Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].[OH-].[CH2:8]([N+:15]([CH3:18])([CH3:17])[CH3:16])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>CC(C)=O.CO>[C:1]([O-:6])(=[O:5])[C:2]([O-:4])=[O:3].[CH2:8]([N+:15]([CH3:18])([CH3:17])[CH3:16])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[CH2:8]([N+:15]([CH3:18])([CH3:17])[CH3:16])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C(O)C(=O)O
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [OH-]
Solvent: CC(C)=O
Solvent: CO
Product: O=C([O-])C(=O)[O-]

Procedure:
Oxalic acid in an amount of 10.78 g (0.120 mol) was dissolved in acetone, making a total of 100 g. The resultant solution was mixed with 100 g of 40% by weight solution of benzyltrimethylammonium hydroxide (0.261 mol) in methanol (produced by Tokyo Kasei Kogyo Co., Ltd.), and then 1500 g of acetone was added to the resultant mixture to form white precipitate. Subsequently, the precipitate was collected by means of suction filtration method, dispersed in 500 g of acetone and filtered to collect cake. The resultant cake was subjected to drying treatment under vacuum at 80° C. for 24 hours to form 33.9 g (0.0941 mol) of bis(benzyltrimethylammonium) oxalate at a yield of 78.4% based on the fed oxalic acid. The resultant bis(benzyltrimethylammonium) oxalate, in which a melting point was not recognized, was thermally decomposed in a stream of nitrogen at about 240° C.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]([CH:16]2[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][CH2:24][C:25]([C:27]3[CH:32]=[CH:31][C:30](F)=[CH:29][CH:28]=3)=[O:26])[CH2:18][CH2:17]2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:5][CH:4]=1)[CH3:2]>N1CCCCC1>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]([CH:16]2[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][CH2:24][C:25]([C:27]3[CH:32]=[CH:31][C:30]([N:19]4[CH2:20][CH2:21][CH2:16][CH2:17][CH2:18]4)=[CH:29][CH:28]=3)=[O:26])[CH2:18][CH2:17]2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:5][CH:4]=1)[CH3:2]
Reactant: CCc1ccc(C(c2ccccc2)C2CCN(CCCC(=O)c3ccc(F)cc3)CC2)cc1
Solvent: C1CCNCC1
Product: CCc1ccc(C(c2ccccc2)C2CCN(CCCC(=O)c3ccc(N4CCCCC4)cc3)CC2)cc1

Procedure:
A solution of 14.5 g (0.035 mole) of 4-[4-[α-(p-ethylphenyl)benzyl]piperidino]-4'-fluorobutyrophenone in 100 ml of piperidine is refluxed for 22 hours. The unreacted piperidine is removed under vacuum, and the remaining residue is triturated with water. The water is decanted, the residue is dissolved in methanol and added to a large amount of water. The resulting precipitate is dissolved in ether, dried over magnesium sulfate, treated with charcoal and filtered. The filtrate is concentrated to a solid residue and is recrystallized from ethanol-water to give the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11](/[CH:14]=[CH:15]/[C:16]([N:18]2[CH2:23][CH2:22][CH2:21][C@@H:20]([C:24]([NH:26][C@H:27]([C:32]#[CH:33])[CH2:28][C:29]([OH:31])=[O:30])=[O:25])[CH2:19]2)=[O:17])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:34](O)[CH2:35][CH2:36][CH2:37][CH3:38].Cl.C(N=C=NCCCN(C)C)C>ClCCl>[CH2:34]([O:30][C:29](=[O:31])[CH2:28][C@@H:27]([C:32]#[CH:33])[NH:26][C:24]([C@@H:20]1[CH2:21][CH2:22][CH2:23][N:18]([C:16](=[O:17])/[CH:15]=[CH:14]/[CH:11]2[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])[CH2:13][CH2:12]2)[CH2:19]1)=[O:25])[CH2:35][CH2:36][CH2:37][CH3:38]
Reactant: CCCCCO
Reactant: C#C[C@H](CC(=O)O)NC(=O)[C@@H]1CCCN(C(=O)/C=C/C2CCN(C(=O)OC(C)(C)C)CC2)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: C#C[C@H](CC(=O)OCCCCC)NC(=O)[C@@H]1CCCN(C(=O)/C=C/C2CCN(C(=O)OC(C)(C)C)CC2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94 %

Procedure:
To a mixture of N-[(R)-1-[3-(1-tert-butoxycarbonyl-4-piperidyl)-(E)-acryloyl]-3-piperidylcarbonyl]-3(S)-ethynyl-β-alanine (0.6 g), n-pentylalcohol (0.16 ml) and N,N-dimethylaminopyridine (16 mg) in dichloromethane (6 ml) was added 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (0.27 g) at 0° C. After stirring at room temperature for overnight, the solution was evaporated in vacuo. The residue was poured into water and extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogencarbonate, water and brine, dried over MgSO4, and evaporated in vacuo, subsequently. The residue was purified by column chromatography on silica gel eluting with AcOEt:Hexane=(1:1) to give N-[(R)-1-[3-(1-tert-butoxycarbonyl-4-piperidyl)-(E)-acryloyl]-3-piperidylcarbonyl]-3(S)-ethynyl-β-alanine n-pentyl ester as a colorless oil (0.65 g, 94.0%).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1([C:14]#[N:15])[CH2:13][CH2:12][S:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC#N.[OH2:19]>CCOC(C)=O>[C:1]([O:5][C:6]([C:8]1([C:14]#[N:15])[CH2:13][CH2:12][S:11](=[O:19])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)C1(C#N)CCSCC1
Reactant: O
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC(C)(C)OC(=O)C1(C#N)CCS(=O)CC1
Reaction time: 8 h

Procedure:
A mixture of 4-cyano-tetrahydro-thiopyran-4-carboxylic acid tert-butyl ester (206 mg) and NaIO4 (217 mg) in MeCN/water (3 mL/3 mL) was stirred between 0° C. and rt overnight; then the reaction was diluted with EtOAc, washed with dil. Na2SO3 solution, water and dil. NaCl solution respectively; EtOAc phase was dried over anhydrous sodium sulphate, filtered, concentrated and column-purified to give the desired product (193 mg). 1H NMR in CDCl3, δ in ppm: 3.2-2.6 (m, 6H), 2.4-2.1 (m, 2H), and 1.52 (s, 9H).
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][N+:3]=1[O-].[CH2:10]([N:12](CC)CC)C.[Si](C#N)(C)(C)C>C(#N)C>[Br:1][C:2]1[N:3]=[C:4]([C:10]#[N:12])[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: CCN(CC)CC
Reactant: Cc1ccc[n+]([O-])c1Br
Agent: C[Si](C)(C)C#N
Solvent: CC#N
Product: Cc1ccc(C#N)nc1Br
Temperature: 25 °C
Yield: 33.7 %

Procedure:
To a solution of 2-bromo-3-methylpyridine 1-oxide (compound 350.1, 5.65 g, 30.1 mmol, 1.00 equiv) in acetonitrile (50 mL) were added triethylamine (6.10 g, 60.3 mmol, 2.00 equiv) and TMSCN (8.90 g, 3.00 equiv). The resulting solution was heated to reflux and stiffed overnight in an oil bath, then cooled to ambient temperature and concentrated under reduced pressure. The residue was purified using silica gel column chromatography with ethyl acetate/petroleum ether (1:5) as eluent to yield 2.00 g (34%) of the title compound as a yellow solid.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:19]=[CH:18][C:13]([CH2:14][CH:15]([CH3:17])[NH2:16])=[CH:12][CH:11]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[F:20][C:21]1[CH:26]=[CH:25][C:24]([CH:27]([C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=2)[CH2:28][CH2:29][CH2:30][Cl:31])=[CH:23][CH:22]=1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[ClH:31].[CH2:2]([O:9][C:10]1[CH:11]=[CH:12][C:13]([CH2:14][CH:15]([NH:16][CH2:30][CH2:29][CH2:28][CH:27]([C:24]2[CH:23]=[CH:22][C:21]([F:20])=[CH:26][CH:25]=2)[C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=2)[CH3:17])=[CH:18][CH:19]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CC(N)Cc1ccc(OCc2ccccc2)cc1
Reactant: Fc1ccc(C(CCCCl)c2ccc(F)cc2)cc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(Cc1ccc(OCc2ccccc2)cc1)NCCCC(c1ccc(F)cc1)c1ccc(F)cc1
Reaction time: 60 h

Procedure:
The mixture of 11.1 g of dl-p-benzyloxyamphetamine hydrochloride, 11.2 g of 4,4-di-(4-fluorophenyl)-butyl chloride, 10.34 g of diisopropyl-ethylamine and 50 ml of dimethylformamide is stirred at 100° for 60 hours. It is evaporated, the residue taken up in benzene and the solution washed three times with water. The organic layer is dried, evaporated, the residue taken up in diethyl ether and the solution acidified with hydrogen chloride in isopropanol to afford the dl-1-(p-benzyloxyphenyl)-2-[4,4-di-(4-fluorophenyl)-butylamino]-propane hydrochloride, melting at 130°-133°.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[C:4]([NH:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH:3]=1.[CH3:17][Si:18]([C:21]#[CH:22])([CH3:20])[CH3:19]>C(NC(C)C)(C)C.C(OCC)C.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.[Cu]I>[C:13]([O:12][C:10]([NH:9][C:4]1[CH:3]=[C:2]([C:22]#[C:21][Si:18]([CH3:20])([CH3:19])[CH3:17])[CH:7]=[CH:6][C:5]=1[F:8])=[O:11])([CH3:16])([CH3:15])[CH3:14]
Reactant: C#C[Si](C)(C)C
Reactant: CC(C)(C)OC(=O)Nc1cc(Br)ccc1F
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CC(C)NC(C)C
Solvent: CCOCC
Product: CC(C)(C)OC(=O)Nc1cc(C#C[Si](C)(C)C)ccc1F
Temperature: 80 °C
Reaction time: 8 h

Procedure:
A mixture of 4-bromo-2-(tert-butoxycarbonylamino)-1-fluorobenzene (0.57 g), trimethylsilylacetylene (0.55 mL), tetrakis(triphenylphosphine)palladium(0) (23 mg)and copper (I) iodide (7 mg) in N,N-diisopropylamine (5.7 mL) was stirred at 80° C. overnight. The reaction mixture was cooled to room temperature, and the mixture was diluted with diethyl ether. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=15/1) to give 1-(tert-butoxy -carbonylamino)-2-fluoro-5-trimethylsilylethynylbenzene (0.6 g). This material was dissolved in tetrahydrofuran (10 mL). To the solution was added tetra(n-butyl)ammonium fluoride (1 mol/L tetrahydrofuran solution, 2.4 mL), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=20/1 -10/1) to give the title compound (0.34 g).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH2:8][CH2:7]2)([O-:3])=[O:2].[H-].[Na+].Br[C:16]1[N:21]=[CH:20][CH:19]=[CH:18][N:17]=1>CN1CCCC1.C(OCC)C>[N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([C:16]1[N:21]=[CH:20][CH:19]=[CH:18][N:17]=1)[CH2:8][CH2:7]2)([O-:3])=[O:2]
Reactant: Brc1ncccn1
Reactant: O=[N+]([O-])c1ccc2c(c1)CCN2
Agent: CN1CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Product: O=[N+]([O-])c1ccc2c(c1)CCN2c1ncccn1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
300 mg 5-nitro-2,3-dihydro-1H-indole are dissolved in 4 ml N-methyl-pyrrolidine. 80 mg NaH (60% suspension in mineral oil) are added and the mixture is stirred for 15 minutes at ambient temperature. Then 380 mg of 2-bromopyrimidine are added and the mixture is then heated to 60° C. for 3 hours. It is then diluted with diethyl ether and washed with dilute citric acid solution and saturated sodium chloride solution. After drying with magnesium sulphate the solvents are eliminated in vacuo.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[N:9]=[C:8]([CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]([F:22])([F:21])[F:20])[CH:13]=3)[N:7]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][N:25]=3)[C:6]=2[C:5](=[O:31])[NH:4][C:3]1=[O:32].[OH:33][CH:34]([CH3:48])[CH2:35][CH2:36]OS(C1C=CC(C)=CC=1)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[OH:33][CH:34]([CH3:48])[CH2:35][CH2:36][N:4]1[C:5](=[O:31])[C:6]2[N:7]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][N:25]=3)[C:8]([CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]([F:22])([F:21])[F:20])[CH:13]=3)=[N:9][C:10]=2[N:2]([CH3:1])[C:3]1=[O:32]
Reactant: Cc1ccc(S(=O)(=O)OCCC(C)O)cc1
Reactant: Cc1ccc(Cn2c(Cc3cccc(OC(F)(F)F)c3)nc3c2c(=O)[nH]c(=O)n3C)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(Cn2c(Cc3cccc(OC(F)(F)F)c3)nc3c2c(=O)n(CCC(C)O)c(=O)n3C)nc1
Temperature: 70 °C
Reaction time: 4 h
Yield: 26 %

Procedure:
To a solution of 3-methyl-7-((5-methylpyridin-2-yl)methyl)-8-(3-(trifluoromethoxy)benzyl)-1H-purine-2,6(3H,7H)-dione (30 mg, 0.067 mmol, intermediate 51) in DMF (3 mL) was added 3-hydroxybutyl-4-methylbenzenesulfonate (24.68 mg, 0.10 mmol), followed by potassium carbonate (27.93 mg, 0.20 mmol). The reaction was stirred at 70° C. for 4 h. The mixture was partitioned between ethyl acetate and water. The organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated to give crude product, which was purified by preparative HPLC to give 1-(3-hydroxybutyl)-3-methyl-7-((5-methylpyridin-2-yl)methyl)-8-(3-(trifluoromethoxy)benzyl)-1H-purine-2,6(3H,7H)-dione (9 mg, 25.8%) as white solid. 1H-NMR (CD3OD) δ 8.216(s,1H), 7.491-7.467(d,1H), 7.312-7.272(m,1H), 7.154-6.995(m,4H), 5.688(s,2H), 4.305(s,2H), 4.143-4.011(m,2H), 3.772-3.440(m,1H), 3.585(s, 3H), 2.283(s,3H), 1.761-1.703(m,2H), 1.194-1.179(d,3H). LCMS retention time 2.569 min; LCMS MH+ 518.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@:13]([CH2:22][CH2:23][C:24]([NH2:26])=[O:25])([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[O:12][C:11]2=[O:27])[CH3:9])=[CH:4][CH:3]=1.[CH3:28][O:29][C:30]1[N:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1>>[CH3:28][O:29][C:30]1[N:35]=[CH:34][C:33]([C:2]2[CH:3]=[CH:4][C:5]([C@@H:8]([N:10]3[CH2:15][CH2:14][C@:13]([CH2:22][CH2:23][C:24]([NH2:26])=[O:25])([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[O:12][C:11]3=[O:27])[CH3:9])=[CH:6][CH:7]=2)=[CH:32][CH:31]=1
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CCC(N)=O)(c2ccccc2)OC1=O
Reactant: COc1ccc(B(O)O)cn1
Product: COc1ccc(-c2ccc([C@H](C)N3CC[C@](CCC(N)=O)(c4ccccc4)OC3=O)cc2)cn1

Procedure:
The title compound was prepared from 3-((R)-3-((S)-1-(4-bromophenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)propanamide and 6-methoxypyridine-3-boronic acid following a procedure analogous to that described in Example 14. LC-MS Method 3 tR=1.106 min, m/z=460.2; 1H NMR (CD3OD) 1.54 (m, 3H), 1.95 (m, 1H), 2.16-2.29 (m, 4H), 2.40 (m, 2H), 2.44 (m, 1H), 3.10 (m, 1H), 3.99 (s, 3H), 5.56 (m, 1H), 6.94 (m, 1H), 7.03 (m, 2H), 7.28-7.39 (m, 8H), 7.93 (m, 1H), 8.28 (m, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:11]2[O:12][C:13]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:14]=3[N:15]=2)[C:7](F)=[CH:8][CH:9]=1)([O-:3])=[O:2].[CH2:21]([NH2:24])[CH2:22][CH3:23]>>[N+:1]([C:4]1[CH:5]=[C:6]([C:11]2[O:12][C:13]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:14]=3[N:15]=2)[C:7]([NH:24][CH2:21][CH2:22][CH3:23])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CCCN
Reactant: Cc1ccc2oc(-c3cc([N+](=O)[O-])ccc3F)nc2c1
Product: CCCNc1ccc([N+](=O)[O-])cc1-c1nc2cc(C)ccc2o1

Procedure:
Prepared by the method of Example 54a), from 2-(3-nitro-6-fluorophenyl)-5-methylbenzoxazole (218 mg, 0.8 mmol) and propylamine (328 μL, 4.0 mmol) the subtitle compound was obtained. The product was used directly in the next step without purification.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]([C@H:8]1[NH:11][C:10](=[O:12])[C@@H:9]1[C@H:13]([O:15][C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17])[CH3:14])=[CH2:7])=[O:5])[CH3:2].[BH4-].[Na+]>C(O)(C)C.O.C(OCC)(=O)C.[Ni](Cl)Cl>[CH2:1]([O:3][C:4]([CH:6]([C@H:8]1[NH:11][C:10](=[O:12])[C@@H:9]1[C@H:13]([O:15][C:16]([O:18][CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)=[O:17])[CH3:14])[CH3:7])=[O:5])[CH3:2]
Reactant: C=C(C(=O)OCC)[C@H]1NC(=O)[C@@H]1[C@@H](C)OC(=O)OCc1ccccc1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C)[C@H]1NC(=O)[C@@H]1[C@@H](C)OC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of (3S,4S)-4-(1-ethoxycarbonylethenyl)-3-(1-(R)-benzyloxycarbonyloxyethyl)-2-azetidinone (1.04 g) in isopropanol (20 ml) and water (10 ml) was treated with sodium borohydride (230 mg) in the presence of nickel chloride (40 mg) at 0°-5° C. for 15 minutes. After stirring at room temperature for additional 1 hour, the reaction mixture was diluted with ethyl acetate (300 ml), washed with brine and dried over anhydrous sodium sulfate. Filtration and concentration of the filtrate in vacuo gave an oily residue, which was purified by silica gel chromatography to yield (3S,4S)-4-(1-ethoxycarbonylethyl)-3-(1-(R)-benzyloxycarbonyloxyethyl)-2-azetidinone.
Reaction SMILES: [CH:1]1([C:7]2[CH:8]=[C:9]([C:19]([OH:21])=O)[CH:10]=[N:11][C:12]=2[O:13][CH2:14][C:15]([F:18])([F:17])[F:16])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:22][O:23][CH2:24][C@@H:25]1[CH2:29][CH2:28][CH2:27][N:26]1[NH2:30]>>[CH:1]1([C:7]2[CH:8]=[C:9]([C:19]([NH:30][N:26]3[CH2:27][CH2:28][CH2:29][C@H:25]3[CH2:24][O:23][CH3:22])=[O:21])[CH:10]=[N:11][C:12]=2[O:13][CH2:14][C:15]([F:17])([F:16])[F:18])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC[C@@H]1CCCN1N
Reactant: O=C(O)c1cnc(OCC(F)(F)F)c(C2CCCCC2)c1
Product: COC[C@@H]1CCCN1NC(=O)c1cnc(OCC(F)(F)F)c(C2CCCCC2)c1

Procedure:
The title compound was synthesized in analogy to Example 1 using 5-cyclohexyl-6-(2,2,2-trifluoro-ethoxy)-3-pyridinecarboxylic acid (example 12c) and (2S)-2-(methoxymethyl)-1-pyrrolidinamine (CAN 59983-39-0) as starting materials; LC-MS (UV peak area/ESI) 98.8%, 416.2159 (M+H)+.
Reaction SMILES: [C:1]([O-:4])(=[O:3])[CH3:2].[Na+].CS(O[C@H:11]([CH3:27])[CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:16][CH:15]=1)(=O)=O>CN(C)C=O>[C:1]([O:4][C@@H:11]([CH3:27])[CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:16][CH:15]=1)(=[O:3])[CH3:2]
Reactant: C[C@H](COc1ccc(Oc2ccccc2)cc1)OS(C)(=O)=O
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)O[C@@H](C)COc1ccc(Oc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 5 h
Yield: 70.7 %

Procedure:
A mixture of anhydrous sodium acetate (82 mg, 1.0 mmol), (R)-1-methyl-2-(4-phenoxyphenoxy)ethyl methanesulfonate (250 mg, 0.78 mmol; ee.: 99.4%) and dimethylformamide (5 ml) was stirred at an inner temperature of 100° to 110° C. for 5 hours. After allowed to cool, ice-water was added thereto, and the reaction mixture was extracted with toluene three times. The toluene layer was dried over anhydrous magnesium sulfate. The solvent was removed, and the residue was purified by thin layer chromatography using silica gel to give (S)-(-)-1-methyl-2-(4-phenoxyphenoxy)ethyl acetate (158 mg). [α]D23 =-30.6° (CHCL3, c=1). ee.: 88.8%.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([O:9]CC)=[O:8])=[CH:5][N:4]=[N:3]1.[OH-].[Na+]>CO>[CH3:1][N:2]1[C:6]([C:7]([OH:9])=[O:8])=[CH:5][N:4]=[N:3]1
Reactant: CCOC(=O)c1cnnn1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cn1nncc1C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 15.7 %

Procedure:
To a solution of ethyl 1-methyl-1H-1,2,3-triazole-5-carboxylate (1.15 g, 7.41 mmol) in methanol (17 mL) was added 1N sodium hydroxide (11.5 mL), and the mixture was stirred at room temperature for 1 hr. Methanol was evaporated under reduced pressure, 1N hydrochloric acid (12 mL) was added to the mixture, the precipitated crystals were collected by filtration and washed with water. The crystals were vacuum dried at 90° C. to give the title compound (148 mg, 16%) as a white powder.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[S:7])=[CH:4][C:3]=1[C:11]#[C:12][C:13]1[CH:14]=[N:15][C:16]2[C:21]([CH:22]=1)=[CH:20][CH:19]=[CH:18][CH:17]=2.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[Cl:45][C:46]1[CH:55]=[CH:54][CH:53]=[C:52]([CH3:56])[C:47]=1[C:48]([NH:50][NH2:51])=[O:49]>CN(C)C=O>[Cl:45][C:46]1[CH:55]=[CH:54][CH:53]=[C:52]([CH3:56])[C:47]=1[C:48]([N:50]([C:6](=[S:7])[C:5]1[CH:9]=[CH:10][C:2]([CH3:1])=[C:3]([C:11]#[C:12][C:13]2[CH:14]=[N:15][C:16]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:4]=1)[NH2:51])=[O:49]
Reactant: Cc1ccc(C(O)=S)cc1C#Cc1cnc2ccccc2c1
Reactant: Cc1cccc(Cl)c1C(=O)NN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: Cc1ccc(C(=S)N(N)C(=O)c2c(C)cccc2Cl)cc1C#Cc1cnc2ccccc2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 4-methyl-3-[(quinolin-3-yl)ethynyl]thiobenzoic acid (0.15 g, 0.5 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.15 g, 0.7 mmol) and 1-hydroxybenzotriazole (0.1 g, 0.7 mmol) in N,N-dimethylformamide (15 ml) was stirred at ambient temperature for 1 hr. 2-Chloro-6-methylbenzohydrazide (0.125 g, 0.5 mmol) was added and the mixture stirred for 12 hrs at ambient temperature. Concentration and trituration of the residue with water produced a solid which was filtered, washed with water and finally purified by flash chromatography on silica gel (elution with 10% methanol in dichloromethane) to get 2-chloro-6-methyl-N-[4-methyl-3-[2-(3-quinolyl)ethynyl]thiobenzoyl]benzohydrazide as a white solid.
Reaction SMILES: [CH:1]1([O:5][C:6]2[C:26]([CH3:27])=[CH:25][CH:24]=[CH:23][C:7]=2[C:8]([NH:10][C:11]2([C:20](O)=[O:21])[CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12]2)=[O:9])[CH2:4][CH2:3][CH2:2]1.[CH3:28][S:29]([NH2:32])(=[O:31])=[O:30].Cl.CN(C)CCCN=C=NCC.CO>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH:1]1([O:5][C:6]2[C:26]([CH3:27])=[CH:25][CH:24]=[CH:23][C:7]=2[C:8]([NH:10][C:11]2([C:20]([NH:32][S:29]([CH3:28])(=[O:31])=[O:30])=[O:21])[CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12]2)=[O:9])[CH2:4][CH2:3][CH2:2]1
Reactant: Cc1cccc(C(=O)NC2(C(=O)O)Cc3ccccc3C2)c1OC1CCC1
Reactant: CS(N)(=O)=O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: Cc1cccc(C(=O)NC2(C(=O)NS(C)(=O)=O)Cc3ccccc3C2)c1OC1CCC1
Reaction time: 144 h
Yield: 87.7 %

Procedure:
A 30 mL vial is charged with 2-[(2-cyclobutoxy-3-methyl-benzoyl)-amino]-indan-2-carboxylic acid (245 mg, 0.67 mmol) and dry DCM (5.0 mL). A stirring bar is added and stirring is initiated. The methanesulfonamide (89 mg, 0.936 mmol) is added. To the resultant suspension, (N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (120 mg, 0.624 mmol) and 4-dimethylaminopyridine (76 mg, 0.62 mmol) are added. After 6 days, tlc analysis (silica, 10% MeOH in DCM) indicates that the starting acid is consumed. The reaction mixture is diluted with EtOAc (50 mL), transferred to a separatory funnel and washed with dilute aqueous HCl (3 N, 3×20 mL) and brine, dried over MgSO4, filtered and evaporated by pumping to constant weight gives 0.26 g of amorphous white foam. This material is dissolved in DCM (5 mL) and applied to a 12 g column (silica) on an ISCO Companion. The column is eluted with 1% iPrOH in DCM for 3 column volumes followed by a linear gradient to 30% iPrOH in DCM over 15 column volumes. 12 mL fractions of UV active eluent are collected. Fractions 4 through 9 are combined and evaporated to a constant weight to give 0.2 g of white solid.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[CH2:11]1[CH2:43][O:42][C:13]([CH2:34][O:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)([CH2:14][CH2:15][C@H:16]2[C@H:23]([O:24]C(=O)C3C=CC=CC=3)[CH2:22][C@H:21]3[C@@H:17]2[CH2:18][C:19](=[O:33])[O:20]3)[O:12]1>C1(C)C=CC=CC=1>[CH2:43]1[CH2:11][O:12][C:13]([CH2:34][O:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)([CH2:14][CH2:15][C@@H:16]2[C@@H:17]3[C@@H:21]([O:20][CH:19]([OH:33])[CH2:18]3)[CH2:22][C@H:23]2[OH:24])[O:42]1
Reactant: O=C1C[C@@H]2[C@@H](CCC3(COc4ccccc4)OCCO3)[C@H](OC(=O)c3ccccc3)C[C@@H]2O1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Product: OC1C[C@@H]2[C@@H](CCC3(COc4ccccc4)OCCO3)[C@H](O)C[C@@H]2O1
Reaction time: 0.5 h

Procedure:
At -60° under argon, 16 ml. of a 20% solution of diisobutylaluminum hydride in toluene was added dropwise to a solution of 1.65 g. of (1S,5R,6R,7R)-6-(3,3-ethylenedioxy-4-phenoxy-1-butyl)-7-benzoyloxy-2-oxabicyclo[3,3,0]octan-3-one (produced in accordance with Example 2[a]) in 100 ml. of absolute toluene; the mixture was stirred for 30 minutes. By the dropwise addition of 5 ml. of isopropanol, the reaction was terminated, and the mixture was stirred for 30 minutes at 0° while adding 100 ml. of brine. Then, the mixture was extracted with ethyl acetate, shaken with brine, dried with magnesium sulfate, and evaporated under vacuum. Filtration of the residue with ether over 35 g. of silica gel yielded 1.1 g. of the title compound as a colorless oil. IR: 3600,1500 cm-1.