Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1[S:9]([NH:12][C:13]1[CH:14]=[CH:15][C:16]2[CH2:20][O:19][B:18]([OH:21])[C:17]=2[CH:22]=1)(=[O:11])=[O:10].[N:23]([CH2:26][CH3:27])=[C:24]=[O:25]>CN(C=O)C.C(OCC)(=O)C>[NH2:8][C:6]1[CH:5]=[CH:4][C:3]([S:9]([NH:12][C:13]2[CH:14]=[CH:15][C:16]3[CH2:20][O:19][B:18]([OH:21])[C:17]=3[CH:22]=2)(=[O:10])=[O:11])=[C:2]([NH:1][C:24]([NH:23][CH2:26][CH3:27])=[O:25])[CH:7]=1
Reactant: CCN=C=O
Reactant: Nc1ccc(S(=O)(=O)Nc2ccc3c(c2)B(O)OC3)c(N)c1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCNC(=O)Nc1cc(N)ccc1S(=O)(=O)Nc1ccc2c(c1)B(O)OC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 24.6 %

Procedure:
To a solution of 2,4-diamino-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)benzenesulfonamide (1.0 g, 3.13 mmol) in DMF (15 ml) was added isocyanatoethane (0.5 g, 7.0 mmol) dropwise at room temperature. The reaction mixture was stirred at room temperature overnight, diluted with ethyl acetate and washed with H2O, brine. The organic fraction was then dried (MgSO4) and concentrated in vacuo. The residue was purified by Prep-HPLC to give the title compound as a white powder (0.3 g). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.87 (s, 1H), 9.17 (s, 1H), 7.99 (s, 1H), 7.43 (d, J=1.6 Hz, 1H), 7.34 (d, J=2.0 Hz, 1H), 7.31 (d, J=8.4 Hz, 1H), 7.24 (d, J=8.0 Hz, 1H), 7.12 (dd, J=2.0, 8.4 Hz, 1H), 7.02 (t, J=5.2 Hz, 1H), 6.08 (dd, J=2.0, 8.4 Hz, 1H), 5.88 (s, 2H), 4.87 (s, 2H), 3.04˜3.11 (m, 2H), 1.07 (t, J=7.2 Hz, 3H); MS (ESI) m/z=389 (M−1, negative); HPLC purity: 93.6% (MaxPlot 200-400 nm), 90.3% (220 nm).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]=[O:11])=[CH:9][C:4]=2[CH2:3][CH2:2]1.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl.O>C1(C)C=CC=CC=1>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]=[O:11])=[CH:9][C:4]=2[CH:3]=[CH:2]1
Reactant: O=Cc1ccc2c(c1)CCO2
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: Cc1ccccc1
Solvent: O
Product: O=Cc1ccc2occc2c1
Temperature: 25 °C
Yield: 21 %

Procedure:
To a solution of 2,3-dihydro-benzofuran-5-carbaldehyde described in Preparation Example 174 (6.00 g, 40.5 mmol) in toluene (120 mL) was added 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (18.3 g, 81 mmol), and the solution was refluxed for 4 hours 30 minutes. The reaction solution was cooled to room temperature, water was added, the solution was extracted with ethyl acetate and tetrahydrofuran, and the organic layer was washed with brine. Anhydrous magnesium sulfate was added to the organic layer for drying, which was then filtered, the filtrate was concentrated in vacuo, the residue was purified by silica gel column chromatography (hexane/ethyl acetate=5/1), and the title compound (1.24 g, 21%) was obtained as a pale yellow oil.
Reaction SMILES: [N:1]1([C:7]2[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[F:15][C:16]1[C:24]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:23][CH:22]=[C:21]([F:29])[C:17]=1[C:18](O)=[O:19]>>[F:15][C:16]1[C:24]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:23][CH:22]=[C:21]([F:29])[C:17]=1[C:18]([N:4]1[CH2:5][CH2:6][N:1]([C:7]2[CH:8]=[CH:9][C:10]([C:11]#[N:12])=[CH:13][CH:14]=2)[CH2:2][CH2:3]1)=[O:19]
Reactant: N#Cc1ccc(N2CCNCC2)cc1
Reactant: CS(=O)(=O)c1ccc(F)c(C(=O)O)c1F
Product: CS(=O)(=O)c1ccc(F)c(C(=O)N2CCN(c3ccc(C#N)cc3)CC2)c1F

Procedure:
Prepared in analogy to example 5 from 4-piperazin-1-yl-benzonitrile and 2,6-difluoro-3-methanesulfonyl-benzoic acid. MS (m/e): 406.3 (MH+, 84%)
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[CH:10][N:11]([CH3:23])[C:12]=2[C:13]2[S:22][C:16]3[N:17]=[CH:18][N:19]=[C:20]([NH2:21])[C:15]=3[CH:14]=2)[CH:5]=[CH:6][CH:7]=1.[C:24](=[O:31])([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[NH2:25].CNCCNC.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.[Cu]I>[NH2:21][C:20]1[C:15]2[CH:14]=[C:13]([C:12]3[N:11]([CH3:23])[CH:10]=[N:9][C:8]=3[C:4]3[CH:3]=[C:2]([NH:25][C:24](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH:7]=[CH:6][CH:5]=3)[S:22][C:16]=2[N:17]=[CH:18][N:19]=1
Reactant: Cn1cnc(-c2cccc(I)c2)c1-c1cc2c(N)ncnc2s1
Reactant: CC(C)(C)OC(N)=O
Agent: [Cu]I
Agent: CNCCNC
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: Cn1cnc(-c2cccc(NC(=O)OC(C)(C)C)c2)c1-c1cc2c(N)ncnc2s1
Temperature: 100 °C
Yield: 9.5 %

Procedure:
6-[4-(3-Iodophenyl)-1-methyl-1H-imidazol-5-yl]thieno[2,3-d]pyrimidin-4-amine (Example 49) (43 mg) was stirred with tert-butyl carbamate (24 mg), N,N′-dimethylethylenediamine (9 mg), copper(I) iodide (10 mg), and potassium phosphate (42 mg) in 1,4-dioxane (2 mL), degassed, and heated under an inert atmosphere at 100° C. for 24 hours. The mixture was partitioned between EtOAc and dilute aqueous NH3. The organic phase was dried and evaporated. The residue was purified by flash chromatography on silica using a gradient of 0-100% EtOAc in DCM then 0-20% MeOH in DCM as eluent. Fractions were evaporated to give the title compound as a gum (4 mg, 9%);
Reaction SMILES: C([O:3][C:4](=[O:18])[CH:5]([CH3:17])[C:6]([NH:8][CH2:9][C:10]([F:16])([F:15])[C:11]([F:14])([F:13])[F:12])=[O:7])C.[OH-].[Li+]>O1CCCC1.O>[CH3:17][CH:5]([C:6]([NH:8][CH2:9][C:10]([F:15])([F:16])[C:11]([F:12])([F:14])[F:13])=[O:7])[C:4]([OH:18])=[O:3]
Reactant: CCOC(=O)C(C)C(=O)NCC(F)(F)C(F)(F)F
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C(=O)O)C(=O)NCC(F)(F)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1.8 g (6.5 mmol) 2-Methyl-N-(2,2,3,3,3-pentafluoro-propyl)-malonamic acid ethyl ester in 40 ml of tetrahydrofurane, 20 ml of water and 1.09 g (26 mmol) of lithium hydroxide were added and the mixture was stirred overnight at room temperature. After concentration in vacuo water (50 ml) was added and the mixture was extracted with dichloromethane (three times 30 ml). The aqueous phase was acidified with 8 N hydrochloric acid and extracted with dichloromethane (three times 30 ml).
Reaction SMILES: [CH2:1]([N:3]([CH:7]1[CH2:12][CH2:11][S:10](=[O:14])(=[O:13])[C:9]2[S:15][C:16]([S:18]([NH2:21])(=[O:20])=[O:19])=[CH:17][C:8]1=2)[C:4](=O)[CH3:5])[CH3:2].CSC.B>C1COCC1>[CH2:1]([N:3]([CH:7]1[CH2:12][CH2:11][S:10](=[O:13])(=[O:14])[C:9]2[S:15][C:16]([S:18]([NH2:21])(=[O:20])=[O:19])=[CH:17][C:8]1=2)[CH2:4][CH3:5])[CH3:2]
Reactant: CCN(C(C)=O)C1CCS(=O)(=O)c2sc(S(N)(=O)=O)cc21
Agent: B
Solvent: C1CCOC1
Solvent: CSC
Product: CCN(CC)C1CCS(=O)(=O)c2sc(S(N)(=O)=O)cc21
Reaction time: 1 h
Yield: 65 %

Procedure:
To a suspension of product from Step A (1.8 g, 0.005 mol) in THF (40 ml) heated at reflux under N2 was added dropwise borane dimethylsulfide (10M, 1.5 ml, 0.015 mol) with the continuous removal of dimethylsulfide by way of a short path distillation apparatus. After 1 hour, the mixture was concentrated to dryness and the residue treated carefully with 6N HCl (12 ml). After heating at reflux for 0.5 hour, the mixture was concentrated to dryness. The residue was treated with NaHCO3 and the suspension extracted with ethyl acetate (4x). The organic extracts were dried, filtered and concentrated to dryness. The residue was chromatographed on silica gel and the product eluted with 5% CH3OH--CHCl3 saturated with NH3 gas. The product was crystallized as the hydrochloride salt from ethanol to yield 1.1 g of product (56%), m.p. 236°-238° C.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH2:6]([O:8][C:9](=[O:20])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][CH2:18][OH:19])[CH:12]=1)[CH3:7].C(N(CC)CC)C>ClCCl>[CH2:6]([O:8][C:9](=[O:20])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][CH2:18][O:19][S:2]([CH3:1])(=[O:4])=[O:3])[CH:12]=1)[CH3:7]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)Cc1cccc(CCO)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)Cc1cccc(CCOS(C)(=O)=O)c1
Temperature: 25 °C
Yield: 98 %

Procedure:
Methane sulfonyl chloride (2.78 g, 24.3 mmol) was added dropwise to a solution of ethyl[3-(2-hydroxyethyl)phenyl]acetate (Preparation 55) (4.60 g, 22.1 mmol) and triethylamine (3.40 ml, 24.3 mmol) in dichloromethane (250 ml) at 0° C. under nitrogen. The reaction was allowed to warm to room temperature over 1 hour and washed with saturated aqueous sodium hydrogen carbonate (75 ml). The aqueous was washed with dichloromethane (2×100 ml) and the combined organics washed with water (25 ml), dried (sodium sulfate) and the solvent removed in vacuo to furnish the title compound as a colourless oil (6.2 g). 1H NMR (400 MHz, CDCl3): δ=7.29-7.25 (1H, t), 7.17-7.12 (3H, t), 4.41-4.38 (2H, t), 4.16-4.10 (2H, m), 3.58 (2H, s), 3.04-3.00 (2H, t), 2.81 (3H, s), 1.26-1.22 (3H, t) ppm. LRMS (electrospray): m/z [M+H]+ 578, [M−H]− 576.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([F:10])([F:9])[F:8])=[CH:5][C:4](OS(C2C=CC(C)=CC=2)(=O)=O)=[N:3]1.[C:22]1([C:28]#[CH:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CCCCCCC.C(Cl)Cl>[CH3:1][N:2]1[C:6]([C:7]([F:8])([F:9])[F:10])=[CH:5][C:4]([C:29]#[C:28][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[N:3]1
Reactant: Cc1ccc(S(=O)(=O)Oc2cc(C(F)(F)F)n(C)n2)cc1
Reactant: C#Cc1ccccc1
Solvent: ClCCl
Solvent: CCCCCCC
Product: Cn1nc(C#Cc2ccccc2)cc1C(F)(F)F

Procedure:
This product was prepared from toluene-4-sulfonic acid 1-methyl-5-trifluoromethyl-1H-pyrazol-3-yl ester and phenylacetylene following the general procedure for the Sonogashira cross-coupling reaction described above. Chromatography eluent: heptane/DCM 7:3; yield (19 mg, 15%); 1H NMR δ (CDCl3): 7.66-7.55 (m, 5H), 6.64 (s, 1H), 3.98 (s, 3H), LCMS m/z: 250.
Reaction SMILES: CC([N:5]([C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:18]=1[Br:19])=[CH:16][C:15]([O:20][CH3:21])=[CH:14][C:13]=2[F:22])C(=O)[O-])(C)C.FC(F)(F)C(O)=O>ClCCl>[Br:19][C:18]1[C:17]2[C:12](=[C:13]([F:22])[CH:14]=[C:15]([O:20][CH3:21])[CH:16]=2)[N:11]=[CH:10][C:9]=1[NH2:5]
Reactant: COc1cc(F)c2ncc(N(C(=O)[O-])C(C)(C)C)c(Br)c2c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc(F)c2ncc(N)c(Br)c2c1
Yield: 100.2 %

Procedure:
1,1-Dimethylethyl[4-bromo-8-fluoro-6-(methoxy)-3-quinolinyl]carbamate (6.4 g, 17.3 mmol)) was treated with trifluoroacetic acid (50 ml) in dichloromethane (50 ml) at room temperature for two hours then evaporated to dryness. The residue was basified with sodium bicarbonate. A precipitate was formed which was filtered and dried in vacuo to afford the product as a white solid (4.7 g, 100%). MS (+ve ion electrospray) m/z 272 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:13]([C:14]([OH:16])=O)=[C:12]([CH3:17])[O:11][N:10]=1.[Cl:18][C:19]1[C:25]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[CH:24][C:22]([NH2:23])=[C:21]([N+:32]([O-:34])=[O:33])[CH:20]=1.C(Cl)CCl.CN(C=O)C>CN(C)C1C=CN=CC=1.C(Cl)Cl>[NH2:23][C:22]1[C:21]([N+:32]([O-:34])=[O:33])=[CH:20][C:19]([Cl:18])=[C:25]([N:26]2[CH2:31][CH2:30][N:29]([C:14]([C:13]3[C:9]([C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=4[O:2][CH3:1])=[N:10][O:11][C:12]=3[CH3:17])=[O:16])[CH2:28][CH2:27]2)[CH:24]=1
Reactant: Nc1cc(N2CCNCC2)c(Cl)cc1[N+](=O)[O-]
Reactant: COc1ccccc1-c1noc(C)c1C(=O)O
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: ClCCl
Product: COc1ccccc1-c1noc(C)c1C(=O)N1CCN(c2cc(N)c([N+](=O)[O-])cc2Cl)CC1
Yield: 38.9 %

Procedure:
A mixture of 3-(2-methoxyphenyl)-5-methylisoxazole-4-carboxylic acid (363 mg, 1.558 mmol, Preparation A), 4-chloro-2-nitro-5-(piperazin-1-yl)aniline (400 mg, 1.558 mmol, prepared as described in [El-Abadelah, M. M.; Nazer, M. Z.; El-Abadla, N. S.; Awadallah, A. M. Asian Journal of Chemistry 1999, 11(4), 1463-1468.]), EDC (448 mg, 2.337 mmol), and N,N-dimethylpyridin-4-amine (571 mg, 4.67 mmol) in DCM (5 mL)/DMF (3 mL) was stirred overnight. The solution was diluted with DCM, then washed with water for three times. Purification via flash chromatography with 20% EtOAc in DCM provided the title compound (286 mg, 0.606 mmol, 38.9% yield). 1H-NMR (CDCl3, 400 MHz): δ8.11 (1H, s), 7.59 (1H, d, J=7.53 Hz), 7.47 (1H, t, J=8.53 Hz), 7.08 (1H, t, J=7.53 Hz), 6.99 (1H, d, J=7.28 Hz), 6.03 (1H, s), 3.80 (3H, s), 3.8 (2H, s) 3.22 (2H, s), 3.01 (2H, s), 2.57 (3H, s), 2.46 (2H, s).
Reaction SMILES: C(OC([N:8]1[CH2:15][CH2:14][C@:13]2([CH3:18])[C@H:16]([CH3:17])[C@H:9]1[CH2:10][C:11]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][C:12]=12)=O)(C)(C)C.Cl[C:27]1[CH:32]=[CH:31][N:30]=[C:29]([CH3:33])[N:28]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1>C(O)CCC.CC([O-])=O.CC([O-])=O.[Pd+2].C(OCC)(=O)C>[CH3:18][C@:13]12[C@H:16]([CH3:17])[C@H:9]([NH:8][CH2:15][CH2:14]1)[CH2:10][C:11]1[CH:22]=[CH:21][C:20]([C:27]3[CH:32]=[CH:31][N:30]=[C:29]([CH3:33])[N:28]=3)=[CH:19][C:12]2=1
Reactant: Cc1nccc(Cl)n1
Reactant: C[C@@H]1[C@H]2Cc3ccc(B(O)O)cc3[C@]1(C)CCN2C(=O)OC(C)(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: CCOC(C)=O
Solvent: CCCCO
Product: Cc1nccc(-c2ccc3c(c2)[C@]2(C)CCN[C@H](C3)[C@H]2C)n1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
Pd(OAc)2 (3.3 mg) is added to a mixture of (2R,6R,11S)-6,11-dimethyl-8-borono-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocine-3-carboxylic acid tert-butyl ester (0.30 g), 4-chloro-2-methyl-pyrimidine (93 mg), K3PO4 (0.31 g), and 2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl (11.5 mg) in n-butanol (2 mL) under argon atmosphere. The resulting mixture is heated to 100° C. and stirred at this temperature overnight. After cooling to room temperature, ethyl acetate is added, the resulting mixture is filtered, and the filtrate is concentrated under reduced pressure. The residue is taken up in CH2Cl2 (3 mL) and treated with F3CCO2H (0.5 mL) for 1 h. Then, the solution is concentrated and the residue is purified by HPLC on reversed phase (MeCN/H2O/NH3) to afford the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[S:16][C:15]([C:17]3[C:18]([CH2:26][CH3:27])=[C:19]([CH2:23][CH:24]=O)[CH:20]=[CH:21][CH:22]=3)=[N:14][N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].[NH:28]1[CH2:36][CH2:35][CH2:34][C@H:29]1[C:30]([O:32]C)=[O:31].CC(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[S:16][C:15]([C:17]3[C:18]([CH2:26][CH3:27])=[C:19]([CH2:23][CH2:24][N:28]4[CH2:36][CH2:35][CH2:34][C@H:29]4[C:30]([OH:32])=[O:31])[CH:20]=[CH:21][CH:22]=3)=[N:14][N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10]
Reactant: COC(=O)[C@@H]1CCCN1
Reactant: CCc1c(CC=O)cccc1-c1nnc(-c2ccc(OC(C)C)c(Cl)c2)s1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCc1c(CCN2CCC[C@H]2C(=O)O)cccc1-c1nnc(-c2ccc(OC(C)C)c(Cl)c2)s1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 21.4 %

Procedure:
To a solution of [3-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,3,4-thiadiazol-2-yl)-2-ethylphenyl]acetaldehyde (90 mg, 0.224 mmol) (D15) in Dichloromethane (DCM) (20 mL) stirred at room temperature was added methyl L-prolinate (149 mg, 0.898 mmol) and AcOH (0.15 mL, 2.62 mmol). The reaction mixture was stirred at room temperature for 10 min, and sodium triacetoxyborohydride (110 mg, 0.522 mmol) was added. The reaction mixture was continuously stirred overnight. The reaction was quenched with water, and EtOH was evaporated in vacuo. i-PrOH was added, followed by sodium hydroxide (8.98 mg, 0.224 mmol). The reaction mixture was stirred for another 2 hours. i-PrOH was evaporated in vacuo. The aqeuous layer was extracted by EA/THF for 3 times. The combined organic solution was washed by brine. The organic layers were concentrated, and purified by Mass Directed AutoPrep to afford 1-{2-[3-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,3,4-thiadiazol-2-yl)-2-ethylphenyl]ethyl}-L-proline (E52) (24 mg) as a off-white solid.
Reaction SMILES: [Br:1][C:2]1[C:11]([O:12][CH2:13][C:14]#[N:15])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([NH:16][C:17]([C:19]1[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[O:21][C:20]=1[CH2:28][CH2:29][CH2:30][CH3:31])=[O:18])=[CH:7]2.[N-:32]=[N+:33]=[N-:34].[Na+].[Cl-].[NH4+].[OH-].[Na+]>CN(C=O)C.O>[Br:1][C:2]1[C:11]([O:12][CH2:13][C:14]2[N:32]=[N:33][NH:34][N:15]=2)=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([NH:16][C:17]([C:19]1[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[O:21][C:20]=1[CH2:28][CH2:29][CH2:30][CH3:31])=[O:18])=[CH:7]2
Reactant: CCCCc1oc2ccccc2c1C(=O)Nc1ccc2c(Br)c(OCC#N)ccc2c1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCc1oc2ccccc2c1C(=O)Nc1ccc2c(Br)c(OCc3nn[nH]n3)ccc2c1
Temperature: 100 °C
Reaction time: 5 h
Yield: 72.5 %

Procedure:
A mixture of 2-butyl-benzofuran-3-carboxylic acid (5-bromo-6-cyanomethoxy-naphthalen-2-yl)-amide (266 mg, 0.557 mmol), prepared in the previous step, sodium azide (110 mg, 1.69 mmol) and ammonium chloride (90.2 mg, 1.69 mmol) in 15 ml of DMF was stirred under nitrogen at 100° C. for 5 h. The reaction was diluted with water, made basic with 1 N NaOH and extracted five times with ethyl acetate. The ethyl acetate extract was acidified with 1 N HCl, filtered and the solvent concentrated under reduced pressure and then diluted with water. The solid present was collected by filtration, rinsed with water and dried under reduced pressure to give the title compound (210 mg, 72%) as an off-white solid, mp 242-245° C.
Reaction SMILES: Cl.[NH2:2][OH:3].O=[C:5]([C:27]1[C:36]2[C:31](=[CH:32][CH:33]=[C:34]([O:37][CH3:38])[CH:35]=2)[N:30]=[CH:29][C:28]=1[F:39])[CH2:6][CH2:7][CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][S:16][C:17]2[S:18][CH:19]=[CH:20][CH:21]=2)[CH2:10][CH:9]1[CH2:22][C:23]([O:25][CH3:26])=[O:24]>N1C=CC=CC=1>[OH:3][N:2]=[C:5]([C:27]1[C:36]2[C:31](=[CH:32][CH:33]=[C:34]([O:37][CH3:38])[CH:35]=2)[N:30]=[CH:29][C:28]=1[F:39])[CH2:6][CH2:7][CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][S:16][C:17]2[S:18][CH:19]=[CH:20][CH:21]=2)[CH2:10][CH:9]1[CH2:22][C:23]([O:25][CH3:26])=[O:24]
Reactant: COC(=O)CC1CN(CCSc2cccs2)CCC1CCC(=O)c1c(F)cnc2ccc(OC)cc12
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Product: COC(=O)CC1CN(CCSc2cccs2)CCC1CCC(=NO)c1c(F)cnc2ccc(OC)cc12
Temperature: 60 °C

Procedure:
0.363 g of hydroxylamine hydrochloride was added in several portions to a mixture of 0.99 g of methyl (3RS,RS)-4-[3-oxo-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl)-1-[2-(2-thienylthio)ethyl]piperidine-3-acetate in 10-cm3 of pyridine, with stirring and under an inert atmosphere, and the resulting mixture was heated in the region of 60° C. for 16 hours. After cooling in the region of 20° C., the reaction mixture was concentrated to dryness under reduced pressure (8 kPa) at a temperature in the region of 55° C. The evaporation residue was taken up in 75-cm3 of ethyl acetate and 40-cm3 of distilled water. The organic phase was washed three times with 40-cm3 of distilled water and 40-cm3 of a saturated sodium chloride solution, dried over magnesium sulfate for 30 minutes, filtered and concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. 0.98 g of methyl (3RS,4RS)-4-[3-hydroxyimino-3-(fluoro-6-methoxyquinolin-4-yl)propyl)-1-[2-(2-thienylthio)ethyl]piperidine-3-acetate wereobtained in the form of a yellow gum.
Reaction SMILES: [O:1]1CCCC1.[CH2:6]1[O:16][C:9]2([CH2:15][CH2:14][CH2:13][CH2:12][CH:11]=[CH:10]2)[O:8][CH2:7]1.[BH4-].[Na+].[Cl-].[Na+]>O.[OH-].[Na+].C([O-])(=O)C.[Hg+2].C([O-])(=O)C>[CH2:7]1[O:8][C:9]2([CH2:15][CH2:14][CH2:13][CH2:12][CH:11]([OH:1])[CH2:10]2)[O:16][CH2:6]1
Reactant: C1=CC2(CCCC1)OCCO2
Reactant: C1CCOC1
Agent: CC(=O)[O-]
Agent: [BH4-]
Agent: [Cl-]
Solvent: O
Product: OC1CCCCC2(C1)OCCO2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Mercury (II) acetate (80.7 g, 0.25 mol) was dissolved in water (150 mL), then tetrahydrofuran (150 mL) was added to give a suspension. To this stirring suspension was added 2-cycloheptenone ethylene ketal (39 g, 0.25 mol). After stirring at ambient temperature for 3 hours, the mixture was cooled in an ice water bath. A 10% aqueous sodium hydroxide solution (150 mL) was added, followed by a solution of sodium borohydride (4.8 g, 0.13 mol) in 10% aqueous sodium hydroxide (150 mL). The mixture was allowed to reach ambient temperature and stirred overnight. The mixture was saturated with sodium chloride, stirred for 30 minutes, then allowed to settle; the solution was decanted into brine and extracted with ethyl acetate, dried over sodium sulfate, filtered, and concentrated in vacuo to give 3-Hydroxycycloheptanone ethylene ketal (36 g).
Reaction SMILES: [NH2:1]/[C:2](/[C@@H:25]1[CH2:30][CH2:29][CH2:28][CH2:27][N:26]1[C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])=[N:3]\[O:4][C:5](=O)[C@@H:6]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[NH:7][C:8](=[O:17])[O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>N1C=CC=CC=1>[CH2:10]([O:9][C:8]([NH:7][C@H:6]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:5]1[O:4][N:3]=[C:2]([C@@H:25]2[CH2:30][CH2:29][CH2:28][CH2:27][N:26]2[C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[N:1]=1)=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CC(C)(C)OC(=O)N1CCCC[C@H]1/C(N)=N/OC(=O)[C@H](NC(=O)OCc1ccccc1)c1ccccc1
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CCCC[C@H]1c1noc([C@H](NC(=O)OCc2ccccc2)c2ccccc2)n1

Procedure:
The title compound was prepared by a similar method to Preparation 6 from tert-butyl (2S)-2-[(Z,5R)-1-amino-4,7-dioxo-5,9-diphenyl-3,8-dioxa-2,6-diaza-1-nonen-1-yl]-1-piperidinecarboxylate [see Preparation 10 1] and pyridine to afford tert-butyl (2S)-2-{5-[(R)-{[(benzyloxy)carbonyl]amino}(phenyl)methyl]-1,2,4-oxadiazol-3-yl}-1-piperidinecarboxylate as an oil.
Reaction SMILES: [C:1]([C:4]1[CH:22]=[CH:21][CH:20]=[CH:19][C:5]=1[O:6][C:7]1[CH:16]=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:9][C:8]=1[O:17][CH3:18])(=[O:3])[CH3:2].[BH4-].[Na+]>CO>[OH:3][CH:1]([C:4]1[CH:22]=[CH:21][CH:20]=[CH:19][C:5]=1[O:6][C:7]1[CH:16]=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:9][C:8]=1[O:17][CH3:18])[CH3:2]
Reactant: COC(=O)c1ccc(Oc2ccccc2C(C)=O)c(OC)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1ccc(Oc2ccccc2C(C)O)c(OC)c1
Reaction time: 2 h
Yield: 66.8 %

Procedure:
Methyl 4-(2-acetylphenoxy)-3-methoxybenzoate (1.24 g) obtained in Step 1 was dissolved in methanol (20 ml), and after ice-cooling, sodium borohydride (312 mg) was added. The mixture was stirred for 2 hrs. The reaction mixture was concentrated under reduced pressure, and water was added. The mixture was extracted with ethyl acetate. The organic layer was washed successively with 5% aqueous citric acid solution and brine, and dried over sodium sulfate. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:1) to give the title compound (834 mg).
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]([CH3:13])[C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[H-].[Na+].C1(C)C=CC(S(O[CH2:26][CH2:27][O:28][C@@H:29]2[CH2:34][CH2:33][CH2:32][C@H:31]([O:35][CH2:36][C:37]3[N:38]=[C:39]([C:43]4[CH:44]=[C:45]([CH3:49])[CH:46]=[CH:47][CH:48]=4)[O:40][C:41]=3[CH3:42])[CH2:30]2)(=O)=O)=CC=1>CN(C=O)C.[Na+].[Cl-].C(OCC)(=O)C>[CH3:13][C:9]1[CH:10]=[CH:11][CH:12]=[C:2]([O:1][CH2:26][CH2:27][O:28][C@@H:29]2[CH2:34][CH2:33][CH2:32][C@H:31]([O:35][CH2:36][C:37]3[N:38]=[C:39]([C:43]4[CH:44]=[C:45]([CH3:49])[CH:46]=[CH:47][CH:48]=4)[O:40][C:41]=3[CH3:42])[CH2:30]2)[C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: Cc1ccc(S(=O)(=O)OCCO[C@@H]2CCC[C@H](OCc3nc(-c4cccc(C)c4)oc3C)C2)cc1
Reactant: CCOC(=O)c1c(C)cccc1O
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(C)cccc1OCCO[C@@H]1CCC[C@H](OCc2nc(-c3cccc(C)c3)oc2C)C1
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
90 mg of ethyl 2-hydroxy-6-methylbenzoate are dissolved in 2 ml of dry DMF, and 23 mg of a 60 percent strength sodium hydride suspension are added. After 30 min at room temperature, 100 mg of ((1R,3S)-[3-(5-methyl-2-m-tolyloxazol-4-ylmethoxy)cyclohexyloxy]ethyl toluene-4-sulfonate in 2 ml of DMF are added. The mixture is stirred at 40° C. until the reaction has gone to completion (monitored by LC-MS). After cooling, the mixture is diluted with sat. NaCl solution and ethyl acetate. The organic phase is dried over sodium sulfate and the solvent is removed under reduced pressure. This gives ethyl (1R,3S)-2-methyl-6-{2-[3-(5-methyl-2-m-tolyloxazol-4-ylmethoxy)cyclohexyloxy]ethoxy}benzoate as a yellowish oil. C30H37NO6 (507.63), MS (ESI): 508 (M+H+).