([CH2:11][NH2:12])([CH2:7][C:8]([OH:10])=[O:9])[CH2:3][CH2:2]1.[CH2:13](O)[CH:14]=[CH2:15].S(Cl)([Cl:19])=O>C(OCC)C>[ClH:19].[NH2:12][CH2:11][C:4]1([CH2:7][C:8]([O:10][CH2:15][CH:14]=[CH2:13])=[O:9])[CH2:3][CH2:2][CH2:1][CH2:6][CH2:5]1
Reactant: C=CCO
Reactant: NCC1(CC(=O)O)CCCCC1
Reactant: O=S(Cl)Cl
Solvent: CCOCC
Product: C=CCOC(=O)CC1(CN)CCCCC1
Product: Cl
Temperature: 0 °C
Reaction time: 16 h
Yield: 88.8 %

Procedure:
A dry 3 L, three-neck, round-bottomed flash fitted with a magnetic stirring bar and a 500 mL pressure-equalizing addition funnel is flushed with nitrogen gas. The flask is charged with gabapentin (171 g, 1.0 mol) and allyl alcohol (1 L, 852 g, 14.6 mol) and the entire mixture is cooled to 0° C. in an ice-water bath. Thionyl chloride (225 mL, 360 g, 3.0 mol) is added dropwise over a period of 1 h to the stirred solution. The reaction mixture is allowed to stir at room temperature for 16 h, then is diluted with ethyl ether (2 L) and cooled to 0° C. while stirring. After several minutes white crystals form, which are collected by filtration. The crude product is recrystallized from a 1/3 (v/v) mixture of ethanol and ethyl ether (2 L) to give the product as a white solid (220 g 88%). m.p.: 138-142° C.
Reaction SMILES: [C:1]([O:6]CC)(=[O:5])[C:2]([CH3:4])=[CH2:3].[CH2:9]([O:11][CH:12]([O:15][CH2:16][CH3:17])[CH2:13]Br)[CH3:10]>>[CH2:9]([O:11][CH:12]([O:15][CH2:16][CH3:17])[CH2:13][CH:3]=[C:2]([CH3:4])[C:1]([O-:6])=[O:5])[CH3:10].[CH2:9]([O:11][CH:12]([O:15][CH2:16][CH3:17])[CH2:13][O:6][C:1](=[O:5])[C:2]([CH3:4])=[CH2:3])[CH3:10]
Reactant: C=C(C)C(=O)OCC
Reactant: CCOC(CBr)OCC
Product: C=C(C)C(=O)OCC(OCC)OCC
Product: CCOC(CC=C(C)C(=O)[O-])OCC
Yield: 29 %

Procedure:
Analysis indicated that fraction #1 was predominantly ethyl methacrylate. Fraction #2 was predominantly bromoacetaldehyde diethylacetal. Fraction #3 was the desired product, 2,2 diethoxy-ethyl-methacrylate (29% yield).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]2[S:11][CH:12]=[CH:13][N:14]=2)O)=[CH:4][C:3]=1[F:15].C(O)(C(F)(F)F)=O.C([SiH](CC)CC)C>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:10]2[S:11][CH:12]=[CH:13][N:14]=2)=[CH:4][C:3]=1[F:15]
Reactant: OC(c1ccc(Br)c(F)c1)c1nccs1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: Fc1cc(Cc2nccs2)ccc1Br

Procedure:
A solution of (4-Bromo-3-fluoro-phenyl)-thiazol-2-yl-methanol (3.4 g, 12.6 mmol), TFA (25 mL), and Triethylsilane (10 mL, 63 mmol), were refluxed overnight. The reaction was then concentrated under vacuum, and purified by silica gel chromatography (gradient elution 10-40% Ethylacetate/Hexanes). Yield 1.96 g, 61%.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[CH2:19]([NH2:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(OCC)(=O)C>[O:12]([CH2:11][CH2:10][CH2:9][O:8][CH2:7][CH2:6][O:5][CH2:4][CH2:3][CH2:2][NH:26][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: NCc1ccccc1
Reactant: BrCCCOCCOCCCOc1ccccc1
Solvent: CCOC(C)=O
Product: c1ccc(CNCCCOCCOCCCOc2ccccc2)cc1
Reaction time: 2 h
Yield: 69.8 %

Procedure:
[3-[2-(3-Bromopropoxy)ethoxy]propoxy]benzene (1.6 g) was added dropwise with stirring to benzylamine (2.70 g) at 130° under nitrogen. The solution was stirred at 130° under nitrogen for 2 h, cooled and diluted with ethyl acetate (150 ml), and washed with 2N hydrochloric acid (100 ml). The aqueous phase was re-extracted with ethyl acetate (2×100 ml) and the combined organic phases washed with 8% sodium bicarbonate solution (150 ml), dried and evaporated in vacuo to give the title compound (1.21 g) as an oil. T.l.c. (System E 40:10:1) Rf 0.52
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[C:3]=1[CH3:11].[CH2:12]=[O:13]>C(O)(C)(C)C.CS(C)=O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[C:3]=1[CH2:11][CH2:12][OH:13]
Reactant: Cc1c(F)cccc1[N+](=O)[O-]
Reactant: C=O
Solvent: CS(C)=O
Solvent: CC(C)(C)O
Product: O=[N+]([O-])c1cccc(F)c1CCO
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 70.5 %

Procedure:
A solution of potassium tertiary-butylate (90 mg, 0.8 mmol) in tert.-butanol (1 ml, synthesis quality, 99%) was added to 2-fluoro-6-nitrotoluene (776 mg, 5 mmol) and paraformaldehyde (150 mg, 5 mmol) in DMSO (2.5 ml, synthesis quality, additionally dried for 2 d over molecular sieve 4 Å). After the addition of the potassium tertiary-butylate solution, a color change from yellow to deep violet occurred. The solution was stirred for 5 min at room temperature and for 30 min at 70° C. (oil bath temperature). It was then left to cool down to room temperature and neutralized with a few drops of conc. HCl. The mixture was diluted with EtOAc (30 ml) and washed with H2O (20 ml). The aqueous phase was post-extracted with EtOAc (2×20 ml). Drying the organic phases over Na2SO4, filtering and evaporating the solvent under reduced pressure yielded the crude product (1.11 g) which was purified by column chromatography (20 g SiO2, 12×2 cm, solvent: PE 40 ml, PE/EtOAc 10:1 110 ml, 8:1 270 ml, 6:1 210 ml, 5:1 60 ml, 4:1 50 ml). 2-(2-fluoro-6-nitrophenyl)ethanol (653 mg, 71%) was obtained as a yellow solid.
Reaction SMILES: [CH2:1]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][O:19]C1CCCCO1)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>C(O)(=O)C.O1CCCC1.O>[CH2:1]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][OH:19])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: c1ccc(CCOCCCCCCCCCOC2CCCCO2)cc1
Solvent: CC(=O)O
Solvent: O
Solvent: C1CCOC1
Product: OCCCCCCCCCOCCc1ccccc1
Yield: 76.1 %

Procedure:
A solution of 2-(9-phenethyloxy-nonyloxy)-tetrahydro-pyran (890 mg, 2.55 mmol) in acetic acid/tetrahydrofuran/water 4:2:1 (23 mL) was stirred at 45° C. for 4 h. After evaporation, the residue was purified by chromatography (SiO2; heptane-ethyl acetate gradient), affording 9-phenethyloxy-nonan-1-ol (513 mg, 76%). Colorless oil, m/e=265.3 ([M+H]+).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:21]=[C:20]([S:22][CH3:23])[CH:19]=[CH:18][C:14]=1[C:15]([OH:17])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:24][C:25]1[CH:26]=[CH:27][C:28]([NH:31][C:32](=[O:41])[C:33]2[CH:38]=[C:37]([Cl:39])[CH:36]=[CH:35][C:34]=2[NH2:40])=[N:29][CH:30]=1>>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:21]=[C:20]([S:22][CH3:23])[CH:19]=[CH:18][C:14]=1[C:15]([NH:40][C:34]1[CH:35]=[CH:36][C:37]([Cl:39])=[CH:38][C:33]=1[C:32]([NH:31][C:28]1[CH:27]=[CH:26][C:25]([Cl:24])=[CH:30][N:29]=1)=[O:41])=[O:17])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CSc1ccc(C(=O)O)c(OCCCNC(=O)OC(C)(C)C)c1
Reactant: Nc1ccc(Cl)cc1C(=O)Nc1ccc(Cl)cn1
Product: CSc1ccc(C(=O)Nc2ccc(Cl)cc2C(=O)Nc2ccc(Cl)cn2)c(OCCCNC(=O)OC(C)(C)C)c1

Procedure:
2-[2-(3-tert-Butoxycarbonylaminopropoxy)-4-(methylthio)benzoylamino]-5-chloro-N-(5-chloropyridin-2-yl)benzamide was prepared by methods described in Example 4-E from 2-(3-tert-butoxycarbonylaminopropoxy)-4-(methylthio)benzoic acid and N-(5-chloropyridin-2-yl)-2-amino-5-chlorobenzamide (1.63 g, 49%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][OH:9])=[C:4]([S:10]([CH3:13])(=[O:12])=[O:11])[CH:3]=1.[H-].[Na+].[CH2:16]1COCC1.IC>C(Cl)Cl.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9][CH3:16])=[C:4]([S:10]([CH3:13])(=[O:12])=[O:11])[CH:3]=1
Reactant: C1CCOC1
Reactant: CS(=O)(=O)c1cc(Br)ccc1CO
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CI
Solvent: ClCCl
Product: COCc1ccc(Br)cc1S(C)(=O)=O
Reaction time: 1 h

Procedure:
To a mixture of (4-bromo-2-methansulfonyl-phenyl)-methanol (0.73 g, 2.78 mmol), sodium hydride (0.030 g, 8.4 mmol), and THF (10 mL) was added iodomethane (0.21 mL, 3.36 mmol). After 1 h, the reaction was poured into water (40 mL), diluted in CH2Cl2, and washed with brine (40 mL). The organic layer was dried over (Na2SO4), filtered, concentrated and purified by silica gel column chromatography to give 600 mg of 4-bromo-2-methansulfonyl-1-methoxymethyl-benzene.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH2:21][CH3:22])[CH2:9][C:8]2([CH3:24])[CH3:23])=[O:4].[OH-].[Na+].Cl>CO.O1CCCC1.O>[CH2:21]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[CH:10]1[CH2:9][C:8]([CH3:24])([CH3:23])[C:7]2[C:12](=[CH:13][CH:14]=[C:5]([C:3]([OH:4])=[O:2])[CH:6]=2)[NH:11]1)[CH3:22]
Reactant: CCc1ccccc1C1CC(C)(C)c2cc(C(=O)OC)ccc2N1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CCc1ccccc1C1CC(C)(C)c2cc(C(=O)O)ccc2N1
Temperature: 60 °C
Reaction time: 12 h
Yield: 90.8 %

Procedure:
To a stirred mixture solution of 2-(2-ethyl-phenyl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid methyl ester (0.6 g, 1.78 mmol) in methanol (10 mL) and tetrahydrofuran (20 mL) was added 30% sodium hydroxide in water (10 mL). The reaction mixture was stirred at 60° C. for 12 h. The mixture was neutralized with a 3 N aqueous hydrochloric acid solution and extracted with ethyl acetate (2×100 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo to afford 2-(2-ethyl-phenyl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (0.5 g, 90%) as a light white solid which was used for next step without further purification: MS (ESI) M+1=310.1.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([F:9])[C:3]=1[NH:10][C:11]([NH:13][CH:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1)=[O:12]>O1CCOCC1.C(OCC)(=O)C.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[F:9][C:4]1[C:3]2[NH:10][C:11](=[O:12])[N:13]([CH:14]3[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]3)[C:2]=2[CH:7]=[C:6]([CH3:8])[CH:5]=1
Reactant: Cc1cc(F)c(NC(=O)NC2CCN(C(=O)OC(C)(C)C)CC2)c(Br)c1
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Cc1cc(F)c2[nH]c(=O)n(C3CCN(C(=O)OC(C)(C)C)CC3)c2c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Under an argon atmosphere, bis(3,5,3′,5′-dimethoxy-dibenzylideneacetone) palladium (0) (6% mol, 1.1 mmol, 0.9 g), 1,1′-bis(diphenylphosphino)ferrocene (6% mol, 0.61 g), NatBuO (2 eq., 36 mmol, 3.5 g), were all dissolved in 1,4-dioxane (40 ml) and the system was purged through with argon. The mixture was stirred at room temperature for 15 minutes and 1,1-dimethylethyl 4-({[(2-bromo-6-fluoro-4-methylphenyl)amino]-carbonyl}amino)-1-piperidinecarboxylate (D32) (7.7 g, 17.9 mmol) was added at room temperature and the mixture was heated to 80° C. for 1.5 hours and then to 100° C. for extra 2 hours; the mixture was then cooled to room temperature, diluted with ethyl acetate and the organic phase obtained was washed with water and brine. Organics were dried over Na2SO4, filtered and the solvent was evaporated to afford the crude product that was purified by chromatography (ethyl acetate-n-hexane) to afford the title compound, 4.3 g, 70%, pale-grey solid, M+-H=348.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[OH:7][C:8]1[C:21]2[C:20](=[O:22])[C:19]3[CH:18]=[C:17]4[CH:23]=[CH:24][CH:25]=[CH:26][C:16]4=[CH:15][C:14]=3[NH:13][C:12]=2[CH:11]=[C:10]([OH:27])[CH:9]=1.[I-].[K+].Cl[C:31]([CH3:35])([CH3:34])[C:32]#[CH:33]>CN(C)C=O>[OH:7][C:8]1[CH:9]=[C:10]2[O:27][C:31]([CH3:35])([CH3:34])[CH:32]=[CH:33][C:11]2=[C:12]2[C:21]=1[C:20](=[O:22])[C:19]1[CH:18]=[C:17]3[CH:23]=[CH:24][CH:25]=[CH:26][C:16]3=[CH:15][C:14]=1[NH:13]2
Reactant: O=c1c2cc3ccccc3cc2[nH]c2cc(O)cc(O)c12
Reactant: C#CC(C)(C)Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC1(C)C=Cc2c(cc(O)c3c(=O)c4cc5ccccc5cc4[nH]c23)O1
Temperature: 65 °C
Reaction time: 0.25 h
Yield: 44.4 %

Procedure:
2 g of anhydrous potassium carbonate are added, under an inert atmosphere, to a solution of 2 g of the product of Step A in 50 ml of anhydrous dimethylformamide. After stirring for 15 minutes at 65° C., 2.4 g of anhydrous potassium iodide and 4.4 g of 3-chloro-3-methyl-1-butyne are added and the reaction mixture is maintained at 65° C. for 24 hours and then at 130° C. for 1 hour 30 minutes. After cooling, the solution is hydrolysed and then extracted with dichloromethane. The combined organic phases are washed with water and then with a 1M potassium hydroxide solution, dried over sodium sulphate and then evaporated. Chromatography over silica gel (cyclohexane/acetone: 90/10) yields 1.10 g of the expected product.
Reaction SMILES: [S:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:16]3[C:11](=[C:12]([Cl:17])[CH:13]=[CH:14][CH:15]=3)[CH:10]=[C:9](Cl)[N:8]=2)[CH2:3][CH2:2]1.[NH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1.Cl.O>C1(OC2C=CC=CC=2)C=CC=CC=1>[S:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:16]3[C:11](=[C:12]([Cl:17])[CH:13]=[CH:14][CH:15]=3)[CH:10]=[C:9]([N:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)[N:8]=2)[CH2:3][CH2:2]1
Reactant: C1CNCCN1
Reactant: Clc1cc2c(Cl)cccc2c(N2CCSCC2)n1
Agent: Cl
Solvent: O
Solvent: c1ccc(Oc2ccccc2)cc1
Product: Clc1cccc2c(N3CCSCC3)nc(N3CCNCC3)cc12
Yield: 97 %

Procedure:
1-Thiomorpholino-3-piperazino-5-chloro-isoquinoline was prepared analogous to Example 3 from 1-thiomorpholino-3,5-dichloro-isoquinoline and piperazine by heating in diphenyl ether at 200°C. M.p. of its hydrochloride: 273°-275°C (from water); yield: 97% of theory.
Reaction SMILES: [CH3:1][N:2]=[C:3]=[O:4].[CH:5]1([NH2:11])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1>C(OCC)C>[CH3:1][NH:2][C:3]([NH:11][CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:4]
Reactant: CN=C=O
Reactant: NC1CCCCC1
Solvent: CCOCC
Product: CNC(=O)NC1CCCCC1
Yield: 67.3 %

Procedure:
In 500 ml of ethyl ether is dissolved 57 g of methyl isocyanate and, then, 99 g of cyclohexylamine is added dropwise, whereupon crystals separate. The crystals are washed with ether. By the above procedure is obtained 105 g of N-methyl-N'-cyclohexylurea. melting point: 160°-161° C.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=1.[OH-].[K+].[C:14](=O)([O-:16])[O-:15].[K+].[K+].[C:20](=[O:22])=[O:21]>>[OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:14]([OH:16])=[O:15])[CH:6]=[CH:5]2.[OH:1][C:2]1[C:11]([C:20]([OH:22])=[O:21])=[CH:10][C:9]2[C:4]([CH:3]=1)=[CH:5][CH:6]=[CH:7][CH:8]=2
Reactant: O=C([O-])[O-]
Reactant: O=C=O
Reactant: Oc1ccc2ccccc2c1
Agent: [K+]
Agent: [OH-]
Product: O=C(O)c1cc2ccccc2cc1O
Product: O=C(O)c1ccc2cc(O)ccc2c1
Yield: 48.1 %

Procedure:
The procedure of Example 1 is followed in every detail except that a mixture of 2-hydroxynaphthalene (83 grams; 0.576 mole), 45% potassium hydroxide (69.7 grams; 0.559 mole), and potassium carbonate (20 grams; 0.145 mole) is employed initially, the dehydrated reaction mixture is heated under 60 psi of carbon dioxide for 10 hours, and the aqueous phase is washed twice with 100-ml portions of isopropylnaphthalene at 85°-95° C. There is obtained 25.5 grams of 6-hydroxy-2-naphthoic acid (48.1% of theoretical), and 4.6 grams of 3-hydroxy-2-naphthoic acid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[CH:4]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][CH:18]=2)[CH2:13][CH2:12]1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[C:25](O)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[N:28][CH:27]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O>[CH3:1][O:2][C:3](=[O:24])[CH:4]([C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)[N:11]1[CH2:12][CH2:13][N:14]([C:17]2[CH:18]=[CH:19][C:20]([NH:23][C:25]([C:26]3[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=3)=[O:32])=[CH:21][CH:22]=2)[CH2:15][CH2:16]1
Reactant: COC(=O)C(c1ccccc1)N1CCN(c2ccc(N)cc2)CC1
Reactant: O=C(O)c1cccnc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)C(c1ccccc1)N1CCN(c2ccc(NC(=O)c3cccnc3)cc2)CC1
Reaction time: 16 h
Yield: 79 %

Procedure:
A mixture of [4-(4-amino-phenyl)-piperazin-1-yl]-phenyl-acetic acid methyl ester (50 mg, 0.15 mmol), nicotinic acid (23 mg, 0.18 mmol), and HATU (70 mg, 0.18 mmol) in DMF (2 mL) was treated with iPr2NEt (32 μL, 0.18 mmol). After 16 h, the mixture was diluted with H2O and extracted with DCM. The organic layer was washed with satd. aq. NaHCO3 and brine, dried (MgSO4), and concentrated to give an oil, which was purified by PTLC to give a tan solid (51 mg, 77%). MS (ESI): mass calcd. for C25H26N4O3, 430.50; m/z found, 431.4 [M+H]+. 1H NMR (CDCl3): 9.07-9.06 (m, 1H), 8.77-8.76 (m, 1H), 8.20-8.18 (m, 1H), 8.01 (s, 1H), 7.68 (br s, 1H), 7.51-7.42 (m, 4H), 7.38-7.32 (m, 3H), 6.92-6.90 (m, 2H), 4.06 (s, 1H), 3.71 (s, 3H), 3.22-3.20 (m, 4H), 2.64-2.62 (m, 4H).
Reaction SMILES: [I:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)=O.[F:9][C:10]([F:21])([F:20])[CH:11]([F:19])[C:12]([F:18])([F:17])[S:13]([OH:16])(=[O:15])=[O:14].[C:22]1([CH3:28])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>ClCCl>[F:21][C:10]([F:9])([F:20])[CH:11]([F:19])[C:12]([F:17])([F:18])[S:13]([O-:16])(=[O:14])=[O:15].[CH3:28][C:22]1[CH:27]=[CH:26][C:25]([I+:1][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)=[CH:24][CH:23]=1
Reactant: Cc1ccccc1
Reactant: O=S(=O)(O)C(F)(F)C(F)C(F)(F)F
Reactant: O=Ic1ccccc1
Solvent: ClCCl
Product: Cc1ccc([I+]c2ccccc2)cc1
Product: O=S(=O)([O-])C(F)(F)C(F)C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred suspension of 4.40 g (20 mmol) of iodosylbenzene in 100 ml of dichloromethane was added dropwise 4.64 g (20 mmol) of 3,3,3,2,1,1-hexafluoropropane sulfonic acid at 0° C. under exclusion of moisture. The mixture was stirred at room temperature for 2 hours. The temperature was returned to 0° C. again. 1.84 mg (20 mmol) of toluene was added dropwise. After the addition, stirring was continued at room temperature for additional 1 hour. The solvent was evaporated. The oily residue was dissolved in diethyl ether. After cooling, crystals of 4-methylphenyl phenyl iodonium 3,3,3,2,1,1-hexafluoropropane sulfonate were obtained. The crystals were washed with hexane.
Reaction SMILES: ClC1C=C(Cl)C=CC=1C[O:10][C@@H:11]1[C@@H:15]([CH2:16][O:17]CC2C=CC(Cl)=CC=2Cl)[O:14][C@@H:13]([N:27]2[CH:39]=[C:31]3[CH:32]=[CH:33][C:34]4[CH2:35][NH:36][N:37]=[CH:38][C:29]([C:30]=43)=[N:28]2)[C@:12]1([CH3:41])[OH:40].B(Cl)(Cl)Cl.CO>C(Cl)Cl>[CH3:41][C@@:12]1([OH:40])[C@H:11]([OH:10])[C@@H:15]([CH2:16][OH:17])[O:14][C@H:13]1[N:27]1[CH:39]=[C:31]2[CH:32]=[CH:33][C:34]3[CH2:35][NH:36][N:37]=[CH:38][C:29]([C:30]=32)=[N:28]1
Reactant: C[C@@]1(O)[C@H](OCc2ccc(Cl)cc2Cl)[C@@H](COCc2ccc(Cl)cc2Cl)O[C@H]1n1cc2ccc3c-2c(n1)C=NNC3
Agent: ClB(Cl)Cl
Solvent: CO
Solvent: ClCCl
Product: C[C@@]1(O)[C@H](O)[C@@H](CO)O[C@H]1n1cc2ccc3c-2c(n1)C=NNC3
Temperature: -78 °C
Reaction time: 2.5 h
Yield: 20.1 %

Procedure:
To compound 24.1 (160 mg, 0.25 mmol) in CH2Cl2 (10 mL) at −78° C. was added 1M solution of boron trichloride in CH2Cl2 dropwise over 5 minutes and the solution stirred at −78° C. for 2.5 h and then at −25° C. for 3 hr. To this mixture was added 25 mL of 1:1 v/v CH2Cl2:MeOH and the solution stirred at −15° C. for 30 minutes. The mixture was brought to room temperature and the solvent was evaporated under reduced pressure. The residue was co-evaporated with MeOH (5×10 mL) and a 10 mL MeOH solution was neutralized with NH4OH and evaporated again. The residue was adsorbed on 2 g silica gel and loaded on a silica column and eluted successively with 50:1, 20:1 and 15:1 CH2Cl2:MeOH. Fractions eluting at 20:1 and 15:1 were collected. Pooling of fraction and evaporation gave 16 mg product 24.2. 1H NMR (DMSO-d6) δ 8.10 (s, 1H), 7.51 (s, 11H), 7.30 (t, 1H), 6.61 (d, J 9 Hz, 1H), 6.11 (s, 1H), 5.71 (dt, J6, 12 Hz, 1H), 5.08 (m, 3H), 3.86 (m, 5H), 3.78 (m, 1H), 0.72 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH2:7][S:8][CH2:9][CH2:10][NH2:11])=[N:5][N:6]=1.[C:12]([C:14]([C:29]#[N:30])=[C:15](SC)[NH:16][CH2:17][CH2:18][S:19][CH2:20][C:21]1[NH:25][CH:24]=[N:23][C:22]=1[CH3:26])#[N:13]>>[C:12]([C:14]([C:29]#[N:30])=[C:15]([NH:11][CH2:10][CH2:9][S:8][CH2:7][C:4]1[S:3][C:2]([NH2:1])=[N:6][N:5]=1)[NH:16][CH2:17][CH2:18][S:19][CH2:20][C:21]1[NH:25][CH:24]=[N:23][C:22]=1[CH3:26])#[N:13]
Reactant: NCCSCc1nnc(N)s1
Reactant: CSC(NCCSCc1[nH]cnc1C)=C(C#N)C#N
Product: Cc1nc[nH]c1CSCCNC(NCCSCc1nnc(N)s1)=C(C#N)C#N

Procedure:
By the procedure of Example 24(iii) reacting 2-amino-5-[(2-aminoethyl)thiomethyl]-1,3,4-thiadiazole with 1,1-dicyano-2-methylthio-2-[2-((4-methyl-5-imidazolyl)methylthio)ethylamino]ethylene, gives the title compound.
Reaction SMILES: [Cl-].[C:2]([C:4]1[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][CH:14]=[CH:13][C:5]=1[O:6][CH2:7][C@H:8]1[CH2:12][CH2:11][CH2:10][NH2+:9]1)#[N:3].[C:20]([N:24]=[C:25]=[O:26])([CH3:23])([CH3:22])[CH3:21]>>[C:2]([C:4]1[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][CH:14]=[CH:13][C:5]=1[O:6][CH2:7][C@H:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:25]([NH:24][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:26])#[N:3]
Reactant: N#Cc1c(OC[C@H]2CCC[NH2+]2)cccc1[N+](=O)[O-]
Reactant: CC(C)(C)N=C=O
Agent: [Cl-]
Product: CC(C)(C)NC(=O)N1CCC[C@@H]1COc1cccc([N+](=O)[O-])c1C#N
Yield: 100 %

Procedure:
Prepared as in Example 165b from (R)-2-((2-cyano-3-nitrophenoxy)methyl)pyrrolidinium chloride (Example 176c) and tert-butyl isocyanate in 100% yield as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ 1.s7 (s, 9H), 1.86 (m, 1H), 1.95 (m, 2H), 2.12 (m, 1H), 3.18 (m, 1H), 3.37 (m, 1H), 4.20 (m, 1H), 4.23 (dd, J=16.0, 6.3 Hz, 1H), 4.31 (dd, J=9.7, 2.7 Hz, 1H), 5.36 (s, 1H), 7.84 (dd, J=7.4, 0.9 Hz, 1H), 7.91 (m, 2H).