Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]([S:13][CH:14]2[NH:17][C:16](=[O:18])[CH2:15]2)[CH:8]=[CH:9][C:10]=1[O:11][CH3:12].[CH3:19][O:20][C:21](=[O:24])[CH2:22]Br.C(OCC)(=O)C>CN(C=O)C>[CH3:19][O:20][C:21](=[O:24])[CH2:22][N:17]1[CH:14]([S:13][C:7]2[CH:8]=[CH:9][C:10]([O:11][CH3:12])=[C:5]([O:4][CH3:3])[CH:6]=2)[CH2:15][C:16]1=[O:18]
Reactant: COC(=O)CBr
Reactant: COc1ccc(SC2CC(=O)N2)cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)CN1C(=O)CC1Sc1ccc(OC)c(OC)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 25.7 %

Procedure:
Sodium hydride (0.5 g, 12 mmol) in dry DMF (10 ml) was cooled to -5° C. and a solution of 4-(3,4-dimethoxyphenylthio)azetidin-2-one (3 g, 12 mmol) in dry DMF (20 ml) was added dropwise over 15 mins under a nitrogen atmosphere at -5° C. After 15 mins methylbromoacetate (2 g, 12 mmol) was added in one portion, and the mixture stirred for 30 mins at room temperature. The reaction mixture was carefully poured into brine/ice water and ethyl acetate (100 ml) was added. The organic layer was washed with brine (x2), dried (MgSO4) and evaporated to a yellow oil which was purified by flash column chromatography eluted with petroleum ether/ethyl acetate to give the product as a yellow oil (0.96 g, 25% yield).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][C@H:3]([OH:6])[CH2:2]1.[C:7](Cl)([Cl:9])=[O:8].C1(C)C=CC=CC=1>C(Cl)Cl>[Cl:9][C:7]([O:6][C@H:3]1[CH2:4][CH2:5][O:1][CH2:2]1)=[O:8]
Reactant: O[C@H]1CCOC1
Reactant: O=C(Cl)Cl
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: O=C(Cl)O[C@H]1CCOC1
Temperature: 25 °C
Yield: 85 %

Procedure:
A stirred solution of (S)-tetrahydrofuran-3-ol (7.9 g, 90 mmol) in anhydrous CH2Cl2 (50 mL) under an N2 atmosphere was cooled in an ice bath, and a 20% solution of phosgene in toluene (134 mL, 270 mmol) was slowly added. The reaction was allowed to warm to room temperature overnight, and the solvent was removed under vacuum to afford (S)-tetrahydrofuran-3-yl chloroformate (12.1 g, 85%) as a clear liquid. 1H NMR (400 MHz, CDCl3) d 5.42-5.39 (m, 1H), 4.01-3.84 (m, 4H), 2.31-2.13 (m, 2H) ppm.
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:3]=1[NH2:4].[N:10]([O-])=O.[Na+].C([O-])(=O)C.[Na+].[C:19]([CH2:22][C:23](=[O:25])[CH3:24])(=[O:21])[CH3:20]>C(O)(=O)C.Cl.O>[F:1][C:2]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:3]=1[NH:4][N:10]=[C:22]([C:23](=[O:25])[CH3:24])[C:19](=[O:21])[CH3:20]
Reactant: Nc1ccc(F)cc1F
Reactant: CC(=O)CC(C)=O
Reactant: O=N[O-]
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)C(=NNc1ccc(F)cc1F)C(C)=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 29.5 %

Procedure:
To a solution of 2,4-difluoroaniline (1.0 g, 7.75 mmol) in 11.1 mL of acetic acid and 1.69 mL of concentrated hydrochloride solution, sodium nitrite (600 mg, 9.3 mmol) in 2.7 mL of water was added dropwise at 0° C., and the mixture was stirred at 0° C. for 1 h. Then to the reaction mixture was added dropwise a mixture of sodium acetate (1.78 g, 21.7 mmol) and acetylacetone (1 g, 10 mmol). The mixture was stirred at room temperature for 2 h, filtered, washed with water, EtOH/H2O (1/1) and hexane, and dried to give the title compound (550 mg, 30% yield): 1H NMR (400 MHz, CDCl3): δ ppm 2.48 (s, 3H), 2.61 (s, 3H), 6.91-7.00 (m, 2H), 7.70-7.76 (m, 1H), 14.72 (s, 1H).
Reaction SMILES: [PH:1]([O:4][PH:5]([OH:7])=[O:6])([OH:3])=[O:2].[O:8]1[CH:10]=[CH:9]1.O.O1CCOCC1>CC(C)=O>[PH:1]([O:4][PH:5]([OH:7])=[O:6])([OH:3])=[O:2].[O:8]1[CH2:10][CH2:9]1
Reactant: C1=CO1
Agent: O=[PH](O)O[PH](=O)O
Solvent: C1COCCO1
Solvent: CC(C)=O
Solvent: O
Product: C1CO1

Procedure:
The hydrolysis of epoxy ethane diphosphonate to produce the dihydroxy ethane diphosphonate proceeds according to the following general reaction: ##EQU6## wherein R3 is the same as defined above. The aforementioned reaction may be carried out by mixing the epoxy ethene diphosphonate in a sufficient volume of water, i.e., at least stoichiometric quantities, preferably a molar ratio of water to EEDP of 1:1 to 20:1, and heating the resultant mass until substantially complete hydrolysis occurs. The use of greater than stoichiometric quantities of water functions as a diluent for the reaction system. It is also found that substantially water-miscible organic diluents which have a boiling point between about 50°C and 150°C, preferably from about 70°C to about 100°C, such as dioxane, acetone, lower alcohols (e.g., methanol, ethanol, propanol and butanol) are suitable as a reaction medium or diluent in which the above-described hydrolysis reaction can be conducted.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][CH2:9][CH2:10][C:11]([O:13]C)=[O:12])[CH2:3][CH2:2]1.[OH-:15].[Na+].[CH3:17][OH:18]>OS([O-])(=O)=O.[K+].C(OCC)(=O)C>[C:17]([N:1]1[CH2:2][CH2:3][CH:4]([CH2:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])[CH2:5][CH2:6]1)([O:18][C:4]([CH3:7])([CH3:5])[CH3:3])=[O:15]
Reactant: [OH-]
Reactant: COC(=O)CCCCC1CCNCC1
Reactant: CO
Agent: O=S(=O)([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(CCCCC(=O)O)CC1

Procedure:
A mixture of ester 15 (200 mg, 0.7 mmol), in NaOH (1.0 mL, 1.0 mmol), and CH3OH (4.0 mL) was stirred at ambient temperature for 20 hours. The reaction mixture was then diluted sequentially with 5% KHSO4 and ethyl acetate. The ethyl acetate portion was washed with brine, dried (MgSO4), and concentrated to give the carboxylic acid 16 (190 mg) as a colorless oil.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH2:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][CH2:21][NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH:15]=1.C([O-])(=O)C.[Na+]>CN(C)C(=O)C.C(OCC)(=O)C.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:26]([O:25][C:23]([NH:22][CH2:21][CH2:20][C:16]1[CH:15]=[C:14]2[C:19]([C:2]3[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=3[CH2:12][O:13]2)=[CH:18][CH:17]=1)=[O:24])([CH3:29])([CH3:28])[CH3:27]
Reactant: COC(=O)c1ccc(Br)c(COc2cccc(CCNC(=O)OC(C)(C)C)c2)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1ccc2c(c1)COc1cc(CCNC(=O)OC(C)(C)C)ccc1-2
Temperature: 130 °C
Reaction time: 1.5 h
Yield: 56.1 %

Procedure:
To a solution of methyl 4-bromo-3-[[3-[2-[(tert-butoxycarbonyl)amino]ethyl]phenoxy]methyl]benzoate (410 mg) in N,N-dimethylacetamide (4.0 ml) was added dichlorobis(triphenylphosphine)palladium(II) (124 mg) and sodium acetate (362 mg), and the mixture was stirred at 130° C. for 1.5 hours under nitrogen. The mixture was cooled to room temperature, diluted with ethyl acetate and water. The organic layer was separated, washed with brine, dried over magnesium sulfate and evaporated. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate=3/1) to give methyl 3-[2-[(tert-butoxycarbonyl)amino]ethyl]-6H-benzo[c]chromene-8-carboxylate (190 mg).
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1.[OH:28][C:29]1([C:33](O)=[O:34])[CH2:32][CH2:31][CH2:30]1>>[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:33]([C:29]5([OH:28])[CH2:32][CH2:31][CH2:30]5)=[O:34])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1
Reactant: O=C(O)C1(O)CCC1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1)C1(O)CCC1

Procedure:
The title compound, off-white solid (68 mg, 64%), MS (ISP) m/z=429.4 [(M+H)+], mp 250° C., was prepared in accordance with the general method of example 6 from trans-4-{2-[4-(2,3-dihydro-furo[2,3-c]pyridin-7-yl)-piperazin-1-yl]-ethyl}-cyclohexylamine trihydrochloride (intermediate B) (110 mg, 0.25 mmol) and 1-hydroxy-cyclobutane-carboxylic acid.
Reaction SMILES: [CH3:1][C:2]1([CH3:7])[NH:6][CH2:5][CH2:4][O:3]1.C(N(CC)CC)C.[Cl:15][CH:16]([Cl:24])[C:17]([O:19][CH2:20][C:21](Cl)=[O:22])=[O:18].O>C(Cl)Cl>[CH3:1][C:2]1([CH3:7])[N:6]([C:21](=[O:22])[CH2:20][O:19][C:17](=[O:18])[CH:16]([Cl:24])[Cl:15])[CH2:5][CH2:4][O:3]1
Reactant: CC1(C)NCCO1
Reactant: O=C(Cl)COC(=O)C(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CC1(C)OCCN1C(=O)COC(=O)C(Cl)Cl
Temperature: 25 °C
Yield: 69.1 %

Procedure:
A solution was made by combining while cooling in an ice bath, 1.51 g (0.015 mole) of 2,2-dimethyloxazolidine, 1.6 g (0.015 mole) of triethylamine, and 100 ml of methylene chloride. A second solution containing 3.08 g (0.015 mole) of dichloroacetoxyacetyl chloride dissolved in 10 ml of methylene chloride was added dropwise to the first solution. The mixture was stirred in the ice bath for ten minutes. After refluxing for one hour, it was allowed to cool to room temperature. The reaction product was water washed twice and dried over magnesium sulfate. It was decolorized with a decolorizing agent and charcoal. The solvent was removed by reduced pressure evaporation leaving 2.8 g (69% yield) of 2,2-dimethyl-3-dichloroacetoxyacetyloxazolidine. The structure was confirmed by IR.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1.[Br:13]Br>C(O)(=O)C>[Br:13][C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:11]=[CH:12][C:3]=1[O:2][CH3:1]
Reactant: BrBr
Reactant: COc1ccc2ccccc2c1
Solvent: CC(=O)O
Product: COc1ccc2ccccc2c1Br

Procedure:
A stirred solution of 2-methoxynaphthalene (5g.) in acetic acid (100 ml.) is treated dropwise with a solution of 1.1 molar equivalents of bromine in acetic acid (50 ml.). Upon disappearance of the bromine color, wtaer is added. The solid which forms is collected by filtration, washed with water until neutral, recrystallized, rewashed, and dried to yield 1-bromo-2-methoxynaphthalene.
Reaction SMILES: [C:1]([CH:4]([C:10]1[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=1)[CH:5]([CH3:9])[CH2:6][C:7]#[N:8])(=O)[CH3:2].C([OH:18])C>>[CH3:9][CH:5]1[C:4]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)=[C:1]([CH3:2])[NH:8][C:7](=[O:18])[CH2:6]1
Reactant: CCO
Reactant: CC(=O)C(c1ccncc1)C(C)CC#N
Product: CC1=C(c2ccncc2)C(C)CC(=O)N1
Reaction time: 1 h

Procedure:
The same compound was prepared by the following procedure: Into a solution containing 81 g of 4-acetyl-3-methyl-4-(4-pyridinyl)butanenitrile dissolved in 250 ml of absolute ethanol was bubbled hydrogen chloride gas at ambient temperature with no cooling. After about 1 hour, a white solid began to crystallize. The reaction vessel was then stoppered and allowed to stand overnight at room temperature. The reaction mixture was evaporated to dryness in vacuo and the residue was dissolved in a small amount of water. The aqueous solution was made alkaline with concentrated ammonia hydroxide and the mixture was extracted with ethyl acetate. The ethyl acetate solution was dried over anhydrous magnesium sulfate, the mixture filtered and the filtrate evaporated in vacuo. The residue was slurried with acetonitrile and the solid, 5.4 g, was collected. This solid was combined with the product obtained as described in the immediately preceding paragraph along with the product obtained hereinbelow in Example C-3 and the combined material was recrystallized from about 250 ml of acetonitrile to yield 9.9 g of 3,4-dihydro-4,6-dimethyl-5-(4-pyridinyl)-2(1H)-pyridinone, m.p. 186°-188° C.
Reaction SMILES: Cl.C1([N:8]([C:10](=[NH:17])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[NH2:9])C=CC=CC=1.[CH2:18]([O:20][C:21](=[O:26])[CH2:22][C:23](Cl)=O)[CH3:19].C(N([CH2:32][CH3:33])CC)C>C(Cl)Cl>[C:21]([CH2:22][C:23]1[N:9]([C:33]2[CH:32]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:8]=[C:10]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:17]=1)([O:20][CH2:18][CH3:19])=[O:26]
Reactant: CCOC(=O)CC(=O)Cl
Reactant: CCN(CC)CC
Reactant: N=C(c1ccccc1)N(N)c1ccccc1
Agent: Cl
Solvent: ClCCl
Product: CCOC(=O)Cc1nc(-c2ccccc2)nn1-c1ccccc1
Reaction time: 4 h

Procedure:
A solution of 38 g. (0.227 mole) of the hydrochloride of benzimidic acid phenyl hydrazide, 25 ml. (0.166 mole) of α-chloroformyl acetic acid ethyl ester and 47.5 ml. (0.335 mole) of triethylamine in 420 ml. of methylene chloride is kept at room temperature for about 3 hours, and to it is subsequently added a solution of 38 ml. (0.271 mole) of triethylamine and 25 ml. (0.166 mole) of α-chloroformyl acetic acid ethyl ester in 30 ml. of methylene chloride. The resulting mixture is stirred for about 4 hours and allowed to stand overnight at room temperature. 48 Grams of the crude intermediate compound of formula V, namely 5-carbethoxymethyl-1,3-diphenyl-1,2,4-triazole is so obtained, which is used as such for the subsequent hydrolysis step.
Reaction SMILES: [CH2:1](Br)[C:2]#[CH:3].[C:5]([NH:24][C:25]1[S:26][CH:27]=[C:28]([C:30](=[N:36][OH:37])[C:31]([O:33][CH2:34][CH3:35])=[O:32])[N:29]=1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:5]([NH:24][C:25]1[S:26][CH:27]=[C:28]([C:30](=[N:36][O:37][CH2:3][C:2]#[CH:1])[C:31]([O:33][CH2:34][CH3:35])=[O:32])[N:29]=1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CCOC(=O)C(=NO)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C#CCON=C(C(=O)OCC)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 1.67 h
Yield: 77 %

Procedure:
Propargyl bromide (4.16 g.) was added to a suspension of ethyl 2-(2-tritylaminothiazol-4-yl)-2-hydroxyiminoacetate (syn isomer, 10 g.), potassium carbonate (4.84 g.) and N,N-dimethylformamide (22 ml.) under atmosphere of nitrogen gas and stirred at room temperature for 100 minutes. The insoluble substance was filtered off and washed with a little of N,N-dimethylformamide. The filtrate and washing solution were combined together, and water (400 ml.) was added to the solution. After the suspension was extracted with ethyl acetate (400 ml.), the extract was washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. After treating the solution with activated charcoal, the solution was concentrated in vacuo. The residue was triturated with diisopropyl ether. The precipitates were collected by filtration, and washed with diisopropyl ether to give ethyl 2-(2-tritylaminothiazol-4-yl)-2-propargyloxyiminoacetate (syn isomer, 8.34 g.).
Reaction SMILES: C([C:3]1[CH:14]=[C:13]([N+:15]([O-])=O)[CH:12]=[CH:11][C:4]=1[O:5][CH2:6][C:7](OC)=O)=O.O[C:19]1[CH:26]=[CH:25][C:24]([N+]([O-])=O)=[CH:23][C:20]=1[CH:21]=O.[OH-].[K+].[CH3:32][CH2:33][OH:34]>>[O:5]1[CH:6]=[CH:7][C:11]2[CH:12]=[C:13]([NH:15][C:33](=[O:34])/[CH:32]=[CH:21]/[C:20]3[CH:23]=[CH:24][C:25]([C:20]([CH3:23])([CH3:21])[CH3:19])=[CH:26][CH:19]=3)[CH:14]=[CH:3][C:4]1=2
Reactant: CCO
Reactant: O=Cc1cc([N+](=O)[O-])ccc1O
Reactant: COC(=O)COc1ccc([N+](=O)[O-])cc1C=O
Agent: [K+]
Agent: [OH-]
Product: CC(C)(C)c1ccc(/C=C/C(=O)Nc2ccc3occc3c2)cc1
Temperature: 65 °C
Reaction time: 0.75 h

Procedure:
Methyl 2-(2-formyl-4-nitrophenoxy)acetate. To a round-bottomed flask was added a suspension of 2-hydroxy-5-nitrobenzaldehyde (10 g, 60 mmol, Aldrich) in anhydrous EtOH (180 mL). The suspension was treated with KOH (4.4 g, 66 mmol) and heated under N2 with magnetic stirring in a 65° C. oil bath for 45 min. The reaction mixture was allowed to cool to 25° C. and concentrated in vacuo. Anhydrous DMF (180 mL) was added, and the reaction flask was cooled in an ice bath and charged with methyl bromoacetate (10 mL, 110 mL, Aldrich). The reaction mixture was stirred for 3.5 h at 25° C., then the solvent was removed in vacuo. Water (200 mL) was added, and the mixture was extracted with EtOAc (3×50 mL). The combined organic extract was washed with 1 M H3PO4, satd NaHCO3, and satd NaCl. After drying over MgSO4, the organic layer was filtered and concentrated in vacuo. The residue was recrystallized from CH2Cl2 and hexane to afford the title product as a pale yellow solid. MS (ESI, pos. ion) m/z: 240 (M+1).
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][N:8]=2)[N:5]=[CH:4][C:3]=1[C:16]1[CH:21]=[CH:20][N:19]=[C:18]([O:22][CH3:23])[CH:17]=1.Cl.[CH3:25][O:26][CH2:27][C:28]1([NH2:31])[CH2:30][CH2:29]1>>[OH:1][C:2]1[N:6]([C:7]2[CH:15]=[CH:14][C:10]([C:11]([NH:31][C:28]3([CH2:27][O:26][CH3:25])[CH2:30][CH2:29]3)=[O:13])=[CH:9][N:8]=2)[N:5]=[CH:4][C:3]=1[C:16]1[CH:21]=[CH:20][N:19]=[C:18]([O:22][CH3:23])[CH:17]=1
Reactant: COCC1(N)CC1
Reactant: COc1cc(-c2cnn(-c3ccc(C(=O)O)cn3)c2O)ccn1
Agent: Cl
Product: COCC1(NC(=O)c2ccc(-n3ncc(-c4ccnc(OC)c4)c3O)nc2)CC1

Procedure:
The title compound was prepared in a manner similar to Example 198 using 6-(5-hydroxy-4-(2-methoxypyridin-4-yl)-1H-pyrazol-1-yl)nicotinic acid and 1-(methoxymethyl)cyclopropanamine hydrochloride. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.80 (s, 4 H) 3.28 (s, 3 H) 3.48 (s, 2 H) 3.90 (s, 3 H) 7.49 (br. s., 1 H) 7.57 (d, J=5.3 Hz, 1 H) 8.08 (d, J=5.6 Hz, 1 H) 8.35-8.50 (m, 2 H) 8.68 (br. s., 1 H) 8.90 (t, J=1.4 Hz, 1 H) 8.98 (s, 1 H). MS m/z 396 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][CH:7]2[CH2:12][CH2:11][CH2:10][NH:9][CH2:8]2)=[CH:4][CH:3]=1.[C:15]([OH:25])(=[O:24])[C@@H:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[OH:17]>C(#N)C>[C:15]([OH:25])(=[O:24])[CH:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[OH:17].[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C@@H:7]2[CH2:12][CH2:11][CH2:10][NH:9][CH2:8]2)=[CH:13][CH:14]=1
Reactant: O=C(O)[C@H](O)c1ccccc1
Reactant: Fc1ccc(CC2CCCNC2)cc1
Solvent: CC#N
Product: Fc1ccc(C[C@@H]2CCCNC2)cc1
Product: O=C(O)C(O)c1ccccc1

Procedure:
The crude racemic 3-(4-fluorobenzyl)piperidine (2.0 g) was dissolved in 25 mL acetonitrile and heated to reflux. The solution was hazy. To this was added 1.56 g (1 equivalent) of (R)-(−) mandelic acid dissolved in 15 mL acetonitrile. Some initial precipitation occurred when the cooler solution was added but it redissolved when refluxing resumed. The heat was turned off and small amounts of enantiomerically pure salt were added as the temperature dropped. At first the seed crystals dissolved, but when the temperature dropped to 75° C., they remained suspended in the stirred solution. After a few more degrees of cooling, crystal growth was obvious. Cooling was continued at the rate of 1 degree/min. At 50° C., the solution was filtered to recover 0.9 g of salt, which melted at 164° C. It was recrystallized from acetonitrile twice to give (S)-(+)-3-(4-fluorobenzyl)piperidine mandelic acid salt in 98% enantiomeric excess, mp 168-171° C.
Reaction SMILES: [S:1]1[CH:5]=[C:4](B(O)O)[C:3]2[CH:9]=[CH:10][CH:11]=[CH:12][C:2]1=2.O.O=[CH:15][C:16]([OH:18])=[O:17].[CH2:19]([C:21]1[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=1[NH2:23])[CH3:20]>C(#N)C>[S:1]1[CH:5]=[C:4]([CH:15]([NH:23][C:22]2[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=2[CH2:19][CH3:20])[C:16]([OH:18])=[O:17])[C:3]2[CH:9]=[CH:10][CH:11]=[CH:12][C:2]1=2
Reactant: CCc1ccccc1N
Reactant: OB(O)c1csc2ccccc12
Reactant: O=CC(=O)O
Solvent: CC#N
Solvent: O
Product: CCc1ccccc1NC(C(=O)O)c1csc2ccccc12
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Benzo[b]thiophen-3-ylboronic acid (500 mg, 2.81 mmol) and 2-oxoacetic acid hydrate (259 mg, 2.81 mmol) were dissolved in acetonitrile (20 ml), and then 2-ethylaniline (346 μl, 2.81 mmol) was added. The mixture was stirred at r.t. for 72 hours. The solvent was evaporated and the crude was used in the next step without any further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:22]=[CH:23][CH:24]=1)[CH:7]=[C:8]([C:19]([CH3:21])=O)[C:9]([O:11][CH2:12][CH2:13][CH2:14][O:15][N+:16]([O-:18])=[O:17])=[O:10])([O-:3])=[O:2].C(O)(=O)C.[C:29]([CH2:32][C:33]([O:35][CH2:36][CH2:37][CH2:38][O:39][N+:40]([O-:42])=[O:41])=[O:34])(=[NH:31])[NH2:30].C[O-].[Na+]>C(O)(C)C>[NH2:30][C:29]1[NH:31][C:19]([CH3:21])=[C:8]([C:9]([O:11][CH2:12][CH2:13][CH2:14][O:15][N+:16]([O-:18])=[O:17])=[O:10])[CH:7]([C:6]2[CH:22]=[CH:23][CH:24]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[C:32]=1[C:33]([O:35][CH2:36][CH2:37][CH2:38][O:39][N+:40]([O-:42])=[O:41])=[O:34]
Reactant: N=C(N)CC(=O)OCCCO[N+](=O)[O-]
Reactant: CC(=O)C(=Cc1cccc([N+](=O)[O-])c1)C(=O)OCCCO[N+](=O)[O-]
Agent: C[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(C)O
Product: CC1=C(C(=O)OCCCO[N+](=O)[O-])C(c2cccc([N+](=O)[O-])c2)C(C(=O)OCCCO[N+](=O)[O-])=C(N)N1
Yield: 65.9 %

Procedure:
500 ml of an isopropanol solution containing 18.8 g (55.7 mmoles) of 3-nitrooxypropyl 2-(3-nitrobenzylidene)acetoacetate, 14.76 g (55.7 mmoles) of 3-nitrooxypropyl amidinoacetate acetate and 3.00 g (55.7 mmoles) of sodium methoxide were heated under reflux for 90 minutes. The solution was then cooled and insolubles were filtered off. The isopropanol was then evaporated off under reduced pressure. The resulting residue was dissolved in methylene chloride, and the solution was washed with water and dried over anhydrous sodium sulfate. The methylene chloride was evaporated off under reduced pressure, to give a residue, which was purified by silica gel column chromatography, eluted with a 3:1 by volume mixture of toluene and ethyl acetate, and the product was recrystallized from toluene, to afford 19.3 g (yield 65.9%) of the title compound as yellow powdery crystals, melting at 145°-146° C.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[CH2:6][NH2:7].[I:8][C:9]1[CH:14]=[CH:13][C:12]([S:15](Cl)(=[O:17])=[O:16])=[CH:11][CH:10]=1>>[I:8][C:9]1[CH:14]=[CH:13][C:12]([S:15]([NH:7][CH2:6][CH:2]2[CH2:3][CH2:4][CH2:5][O:1]2)(=[O:17])=[O:16])=[CH:11][CH:10]=1
Reactant: NCC1CCCO1
Reactant: O=S(=O)(Cl)c1ccc(I)cc1
Product: O=S(=O)(NCC1CCCO1)c1ccc(I)cc1

Procedure:
The title compound was prepared from (tetrahydro-2-furanylmethyl)amine and 4-iodobenzenesulfonyl chloride using a similar procedure to that described for Description 30.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:7]=[CH:6][C:5]=1[OH:18])[CH:2]=[CH2:3].[H][H]>C(OCC)(=O)C.[Pd]>[CH2:11]([O:10][C:8]1[CH:7]=[CH:6][C:5]([OH:18])=[C:4]([CH2:1][CH2:2][CH3:3])[CH:9]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: [H][H]
Reactant: C=CCc1cc(OCc2ccccc2)ccc1O
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCc1cc(OCc2ccccc2)ccc1O
Yield: 56 %

Procedure:
2-Allyl-4-benzyloxyphenol (WO 9728137 A1 19970807, Adams, A. D. et al.) (5.00 g, 20.8 mmol) in ethyl acetate (40 mL) is treated with 5% Pd/C (0.25 g) and hydrogen (1 atm) at ambient temperature for 18 h. The mixture is filtered and concentrated. The crude product is purified on a Biotage medium pressure chromatography system using a 40 L normal phase cartridge and eluted with 10% ethyl acetate in hexanes to give a tan solid (2.8 g, 56%). Rf=0.33 (25% EtOAc/Hexanes); 1H NMR (400 MHz, CDCl3) δ 7.44-7.31 (m, 5H), 6.78 (s, 1H), 6.69 (d, J=1.5 Hz, 2H), 5.00 (s, 2H), 4.31 (s, 1H), 2.55 (t, J=7.6 Hz, 2H), 1.64 (q, J=7.5 Hz, 2H), 0.97 (t, J=7.3 Hz, 3H).