Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N:8]([S:14]([C:17]1[CH:23]=[CH:22][C:20]([CH3:21])=[CH:19][CH:18]=1)(=[O:16])=[O:15])[C:7](B1OC(C)(C)C(C)(C)O1)=[CH:6]2.[Cl:33][C:34]1[CH:35]=[CH:36][C:37]2[N:38]([C:40](I)=[CH:41][N:42]=2)[N:39]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.[Pd]>[Cl:33][C:34]1[CH:35]=[CH:36][C:37]2[N:38]([C:40]([C:7]3[N:8]([S:14]([C:17]4[CH:23]=[CH:22][C:20]([CH3:21])=[CH:19][CH:18]=4)(=[O:16])=[O:15])[C:9]4[C:5]([CH:6]=3)=[CH:4][C:3]([O:2][CH3:1])=[C:11]([O:12][CH3:13])[CH:10]=4)=[CH:41][N:42]=2)[N:39]=1
Reactant: Clc1ccc2ncc(I)n2n1
Reactant: COc1cc2cc(B3OC(C)(C)C(C)(C)O3)n(S(=O)(=O)c3ccc(C)cc3)c2cc1OC
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: COc1cc2cc(-c3cnc4ccc(Cl)nn34)n(S(=O)(=O)c3ccc(C)cc3)c2cc1OC
Temperature: 150 °C
Reaction time: 0.17 h
Yield: 63.2 %

Procedure:
To a solution of 5,6-dimethoxy-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-indole (120 mg, 0.262 mmol, 1.0 equiv) in acetonitrile (3.41 mL) was added 6-chloro-3-iodoimidazo[1,2-b]pyridazine (95 mg, 0.341 mmol, 1.3 equiv), palladium catalyst (25 mg, 0.0341 mmol, 0.1 equiv) and sodium carbonate (3.41 mL, 1.0 M, 10.0 equiv). The solution was stirred at 150° C. in the microwave for 10 minutes. Purification using column chromatography gave 80 mg of the yellow solid, 63%.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:8]([CH2:9][CH2:10][C:11]([O:13]CC)=[O:12])=[CH:7][N:6]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)[N:5]=1)[CH3:2].Cl[CH2:25][C:26]1[N:27]=[C:28]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[S:29][CH:30]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:1]([O:3][C:4]1[C:8]([CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:7][N:6]([CH2:16][C:17]2[CH:18]=[CH:19][C:20]([O:23][CH2:25][C:26]3[N:27]=[C:28]([C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=4)[S:29][CH:30]=3)=[CH:21][CH:22]=2)[N:5]=1)[CH3:2]
Reactant: ClCc1csc(-c2ccccc2)n1
Reactant: CCOC(=O)CCc1cn(Cc2ccc(O)cc2)nc1OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1nn(Cc2ccc(OCc3csc(-c4ccccc4)n3)cc2)cc1CCC(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.3 %

Procedure:
A mixture of ethyl 3-[3-ethoxy-1-(4-hydroxybenzyl)-1H-pyrazol-4-yl]propionate (1.50 g), 4-chloromethyl-2-phenylthiazole (1.05 g), potassium carbonate (1.30 g), and N,N-dimethylformamide (20 ml) was stirred at room temperature overnight. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with water, then, with saturated aqueous sodium chloride solution, and dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and a colorless oily substance was obtained from the fraction eluted with ethyl acetate-hexane (1:2, volume ratio). A mixture of the obtained oily substance, 1 N aqueous sodium hydroxide solution (10 ml), tetrahydrofuran (10 ml), and ethanol (10 ml) was stirred at room temperature for two hours, diluted with 1 N hydrochloric acid (10 ml), and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The obtained colorless crystals were collected by filtration and 3-[3-ethoxy-1-[4-(2-phenyl-4-thiazolylmethoxy)benzyl]-1H-pyrazol-4-yl]propionic acid (1.60 g, yield: 73%) was obtained. This was recrystallized from acetone-hexane. Melting point: 114–115° C.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[C:11]([OH:16])[CH:12]=[CH:13][CH:14]=3)[CH:9]=[C:8]2[CH2:17][C:18]([CH3:24])([CH3:23])[C:19]([O:21]C)=[O:20])=[CH:4][CH:3]=1.[C:27]([O-])(=O)[CH2:28][CH3:29]>>[Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[C:11]([O:16][CH2:29][C:28]4[CH:27]=[CH:9][C:10]5[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=5)[N:7]=4)[CH:12]=[CH:13][CH:14]=3)[CH:9]=[C:8]2[CH2:17][C:18]([CH3:24])([CH3:23])[C:19]([OH:21])=[O:20])=[CH:4][CH:3]=1
Reactant: COC(=O)C(C)(C)Cc1cc2c(O)cccc2n1Cc1ccc(Cl)cc1
Reactant: CCC(=O)[O-]
Product: CC(C)(Cc1cc2c(OCc3ccc4ccccc4n3)cccc2n1Cc1ccc(Cl)cc1)C(=O)O

Procedure:
The title product was prepared according to conditions described in Steps D and E of Example 1 substituting methyl 3-[N-(p-chlorobenzyl)-4-hydroxy indol-2-yl]-2,2-dimethylpropanoate for the propanoate in Example 1 (Step D), m.p. 158°-160° C.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[N:33]1[C:37](=[O:38])[C:36]2=[CH:39][CH:40]=[CH:41][CH:42]=[C:35]2[C:34]1=[O:43].CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:11]=[CH:12][C:3]=1[CH2:2][O:1][N:33]1[C:34](=[O:43])[C:35]2=[CH:42][CH:41]=[CH:40][CH:39]=[C:36]2[C:37]1=[O:38]
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: OCc1ccc2ccccc2n1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1OCc1ccc2ccccc2n1
Reaction time: 8 h
Yield: 75.8 %

Procedure:
2-(hydroxymethyl)quinoline (1.20 g, 7.55 mmol), triphenyl phosphine (1.00 g, 6.29 mmol, 1.05 equiv) and N-hydroxyphthalimide (1.08 g, 6.63 mmol, 1.05 equiv) were dissolved in 25 mL of dry THF. Diethylazodicarboxylate (1.09 mL, 6.93 mmol, 1.10 equiv) was then added dropwise and the reaction was stirred overnight. The reaction mixture filtered to give a white solid. The filtrate was concentrated and a second crop of material was obtained by triturating with Et2O. This was combined with the original solid and recrystallization from EtOH gave the desired product (1.53 g) as a fluffy white solid. MS(CI) m/e 305 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([S:11]([N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1)(=[O:13])=[O:12])=[CH:5]2.[C:20]([C:23]1[CH:28]=[CH:27][C:26]([B:29]([OH:31])[OH:30])=[CH:25][CH:24]=1)(O)=[O:21].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([S:11]([N:14]1[CH2:19][CH2:18][N:17]([C:20]([C:23]3[CH:24]=[CH:25][C:26]([B:29]([OH:31])[OH:30])=[CH:27][CH:28]=3)=[O:21])[CH2:16][CH2:15]1)(=[O:13])=[O:12])=[CH:5]2
Reactant: O=S(=O)(c1cc2cc(Cl)ccc2[nH]1)N1CCNCC1
Reactant: O=C(O)c1ccc(B(O)O)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: O=C(c1ccc(B(O)O)cc1)N1CCN(S(=O)(=O)c2cc3cc(Cl)ccc3[nH]2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 56 %

Procedure:
5-Chloro-2-(piperazin-1-ylsulphonyl)-1H-indole (5.42 g, 18.1 mmol) was added to a solution of 4-carboxyphenyl boronic acid (3.00 g, 18.1 mmol) N,N-diisopropylethylamine (2.34 g, 18.1 mmol) and O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (5.81 g, 18.1 mmol) in 80 mL N,N-dimethylformamide, the mixture was stirred for 2 hours at room temperature. N,N-Dimethylformamide was removed in vacuo and the crude was purified by flash chromatography three times (dichloromethane/methanol, 100-98/2) to give 4-({4-[(5-chloro-1H-indol-2-yl)sulphonyl]piperazin-1-yl}carbonyl)phenyl boronic acid as a colourless solid (56% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:20](O)=[O:21])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:4][CH:3]=1.[NH2:23][N:24]1[CH2:28][CH:27]([CH2:29][N:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)[O:26][C:25]1=[O:36]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([C:20]([NH:23][N:24]3[CH2:28][CH:27]([CH2:29][N:30]4[CH2:31][CH2:32][O:33][CH2:34][CH2:35]4)[O:26][C:25]3=[O:36])=[O:21])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:17])([F:18])[F:19])=[CH:6][CH:7]=1
Reactant: NN1CC(CN2CCOCC2)OC1=O
Reactant: O=C(O)c1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1
Product: O=C(NN1CC(CN2CCOCC2)OC1=O)c1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1

Procedure:
The title compound was synthesized in analogy to Example 1 using 5-(4-chlorophenyl)-6-(2,2,2-trifluoroethoxy)-3-pyridinecarboxylic acid (CAN 1018782-82-5) and 3-amino-5-(4-morpholinylmethyl)-2-oxazolidinone (CAN 43056-63-9) as starting materials; LC-MS (UV peak area/ESI) 97.7%, 515.1292 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[N:11]=[N:12][C:13]([CH:16]([NH:18][C:19]([C:21]3O[CH:23]=[CH:24][CH:25]=3)=[O:20])[CH3:17])=[CH:14][N:15]=2)=[CH:5][CH:4]=1.NC(C1N=NC(NC2C=CC(OC)=CC=2)=NC=1)C.[S:44]1C=CC=C1C(Cl)=O>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[N:11]=[N:12][C:13]([CH:16]([NH:18][C:19]([C:21]3[S:44][CH:23]=[CH:24][CH:25]=3)=[O:20])[CH3:17])=[CH:14][N:15]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(Nc2ncc(C(C)NC(=O)c3ccco3)nn2)cc1
Reactant: O=C(Cl)c1cccs1
Agent: COc1ccc(Nc2ncc(C(C)N)nn2)cc1
Product: COc1ccc(Nc2ncc(C(C)NC(=O)c3cccs3)nn2)cc1

Procedure:
In a similar manner as described for Intermediate 59, using 6-(1-aminoethyl)-N-[4-(methyloxy)phenyl]-1,2,4-triazin-3-amine (Intermediate 47) (100 mg, 0.41 mmol), and thiophene-2-carbonyl chloride (0.048 mL, 0.45 mmol) to afford N-[1-(3-{[4-(methyloxy)phenyl]amino}-1,2,4-triazin-6-yl)ethyl]-2-thiophenecarboxamide (115 mg) as a yellow solid. MS m/z 356 (M+1).
Reaction SMILES: CC(C)([O-])C.[K+].C1(C)C=CC(S([CH2:16][N+:17]#[C-])(=O)=O)=CC=1.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH:40]=[CH:41][C:42]=1[O:43][CH2:44][C:45]1[N:46]=[C:47]([C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[O:48][C:49]=1[CH3:50])[CH2:25][O:26][C:27]1[C:31]([CH:32]=O)=[CH:30][N:29]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[N:28]=1.[Cl-].[NH4+]>C(COC)OC.CO>[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH:40]=[CH:41][C:42]=1[O:43][CH2:44][C:45]1[N:46]=[C:47]([C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[O:48][C:49]=1[CH3:50])[CH2:25][O:26][C:27]1[C:31]([CH2:32][C:16]#[N:17])=[CH:30][N:29]([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[N:28]=1
Reactant: COc1cc(COc2nn(-c3ccccc3)cc2C=O)ccc1OCc1nc(-c2ccccc2)oc1C
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: COCCOC
Solvent: CO
Product: COc1cc(COc2nn(-c3ccccc3)cc2CC#N)ccc1OCc1nc(-c2ccccc2)oc1C
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 46.9 %

Procedure:
To a mixture of potassium tert-butoxide (700 mg) and dimethoxyethane (10 mL) was added a solution of p-toluenesulfonylmethylisocyanide (650 mg) in dimethoxyethane (10 mL) at −78° C., and the mixture was stirred for 5 min. To the reaction mixture was added a solution of 3-{[3-methoxy-4-(5-methyl-2-phenyl-1,3-oxazol-4-ylmethoxy)benzyl]oxy}-1-phenyl-1H-pyrazole-4-carbaldehyde (1.46 g) in dimethoxyethane (10 mL). After stirring at the same temperature for 1 hr, the mixture was stirred for 1 hr while warming to room temperature. To the reaction mixture was added methanol (20 mL), and the mixture was refluxed for 1 hr. After cooling, the reaction mixture was poured into saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give (3-{[3-methoxy-4-(5-methyl-2-phenyl-1,3-oxazol-4-ylmethoxy)benzyl]oxy}-1-phenyl-1H-pyrazol-4-yl)acetonitrile (700 mg, yield 47%) as colorless crystals from a fraction eluted with ethyl acetate-hexane (1:2, v/v). The crystals were recrystallized from ethyl acetate-hexane. melting point: 137-138° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:30])[CH2:5][N:6]1[C:14]2[CH2:13][CH2:12][CH2:11][CH:10]([NH:15][S:16]([C:19]3[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[C:21](F)[CH:20]=3)(=[O:18])=[O:17])[C:9]=2[CH:8]=[N:7]1)[CH3:2].[H-].[Na+].[CH2:33]([OH:35])[CH3:34].Cl>CN(C)C=O>[CH2:1]([O:3][C:4](=[O:30])[CH2:5][N:6]1[C:14]2[CH2:13][CH2:12][CH2:11][CH:10]([NH:15][S:16]([C:19]3[CH:24]=[C:23]([C:25]([F:28])([F:26])[F:27])[CH:22]=[C:21]([O:35][CH2:33][CH3:34])[CH:20]=3)(=[O:18])=[O:17])[C:9]=2[CH:8]=[N:7]1)[CH3:2]
Reactant: CCOC(=O)Cn1ncc2c1CCCC2NS(=O)(=O)c1cc(F)cc(C(F)(F)F)c1
Reactant: CCO
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1ncc2c1CCCC2NS(=O)(=O)c1cc(OCC)cc(C(F)(F)F)c1
Temperature: 150 °C
Yield: 78 %

Procedure:
[4-(3-Fluoro-5-trifluoromethyl-benzenesulfonylamino)-4,5,6,7-tetrahydro-indazol-1-yl]-acetic acid ethyl ester (prepared by the method analogous to example 1-1, 200 mg, 0.44 mmol), sodium hydride (60% dispersed in mineral oil, 89 mg, 2.22 mmol) and ethanol (202 mg, 4.4 mmol) were dissolved in N,N-dimethylformamide (2 mL). The mixture was heated in a microwave oven at 150° C. for 40 minutes. The resulting mixture was acidified with 0.1N hydrochloric acid to pH 5 and extracted with ethyl acetate. The organic layers were washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash column (gradient elution, 0-5% methanol in dichloromethane) to afford [4-(3-ethoxy-5-trifluoromethyl-benzenesulfonylamino)-4,5,6,7-tetrahydro-indazol-1-yl]-acetic acid ethyl ester (180 mg, 78%). MS cald. for C20H24F3N3O5S 475, obsd. (ESI+) [(M+H)+] 476.
Reaction SMILES: [CH:1]1([OH:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:7][S:8](Cl)(=[O:10])=[O:9].C(N(CC)CC)C>C(Cl)Cl>[CH:1]1([O:6][S:8]([CH3:7])(=[O:10])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OC1CCCC1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OC1CCCC1
Reaction time: 1.5 h

Procedure:
To a stirred solution of cyclopentanol (Aldrich, 2.58 g, 30 mmol) in methylene chloride (150 mL) at 0° C., Methane sulfonyl chloride (2.55 mL, 33 mmol) and triethyl amine (5.23 mL, 37.5 mmol) were added slowly and the mixture was stirred for 1.5 hrs. The reaction was quenched with water and the mixture was washed with 0.5 N HCl and brine solution. The organic layer was dried with sodium sulfate. Removal of solvent gave a colorless oil. 5.1 g.
Reaction SMILES: [C:1]1([C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:8]/[CH:9]=[C:10](\[CH3:14])/[C:11]([OH:13])=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+:21]([C:24]1[CH:29]=[CH:28][C:27](O)=[CH:26][CH:25]=1)([O-:23])=[O:22].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[N+:21]([C:24]1[CH:29]=[CH:28][C:27]([O:12][C:11](=[O:13])/[C:10](/[CH3:14])=[CH:9]/[CH:8]=[C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:26][CH:25]=1)([O-:23])=[O:22]
Reactant: C/C(=C\C=C(c1ccccc1)c1ccccc1)C(=O)O
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: C/C(=C\C=C(c1ccccc1)c1ccccc1)C(=O)Oc1ccc([N+](=O)[O-])cc1
Reaction time: 0.5 h
Yield: 89 %

Procedure:
A solution of (E)-5,5-diphenyl-2-methyl-2,4-pentadienoic acid (1.85 g) and 4-nitrophenol (1.12 g) in dichloromethane (25 mL), stirred at 0°-5° C. in an ice-water bath, was treated with 1,3-dicyclohexylcarbodiimide (1.44 g). The mixture was stirred at 0°-5° C. for 30 minutes, then at room temperature for 1 hour. After the precipitated dicyclohexylurea was filtered off, the concentrated filtrate was passed through a short column of silica gel (~25 g) made up in dichloromethane-hexane (3:2). The appropriate fractions were combined and evaporated to give 2.4 g of (E)-5,5-diphenyl-2-methyl-2,4-pentadienoic acid 4-nitrophenyl ester. Crystallization of the material from 2-propanol furnished 1.64 g of (E)-5,5-diphenyl-2-methyl-2,4-pentadienoic acid 4-nitrophenyl ester mp 139°-141° C. Anal. Calculated for C24H19NO4 : C, 74.79; H, 4.97; N, 3.63 Found: C, 74.83; H, 5.05 ; N, 3.68.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)=[C:6]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[CH:5]=[CH:4][N:3]=1.O.[NH2:22][NH2:23]>N1C=CC=CC=1>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:22][NH2:23])[C:7]=2[C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)=[CH:15][CH:16]=1
Reactant: NN
Reactant: Clc1ccc(-c2ccnc(Cl)c2-c2ccncc2)cc1
Solvent: c1ccncc1
Solvent: O
Product: NNc1nccc(-c2ccc(Cl)cc2)c1-c1ccncc1
Temperature: 25 °C
Yield: 78.4 %

Procedure:
To a stirring solution of 2-chloro-4-(4-chlorophenyl)-3,4′-bipyridine (1.3 g, 4.3 mmol) in pyridine (5 mL) at room temperature under argon was added hydrazine monohydrate (2.5 mL, 51.5 mmol). The reaction mixture was stirred at reflux under argon for 15 h. After cooling the reaction mixture to room temperature, most of the solvent was removed under reduced pressure. Water (25 mL) was added to the residue while stirring and a precipitate formed. The precipitate was collected by filtration and washed with water (15 mL×2). After drying under reduced pressure at elevated temperature, 1.0 g of the title compound was obtained as a yellow solid. HPLC/MS: retention time=1.68 min, [M+H]+=297.
Reaction SMILES: [OH:1][N:2]=[C:3]([C:26]1[CH:31]=[CH:30][N:29]=[C:28]([CH3:32])[CH:27]=1)[CH2:4][CH:5]([C:13]1[CH:18]=[CH:17][C:16]([C:19]#[C:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24])=[CH:15][CH:14]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH3:12]>CO.[Pd]>[OH:1][N:2]=[C:3]([C:26]1[CH:31]=[CH:30][N:29]=[C:28]([CH3:32])[CH:27]=1)[CH2:4][CH:5]([C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24])=[CH:15][CH:14]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH3:12]
Reactant: Cc1cc(C(CC(c2ccc(C#CCCC(=O)O)cc2)c2ccccc2C)=NO)ccn1
Agent: [Pd]
Solvent: CO
Product: Cc1cc(C(CC(c2ccc(CCCCC(=O)O)cc2)c2ccccc2C)=NO)ccn1

Procedure:
5-{4-[3-[Hydroxyimino]-3-(2-methyl-pyridin-4-yl)-1-o-tolyl-propyl]-phenyl}-pent-4-ynoic acid as a mixture of E and Z isomers (4.2:1) (example 84; 50 mg) in methanol (2 mL) was hydrogenated in the presence of Pd (5% on carbon, 6 mg) at room temperature for 5 hours. The solution was filtered over decalite, the filter residue was washed with methanol, and the solution was evaporated. The crude product was purified by flash chromatography on silica gel (gradient CH2Cl2 to CH2Cl2/MeOH 1:1) to yield 5-{4-[3-[hydroxyimino]-3-(2-methyl-pyridin-4-yl)-1-o-tolyl-propyl]-phenyl}-pentanoic acid as a mixture of E and Z isomers (4.4:1) as a colorless oil, MS (ESI+): m/z=431.4 ([M+H]+).
Reaction SMILES: [ClH:1].[Cl:2][CH2:3][CH:4]1[CH2:15][N:14]2[C:6]([C:7]3[NH:8][C:9]([CH:20]4[CH2:24][CH2:23][CH2:22][CH2:21]4)=[N:10][C:11]=3[N:12]([CH2:17][CH2:18][CH3:19])[C:13]2=[O:16])=[N:5]1.[NH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(=O)([O-])O.[Na+]>O>[ClH:2].[ClH:1].[CH:20]1([C:9]2[NH:8][C:7]3[C:6]4=[N:5][CH:4]([CH2:3][NH:25][C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=5)[CH2:15][N:14]4[C:13](=[O:16])[N:12]([CH2:17][CH2:18][CH3:19])[C:11]=3[N:10]=2)[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: CCCN1C(=O)N2CC(CCl)N=C2c2[nH]c(C3CCCC3)nc21
Reactant: Nc1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CCCN1C(=O)N2CC(CNc3ccccc3)N=C2c2[nH]c(C3CCCC3)nc21
Temperature: 70 °C
Yield: 16.1 %

Procedure:
To Compound 26 (12 mg, 0.04 mmol) obtained in Example 26 were added water (3 mL), aniline (20 mg, 0.24 mmol, 6.0 equivalents) and sodium hydrogen carbonate (62 mg, 0.74 mmol, 18.5 equivalents), and the mixture was stirred with heating at 70° C. for 2 hours. To the reaction solution was added water, the mixture was extracted with ethyl acetate, and the extract was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (chloroform:methanol=95:5), to the product was added a 4 mol/L solution of hydrogen chloride in ethyl acetate, and then the mixture was concentrated. The residue was crystallized from acetone and methanol to obtain the title compound (3 mg, 19%) as a light yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:11])[CH3:10])=[CH:5][CH:4]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Cl[Si](C)(C)C.[C:27]1([CH2:33][S:34][CH:35]([C:39](O)=[O:40])[C:36](O)=[O:37])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C1COCC1>[OH:40][C:39]1[CH:10]=[C:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[O:11][C:36](=[O:37])[C:35]=1[S:34][CH2:33][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: COc1ccc(C(C)=O)cc1
Reactant: O=C(O)C(SCc1ccccc1)C(=O)O
Agent: C[Si](C)(C)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(-c2cc(O)c(SCc3ccccc3)c(=O)o2)cc1

Procedure:
The title compound was prepared by Method A using 4'-methoxyacetophenone (0.797 g, 5.31 mmol), lithium bis(trimethylsilyl)amide (0.977 g, 5.84 mmol), chlorotrimethylsilane (0.741 mL, 5.84 mmol), THF (58 mL), and diethyl ester of [(phenylmethyl)thio]propanedioic acid (1.00 g, 3.54 mmol). m.p. dec. 187° C.; 1H NMR (400 MHz, DMSO-d6) δ3.83 (s, 3 H), 3.98 (s, 2 H), 6.62 (s, 1 H), 7.06 (m, 2 H), 7.22 (m, 5 H), 7.73 (m, 2 H), 11.76 (bs, 1 H).
Reaction SMILES: C(C1C=CC(OC)=CC=1)C#C.C([C:14]1([C:17]2[CH:18]=[CH:19][C:20]([O:25][CH3:26])=[C:21]([CH:24]=2)[CH:22]=[O:23])[CH2:16][CH2:15]1)#N>>[CH2:14]([C:17]1[CH:18]=[CH:19][C:20]([O:25][CH3:26])=[C:21]([CH:24]=1)[CH:22]=[O:23])[C:15]#[CH:16]
Reactant: COc1ccc(C2(C#N)CC2)cc1C=O
Agent: C#CCc1ccc(OC)cc1
Product: C#CCc1ccc(OC)c(C=O)c1

Procedure:
This compound was prepared from Compound 76 in the same manner of Compound 2.
Reaction SMILES: Cl.Cl.[N:3]12[CH2:10][CH2:9][CH:6]([CH2:7][CH2:8]1)[C@H:5]([NH2:11])[CH2:4]2.[N+:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1/[CH:21]=[CH:22]/[C:23](O)=[O:24])([O-:14])=[O:13]>>[N:3]12[CH2:10][CH2:9][CH:6]([CH2:7][CH2:8]1)[C@H:5]([NH:11][C:23](=[O:24])/[CH:22]=[CH:21]/[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[N+:12]([O-:14])=[O:13])[CH2:4]2
Reactant: O=C(O)/C=C/c1ccccc1[N+](=O)[O-]
Reactant: N[C@@H]1CN2CCC1CC2
Agent: Cl
Product: O=C(/C=C/c1ccccc1[N+](=O)[O-])N[C@@H]1CN2CCC1CC2

Procedure:
Prepared as a free base by a method analogous to that described in Example 1 from (S)-1-azabicyclo[2.2.2]oct-3-ylamine dihydrochloride and E-3-(2-nitrophenyl)propenoic acid as a solid; MS (ES+) 302 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH2:5][N:6]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:2].C([N-]C(C)C)(C)C.[Li+].[CH:30]1([CH:33]=[O:34])[CH2:32][CH2:31]1.[Cl-].[NH4+]>O1CCCC1>[CH2:1]([O:3][C:4](=[O:21])[CH:5]([N:6]([CH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH:33]([CH:30]1[CH2:32][CH2:31]1)[OH:34])[CH3:2]
Reactant: O=CC1CC1
Reactant: CCOC(=O)CN(Cc1ccccc1)Cc1ccccc1
Agent: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C(C(O)C1CC1)N(Cc1ccccc1)Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 44.2 g (156 mmol) dibenzylamino-acetic acid ethyl ester in 300 ml tetrahydrofuran was stirred at −70° C. with 92.0 ml (184 mmol) lithium diisopropylamide (2M in heptane) for 60 minutes. 14.0 ml (184 mmol) cyclopropanecarboxaldehyde were added and stirring was continued overnight. The mixture was allowed to warm to room temperature an poured on saturated aqueous ammonium chloride. Extraction with diethyether and chromatography on silicagel with diethyether/heptane 1/2 yielded as first eluting fraction 17.1 g (31%) racemic (2R,3S and 2S,3R)-3-cyclopropyl-2-dibenzylamino-3-hydroxy-propionic acid ethyl ester, MS m/e (%): 354.1 (M+H+, 100) and as second eluting fraction 20.1 g (36%) racemic (2R,3R and 2S,3S)-3-cyclopropyl-2-dibenzylamino-3-hydroxy-propionic acid ethyl ester, MS m/e (%): 354.3 (M+H+, 100).