Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1](=[C:3]1[CH:12]=[CH:11][C:10]2[C:9]([S:13](Cl)(=[O:15])=[O:14])=[CH:8][CH:7]=[CH:6][C:5]=2[C:4]1=[O:17])=[N-:2].[K].[OH:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]=[N+:27]=[N-:28])=[CH:22][CH:21]=1.Cl>O1CCOCC1.O>[N+:1](=[C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[S:13]([O:19][C:20]2[CH:25]=[CH:24][C:23]([N:26]=[N+:27]=[N-:28])=[CH:22][CH:21]=2)(=[O:15])=[O:14])[C:4]1=[O:17])=[N-:2]
Reactant: [N-]=[N+]=C1C=Cc2c(cccc2S(=O)(=O)Cl)C1=O
Reactant: [N-]=[N+]=Nc1ccc(O)cc1
Agent: Cl
Agent: [K]
Solvent: C1COCCO1
Solvent: O
Product: [N-]=[N+]=Nc1ccc(OS(=O)(=O)c2cccc3c2C=CC(=[N+]=[N-])C3=O)cc1

Procedure:
1,2-Dihydro-2-diazo-1-oxo-naphthalene-5-sulfonyl chloride (2.2 grams) is dissolved in dioxane (16 mls.) and the potassium salt of 4-hydroxyphenylazide (1.6 grams) in a mixture of water (4 ml.) and dioxane (4 ml.) is added gradually over a period of 10 minutes with stirring. The mixture is then stirred at room temperature (22°C) for 30 minutes to complete the reaction and then diluted with water (60 ml.) containing 3N hydrochloric acid (8 ml.). An oil separates out which solidifies on standing. The product is then collected and dried (2.5 grams). It is dissolved in benzene treated with carbon and filtered. Addition of 60°-80° pet. ether to the filtrate yields Compound 1. (1.7 grams) m.p. 136°-7° with decomposition.
Reaction SMILES: C([O:3][C:4](=[O:33])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10]/[N:11]=[C:12]1\[CH:13]([N:28]2[CH:32]=[CH:31][N:30]=[CH:29]2)[CH:14]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]\1=2)C.C[O-].[Na+].C(O)(=O)C>CO.O.O>[C:22]1([CH:14]2[CH:13]([N:28]3[CH:32]=[CH:31][N:30]=[CH:29]3)/[C:12](=[N:11]\[O:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][C:4]([OH:33])=[O:3])/[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[O:15]2)[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CCOC(=O)CCCCCO/N=C1/c2ccccc2OC(c2ccccc2)C1n1ccnc1
Agent: C[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: CO
Product: O=C(O)CCCCCO/N=C1/c2ccccc2OC(c2ccccc2)C1n1ccnc1
Temperature: 25 °C
Reaction time: 28 h
Yield: 67.6 %

Procedure:
(+-)-(Z)-Ethyl-6-[[2-phenyl-3-(1H-imidazol-1-yl)-2,3-dihydro-4H-benzopyranylidene]aminoxy]hexanoate (300 mg; 0.67 mmoles) is dissolved in methanol-water (5:2; 7 ml), and to this solution sodium methylate (90 mg; 1.61 mmoles) is added portion-wise at 0° C. The resulting solution is stirred at r.t. for 28 hrs., then diluted with water, cooled at 0° C. and neutralized with acetic acid. The so formed precipitate is collected and recrystallized from ethyl acetate to give a white solid (190 mg), melting at 176°-178° C.
Reaction SMILES: [C:1]([CH2:3][C:4]1[S:5][CH:6]=[CH:7][C:8]=1[C:9]#[N:10])#[N:2].[BrH:11].[OH-].[Na+]>C(O)(=O)C>[NH2:2][C:1]1[N:10]=[C:9]([Br:11])[C:8]2[CH:7]=[CH:6][S:5][C:4]=2[CH:3]=1
Reactant: N#CCc1sccc1C#N
Reactant: Br
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: Nc1cc2sccc2c(Br)n1
Yield: 70 %

Procedure:
2-Cyanomethyl-3-cyanothiophene (823 mg) was added to a solution (30 ml) of 25% hydrogen bromide in acetic acid, and the resulting mixture was stirred under ice-cooling for 90 min, which was neutralized with a 8N aqueous solution of sodium hydroxide and then extracted with ethyl acetate. The organic layer was washed with water, dried (over MgSO4) and evaporated. The residue was purified by silica gel column chromatography (ethyl acetate/hexane system), to give the title compound as a yellow solid (894 mg, yield; 70%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12]([OH:14])=O)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.S(Cl)(Cl)=O.ClC1C(C(Cl)=O)=NC=C(C(F)(F)F)C=1.Cl.[CH3:34][O:35][NH2:36].C(=O)([O-])[O-].[K+].[K+]>>[CH3:34][O:35][N:36]=[C:12]([C:3]1[C:2]([Cl:1])=[CH:7][C:6]([C:8]([F:11])([F:10])[F:9])=[CH:5][N:4]=1)[OH:14]
Reactant: O=C(O)c1ncc(C(F)(F)F)cc1Cl
Reactant: CON
Agent: Cl
Agent: O=C(Cl)c1ncc(C(F)(F)F)cc1Cl
Agent: O=C([O-])[O-]
Solvent: O=S(Cl)Cl
Product: CON=C(O)c1ncc(C(F)(F)F)cc1Cl

Procedure:
For example, 3-chloro-5-trifluoromethylpyridine-2-carboxylic acid is reacted with thionyl chloride whereby 3-chloro-5-trifluoromethylpicolinoyl chloride can be obtained. This compound is reacted with O-methylhydroxyamine hydrochloride at room temperature for 4 hours in the presence of potassium carbonate to obtain N-methoxy-3-chloro-5-trifluoromethylpyridine-2-carboximidic acid which is then reacted with O,O-diethylthionophospholic acid diester chloride at 50° C. for 24 hours in the presence of potassium carbonate to thereby obtain O,O-diethyl-O-(N-methoxy-3-chloro-5-trifluoromethylpyridine-2-carboximidoyl)thionophosphate (nD16.0 = 1.5054).
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][N:5]=[CH:4]1.F[C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[O:17][CH2:18][CH:19]([CH3:21])[CH3:20])[C:12]#[N:13].O>CS(C)=O>[N:3]1([C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=2[O:17][CH2:18][CH:19]([CH3:21])[CH3:20])[C:12]#[N:13])[CH:7]=[CH:6][N:5]=[CH:4]1
Reactant: c1c[nH]cn1
Reactant: CC(C)COc1ccc(C#N)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)COc1ccc(C#N)cc1-n1ccnc1
Temperature: 110 °C

Procedure:
A reaction mixture solution prepared by suspending 41.1 mg of 3-fluoro-4-hydroxybenzonitrile, 33.4 mg of isobutyl bromide and 62.2 mg of potassium carbonate in 1 mL of dimethylformamide was heated at 110° C. for 5 hours under a nitrogen atmosphere. After the addition of water to the reaction mixture solution, extraction was performed using ethyl acetate. The organic layer was washed with saline, followed by drying and concentrating under reduced pressure to obtain a crude product of 3-fluoro-4-(2-methylpropoxy)benzonitrile. (2) A reaction mixture prepared by adding 15.7 mg of sodium hydride and 24.5 mg of imidazole to the crude product of 3-fluoro-4-(2-methylpropoxy)benzonitrile obtained above and suspending the above in 1 mL of dimethylsulfoxide was heated at 110° C. for 5 hours under a nitrogen atmosphere. After the addition of water to the reaction mixture solution, extraction was performed using ethyl acetate. The organic layer was washed with saline, followed by drying and concentrating under reduced pressure to obtain a crude product of 3-(1H-imidazol-1-yl)-4-(2-methylpropoxy)benzonitrile.
Reaction SMILES: [CH2:1]([O:7][C:8]1[CH:9]=[C:10]([CH:18]=[CH:19][CH:20]=1)[O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].C1COCC1.[CH3:26][NH2:27].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>O>[CH2:1]([O:7][C:8]1[CH:9]=[C:10]([CH:18]=[CH:19][CH:20]=1)[O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][NH:27][CH3:26])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CN
Reactant: CCCCCCOc1cccc(OCCCCC=O)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCCCCCOc1cccc(OCCCCCNC)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 22.3 %

Procedure:
5-(3-(hexyloxy)phenoxy)pentanal (72 mg, 0.26 mmol) in 1,2-C12C2H4 (5 mL) was treated with a THF solution of MeNH2 (2.0 M, 0.4 mL, 0.8 mmol). The reaction was stirred in a sealed vial for several min at rt before NaBH(OAc)3 (76 mg, 0.36 mmol) was added in one portion. Again the vial was sealed and stirred at rt for 3 d. The reaction was diluted with H2O and extracted into DCM. The organic extracts were concentrated and the resulting material was purified by preparative TLC on silica gel (5% MeOH:DCM) to afford the title compound as clear oil (17 mg, 23%). 1H NMR (400 MHz, CDCl3) δ ppm 7.15 (t, J=8.21 Hz, 1 H), 6.44-6.51 (m, 3 H), 3.90-3.98 (m, 4 H), 2.64 (t, J=7.07 Hz, 2 H), 2.46 (s, 3 H), 2.28 (br. s, 1 H), 1.72-1.85 (m, 4 H), 1.40-1.67 (m, 6 H), 1.29-1.40 (m, 4 H), 0.91 (t, J=6.57 Hz, 3 H). MS ESI [M+H]+, calcd for [C18H31NO2+H]+: 294.45 found m/z 294.2 (100).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:3]=1[C:4](=O)[CH2:5][N:6]1[CH:10]=[CH:9][N:8]=[CH:7]1.[NH2:17][CH2:18][CH2:19][CH2:20][OH:21].O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:3]=1[C:4](=[N:17][CH2:18][CH2:19][CH2:20][OH:21])[CH2:5][N:6]1[CH:10]=[CH:9][N:8]=[CH:7]1
Reactant: O=C(Cn1ccnc1)c1ccc(Cl)cc1Cl
Reactant: NCCCO
Solvent: O
Solvent: Cc1ccccc1
Product: OCCCN=C(Cn1ccnc1)c1ccc(Cl)cc1Cl
Yield: 95.6 %

Procedure:
153.2 g (0.60 mole) of N-(2,4-dichlorophenacyl)-imidazole and 53.0 g (0.705 mole) of 3-amino-1-propanol are suspended or dissolved in 400 ml of toluene, and the mixture is heated under reflux with a water trap until no more water of reaction separates out. The reaction solution is then washed 3 times with water, the organic phase is dried with sodium sulfate and, after the solvent has been evaporated off, 179 g of 1-(2-(2,4-dichlorophenyl)-2-(3-hydroxypropylimino)ethyl)-1H-imidazole are obtained as a highly viscous oil. (Yield: 95.6%). 1-(2-(2,4-Dichlorophenyl)-2-(3-hydroxypropylamino)ethyl)-1H-imidazole
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:6][CH:7]=1.[OH-].[K+].Br[CH:15]([C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=1)[C:16]([O:18][CH2:19][CH2:20][NH:21][C:22](=[O:24])[CH3:23])=[O:17].C(O)(C)C.[O-]C1C=CC=CC=1>C(O)(C)C>[Cl:31][C:28]1[CH:29]=[CH:30][C:25]([CH:15]([O:1][C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([F:9])([F:10])[F:11])[CH:3]=2)[C:16]([O:18][CH2:19][CH2:20][NH:21][C:22](=[O:24])[CH3:23])=[O:17])=[CH:26][CH:27]=1
Reactant: CC(=O)NCCOC(=O)C(Br)c1ccc(Cl)cc1
Reactant: Oc1cccc(C(F)(F)F)c1
Agent: [K+]
Agent: [O-]c1ccccc1
Agent: [OH-]
Solvent: CC(C)O
Product: CC(=O)NCCOC(=O)C(Oc1cccc(C(F)(F)F)c1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
3-Hydroxybenzotrifluoride was added to a solution of potassium hydroxide in isopropanol. N-acetylaminoethyl 2-bromo-2-(4-chlorophenyl)acetate in isopropanol was added to the isopropanol/phenoxide solution and stirred at room temperature for 4 hours. The isopropanol was removed by vacuum distillation, and the resulting slush was dissolved in ethyl acetate and washed twice with water and once with brine. After drying over magnesium sulfate and filtration, the solvent was removed to give crude product as an oil. The crude product was dissolved in hot toluene/hexanes (1:1 v/v) and cooled to between 0 and 10° C. to crystallize the product. The filter cake was washed with hexanes/toluene (1:1 v/v) and then dried under vacuum at 50° C. The isolated solid was dissolved in hot 1:6 (v/v) isopropanol in hexanes. After cooling, the pure racemic 2-Acetamidoethyl 4-Chlorophenyl-(3-trifluoro methylphenoxy)-acetate formed as a crystalline solid. The solid was collected by filtration, the filter cake washed with 1:6 (v/v) isopropanol in hexanes and dried under vacuum at 50° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([OH:16])=O)=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[C:21]1([C:27]2[CH:31]=[C:30]([NH2:32])[NH:29][N:28]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[Cl:20][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:32][C:30]2[NH:29][N:28]=[C:27]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:31]=2)=[O:16])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18]
Reactant: Nc1cc(-c2ccccc2)n[nH]1
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Product: O=C(Nc1cc(-c2ccccc2)n[nH]1)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1

Procedure:
Prepared according to the procedure described for example 44 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carboxylic acid (35 mg, 0.1 mmol) and 3-phenyl-1H-pyrazol-5-amine (16.0 mg, 0.12 mmol). The title compound was obtained as a solid (22.7 mg, 46.0% yield). MS m/z: 491.97, 493.97 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]2[NH:12][C:13](=[O:15])[NH:14][C:7]=12.[F:19][C:20]1[CH:21]=[C:22]([N:27]=[C:28]=[O:29])[CH:23]=[CH:24][C:25]=1[F:26]>>[F:19][C:20]1[CH:21]=[C:22]([NH:27][C:28]([NH:1][C:2]2[CH:18]=[CH:17][CH:16]=[C:4]([O:5][C:6]3[CH:11]=[CH:10][N:9]=[C:8]4[NH:12][C:13](=[O:15])[NH:14][C:7]=34)[CH:3]=2)=[O:29])[CH:23]=[CH:24][C:25]=1[F:26]
Reactant: Nc1cccc(Oc2ccnc3[nH]c(=O)[nH]c23)c1
Reactant: O=C=Nc1ccc(F)c(F)c1
Product: O=C(Nc1cccc(Oc2ccnc3[nH]c(=O)[nH]c23)c1)Nc1ccc(F)c(F)c1
Yield: 23 %

Procedure:
Method G was used with 7-(3-aminophenoxy)-1H-imidazo[4,5-b]pyridin-2(3H)-one and 3,4-difluoro-phenylisocyanate to afford the title compound (16 mg, 23%). 1H-NMR (DMSO), δ (ppm), J (Hz): 6.45 (d, 1H, HPyr, J=5.9), 6.76 (s, 1H, Harom2′, J=2.2, J=11.05), 7.26-7.40 (m, 5H, Harom 6′, Harom 2, Harom 4, Harom 5, Harom 6), 7.56-7.68 (m, 1H, Harom 5′), 7.78 (d, 1H, HPyr), 8.55 (d, 1H, Harom 4′, J=7.2), 9.00 (s, 1H, NHurea), 9.01 (s, 1H, NHurea), 11.17 (s, 1H, NHim), 11.36 (s, 1H, NHim); MS-LC, Rf=7.07 min, (C19H13F2N5O3), m/z: 398.1 [M++1], 100.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:14]3=[N:15][CH:16]=[C:17]([CH3:19])[CH:18]=[C:13]3[NH:12][C:11]=2[C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)=[CH:6][CH:5]=1.[CH3:26][O:27][CH2:28]Cl.[Cl-].[NH4+]>CN(C)C=O>[F:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[C:14]3=[N:15][CH:16]=[C:17]([CH3:19])[CH:18]=[C:13]3[N:12]([CH2:26][O:27][CH3:28])[C:11]=2[C:20]2[CH:21]=[CH:22][N:23]=[CH:24][CH:25]=2)=[CH:8][CH:9]=1
Reactant: Cc1cnc2c(-c3ccc(F)cc3)c(-c3ccncc3)[nH]c2c1
Reactant: COCCl
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: COCn1c(-c2ccncc2)c(-c2ccc(F)cc2)c2ncc(C)cc21
Reaction time: 0.5 h
Yield: 40.3 %

Procedure:
Sodium hydride (22 mg, 0.55 mmole 60% in oil) is added to a solution of 150 mg (0.5 mmole) of 3-(4-Fluoro-phenyl)-6-methyl-2-pyridin-4-yl-1H-pyrrolo[3,2-b]pyridine (prepared as described in example 1) in 5 mL of dimethylformamide at room temperature. After 30 min. at room temperature, a solution of 44.5 mg of chloromethyl methyl ether in 0.5 mL of DMF is added to the reaction mixture. After 45 min. at room temperature, the reaction mixture is poured into ammonium chloride solution and extracted with ethyl acetate. The organic phase is washed with water and dried over magnesium sulfate. The solid residue after concentration is recrystallized into ethyl acetate/hexane mixture (1/2) to afford 70 mg of pure 3-(4-Fluoro-phenyl)-1-methoxymethyl-6-methyl-2-pyridin-4-yl-1H-pyrrolo[3,2-b]pyridine as a yellowish solid.
Reaction SMILES: C([O:3][C:4]([C@@H:6]1[C@@H:8]([C:9](=[O:34])[NH:10][C@@H:11]([CH2:28][C:29]2[N:30]=[CH:31][S:32][CH:33]=2)[C:12]([NH:14][CH2:15][C:16]2[N:17]=[N:18][N:19]([C:21]3[CH:26]=[CH:25][C:24]([Br:27])=[CH:23][CH:22]=3)[CH:20]=2)=[O:13])[O:7]1)=[O:5])C.[Li+].[OH-]>>[Br:27][C:24]1[CH:23]=[CH:22][C:21]([N:19]2[CH:20]=[C:16]([CH2:15][NH:14][C:12](=[O:13])[C@@H:11]([NH:10][C:9]([C@H:8]3[O:7][C@@H:6]3[C:4]([OH:5])=[O:3])=[O:34])[CH2:28][C:29]3[N:30]=[CH:31][S:32][CH:33]=3)[N:17]=[N:18]2)=[CH:26][CH:25]=1
Reactant: CCOC(=O)[C@H]1O[C@@H]1C(=O)N[C@@H](Cc1cscn1)C(=O)NCc1cn(-c2ccc(Br)cc2)nn1
Agent: [Li+]
Agent: [OH-]
Product: O=C(NCc1cn(-c2ccc(Br)cc2)nn1)[C@H](Cc1cscn1)NC(=O)[C@H]1O[C@@H]1C(=O)O
Yield: 86.3 %

Procedure:
Followed general procedure using: the corresponding peptidomimetic epoxide ethyl ester 44 (25 mg, 0.04 mmol); LiOH (1.1 mg, 0.04 mmol); after extraction afforded the desired product as a white solid (18 mg, 75.9%). 1H NMR (DMSO-d6, 400 MHz): δ 8.99-8.98 (d, 1H, J=1.87 Hz); 8.74-8.71 (t, 1H); 8.58-8.56 (d, 1H, J=8.27 Hz); 8.54 (s, 1H); 7.86-7.79 (q, 4H); 7.34-7.33 (d, 1H, J=1.75 Hz); 4.70-4.65 (q, 1H); 4.40-4.38 (d, 2H, J=5.59 Hz); 3.60-3.59 (d, 1H, J=1.77 Hz); 3.38-3.37 (d, 1H, J=1.77 Hz); 3.28-3.10 (m, 2H). 13C NMR (DMSO-d6, 100 MHz): 170.62, 169.08, 165.74, 154.06, 153.29, 146.57, 136.25, 133.27, 122.31, 121.67, 121.54, 116.20, 53, 25, 52.94, 51.89, 34.76, 33.49. HRMS-ESI: m/z [M+H+] calculated for C19H17BrN6O5S: 521.34, observed: m/z 523.0229 (M+H+); m/z 519.0123 (M−H+); HPLC Method 2: Rt=21.8 min; 97.2%.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([CH2:24][OH:25])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:26]([F:29])([F:28])[F:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:30][C:31]1[C:36]([C:37]([F:40])([F:39])[F:38])=[CH:35][CH:34]=[CH:33][C:32]=1O>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][O:25][C:32]3[CH:33]=[CH:34][CH:35]=[C:36]([C:37]([F:40])([F:39])[F:38])[C:31]=3[Cl:30])[CH:19]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:26]([F:29])([F:27])[F:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Reactant: Oc1cccc(C(F)(F)F)c1Cl
Product: FC(F)(F)c1cccc(OCc2cccc(-c3c(Cc4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)c1Cl

Procedure:
The title compound was prepared from {3-[3-benzyl-8-(trifluoromethyl)quinolin-4-yl]phenyl}methanol and 2-chloro-3-trifluoromethylphenol according to the procedure of Example 69. MS (ESI) m/z 572.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[C:5]([CH:6]=[O:7])=[C:4]([F:12])[CH:3]=1.Cl([O-])=[O:14].[Na+].O.O.P(O)(O)([O-])=O.[Na+].CC(=CC)C>C(O)(C)(C)C.O>[Br:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[C:5]([C:6]([OH:14])=[O:7])=[C:4]([F:12])[CH:3]=1
Reactant: COc1cc(Br)cc(F)c1C=O
Reactant: [O-][Cl+][O-]
Agent: CC=C(C)C
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: O
Product: COc1cc(Br)cc(F)c1C(=O)O
Reaction time: 2 h
Yield: 68.5 %

Procedure:
To a solution of 4-bromo-2-fluoro-6-methoxy-benzaldehyde (3.4 g, 14.6 mmol) in tert-butanol (70 ml) and water (35 ml), sodium chlorite (2.64 g, 29.2 mmol), monosodium phosphate dihydrate (11.4 g, 72.9 mmol) and 2-methyl-2-butene (12.4 ml, 116.7 mmol) are added successively at room temperature and the mixture is stirred for 2 h. After completion of the reaction (monitored by TLC), the mixture is concentrated under reduced pressure and the residue is diluted with ice water (50 ml) and acidified to pH 5 by adding 2N hydrochloric acid. The mixture is extracted with methyl tert-butyl ether (2×100 ml). The methyl tert-butyl ether layer is extracted again with 10% aqueous sodium hydroxide (100 ml). The aqueous layer is acidified to pH 2 with 5N hydrochloric acid and extracted with dichloromethane (2×50 ml). The organic layer is washed with brine (50 ml), dried over sodium sulfate and evaporated to dryness to obtain 4-bromo-2-fluoro-6-methoxy-benzoic acid (2.5 g, 10.0 mmol, 68%).
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[CH2:11]([N:17]1[C:21]([CH2:22][OH:23])=[CH:20][N:19]=[CH:18]1)[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].C(N(CC)CC)C>ClCCl>[CH2:11]([N:17]1[C:21]([CH:22]=[O:23])=[CH:20][N:19]=[CH:18]1)[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCn1cncc1CO
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CCCCCCn1cncc1C=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 90.3 %

Procedure:
A solution of dimethyl sulphoxide (0.49 ml, 7.74 mmol) in dichloromethane (2.5 ml) was added dropwise to a solution of oxalyl chloride (0.3 ml, 3.78 mmol) in dichloromethane (15 ml) at -78° C. with stirring under argon. After effervescence had ceased (15 min), a solution of the product of step (ii) (313 mg, 1.72 mmol) in dichloromethane (7.5 ml) was added dropwise. The solution was stirred for 15 minutes before triethylamine (2.3 ml, 19 mmol) was added slowly. After a further 15 minutes the solution was allowed to warm to room temperature, stirred for 30 minutes and then quenched by the addition of a saturated aqueous solution of sodium bicarbonate (10 ml). The mixture was extracted with ethyl acetate (3×10 ml). The extracts were washed with brine (1×10 ml), dried (MgSO4) and concentrated. The residue was purified by column chromatography, eluting with 10% methanol/dichloromethane (v/v), to give 1-hexyl-imidazole-5-carboxaldehyde (280mg, 90% yield) as an oil;
Reaction SMILES: [Br:1][C:2]1[C:7]([Cl:8])=[C:6]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH3:17])=[CH:12][CH:11]=2)[CH:5]=[C:4]([CH:18]2[C@H:23]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C@@H:22]([O:32][CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C@H:21]([O:40][CH2:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[C@@H:20]([CH2:48][O:49][CH2:50][C:51]3[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=3)[O:19]2)[C:3]=1[OH:57].C([O-])([O-])=O.[K+].[K+].Br[CH2:65][CH2:66][OH:67]>CC(C)=O>[Br:1][C:2]1[C:7]([Cl:8])=[C:6]([CH2:9][C:10]2[CH:11]=[CH:12][C:13]([CH2:16][CH3:17])=[CH:14][CH:15]=2)[CH:5]=[C:4]([CH:18]2[C@H:23]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C@@H:22]([O:32][CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C@H:21]([O:40][CH2:41][C:42]3[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=3)[C@@H:20]([CH2:48][O:49][CH2:50][C:51]3[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=3)[O:19]2)[C:3]=1[O:57][CH2:65][CH2:66][OH:67]
Reactant: CCc1ccc(Cc2cc(C3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)c(O)c(Br)c2Cl)cc1
Reactant: OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCc1ccc(Cc2cc(C3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)c(OCCO)c(Br)c2Cl)cc1
Temperature: 50 °C
Reaction time: 15 h

Procedure:
To a mixture of the intermediate 32 (2.99 g, 3.53 mmol) and K2CO3 (0.73 g, 5.29 mmol) in acetone (35 mL) was added 2-bromoethanol (0.38 mL, 5.29 mmol) at rt. After stirring for 15 h at 50° C., the reaction mixture was cooled to rt. The precipitate was removed by filtration and the filtrate was concentrated in vacuo. The residue was dissolved in EtOAc (100 mL), washed with brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo to provide the crude intermediate 33, which was used without further purification (3.04 g, 3.41 mmol, 97%).
Reaction SMILES: [C:1]([Cl:4])(Cl)=[O:2].[C:5]1([CH2:11][CH2:12][CH2:13][CH:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.N1C=CC=CC=1>C1(C)C=CC=CC=1>[C:5]1([CH2:11][CH2:12][CH2:13][CH:14]2[CH2:15][CH2:16][N:17]([C:1]([Cl:4])=[O:2])[CH2:18][CH2:19]2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: c1ccc(CCCC2CCNCC2)cc1
Reactant: O=C(Cl)Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: O=C(Cl)N1CCC(CCCc2ccccc2)CC1
Reaction time: 1 h

Procedure:
Phosgene is passed into 150 ml. of dry toluene at 0° C. until 17 g. of gas has been absorbed. The cooling bath is removed, and to the phosgene solution is added, dropwise, with stirring, during 1 hour, a solution prepared from 27.6 g. of 4-(3-phenylpropyl)piperidine, and 12.3 ml. of pyridine and 100 ml. of toluene. After the end of the addition, the reaction mixture is stored at ambient temperature for 16 hours. At this point, the reaction mixture is filtered, and the filtrate is evaporated in vacuo, leaving 39 g. of the title compound in crude state. The product is contaminated with toluene, but it is sufficiently pure for coupling with alkenesulfonamides.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH3:10])[C:4]=1[C:11]1[N:16]=[C:15]([CH3:17])[C:14]([CH2:18]O)=[C:13]([O:20][CH2:21][CH3:22])[CH:12]=1)[CH3:2].O=S(Cl)[Cl:25]>C(Cl)Cl>[Cl:25][CH2:18][C:14]1[C:15]([CH3:17])=[N:16][C:11]([C:4]2[C:3]([CH2:1][CH3:2])=[CH:8][CH:7]=[CH:6][C:5]=2[CH2:9][CH3:10])=[CH:12][C:13]=1[O:20][CH2:21][CH3:22]
Reactant: O=S(Cl)Cl
Reactant: CCOc1cc(-c2c(CC)cccc2CC)nc(C)c1CO
Solvent: ClCCl
Product: CCOc1cc(-c2c(CC)cccc2CC)nc(C)c1CCl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of [6-(2,6-diethyl-phenyl)-4-ethoxy-2-methyl-pyridin-3-yl]-methanol (1.8 g) and SOCl2 (2 mL) in CH2Cl2 (10 mL) is stirred at room temperature for one hour. The volatile materials are removed in vacuo to give 3-chloromethyl-6-(2,6-diethyl-phenyl)-4-ethoxy-2-methyl-pyridine.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[NH2:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][OH:24])=[CH:18][CH:17]=1>>[Cl:8][C:6]1[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]([N+:12]([O-:14])=[O:13])=[C:2]([CH:7]=1)[NH:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][OH:24])=[CH:18][CH:17]=1
Reactant: Nc1ccc(CCO)cc1
Reactant: O=[N+]([O-])c1cc([N+](=O)[O-])c(Cl)cc1Cl
Product: O=[N+]([O-])c1cc([N+](=O)[O-])c(Nc2ccc(CCO)cc2)cc1Cl

Procedure:
The title compound was prepared according to the procedure described in step 3 of Example 1 from 2,4-dichloro-1,5-dinitrobenzene and 4-aminophenylethyl alcohol.