Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]([CH:9]=O)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:11][C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[CH2:19][CH:20]([CH3:22])[NH2:21]>>[CH3:11][C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[CH2:19][CH:20]([NH:21][CH2:9][CH:7]([OH:8])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH3:22]
Reactant: O=CC(=O)c1ccccc1
Reactant: Cc1ccc(CC(C)N)c(C)c1
Product: Cc1ccc(CC(C)NCC(O)c2ccccc2)c(C)c1

Procedure:
The title compound was prepared in the manner described in Example 9 using phenylglyoxal and 2-(2,4-dimethylphenyl)-1-methylethanamine. The residual oil was chromatographed on Kieselgel 60 using 3% methanol-chloroform. Recrystallization of the resulting solid from hexane gave the title compound m.p. 91-92 as a 6:94 mixture of diastereoisomers. τ(CDCl3) 8.9 (3H, d, J=6 Hz), 7.7 (6H, s), 6.9-7.6 (5H, (m) +2H, disappears with D2O) 5.35 (1H, m), 3.05 (3H, s), 2.68 (5H, m).
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)[O:14][C:12](=O)[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]1=2)=O>O>[CH3:7][C:6]1[O:14][C:12]([C:11]2[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=2)=[CH:10][C:11]=1[CH:12]=[O:14]
Reactant: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: O
Product: Cc1oc(-c2ccccc2)cc1C=O
Temperature: 0 °C
Reaction time: 2 h
Yield: 129.1 %

Procedure:
To a solution of (2-methyl-5-phenylfuran-3-yl)methanol (4.7 g) obtained by the above-mentioned reaction in methylene chloride (30 mL) was added a Dess-Martin reagent (12.7 g) at 0° C., and the mixture was stirred at 0° C. for 2 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (0% ethyl acetate/hexane to 20% ethyl acetate/hexane) to give the title compound (3.6 g, 78%) as a yellow crystal.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[CH3:11][C@H:12]1[C:16](=[O:17])[O:15][C:14](=[O:18])[NH:13]1>C(OCC)(=O)C.CN(C)C1C=CN=CC=1>[CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:13]2[C@@H:12]([CH3:11])[C:16](=[O:17])[O:15][C:14]2=[O:18])=[O:7])=[CH:4][CH:3]=1
Reactant: Cc1ccc(C(=O)Cl)cc1
Reactant: C[C@@H]1NC(=O)OC1=O
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Product: Cc1ccc(C(=O)N2C(=O)OC(=O)[C@@H]2C)cc1
Reaction time: 2 h
Yield: 32.6 %

Procedure:
p-Methylbenzoyl chloride (309 mg, 2.0 mmol) was dissolved in ethyl acetate (5 mL), followed by the addition of (S)-4-methyl-2,5-oxazolidinedione (L-alanine-NCA) (230 mg, 2.0 mmol) under ice cooling. Further, a solution of 4-dimethylaminopyridine (244 mg, 2.0 mmol) in ethyl acetate (10 mL) was added dropwise under ice cooling over 20 minutes. After the resulting mixture was stirred as was at 0° C. for 2 hours, a precipitated salt was filtered off, and the filtrate was concentrated under reduced pressure. The concentration residue was re-dissolved in a mixed solvent consisting of ethyl acetate (5 mL) and hexane (5 mL), and insoluble matter was filtered off. The filtrate was concentrated under reduced pressure to afford the title compound (152 mg, 33%) as a colorless clear syrup.
Reaction SMILES: [Cl:1][C:2]1[NH:7][C:6](=[O:8])[NH:5][C:4](=[O:9])[CH:3]=1.[H-].[Na+].[Br-].[Li+].Br[CH2:15][C:16]1[C:17]([C:22]#[N:23])=[CH:18][CH:19]=[CH:20][CH:21]=1.[H-].[Li+].[Li+].[I-].[Na+].[I-]>CN(C=O)C.CS(C)=O.CN(C=O)C.C1COCC1.CS(C)=O>[Cl:1][C:2]1[N:7]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:22]#[N:23])[C:6](=[O:8])[NH:5][C:4](=[O:9])[CH:3]=1
Reactant: O=c1cc(Cl)[nH]c(=O)[nH]1
Reactant: N#Cc1ccccc1CBr
Agent: [Br-]
Agent: [H-]
Agent: [I-]
Solvent: CN(C)C=O
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: N#Cc1ccccc1Cn1c(Cl)cc(=O)[nH]c1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 59.5 %

Procedure:
To a solution of 6-chlorouracil (20 g, 122 mmol) in a mixture of DMF-DMSO (6:1, 600 mL) under nitrogen at 0° C., was added sodium hydride (60%, 5.5 g, 137 mmol) in portions. After 0.5 h, lithium bromide (8 g, 96 mmol) was added into the mixture and stirred for 15 min at 0° C. A solution of α-Bromo-o-tolunitrile (25.1 g, 128 mmol) in DMF (30 mL) was added dropwise, and stirred at this temperature for 1 h, and then RT overnight. It will be understood that alkylation of the amine may be performed under standard conditions known in the art, including the use of a base such as NaH, LiH or the like in an organic solvent or mixture of solvents. The solvent may include DMSO, THF, DMF and the like, or mixtures thereof. In addition, additives may be used, including LiBr, LiI, NaI and the like. The mixture was evaporated and co-evaporated with water in vacuo to remove most of the DMF, and then poured into ice water (1 L). The precipitate was collected by filtration. The crude product was suspended in hot AcOEt-CHCl3 and sonicated for 5 min, allowed to stand at 0° C. for 1 h, and then filtered to give a white solid of the title compound (19 g) in 54% yield. It will also be understood by those skilled in the art that purification may be accomplished using various methods known in the art, including washing with an aqueous/organic solvent or mixture of solvents, recrystallization and/or column chromatography. Non-limiting examples of organic solvents and solvent mixtures may include ethyl acetate, isopropyl acetate, acetone, THF and the like. 1H-NMR (400 MHz, DMSO): δ 11.82 (s, 1H), 7.87 (d, 1H, J=7.6 Hz), 7.71 (t, 1H, J=7.6 Hz), 7.51 (t, 1H, J=7.6 Hz), 7.37 (d, 1H, J=8 Hz), 6.06 (s, 1H), 5.31 (s, 2H). MS (ES) [m+H] calc'd for C12H9ClN3O2, 262.0; found 262.0.
Reaction SMILES: [F:1][C:2]1[C:3]([N:20]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([N:34]([OH:39])[C:35](=[O:38])[CH:36]=[CH2:37])[CH:29]=2)C(=O)OC(C)(C)C)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][O:18][CH3:19])=[CH:11][CH:10]=2)=[N:6][CH:7]=1.FC(F)(F)C(O)=O.CCCCCC.C(OCC)(=O)C>C(Cl)Cl>[F:1][C:2]1[C:3]([NH:20][C:28]2[CH:29]=[C:30]([N:34]([OH:39])[C:35](=[O:38])[CH:36]=[CH2:37])[CH:31]=[CH:32][CH:33]=2)=[N:4][C:5]([NH:8][C:9]2[CH:10]=[CH:11][C:12]([O:15][CH2:16][CH2:17][O:18][CH3:19])=[CH:13][CH:14]=2)=[N:6][CH:7]=1
Reactant: C=CC(=O)N(O)c1cccc(N(C(=O)OC(C)(C)C)c2nc(Nc3ccc(OCCOC)cc3)ncc2F)c1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: ClCCl
Product: C=CC(=O)N(O)c1cccc(Nc2nc(Nc3ccc(OCCOC)cc3)ncc2F)c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 4.1 %

Procedure:
In a 25 ml, 3-neck RBF equipped with a calcium chloride guard tube, to a solution of tert-butyl (5-fluoro-2-((4-(2-methoxyethoxy)phenyl)amino)pyrimidin-4-yl)(3-(N-hydroxyacrylamido)phenyl)carbamate (0.250 g) in DCM (10 ml) was added trifluoroacetic acid (5.0 ml) drop wise into the reaction mixture at 0° C. The reaction mixture was stirred at 0° C. for 15 minutes and then at room temperature for 30 minutes. The reaction was monitored by TLC using hexane:ethyl acetate (3:7) as mobile phase. After completion of the reaction, the reaction mixture was quenched in water and neutralized with sodium bicarbonate. Product was extracted into DCM and the organic layer was washed with brine, dried over sodium sulfate and concentrated completely under reduce pressure at 40° C. Crude material was purified by preparative-HPLC to give 8.3 mg of N-(3-((5-fluoro-2-((4-(2-methoxyethoxy)phenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-hydroxyacrylamide. 1H NMR: DMSO-d6 (400 MHz): 3.236-3.208 (t, 2H, J=8), 3.356 (s, 3H), 3.628-3.250 (t, 2H, J=4.4), 4.018-4.040 (t, 2H, J=4.4), 4.488-4.528 (t, 2H, J=8), 6.798 (d, 2H, J=8.8), 7.35 (d, 2H, J=6.4), 7.72 (d, 2H, J=6), 7.84 (s, 1H), 8.085 (d, 1H, J=3.6), 9.011 (s, 1H), 9.457 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([C:12](O)=[O:13])=[CH:7][CH:6]=2.C(OC(Cl)=O)C.[BH4-].[Na+]>C1COCC1.O>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([CH2:12][OH:13])=[CH:7][CH:6]=2
Reactant: O=C(O)c1ccc2ncc(Br)cc2c1
Agent: CCOC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: OCc1ccc2ncc(Br)cc2c1
Reaction time: 0.5 h
Yield: 17.6 %

Procedure:
To a mixture of 3-bromoquinoline-6-carboxylic acid (1.32 g, 5.24 mmol) and TEA (876 uL, 6.29 mmol) in THF (30 mL) was added EtOCOCl (599 uL, 6.29 mmol) at 0° C. and stirred for 30 min. Then, a solution of NaBH4 (793 mg, 21.0 mmol) in H2O (6 mL) was added at the same temperature. The resulting reaction mixture was stirred at 0° C. for 30 min before being warmed to it and stirred overnight. THF was removed. The residue was diluted with H2O, acidified with 4 N HCl, then neutralized with NaHCO3, extracted with EtOAc, and purified by a SiO2 column (0-50% EtOAc/Hexanes, Rf=0.35 in 50% EtOAc) to afford the titled compound as a colorless oil (220 mg).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([Cl:15])[C:12]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][O:25][CH2:26][O:27][CH3:28])=[CH:19][CH:18]=2)=[CH:11][C:10]=1Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.[CH2:35]([O:42][C@@H:43]1[C@@H:49]([O:50][CH2:51][C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)[C@H:48]([O:58][CH2:59][C:60]2[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=2)[C@@H:47]([CH2:66][O:67][CH2:68][C:69]2[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=2)[O:46][C:44]1=[O:45])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.[Cl-].[NH4+]>O1CCCC1.CCCCCC>[CH2:35]([O:42][C@@H:43]1[C@@H:49]([O:50][CH2:51][C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)[C@H:48]([O:58][CH2:59][C:60]2[CH:61]=[CH:62][CH:63]=[CH:64][CH:65]=2)[C@@H:47]([CH2:66][O:67][CH2:68][C:69]2[CH:70]=[CH:71][CH:72]=[CH:73][CH:74]=2)[O:46][C:44]1([C:10]1[CH:11]=[C:12]([CH2:16][C:17]2[CH:18]=[CH:19][C:20]([CH2:23][CH2:24][O:25][CH2:26][O:27][CH3:28])=[CH:21][CH:22]=2)[C:13]([Cl:15])=[CH:14][C:9]=1[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[OH:45])[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: COCOCCc1ccc(Cc2cc(Br)c(OCc3ccccc3)cc2Cl)cc1
Reactant: O=C1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COCOCCc1ccc(Cc2cc(C3(O)O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)c(OCc3ccccc3)cc2Cl)cc1
Reaction time: 0.08 h
Yield: 21.8 %

Procedure:
To a tetrahydrofuran solution (3 mL) of 1-(benzyloxy)-2-bromo-5-chloro-4-[4-[2-(methoxymethoxy)ethyl]benzyl]benzene (290 mg, 0.609 mmol) was added dropwise under nitrogen atmosphere at −78° C. a 2.6 M hexane solution of n-butyllithium (234 μL, 0.609 mmol), and the mixture was stirred for 5 minutes at the same temperature. Then a tetrahydrofuran solution (3 mL) of 2,3,4,6-tetra-O-benzyl-D-glucono-1,5-lactone (328 mg, 0.609 mmol) was added dropwise, and the mixture was stirred for an hour at the same temperature. To the reaction solution was added a saturated aqueous solution of ammonium chloride, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of ammonium chloride and brine, and dried with anhydrous magnesium sulfate. The drying agent was filtered off, and the solvent was evaporated under reduced pressure. Thus obtained residue was purified with silica gel column chromatography (hexane:ethyl acetate=3:1) to obtain the title compound (124 mg, 22%) as a colorless oily compound.
Reaction SMILES: [C:1]([C:4]1[NH:8][N:7]=[C:6]([C:9]([NH:11][CH2:12][CH2:13][N:14]2[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[C:21]([N+:27]([O-:29])=[O:28])[CH:20]=3)=[N:15]2)=[O:10])[CH:5]=1)(=O)[CH3:2].C([O-])(=O)C.[Na+].Cl.[NH2:36][OH:37].N1C=CC=CC=1>C(O)C>[C:25]([C:22]1[CH:23]=[CH:24][C:19]([C:16]2[CH:17]=[CH:18][N:14]([CH2:13][CH2:12][NH:11][C:9]([C:6]3[NH:7][N:8]=[C:4]([C:1](=[N:36][OH:37])[CH3:2])[CH:5]=3)=[O:10])[N:15]=2)=[CH:20][C:21]=1[N+:27]([O-:29])=[O:28])#[N:26]
Reactant: NO
Reactant: CC(=O)c1cc(C(=O)NCCn2ccc(-c3ccc(C#N)c([N+](=O)[O-])c3)n2)n[nH]1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CCO
Product: CC(=NO)c1cc(C(=O)NCCn2ccc(-c3ccc(C#N)c([N+](=O)[O-])c3)n2)[nH]n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 19.4 %

Procedure:
5-Acetyl-N-(2-(3-(4-cyano-3-nitrophenyl)-1H-pyrazol-1-yl)ethyl)-1H-pyrazole-3-carboxamide (0.17 g, 0.43 mmol) was dissolved in ethanol (15 ml). Sodium acetate (0.071 g, 0.86 mmol) and hydroxylamine hydrochloride (0.060 g, 0.86 mmol) was added and the reaction mixture was stirred at RT for 1.5 h. After addition of pyridine (5 ml) stirring was continued for 65 h. The reaction mixture was evaporated to dryness, co-evaporated two times with toluene and dissolved the residue in ethyl acetate. It was then washed two times with water, dried with Na2SO4 and purified with CombiFlash using DCM and methanol as eluents affording 0.034 g of the title compound. 1H-NMR (400 MHz; d6-DMSO): δ 2.11-2.15 (m, 3H), 3.68-3.71 (m, 2H), 4.39 (t, 2H), 7.05-7.06 (m, 1H), 7.88 (d, 1H), 8.17-8.20 (m, 1H), 8.32-8-35 (m, 1H), 8.68 (d, 1H).
Reaction SMILES: [B-](F)(F)(F)F.CCOC(C(C#N)=NOC(N(C)C)=[N+](C)C)=O.[NH2:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]2[CH:34]=[CH:33][N:32]([C:35]3[CH:40]=[CH:39][C:38]([O:41][C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=4)=[CH:37][CH:36]=3)[C:31]2=[O:48])=[CH:26][CH:25]=1.CCN(C(C)C)C(C)C.[CH3:58][N:59]([CH3:64])[CH2:60][C:61](O)=[O:62]>CN(C=O)C.O>[CH3:58][N:59]([CH3:64])[CH2:60][C:61]([NH:23][C:24]1[CH:25]=[CH:26][C:27]([N:30]2[CH:34]=[CH:33][N:32]([C:35]3[CH:40]=[CH:39][C:38]([O:41][C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=4)=[CH:37][CH:36]=3)[C:31]2=[O:48])=[CH:28][CH:29]=1)=[O:62]
Reactant: CN(C)CC(=O)O
Reactant: Nc1ccc(-n2ccn(-c3ccc(Oc4ccccc4)cc3)c2=O)cc1
Agent: CCOC(=O)C(C#N)=NOC(N(C)C)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(C)CC(=O)Nc1ccc(-n2ccn(-c3ccc(Oc4ccccc4)cc3)c2=O)cc1
Reaction time: 0.17 h

Procedure:
TOTU (327 mg) was added to a solution of 1-(4-aminophenyl)-3-(4-phenoxyphenyl)-1,3-dihydroimidazol-2-one (343 mg) in DMF (3 ml) at 0° C. After 10 minutes, Hünig base (130 mg) and then a solution of dimethylglycine (103 mg) in DMF (1 ml) was added. After a reaction time of 12 hours at room temperature, the mixture was mixed with water and extracted with ethyl acetate. The organic phase was washed with sodium bicarbonate solution, dried over magnesium sulfate and concentrated. The residue was purified by preparative HPLC. The product with the molecular weight of 428.50 (C25H24N4O3); MS (ESI): 429 ([M+H]+) was obtained as hydrotrifluoroacetate in this way.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])C.[CH3:8][C:9]1[C:17]([OH:18])=[CH:16][C:15]([CH3:19])=[C:14]2[C:10]=1[CH2:11][CH2:12][NH:13]2>C(O)=O>[OH:18][C:17]1[C:9]([CH3:8])=[C:10]2[C:14](=[C:15]([CH3:19])[CH:16]=1)[N:13]([CH:1]=[O:3])[CH2:12][CH2:11]2
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cc(O)c(C)c2c1NCC2
Solvent: O=CO
Product: Cc1cc(O)c(C)c2c1N(C=O)CC2
Reaction time: 0.5 h
Yield: 36.8 %

Procedure:
Acetic anhydride (25 ml, 264 mmol) was added at room temperature to formic acid (75 ml) and stirred for 30 minutes. To the solution, 2,3-dihydro-4,7-dimethyl-1H-indol-5-ol (14.4 g, 88 mmol) was added and the mixture was stirred for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in a chloroform methanol solution and washed: with a saturated aqueous solution of sodium hydrogen carbonate. The organic layer was washed with saturated brine and dried over sodium sulfate, and then the solvent was removed under reduced pressure. The resultant residue was washed with diisopropyl ether to obtain 6.2 g of the title compound.
Reaction SMILES: C(Br)(=O)C.[C@@H:5]1([N:14]2[CH:21]=[CH:20][C:18]([NH2:19])=[N:17][C:15]2=[O:16])[O:13][C@H:10]([CH2:11][OH:12])[C@@H:8]([OH:9])[C@H:6]1O>CC#N.Br.C(O)(=O)C>[C@@H:5]1([N:14]2[CH:21]=[CH:20][C:18]([NH2:19])=[N:17][C:15]2=[O:16])[O:13][C@H:10]([CH2:11][OH:12])[C@@H:8]([OH:9])[CH2:6]1
Reactant: Nc1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)n1
Agent: Br
Agent: CC(=O)Br
Solvent: CC#N
Solvent: CC(=O)O
Product: Nc1ccn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)n1
Temperature: 100 °C
Reaction time: 3 h
Yield: 96.9 %

Procedure:
Acetyl bromide (16.5 g, 134 mmol, 3.3 eq.) was added dropwise over 0.5 hours to a suspension of cytidine (10 g, 41.1 mmol) in CH3CN (250 mL) and HBr in acetic acid (10 mL, 30% weight) heated at 60°-65° C. The mixture was stirred at 100° C. for 3 hours, and then 10 mL more HBr in acetic acid was added. The mixture was stirred at 100° C. for an additional 28 hours. The solution was removed under vacuum to get a solid, which was purified with silica gel chromatography, to get 9.05 g of a solid (yield 56%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C[O:16][C:17](=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24]Br)[CH:19]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:24][C:20]3[CH:19]=[C:18]([CH:23]=[CH:22][CH:21]=3)[C:17]([OH:26])=[O:16])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: COC(=O)c1cccc(CBr)c1
Reactant: Oc1ccc(-c2ccc(Br)cc2)cc1
Product: O=C(O)c1cccc(COc2ccc(-c3ccc(Br)cc3)cc2)c1

Procedure:
3-(4′-Bromo-biphenyl-4-yloxymethyl)-benzoic acid was prepared using general procedure A from 4-bromo-4′-hydroxybiphenyl (available from TCI America, Portland, Oreg.) and 3-(bromomethyl)benzoic acid methyl ester (available from Lancaster Synthesis Ltd., Morcambe, Lancashire, UK). Yield: 91 mg. Mass spectrum (ES) MH+=383.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].[CH3:15][C:16]1[NH:17][CH:18]=[CH:19][N:20]=1>CO.C(Cl)Cl>[CH3:15][C:16]1[N:17]([C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=2[C:11]([F:14])([F:13])[F:12])[CH:18]=[CH:19][N:20]=1
Reactant: Cc1ncc[nH]1
Reactant: O=[N+]([O-])c1ccc(Br)c(C(F)(F)F)c1
Solvent: ClCCl
Solvent: CO
Product: Cc1nccn1-c1ccc([N+](=O)[O-])cc1C(F)(F)F

Procedure:
The title compound is prepared by hearing 1-bromo-4-nitro-2-trifluoromethyl-benzene and 2-methyl-imidazole between 100-150° C. during 15 h: M+H=272.0; Rf (MeOH/CH2Cl2=1:5): 0.60.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C:11]([F:14])([F:13])[CH2:10][CH:9]1[C:15]1[NH:16][C:17]([C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:35]=[CH:34][C:33]4[C:28](=[CH:29][CH:30]=[C:31]([C:36]5[NH:37][C:38]([CH:41]6[CH2:45][CH2:44][CH2:43][N:42]6C(OCC6C=CC=CC=6)=O)=[N:39][CH:40]=5)[CH:32]=4)[CH:27]=3)=[CH:22][CH:21]=2)=[CH:18][N:19]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH3:62][O:63][C:64]([NH:66][CH:67]([CH:71]1[CH2:76][CH2:75][O:74][CH2:73][CH2:72]1)[C:68](O)=[O:69])=[O:65].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CCO.[Pd].C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][C:11]([F:13])([F:14])[CH2:10][CH:9]1[C:15]1[NH:16][C:17]([C:20]2[CH:21]=[CH:22][C:23]([C:26]3[CH:35]=[CH:34][C:33]4[C:28](=[CH:29][CH:30]=[C:31]([C:36]5[NH:37][C:38]([CH:41]6[CH2:45][CH2:44][CH2:43][N:42]6[C:68](=[O:69])[CH:67]([NH:66][C:64]([O:63][CH3:62])=[O:65])[CH:71]6[CH2:76][CH2:75][O:74][CH2:73][CH2:72]6)=[N:39][CH:40]=5)[CH:32]=4)[CH:27]=3)=[CH:24][CH:25]=2)=[CH:18][N:19]=1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC(F)(F)CC1c1ncc(-c2ccc(-c3ccc4cc(-c5cnc(C6CCCN6C(=O)OCc6ccccc6)[nH]5)ccc4c3)cc2)[nH]1
Reactant: COC(=O)NC(C(=O)O)C1CCOCC1
Agent: [Pd]
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc3cc(-c4ccc(-c5cnc(C6CC(F)(F)CN6C(=O)OC(C)(C)C)[nH]5)cc4)ccc3c2)[nH]1)C1CCOCC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 14.5 %

Procedure:
To a solution of 2-[5-(4-{6-[2-(1-Benzyloxycarbonyl-pyrrolidin-2-yl)-3H-imidazol-4-yl]-naphthalen-2-yl}-phenyl)-1H-imidazol-2-yl]-4,4-difluoro-pyrrolidine-1-carboxylic acid tert-butyl ester (0.25 g, 0.34 mmol) in EtOH (3.5 mL) was added Palladium on carbon (10%, 0.18 g, 0.02 mmol) and Potassium Carbonate (0.14 g, 1.0 mmol). The slurry was stirred at room temperature under an atmosphere of H2 for 5 h. The slurry was filtered through celite and washed with EtOH. The filtrate was concentrated to an oil and diluted with CH2Cl2 (3 mL) and DMF (2 mL). Methoxycarbonylamino-(tetrahydro-pyran-4-yl)-acetic acid (0.11 g, 0.50 mmol), HATU (0.15 g, 0.40 mmol), and DIPEA (0.3 mL, 1.7 mmol) were added. The resulting solution was stirred at room temperature for 5 h. The solution was diluted with CH2Cl2 and washed with saturated sodium bicarbonate. The organic layer was dried over Na2SO4 and concentrated. The crude oil was concentrated and purified by preparative HPLC (Gemini, 15→50% MeCN in H2O (0.1% TFA)) to provide to provide 4,4-Difluoro-2-(5-{4-[6-(2-{1-[2-methoxycarbonylamino-2-(tetrahydro-pyran-4-yl)-acetyl]-pyrrolidin-2-yl}-3H-imidazol-4-yl)-naphthalen-2-yl]-phenyl}-1H-imidazol-2-yl)-pyrrolidine-1-carboxylic acid tert-butyl ester (0.04 g, 14%). LCMS-ESI+: calc'd for C44H49F2N7O6: 809.37 (M+); Found: 810.79 (M+H+).
Reaction SMILES: [ClH:1].[NH2:2][C:3]1[C:4]2[CH:14]=[CH:13][CH:12]=[CH:11][C:5]=2[S:6][C:7]=1[N+:8]([O-])=O>C(O)C.[Pd]>[ClH:1].[NH2:8][C:7]1[S:6][C:5]2[CH:11]=[CH:12][CH:13]=[CH:14][C:4]=2[C:3]=1[NH2:2]
Reactant: Nc1c([N+](=O)[O-])sc2ccccc12
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: Nc1sc2ccccc2c1N
Yield: 101.5 %

Procedure:
Fuming hydrochloric acid (1.92 ml, 24 mmol) was added to a suspension of 3-amino-2-nitrobenzo[b]thiophene (4.66 g, 24 mmol) (G. Van Zyl et al., Can. J. Chem., 44, 2283 (1966)) in 500 ml of 96% ethanol, and the mixture was hydrogenated in a Parr hydrogenation apparatus for 7 h at 40 psi and room temperature in the presence of 1 g of 5% palladium on carbon. The catalyst was filtered off under nitrogen, and the filtrate was evaporated to dryness to give 4.89 g (100%) of 2,3-diaminobenzo[b]thiophene hydrochloride, which was used in the next step without further purification.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:14]([NH2:16])=[O:15])=[N:4][C:5]([C:9]([O:11]CC)=[O:10])=[C:6]([OH:8])[N:7]=1.[OH-].[Na+].Cl>O.C(O)C>[OH:1][C:2]1[C:3]([C:14]([NH2:16])=[O:15])=[N:4][C:5]([C:9]([OH:11])=[O:10])=[C:6]([OH:8])[N:7]=1
Reactant: CCOC(=O)c1nc(C(N)=O)c(O)nc1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: NC(=O)c1nc(C(=O)O)c(O)nc1O
Reaction time: 16 h
Yield: 61.4 %

Procedure:
In a mixture of 1.0 mL of water and 1.0 mL of ethanol is suspended 0.13 g of 3,5-dihydroxy-6-ethoxycarbonyl-2-pyrazinecarboxamide. At ambient temperature, 0.34 mL of 5 mol/mL sodium hydroxide is added to the suspension, which is then stirred for 16 hours. The reaction mixture is adjusted to pH 2 by adding 1 mol/mL hydrochloric acid. The deposited crystals are collected by filtration and washed with water to obtain 0.07 g of 3,5-dihydroxy-6-carboxy-2-pyrazinecarboxamide.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH:21]=[C:20]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:19]=[C:18]2I)=[CH:13][CH:12]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:29]1(B(O)O)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C([O-])([O-])=O.[K+].[K+]>C(COC)OC.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Si:1]([O:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH:21]=[C:20]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:19]=[C:18]2[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:13][CH:12]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: OB(O)c1ccccc1
Reactant: CC(C)(C)[Si](C)(C)OCCc1ccc(-n2cc(-c3ccccc3)nc2I)cc1
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: CC(C)(C)[Si](C)(C)OCCc1ccc(-n2cc(-c3ccccc3)nc2-c2ccccc2)cc1
Temperature: 90 °C
Yield: 71.5 %

Procedure:
A mixture of 1-[4-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)phenyl]-2-iodo-4-phenyl-1H-imidazole (594 mg, 1.2 mmol), phenylboronic acid (287 mg, 2.4 mmol), 2M aqueous K2CO3 (3 mL) and bis(triphenylphosphine) palladium(II) chloride (165 mg, 0.24 mmol) in dimethoxyethane (10 mL) was heated at 90° C. for 16 h. After cooling, insoluble materials were removed by Celite pad and the filtrate was washed with 2N NaOH and brine, dried over (MgSO4) and concentrated under reduced pressure. Purification by flash column chromatography on silica gel eluting with hexane/ethyl acetate (gradient elution from 30:1 to 10:1) to afford 390 mg (73%) of the title compound as pale yellow amorphous: 1H-NMR (CDCl3)δ0.00 (6H, s), 0.89 (9H, s), 2.87 (2H, t, J=6.6 Hz), 3.86 (2H, t, J=6.6 Hz), 7.18-7.33 (7H, m), 7.39-7.52 (5H, m), 7.82 (1H, s), 7.89-7.93 (2H, m).