Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]4[CH:24]=[CH:23][CH:22]=[CH:21][C:19]4=3)[C:14]3[C:9]2=[CH:10][C:11]([O:25][CH3:26])=[CH:12][CH:13]=3)=[CH:4][CH:3]=1.C(C(C)=O)C.C(=O)([O-])[O-].[K+].[K+].Cl.[CH3:39][N:40]([CH3:44])[CH2:41][CH2:42]Cl>C(OCC)(=O)C>[CH3:26][O:25][C:11]1[CH:10]=[C:9]2[C:14]([C:15]3[C:20]([CH:8]2[C:5]2[CH:4]=[CH:3][C:2]([O:1][CH2:42][CH2:41][N:40]([CH3:44])[CH3:39])=[CH:7][CH:6]=2)=[C:19]2[CH:21]=[CH:22][CH:23]=[CH:24][C:18]2=[CH:17][CH:16]=3)=[CH:13][CH:12]=1
Reactant: CN(C)CCCl
Reactant: COc1ccc2c(c1)C(c1ccc(O)cc1)c1c-2ccc2ccccc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCC(C)=O
Product: COc1ccc2c(c1)C(c1ccc(OCCN(C)C)cc1)c1c-2ccc2ccccc12
Temperature: 25 °C

Procedure:
A 3.4 g portion of the compound of Example 1 was combined with 75 ml of methyl ethyl ketone, 6.1 g of potassium carbonate, and 2.45 g of dimethyl-(2-chloroethyl)amine hydrochloride. The mixture was stirred under reflux for 24 hours. After cooling to 25° C., 50 g of ice and 100 ml of ethyl acetate were added. The organic layer was separated, washed with brine, and concentrated to provide the crude product which was then purified on a silica gel column (120 mm high and 70 mm in diameter). The elution started with 500 ml of toluene, and proceeded through 300 ml increments of toluene containing from 1 to 10% triethylamine, in 1% increments. The product-containing fractions were combined and concentrated to dryness under vacuum to obtain 3.1 g of partially purified product, which was chromatographed again on a similar column, beginning with 100 ml of toluene. The gradient solvent was then changed in 100 ml increments from toluene containing 10% of 5:3 ethyl acetate:acetonitrile, to 10% of toluene in the ethyl acetate:acetonitrile mixture. Then a second gradient solvent was used, again in 100 ml increments, starting with the 5:3 ethyl acetate:acetonitrile mixture, going to the same solvent containing 10% of triethylamine. The product-containing fractions were then evaporated under vacuum to obtain 2.9 g of purified desired product, m.p. 159°-160° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:8](Cl)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[NH2:12][C:13]1[CH:19]=[CH:18][C:17]([N:20]2[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]2)=[CH:16][C:14]=1[NH2:15].N1C=CC=CC=1>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([S:8]([NH:12][C:13]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:21][CH2:22][N:23]([CH3:26])[CH2:24][CH2:25]3)=[CH:16][C:14]=2[NH2:15])(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: CN1CCN(c2ccc(N)c(N)c2)CC1
Reactant: O=S(=O)(Cl)c1cccc(F)c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CN1CCN(c2ccc(NS(=O)(=O)c3cccc(F)c3)c(N)c2)CC1
Yield: 56.5 %

Procedure:
A mixture of 2-nitro-3-chloroaniline (4.47 g, 25.9 mmol), methylpiperazine (3.1 g, 31 mmol) and K2CO3 (5.41 g, 39 mmol) in acetonitrile was stirred at 70° C. for 48 h. The mixture was filtered and purified by column chromatography (SiO2, CH2Cl2/MeOH/Heptane/NH3 4:1:5×0.2%) to give 1.6 g of product (unreacted starting material was isolated): 1H-NMR δ 7.66-7.45 (m, 5H), 6.78 (d, 1H), 6.62 (d, 1H), 6.50 (dd, 1H), 3.39-3.35 (m, 4H), 3.02-2.99 (m, 4H); MS (posES-FIA) m/z 333.0 (M++H). The product (1.06 g, 4.49 mmol) was dissolved in EtOH:THF (4:1). Raney-Ni and hydrazine (1.12 mL, 22 mmol) were added. The reaction was stirred at room temperature for 3 h until the yellow color disappeared. Filtration through wet Celite pad, followed by removal of the solvent afforded 0.802 g of 2-amino-5-(4-methyl-1-piperazinyl)aniline which was used without further purification in the next step. 3-Fluorobenzenesulfonyl chloride (0.133 g, 0.68 mmol) was added to a solution of 2-amino-5-(4-methyl-1-piperazinyl)aniline (0.141 g, 0.68 mmol) and pyridine (514 mL, 6.39 mmol) in CH2Cl2. After 1 h the mixture was washed with aq NaHCO3 (10%), dried (MgSO4) and the solvent was removed. Purification by chromatography (SiO2, CH2Cl2/methanol/heptane, 4:1:5) gave 3-fluoro-N-[2-amino-4-(4-methyl-1-piperazinyl)-phenyl]benzenesulfonamide (0.140 g, 57%). MS (posES-FIA) m/z=found: 365.2. calcd: 364.14. Anal. (C17H22ClFN4O2S.3H2O) C, H, N, S. The reaction produced a small amount of bis-sulfonylated compound 3-fluoro-N-[2-{[(3-fluorophenyl)sulfonyl]amino}-4-(4-methyl-1-piperazinyl)-phenyl]benzenesulfonamide (0.010 g, 3%). The products were transformed into their HCl-salt before analysis; MS (posES-FIA) m/z=found. 523.5. calcd: 522.12. Anal. (C23H25ClF2N4O4S2) C, H, N, S.
Reaction SMILES: S(=O)(=O)(O)O.[N+:6]([O-:9])(O)=[O:7].[Br:10][C:11]1[CH:20]=[C:19]2[C:14]([C:15](=[O:21])[NH:16][CH:17]=[N:18]2)=[CH:13][CH:12]=1>O>[Br:10][C:11]1[CH:20]=[C:19]2[C:14]([C:15](=[O:21])[NH:16][CH:17]=[N:18]2)=[CH:13][C:12]=1[N+:6]([O-:9])=[O:7]
Reactant: O=c1[nH]cnc2cc(Br)ccc12
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: O
Product: O=c1[nH]cnc2cc(Br)c([N+](=O)[O-])cc12
Yield: 65 %

Procedure:
To a mixed solution of concentrated sulfuric acid (3 mL) and fuming nitric acid (3 mL) was added 7-bromo-3H-quinazolin-4-one (1.67 g, 7.42 mmol), and the mixture was heated at an oil bath temperature of 95° C. to 100° C. for 1 hr. The reaction mixture was poured into water (50 mL), and the product was collected by filtration, washed with water and dried under reduced pressure to give an about 5.6:1 mixture (1.3 g, 65%) of the objective 7-bromo-6-nitro-3H-quinazolin-4-one and 7-bromo-8-nitro-3H-quinazolin-4-one.
Reaction SMILES: [OH:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[O:7])=[CH:4][CH:3]=1.[C:19](Cl)(=[O:29])[C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[O:25])=[CH:22][CH:21]=1>>[CH2:9]([O:8][C:6]([C:5]1[CH:4]=[CH:3][C:2]([O:1][C:19](=[O:29])[C:20]2[CH:28]=[CH:27][C:23]([C:24]([O:1][C:2]3[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[O:7])=[CH:17][CH:18]=3)=[O:25])=[CH:22][CH:21]=2)=[CH:18][CH:17]=1)=[O:7])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCOC(=O)c1ccc(O)cc1
Reactant: O=C(Cl)c1ccc(C(=O)Cl)cc1
Product: CCCCCCCCOC(=O)c1ccc(OC(=O)c2ccc(C(=O)Oc3ccc(C(=O)OCCCCCCCC)cc3)cc2)cc1

Procedure:
Octyl p-hydroxybenzoate and terephthalic dichloride are allowed to react and treated in a similar procedure to Example 4. The residue obtained is recrystallized from ethyl acetate-chloroform (1:1) to give di(p-octyloxycarbonylphenyl)terephthalate, m.p. 108°-110° C., as white crystals.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[CH:23]=[CH:22][C:12]([C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[CH3:21])=[O:14])=[C:11]([Cl:24])[CH:10]=2)=[C:4]([CH3:25])[CH:3]=1.[H-].[Na+].[CH2:28](I)[CH3:29].O>O1CCCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([C:9]2[CH:23]=[CH:22][C:12]([C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[CH3:21])=[O:14])=[C:11]([Cl:24])[CH:10]=2)[CH2:28][CH3:29])=[C:4]([CH3:25])[CH:3]=1
Reactant: CCI
Reactant: Cc1cc(Br)ccc1Nc1ccc(C(=O)c2ccccc2C)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCN(c1ccc(C(=O)c2ccccc2C)c(Cl)c1)c1ccc(Br)cc1C

Procedure:
A solution of 4-(4-bromo-2-methyl-phenylamino)-2-chloro-2′-methylbenzophenone (Compound 136)(110 mg) in dry tetrahydrofurane (2.0 ml was added sodium hydride (19 mg) in one portion under stirring. After 10 min at room temperature ethyl iodide (124 mg ) was added and the reaction mixture was stirred for 18 hours under reflux, then poured into water and extracted with EtOAc. The organic phases were separated, dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by chromatography using a mixture of EtOAc/pentane 1:8 as eluant to yield the title compound as an oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[C:24]3[C:19](=[N:20][CH:21]=[C:22]([O:25][CH3:26])[CH:23]=3)[N:18]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:17]=2Cl)=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:34][C:35]1[CH:36]=[CH:37][C:38]([CH3:42])=[C:39]([OH:41])[CH:40]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[C:24]3[C:19](=[N:20][CH:21]=[C:22]([O:25][CH3:26])[CH:23]=3)[N:18]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:17]=2[O:41][C:39]2[CH:40]=[C:35]([F:34])[CH:36]=[CH:37][C:38]=2[CH3:42])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1cnc2c(c1)c(C(=O)N1CCN(C(=O)OC(C)(C)C)CC1)c(Cl)n2-c1ccccc1
Reactant: Cc1ccc(F)cc1O
Product: COc1cnc2c(c1)c(C(=O)N1CCN(C(=O)OC(C)(C)C)CC1)c(Oc1cc(F)ccc1C)n2-c1ccccc1

Procedure:
The title compound was prepared from the compound of step 5 (100 mg, 212 μmol) and 5-fluoro-2-methylphenol analogously as described in example 1, step 6. Yield: 99.0 mg.
Reaction SMILES: C[O:2][C:3](=[O:21])[C@H:4]([N:10]1C(=O)C2C(=CC=CC=2)C1=O)[C@H:5]([CH3:9])[CH2:6][CH:7]=[CH2:8]>Cl.C(O)(=O)C>[NH2:10][C@H:4]([C@H:5]([CH3:9])[CH2:6][CH:7]=[CH2:8])[C:3]([OH:21])=[O:2]
Reactant: C=CC[C@@H](C)[C@H](C(=O)OC)N1C(=O)c2ccccc2C1=O
Agent: Cl
Solvent: CC(=O)O
Product: C=CC[C@@H](C)[C@@H](N)C(=O)O
Temperature: 25 °C
Yield: 50 %

Procedure:
(2R,3R)-2-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-3-methyl-hex-5-enoic acid methyl ester (2.01 g, 7.00 mmol) is dissolved in a 2:1 mixture of 6 N hydrochloric acid and glacial acetic acid (62.5 mL), and the solution is heated at reflux for 4 h. The solution is cooled to room temperature and concentrated under reduced pressure. The product is taken up in water and the solution is filtered. The filtrate is concentrated under reduced pressure and the residue is dissolved in water, then the solution is applied to a column of Amberlite™ IR 120 cation exchange resin (NH4+ form.). The column is washed with water (2.5 L), then eluted with aqueous ammonia solution (2.5 L). The eluate is boiled until no ammonia can be detected, then concentrated under reduced pressure affording the title compound (0.5 g, 3.50 mmol).
Reaction SMILES: [C:1]([CH:6]1[C:11](=[O:12])[CH2:10][CH:9]([CH:13]2[CH2:19][CH2:18][O:17][CH:16]([CH:20]([CH3:22])[CH3:21])[O:15][CH2:14]2)[CH2:8][C:7]1=[O:23])(=O)[CH2:2][CH2:3][CH3:4].[Cl-].[CH2:25]([O:27][NH3+:28])[CH3:26].C(=O)(O)[O-].[Na+]>CO>[CH2:25]([O:27][NH:28][C:1](=[C:6]1[C:11](=[O:12])[CH2:10][CH:9]([CH:13]2[CH2:19][CH2:18][O:17][CH:16]([CH:20]([CH3:22])[CH3:21])[O:15][CH2:14]2)[CH2:8][C:7]1=[O:23])[CH2:2][CH2:3][CH3:4])[CH3:26]
Reactant: CCO[NH3+]
Reactant: CCCC(=O)C1C(=O)CC(C2CCOC(C(C)C)OC2)CC1=O
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Product: CCCC(NOCC)=C1C(=O)CC(C2CCOC(C(C)C)OC2)CC1=O

Procedure:
6.5 parts by weight of 2-butyryl-5-(2-isopropyl-1,3-dioxepan-5-yl)-cyclohexane-1,3-dione, 2.1 parts by weight of ethoxyammonium chloride and 1.8 parts by weight of sodium bicarbonate in 80 parts by volume of methanol are stirred for 16 hours at room temperature. The solvent is distilled off under reduced pressure, the residue is stirred with 50 parts by volume of water and 50 parts by volume of dichloromethane, the organic phase is separated off, the aqueous phase is extracted once with 50 parts by volume of dichloromethane, the combined organic phases are dried over sodium sulfate, and the solvent is distilled off under reduced pressure. 6.2 parts by weight of 2-(1-ethoxyamino-n-butylidene)-5-(2-isopropyl1,3-dioxepan-5-yl)-cyclohexane-1,3-dione are obtained as an oil (active ingredient No. 1).
Reaction SMILES: O.[C:2]([O:6][C:7]([NH:9][C@H:10]([C:15]([OH:17])=O)[CH2:11][CH:12]([CH3:14])[CH3:13])=[O:8])([CH3:5])([CH3:4])[CH3:3].ON1C(=O)CCC1=O.C1(N=C=NC2CCCCC2)CCCCC1.[C:41]1([CH:47]([C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=2)[N:48]2[CH2:53][CH2:52][NH:51][CH2:50][CH2:49]2)[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>C(Cl)Cl>[C:54]1([CH:47]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[N:48]2[CH2:49][CH2:50][N:51]([C:15]([C@@H:10]([NH:9][C:7](=[O:8])[O:6][C:2]([CH3:3])([CH3:4])[CH3:5])[CH2:11][CH:12]([CH3:13])[CH3:14])=[O:17])[CH2:52][CH2:53]2)[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=1
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C1CCC(=O)N1O
Solvent: ClCCl
Solvent: O
Product: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCN(C(c2ccccc2)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 88.7 %

Procedure:
To a methylene chloride solution (100 ml) containing tert-butoxycarbonyl-L-leucine monohydrate (9.96 g) and N-hydroxy succinimide (4.6 g) was added dropwise a methylene chloride solution (50 ml) of N,N'-dicyclohexylcarbodiimide (8.24 g) with a length of time for 1 hour under cooling with ice. After being stirred at room temperature for 4 hours, the reaction mixture was again cooled with ice, and a methylene chloride solution (50 ml) of 1-(diphenylmethyl)piperazine (10.08 g) was added dropwise in 20 minutes. The mixture was stirred overnight at room temperature. Following the removal of the precipitate by filtration, the solvent was removed by distillation under reduced pressure, and ethyl acetate was added. After any insoluble matters were again removed by filtration, the filtrate was washed first with an aqueous sodium bicarbonate solution and then with a saturated sodium chloride solution, dried over magnesium sulfate and distilled under reduced pressure to remove the solvent, whereupon a crude reaction mixture was obtained. This reaction mixture was purified by silica gel column chromatography (developing solvent: chloroform followed by chloroform:methanol=50:1) to yield 16.5 g of tert-butyl (s)-1-(4-diphenylmethylpiperazine-1-yl carbonyl)-3-methylbutylcarbamate as a colorless amorphous substance (yield: 89%).
Reaction SMILES: [C:1]([C:14]1[CH:25]=[CH:24][C:17]([CH:18]=[CH:19][C:20]([O:22]C)=[O:21])=[CH:16][CH:15]=1)#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].O.[OH-].[Li+].Cl>O1CCCC1.O>[C:1]([C:14]1[CH:15]=[CH:16][C:17]([CH:18]=[CH:19][C:20]([OH:22])=[O:21])=[CH:24][CH:25]=1)#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCCCCCCCCC#Cc1ccc(C=CC(=O)OC)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCCCCCCCCCCC#Cc1ccc(C=CC(=O)O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 4-(1-tridecynyl)cinnamate (680 mg, 2 mmole) in tetrahydrofuran (25 ml) was added a solution of lithium hydroxide monohydrate (0.84 g) in water (25 ml) and the mixture was stirred overnight at room temperature. The cloudy mixture was acidified with dilute hydrochloric acid and then extracted with ether. The ethereal extracts were washed with brine, dried (MgSO4) and evaporated to a white crystalline solid. Yield 0.650 g (100%). Recrystallisation from methanol afforded material of mp 156°-157° C., υmax mull, 2650 (broad), 1710, 1685, 1630 cm-1, δ(DMSO), 0.85 (3H, distorted t, terminal CH3), 1.25 (18H, m, alkylene chain), ca 2.43 (2H, m, C≡C--CH2), 6.50 (1H, d, J 15.8 Hz, =CHCO2), 7.51 (4H, ABq, J 8.4 Hz, Δν22.4 Hz, arom), 7.57 (1 H, d, J 15.8 Hz, ArCH=), 12.5 (1H, broad, exchangeable, CO2H).
Reaction SMILES: [CH3:1][NH:2][C:3]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH2:6][CH3:7])[CH2:4][OH:5].[Li]CCCC.[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH:27]=[C:28]([O:32][CH3:33])[C:29]=1[O:30][CH3:31])[C:24](Cl)=[O:25].C(O)(=O)C>C1COCC1>[CH3:7][CH2:6][C:3]([NH:2][CH3:1])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:4][O:5][C:24]([C:23]1[CH:27]=[C:28]([O:32][CH3:33])[C:29]([O:30][CH3:31])=[C:21]([O:20][CH3:19])[CH:22]=1)=[O:25]
Reactant: CCC(CO)(NC)c1ccccc1
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Agent: [Li]CCCC
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCC(COC(=O)c1cc(OC)c(OC)c(OC)c1)(NC)c1ccccc1
Reaction time: 0.25 h
Yield: 37.5 %

Procedure:
To a solution of 1.84 g of 8 (10.3 mmol) in 28 mL of anhydrous THF were added dropwise, at −78° C., 4.11 mL of n-BuLi (2.5 mol/L in hexanes). After 15 minutes, a solution of 2.31 g (10.01 mmol) of 3,4,5-trimethoxybenzoyl chloride in 15.8 mL of anhydrous THF was added. The reaction mixture was then allowed to warm to −30° C. (ca 1 h) and 19 mL of acetic acid were cautiously added. Solvents were removed under vacuum and 55 mL of diethyl ether and 55 mL of water were added to the previously obtained oil. After stirring until complete dissolution, the resulting mixture was then decanted and the aqueous layer alcalinized completely with solid Na2CO3 and re-extracted with diethyl ether. The organic layers were washed twice with a saturated aqueous solution of sodium carbonate and with brine and then dried over sodium sulphate. Diethyl ether was evaporated under vacuum and the ester 9 was purified by chromatography on silica gel column (ethyl acetate/n-hexane, 7:3) to give 1.4 g of pure N-desmethyltrimebutine 9 (49% yield) as a yellow pale oil. MS(ESI), m/e 374.1 (M+).
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]([CH:41]=[CH: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])[CH:41]=[CH: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)C=Cc1ccc(B(O)O)cc1
Reactant: O=C1CN(c2ccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(Br)cc3)cc2)S(=O)(=O)N1
Product: CCOC(=O)C=Cc1ccc(-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 (200 mg, 0.34 mmol) was treated as described in general procedure G using 4-(2-ethoxycarbonyl-vinyl)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)-acrylic acid ethyl ester.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:17][C:18](=O)[CH:19]([CH3:21])[CH3:20])[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=O)=[CH:4][CH:3]=1.Cl.[NH2:24][N:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:17]=[C:18]([CH:19]([CH3:21])[CH3:20])[N:24]([N:25]3[CH2:29][CH2:28][CH2:27][CH2:26]3)[C:9]=2[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:4][CH:3]=1
Reactant: CC(C)C(=O)CC(C(=O)c1ccccc1)c1ccc(F)cc1
Reactant: NN1CCCC1
Agent: Cl
Solvent: Cc1ccccc1
Product: CC(C)c1cc(-c2ccc(F)cc2)c(-c2ccccc2)n1N1CCCC1

Procedure:
20 g of molecular sieve 3 Å are added to 15 g (50 mmol) of the compound from Example 2 and 20 g (164 mmol) of N-aminopyrrolidine hydrochloride in 150 ml of toluene AR and the mixture is heated to reflux for 48 hours. The mixture is cooled, filtered and washed well with toluene. The toluene solutions are combined and extracted 3×using 1N hydrochloric acid. The organic phase is subsequently washed using saturated sodium hydrogen carbonate solution, dried over magnesium sulphate and concentrated in vacuo. The residue is stirred with a little ethanol, cooled and filtered off with suction. After drying in a desiccator, 2.3 g of substance are obtained.
Reaction SMILES: [CH3:1][Mg]Br.[O:4]1[CH2:8][CH2:7][O:6][CH:5]1[C:9]1[CH:14]=[C:13]([O:15][CH3:16])[N:12]=[CH:11][C:10]=1[O:17][CH2:18][C:19]1[C:20]([C:25](=[O:28])[CH2:26]C)=[N:21][CH:22]=[CH:23][CH:24]=1>C1COCC1>[O:6]1[CH2:7][CH2:8][O:4][CH:5]1[C:9]1[CH:14]=[C:13]([O:15][CH3:16])[N:12]=[CH:11][C:10]=1[O:17][CH2:18][C:19]1[C:20]([C:25]([OH:28])([CH3:1])[CH3:26])=[N:21][CH:22]=[CH:23][CH:24]=1
Reactant: C[Mg]Br
Reactant: CCC(=O)c1ncccc1COc1cnc(OC)cc1C1OCCO1
Solvent: C1CCOC1
Product: COc1cc(C2OCCO2)c(OCc2cccnc2C(C)(C)O)cn1
Temperature: 25 °C
Yield: 43.9 %

Procedure:
Methylmagnesium bromide (3M/ether, 0.25 mL, 0.75 mmol, 3.0 eq.) was added to a stirred solution of 1-(3-((4-(1,3-dioxolan-2-yl)-6-methoxypyridin-3-yloxy)methyl)pyridin-2-yl)propan-1-one (82 mg, 0.25 mmol, 1 eq.) in THF (5.0 mL) at −78° C. After addition, the reaction mixture was warm to rt and quenched with aqueous citric acid solution. The aqueous layer was extracted with EtOAc (20 mL) twice. The combined organic layers were washed with NaHCO3(sat) solution and brine, dried over Na2SO4, concentrated, and purified on silica gel using a mixture of EtOAc and hexanes as eluent to give 2-(3-((4-(1,3-dioxolan-2-yl)-6-methoxypyridin-3-yloxy)methyl)pyridin-2-yl)propan-2-ol (38 mg, 44%) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 8.43 (dd, J=7.7, 1.6 Hz, 1H), 7.84 (dd, J=7.7, 1.5 Hz, 1H), 7.74 (s, 1H), 7.18 (dd, J=7.7, 4.7 Hz, 1H), 6.84 (s, 1H), 6.01 (s, 1H), 5.27 (s, 2H), 4.07-3.88 (m, 4H), 3.82 (s, 3H), 1.55 (s, 6H). LRMS (M+H+) m/z 347.1.
Reaction SMILES: Br[C:2]1[N:6]=[C:5]([C:7]2[CH:8]=[CH:9][C:10]([O:15][CH:16]([CH3:18])[CH3:17])=[C:11]([CH:14]=2)[C:12]#[N:13])[S:4][N:3]=1.[CH2:19]([C:21]1[C:26](/[CH:27]=[CH:28]/[O:29][CH3:30])=[CH:25][CH:24]=[CH:23][C:22]=1B1OC(C)(C)C(C)(C)O1)[CH3:20].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C)C=O.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:19]([C:21]1[C:26](/[CH:27]=[CH:28]/[O:29][CH3:30])=[CH:25][CH:24]=[CH:23][C:22]=1[C:2]1[N:6]=[C:5]([C:7]2[CH:8]=[CH:9][C:10]([O:15][CH:16]([CH3:18])[CH3:17])=[C:11]([CH:14]=2)[C:12]#[N:13])[S:4][N:3]=1)[CH3:20]
Reactant: CC(C)Oc1ccc(-c2nc(Br)ns2)cc1C#N
Reactant: CCc1c(/C=C/OC)cccc1B1OC(C)(C)C(C)(C)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCc1c(/C=C/OC)cccc1-c1nsc(-c2ccc(OC(C)C)c(C#N)c2)n1
Temperature: 120 °C
Yield: 85 %

Procedure:
To a solution of 5-(3-bromo-1,2,4-thiadiazol-5-yl)-2-[(1-methylethyl)oxy]benzonitrile (D44) (630 mg), 2-{2-ethyl-3-[(E)-2-(methyloxy)ethenyl]phenyl}-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (560 mg) and tripotassium phosphate (1237 mg) in N,N-dimethylformamide (DMF) (5 mL) and water (1.25 mL) stirred under nitrogen was added Pd(Ph3P)4 (225 mg). The mixture was sealed and heated under microwave at 120° C. for 15 min. After cooling the reaction, the mixture was concentrated and purified by column chromatography to give 5-(3-{2-ethyl-3-[(E)-2-(methyloxy)ethenyl]phenyl}-1,2,4-thiadiazol-5-yl)-2-[(1-methylethyl)oxy]benzonitrile (D54) (670 mg) as a colorless oil. MS (ES): C23H23N3O2S requires 405. found 406.2 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([CH2:12][O:13][CH3:14])[CH:3]=1.S(=O)(=O)(O)O.[N+:20]([O-])([O-:22])=[O:21].[K+]>>[F:1][C:2]1[C:11]([N+:20]([O-:22])=[O:21])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([CH2:12][O:13][CH3:14])[CH:3]=1
Reactant: COCc1cc(F)ccc1C(=O)OC
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: COCc1cc(F)c([N+](=O)[O-])cc1C(=O)OC
Temperature: -10 °C
Reaction time: 4 h
Yield: 87.1 %

Procedure:
To a mixture of 1.75 g of methyl 4-fluoro-2-(methoxymethyl)benzoate and 8.7 mL of concentrated sulfuric acid was added 964 mg of potassium nitrate over 5 minutes under cooling at −10° C. After stirring at the same temperature for 4 hours and a half, the reaction mixture was added to 300 mL of ice water, followed by stirring. The solid was collected by filtration, washed with water, and dried under reduced pressure to obtain 1.87 g of methyl 4-fluoro-2-(methoxymethyl)-5-nitrobenzoate.