Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[O:19][C:4]([CH2:17][CH3:18])([CH2:5][C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([C:12]([O:14][CH3:15])=[O:13])[C:7]=2[NH2:16])[O:3][CH2:2]1.[C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[C:28]1[CH:33]=[CH:32][C:31]([CH2:34]Br)=[CH:30][CH:29]=1)#[N:21].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[CH2:2]1[O:3][C:4]([CH2:17][CH3:18])([CH2:5][C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([C:12]([O:14][CH3:15])=[O:13])[C:7]=2[NH:16][CH2:34][C:31]2[CH:30]=[CH:29][C:28]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[C:20]#[N:21])=[CH:33][CH:32]=2)[O:19][CH2:1]1
Reactant: CCC1(Cc2cccc(C(=O)OC)c2N)OCCO1
Reactant: N#Cc1ccccc1-c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCC1(Cc2cccc(C(=O)OC)c2NCc2ccc(-c3ccccc3C#N)cc2)OCCO1
Yield: 43.2 %

Procedure:
A mixture of 1-(2-amino-3-methoxycarbonylphenyl)butan-2-one ethylene ketal (T) (0.7 g) (prepared, e.g., as described in Preparation 14), 2'-(cyano)biphenyl-4-yl-methylbromide (0.826 g) and potassium carbonate (0.41 g) in dimethylformamide (20 ml) was heated at 80°-90° C. for 16 hours under an inert atmosphere. The reaction mixture was concentrated under reduced pressure, and the residue obtained was diluted with ethyl acetate (100 ml), washed twice with cold water, and then brine. The solvent was removed under reduced pressure and the residue was chromatographed on silica gel, eluting with 20% ethyl acetate/hexane, to give 1-[2-(2"-cyanobiphenyl-4'-ylmethylamino)-3-methoxycarbonylphenyl]butan-2-one ethylene ketal (0.52 g), a compound of Formula (U), as an oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:18])[CH2:15][CH2:16][CH3:17])[C:11]([C:19]([F:22])([F:21])[F:20])=[CH:10][C:9]=1[NH2:23])([CH3:4])([CH3:3])[CH3:2].C([O:29][C:30](=O)[CH2:31][C:32](=[O:45])[C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([C:39]2[CH:40]=[N:41][CH:42]=[N:43][CH:44]=2)[CH:34]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:18])[CH2:15][CH2:16][CH3:17])[C:11]([C:19]([F:22])([F:21])[F:20])=[CH:10][C:9]=1[NH:23][C:30](=[O:29])[CH2:31][C:32](=[O:45])[C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([C:39]2[CH:44]=[N:43][CH:42]=[N:41][CH:40]=2)[CH:34]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2cncnc2)c1
Reactant: CCCN(C)c1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Product: CCCN(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3cncnc3)c2)cc1C(F)(F)F

Procedure:
The title compound was prepared from [2-amino-5-(methyl-propyl-amino)-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example J17) (347 mg, 1.0 mmol) and 3-oxo-3-(3-pyrimidin-5-yl-phenyl)-propionic acid tert-butyl ester (Example K13) (298 mg, 1.0 mmol) according to the general procedure M. Obtained as a red oil (370 mg, 65%).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([I:11])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@H:12]1[C@H:19]2[C@@H:15]([O:16]C(C)(C)[O:18]2)[C@@H:14]([C:22]([OH:24])=[O:23])[O:13]1>C(O)=O>[NH2:1][C:2]1[N:10]=[C:9]([I:11])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@@H:12]1[O:13][C@H:14]([C:22]([OH:24])=[O:23])[C@@H:15]([OH:16])[C@H:19]1[OH:18]
Reactant: CC1(C)O[C@@H]2[C@@H](O1)[C@H](n1cnc3c(N)nc(I)nc31)O[C@@H]2C(=O)O
Solvent: O=CO
Product: Nc1nc(I)nc2c1ncn2[C@@H]1O[C@H](C(=O)O)[C@@H](O)[C@H]1O
Yield: 84.9 %

Procedure:
A solution of 1.72 g (3.85 mmol) of (2S,1R,4R,5R)-4-(6-amino-2-iodopurin-9-yl)-7,7-dimethyl-3,6,8-trioxabicyclo[3.3.0]octane-2-carboxylic acid (6.7) in 80 mL of 50% HCOOH was stirred at 80° C. for 1.5 hours. The reaction mixture was evaporated under reduced pressure, dissolved in H2O, and the solvent was evaporated again. This process was repeated until there was no odor of formic acid in the residue. Recrystallization from water provided 1.33 g (85%) 6.8 as a white solid, m.p. 221-223° C., dec. 1H NMR (300 MHz, DMSO-d6) 8.31 (s, 1H, H-8), 7.68 (s, 2H, NH2), 5.90 (d, J=6.55 Hz, 1H, H-1), 4.42 (m, 1H, H-2), 4.35 (d, J=2.31 Hz, 1H, H-4), 4.22 (m, 1H, H-3).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([OH:11])[C:7](=[CH:9][CH:10]=1)[OH:8])([O-:3])=[O:2].Br[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]>>[CH2:13]([O:11][C:6]1[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:10]=[CH:9][C:7]=1[O:8][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: O=[N+]([O-])c1ccc(O)c(O)c1
Reactant: CCCCCCCCCCBr
Product: CCCCCCCCCCOc1ccc([N+](=O)[O-])cc1OCCCCCCCCCC

Procedure:
Using this procedure, the reaction of 4-nitrocatechol with 1-bromodecane gave 3,4-bis-(decyloxy)nitrobenzene (mp 60°-61°, Anal, Calcd for C26H45NO4 : C, 71.68; H, 10.41; N, 3.22. Found: C, 71.63; H, 10.55; N, 3.21.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:12](=O)[CH2:13]Br)=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:6]=1.[NH2:16][C:17]1[N:22]=[CH:21][CH:20]=[CH:19][N:18]=1.C(N(CC)CC)C>C(O)C>[NH2:1][C:2]1[S:3][C:4]([C:12]2[N:16]=[C:17]3[N:22]=[CH:21][CH:20]=[CH:19][N:18]3[CH:13]=2)=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:6]=1
Reactant: CCOC(=O)c1nc(N)sc1C(=O)CBr
Reactant: Nc1ncccn1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)c1nc(N)sc1-c1cn2cccnc2n1
Yield: 27.5 %

Procedure:
A solution of ethyl 2-amino-5-(2-bromoacetyl)-4-thiazolecarboxylate (5.9 g), 2-aminopyrimidine (5.7 g) and triethylamine (8.4 ml) in ethanol (100 ml) was refluxed for 6 hours. The reaction mixture was evaporated in vacuo. To the residue was added a mixture of water and ethyl acetate, and the resulting mixture was acidified to pH 0.5 with conc. hydrochloric acid. The separated aqueous layer was treated with charcoal and filtered. To the filtrate was added ethyl acetate and the resulting mixture was adjusted to pH 7.0 with 20% aqueous potassium carbonate. The precipitate was collected by filtration, washed successively with water, ethyl acetate and ethanol, and dried over phosphorus pentoxide to give 2-(2-amino-4-ethoxycarbonyl-5-thiazolyl)imidazo[1,2-a]pyrimidine (1.6 g). mp 282° C. (dec.).
Reaction SMILES: N([O-])=O.[Na+].N[C:6]1[CH:7]=[C:8]([CH:16]([CH2:25][CH:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)[C:17]([NH:19][C:20]2[S:21][CH:22]=[CH:23][N:24]=2)=[O:18])[CH:9]=[CH:10][C:11]=1[S:12]([CH3:15])(=[O:14])=[O:13].[ClH:32]>O>[Cl:32][C:6]1[CH:7]=[C:8]([CH:16]([CH2:25][CH:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)[C:17]([NH:19][C:20]2[S:21][CH:22]=[CH:23][N:24]=2)=[O:18])[CH:9]=[CH:10][C:11]=1[S:12]([CH3:15])(=[O:14])=[O:13]
Reactant: Cl
Reactant: CS(=O)(=O)c1ccc(C(CC2CCOCC2)C(=O)Nc2nccs2)cc1N
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: CS(=O)(=O)c1ccc(C(CC2CCOCC2)C(=O)Nc2nccs2)cc1Cl
Temperature: 0 °C
Reaction time: 0.58 h

Procedure:
A solution of NaNO2 (34 mg, 498 μmol) in H2O (0.8 mL) was added to a solution of 2-(3-amino-4-methanesulfonylphenyl)-3-(tetrahydropyran-4-yl)-N-thiazol-2-ylpropionamide (EXAMPLE 171, 200 mg, 488 μmol) in 6M HCl (1.6 mL) at 0° C. The reaction was stirred at 0° C. for 35 min, before being added slowly to a stirred mixture of Cu powder (80 mg, 1.26 mmol) and 12M HCl (0.8 mL) at 0° C. The temperature was increased to 20° C., then stirring was continued for 1 h. The mixture was then heated at 60° C. for 1 h, before being cooled down to 20° C. and extracted with CH2Cl2 (3×15 mL). The organic extracts were dried (MgSO4), filtered, and concentrated to give a residue that was purified by RP-HPLC to furnish the title compound: RTA=3.17 min; m/z (ES+)=429.2 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]([CH:8]2[O:12][CH:11]([CH2:13][OH:14])[CH:10]([O:15][C:16](=[O:29])[CH:17]([NH:21]C(OC(C)(C)C)=O)[CH:18]([CH3:20])[CH3:19])[C:9]2([OH:31])[CH3:30])[C:4](=[O:32])[N:3]=1.[ClH:33]>CCOC(C)=O>[ClH:33].[ClH:33].[NH2:1][C:2]1[CH:7]=[CH:6][N:5]([CH:8]2[O:12][CH:11]([CH2:13][OH:14])[CH:10]([O:15][C:16](=[O:29])[CH:17]([NH2:21])[CH:18]([CH3:20])[CH3:19])[C:9]2([OH:31])[CH3:30])[C:4](=[O:32])[N:3]=1
Reactant: CC(C)C(NC(=O)OC(C)(C)C)C(=O)OC1C(CO)OC(n2ccc(N)nc2=O)C1(C)O
Agent: Cl
Solvent: CCOC(C)=O
Product: CC(C)C(N)C(=O)OC1C(CO)OC(n2ccc(N)nc2=O)C1(C)O

Procedure:
The prior art process shown in FIG. 5 comprised reacting benzoylcytosine, BSA and SnCl4/acetonitrile with 1,2,3,5-tetra-O-benzoyl-2-C-methyl-β-D-ribofuranose (4) to form 4-benzoylamino-1-(3,4-dibenzoyloxy-5-benzoyloxymethyl-3-methyl-tetrahydrofuran-2-yl)-1H-pyrimidin-2-one (5a); reacting (5a) with NH3 in methanol and chromatographically separating the product, 4-amino-1-(3,4-dihydroxy-5-hydroxymethyl-3-methyl-tetrahydro-furan-2-yl)-1H-pyrimidin-2-one (6), also known as β-D-2′-C-methyl-cytidine; reacting (6) with Me2NCH(OMe)2 in DMF at room temperature for 1.5 hours to form N-[1-(3,4-dihydroxy-5-hydroxymethyl-3-methyl-tetrahydro-furan-2-yl)-2-oxo-1,2-dihydro-pyrimidin-4-yl]-N,N-dimethyl-formamidine (7); reacting (7) with TBDPSCl and pyridine at room temperature for 6 hours to provide N′-{1-[5-(tert-butyl-diphenyl-silanyloxymethyl)-3,4-dihydroxy-3-methyl-tetrahydro-furan-2-yl]-2-oxo-1,2-dihydro-pyrimidin-4-yl}-N,N-dimethyl-formamidine (8); reacting (8) with N-Boc-L-valine, DEC and DMAP in THF/DMF at room temperature for 2 days and subjecting the product formed from this reaction to HPLC in order to provide 2-tert-butoxycarbonylamino-3-methyl-butyric acid 2-(tert-butyl-diphenyl-silanyloxy-methyl)-5-[4-(dimethylaminomethyleneamino)-2-oxo-2H-pyrimidin-1-yl]-4-hydroxy-4-methyl-tetrahydro-furan-3-yl ester (9a); refluxing (9a) with NH4F in MeOH for about 3 hours to remove the silyl and amino-protecting groups, and subjecting the product to chromatographic purification to provide 2-tert-butoxycarbonylamino-3-methyl-butyric acid-5-(4-amino-2-oxo-2H-pyrimidin-1-yl)-4-hydroxy-2-hydroxymethyl-4-methyl-tetrahydro-furan-3-yl ester (10); and finally reacting (10) with HCl in EtOAc at room temperature to provide 2-amino-3-methyl-butyric acid 5-(4-amino-2-oxo-2H-pyrimidin-1-yl)-4-hydroxy-2-hydroxymethyl-4-methyl-tetrahydro-furan-3-yl ester, dihydrochloride salt (11) as a final product.
Reaction SMILES: [CH2:1]([C:8]1([N:15]([CH3:17])[CH3:16])[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:18]([NH2:20])[CH3:19].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>O1CCCC1.C(O)(=O)C>[CH2:1]([C:8]1([N:15]([CH3:17])[CH3:16])[CH2:13][CH2:12][CH:11]([NH:20][CH2:18][CH3:19])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)C1(Cc2ccccc2)CCC(=O)CC1
Reactant: CCN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCNC1CCC(Cc2ccccc2)(N(C)C)CC1
Reaction time: 8 h
Yield: 72.5 %

Procedure:
15.0 g 4-benzyl-4-dimethylamino-cyclohexanone (see example 3) were dissolved in 225 ml analytical grade tetrahydrofuran, and 2.89 g ethylamine followed by 8.40 ml glacial acetic acid were added, while stirring in an ice-bath. 19.2 g sodium triacetoxyborohydride were then added in portions in the course of 15 minutes and the mixture was subsequently stirred overnight. For working up, 110 ml two molar sodium hydroxide solution were added dropwise (pH>10) and the mixture was extracted three times with 200 ml diethyl ether each time. The combined organic phases were washed twice with 200 ml water each time, dried over sodium sulfate and filtered and the filtrate was concentrated. The crude product obtained (15.7 g) was chromatographed over silica gel with methanol with the addition of one percent by volume of aqueous ammonia solution (25 wt. %). 14.1 g of the still significantly contaminated product were obtained, and were chromatographed again over silica gel with methanol with the addition of one percent by volume of aqueous ammonia solution (25 wt. %). 12.1 g 1-benzyl-N′-ethyl-N,N-dimethyl-cyclohexane-1,4-diamine were obtained as a cis/trans mixture.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7](Br)=[C:6]([N+:11]([O-:13])=[O:12])[CH:5]=1.I[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>ClCCl.[Cu]>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[CH:8][C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:6]([N+:11]([O-:13])=[O:12])[CH:5]=1)=[O:14]
Reactant: Ic1ccccc1
Reactant: COC(=O)c1ccc(Br)c([N+](=O)[O-])c1
Agent: [Cu]
Solvent: ClCCl
Product: COC(=O)c1ccc(-c2ccccc2)c([N+](=O)[O-])c1
Temperature: 218 °C

Procedure:
The product from Example 212a (0.100 g, 0.384 mmol) was combined with iodobenzene (0.375 mL, 3.35 mmol) and copper powder (0.188 g, 2.96 mmol) and the mixture heated in a sealed tube to 218° C. for 90 minutes. The reaction mixture was subsequently diluted with dichloromethane and filtered through celite. The crude product, obtained by concentration under vacuum, was purified by flash chromatography on silica gel (ethyl acetate-hexanes) to give the title compound (0.0847 g, 86
Reaction SMILES: [Br:1][C:2]1[C:3]([CH2:8][NH:9][C:10](=O)[C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.O.C(=O)([O-])[O-].[K+].[K+]>O=P(Cl)(Cl)Cl>[Br:1][C:2]1[C:3]2[N:4]([C:10]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)=[N:9][CH:8]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(NCc1ncccc1Br)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: Fc1ccc(-c2ncc3c(Br)cccn23)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A mixture of N-(3-bromopyridin-2-ylmethyl)-4-fluoro-benzamide (594 mg, 1.92 mmol) in POCl3 (5.0 mL) is warmed at reflux. After 1.5 hours, the mixture is cooled to room temperature and poured into water while adding crushed ice to control the exotherm. The mixture is made basic with potassium carbonate and the precipitate is collected by filtration to afford 8-bromo-3-(4-fluorophenyl)-imidazo[1,5-a]pyridine.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[CH2:16][NH:15][C:14]3=[O:19])[CH:10]=[N:9]2)=[C:5]([CH3:20])[O:4][N:3]=1.Br[CH2:22][CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>>[CH:23]1([CH2:22][N:15]2[CH2:16][C:17](=[O:18])[N:13]([C:11]3[CH:10]=[N:9][N:8]([CH2:7][C:6]4[C:2]([CH3:1])=[N:3][O:4][C:5]=4[CH3:20])[CH:12]=3)[C:14]2=[O:19])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: BrCC1CCCCC1
Reactant: Cc1noc(C)c1Cn1cc(N2C(=O)CNC2=O)cn1
Product: Cc1noc(C)c1Cn1cc(N2C(=O)CN(CC3CCCCC3)C2=O)cn1
Yield: 20 %

Procedure:
Prepared as in example 10-52 from 3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)imidazolidine-2,4-dione (example 10-1) and bromomethylcyclohexane. Yield: 20%. 1H NMR (DMSO-d6, 400 MHz): δ0.88 (q, J=10.4 Hz, 2H), 1.09-1.19 (m, 3H), 1.58-1.65 (m, 6H), 2.12 (s, 3H), 2.38 (s, 3H), 3.13 (d, J=7.2 Hz, 2H), 4.06 (s, 2H), 5.17 (s, 2H), 7.75 (s, 1H), 8.14 (s, 1H). MS M+H calculated 372.2. found 372.1. The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 0.28 μM.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([NH:6][C@@H:7]([CH3:19])[CH2:8][N:9]2[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[CH:4][CH:3]=1.N1C=CC=CC=1.Cl[C:27]([O:29][CH3:30])=[O:28]>ClCCCl>[Br:1][C:2]1[CH:11]=[C:10]2[C:5](=[CH:4][CH:3]=1)[N:6]([C:27]([O:29][CH3:30])=[O:28])[C@@H:7]([CH3:19])[CH2:8][N:9]2[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13]
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)c2cc(Br)ccc2N1
Reactant: COC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCCl
Product: COC(=O)N1c2ccc(Br)cc2N(C(=O)OC(C)(C)C)C[C@@H]1C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
A 100-mL round bottom flask fitted with nitrogen inlet and magnetic stir bar was charged with (S)-tert-butyl 7-bromo-3-methyl-3,4-dihydroquinoxaline-1(2H)-carboxylate (4.95 g, 15.13 mmol), 1,2-dichloroethane (50 mL), and pyridine (2.45 mL, 30.3 mmol). The reaction was cooled to 0° C. and methyl chloroformate (1.758 ml, 22.69 mmol) was added slowly. The reaction mixture stirred at 0° C. for 30 min and was then warmed to room temperature. After 2 h the reaction was diluted with 1,2-dichloroethane (20 mL) and washed with 1 M aqueous HCl solution (25 mL). The organic was concentrated under reduced pressure to afford (S)-4-tert-butyl 1-methyl 6-bromo-2-methyl-2,3-dihydroquinoxaline-1,4-dicarboxylate (5.83 g, 100%) as an amber oil. The material was used without further purification. MS (ESI, pos. ion) m/z 385 [M+1]+.
Reaction SMILES: [H-].[Na+].O1CCCC1.C(OCC)(=O)[CH2:9][C:10]([CH3:12])=[O:11].F[C:18]1[C:23]([F:24])=[C:22]([F:25])[CH:21]=[CH:20][C:19]=1[N+:26]([O-:28])=[O:27]>C(O)(=O)C>[F:24][C:23]1[C:18]([CH2:9][C:10](=[O:11])[CH3:12])=[C:19]([N+:26]([O-:28])=[O:27])[CH:20]=[CH:21][C:22]=1[F:25]
Reactant: CCOC(=O)CC(C)=O
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(=O)Cc1c([N+](=O)[O-])ccc(F)c1F
Reaction time: 1 h
Yield: 90 %

Procedure:
12.1 g (303 mmol) of 60% sodium hydride was added to 45 ml of tetrahydrofuran, and while cooling with a freezing mixture, 90 ml of tetrahydrofuran containing 39.0 g (300 mmol) of ethyl acetoacetate was dropped to the solution below 20° C. through 30 minutes. After the solution was stirred for 1 hour as was, 90 ml of tetrahydrofuran solution containing 26.6 g (150 mmol) of 2,3,4-trifluoronitrobenzene was dropped to the solution below 10° C. through 30 minutes, and the solution was stirred overnight at room temperature. 27 ml of acetic acid was added to the solution, and the solvent was removed by distillation. The solution was extracted with 500 ml of chloroform, and after drying over magnesium sulfate, the solvent was removed by distillation. 30 ml of 4N hydrochloric acid and 25 ml of acetic acid were added to the solution, and the solution was heated at reflux for 24 hours. 550 ml of concentrated hydrochloric acid and 550 ml of acetic acid were added to the solution, and the solution was heated at reflux for 16 hours. After air-cooling, the solution was extracted with 1 l of chloroform and was washed with 500 ml of water two times. The solution was further washed with 300 ml of aqueous saturated sodium hydrogen carbonate solution two times, and after drying over magnesium sulfate, the solvent was removed by distillation. The residue was separated by the column chromatography (silica gel 300 g, eluent solvent; chloroform: n-hexane=1:3) to obtain 31.2 g of the subject compound (148) in a 90% yield.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH3:9])=[CH:4][CH:3]=1.Br[C:19]1[C:20]2[C:21]3[CH:35]=[CH:34][S:33][C:22]=3[C:23](=[O:32])[NH:24][C:25]=2[C:26]([CH3:31])=[CH:27][C:28]=1[O:29][CH3:30]>>[CH3:30][O:29][C:28]1[CH:27]=[C:26]([CH3:31])[C:25]2[NH:24][C:23](=[O:32])[C:22]3[S:33][CH:34]=[CH:35][C:21]=3[C:20]=2[C:19]=1[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH3:9])=[CH:4][CH:3]=1
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1ccc(Br)cc1
Reactant: COc1cc(C)c2[nH]c(=O)c3sccc3c2c1Br
Product: COc1cc(C)c2[nH]c(=O)c3sccc3c2c1-c1ccc([C@H](C)NC(=O)OC(C)(C)C)cc1
Yield: 56 %

Procedure:
Following General Procedure E, (S)-tert-butyl 1-(4-bromophenyl)ethylcarbamate (60 mg, 0.20 mmol) was reacted with 9-bromo-8-methoxy-6-methylthieno[2,3-c]quinolin-4(5H)-one (60 mg, 0.20 mmol) to afford the desired product (52 mg, 62%) as a brown solid: ESI MS m/z 465 [C26H28N2O4S+H]+.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[NH:7][C:6]2[CH:8]=[CH:9][CH:10]=[CH:11][C:5]=2[N:4]=1.[CH3:12][C:13](OC(C)=O)=[O:14]>CN(C1C=CN=CC=1)C>[C:13]([N:7]1[C:6]2[CH:8]=[CH:9][CH:10]=[CH:11][C:5]=2[N:4]=[C:3]1[CH2:2][Cl:1])(=[O:14])[CH3:12]
Reactant: ClCc1nc2ccccc2[nH]1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Product: CC(=O)n1c(CCl)nc2ccccc21
Yield: 57 %

Procedure:
2-(Chloromethyl)-1H-benzimidazole (3.32 g, 0.02 mol) and DMAP (0.2 g) in Ac2O (50 ml) were refluxed for 8 h. The excess Ac2O was evaporated under vacuum and the residue was purified by column chromatography (silica, EtOAc:hexanes 2:1, first fraction) to obtain 2.37 g of product 7 (57%)
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([C:6]1[N:23]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C:9]2=[N:10][CH:11]=[C:12]([O:14]C(=O)C3C=CC=CC=3)[CH:13]=[C:8]2[CH:7]=1)=[O:5].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CO>[CH3:1][CH2:2][O:3][C:4]([C:6]1[N:23]([C:24]([O:26][C:27]([CH3:28])([CH3:30])[CH3:29])=[O:25])[C:9]2=[N:10][CH:11]=[C:12]([OH:14])[CH:13]=[C:8]2[CH:7]=1)=[O:5]
Reactant: CCOC(=O)c1cc2cc(OC(=O)c3ccccc3)cnc2n1C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCOC(=O)c1cc2cc(O)cnc2n1C(=O)OC(C)(C)C
Yield: 100 %

Procedure:
To a solution of 2.20 g (5.36 mmol) 5-benzoyloxy pyrrolo[2,3-b]pyridine-1,2-dicarboxylic acid 1-tert-butyl ester 2-ethyl ester in 20 mL methanol was added 0.81 g (5.90 mmol) potassium carbonate. After 1 h the reaction was poured into ethyl acetate and extracted with 10% aqueous citric acid solution. The phases were separated and the organic layer was washed with brine, dried over magnesium sulfate and evaporated. The residue was purified by column chromatography over silica gel (0.030–0.063 mm) with ethyl acetate:n-hexane (1:1) to give the product as a colourless oil (100%).
Reaction SMILES: C[O:2][C:3](=[O:31])[C@H:4]([CH2:25][C:26]1[N:30]=[CH:29][NH:28][CH:27]=1)[NH:5][C:6]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[OH-].[K+].Cl.C(OCC)(=O)C>CCCCCC.C(OCC)(=O)C>[C:7]1([C:6]([NH:5][C@H:4]([C:3]([OH:31])=[O:2])[CH2:25][C:26]2[N:30]=[CH:29][NH:28][CH:27]=2)([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: COC(=O)[C@H](Cc1c[nH]cn1)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: O=C(O)[C@H](Cc1c[nH]cn1)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.83 h

Procedure:
53 mg of L-Nα -[(2RS)-3-ethylsulfonyl-2-(1-naphthylmethyl)propionyl]-Nim -triphenylmethylhistidine methyl ester was dissolved in 0.8 ml of methanol/water (10/1), and 0.387 ml of a solution of 1N potassium hydroxide in methanol/water (10/1) was added thereto. The mixture was stirred at room temperature for 50 minutes. The mixture was neutralized with 1N hydrochloric acid under cooling with ice, and 20 ml of ethyl acetate was added thereto. The ethyl acetate layer was washed with water and with a saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue thereby obtained was purified by silica gel column chromatography (chloroform/methanol/acetic acid=15/1/0.15). The fractions containing the desired product were collected, and the organic layer was washed with a 4% sodium hydrogencarbonate aqueous solution and with a saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. Then, the solvent was distilled off to obtain 49 mg of L-Nα -[(2RS)-3-ethylsulfonyl-2-(1-naphthylmethyl)propionyl]-Nim -triphenylmethylhistidine as colorless solid.
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]([F:18])=[CH:14][C:13]=3[F:19])[N:11]=2)=[CH:4][CH:3]=1.[C:36]([C:40]1[CH:45]=[CH:44][C:43](B(O)O)=[CH:42][CH:41]=1)([CH3:39])([CH3:38])[CH3:37]>>[C:36]([C:40]1[CH:45]=[CH:44][C:43]([C:2]2[CH:35]=[CH:34][C:5]([CH2:6][C:7]3[N:8]([C:20]4[CH:25]=[CH:24][C:23]([N:26]5[S:30](=[O:31])(=[O:32])[NH:29][C:28](=[O:33])[CH2:27]5)=[CH:22][CH:21]=4)[CH:9]=[C:10]([C:12]4[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=4[F:19])[N:11]=3)=[CH:4][CH:3]=2)=[CH:42][CH:41]=1)([CH3:39])([CH3:38])[CH3:37]
Reactant: CC(C)(C)c1ccc(B(O)O)cc1
Reactant: O=C1CN(c2ccc(-n3cc(-c4ccc(F)cc4F)nc3Cc3ccc(Br)cc3)cc2)S(=O)(=O)N1
Product: CC(C)(C)c1ccc(-c2ccc(Cc3nc(-c4ccc(F)cc4F)cn3-c3ccc(N4CC(=O)NS4(=O)=O)cc3)cc2)cc1

Procedure:
5-{4-[2-(4-Bromo-benzyl)-4-(2,4-difluoro-phenyl)-imidazol-1-yl]-phenyl}-1,2,5-thiadiazolidine-3-one-1,1-dioxide (prepared according to general procedures A, B and C subsequently) (56 mg, 0.1 mmol) was treated as described in general procedure G using 4-tert-butylphenylboronic acid (36 mg, 0.2 mmol) to give 5-{4-[2-(4′-tert-butyl-biphenyl-4-ylmethyl)-4-(2,4-difluoro-phenyl)-imidazol-1-yl]-phenyl}-1,2,5-thiadiazolidine-3-one-1,1-dioxide.