Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:4]([O:12][Si:13]([CH3:16])([CH3:15])[CH3:14])([CH2:8][CH2:9][CH2:10][CH3:11])[CH2:5][C:6]#[CH:7])=[C:2]=[CH2:3].CC(C)C(BC(C(C)C)C)C.C([N+]([O-])(CC)CC)C.[I:36]I>O1CCCC1.C(COC)OC>[I:36]/[CH:3]=[CH:2]/[CH2:1][C:4]([CH:5]=[C:6]=[CH2:7])([O:12][Si:13]([CH3:16])([CH3:15])[CH3:14])[CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: C#CCC(C=C=C)(CCCC)O[Si](C)(C)C
Reactant: II
Agent: CC(C)C(C)BC(C)C(C)C
Agent: CC[N+]([O-])(CC)CC
Solvent: C1CCOC1
Solvent: COCCOC
Product: C=C=CC(C/C=C/I)(CCCC)O[Si](C)(C)C
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a stirred solution of 2.36 g. (10 mmol.) of 4-propadienyl-4-trimethylsilyloxy-1-octyne in 5 ml. of glyme is added to a solution of 11 mmol. of bis-(3-methyl-2-butyl)borane in 15 ml. of glyme at 0° C. The mixture is stirred at 25° C. for 90 minutes, cooled to 0° C., and treated portionwise with 3.0 g. of triethylamine oxide. The stirred mixture is maintained at 25°-30° C. for 45 minutes, diluted with 20 ml. of tetrahydrofuran and poured into 100 ml. of ice-cold 15% sodium hydroxide solution, followed immediately with a solution of 8.0 g. of iodine in 20 ml. of tetrahydrofuran. The mixture is stirred at ambient temperature for 30 minutes and then extracted with ether. The extract is washed successively with water, sodium thiosulfate solution and brine; dried over magnesium sulfate; and filtered. The residue obtained after solvent evaporation is subjected to chromatography on silica gel with heptane solvent to afford the title compound as a liquid.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[P:7](Cl)([O:12][CH2:13][CH3:14])([O:9][CH2:10][CH3:11])=[S:8].[C:16]([C:18]1[S:19][C:20]([O:24][CH2:25][CH2:26][CH2:27][CH3:28])=[CH:21][C:22]=1[OH:23])#[N:17]>C(#N)C>[C:16]([C:18]1[S:19][C:20]([O:24][CH2:25][CH2:26][CH2:27][CH3:28])=[CH:21][C:22]=1[O:23][P:7]([O:12][CH2:13][CH3:14])([O:9][CH2:10][CH3:11])=[S:8])#[N:17]
Reactant: CCCCOc1cc(O)c(C#N)s1
Reactant: CCOP(=S)(Cl)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCCOc1cc(OP(=S)(OCC)OCC)c(C#N)s1
Temperature: 20 °C
Reaction time: 24 h
Yield: 80.6 %

Procedure:
7 g of potassium carbonate and 9.4 g of O,O-diethyl chlorothiophosphate were added to a solution of 9.8 g of 2-cyano-3-hydroxy-5-n-butoxy-thiophene in 150 ml of acetonitrile and the mixture was stirred for 24 hours at 20° C. and was filtered. The filtrate was evaporated to dryness under reduced pressure and the residue was chromatographed over silica gel. Elution with benzene yielded 14 g of 2-cyano-3-(diethoxythiophosphoryloxy)-5-n-butoxy-thiophene with a refractive index of nD20 =1.525.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:13]3[CH:18]=[CH:17][C:16]([N+:19]([O-])=[O:20])=[CH:15][CH:14]=3)[O:12][CH2:11][CH2:10][O:9]2)=[CH:4][CH:3]=1.[C:22]1([CH2:28]C#N)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[OH-].[Na+]>CO.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:13]3[CH:18]=[CH:17][C:16]4[C:15]([CH:14]=3)=[C:28]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[O:20][N:19]=4)[O:9][CH2:10][CH2:11][O:12]2)=[CH:6][CH:7]=1
Reactant: N#CCc1ccccc1
Reactant: O=[N+]([O-])c1ccc(C2(c3ccc(Cl)cc3)OCCO2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Clc1ccc(C2(c3ccc4noc(-c5ccccc5)c4c3)OCCO2)cc1
Yield: 16.3 %

Procedure:
2-(4-chlorophenyl)-2-(4-nitrophenyl)-1,3-dioxolane (prepared as described in WO 97/21701) (0.0373 mol) was added to a vigorously stirring mixture of benzene acetonitrile (0.041 mol) and NaOH (0.186 mol) in methanol (37.3 ml) (an exothermic effect was observed and the temperature rose to 45° C.) and the mixture was stirred vigorously for 20 h. The mixture was diluted with water and filtered off. The precipitate was washed with water and a few methanol and dried. A part (3.5 g) of the residue (10.59 g, 75%) was purified by column chromatography over silica gel (eluent: DCM). The pure fractions were collected and evaporated. The residue (2.94 g) was crystallized from DIPE, yielding 2.3 g of 5-[2-(4-chlorophenyl)-1,3-dioxolan-2-yl]-3-phenyl-2,1-benzisoxazole, mp. 143.4° C. (intermediate 23).
Reaction SMILES: Cl[C:2]1[C:7]([C:8](=O)[CH2:9][CH3:10])=[CH:6][CH:5]=[CH:4][N:3]=1.Cl.[CH2:13]([O:20][C:21]1[CH:26]=[CH:25][C:24]([NH:27][NH2:28])=[CH:23][CH:22]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(O)C>[CH2:13]([O:20][C:21]1[CH:22]=[CH:23][C:24]([N:27]2[C:2]3=[N:3][CH:4]=[CH:5][CH:6]=[C:7]3[C:8]([CH2:9][CH3:10])=[N:28]2)=[CH:25][CH:26]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: NNc1ccc(OCc2ccccc2)cc1
Reactant: CCC(=O)c1cccnc1Cl
Agent: Cl
Solvent: CCO
Product: CCc1nn(-c2ccc(OCc3ccccc3)cc2)c2ncccc12
Temperature: 170 °C
Reaction time: 3 h
Yield: 25.7 %

Procedure:
1-(2-Chloropyridin-3-yl)propan-1-one (600 mg) and [4-(benzyloxy)phenyl]hydrazine hydrochloride (976 mg) were dissolved in ethanol (10 ml), and the mixture was stirred under microwave irradiation at 170° C. for 3 hr, and concentrated. The residue was purified by basic silica gel column chromatography (hexane/ethyl acetate) to give the title compound (300 mg). MS (API+): [M+H]+ 330.1.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][C:9]=2[C:17]2[CH:18]=[C:19]([CH:24]=[CH:25][CH:26]=2)[C:20]([O:22][CH3:23])=[O:21])[CH:5]=[CH:4][N:3]=1.[F:27][C:28]1[C:29]([CH2:37][CH2:38][N:39]2[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]2)=[CH:30][C:31]([O:35][CH3:36])=[C:32]([CH:34]=1)[NH2:33].C1(C)C=CC(S(O)(=O)=O)=CC=1.CC(O)C>C(Cl)Cl>[F:27][C:28]1[C:29]([CH2:37][CH2:38][N:39]2[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]2)=[CH:30][C:31]([O:35][CH3:36])=[C:32]([NH:33][C:2]2[N:7]=[C:6]([C:8]3[N:12]4[CH:13]=[CH:14][CH:15]=[CH:16][C:11]4=[N:10][C:9]=3[C:17]3[CH:18]=[C:19]([CH:24]=[CH:25][CH:26]=3)[C:20]([O:22][CH3:23])=[O:21])[CH:5]=[CH:4][N:3]=2)[CH:34]=1
Reactant: COc1cc(CCN2CCCCC2)c(F)cc1N
Reactant: COC(=O)c1cccc(-c2nc3ccccn3c2-c2ccnc(Cl)n2)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: CC(C)O
Product: COC(=O)c1cccc(-c2nc3ccccn3c2-c2ccnc(Nc3cc(F)c(CCN4CCCCC4)cc3OC)n2)c1
Temperature: 180 °C
Yield: 51.4 %

Procedure:
Methyl 3-[3-(2-chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]benzoate (Intermediate Example 3) (300 mg, 0.82 mmol), 5-fluoro-2-(methyloxy)-4-[2-(1-piperidinyl)ethyl]aniline (Example 127, step D) (187 mg, 0.74 mmol), and p-toluenesulfonic acid (375 mg, 1.97 mmol) were weighed into a 10 mL microwave vial. 7 mL of iPrOH was added and the mixture was heated in the microwave to 180° C. for 17 min. The mixture was transferred to a 50 mL round bottom and diluted with 10 mL of DCM. 2 g of silica gel was added. The solvent was rotovaped down and the residue purified by flash chromatography to give the title compound of step A (220 mg, 0.38 mmol, 46%). 1H NMR (400 MHz, CDCl3) δ ppm 9.51 (d, J=6.97 Hz, 1H), 8.37-8.39 (m, 1H), 8.23-8.30 (m, 2H), 8.08-8.11 (m, 1H), 7.84-7.87 (m, 1H), 7.79 (s, 1H), 7.74 (d, J=8.80 Hz, 1H), 7.50 (t, J=7.70 Hz, 1H), 7.35-7.41 (m, 1H), 6.95 (t, J=6.97 Hz, 1H), 6.76 (d, J=6.97 Hz, 1H), 6.60 (d, J=5.50 Hz, 1H), 3.91 (s, 3H), 3.90 (s, 3H), 2.79-2.86 (m, 2H), 2.54-2.60 (m, 2H), 2.46-2.54 (m, 4H), 1.60-1.66 (m, J=5.68, 5.68, 5.68, 5.68 Hz, 4H), 1.43-1.50 (m, J=5.13 Hz, 2H).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][C:7]1[S:8][C:9]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:11]=1.N1C=CC=CC=1>ClCCl>[CH3:1][S:2]([NH:6][C:7]1[S:8][C:9]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:11]=1)(=[O:4])=[O:3]
Reactant: Nc1nc(-c2ccccc2)c(-c2ccccc2)s1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1nc(-c2ccccc2)c(-c2ccccc2)s1
Temperature: 25 °C
Yield: 24.4 %

Procedure:
2.5 g of methanesulfonyl chloride was dropped into a solution of 5.0 g of 2-amino-4,5-diphenylthiazole and 3.3 ml of pyridine in dichloromethane under stirring at room temperature, and the resulting mixture was stirred as such overnight. Then the reaction mixture was successively washed with diluted hydrochloric acid, a saturated aqueous solution of sodium hydrogencarbonate and water in this order and dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, the reaction product was separated with a silica gel column by using isopropyl ether and ethyl acetate as a developer. The crystals thus obtained were recovered by filtration from isopropyl ether and washed with diethyl ether to give 1.6 g of 2-methanesulfonylamino-4,5-diphenylthiazole. The melting point of this product was from 225° to 227° C.
Reaction SMILES: O1CCOCC1.[ClH:7].[O:8]=[C:9]1[NH:13][C:12](=[O:14])[O:11][N:10]1[CH2:15][C:16]1[CH:49]=[CH:48][C:19]([O:20][CH2:21][C:22]2[C:23]([CH3:47])=[C:24]([C:28]3[CH:33]=[CH:32][C:31]([O:34][CH2:35][CH2:36][CH2:37][NH:38]C(=O)OC(C)(C)C)=[CH:30][C:29]=3[CH3:46])[CH:25]=[CH:26][CH:27]=2)=[CH:18][CH:17]=1>C(OCC)(=O)C>[ClH:7].[NH2:38][CH2:37][CH2:36][CH2:35][O:34][C:31]1[CH:32]=[CH:33][C:28]([C:24]2[CH:25]=[CH:26][CH:27]=[C:22]([CH2:21][O:20][C:19]3[CH:48]=[CH:49][C:16]([CH2:15][N:10]4[C:9](=[O:8])[NH:13][C:12](=[O:14])[O:11]4)=[CH:17][CH:18]=3)[C:23]=2[CH3:47])=[C:29]([CH3:46])[CH:30]=1
Reactant: Cc1cc(OCCCNC(=O)OC(C)(C)C)ccc1-c1cccc(COc2ccc(Cn3oc(=O)[nH]c3=O)cc2)c1C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Cc1cc(OCCCN)ccc1-c1cccc(COc2ccc(Cn3oc(=O)[nH]c3=O)cc2)c1C
Temperature: 0 °C

Procedure:
Under ice-cooling, a 4 M hydrogen chloride dioxane solution (15 ml) was added dropwise to a mixture of tert-butyl (3-{[3′-({4-[(3,5-dioxo-1,2,4-oxadiazolidin-2-yl)methyl]phenoxy}methyl)-2,2′-dimethylbiphenyl-4-yl]oxy}propyl)carbamate (1.95 g) and ethyl acetate (5 ml), followed by stirring at 0° C. for a while and then stirring at room temperature for 1.5 hours. The solvent was evaporated under a reduced pressure, and the solid precipitated was collected by filtration and dried by heating under a reduced pressure to obtain 2-(4-{[4′-(3-aminopropoxy)-2,2′-dimethylbiphenyl-3-yl]methoxy}benzyl)-1,2,4-oxadiazolidine-3,5-dione hydrochloride (1.53 g) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1Br.[Cl:10][C:11]1[CH:18]=[CH:17][C:14]([CH:15]=[O:16])=[C:13]([F:19])[CH:12]=1.ClC1C=CC(C(C2C=CC(OC)=CC=2)O)=CC=1>>[Cl:10][C:11]1[CH:18]=[CH:17][C:14]([CH:15]([C:3]2[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[F:1])[OH:16])=[C:13]([F:19])[CH:12]=1
Reactant: O=Cc1ccc(Cl)cc1F
Reactant: Fc1ccc(Br)c(F)c1
Agent: COc1ccc(C(O)c2ccc(Cl)cc2)cc1
Product: OC(c1ccc(F)cc1F)c1ccc(Cl)cc1F

Procedure:
The title compound was prepared starting from 5.00 g (25.91 mmol) of 2,4-difluorobromobenzene and 4.93 g (31.09 mmol) of 4-chloro-2-fluorobenzaldehyde in analogy to the synthesis of the compound from Example 175A. 3.34 g (47% of theory) of the title compound were obtained.
Reaction SMILES: Cl.[NH2:2][C:3]1[S:4][CH:5]=[C:6]([CH2:8][Cl:9])[N:7]=1.CN(C)C=O.[C:15](Cl)(=[O:18])[CH2:16][CH3:17]>N1C=CC=CC=1>[C:15]([NH:2][C:3]1[S:4][CH:5]=[C:6]([CH2:8][Cl:9])[N:7]=1)(=[O:18])[CH2:16][CH3:17]
Reactant: Nc1nc(CCl)cs1
Reactant: CCC(=O)Cl
Agent: Cl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CCC(=O)Nc1nc(CCl)cs1
Temperature: 0 °C
Yield: 50.9 %

Procedure:
To a mixture of 2-amino-4-chloromethylthiazole hydrochloride (50 g), anhydrous N,N-dimethylformamide (250 ml) and anhydrous pyridine (50 ml) was added dropwise propionyl chloride (30 g) keeping the temperature below 3° C. with stirring and the mixture was stirred for 20 minutes at the same temperature. The reaction mixture was poured into ice water (1500 ml) and stirred. The crystal was collected by filtration and washed with water to give 2-propionylamino-4-chloromethylthiazole (28.15 g).
Reaction SMILES: [C:1]([C:5]1[S:9][C:8]([C:10]2[CH:15]=[C:14]([OH:16])[CH:13]=[CH:12][C:11]=2[C:17]2[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][C:18]=2[F:25])=[N:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH:26]1([CH:29]([C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([CH2:42]O)[CH:37]=2)[CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH2:28][CH2:27]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1.C1(C)C=CC=CC=1>[C:1]([C:5]1[S:9][C:8]([C:10]2[CH:15]=[C:14]([O:16][CH2:42][C:38]3[CH:37]=[C:36]([CH:29]([CH:26]4[CH2:27][CH2:28]4)[CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH:41]=[CH:40][CH:39]=3)[CH:13]=[CH:12][C:11]=2[C:17]2[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][C:18]=2[F:25])=[N:7][N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(F)c(-c2ccc(O)cc2-c2nnc(C(C)(C)C)s2)c1
Reactant: CCOC(=O)CC(c1cccc(CO)c1)C1CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCOC(=O)CC(c1cccc(COc2ccc(-c3cc(OC)ccc3F)c(-c3nnc(C(C)(C)C)s3)c2)c1)C1CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 74.8 %

Procedure:
To a solution of 2-(5-(tert-butyl)-1,3,4-thiadiazol-2-yl)-2′-fluoro-5′-methoxy-[1,1′-biphenyl]-4-ol (109 mg), ethyl 3-cyclopropyl-3-(3-(hydroxymethyl)phenyl)propanoate (91 mg) and triphenylphosphine (319 mg) in THF (6.0 mL) was added a 40% solution of diethyl azodicarboxylate in toluene (480 μL) at 0° C., and the mixture was stirred at room temperature for 12 hr. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (134 mg) as a colorless oil.
Reaction SMILES: [C:1]1(=[O:32])[N:5]([C@H:6]2[C@@H:9](/[CH:10]=[CH:11]/[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:8](C3C=CC(OC)=CC=3)[C:7]2=[O:26])[C:4](=[O:27])[C:3]2=[CH:28][CH:29]=[CH:30][CH:31]=[C:2]12.[NH4+].[N+]([O-])([O-])=O.[Ce+4].[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O>O1CCCC1.O>[C:4]1(=[O:27])[N:5]([C@H:6]2[C@@H:9](/[CH:10]=[CH:11]/[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[NH:8][C:7]2=[O:26])[C:1](=[O:32])[C:2]2=[CH:31][CH:30]=[CH:29][CH:28]=[C:3]12
Reactant: COc1ccc(N2C(=O)[C@@H](N3C(=O)c4ccccc4C3=O)[C@H]2/C=C/c2ccccc2)cc1
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: O=C1N[C@H](/C=C/c2ccccc2)[C@@H]1N1C(=O)c2ccccc2C1=O

Procedure:
In 25 ml of tetrahydrofuran is dissolved 1 g of cis-3-phthalimido-4-(E)-styryl-1-(p-methoxyphenyl)-2-oxoazetidine and under stirring at -5° C. to -10° C., solution of ammonium, cerium (IV) nitrate (3 g) in 10 ml of water is added dropwise over a period of 5 minutes. Then, the mixture is stirred at -5° C. to 0° C. for 20 minutes. The tetrahydrofuran is distilled off under reduced pressure and the residue is shaken with ethyl acetate and water. The ethyl acetate layer is taken, washed with aqueous sodium sulfite and aqueous sodium chloride in this order and dried over anhydrous sodium sulfate. The solvent is then distilled off and the residue is purified by silica gel column chromatography [eluent:chloroform-ethyl acetate (7:3)] and crystallized from ethyl acetate-ether to give cis-3phthalimido-4-(E)-styryl-2-oxoazetidine, melting at 168°-170° C.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C1C(=O)N([Br:19])C(=O)C1>CN(C=O)C.O>[Br:19][C:9]1[CH:10]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH:6]=[CH:7][C:8]=1[NH2:11]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)c1ccc(N)cc1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccc(N)c(Br)c1

Procedure:
To a solution of 4-tert-butyl-phenylamine (447 g, 3 mol) in DMF (500 mL) was added dropwise NBS (531 g, 3 mol) in DMF (500 mL) at room temperature. Upon completion, the reaction mixture was diluted with water and extracted with EtOAc. The organic layer was washed with water, brine, dried over Na2SO4 and concentrated. The crude product was directly used in the next step without further purification.
Reaction SMILES: [CH:1]1([C:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([O:18][CH3:19])=[O:17])=[CH:13][CH:14]=3)[NH:9][C:8]=2[C:20]2[N:21]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[C:22]([Br:26])=[C:23]([Br:25])[N:24]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:35](Br)[CH:36]=[CH2:37].C(Cl)Cl>CN(C=O)C>[CH2:37]([N:9]1[C:10]2[C:15](=[CH:14][CH:13]=[C:12]([C:16]([O:18][CH3:19])=[O:17])[CH:11]=2)[C:7]([CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[C:8]1[C:20]1[N:21]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:33])([CH3:32])[CH3:34])[C:22]([Br:26])=[C:23]([Br:25])[N:24]=1)[CH:36]=[CH2:35]
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(-c3nc(Br)c(Br)n3COCC[Si](C)(C)C)[nH]c2c1
Reactant: C=CCBr
Solvent: ClCCl
Solvent: CN(C)C=O
Product: C=CCn1c(-c2nc(Br)c(Br)n2COCC[Si](C)(C)C)c(C2CCCCC2)c2ccc(C(=O)OC)cc21
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of methyl 3-cyclohexyl-2-(4,5-dibromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)-1H-indole-6-carboxylate (428 mg, 0.7 mmol) in dry DMF (5 mL) was added KH (30% in oil, 0.8 mmol, 109 mg) proportion-wise at RT. The mixture was stirred at RT for 10 min until no further effervescence was observed. Allyl bromide (420 mg, 3.5 mmol) was added and the resulting mixture was stirred at RT for 15 min. Methylene chloride (10 mL) was added and the solution was washed with 1N HCl (3×10 mL), dried (Na2SO4), filtered and evaporated to give the title compound in a form pure enough for use in the following step (100%). 1H NMR (300 MHz, CDCl3) δ 0.04 (s, 9H), 0.80 (m, 2H), 1.00–2.00(m, 10H), 2.45 (m, 1H), 3.43 (dd, 2H, J=7.5, 9.6 Hz), 3.91 (s, 3H), 4.50 (dd, 1H, J=4.8, 15.0), 4.60 (dd, 1H, J=6.0, 15.0), 4.88 (dd, 1H, J=1.2, 17.1 Hz), 5.03 (s, 2H), 5.04 (dd, 1H, J=0.9, 9.0 Hz), 5.78 (m, 1H), 7.75 (dd, 1H, J=1.5, 8.5 Hz), 7.82 (d, 1H, J=8.5 Hz), 8.02 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([Cl:8])[CH:3]=1.[Br:9]NC(=O)CCC(N)=O>C(O)(=O)C>[NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([Cl:8])[C:3]=1[Br:9]
Reactant: NC(=O)CCC(=O)NBr
Reactant: Nc1ccnc(Cl)c1
Solvent: CC(=O)O
Product: Nc1ccnc(Cl)c1Br
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-amino-2-chloropyridine (50 g, 388 mmol) was dissolved in glacial acetic acid (500 mL). To this solution was added N-bromosuccinamide (75 g, 426 mmol,) portionwise at room temperature (water bath cooling was provided to control the exothermicity). The reaction mixture was stirred at RT for 1 h at which point the reaction was found complete (as monitored by TLC). Solvent was removed under reduced pressure followed by azeotropic distillation with ethanol. The crude product was purified by column chromatography on silica gel (230-400 mesh) eluting with ethyl acetate hexane mixture.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([Br:9])=[CH:5][CH:4]=1)#[N:2].Cl.[NH2:11][OH:12].C([O-])([O-])=O.[Na+].[Na+]>CCO.O>[Br:9][C:6]1[CH:7]=[CH:8][C:3]([C:1](=[NH:2])[NH:11][OH:12])=[CH:4][CH:5]=1
Reactant: NO
Reactant: N#Cc1ccc(Br)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: N=C(NO)c1ccc(Br)cc1
Reaction time: 7 h
Yield: 86.2 %

Procedure:
A mixture of 4-cyano-bromobenzene (0.5 g, 2.75 mmol), HCl×NH2OH (0.476 g, 6.9 mmol) and Na2CO3 (0.731 g, 6.9 mmol) in a mixture of EtOH and H2O (25 ml: 5 ml) was stirred for 7 h at reflux. The solvent was evaporated to dryness and the residue was taken in EtOAc (100 ml) and washed with H2O. The organic layer was separated, dried over MgSO4 and filtered. The filtrate was evaporated to dryness to give the product as colourless solid (0.51 g, 87%). 1H-NMR (DMSO-d6) 5.81 (broad s, 2H); 7.53 (d, 2H, J=6.66 Hz); 7.58 (d, 2H, J=6.54 Hz); 9.69 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[C:11]([C:13](O)=[O:14])[N:10]=[C:9]2[C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=2[Cl:23])=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)[C:44]2[CH:45]=[CH:46][CH:47]=C[C:43]=2[N:42]=[N:41]1.NN1CCCCC1>C(#N)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[C:11]([C:13]([NH:41][N:42]3[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]3)=[O:14])[N:10]=[C:9]2[C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=2[Cl:23])=[CH:4][CH:3]=1
Reactant: O=C(O)c1cn(-c2ccc(Br)cc2)c(-c2ccc(Cl)cc2Cl)n1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: NN1CCCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: O=C(NN1CCCCC1)c1cn(-c2ccc(Br)cc2)c(-c2ccc(Cl)cc2Cl)n1
Reaction time: 16 h
Yield: 56.2 %

Procedure:
Part B: To a stirred suspension of 1-(4-bromophenyl)-2-(2,4-dichlorophenyl)-1H-imidazole-4-carboxylic acid (1.23 gram, 2.99 mmol) in dry acetonitrile (40 mL) is successively added diisopropylethylamine (DIPEA) (1.15 mL, 6.6 mmol), O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophos-phate (HBTU) (1.36 gram, 3.6 mmol) and 1-aminopiperidine (0.39 mL, 3.6 mmol). After stirring for 16 hours, the resulting mixture is concentrated in vacuo. The residue is dissolved in ethylacetate and an aqueous NaHCO3 solution is added. The ethylacetate layer is collected, washed with water and brine, dried over Na2SO4, filtered and concentrated in vacuo to give a crude solid. This solid is further purified by recrystallisation from acetonitrile to give 1-(4-bromophenyl)-2-(2,4-dichlorophenyl)-N-(piperidin-1-yl)-1H-imidazole-4-carboxamide (830 mg, 56% yield). Melting point: 219-221° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@H:4]1[CH2:8][CH2:7][CH2:6][NH:5]1.Br[CH2:10][CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16].C(N(CC)CC)C.C(=O)([O-])[O-].[K+].[K+]>CC#N>[CH3:1][O:2][CH2:3][C@@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[CH2:10][CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16]
Reactant: COC[C@@H]1CCCN1
Reactant: CC(C)(C)OC(=O)NCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC[C@@H]1CCCN1CCNC(=O)OC(C)(C)C
Temperature: 85 °C

Procedure:
A suspension comprising (S)-2-(methoxymethyl)pyrrolidine (1 g, 8.68 mmol), tert-butyl 2-bromoethylcarbamate (1.946 g, 8.68 mmol), triethylamine (1.210 ml, 8.68 mmol) and potassium carbonate (1.200 g, 8.68 mmol) in MeCN (10 ml) was heated at 85° C. overnight. The resulting mixture was filtered and washed with MeCN. Purification of the crude product by chromatography on silica eluting with 0-5% MeOH in DCM afforded the title compound as a colourless oil;
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C:22]2[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:23]=2[Cl:29])[C@H:12]([CH3:21])[CH2:13][CH2:14][CH2:15][S:16]([NH:19][CH3:20])(=[O:18])=[O:17])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH2:30](S(Cl)(=O)=O)[CH2:31][CH2:32][CH2:33][CH3:34].C1(NC)CCCC1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C:22]2[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:23]=2[Cl:29])[C@H:12]([CH3:21])[CH2:13][CH2:14][CH2:15][S:16]([NH:19][CH2:20][CH:30]2[CH2:34][CH2:33][CH2:32][CH2:31]2)(=[O:17])=[O:18])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CNS(=O)(=O)CCC[C@@H](C)N(c1cc(Cl)ccc1Cl)S(=O)(=O)c1ccc(Cl)cc1
Reactant: CCCCCS(=O)(=O)Cl
Agent: CNC1CCCC1
Product: C[C@H](CCCS(=O)(=O)NCC1CCCC1)N(c1cc(Cl)ccc1Cl)S(=O)(=O)c1ccc(Cl)cc1
Yield: 15 %

Procedure:
4-chloro-N-[2,5-dichlorophenyl]-N-[4-[[N-(cyclopentyl)methylamino]sulfonyl]-1(R)-methylbutyl]benzenesulfonamide was prepared analogous to 4-chloro-N-[2,5-dichlorophenyl]-N-[4-[(methylamino)sulfonyl]-1(R)-methylbutyl]benzenesulfonamide by reacting (4R)-4-[2,5-dichlorophenyl][4-chlorophenyl)sulfonyl]-amino]pentylsulfonyl chloride with N-(cyclopentyl)-methylamine. Yield=15%; MS (ESI+), 567 (M+H)+.