Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[O:14][C:13]([C:15]2[CH:23]=[CH:22][C:18]([C:19]([OH:21])=[O:20])=[CH:17][CH:16]=2)=[N:12][N:11]=1)([O-:3])=[O:2].S(=O)(=O)(O)O.[CH2:29](O)[CH3:30]>>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[O:14][C:13]([C:15]2[CH:23]=[CH:22][C:18]([C:19]([O:21][CH2:29][CH3:30])=[O:20])=[CH:17][CH:16]=2)=[N:12][N:11]=1)([O-:3])=[O:2]
Reactant: O=C(O)c1ccc(-c2nnc(-c3ccccc3[N+](=O)[O-])o2)cc1
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1ccc(-c2nnc(-c3ccccc3[N+](=O)[O-])o2)cc1
Yield: 24 %

Procedure:
A mixture of 4-[5-(2-nitrophenyl)-1,3,4-oxadiazol-2-yl]benzoic acid (2.00 g), conc. sulfuric acid (0.5 ml) and ethanol (50 ml) was heated under reflux for 6 hrs. After cooling, the reaction mixture was concentrated, and the residue was diluted with ethyl acetate. This solution was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1-2:1, volume ratio) to give ethyl 4-[5-(2-nitrophenyl)-1,3,4-oxadiazol-2-yl]benzoate (0.51 g, yield 24%). Recrystallization from hexane-ethyl acetate gave pale-yellow prism crystals. melting point: 127–128° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][C:11]2[S:12][C:13]3[N:14]=[C:15]([NH2:26])[N:16]=[C:17]([N:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)[C:18]=3[N:19]=2)=[CH:4][CH:3]=1.[Cl:27][C:28]1[CH:38]=[CH:37][C:31]([O:32][CH2:33][C:34](O)=[O:35])=[CH:30][CH:29]=1>>[NH2:26][C:15]1[N:16]=[C:17]([N:20]2[CH2:21][CH2:22][N:23]([C:34](=[O:35])[CH2:33][O:32][C:31]3[CH:37]=[CH:38][C:28]([Cl:27])=[CH:29][CH:30]=3)[CH2:24][CH2:25]2)[C:18]2[N:19]=[C:11]([CH2:10][CH2:9][CH2:8][C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[S:12][C:13]=2[N:14]=1
Reactant: O=C(O)COc1ccc(Cl)cc1
Reactant: Nc1nc(N2CCNCC2)c2nc(CCCc3ccc(F)cc3)sc2n1
Product: Nc1nc(N2CCN(C(=O)COc3ccc(Cl)cc3)CC2)c2nc(CCCc3ccc(F)cc3)sc2n1
Yield: 33 %

Procedure:
This compound was prepared from 2-(3-(4-fluorophenyl)propyl)-7-(piperazin-1-yl)thiazolo[5,4-d]pyrimidin-5-amine using 4-chlorophenoxyacetic acid in a yield of 33%, according to the procedure for the synthesis of example 50.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][F:14])[C@@H:11]([C:15]2[CH:20]=[CH:19][C:18]([S:21][CH2:22][F:23])=[CH:17][CH:16]=2)[O:10][C:9]1([CH3:25])[CH3:24])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=C(Cl)C=C(C(OO)=[O:34])C=1>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][F:14])[C@@H:11]([C:15]2[CH:16]=[CH:17][C:18]([S:21]([CH2:22][F:23])=[O:34])=[CH:19][CH:20]=2)[O:10][C:9]1([CH3:25])[CH3:24])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1[C@@H](CF)[C@@H](c2ccc(SCF)cc2)OC1(C)C
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1[C@@H](CF)[C@@H](c2ccc(S(=O)CF)cc2)OC1(C)C
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 67.4 %

Procedure:
To a solution of (4R,5R)-4-Fluoromethyl-5-(4-fluoromethylsulfanyl-phenyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (2.67 g, 7.158 mmol) in DCM (250 mL) is cooled to −78° C. followed by addition of solution of m-CPBA (1.59 g, 7.158 mmol) in DCM (25 mL). Reaction mixture is allowed to stir −78° C. for 20 minutes. After completion of the reaction mixture is quenched with aqueous bicarbonate solution and extracted with DCM. Organic layer is dried over sodium sulphate, concentrated and purified by combi-flash chromatography (40 g column) using 78% ethyl acetate in hexane as an eluent to afford title compound (1.88 g) as colorless oil. 1H-NMR (400 MHz, DMSO): δ 1.42 (s, 9H), 1.50 (s, 3H), 1.62 (s, 3H), 383-.388 (m, 1H), 4.46-4.58 (m, 1.5H), 4.75-4.84 (m, 1.5H), 5.17 (d, J=7.2 Hz, 1H), 5.25-5.27 (dd, J=1.12 Hz, J=8.8 Hz, 0.5H), 5.37-5.39 (m, 0.5H), 5.51-5.54 (dd, J=2.44 Hz, J=8.84 Hz, 0.5H), 5.63-5.64 (m, 0.5H), 7.70-7.77 (m, 4H). LC-MS (m/z): M+H=390.4.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[F:20])[CH2:5][O:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=O.C(N(CC)C(C)C)(C)C.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F.Cl.Cl.[CH2:56]([O:63][C:64](=[O:72])[CH2:65][C@@H:66]([NH2:71])[CH2:67][N:68]([CH3:70])[CH3:69])[C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1>CN(C)C=O>[CH2:56]([O:63][C:64](=[O:72])[CH2:65][C@@H:66]([NH:71][C:14](=[O:16])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][O:6][CH2:5][C:4]1[CH:17]=[CH:18][C:19]([F:20])=[C:2]([F:1])[CH:3]=1)[CH2:67][N:68]([CH3:69])[CH3:70])[C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1
Reactant: CN(C)C[C@H](N)CC(=O)OCc1ccccc1
Reactant: O=C(O)CCCCCCCOCc1ccc(F)c(F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C[C@@H](CC(=O)OCc1ccccc1)NC(=O)CCCCCCCOCc1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 50.9 %

Procedure:
A solution of 8-(3,4-difluoro-benzyloxy)-octanoic acid (153 mg, 0.53 mmol), N,N-diisopropylethylamine (414 mg, 3.21 mmol), and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium-hexafluorophophate (244 mg, 0.64 mmol) in N,N-dimethylformamide was stirred for 1 h at room temperature, then a solution of (R)-3-amino-4-dimethylamino-butyric acid benzyl ester dihydrochloride (198 mg, 0.64 mmol) in N,N-dimethylformamide (1 mL) was added. The reaction mixture was stirred for 16 h at room temperature, then evaporated. Chromatography (SiO2, dichloromethane-[dichloromethane/methanol/25% aq. ammonia solution 110:10:1] gradient) produced (R)-3-[8-(3,4-difluoro-benzyloxy)-octanoylamino]-4-dimethylamino-butyric acid benzyl ester (136 mg, 50%). Light yellow oil, m/e=505.4 ([M+H]+).
Reaction SMILES: [CH3:1][O:2][CH2:3][C@H:4]([CH3:38])[O:5][C:6]1[CH:7]=[C:8]2[C:12](=[C:13]([N:15]([CH3:25])[S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)(=[O:18])=[O:17])[CH:14]=1)[NH:11][C:10]([C:26]1[S:27][CH:28]([CH2:31][N:32]3[CH2:37][CH2:36][S:35][CH2:34][CH2:33]3)[CH2:29][N:30]=1)=[CH:9]2.ClC1C=CC=C(C(OO)=[O:47])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl.C(OCC)(=O)C>[CH3:1][O:2][CH2:3][C@H:4]([CH3:38])[O:5][C:6]1[CH:7]=[C:8]2[C:12](=[C:13]([N:15]([CH3:25])[S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)(=[O:18])=[O:17])[CH:14]=1)[NH:11][C:10]([C:26]1[S:27][CH:28]([CH2:31][N:32]3[CH2:37][CH2:36][S:35](=[O:47])[CH2:34][CH2:33]3)[CH2:29][N:30]=1)=[CH:9]2
Reactant: COC[C@H](C)Oc1cc(N(C)S(=O)(=O)c2ccccn2)c2[nH]c(C3=NCC(CN4CCSCC4)S3)cc2c1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC[C@H](C)Oc1cc(N(C)S(=O)(=O)c2ccccn2)c2[nH]c(C3=NCC(CN4CCS(=O)CC4)S3)cc2c1
Reaction time: 0.5 h
Yield: 68.3 %

Procedure:
To a solution of N-{5-[(1S)-2-methoxy-1-methylethoxy]-2-[5-(thiomorpholinomethyl)-4,5-dihydro-1,3-thiazol-2-yl]-1H-indol-7-yl}-N-methylpyridine-2-sulfonamide (80 mg) in dichloromethane (2 mL) was added m-chloroperbenzoic acid (16 mg) under ice-cooling, and the mixture was stirred for 30 min. Aqueous sodium thiosulfate solution was added, and the mixture was diluted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was recrystallized (acetone-hexane-diisopropyl ether) to give the title compound (37.5 mg, yield 46%) as a colorless solid. melting point 175-176° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][CH:26]=1)[C:5]([NH:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][C:16]2[C:21]([Cl:22])=[CH:20][N:19]=[C:18](Cl)[N:17]=2)[CH:10]=1)=[O:6].Cl>COCCO.O1CCOCC1>[ClH:22].[Cl:22][C:21]1[CH:20]=[N:19][C:18]2[NH:1][C:2]3[CH:26]=[CH:25][CH:24]=[C:4]([CH:3]=3)[C:5](=[O:6])[NH:7][CH2:8][C:9]3[CH:10]=[C:11]([NH:15][C:16]=1[N:17]=2)[CH:12]=[CH:13][CH:14]=3
Reactant: Nc1cccc(C(=O)NCc2cccc(Nc3nc(Cl)ncc3Cl)c2)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: COCCO
Product: O=C1NCc2cccc(c2)Nc2nc(ncc2Cl)Nc2cccc1c2
Temperature: 150 °C
Yield: 62.5 %

Procedure:
To a solution of 3-amino-N-{3-[(2,5-dichloropyrimidin-4-yl)amino]benzyl}benzamide (80.0 mg, 0.206 mmol) in 2-methoxyethanol (1.1 mL) was added 4.0 M of hydrogen chloride in 1,4-dioxane (154 μL). The resulting mixture was heated at 150° C. in a microwave for 15 min. The cloudy mixture was filtered. The crude cake was recrystallized from MeOH to give the desired product as an off-white powder (25 mg, 34%). LCMS for C18H14ClN5O (M+H)+: m/z=352.0. 1H NMR (400 MHz, DMSO-d6): δ 10.06 (s, 1H), 9.50 (t, J=2.0 Hz, 1H), 9.05 (t, J=2.0 Hz, 1H), 8.24 (m, 1H), 7.86 (s, 1H), 7.75 (d, J=8.0 Hz, 1H), 7.50 (t, J=8.0 Hz, 1H), 7.42 (d, J=8.0 Hz, 1H), 7.28 (m, 2H), 7.10 (t, J=7.6 Hz, 1H), 6.96 (d, J=8.0 Hz, 1H), 4.42 (d, J=6.0 Hz, 2H).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][CH:12]=3)=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.S(O[CH:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1)(C1C=CC(C)=CC=1)(=O)=O>>[O:17]([C:14]1[CH:13]=[CH:12][C:11]([C:10]2[C:3]3[C:2]([NH2:1])=[N:7][CH:6]=[N:5][C:4]=3[N:8]([CH:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)[CH:9]=2)=[CH:16][CH:15]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Cc1ccc(S(=O)(=O)OC2CCOCC2)cc1
Reactant: Nc1ncnc2[nH]cc(-c3ccc(Oc4ccccc4)cc3)c12
Product: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)cn2C1CCOCC1

Procedure:
In a similar manner to Example 1, 4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidine was reacted with 4-tosyloxytetrahydropyran to give after flash column chromatography 5-(4-phenoxyphenyl)-7-(4-tetrahydropyranyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine, m.p. 193-193.5° C.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[CH2:5]Cl)[CH3:2].[CH2:10]([NH2:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[OH-].[Na+]>O>[CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[CH2:5][NH:17][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:2]
Reactant: NCc1ccccc1
Reactant: CCOC(CCl)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCOC(CNCc1ccccc1)OCC
Reaction time: 8 h

Procedure:
A stirred mixture of chloroacetaldehyde diethyl acetal (50 g, 0.328 mol), and benzylamine (150.0 g, 1.4 mol) was heated at 130° for 3 h. The mixture was then left at ambient temperature overnight. Next day, water (150 ml) was added, and the resulting solution was basified with sodium hydroxide solution (25 ml, 10 M). The mixture was then extracted with ether (2×100 ml), and the extracts were combined and dried over magnesium sulphate. Evaporation of the ether under reduced pressure afforded a brown oil which was distilled to afford N-benzylaminoacetaldehyde diethyl acetal, b.p. 148°-150°/20 mmHg.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([N+:12]([O-:14])=[O:13])=[CH:5][C:6](C)=[C:7]([CH:10]=1)C#N.C(Cl)Cl.[CH3:18][C:19]([OH:21])=[O:20]>O.S(=O)(=O)(O)O>[CH3:1][O:2][C:3]1[C:4]([N+:12]([O-:14])=[O:13])=[CH:5][C:6]([CH3:7])=[C:18]([CH:10]=1)[C:19]([OH:21])=[O:20]
Reactant: CC(=O)O
Reactant: COc1cc(C#N)c(C)cc1[N+](=O)[O-]
Agent: O=S(=O)(O)O
Solvent: O
Solvent: ClCCl
Product: COc1cc(C(=O)O)c(C)cc1[N+](=O)[O-]
Temperature: 120 °C
Yield: 58 %

Procedure:
A mixture of 5-methoxy-2-methyl-4-nitrobenzonitrile (2 g, 10.4 mmol) in AcOH (20 mL), water (20 mL) and conc. sulphuric acid (20 mL) was heated to 120° C. for 5 h. Water (100 mL) and DCM (100 mL) were added and the mixture was passed through a hydrophobic frit. The solvent was removed in vacuo to give 5-methoxy-2-methyl-4-nitrobenzoic acid (1.27 g, 58%) as an off-white solid. LCMS (10 cm_ESCI_Formic_MeCN): [M−H]−=210 at 3.37 min. 1H NMR (400 MHz, CDCl3): δ 7.75 (s, 1H), 7.70 (s, 1H), 3.99 (s, 3H), 2.62 (s, 3H).
Reaction SMILES: Cl[CH2:2][C:3]1[C:8]([CH3:9])=[CH:7][CH:6]=[CH:5][C:4]=1[Cl:10].[C-:11]#[N:12].[K+]>C(O)C.O>[Cl:10][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]([CH3:9])[C:3]=1[CH2:2][C:11]#[N:12]
Reactant: Cc1cccc(Cl)c1CCl
Reactant: [C-]#N
Agent: [K+]
Solvent: CCO
Solvent: O
Product: Cc1cccc(Cl)c1CC#N
Yield: 55.1 %

Procedure:
A solution of 9.4 g of alpha,2-dichloro-6-methyltoluene in 30 ml of 95% ethanol is treated with a solution of 3.8 g of potassium cyanide in 5 ml of water and heated at reflux for 6 hours. The crude product is isolated by pouring the cooled reaction mixture into water and filtering the precipitated solid. Recrystallization from aqueous ethanol gives 4.9 g of pure 2-chloro-6-methylphenylacetonitrile, mp 49°-51° C., in two crops.
Reaction SMILES: C[N:2]([CH2:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=O)[C:20]2[CH:25]=[CH:24][C:23]([O:26]C3CCCCO3)=[CH:22][CH:21]=2)=[CH:15][N:14]=1)[C:3](=O)OC(C)(C)C.[C:34]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)(=O)[CH2:35][CH3:36]>>[CH3:3][NH:2][CH2:10][CH2:11][CH2:12][C:13]1[N:14]=[CH:15][C:16]([C:19]([C:20]2[CH:21]=[CH:22][C:23]([OH:26])=[CH:24][CH:25]=2)=[C:34]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH2:35][CH3:36])=[CH:17][CH:18]=1
Reactant: CCC(=O)c1ccccc1
Reactant: CN(CCCc1ccc(C(=O)c2ccc(OC3CCCCO3)cc2)cn1)C(=O)OC(C)(C)C
Product: CCC(=C(c1ccc(O)cc1)c1ccc(CCCNC)nc1)c1ccccc1
Yield: 19.5 %

Procedure:
Following general procedure of McMurry reaction as described in example 1, step B, tert-butyl methyl(3-(5-(4-(tetrahydro-2H-pyran-2-yloxy)benzoyl)pyridin-2-yl)propyl)carbamate (100 mg, 0.22 mmol) was reacted with propiophenone (88 mg, 0.66 mmol) to give 16 mg desired product (20% yield, Z/E=1/1). m/z=373[M+1]+.
Reaction SMILES: [H-].[Na+].[C:3]([O:10][CH2:11][CH3:12])(=[O:9])[C:4]([O:6]CC)=O.[CH2:13]([O:20][C:21]1[CH:26]=[CH:25][C:24]([C:27](=[O:29])[CH3:28])=[CH:23][CH:22]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C1COCC1>[CH2:11]([O:10][C:3](=[O:9])[C:4](=[O:6])[CH2:28][C:27]([C:24]1[CH:25]=[CH:26][C:21]([O:20][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:22][CH:23]=1)=[O:29])[CH3:12]
Reactant: CCOC(=O)C(=O)OCC
Reactant: CC(=O)c1ccc(OCc2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(=O)CC(=O)c1ccc(OCc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 147 %

Procedure:
To a solution of 1-(4-hydroxy-phenyl)-ethanone (10 g, 0.0735 mole) in DMF (50 mL) was added K2CO3 (20.2 g, 0.147 mole) at ambient temperature. Benzyl bromide (13.83 g, 0.0808 mole) was then added and the resulting mixture was stirred at ambient temperature for 5 hours. The reaction mixture was then quenched with iced water. The resulting precipitate was isolated by filtration and dried to afford 16.2 g (98%) of 1-(4-benzyloxy-phenyl)-ethanone. LCMS: 227.1 (M+1)+, 98.38%. A mixture of THF (130 mL) and NaH (60% w/w dispersion in oil) (5.28 g, 0.132 mole) was cooled to 0° C. with stirring for 5 minutes. Diethyl oxalate (12.87 g, 0.0886 mole) was added and the mixture was heated to reflux for 15 minutes. after cooling to ambient temperature 1-(4-benzyloxy-phenyl)-ethanone (10 g, 0.0442 mole) in THF (50 mL) was added dropwise over a period of 45 minutes. The resulting mixture was heated to 70° C. for 1 hour. The reaction mixture was then quenched with cold aqueous NH4Cl solution. The resulting precipitate was isolated by filtration and dried to afford 21.2 g of 4-(4-benzyloxy-phenyl)-2,4-dioxo-butyric acid ethyl ester. LCMS: 327.12 (M+1)+, 36.5%. A solution of 4-(4-benzyloxy-phenyl)-2,4-dioxo-butyric acid ethyl ester (10 g, 0.03064 mole), acetic acid (20 mL) and hydrazine hydrate (1.685 g, 0.0337 mole) was heated to reflux for 8 hours. The reaction mixture was then poured into iced water and basified with saturated aqueous NaHCO3 solution. The product was extracted with ethyl acetate. The ethyl acetate layer was washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure to afford 6.3 g (64%) of 5-(4-benzyloxy-phenyl)-1H-pyrazole-3-carboxylic acid ethyl ester. LCMS: 323.13 (M+1)+, 95.10%.
Reaction SMILES: C([O:8][C:9]1[CH:21]=[CH:20][C:12]([O:13][C@@H:14]2[CH2:18][CH2:17][NH:16][C:15]2=[O:19])=[CH:11][CH:10]=1)C1C=CC=CC=1>[Pd].CO.C(Cl)Cl>[OH:8][C:9]1[CH:21]=[CH:20][C:12]([O:13][C@@H:14]2[CH2:18][CH2:17][NH:16][C:15]2=[O:19])=[CH:11][CH:10]=1
Reactant: O=C1NCC[C@H]1Oc1ccc(OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CO
Solvent: ClCCl
Product: O=C1NCC[C@H]1Oc1ccc(O)cc1
Reaction time: 20 h

Procedure:
A mixture of (R)-3-(4-benzyloxy-phenoxy)-pyrrolidin-2-one (61 g), MeOH/DCM (2:1, 2 L) and Pd (10% on carbon, 6 g) was shaken under an atmosphere of hydrogen for 20 hours. The catalyst was removed by filtration and the filtrate concentrated to provide the subtitle compound. MS ESI+: m/z=194 [M+H]+.
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=[O:9])(=[O:4])=[O:3].[CH2:14]([NH2:17])[CH:15]=[CH2:16].[OH-].[Na+]>C1COCC1.Cl>[CH2:14]([NH:17][S:2]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=[O:9])(=[O:4])=[O:3])[CH:15]=[CH2:16]
Reactant: C=CCN
Reactant: O=C(O)c1cccc(S(=O)(=O)Cl)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: C=CCNS(=O)(=O)c1cccc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 95.1 %

Procedure:
To a solution of 3-(chlorosulfonyl)benzoic acid (5 g, 22.66 mmol) in THF (50.4 mL) at 0° C. was added allylamine (2.038 mL, 27.2 mmol) followed by NaOH (1N aqueous) (49.9 mL, 49.9 mmol). The mixture was allowed to warm to RT over 1 hour and stirred an additional 16 hours. The mixture was diluted with 1N HCl (250 mL), and the aqeuous layer was extracted with EtOAc (300 mL). The organic layer was dried over sodium sulfate and concentrated to dryness to afford 3-(N-allylsulfamoyl)benzoic acid as white solid (5.2 g, 95% yield). MS m/z=242.0 [M+H]. Calc'd for C10H11NO4S: 241.0.
Reaction SMILES: [C:1]([CH2:4][N:5]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12][N:11]([CH2:17][C:18]([OH:20])=[O:19])[CH2:10][CH2:9][N:8]([CH2:21][C:22]([OH:24])=[O:23])[CH2:7][CH2:6]1)([OH:3])=[O:2].[OH-].[Na+].CC1(C)[O:32][CH:31]([CH:33]2[O:35][CH2:34]2)[CH2:30][O:29]1>O.O1CCOCC1>[OH:35][CH:33]([CH:31]([OH:32])[CH2:30][OH:29])[CH2:34][N:14]1[CH2:13][CH2:12][N:11]([CH2:17][C:18]([OH:20])=[O:19])[CH2:10][CH2:9][N:8]([CH2:21][C:22]([OH:24])=[O:23])[CH2:7][CH2:6][N:5]([CH2:4][C:1]([OH:3])=[O:2])[CH2:16][CH2:15]1
Reactant: O=C(O)CN1CCNCCN(CC(=O)O)CCN(CC(=O)O)CC1
Reactant: CC1(C)OCC(C2CO2)O1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)CN1CCN(CC(=O)O)CCN(CC(O)C(O)CO)CCN(CC(=O)O)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
10.0 g (28.87 mmol) of 1,4,7-triscarboxymethyl-1,4,7,10-tetraazacyclododecane (DO3A) is dissolved in 40 ml of water, and the pH is set at 13 with 5N sodium hydroxide solution. A solution of 6.24 g (43.30 mmol) of 2-(2,2-dimethyl-1,3-dioxolan-4-yl)ethylene oxide (DE 3,150,917) in 10 ml of dioxane is added thereto, and the mixture is stirred for 24 hours at room temperature. The mixture is diluted with 60 ml of water and extracted three times with 50 ml of ether. The aqueous phase is brought to pH 2 with 10% strength hydrochloric acid and evaporated. The residue is dissolved in a small amount of water and passed to a cation exchange column (IR 120). After flushing with water, the ligand is eluted with 0.5-normal aqueous ammonia solution. The fractions are evaporated, the ammonium salt is taken up in a small amount of water and passed over an anion exchange column (IRA 67). The mixture is first washed with water and then eluted with 0.5-normal aqueous formic acid. The product is evaporated under vacuum, the residue is dissolved in a small amount of hot methanol, and acetone is added, thus crystallizing the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]([CH2:23][CH3:24])=[C:11]([CH:13]3[C:19](=[O:20])[CH:18]4[CH2:21][CH:15]([CH2:16][CH2:17]4)[C:14]3=[O:22])[N:12]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:32](Cl)(=[O:37])[C:33]([CH3:36])([CH3:35])[CH3:34]>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]([CH2:23][CH3:24])=[C:11]([C:13]3[C:14](=[O:22])[CH:15]4[CH2:21][CH:18]([CH2:17][CH2:16]4)[C:19]=3[O:20][C:32](=[O:37])[C:33]([CH3:36])([CH3:35])[CH3:34])[N:12]=2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: CCc1sc(-c2ccc(Cl)cc2)nc1C1C(=O)C2CCC(C2)C1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCc1sc(-c2ccc(Cl)cc2)nc1C1=C(OC(=O)C(C)(C)C)C2CCC(C2)C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.2 %

Procedure:
To a solution of the 3-[2-(4-chlorophenyl)-5-ethylthiazol-4-yl]bicyclo[3.2.1]octane-2,4-dione (100 mg, 0.28 mmol) in dichloromethane (5 ml) and triethylamine (140 μl, 1 mmol) is added pivaloyl chloride (123 μl, 1 mmol) at room temperature. The reaction mixture is stirred overnight at room temperature. Silica gel is added to the crude reaction mixture, the solvent is evaporated under reduced pressure and the residue is purified by flash chromatography on silica gel to give 2,2-dimethylpropionic acid 3-[2-(4-chlorophenyl)-5-ethylthiazol-4-yl]-4-oxobicyclo[3.2.1]oct-2-en-2-yl ester (101 mg)
Reaction SMILES: [C:1]1([C:7]([C:9]2[NH:17][C:12]3=[CH:13][N:14]=[CH:15][CH:16]=[C:11]3[CH:10]=2)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:18][O:19][CH:20]1[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]1.Cl>CCO.C(OCC)C>[C:1]1([C:7](=[N:18][O:19][CH:20]2[CH2:21][CH2:22][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:24][CH2:25]2)[C:9]2[NH:17][C:12]3=[CH:13][N:14]=[CH:15][CH:16]=[C:11]3[CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)N1CCC(ON)CC1
Reactant: O=C(c1ccccc1)c1cc2ccncc2[nH]1
Agent: Cl
Solvent: CCOCC
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(ON=C(c2ccccc2)c2cc3ccncc3[nH]2)CC1
Reaction time: 3 h
Yield: 21.3 %

Procedure:
A mixture of phenyl(1H-pyrrolo[2,3-c]pyridin-2-yl)methanone (Example 35) (300 mg, 1.34 mmol) and tert-butyl 4-(aminooxy)piperidine-1-carboxylate (Reference Example 10) (289 mg, 1.34 mmol) in EtOH (30 mL) was adjusted to pH 4-5 with HCl (1.9 mL of a 1 N HCl solution in diethyl ether, 1.9 mmol). The reaction mixture was heated to reflux. After 3 h, the reaction mixture was concentrated under reduced pressure. The residue was partitioned between EtOAc and saturated NaHCO3. The aqueous layer was separated and extracted with EtOAc. The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure. Purification by column chromatography (silica gel, 98:2 CH2Cl2/MeOH to 95:5 CH2Cl2/MeOH) gave tert-butyl 4-[[[phenyl(1H-pyrrolo[2,3-c]pyridin-2-yl)methylene]amino]oxy]piperidine-1-carboxylate (120 mg, 23%) as a white amorphous solid (geometry of the oxime double bond undefined).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:12][C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2.C([O-])([O-])=O.[K+].[K+].[CH2:25]([NH:27][CH2:28][CH3:29])[CH3:26]>C(#N)C.O>[CH2:25]([N:27]([CH2:28][CH3:29])[CH2:2][CH2:3][CH2:4][N:5]1[C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:12][C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH3:26]
Reactant: ClCCCN1c2ccccc2Oc2ccccc21
Reactant: CCNCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CCN(CC)CCCN1c2ccccc2Oc2ccccc21

Procedure:
1 g (4.31 mmol) of the product of Example 1 was dissolved in 150 mL of anhydrous acetonitrile, and 1.5 g KI, 2.13 g K2CO3 and 1.6 mL (15.4 mmol) of N,N-diethylamine were added. The mixture was refluxed overnight until a substantial amount of product was formed (TLC, System B, Rf =0.40). The reaction mixture was diluted with water and extracted with ether three times. The ether layer was washed with water and dried over anhydrous Na2SO4 and evaporated. The crude oil was subjected to column chromatography for purification. Ethylacetate-petroleum ether (50 mL+50 mL) eluted the title compound as the free base as a colorless oil, which was dried and used for NMR studies. An ethereal solution of the free base was treated with an excess of tartaric acid to separate the hygroscopic tartrate salt (1.2 g). UV-λmax (MeOH) 215, 238 and 320 nm; IR (CHCl3) 3378, 2974, 2838, 1453, 1375, 1155, 973 and 722 cm-1 ; 1H-NMR (`δ`) 6.51-6.80 (m, 8H, ArH, H1 -H4 and H6 -H9), 1.16 (t, 6H, Hc and Hd), 1.70 (m, 2H, H1), 2.50 (q, 4H, Ha and Hb, J=7 Hz), 3.42-3.63 (m, 4H, Hk and Hm); 13C-NMR 111.54 (C1 and C9), 115.49 (C4 and C6), 121.21 (C3 and C7), 123.85 (C2 and C8), 132.72 (C1' and C9'), 144.95 (C4' and C6'), 8.21 (Cc and Cd), 19.90 (C1), 40.72 (Ca and Cb), 45.87 (Cm), and 48.50 (Ck); EIMS (m/z) 296 (M+).