Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:15]=2[CH2:24][NH:25][CH2:26][CH3:27])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2].C(N(C(C)C)CC)(C)C.[C:38](Cl)(Cl)=[O:39].[OH:42][C:43]1[CH:50]=[CH:49][C:46]([CH2:47][NH2:48])=[CH:45][CH:44]=1.C(N(CC)CC)C>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:28])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:21])[F:22])=[CH:16][C:15]=2[CH2:24][N:25]([CH2:26][CH3:27])[C:38]([NH:48][CH2:47][C:46]2[CH:49]=[CH:50][C:43]([OH:42])=[CH:44][CH:45]=2)=[O:39])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2]
Reactant: NCc1ccc(O)cc1
Reactant: O=C(Cl)Cl
Reactant: CCNCc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)OCC)ccc1OC
Solvent: CCN(C(C)C)C(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CN(CC)C(=O)NCc2ccc(O)cc2)c1
Reaction time: 1 h

Procedure:
To (2′-ethylaminomethyl-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid ethyl ester (0.59 g, 1.49 mmol) and diisopropylethylamine (0.65 mL, 3.73 mmol) in CH2Cl2 (6 mL) at 0° C. was added phosgene (20% in toluene; 1.2 mL, 2.24 mmol), and the reaction was stirred for 1 hour. 4-Hydroxybenzylamine (0.278 g, 2.24 mmol) and triethylamine (1 mL, 7.47 mmol) were then added, and the reaction was stirred for 2 hours. Analytical LCMS indicated the starting material was still present, so additional 4-hydroxybenzylamine (0.184 g, 1.49 mmol) was added, and the reaction was stirred for another 30 minutes. The mixture was partitioned between CH2Cl2 and H2O, and the organic layer was dried over MgSO4, filtered, and concentrated. The residue was purified by silica gel chromatography (0-100% EtOAc in hexanes) to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:31]=[CH:30][C:6]([CH2:7][NH:8][C:9]2[N:14]=[C:13]([CH2:15][CH2:16][CH2:17][CH2:18][CH:19](O)[CH:20]=[CH:21][C:22]3[CH:23]=[N:24][C:25]([CH3:28])=[N:26][CH:27]=3)[CH:12]=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.C(O)(=O)CC.Cl.[Cl-].[Na+].O.[C:41]([CH3:51])(OCC)([O:45]CC)[O:42][CH2:43][CH3:44]>>[CH2:43]([O:42][C:41](=[O:45])[CH2:51][CH:21]([C:22]1[CH:23]=[N:24][C:25]([CH3:28])=[N:26][CH:27]=1)[CH:20]=[CH:19][CH2:18][CH2:17][CH2:16][CH2:15][C:13]1[CH:12]=[CH:11][CH:10]=[C:9]([NH:8][CH2:7][C:6]2[CH:30]=[CH:31][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[N:14]=1)[CH3:44]
Reactant: CCOC(C)(OCC)OCC
Reactant: COc1ccc(CNc2cccc(CCCCC(O)C=Cc3cnc(C)nc3)n2)cc1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCC(=O)O
Product: CCOC(=O)CC(C=CCCCCc1cccc(NCc2ccc(OC)cc2)n1)c1cnc(C)nc1
Temperature: 25 °C
Yield: 86 %

Procedure:
A solution of the allylic alcohol 16-4 (2.3 g, 5.49 mmol) in (EtO)3CMe (10 mL) was treated with 100 uL of a 1 mL solution of (EtO)3CMe containing 10 uL of propionic acid. The yellow solution was heated at 150° for 90 minutes. The solution was cooled to room temperature and poured into 1N HCl/brine. The mixture was extracted with CHCl3, dried, concentrated, and purified on silica gel (90:5:5 CHCl3:EtOAc:MeOH) to give 2.32 g (86%) of 16-7.
Reaction SMILES: [C:1]([Si:5](Cl)([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].[Cl:9][CH2:10][CH2:11][CH2:12][CH2:13][OH:14].N1C=CC=CC=1>C1COCC1.[N+]([O-])([O-])=O.[Ag+]>[Si:5]([O:14][CH2:13][CH2:12][CH2:11][CH2:10][Cl:9])([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:7])[CH3:6]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCCCCCl
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCCCCCl
Reaction time: 4 h

Procedure:
t-Butylchlorodimethylsilane (8.3 g, 55 mmol) was added to a stirred mixture of 4-chlorobutanol (5.0 mL, 50 mmol), silver nitrate (12.8 g, 75.1 mmol), and pyridine (4.0 mL, 50 mmol) in 40 mL of dry THF. After 4 hr, the reaction mixture was filtered through Celite and evaporated to give a yellow oil. The material was purified by distillation to provide 4-chlorobutyl t-butyldimethylsilyl ether as a colorless oil (11 g, quantitative). To a solution of triphenylmethane (5.10 g, 20.8 mmol) in 25 mL of dry THF at -78° C., 13.1 mL (21 mmol) of 1.6M n-butyllithium was added dropwise under nitrogen. Shortly thereafter, 4.29 g (19.3 mmol) of 4-chlorobutyl t-butyldimethylsilyl ether was added. After addition of water and extraction with hexane, the product was purified by chromatography on silica gel with 1:3 dichloromethane-hexane, providing t-butyldimethylsilyl 5,5,5-triphenylpentyl ether as an oil (6.85 g). This material was dissolved in THF (30 mL) and 16 mL of 1.0M tetrabutylammonium fluoride in THF was added. After 3 hr, the mixture was acidified with 1N HCl, extracted with three portions of ethyl acetate, and the extracts dried over magnesium sulfate and evaporated in vacuo. The product was purified by chromatography on silica gel with a 10%-20% gradient of ethyl acetate in hexane, providing the title compound as a white solid, 3.83 g (63% overall).
Reaction SMILES: [CH:1]([C@H:4]1[CH2:8][O:7][C:6](=[O:9])[N:5]1[C:10](=[O:21])[CH2:11][C:12]([CH3:20])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH3:13])([CH3:3])[CH3:2].[Na].I[CH3:24]>O1CCCC1.O.C(OCC)(=O)C>[CH3:24][C@@H:11]([C:12]([CH3:20])([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[CH3:13])[C:10]([N:5]1[C@@H:4]([CH:1]([CH3:3])[CH3:2])[CH2:8][O:7][C:6]1=[O:9])=[O:21]
Reactant: CI
Reactant: CC(C)[C@H]1COC(=O)N1C(=O)CC(C)(C)c1ccccc1
Agent: [Na]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)[C@H]1COC(=O)N1C(=O)[C@@H](C)C(C)(C)c1ccccc1
Temperature: 25 °C
Yield: 70.9 %

Procedure:
A solution of (4S)-4-isopropyl-3-(3-methyl-3-phenylbutanoyl)-1,3-oxazolidin-2-one (0.23 g, 0.79 mmol, from Reference Example 23) in anhydrous tetrahydrofuran (3 mL) is cooled to −78° C. in a dry-ice/acetone bath while stirring under a nitrogen atmosphere. Sodium hexamethylsilazide (1.0 M solution in tetrahydrofuran, 0.95 mL, 0.95 mmol) is added dropwise to the solution via syringe. After stirring for 30 minutes at −78° C., iodomethane (0.25 mL, 4.0 mmol) in tetrahydrofuran (1 mL) is added dropwise. The reaction mixture is stirred overnight (18 hours) while warming to room temperature. The reaction mixture is diluted with water (10 mL) and ethyl acetate (10 mL). The aqueous phase is extracted thrice with ethyl acetate. The combined extracts are washed with saturated aqueous sodium hydrogen carbonate and saturated aqueous sodium chloride, dried over sodium sulfate, decanted, and concentrated under reduced pressure to afford a clear yellow oil, which slowly solidified to an amorphous solid under high vacuum. The crude material is purified by flash chromatography (ethyl acetate/hexanes) to afford a crystalline solid (0.17 g, 71%). MS (ES+): (M+H)=303.9
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[N:14]([S:15]([C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)(=[O:17])=[O:16])[CH:13]=[C:12]([CH2:24][N:25](C)[C:26](=O)[O:27][C:28]([CH3:31])(C)C)[CH:11]=1.[C:34]([O:37]CC)(=[O:36])[CH3:35].Cl.C([OH:43])C>>[C:28]([OH:43])(=[O:27])/[CH:31]=[CH:35]/[C:34]([OH:37])=[O:36].[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[N:14]([S:15]([C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)(=[O:17])=[O:16])[CH:13]=[C:12]([CH2:24][NH:25][CH3:26])[CH:11]=1
Reactant: CCOC(C)=O
Reactant: COc1ccc(F)c(-c2cc(CN(C)C(=O)OC(C)(C)C)cn2S(=O)(=O)c2cccnc2)c1
Reactant: CCO
Agent: Cl
Product: CNCc1cc(-c2cc(OC)ccc2F)n(S(=O)(=O)c2cccnc2)c1
Product: O=C(O)/C=C/C(=O)O
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 78 %

Procedure:
tert-Butyl {[5-(2-fluoro-5-methoxyphenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (475 mg) was dissolved in ethanol (10 mL), a 4 mol/L hydrogen chloride-ethyl acetate solution (2 mL) was added and the mixture was stirred at 70° C. for 30 min. The reaction mixture was concentrated under reduced pressure, a saturated aqueous sodium hydrogencarbonate solution was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was dissolved in ethyl acetate, added to a solution (13 mL) of fumaric acid (116 mg) in methanol, and the obtained crystals were collected by filtration to give the title compound as colorless crystals (yield 385 mg, 78%).
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]1[O:14][C:13](=[O:15])[N:12]([C:16]2[CH:21]=[CH:20][C:19](I)=[CH:18][CH:17]=2)[CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[F:23][C:24]1[CH:25]=[C:26]([N:34]2[CH2:38][C@H:37]([CH2:39][N:40]3[CH:44]=[C:43]([CH3:45])[N:42]=[N:41]3)[O:36][C:35]2=[O:46])[CH:27]=[CH:28][C:29]=1[Sn](C)(C)C>>[Si:1]([O:8][CH2:9][C@@H:10]1[O:14][C:13](=[O:15])[N:12]([C:16]2[CH:21]=[CH:20][C:19]([C:29]3[CH:28]=[CH:27][C:26]([N:34]4[CH2:38][C@H:37]([CH2:39][N:40]5[CH:44]=[C:43]([CH3:45])[N:42]=[N:41]5)[O:36][C:35]4=[O:46])=[CH:25][C:24]=3[F:23])=[CH:18][CH:17]=2)[CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: Cc1cn(C[C@H]2CN(c3ccc([Sn](C)(C)C)c(F)c3)C(=O)O2)nn1
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1CN(c2ccc(I)cc2)C(=O)O1
Product: Cc1cn(C[C@H]2CN(c3ccc(-c4ccc(N5C[C@H](CO[Si](C)(C)C(C)(C)C)OC5=O)cc4)c(F)c3)C(=O)O2)nn1
Yield: 4.3 %

Procedure:
Using essentially the same procedure as Example 28, but starting from (5R)-5-({[tert-butyl(dimethyl)silyl]oxy}methyl)-3-(4-iodophenyl)-1,3-oxazolidin-2-one (0.43 g, 1.00 mM) and adding (5R)-3-[3-fluoro-4-(trimethylstannyl)phenyl]-5-[(4-methyl-1H-1,2,3-triazol-1-yl)methyl]-1,3-oxazolidin-2-one (0.66 g, 1.50 mM) gave the title compound as a white solid (0.025 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=[C:14]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[C:15]2[O:16][C:17]([CH:20]3[CH2:23][N:22](C(OCC4C5C=CC=CC=5C5C4=CC=CC=5)=O)[CH2:21]3)=[N:18][N:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(S)CCCCCC>C1COCC1.C1CCN2C(=NCCC2)CC1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11](=[C:14]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[C:15]2[O:16][C:17]([CH:20]3[CH2:21][NH:22][CH2:23]3)=[N:18][N:19]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(=C(c2ccccc2)c2nnc(C3CN(C(=O)OCC4c5ccccc5-c5ccccc54)C3)o2)CC1
Agent: CCCCCCCS
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(=C(c2ccccc2)c2nnc(C3CNC3)o2)CC1
Reaction time: 18 h
Yield: 74.7 %

Procedure:
To a solution of 4-[1-phenyl-1-(5-(N-(9-fluorenylmethoxycarbonyl)azetidin-3-yl)-1,3,4-oxadiazol-2-yl)methylene]piperidine-1-carboxylic acid tert-butyl ester (0.161 g, 0.260 mmol) and heptanethiol (0.398 mL, 2.60 mmol) in THF (2.6 mL) at rt was added DBU (2 drops). The mixture was allowed to stir for 18 h and then the solvent was removed in vacuo. The residue was dissolved in MeOH and purified by preparative HPLC(NH4OAc) to afford the title compound (0.077 g, 74%) as a colorless solid:
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:18]=[CH:17][CH:16]=[CH:15][C:4]=1[CH2:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:13]O.[BrH:21].[C:22]1([PH+:28]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(#N)C>[Br-:21].[C:35]1([P+:28]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:13][C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[O:6][CH2:5][C:4]2[CH:15]=[CH:16][CH:17]=[CH:18][C:3]=2[C:2]([F:20])([F:19])[F:1])[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: OCc1ccccc1OCc1ccccc1C(F)(F)F
Reactant: Br
Reactant: c1ccc([PH+](c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: FC(F)(F)c1ccccc1COc1ccccc1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Product: [Br-]
Yield: 95.8 %

Procedure:
A solution of 4.913 g (17.41 mmol) of [2-(2-trifluoromethylbenzyloxy)phenyl]methanol from Example 80A in 70 ml of acetonitrile is mixed with 5.675 g (16.54 mmol) of triphenylphosphonium hydrobromide and heated to reflux for 3 hours. The reaction solution is then concentrated to dryness, and the resulting oil is taken up and triturated in diethyl ether. The product crystallizes as a white solid during this. After filtration, the solid is dried in a drying oven at 50° C. overnight. 9.621 g (88% yield) of crystalline product are obtained.
Reaction SMILES: [C:1]1([C:7](=O)[C:8]([O:10][CH2:11][CH2:12][O:13][CH3:14])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[OH:17][NH3+:18].C(OCC)(=O)C.O>N1C=CC=CC=1>[OH:17][N:18]=[C:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:8]([O:10][CH2:11][CH2:12][O:13][CH3:14])=[O:9]
Reactant: [NH3+]O
Reactant: COCCOC(=O)C(=O)c1ccccc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: O
Product: COCCOC(=O)C(=NO)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 102.9 %

Procedure:
61.7 g (0.296 mol) of 2-methoxyethyl phenylglyoxalate are dissolved in 360 ml pyridine. 22.7 g (0.0.326 mol) of hydroxylammonium hydrochloride are added in portions to this solution. When the addition is complete, the reaction mixture is stirred at room temperature for 2 hours. After addition of ethyl acetate and water, the organic layer is separated, washed with diluted HCl and water and dried over magnesium sulfate. Evaporation of the solvent gives 68 g (100%) of crude 2-methoxyethyl α-(hydroxyimino)-2-phenylacetate as a slightly brownish liquid. This compound is used without further purification in the next step.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][N:14]=[CH:13][C:12]=2[Cl:17])=[O:9])=[CH:6][C:5](Br)=[CH:4][N:3]=1.[CH3:19][O:20][CH2:21][CH2:22][N:23]1[CH:27]=[C:26](B2OC(C)(C)C(C)(C)O2)[CH:25]=[N:24]1>>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:26]2[CH:25]=[N:24][N:23]([CH2:22][CH2:21][O:20][CH3:19])[CH:27]=2)=[CH:6][C:7]=1[C:8]([NH:10][C:11]1[CH:16]=[CH:15][N:14]=[CH:13][C:12]=1[Cl:17])=[O:9]
Reactant: COCCn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Nc1ncc(Br)cc1C(=O)Nc1ccncc1Cl
Product: COCCn1cc(-c2cnc(N)c(C(=O)Nc3ccncc3Cl)c2)cn1

Procedure:
Reaction of 2-amino-5-bromo-N-(3-chloro-4-pyridyl)pyridine-3-carboxamide with 1-(2-methoxy-ethyl)-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole gives the compound “A38”; HPLC/MS: 1.39 min, [M+H]=373;
Reaction SMILES: OC(C(F)(F)F)=O.[CH:8]([C@:11]1([C:17]([N:19]2[CH2:28][CH2:27][C:26]3[C:21](=[CH:22][C:23]([C:29]([F:32])([F:31])[F:30])=[CH:24][CH:25]=3)[CH2:20]2)=[O:18])[CH2:15][CH2:14][C@@H:13]([NH2:16])[CH2:12]1)([CH3:10])[CH3:9].[OH:33][C:34]1([C:41]2[S:42][CH:43]=[CH:44][N:45]=2)[CH2:39][CH2:38][C:37](=O)[CH2:36][CH2:35]1.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.C([O-])(O)=O.[Na+]>[CH:8]([C@:11]1([C:17]([N:19]2[CH2:28][CH2:27][C:26]3[C:21](=[CH:22][C:23]([C:29]([F:32])([F:30])[F:31])=[CH:24][CH:25]=3)[CH2:20]2)=[O:18])[CH2:15][CH2:14][C@@H:13]([NH:16][CH:37]2[CH2:38][CH2:39][C:34]([C:41]3[S:42][CH:43]=[CH:44][N:45]=3)([OH:33])[CH2:35][CH2:36]2)[CH2:12]1)([CH3:10])[CH3:9]
Reactant: CC(C)[C@]1(C(=O)N2CCc3ccc(C(F)(F)F)cc3C2)CC[C@@H](N)C1
Reactant: O=C1CCC(O)(c2nccs2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CC(C)[C@]1(C(=O)N2CCc3ccc(C(F)(F)F)cc3C2)CC[C@@H](NC2CCC(O)(c3nccs3)CC2)C1
Reaction time: 8 h

Procedure:
To a solution of (1R,3S)-3-isopropyl-3-{[7-(trifluoromethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}cyclopentanamine TFA salt (46.8 mg, 0.132 mmol) and 4-hydroxy-4-(1,3-thiazol-2-yl)cyclohexanone (30.4 mg, 0.154 mmol) in dichloromethane (10 mL) was added triethylamine (23.6 uL, 0.169 mmol) followed by sodium triacetoxyborohydride (56 mg, 0.26 mmol) at room temperature. After being stirred overnight, the mixture was diluted with dichloromethane and neutralized with NaHCO3. The organic layer was washed with brine, dried over Na2SO4 and concentrated. The residue was purified by flash chromatography on silica to give two isomers. Isomer 1 and isomer 2: LC-MS calculated for C28H36F3N3O2S: (M+H)+536; found 536.2.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][O:8][CH:9]([CH3:12])[CH:10]=O.N[C:14]1[NH:18][CH:17]=[N:16][C:15]=1[C:19]([NH2:21])=[O:20].C(O)(=O)C.C([BH3-])#[N:27].[Na+]>>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][O:8][CH:9]([CH3:12])[CH2:10][NH:27][N:16]1[C:15]([C:19]([NH2:21])=[O:20])=[CH:14][N:18]=[CH:17]1
Reactant: CC(C=O)OCc1ccccn1
Reactant: NC(=O)c1nc[nH]c1N
Reactant: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(CNn1cncc1C(N)=O)OCc1ccccn1
Reaction time: 1 h

Procedure:
The title compound was prepared in accordance with the general method described in Example 17(e) using 2-(pyridin-2-ylmethoxy)-propanal (0.875 g, 5.30 mmol, obtained from Example 20(b)), 5-aminoimidazole-4-carboxamide (0.668 g, 5.30 mmol), acetic acid (0.61 mL, 10.6 mmol) and sodium cyanoborohydride (0.666 g, 10.6 mmol) with the exception that the solution of aldehyde and carboxamide was stirred for 1 h and that sodium cyanoborohydride was added after 15 min. This yielded 1.32 g of the title compound, which was used in the next step without purification. MS (ESI) m/z 276 (M+1).
Reaction SMILES: [Br:1]Br.[F:3][C:4]1[CH:5]=[C:6]([CH2:11][C:12]([CH3:20])([CH3:19])[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:7]=[CH:8][C:9]=1[OH:10]>C(Cl)(Cl)(Cl)Cl>[Br:1][C:8]1[CH:7]=[C:6]([CH2:11][C:12]([CH3:19])([CH3:20])[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:5]=[C:4]([F:3])[C:9]=1[OH:10]
Reactant: CCOC(=O)CC(C)(C)Cc1ccc(O)c(F)c1
Reactant: BrBr
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)CC(C)(C)Cc1cc(F)c(O)c(Br)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Bromine solution (12.4 ml, 12.4 mmol, 1.0 M in CCl4) was added a solution of the product of STEP 6 (1.58 g, 6.2 mmol) in 30 ml CCl4 at 0° C. over 5 min. The reaction was stirred at room temperature for 30 min, and quenched with saturated NaHCO3 solution. The product was extracted with ethyl acetate. The aqueous layer was extracted with ethyl acetate. The combined organic layer was washed brine, dried with Na2SO4, and concentrated. The residue was purified by chromatography (on silica gel, ethyl acetate/ hexane=1/9) to give a colorless oil in 0.73 g. NMR spectra of the product were consistent for the proposed structure.
Reaction SMILES: [F:1]C1C=C(N)C=CC=1OC1C=CN=C2C=C(C3N(C)C=CN=3)SC=12.[F:25][C:26]1[CH:27]=[C:28]([NH:48][C:49](=[O:62])[CH2:50][C:51]([NH:53][C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][C:55]=2[O:60]C)=[O:52])[CH:29]=[CH:30][C:31]=1[O:32][C:33]1[CH:38]=[CH:37][N:36]=[C:35]2[CH:39]=[C:40]([C:42]3[N:43]([CH3:47])[CH:44]=[CH:45][N:46]=3)[S:41][C:34]=12.COC1C=CC=CC=1NC(=O)CC(O)=O.FC1C=CC=CC=1NC(=O)CC(O)=O>>[F:25][C:26]1[CH:27]=[C:28]([NH:48][C:49](=[O:62])[CH2:50][C:51]([NH:53][C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][C:55]=2[O:60][F:1])=[O:52])[CH:29]=[CH:30][C:31]=1[O:32][C:33]1[CH:38]=[CH:37][N:36]=[C:35]2[CH:39]=[C:40]([C:42]3[N:43]([CH3:47])[CH:44]=[CH:45][N:46]=3)[S:41][C:34]=12
Reactant: Cn1ccnc1-c1cc2nccc(Oc3ccc(N)cc3F)c2s1
Reactant: COc1ccccc1NC(=O)CC(=O)Nc1ccc(Oc2ccnc3cc(-c4nccn4C)sc23)c(F)c1
Agent: COc1ccccc1NC(=O)CC(=O)O
Agent: O=C(O)CC(=O)Nc1ccccc1F
Product: Cn1ccnc1-c1cc2nccc(Oc3ccc(NC(=O)CC(=O)Nc4ccccc4OF)cc3F)c2s1
Yield: 5 %

Procedure:
Starting from the amine 9 and following the procedure described above for the compound 28a (example 8, step 2) but substituting acid 27 for the acid 29, title compound 30a was obtained as a white solid in 5% yield. 1H NMR (DMSO-d6) δ (ppm): 10.56 (s, 1H), 10.04 (s, 1H), 8.50 (d, 1H), 7099-7.95 (m, 1H), 7.88 (s, 1H), 7.86 (dd, 1H), 7.50 (t, 2H) 7.42 (dd, 1H), 7.40 (s, 1H), 7.29-7.24 (m, 1H), 7.17-7.14 (m, 1H), 7.03 (s, 1H), 6.69 (d, 1H), 4.00 (s, 3H), 3.64 (s, 2H). MS (m/z): 520.1 (M+H).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[F:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1>CN(C=O)C.O.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>[F:20][C:21]1[CH:26]=[CH:25][C:24]([C:2]2[CH:3]=[N:4][C:5]3[C:10]([CH:11]=2)=[CH:9][CH:8]=[CH:7][CH:6]=3)=[CH:23][CH:22]=1
Reactant: Brc1cnc2ccccc2c1
Reactant: OB(O)c1ccc(F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Fc1ccc(-c2cnc3ccccc3c2)cc1
Temperature: 80 °C
Yield: 65.3 %

Procedure:
3-Bromo quinoline (2 g, 0.0096 mol) was dissolved in DMF:water (3:1, 20 mL), and potassium phosphate (6 g, 0.0288 mol) and 4-fluorophenyl boronic acid (1.6 g, 0.011 mol) were added at RT. The reaction mixture was degassed for 5 min, and Pd(PPh3)4 (0.55 g, 0.00048 mol) was added. The reaction mixture was heated by microwave at 80° C. for 1 h. After completion of reaction (monitored by TLC), the mixture was diluted with water (150 mL) and extracted with EtOAc (3×150 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum, the residue was purified by column chromatography (30% EtOAc:Hexane in silica 100-200 mesh, diameter of column—5.0 cm, height of silica—approx. 5 inch) to provide the desired compound as a white solid (1.4 g, 66% yield).
Reaction SMILES: C1(C)C=CC(S(Cl)(=O)=[O:8])=CC=1.[Br:12][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([CH:23]([C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=3)[C:24]3[S:25][CH:26]=[CH:27][N:28]=3)[CH:21]=2)[N+:16]([O-])=[CH:15][CH:14]=1>ClCCl.C([O-])([O-])=O.[Na+].[Na+].O>[Br:12][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([CH:23]([C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=3)[C:24]3[S:25][CH:26]=[CH:27][N:28]=3)[CH:21]=2)[NH:16][C:15](=[O:8])[CH:14]=1
Reactant: [O-][n+]1ccc(Br)c2cc(C(c3ccc(Cl)cc3)c3nccs3)ccc21
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: O=c1cc(Br)c2cc(C(c3ccc(Cl)cc3)c3nccs3)ccc2[nH]1
Reaction time: 1 h

Procedure:
p-Toluenesulfonyl chloride (628 mg, 3.293 mmol, 1.5 equip) was added to a biphasic mixture of 4-bromo-6-((4-chlorophenyl)(thiazol-2-yl)methyl)quinoline 1-oxide in dichloromethane (6 mL) and 10% Na2CO3 (42 mL) and the resulting mixture stirred for 1 h. The reaction mixture was diluted with dichloromethane and water, the layers were separated, and the aqueous layer was extracted with dichloromethane. The combined organic extracts were dried over Na2SO4, filtered, and concentrated. The residue was purified by MPLC to yield 4-bromo-6-((4-chlorophenyl)(thiazol-2-yl)methyl)quinolin-2(1H)-one as a white solid.
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[S:7][CH:8]=[CH:9][CH:10]=1)CCC.[CH2:19]([O:21][C:22](=[O:31])[CH2:23][C:24]1[CH:29]=[CH:28][C:27](Br)=[CH:26][CH:25]=1)[CH3:20]>C1(C)C=CC=CC=1.[Pd].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.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>[CH2:19]([O:21][C:22](=[O:31])[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:6]2[S:7][CH:8]=[CH:9][CH:10]=2)=[CH:26][CH:25]=1)[CH3:20]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccs1
Reactant: CCOC(=O)Cc1ccc(Br)cc1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)Cc1ccc(-c2cccs2)cc1
Yield: 68 %

Procedure:
Nitrogen was bubbled through a mixture of 2-tributylstannyl thiophene (15.68 ml, 49.4 mmol) and ethyl(4-bromophenyl)acetate (6 g, 24.7 mmol) in toluene (250 ml) before 0.5 g of tetrakis (triphenylphosphine) palladium (0) was added. The mixture was heated at reflux under nitrogen for 4 hours before it was filtered through magnesol and concentrated. The residue was purified using silica-gel column chromatography by eluting it with 20% ethyl acetate: hexane solution. Ethyl[4-(2-thienyl)phenyl]acetate was isolated as a yellow oil (4.15 g). Yield 68%; MS: 247.5 (M+H)+