Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[OH:2]/[N:3]=[C:4](/[C:10]1[N:11]=[C:12]([NH:15][C:16]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[S:13][CH:14]=1)\[C:5]([O:7][CH2:8][CH3:9])=[O:6].C(=O)([O-])[O-].[K+].[K+].Br[CH2:42][F:43]>CS(C)=O.C(Cl)Cl>[F:43][CH2:42][O:2]/[N:3]=[C:4](/[C:10]1[N:11]=[C:12]([NH:15][C:16]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[S:13][CH:14]=1)\[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: FCBr
Reactant: CCOC(=O)/C(=N\O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: ClCCl
Product: CCOC(=O)/C(=N\OCF)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 0 °C
Reaction time: 2 h
Yield: 93.5 %

Procedure:
Ethyl (Z)-2-hydroxyimino-2-(2-triphenylmethylaminothiazol-4-yl)acetate, hydrochloride salt (8.7 g) was stirred with potassium carbonate (15.35 g) in dimethyl sulphoxide (30 ml) under nitrogen at 21° . Bromofluoromethane (ca 3 g) was added. The nitrogen flow was stopped and the stirring continued for two hours. The mixture was poured into an ice-water mixture with stirring and the solid was collected by filtration and washed with water. The solid was dissolved in methylene chloride and the organic layer was separated and dried with magnesium sulphate. Evaporation gave a foam. This was dissolved in methylene chloride and pre-absorbed onto Kieselgel 60 (50 g). This was added to the top of a column of similar silica (125 g) set up in 10% ethyl acetate in cyclohexane. The column was eluted successively with 10%, 20% and 33% ethyl acetate in cyclohexane. After combination of appropriate fractions, evaporation gave the title compound (8.06 g) as a foam; λmax (EtOH) 302 nm (E1 cm1% 92), λinfl include 227.5 nm (E1 cm1% 546) and 259 nm (E1 cm1% 221), νmax (CHBr3) 3400 (NH), 1739 (ester) and 1533 cm-1 (C=N).
Reaction SMILES: [NH2:1][C:2]1[C:3]([OH:10])=[CH:4][C:5]([CH2:8][NH2:9])=[N:6][CH:7]=1.C(N(CC)CC)C.CO[CH:20]=[C:21]1[C:30]2[C:25](=[CH:26][CH:27]=[C:28]([I:31])[CH:29]=2)[C:24](=[O:32])[NH:23][C:22]1=[O:33]>CN(C)C=O>[NH2:1][C:2]1[C:3]([OH:10])=[CH:4][C:5]([CH2:8][NH:9][CH:20]=[C:21]2[C:30]3[C:25](=[CH:26][CH:27]=[C:28]([I:31])[CH:29]=3)[C:24](=[O:32])[NH:23][C:22]2=[O:33])=[N:6][CH:7]=1
Reactant: COC=C1C(=O)NC(=O)c2ccc(I)cc21
Reactant: NCc1cc(O)c(N)cn1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Nc1cnc(CNC=C2C(=O)NC(=O)c3ccc(I)cc32)cc1O
Reaction time: 0.25 h

Procedure:
A mixture of 5-amino-2-aminomethyl-pyridin-4-ol (60 mg, 0.19 mmole as the dihydrobromide), 3 mL of N,N-dimethylformamide and triethylamine (101 uL, 0.72 mmole) were stirred for 15 mins, 4-methoxymethylene-6-iodo-4H-isoquinoline-1,3-dione (63 mg, 0.19 mmole) is added and the reaction mixture stirred for one hour. The reaction mixture is evaporated to dryness, taken up in dimethylsulfoxide and purified by HPLC (acetonitrile-water with 0.2% trifluoroacetic acid). The product is isolated by evaporation in-vacuo to give a brown solid, 5.5 mg, (5%); MS (ES+): m/z 437.0 (M+H).
Reaction SMILES: [CH2:1]([OH:7])/[CH:2]=[CH:3]\[CH2:4][CH2:5][CH3:6].[H-].[Na+].Cl[C:11]1[C:15]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)=[N:14][S:13][N:12]=1.O>O1CCCC1>[CH2:1]([O:7][C:11]1[C:15]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)=[N:14][S:13][N:12]=1)/[CH:2]=[CH:3]\[CH2:4][CH2:5][CH3:6]
Reactant: Clc1nsnc1-c1cccnc1
Reactant: CCC/C=C\CO
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCC/C=C\COc1nsnc1-c1cccnc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of cis-2-hexen-1-ol (900 mg, 9 mmol) and sodium hydride (310 mg, 9 mmol) in dry tetrahydrofuran was added a solution of 3-(3-chloro-1,2,5-thiadiazol-4-yl) pyridine (590 mg, 3 mmol) in dry tetrahydrofuran. The reaction mixture was stirred at room temperature for 1 h. Water was added and the mixture was extracted with ether. The ether phase was dried and evaporated to give the title compound.
Reaction SMILES: CS(O[CH:6]1[CH2:11][CH2:10][CH:9]([NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:8][CH2:7]1)(=O)=O.[F:20][C:21]([F:30])([F:29])[C:22]1[CH:27]=[CH:26][C:25]([SH:28])=[CH:24][CH:23]=1.C([O-])([O-])=O.[K+].[K+]>C1COCC1.O>[F:30][C:21]([F:20])([F:29])[C:22]1[CH:23]=[CH:24][C:25]([S:28][CH:6]2[CH2:7][CH2:8][CH:9]([NH:12][C:13](=[O:14])[O:15][C:16]([CH3:17])([CH3:18])[CH3:19])[CH2:10][CH2:11]2)=[CH:26][CH:27]=1
Reactant: FC(F)(F)c1ccc(S)cc1
Reactant: CC(C)(C)OC(=O)NC1CCC(OS(C)(=O)=O)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1CCC(Sc2ccc(C(F)(F)F)cc2)CC1
Temperature: 130 °C
Yield: 43 %

Procedure:
4-[(tert-Butoxycarbonyl)amino]cyclohexyl methanesulfonate (0.7 g, 2.39 mmol), 4-(trifluoromethyl)thiophenol (1.28 g, 7.16 mmol) and K2CO3 (1.32 g, 9.54 mmol) was dissolved in THF (21 ml) and the reaction mixture was heated in a microwave reactor at 130° C. for 30 mins. The reaction mixture was diluted with water (300 ml) and extracted with EtOAc (2×150 ml). The combined organic phases were dried over Na2SO4, filtrated and evaporated. The residue was purified by silica gel column chromatography using a 85:15 mixture of heptane:EtOAc to give the title compound (0.386 g, 43%) as a 50:50 mixture of cis and trans isomers. 1H-NMR (CDCl3, 500 MHz): δ 7.55-7.50 (m, 4H), 7.45-7.40 (m, 4H), 4.70-4.23 (m, 2H), 3.69-3.36 (m, 3H), 3.16-3.05 (m, 1H), 2.13-2.04 (m, 4H), 1.95-1.64 (m, 9H), 1.54-1.40 (m, 1H), 1.45 (ds, 18H), 1.30-1.15 (m, 2H); 13C-NMR (CDCl3, 125 MHz): δ 155.4, 141.1, 140.7, 130.5, 129.9, 128.6, 128.5, 128.2, 126.0, 125.9, 125.9, 125.9, 125.4, 123.2, 79.5, 49.1, 47.9, 44.8, 43.8, 33.4, 32.0, 29.2, 29.1, 28.6.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:27]=[CH:26][C:9]([C:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH:24]=[CH2:25])=[CH:15][CH:14]=2)=[O:11])=[CH:8][CH:7]=1)[CH2:2][CH:3]=[CH2:4].[CH3:28][SiH:29]([CH3:31])[CH3:30]>ClCCl.C1([Pt](Cl)(Cl)C2C=CC=C2)C=CC=C1>[CH3:28][Si:29]([CH3:31])([CH3:30])[CH:1]([O:5][C:6]1[CH:27]=[CH:26][C:9]([C:10]([O:12][C:13]2[CH:14]=[CH:15][C:16]([O:19][CH:20]([Si:29]([CH3:31])([CH3:30])[CH3:28])[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:17][CH:18]=2)=[O:11])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: C[SiH](C)C
Reactant: C=CCCCCOc1ccc(OC(=O)c2ccc(OCCC=C)cc2)cc1
Agent: Cl[Pt](Cl)(C1C=CC=C1)C1C=CC=C1
Solvent: ClCCl
Product: CCCCCC(Oc1ccc(OC(=O)c2ccc(OC(CCC)[Si](C)(C)C)cc2)cc1)[Si](C)(C)C

Procedure:
0.35 g (0.01 mmol of Pt) of 0.5% strength dicyclopentadienylplatinum dichloride solution in dichloromethane was added as catalyst to a solution of 5.00 g (9.71 mmol) of 4-(5-hexenyloxy)phenyl 4-(3-butenyloxy)benzoate in 10 ml of dichloromethane, and 2.02 g (27.2 mmol) of trimethylsilane were passed into the refluxing mixture over the course of 8 hours. After complete hydrosilylation of the olefin, the reaction mixture was flushed with nitrogen, and the dichloromethane was removed by vacuum distillation on a rotary evaporator. The crude product was purified by chromatography on silica gel, to give 4-(1-trimethylsilylhexyloxy)phenyl 4-(1-trimethylsilylbutyloxy)benzoate, phases: c 72 i.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9](O[Si](C)(C)C)[C:10]#[N:11].C(N(S(F)(F)[F:23])CC)C.C(=O)(O)[O-].[Na+]>ClCCl>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([F:23])[C:10]#[N:11]
Reactant: CCN(CC)S(F)(F)F
Reactant: C[Si](C)(C)OC(C#N)c1ccc(Cl)cc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: N#CC(F)c1ccc(Cl)cc1Cl
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 89.8 %

Procedure:
To a solution of 2-(2,4-dichlorophenyl)-2-(trimethylsilyloxy)acetonitrile (1.57 g, 5.73 mmol) in dichloromethane (20 ml) under argon at −78° C. was added (diethylamino)sulfur trifluoride (1.51 ml, 11.5 mmol) dropwise over 15 minutes. The reaction was stirred at this temperature for 20 minutes, then warmed to 0° C. and allowed to stir for an additional 30 minutes. The reaction was poured onto a mixture of ice water and saturated sodium bicarbonate and allowed to stir for 30 minutes. The mixture was extracted with ether twice, and the combined organic layers were washed with saturated sodium chloride, dried over anhydrous magnesium sulfate, filtered, and concentrated to yield 1.05 g of the title compound (89% yield).
Reaction SMILES: [CH2:1]([Mg]Br)[CH:2]([CH3:4])[CH3:3].N1C=CC=CC=1S[C:14](=[O:25])[CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1>C1COCC1>[CH3:24][O:23][C:20]1[CH:19]=[CH:18][C:17]([CH2:16][CH2:15][C:14](=[O:25])[CH2:1][CH:2]([CH3:4])[CH3:3])=[CH:22][CH:21]=1
Reactant: CC(C)C[Mg]Br
Reactant: COc1ccc(CCC(=O)Sc2ccccn2)cc1
Solvent: C1CCOC1
Product: COc1ccc(CCC(=O)CC(C)C)cc1
Reaction time: 1 h
Yield: 75 %

Procedure:
Isobutylmagnesium bromide (0.88 mL, 1.75 mmol, 2M soln in THF) was added to a cooled −78° C. solution of 3-(4-Methoxy-phenyl)-thiopropionic acid S-pyridin-2-yl ester (0.4 g, 1.46 mmol, from Step 1) dissolved in THF (6 mL). The reaction mixture was stirred for 60 min. The reaction was quenched with saturated NH4Cl and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4 and concentrated to a yellow oil. The residue was purified by silica gel chromatography (5% EtOAc in hexanes) to give the title compound as a clear oil (0.24 g, 75%).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Br:13][C:14]1[CH:15]=[CH:16][C:17]([Cl:20])=[N:18][CH:19]=1.[I:21]I.S([O-])([O-])(=O)=S.[Na+].[Na+]>O1CCCC1>[Br:13][C:14]1[C:15]([I:21])=[CH:16][C:17]([Cl:20])=[N:18][CH:19]=1
Reactant: II
Reactant: Clc1ccc(Br)cn1
Agent: O=S([O-])([O-])=S
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: Clc1cc(I)c(Br)cn1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 76.7 %

Procedure:
To a solution of 12 ml (83 mmol) diisopropylamine in 80 ml dry tetrahydrofuran 52 ml of a solution of n-butyllithium in hexanes (1.6 M, 83 mmol) was added at −78° C. over a period of 15 min under argon. The mixture was stirred at −78° C. for 10 min. A solution of 15.2 g (79.0 mmol) 5-bromo-2-chloro-pyridine in 160 ml dry tetrahydrofuran was added at a rate such that the internal temperature did not exceed −70° C. After completed addition the reaction mixture was stirred at −78° C. for 5 h. A solution of 24 g (95 mmol) iodine in 160 ml dry tetrahydrofuran was added at a rate such that the internal temperature did not exceed −70° C. The reaction mixture was stirred for another 30 min at −78° C. The reaction mixture was allowed to warm to −10° C. and treated with 120 ml of an aqueous solution of sodium thiosulfate (1 M, 120 mmol). The layers were separated and the aqueous layer was extracted with two portions of ethyl acetate. The combined organic layers were washed twice with saturated ammonium hydroxide solution, dried with sodium sulfate and concentrated. The residue was dissolved in hot heptane and allowed to stand over night. Filtration of the precipitate and drying in vacuo gave 19.3 g (77%) of the title compound as a light brown solid.
Reaction SMILES: [OH:1][CH:2]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[CH:13]=[C:14]([NH:18][C:19](=[O:23])[CH:20]([CH3:22])[CH3:21])[CH:15]=[CH:16][CH:17]=2)[CH2:8][CH2:7]1.[Cl:30][C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([Cl:37])[C:32]=1[C:38]1[C:42]([C:43](Cl)=[O:44])=[C:41]([CH3:46])[O:40][N:39]=1>>[Cl:30][C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([Cl:37])[C:32]=1[C:38]1[C:42]([C:43]([O:1][CH:2]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:3][CH2:4][CH2:5][N:6]2[CH2:7][CH2:8][CH:9]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([NH:18][C:19](=[O:23])[CH:20]([CH3:22])[CH3:21])[CH:13]=3)[CH2:10][CH2:11]2)=[O:44])=[C:41]([CH3:46])[O:40][N:39]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCC(O)c3ccccc3)CC2)c1
Reactant: Cc1onc(-c2c(Cl)cccc2Cl)c1C(=O)Cl
Product: Cc1onc(-c2c(Cl)cccc2Cl)c1C(=O)OC(CCCN1CCC(c2cccc(NC(=O)C(C)C)c2)CC1)c1ccccc1

Procedure:
Prepared by Procedure Q1 and Scheme C2 (TEA) using N-{3-[1-(4-hydroxy-4-phenylbutyl)-4-piperidinyl]phenyl}-2-methylpropanamide and 3-(2,6-dichlorophenyl)-5-methyl-4-isoxazolecarbonyl chloride: 1H NMR (400 MHz, CDCl3) δ 7.56 (m, 1H), 7.47 (m, 2H), 7.44-7.39 (m, 3H), 7.25 (m, 2H), 7.09 (s, 1H), 7.03 (m, 2H), 6.95 (m, 1H), 6.83 (m, 1H), 5.75 (t, 1H, J=7.1 Hz), 3.03 (t, 2H, J=7.2 Hz), 2.93 (m, 2H), 2.78 (s, 3H), 2.48 (m, 3H), 2.25 (m, 2H), 1.48 (m, 3H), 1.77 (m, 2H), 1.54 (m, 2H), 1.25 (d, 6H, J=7.3 Hz); ESMS m/e: 647.7 (M+H)+.
Reaction SMILES: C([Li])CCC.[CH3:6][N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:8]1.[C:22]([O:26][CH2:27][CH3:28])(=[O:25])[CH:23]=[O:24].C1(C)C=CC=CC=1>O1CCCC1>[OH:24][CH:23]([C:8]1[N:7]([CH3:6])[C:15]2[C:10]([C:9]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:22]([O:26][CH2:27][CH3:28])=[O:25]
Reactant: CCOC(=O)C=O
Reactant: Cn1cc(-c2ccccc2)c2ccccc21
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCOC(=O)C(O)c1c(-c2ccccc2)c2ccccc2n1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 22 %

Procedure:
A solution of butyllithium (1.6 M, 3.44 mL, 5.5 mmol) was added at −20° C. to a solution of 1-methyl-3-phenyl-1H-indole (1b) (1.08 g, 5.3 mmol) in anhydrous tetrahydrofuran (20 mL) under a nitrogen atmosphere. After 1 hour, a solution of ethyl glyoxylate in toluene (50%, 1.1 mL, 5.5 mmol) was added. The reaction mixture was slowly warmed to room temperature for 2 hours, quenched with water (5 mL) and concentrated in vacuo. The residue was partitioned between dichloromethane (40 mL) and water (15 mL). The organic layer was washed with water (2×15 mL), brine (15 mL), dried over sodium sulfate, filtered and evaporated to dryness. The residue was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate 90/10) to afford the desired alcohol (1c) as a white solid (360 mg, 1.16 mmol, 22%).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][N:12]2[C:20]3[C:15](=[C:16]([O:21]CC4C=CC=CC=4)[CH:17]=[CH:18][CH:19]=3)[CH:14]=[CH:13]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H][H]>[Pd].CO>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][N:12]2[C:20]3[C:15](=[C:16]([OH:21])[CH:17]=[CH:18][CH:19]=3)[CH:14]=[CH:13]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [H][H]
Reactant: c1ccc(CCCCCn2ccc3c(OCc4ccccc4)cccc32)cc1
Agent: [Pd]
Solvent: CO
Product: Oc1cccc2c1ccn2CCCCCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 71.3 %

Procedure:
Under argon atmosphere, 1-(5-phenylpentyl)-4-benzyloxyindole (330 mg) and 5% Pd-C (10 mg) were added to methanol (5 ml) and the atmosphere in the reaction vessel was replaced with hydrogen. The mixture was stirred at room temperature for 2 hours and solids were removed by filtration through Celite. The solvent was removed under reduced pressure, and the obtained crude product was purified by silica gel column chromatography to obtain the desired compound (178 mg, yield: 71%).
Reaction SMILES: [NH2:1][CH2:2][C:3]([OH:5])=[O:4].[OH-].[Na+].[Cl:8][C:9]1[CH:10]=[C:11]([NH:15][C:16](=[N:19][C:20]#[N:21])SC)[CH:12]=[CH:13][CH:14]=1>O.C(O)C>[C:20]([N:19]=[C:16]([NH:15][C:11]1[CH:12]=[CH:13][CH:14]=[C:9]([Cl:8])[CH:10]=1)[NH:1][CH2:2][C:3]([OH:5])=[O:4])#[N:21]
Reactant: CSC(=NC#N)Nc1cccc(Cl)c1
Reactant: NCC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: N#CN=C(NCC(=O)O)Nc1cccc(Cl)c1
Yield: 89.6 %

Procedure:
Three grams (39.9 mmol) of glycine and 1.5 g (37.2 mmol) of sodium hydroxide are mixed in 10 cm3 of water and added to 6 g (26.5 mmol) of N-(3-chlorophenyl)-N'-cyano-S-methylisothiourea in solution in 40 cm3 of 95% ethanol. The mixture is reflux heated for 1 hour. After cooling, the resulting precipitate is filtered and then washed with 2×50 cm3 of ethyl ether. The resulting solid is dissolved in 50 cm3 of 1N sodium hydroxide solution. This solution is washed with 3×10 cm3 of dichloromethane and then acidified with a 3N solution until a pH close to 2 is obtained. The white solid which forms is then filtered and washed in 2×10 cm3 of water, following which it is dried in vacuo. 6 g of N-[cyanoimino(3-clorophenylamino)methyl]-2-aminoethanoic acid (yield 89%) is obtained with a melting point of 109° C.
Reaction SMILES: Br[C:2]1[CH:35]=[CH:34][C:5]([CH2:6][C:7]2[N:8]([C:20]3[CH:25]=[CH:24][C:23]([N:26]4[S:30](=[O:32])(=[O:31])[NH:29][C:28](=[O:33])[CH2:27]4)=[CH:22][CH:21]=3)[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=3[Cl:19])[N:11]=2)=[CH:4][CH:3]=1.[CH2:36]([O:38][C:39]([CH2:41][CH2:42][C:43]1[CH:48]=[CH:47][C:46](B(O)O)=[CH:45][CH:44]=1)=[O:40])[CH3:37]>>[CH2:36]([O:38][C:39](=[O:40])[CH2:41][CH2:42][C:43]1[CH:48]=[CH:47][C:46]([C:2]2[CH:35]=[CH:34][C:5]([CH2:6][C:7]3[N:8]([C:20]4[CH:21]=[CH:22][C:23]([N:26]5[CH2:27][C:28](=[O:33])[NH:29][S:30]5(=[O:31])=[O:32])=[CH:24][CH:25]=4)[CH:9]=[C:10]([C:12]4[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=4[Cl:19])[N:11]=3)=[CH:4][CH:3]=2)=[CH:45][CH:44]=1)[CH3:37]
Reactant: CCOC(=O)CCc1ccc(B(O)O)cc1
Reactant: O=C1CN(c2ccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(Br)cc3)cc2)S(=O)(=O)N1
Product: CCOC(=O)CCc1ccc(-c2ccc(Cc3nc(-c4ccc(Cl)cc4Cl)cn3-c3ccc(N4CC(=O)NS4(=O)=O)cc3)cc2)cc1

Procedure:
5-{-4-[2-(4-bromo-benzyl)-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-1,2,5-thiadiazolidine-3-one-1,1-dioxide (300 mg, 0.51 mmol) was treated as described in general procedure G using 4-(2-ethoxycarbonyl-ethyl)phenyl boronic acid to provide 3-(4′-{4-(2,4-dichloro-phenyl)-1-[4-(1,1,4-trioxo-[1,2,5]thiadiazolidin-2-yl)-phenyl]-1H-imidazol-2-ylmethyl}-biphenyl-4-yl)-propionic acid ethyl ester.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH:6]=O)=[CH:2]1.[CH3:8][C:9]([CH3:14])([CH3:13])[C:10](=[O:12])[CH3:11].C[O-].[Na+].O>CO>[CH3:8][C:9]([CH3:14])([CH3:13])[C:10](=[O:12])[CH:11]=[CH:6][C:3]1[CH:4]=[CH:5][S:1][CH:2]=1
Reactant: O=Cc1ccsc1
Reactant: CC(=O)C(C)(C)C
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(C)(C)C(=O)C=Cc1ccsc1
Yield: 81.4 %

Procedure:
3-Thiophene carbaldehyde (500 μL, 5.71 mmol) and 3,3-dimethylbutan-2-one (710 μL, 5.71 mmol) were dissolved in methanol (5.0 mL). To this was added sodium methoxide (340 mg, 6.29 mmol), and then the mixture was stirred under reflux overnight. After addition of water, the mixture was extracted with ethyl acetate. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate, and then the solvent was evaporated off in vacuo. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate 95/5) to give the title compound (904 mg, 4.65 mmol, yield 81%).
Reaction SMILES: [CH2:1]([NH:5][C:6](=[O:31])[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH2:17][C:16]([C:22]3[CH:27]=[C:26]([Cl:28])[CH:25]=[C:24]([Cl:29])[CH:23]=3)([C:18]([F:21])([F:20])[F:19])[O:15][N:14]=2)=[CH:9][C:8]=1[CH3:30])[CH2:2][CH2:3][CH3:4].C(NC(C)C)(C)C.C([Li])CCC>O1CCCC1>[CH2:1]([NH:5][C:6](=[O:31])[C:7]1[CH:12]=[CH:11][C:10]([C:13](=[N:14][OH:15])[CH:17]=[C:16]([C:22]2[CH:27]=[C:26]([Cl:28])[CH:25]=[C:24]([Cl:29])[CH:23]=2)[C:18]([F:19])([F:21])[F:20])=[CH:9][C:8]=1[CH3:30])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNC(=O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1C
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCCCNC(=O)c1ccc(C(C=C(c2cc(Cl)cc(Cl)c2)C(F)(F)F)=NO)cc1C
Temperature: 0 °C
Yield: 60.4 %

Procedure:
To a solution of N-butyl-4-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-benzamide (made as described in EP 1,731,512) (1670 mg, 4.13 mmol) and N,N-diisopropylamine (880 mg, 8.69 mmol) in dry tetrahydrofuran (10 ml) was added n-butyl lithium (“n-BuLi”) (1.55M in hexane) (5.6 ml, 8.69 mmol) at −90° C. The reaction mixture was allowed to warm to 0° C. over a period of 2 hours and quenched by addition of aqueous ammonium chloride (saturated). The mixture was extracted several times with diethyl ether. The combined organic extracts were dried over magnesium sulfate and concentrated. The residue was purified by chromatography on silica gel (eluent: hexane/ethyl acetate 2:1) to give N-butyl-4-[3-(3,5-dichloro-phenyl)-4,4,4-trifluoro-1-hydroxyimino-but-2-enyl]-2-methyl-benzamide (1180 mg, 70% yield) as a yellow resin. 1H-NMR (CDCl3, 300 MHz): 8.52 (bs, 1H), 7.45-7.36 (m, 6H), 6.75 (s, 1H), 5.81 (m, 1H), 3.46-3.43 (m, 2H), 2.47 (s, 3H), 1.54-1.39 (m, 4H), 0.97 (t, 3H) ppm.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:19]=[CH:20][C:21]4[O:25][C:24]([CH:26]=[O:27])=[CH:23][C:22]=4[CH:28]=3)[N:14]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH3:12])[CH3:2].[OH-:29].[K+]>CCO.[N+]([O-])([O-])=O.[Ag+]>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:19]=[CH:20][C:21]4[O:25][C:24]([C:26]([OH:29])=[O:27])=[CH:23][C:22]=4[CH:28]=3)[N:14]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH3:12])[CH3:2]
Reactant: [OH-]
Reactant: CCOc1ccc(-c2nc(-c3ccc4oc(C=O)cc4c3)no2)cc1OCC
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCOc1ccc(-c2nc(-c3ccc4oc(C(=O)O)cc4c3)no2)cc1OCC
Temperature: 50 °C
Reaction time: 1 h
Yield: 12.8 %

Procedure:
To a suspension of the product of Step E (0.009 g; 0.024 mmol) and AgNO3 (0.06 g; 0.14 mmol) in EtOH (0.2 ml) H2O (0.1 ml) was added at room temperature, followed by 10% KOH (0.1 ml). The resulting black suspension was stirred for 1 h at ˜50° C. and cooled to room temperature and filtered. The insoluble material was washed with H2O (2×0.2 ml). The combined filtrates were acidified to pH=1 with HCl and the product was taken up by extraction with EtOAc (2×5 ml). The organic phase was washed with brine, dried over anhydrous MgSO4, filtered and filtrate evaporated to dryness. The residue was purified by FCC (SiO2, CH2Cl2/acetic acid (AcOH) 98/2) to give the title compound (0.00012 g; 12.8%), as a creamy solid. 1H-NMR (CDCl3+CD3OD) 8.48 (s, 1H); 8.22 (m, 1H); 7.77 (m, 1H); 7.64-7.66 (m, 2H); 7.58 (s, 1H); 6.96 (d, 1H, J=6 Hz); 4.19 (m, 4H); 1.4-1.54 (m, 6H).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:11]([NH2:13])[CH3:12].O>C1COCC1>[CH2:11]([NH:13][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1)[CH3:12]
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: CCN
Solvent: C1CCOC1
Solvent: O
Product: CCNc1ncccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-chloro-3-nitropyridine (51 g, 325 mmol) in THF (650 mL) was added a 2 M solution of ethylamine in THF (365 mL, 731 mmol). The reaction was stirred at room temperature overnight. The reaction mixture was poured into water (˜1.5 L) and the resulting solid was filtered and dried under reduced pressure to give the title compound (52 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]#[CH:12])=[CH:7][CH:6]=1.[CH3:14][O:15][C:16](=[O:27])[CH2:17][CH2:18][C:19]1[C:24]([OH:25])=[CH:23][CH:22]=[C:21](I)[N:20]=1>>[CH3:14][O:15][C:16](=[O:27])[CH2:17][CH2:18][C:19]1[C:24]([OH:25])=[CH:23][CH:22]=[C:21]([C:12]#[C:11][C:8]2[CH:7]=[CH:6][C:5]([CH2:4][C:3]([O:2][CH3:1])=[O:13])=[CH:10][CH:9]=2)[N:20]=1
Reactant: COC(=O)CCc1nc(I)ccc1O
Reactant: C#Cc1ccc(CC(=O)OC)cc1
Product: COC(=O)CCc1nc(C#Cc2ccc(CC(=O)OC)cc2)ccc1O
Yield: 39.6 %

Procedure:
Under the conditions of example 5 A, 5 g of the crude 4-ethinylphenylacetic acid methyl ester is reacted with 7.9 g of 3-(3-hydroxy-6-iodo-2-pyridyl)-propionic acid methyl ester, worked up, and the crude product is chromatographed on silica gel with hexane/0-50% ethyl acetate. 3.6 g of 3-{3-hydroxy-6-[2-(4-methoxycarbonylmethylphenyl)-ethinyl]-2-pyridyl}-propionic acid methyl ester of melting point 122°-125° C. is obtained.