Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].[CH:23](Cl)([Cl:25])[Cl:24]>CN(C=O)C.C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[C:10]([CH:23]([Cl:25])[Cl:24])[CH:9]=2)=[CH:6][CH:7]=1
Reactant: ClC(Cl)Cl
Reactant: O=[N+]([O-])c1ccc(-c2ccc(Cl)cc2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(-c2ccc(Cl)cc2)cc1C(Cl)Cl
Temperature: -73 °C
Reaction time: 0.02 h
Yield: 63 %

Procedure:
4′-Chloro-4-nitro-biphenyl [J. Amer. Chem. Soc; 68; 1946; 404] (2.74 g, 11.7 mmol) was dissolved in DMF (20 ml) and THF (6 ml), then potassium t-butoxide 5.26 g (47 mmol) was added. The stirred mixture was cooled to −73° C. then a solution of chloroform in THF (6 ml) was slowly introduced, maintaining this temperature. After a further 1 minute, the reaction was quenched with acetic acid (5 ml). The mixture was poured into water (200 ml) and extracted with dichloromethane. The crude product was purified by flash chromatography on silica (using dichloromethane-hexane as eluents) to give 4′-chloro-3-(1,1-dichloro-methyl)-4-nitro-biphenyl in 63% yield;
Reaction SMILES: [Se-2:1].[Na+].[Na+].Cl[C:5]([C:9]([CH3:12])([CH3:11])[CH3:10])=[CH:6][C:7]#[N:8].Cl[CH2:14][C:15]#[N:16].C[O-].[Na+]>CN(C=O)C.CO.O>[NH2:8][C:7]1[CH:6]=[C:5]([C:9]([CH3:12])([CH3:11])[CH3:10])[Se:1][C:14]=1[C:15]#[N:16]
Reactant: [Se-2]
Reactant: N#CCCl
Reactant: CC(C)(C)C(Cl)=CC#N
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)c1cc(N)c(C#N)[se]1
Temperature: 65 °C
Reaction time: 2 h

Procedure:
To a suspension of sodium selenide (3.51 g, 27.87 mmol) in DMF (28 mL) was added a solution of 3-chloro-4,4-dimethylpent-2-enenitrile (4.0 g, 27.87 mmol; Ohta, H.; Ishizaka, T.; Tatsuzuki, M.; Yoshinaga, M.; Iida, I.; Yamaguchi, T.; Tomishima, Y.; Futaki, N.; Toda, Y.; Saito, S. Bioorg. Med. Chem., 2008, 16, 1111-1124) in DMF (10 mL) at rt for 5 min and stirred the mixture at 60-70° C. for 2 h. Then chloroacetonitrile (1.76 mL, 27.87 mmol) was added dropwise to the reaction mixture and again stirred at 60-70° C. for 2 h. Then, a solution of sodium methoxide (1.5 g, 27.87 mmol) in dry methanol (18 mL) was added dropwise and stirring was continued for 1 h at the same temperature. The mixture was allowed to rt and poured into cold water and stirred for 30 min. The precipitated solid was filtered and washed with water. The solid was recrystallized from chloroform-hexane to give the product as a brown color solid (3.8 g, 60%), mp 110-112° C. (Thomae, D.; Kirsch, G.; Seck, P. Synthesis, 2008, 1600-1606). 1H NMR (400 MHz, CDCl3): δ 6.59 (1H, s), 4.46 (2H, br s), 1.33 (9H, s); LC-MS (negative ion mode): m/z 225, 227 (M−H)−.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]([NH:14][C:15]([C@@H:17]2[CH2:22][CH2:21][CH2:20][N:19]([C:23](=[O:39])[CH2:24][CH2:25][CH:26]3[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28][CH2:27]3)[CH2:18]2)=[O:16])[CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH:5]=[N:6][CH:7]=1.[OH:40][C:41]1[CH:46]=[CH:45][C:44](B(O)O)=[CH:43][CH:42]=1.[F-].[K+]>C1(C)C=CC=CC=1.C(O)C.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>[OH:40][C:41]1[CH:46]=[CH:45][C:44]([C:2]2[CH:3]=[C:4]([CH:8]([NH:14][C:15]([C@@H:17]3[CH2:22][CH2:21][CH2:20][N:19]([C:23](=[O:39])[CH2:24][CH2:25][CH:26]4[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:36])([CH3:37])[CH3:38])=[O:33])[CH2:28][CH2:27]4)[CH2:18]3)=[O:16])[CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH:5]=[N:6][CH:7]=2)=[CH:43][CH:42]=1
Reactant: OB(O)c1ccc(O)cc1
Reactant: COC(=O)CC(NC(=O)[C@@H]1CCCN(C(=O)CCC2CCN(C(=O)OC(C)(C)C)CC2)C1)c1cncc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [F-]
Agent: [K+]
Solvent: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: COC(=O)CC(NC(=O)[C@@H]1CCCN(C(=O)CCC2CCN(C(=O)OC(C)(C)C)CC2)C1)c1cncc(-c2ccc(O)cc2)c1
Temperature: 100 °C
Reaction time: 4 h
Yield: 71.4 %

Procedure:
To 300.0 mg (0.49 mmol) tert-butyl 4-{3-[(3R)-3-{[1-(5-bromopyridin-3-yl)-3-methoxy-3-oxopropyl]carbamoyl}piperidin-1-yl]-3-oxopropyl}piperidine-1-carboxylate (example 8c) in 12 ml toluene were added 11.4 mg (0.01 mmol) tetrakis(triphenylphosphine)palladium(0), 81.5 mg (0.59 mmol) (4-hydroxyphenyl)boronic acid in 3.0 ml ethanol and 88.7 mg (1.53 mmol) potassium fluoride in 3.0 ml water. The mixture was stirred at 100° C. for 4 hours, diluted with water and extracted with ethyl acetate. The organic phase was dried over sodium sulfate and concentrated in vacuum. Chromatography over 10 g silica gel (dichloromethane/ethanol 100/0-95/5-90/10) gave 218 mg (71%) tert-butyl 4-{3-[(3R)-3-({1-[5-(4-hydroxyphenyl)pyridin-3-yl]-3-methoxy-3-oxopropyl}carbamoyl)piperidin-1-yl]-3-oxopropyl}piperidine-1-carboxylate.
Reaction SMILES: C(OC([NH:8][CH2:9][CH:10]1[CH2:15][CH2:14][CH:13]([C:16]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=2)=[O:17])[CH2:12][CH2:11]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl.CO>[NH2:8][CH2:9][CH:10]1[CH2:15][CH2:14][CH:13]([C:16]([NH:18][CH2:19][C:20]2[CH:21]=[CH:22][C:23]([CH3:26])=[CH:24][CH:25]=2)=[O:17])[CH2:12][CH2:11]1
Reactant: Cc1ccc(CNC(=O)C2CCC(CNC(=O)OC(C)(C)C)CC2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Solvent: ClCCl
Product: Cc1ccc(CNC(=O)C2CCC(CN)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5.5 g of the (4-{[(tert-butoxy)carbonylamino]methyl}cyclohexyl)-N-[(4-methylphenyl)methyl]carboxamide prepared in Example 5A was dissolved in 500 ml of CH2Cl2. 50 ml of trifluoroacetic acid (TFA) was added to the solution and the reaction mixture stirred at room temperature overnight. The volatile components of the reaction mixture were evaporated off leaving a colorless oil which was then dissolved in 500 ml of methanol. 1 Tbs of Bio-Rad AG 1-X8 resin (20-50 mesh) was added and the solution shaken for 48 hours. Additional resin was added until the pH was slightly basic. The resin was then removed by filtration and the methanol evaporated off to give the product [4-(aminomethyl)cyclohexyl]-N-[(4-methylphenyl)methyl]carboxamide.
Reaction SMILES: [CH3:1][C:2]1[NH:8][C:7](=[O:9])[C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[O:4][CH:3]=1.[H-].[Na+].[Br:16][CH2:17][CH2:18][CH2:19][CH2:20]Br>CN(C)C=O>[Br:16][CH2:17][CH2:18][CH2:19][CH2:20][N:8]1[C:7](=[O:9])[C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[O:4][CH:3]=[C:2]1[CH3:1]
Reactant: BrCCCCBr
Reactant: CC1=COc2ccccc2C(=O)N1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1=COc2ccccc2C(=O)N1CCCCBr
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2.0 g of 4,5-dihydro-3-methyl-1,4-benzoxazepin-5-one was dissolved in 120 ml of dimethylformamide, then 548 mg (1.2 equivalents) of 60% sodium hydride was added under ice cooling. This was agitated at room temperature for 1 hour, then 4.1 ml (3 equivalents) of 1,4-dibromobutane was added and the resultant mixture was agitated for 3 hours.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[CH:20]=[CH:19][C:18]2[C:9]3[NH:10][C:11](=[O:17])[C:12]4[N:13]([CH:14]=[CH:15][N:16]=4)[C:8]=3[C:7](=[CH:21][C:22]([OH:24])=[O:23])[C:6]=2[CH:5]=1.O1CCOCC1.C(=O)([O-])[O-].[K+].[K+].[CH3:37][N:38]=[C:39]=[O:40]>CN(C)C=O>[C:22]([CH:21]=[C:7]1[C:8]2[N:13]3[CH:14]=[CH:15][N:16]=[C:12]3[C:11](=[O:17])[NH:10][C:9]=2[C:18]2[CH:19]=[CH:20][C:4]([NH:3][C:39]([NH:38][CH3:37])=[O:40])=[CH:5][C:6]1=2)([OH:24])=[O:23]
Reactant: Nc1ccc2c(c1)c(=CC(=O)O)c1c2[nH]c(=O)c2nccn21
Reactant: CN=C=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: CNC(=O)Nc1ccc2c(c1)c(=CC(=O)O)c1c2[nH]c(=O)c2nccn21
Reaction time: 30 h

Procedure:
To 11 g of 8-amino-10-(carboxymethylene)-5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-4-one dihydrochloride dissolved in 110 ml of dimethylformamide and 110 ml of dioxane at a temperature in the region of 20° C. are added 12.42 g of potassium carbonate, followed by dropwise addition of 5.3 ml of methyl isocyanate. The stirring is continued for 30 hours at the same temperature. The reaction medium is then filtered. The solid recovered is dried under reduced pressure (15 mmHg; 2 kPa). The residue is taken up in 50 ml of water and the precipitate is filtered off. The solid is acidified with 2 ml of concentrated hydrochloric acid in 50 ml of water and then filtered and dried under reduced pressure (15 mmHg; 2 kPa). The insoluble product thus formed is taken up in 700 ml of dimethylformamide and brought to 50° C. in the presence of 1 g of animal black. The solution is filtered on Celite and the filtrate is concentrated on a rotary evaporator at 40° C. under reduced pressure (15 mmHg; 2 kPa). (1 mmHg; 0.13 kPa). The residue is taken up in 200 ml of ethyl ether and then filtered and dried for 8 hours at 50° C. under reduced pressure (1 mmHg; 0.13 kPa). 3.67 g of 10-(carboxymethylene)-8-(3-methylureido)-5H,10H-imidazo(1,2-a]indeno[1,2-e]pyrazin-4-one are obtained in the form of an orange-coloured powder, the melting point of which is greater than 260° C. (Analysis, C17 H13N5O4.0.9 DMF.0.9 H2O, % calculated C: 58.12; H: 3.73; N: 19.93, % found C: 58.1; H: 3.4; N: 19.6).
Reaction SMILES: [NH2:1][CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=2)[NH:5][CH:4]([C:15]([CH3:19])([CH3:18])[CH2:16][OH:17])[CH2:3]1.[C:20](Cl)(=[O:23])[CH2:21][CH3:22].O.C(OCC)(=O)C>N1C=CC=CC=1>[OH:17][CH2:16][C:15]([CH:4]1[CH2:3][CH:2]([NH:1][C:20](=[O:23])[CH2:21][CH3:22])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=2)[NH:5]1)([CH3:19])[CH3:18]
Reactant: CC(C)(CO)C1CC(N)c2cc([N+](=O)[O-])ccc2N1
Reactant: CCC(=O)Cl
Solvent: O
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CCC(=O)NC1CC(C(C)(C)CO)Nc2ccc([N+](=O)[O-])cc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The compound of Example 22 (50 mg) and 0.1 ml of propionyl chloride were dissolved in 1 ml of pyridine. After 2 hours of stirring at room temperature, water and ethyl acetate were added. The ethyl acetate layer was washed with water, and then dried over anhydrous sodium sulfate, followed by distilling off the solvent under reduced pressure. The residue was dissolved in 1 ml of methanol, 0.1 ml of a 4N aqueous solution of sodium hydroxide was added, and the mixture was stirred for 1 hour. Then, a phosphate buffer (pH 7.0) was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate) to obtain 31 mg of the title compound. Its physical properties are shown below.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:51])[NH:4][C@@H:5]([C:47]([CH3:50])([CH3:49])[CH3:48])[C:6](=[O:46])[NH:7][C@@H:8]([CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C@@H:9]([OH:38])[CH2:10][C@H:11]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=2)=[CH:28][CH:27]=1)[NH:12][C:13](=[O:24])[C@H:14]([C:20]([CH3:23])([CH3:22])[CH3:21])[NH:15][C:16](=[O:19])[O:17][CH3:18].[CH2:52]([S:54][CH2:55][CH3:56])[CH3:53].C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(#N)C.C(OCC)(=O)C>[CH2:39]([C@H:8]([NH:7][C:6]([C@@H:5]([NH:4][C:3](=[O:51])[O:2][CH3:1])[C:47]([CH3:50])([CH3:49])[CH3:48])=[O:46])[C@@H:9]([O:38][CH:52]([S:54][CH2:55][CH3:56])[CH3:53])[CH2:10][C@@H:11]([NH:12][C:13](=[O:24])[C@H:14]([C:20]([CH3:23])([CH3:22])[CH3:21])[NH:15][C:16]([O:17][CH3:18])=[O:19])[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=2)=[CH:28][CH:27]=1)[C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1
Reactant: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](NC(=O)OC)C(C)(C)C)C(C)(C)C
Reactant: CCSCC
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCSC(C)O[C@@H](C[C@H](Cc1ccc(-c2ccccn2)cc1)NC(=O)[C@@H](NC(=O)OC)C(C)(C)C)[C@H](Cc1ccccc1)NC(=O)[C@@H](NC(=O)OC)C(C)(C)C
Yield: 104.5 %

Procedure:
To a slurry of the compound of Example 2D (2.00 g, 2.84 mmol) and ethyl sulfide (8.0 mL, 74.06 mmol) in acetonitrile (28.0 mL) at room temperature was added benzoyl peroxide (4.95 g, 20.45 mmol) in three portions over 2 hours. The reaction was diluted with ethyl acetate and washed with 10% Na2CO3 and brine. The organic was dried over MgSO4, filtered and evaporated. The residue was chromatographed on silica gel eluting with a gradient starting with dichloromethane and ending with ethyl acetate to give the title compound (2.35 g, 84% yield).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:16]=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:9][CH:8]=2)[N:4]=[C:3]1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1.C1C(=O)N([I:30])C(=O)C1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[I:30][C:6]1[N:2]([CH3:1])[C:3]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)=[N:4][C:5]=1[C:7]1[CH:16]=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:9][CH:8]=1
Reactant: COC(=O)c1ccc(-c2cn(C)c(-c3ccccn3)n2)cc1
Reactant: O=C1CCC(=O)N1I
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ccc(-c2nc(-c3ccccn3)n(C)c2I)cc1
Reaction time: 0.08 h
Yield: 91.3 %

Procedure:
Methyl 4-(1-methyl-2-pyridin-2-yl-1H-imidazol-4-yl)benzoate (12.5 g, 42.6 mmol) was dissolved in methylene chloride (120 mL), to which was added NIS (10.6 g, 47 mmol) and 0.5 mL of TFA. After stirring for 5 min, the reaction was diluted with 120 mL of methylene chloride and quenched with aq NaHCO3. The organic layer was separated, washed with aq Na2S2O3, water, brine, dried over MgSO4, filtered, and concentrated to give 16.3 g of methyl 4-(5-iodo-1-methyl-2-pyridin-2-yl-1H-imidazol-4-yl)benzoate. 1H NMR (500 MHz, (CDCl3): 8.63 (m, 1H), 8.24 (d, 1H), 8.18 (s, 4H), 7.83 (m, 1H), 7.31 (m, 1H), 4.22 (s, 3H), 3.96 (s, 3H). LCMS: [M+1]=420.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[NH:7][N:6]=[CH:5]2.[H-].[Na+].CN([CH:17]=[O:18])C>C1COCC1>[F:11][C:10]1[CH:9]=[C:8]2[C:4]([CH:5]=[N:6][NH:7]2)=[CH:3][C:2]=1[CH:17]=[O:18]
Reactant: Fc1cc2[nH]ncc2cc1Br
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=Cc1cc2cn[nH]c2cc1F
Temperature: -70 °C
Reaction time: 0.75 h

Procedure:
A solution of 5-bromo-6-fluoro-1H-indazole (3 g, 13.95 mmol) in THF (10 mL) was added to a suspension of NaH (3.38 g, 141 mmol) in THF (100 mL) over 10 min at 0° C. The RM was cooled to −70° C. then the s-Buli solution (1.4 M, 19 mL) was added slowly over 20 min. It was stirred at this temperature for 45 min. A solution of DMF (6.18 mL, 80 mmol) in THF (10 mL) was added over 15 min at −70° C. and the RM was then warmed up to rt over 1 h 30. The reaction was quenched with 100 mL of 1 N HCl. The RM was extracted twice with EtOAc. Then the organics were joined and washed with brine, dried over Na2SO4 and the solvent was removed. The residue was triturated for 1 h with Et2O. The precipitate formed was filtered off and identified as the desired aldehyde. The filtrate was left in the freezer over night and a second batch of the product was filtered off to afford the title compound as a light yellow solid (tR 0.7 min (conditions 2), MH+=165, 1H-NMR in DMSO-d6: 13.50 (s, 1H); 10.15 (s, 1H); 8.39 (d, 1H); 8.32 (s, 1H); 7.45 (d, 1H)).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:5]2.C(=O)([O-])[O-].[K+].[K+].[CH2:22](I)[CH:23]([CH3:25])[CH3:24].C(OCC)(=O)C>CN(C)C=O.O>[CH2:22]([N:7]1[C:8]2[C:4](=[CH:3][C:2]([CH3:1])=[CH:10][CH:9]=2)[CH:5]=[C:6]1[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:23]([CH3:25])[CH3:24]
Reactant: CC(C)CI
Reactant: CCOC(=O)c1cc2cc(C)ccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc2cc(C)ccc2n1CC(C)C
Temperature: 120 °C
Reaction time: 1 h

Procedure:
In 30 ml of N,N-dimethylformamide are suspended 2.81 g of ethyl 5-methyl-1H-indole-2-carboxylate, 17.0 g of potassium carbonate and 11.3 ml of isobutyl iodide. The suspension is stirred at 120° C. for one hour. The reaction mixture is added to a mixture of ethyl acetate and water, and the organic layer is separated. The organic layer thus obtained is washed with water and saturated aqueous solution of sodium chloride successively and dried over anhydrous magnesium sulfate, and then the solvent is distilled off under reduced pressure. The residue thus obtained is purified by silica gel column chromatography (eluent: toluene) to obtain 1.75 g of ethyl 1-isobutyl-5-methyl-1H-indole-2-carboxylate as a light yellow oily product.
Reaction SMILES: [C:1]1([C:7]2[N:12]=[C:11]([CH:13]=O)[CH:10]=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:15][C@@H:16]([CH2:20][OH:21])[CH:17]([CH3:19])[CH3:18].C(O)(=O)C.C([BH3-])#N>CO>[CH3:18][CH:17]([CH3:19])[C@@H:16]([NH:15][CH2:13][C:11]1[CH:10]=[CH:9][CH:8]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:12]=1)[CH2:20][OH:21]
Reactant: O=Cc1cccc(-c2ccccc2)n1
Reactant: CC(C)[C@@H](N)CO
Agent: [BH3-]C#N
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)[C@H](CO)NCc1cccc(-c2ccccc2)n1
Reaction time: 0.08 h
Yield: 58.4 %

Procedure:
To a solution of 6-phenylpicolinaldehyde (Tetrahedron Lett. 2010, 51, 5621-5623; 0.391 g, 2.133 mmol) in methanol (4 mL) at ambient temperature was added D-valinol (0.22 mL, 1.9 mmol) followed by acetic acid (0.4 mL, 8 mmol). After 5 min, MP-cyanoborohydride (2.5 mmol/g, 500 mg) was added and stirring continued overnight. The mixture was filtered and the filtrate partitioned between 1N NaOH and CH2Cl2. The organic phase extracted with 1N aqueous HCl. The organic layer was discarded and the aqueous phase was made basic with 1N NaOH and extracted with EtOAc. The organic extract dried, filtered and concentrated to provide 300 mg (57%) of the title compound. MS (DCI30 ) m/z 271 (M+H); 1H NMR (300 MHz, CDCl3) δ 8.04-7.93 (m, 2H), 7.73 (t, J=7.7 Hz, 1H), 7.62 (d, J=7.6 Hz, 1H), 7.53-7.35 (m, 3H), 7.21 (d, J=7.5 Hz, 1H), 4.06 (s, 2H), 3.72 (dd, J=11.0, 4.0 Hz, 1H), 3.52 (dd, J=11.0, 6.9 Hz, 1H), 2.55 (td, J=6.7, 4.0 Hz, 1H), 1.91 (td, J=13.6, 6.8 Hz, 1H), 1.05 (d, J=6.4 Hz, 3H), 0.96 (d, J=6.8 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15]3[N:16]([C:28]4[CH:33]=[CH:32][C:31]([N:34]5[S:38](=[O:40])(=[O:39])[NH:37][C:36](=[O:41])[CH2:35]5)=[CH:30][CH:29]=4)[CH:17]=[C:18]([C:20]4[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=4[Cl:27])[N:19]=3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.Br[CH2:43][CH:44]([CH3:46])[CH3:45].Cl[C:48]([O:50][CH:51]([CH3:53])[CH3:52])=[O:49]>>[CH:51]([O:50][C:48](=[O:49])[N:1]([C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15]3[N:16]([C:28]4[CH:33]=[CH:32][C:31]([N:34]5[CH2:35][C:36](=[O:41])[NH:37][S:38]5(=[O:40])=[O:39])=[CH:30][CH:29]=4)[CH:17]=[C:18]([C:20]4[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=4[Cl:27])[N:19]=3)=[CH:10][CH:9]=2)=[CH:6][CH:7]=1)[CH2:43][CH:44]([CH3:46])[CH3:45])([CH3:53])[CH3:52]
Reactant: CC(C)CBr
Reactant: CC(C)OC(=O)Cl
Reactant: Nc1ccc(-c2ccc(Cc3nc(-c4ccc(Cl)cc4Cl)cn3-c3ccc(N4CC(=O)NS4(=O)=O)cc3)cc2)cc1
Product: CC(C)CN(C(=O)OC(C)C)c1ccc(-c2ccc(Cc3nc(-c4ccc(Cl)cc4Cl)cn3-c3ccc(N4CC(=O)NS4(=O)=O)cc3)cc2)cc1

Procedure:
5-{4-[2-(4′-Amino-biphenyl-4-ylmethyl)-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-1,2,5-thiadiazolidine-3-one-1,1-dioxide (61 mg, 0.1 mmol) was treated subsequently according to general procedure K using 1-bromo-2-methylpropane (21 mg, 0.15 mmol) and general procedure U using isopropyl chloroformate (1M solution in toluene) (0.2 mL, 0.2 mmol) to give (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)-isobutyl-carbamic acid isopropyl ester.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]=O)=[C:6]([N+]([O-])=O)[CH:5]=1.[CH2:16]([O:18][C:19](=[O:22])[CH2:20][SH:21])[CH3:17].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[CH:8][C:7]2[CH:10]=[C:20]([C:19]([O:18][CH2:16][CH3:17])=[O:22])[S:21][C:6]=2[CH:5]=1)=[O:15]
Reactant: COC(=O)c1ccc(C=O)c([N+](=O)[O-])c1
Reactant: CCOC(=O)CS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2ccc(C(=O)OC)cc2s1
Temperature: 50 °C
Reaction time: 0.67 h

Procedure:
A mixture of 4-formyl-3-nitro-benzoic acid methyl ester (15.22 g, 72.78 mmol), mercapto-acetic acid ethyl ester (8.70 mL, 79.3 mmol) and K2CO3 (12.87 g, 93.12 mmol) in 140 mL of anhydrous DMF was heated at 50° C. overnight. After cooling to rt, the mixture was poured into 1 L of ice-water and die resulting mixture was stirred for 40 min. The solid formed was filtered and washed with 4×70 mL of water. After drying, benzo[b]thiophene-2,6-dicarboxylic acid 2-ethyl ester 6-methyl ester was obtained as a pale solid. 1H NMR (CDCl3, 200 MHz) δ 8.56 (s, 1H), 8.09-7.97 (m, 2H), 7.88 (d, J=8.0 Hz, 1H), 4.40 (q, J=7.2 Hz, 2H), 3.95 (s, 3H), 1.40 (t, J=6.8 Hz, 3H). MS (EI): cal'd 265.0 (MH+), exp 265.0 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[S:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1)[C:5]([NH:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[Br:15])=[O:6].C([C:29]1[C:30]([N:35]=[CH:36][N:37]([CH3:39])C)=[N:31][CH:32]=[CH:33][CH:34]=1)#N.C(C1C=CC2C(NC3C=C(C=CC=3SC3C=CC(OC)=CC=3)C(NC3C=CC=C(C(F)(F)F)C=3)=O)=NC=NC=2N=1)(C)C.NC1C=C(C=CC=1SC1C=CC(O)=CC=1)C(NC1C=CC(Br)=CC=1)=O>>[Br:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[CH2:8][NH:7][C:5](=[O:6])[C:4]1[CH:16]=[CH:17][C:18]([S:19][C:20]2[CH:21]=[CH:22][C:23]([OH:26])=[CH:24][CH:25]=2)=[C:2]([NH:1][C:39]2[C:29]3[CH:34]=[CH:33][CH:32]=[N:31][C:30]=3[N:35]=[CH:36][N:37]=2)[CH:3]=1
Reactant: CN(C)C=Nc1ncccc1C#N
Reactant: Nc1cc(C(=O)NCc2ccccc2Br)ccc1Sc1ccc(O)cc1
Agent: COc1ccc(Sc2ccc(C(=O)Nc3cccc(C(F)(F)F)c3)cc2Nc2ncnc3nc(C(C)C)ccc23)cc1
Agent: Nc1cc(C(=O)Nc2ccc(Br)cc2)ccc1Sc1ccc(O)cc1
Product: O=C(NCc1ccccc1Br)c1ccc(Sc2ccc(O)cc2)c(Nc2ncnc3ncccc23)c1
Yield: 60 %

Procedure:
The product of Example 31A was reacted with the product of Example 29A using the procedure of Example 22C substituting the product of Example 3 1A for the product of Example 22B and substituting the product of Example 29A for the product of Example 8E to provide the crude title compound which was purified by column chromatography on silica gel using methanol/dichloromethane as eluent to provide the title product (58 mg, 60%). 1H NMR (300 MHz, DMSO-D6) δ ppm: 4.48 (d, J=5.88 Hz, 2 H) 6.84 (d, J=8.46 Hz, 2 H) 6.87-7.02 (m, 1 H) 7.13-7.44 (m, 5 H) 7.58-7.64 (m, 1 H) 7.64-7.84 (m, 2 H) 7.93 (s, 1 H) 8.62 (d, J=1.84 Hz, 1 H) 8.82-9.20 (m, 3 H) 9.94 (s, 1 H) 10.30 (s, 1 H); MS (ESI+) m/z 558/560 (M+H)+.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7](N)[CH:6]=[CH:5][N:4]=1)[CH3:2].[N+]([O-])(O)=[O:11].N([O-])=O.[Na+]>O>[CH2:1]([C:3]1[CH:8]=[C:7]([OH:11])[CH:6]=[CH:5][N:4]=1)[CH3:2]
Reactant: CCc1cc(N)ccn1
Reactant: O=[N+]([O-])O
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: CCc1cc(O)ccn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
282.1 g (2.3 mol) 2-Ethyl-pyridin-4-ylamine are dissolved in concentrated HNO3 (789 mL, 11.561 mol) and H2O (1.5 L). Then a solution of NaNO2 (238.9 g, 3.468 mol) in H2O (600 mL) is slowly added to the solution over 2 h at 0° C. After the addition, the mixture is warmed to RT and stirred for additional 2 h. The reaction mixture is stored at −2° C. overnight. The precipitate is collected by filtration, and dried in vaccuo to afford the title compound. Yield: 155.1 g, (54%)