Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([Cl:19])[C:13]=3[CH:12]=[C:11]2I)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:21]([O:25][C:26]([N:28]1[CH2:33][CH:32]=[C:31](B2OC(C)(C)C(C)(C)O2)[CH2:30][CH2:29]1)=[O:27])([CH3:24])([CH3:23])[CH3:22].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:21]([O:25][C:26]([N:28]1[CH2:29][CH:30]=[C:31]([C:11]2[N:10]([S:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)(=[O:9])=[O:8])[C:14]3[N:15]=[CH:16][N:17]=[C:18]([Cl:19])[C:13]=3[CH:12]=2)[CH2:32][CH2:33]1)=[O:27])([CH3:24])([CH3:22])[CH3:23]
Reactant: O=S(=O)(c1ccccc1)n1c(I)cc2c(Cl)ncnc21
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CC=C(c2cc3c(Cl)ncnc3n2S(=O)(=O)c2ccccc2)CC1
Temperature: 90 °C

Procedure:
7-Benzenesulfonyl-4-chloro-6-iodo-7H-pyrrolo[2,3-d]pyrimidine (4.05 g, 9.65 mmol), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (2.985 g, 9.65 mmol), potassium carbonate (2.935 g, 21.25 mmol) and dichlorobis(triphenylphosphine)-palladium(II) (678 mg, 0.96 mmol) were combined in dioxane/water (85 mL:21 mL) and heated to 90° C. for 2 h. After cooling the reaction mixture was extracted with ethyl acetate (3×50 mL), the organic layers were combined and washed with aqueous sodium bicarbonate, brine and finally water. The organic layer was dried over anhydrous magnesium sulphate, filtered and pre-absorbed onto silica in vacuo. Purification on silica gel by gradient elution with isohexane:ethyl acetate (6:1) finishing with isohexane:ethyl acetate (4:1) yielded a yellow solid. 1H NMR (d6-DMSO, 400 MHz) 8.8(1H, s), 8.0 (2H, d), 7.8(1H,m), 7.6(2H,m), 6.8(1H, s), 6.0(1H, s), 4.1(2H, br. s), 3.6(2H,m), 2.5(2H, br. s), and 1.5(9H, s); LC/MS: m/z 474 [M+H]+, Rt=4.42 min
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[OH:7][C:8]1[C:17]2[C:12](=[C:13]([Cl:18])[CH:14]=[CH:15][CH:16]=2)[N:11]=[CH:10][C:9]=1[C:19](Cl)=[O:20]>N1C=CC=CC=1>[S:3]1[CH:4]=[CH:5][N:6]=[C:2]1[NH:1][C:19]([C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:8]=1[OH:7])=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])=[O:20]
Reactant: Nc1nccs1
Reactant: O=C(Cl)c1cnc2c(Cl)cccc2c1O
Solvent: c1ccncc1
Product: O=C(Nc1nccs1)c1cnc2c(Cl)cccc2c1O
Temperature: 25 °C
Reaction time: 16 h
Yield: 73.5 %

Procedure:
A solution of 2.9 g of 2-amino-thiazole in 20 ml of pyridine was added at room temperature to a suspension of 7 g of the acid chloride of Step A in 90 ml of pyridine and the mixture was stirred for 16 hours at room temperature. The pyridine was evaporated and a mixture of potassium carbonate solution and water was added to the residue. The reaction mixture was stirred and vacuum filtered and the recovered precipitate was washed and dried. The product was crystallized from dimethylformamide to obtain 6.5 g of N-[2-thiazolyl] -4-hydroxy-8-chloro-3-quinoline-carboxamide melting above 369° C.
Reaction SMILES: [NH:1]([CH2:5][C:6]([O-:8])=O)[C:2]([NH2:4])=[O:3].[NH2:9][OH:10]>O1CCOCC1>[OH:10][NH:9][C:6](=[O:8])[CH2:5][NH:1][C:2]([NH2:4])=[O:3]
Reactant: NO
Reactant: NC(=O)NCC(=O)[O-]
Solvent: C1COCCO1
Product: NC(=O)NCC(=O)NO

Procedure:
A stock solution of triphosgene was prepared from solid triphosgene (1.48 g, 5 mmol) and DCM (20 mL). The solution was cooled to −78° C. and triethylamine (2 mL, 15 mmol) was slowly added. To ArgoGel-Wang or ArgoGel-OH resin bound 2-aminoacetate 4 (0.5 g) was added the triphosgene solution (3.5 mL) and the resin was shaken at rt for 1 h. The resin was drained, washed with DCM (3×) and then suspended in a solution of secondary amine 7 (e.g., pyrrolidine, 2 mmol) and TEA (3 mmol) in DCM (2 mL). After 16 h, the resin was washed with DCM and MeOH (3× each) to yield ArgoGel-Wang or ArgoGel-OH resin bound 2-ureidoacetate 6 which was then treated with a solution of aqueous 50% hydroxylamine (2 mL) and dioxane (1 mL) for 2 days. The resin was filtered, washed with acetonitrile and the filtrates combined and purified by preparative reverse-phase (C18) HPLC to yield product N-hydroxy-2-ureidoacetamide (I).
Reaction SMILES: [CH2:1]([O:8][NH:9][S:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N+:19]([O-:21])=[O:20])(=[O:12])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O[C@@H:23]1[CH2:28][N:27]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[C@H:26]([C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH2:25][CH2:24]1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[CH2:1]([O:8][N:9]([C@H:23]1[CH2:28][N:27]([C:29]([O:31][C:32]([CH3:33])([CH3:34])[CH3:35])=[O:30])[C@H:26]([C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH2:25][CH2:24]1)[S:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N+:19]([O-:21])=[O:20])(=[O:12])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)NOCc1ccccc1
Reactant: CCOC(=O)[C@@H]1CC[C@H](O)CN1C(=O)OC(C)(C)C
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)[C@@H]1CC[C@@H](N(OCc2ccccc2)S(=O)(=O)c2ccccc2[N+](=O)[O-])CN1C(=O)OC(C)(C)C
Temperature: 20 °C
Reaction time: 8 h
Yield: 79.9 %

Procedure:
To a solution of N-(benzyloxy)-2-nitrobenzenesulfonamide (212 g, 0.69 mol) in THF (1000 mL) was added (2S,5S)-1-tert-butyl 2-ethyl 5-hydroxypiperidine-1,2-dicarboxylate (171 g, 0.63 mol) and PPh3 (275 g, 1.05 mol), followed by dropwise addition of a solution of DEAD (195 g, 1.12 mol) in THF (500 mL). The mixture was then stirred at 20° C. overnight. The reaction mixture was then concentrated in vacuum and purified by silica gel column chromatography (3:1 petroleum ether/EtOAc) to afford (2S,5R)-1-tert-butyl 2-ethyl 5-(N-(benzyloxy)-2-nitrophenylsulfonamido)piperidine-1,2-dicarboxylate (283.8 g, 80%) as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](I)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[Cl:10][C:11]1[CH:12]=[C:13]([SH:18])[CH:14]=[C:15]([Cl:17])[CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([S:18][C:13]2[CH:14]=[C:15]([Cl:17])[CH:16]=[C:11]([Cl:10])[CH:12]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: Sc1cc(Cl)cc(Cl)c1
Reactant: Clc1cc(Cl)cc(I)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Clc1cc(Cl)cc(Sc2cc(Cl)cc(Cl)c2)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 94.9 %

Procedure:
Into a 300 ml three-necked glass flask equipped with a thermometer, a reflux condenser and a stirrer, 3,5-dichloroiodobenzene 22.6 g (82.8 mmol) and dimethylformamide 200 ml were added, and argon was passed through the solution for 2 hours and 15 minutes. Then, 3,5-dichlorothiophenol 14.8 g (82.6 mmol), potassium carbonate 22.8 g (165 mmol) and cuprous iodide 1.57 g (8.24 mmol) were added, which were reacted for 3 hours at 95 to 100° C. with stirring. After completion of the reaction, the reaction mixture was cooled down to room temperature and separated with the addition of water and hexane:ethyl acetate (1:1), and the organic layer obtained was dried with anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the obtained concentrate was purified by recrystallization, simple silica-gel column chromatography (eluent; hexane) to obtain bis(3,5-dichlorophenyl)sulfide 25.4 g as white solid (isolation yield; 95%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.[N:21]([C:24]1[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=1)=[C:22]=[O:23]>CN(C=O)C>[F:31][C:30]([F:32])([F:33])[C:27]1[CH:26]=[CH:25][C:24]([NH:21][C:22]([N:18]2[CH2:19][CH2:20][CH:15]([C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][N:7]=3)[CH2:16][CH2:17]2)=[O:23])=[CH:29][CH:28]=1
Reactant: O=C=Nc1ccc(C(F)(F)F)cc1
Reactant: COc1cc2ncnc(C3CCNCC3)c2cc1OC
Solvent: CN(C)C=O
Product: COc1cc2ncnc(C3CCN(C(=O)Nc4ccc(C(F)(F)F)cc4)CC3)c2cc1OC
Yield: 26.7 %

Procedure:
A solution of 6,7-dimethoxy-4-piperidin-4-yl-quinazoline (20 mg, 0.0733 mmol), as prepared in Example 1d, in DMF (1 mL) was treated with 1-isocyanato-4-trifluoromethyl-benzene (20 mg, 0.107 mmol) at RT overnight. The reaction was then partitioned between EtOAc (10 mL) and H2O (10 mL). The organic phase was dried over Na2SO4 and concentrated in vacuo. Purification by prep tlc (1:9 MeOH/DCM) afforded the title compound as a yellow solid (9.0 mg, 27%). 1H NMR (300 MHz, CDCl3) δ 9.10 (s, 1H), 7.54 (m, 2H), 7.39 (m, 1H), 7.28 (m, 2H), 6.69 (m, 1H), 6.63 (br s, NH), 4.33-4.29 (m, 2H), 4.09 (s, 6H), 3.65 (m, 1H), 3.22 (m, 2H), 2.17 (m, 2H), 2.06-2.01 (m, 2H); LC/MS (ESI) calcd mass 460.2, found 461.3 [M+1]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:31](=[CH:32][CH:33]=1)[O:30][CH2:29][C:25]1([CH2:28][O:27][CH2:26]1)[C:5]12[CH2:9][O:8][C:7]([N:10]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[N:6]1.CC1(C)C(C)(C)OB([C:42]2[CH2:43][CH2:44][O:45][CH2:46][CH:47]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[O:45]1[CH2:44][CH:43]=[C:42]([C:2]2[CH:3]=[C:4]3[C:31](=[CH:32][CH:33]=2)[O:30][CH2:29][C:25]2([CH2:26][O:27][CH2:28]2)[C:5]23[CH2:9][O:8][C:7]([N:10]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:11]([O:13][C:14]([CH3:16])([CH3:15])[CH3:17])=[O:12])=[N:6]2)[CH2:47][CH2:46]1
Reactant: CC1(C)OB(C2=CCOCC2)OC1(C)C
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)C1=NC2(CO1)c1cc(Br)ccc1OCC21COC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)C1=NC2(CO1)c1cc(C3=CCOCC3)ccc1OCC21COC1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
A mixture of di-tert-butyl (6′-bromodispiro[1,3-oxazole-4,4′-chromene-3′,3″-oxetan]-2-yl)imidodicarbonate (300 mg, 0.571 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyran (360 mg, 1.71 mmol), bis(triphenylphosphine)palladium(II) dichloride (40.1 mg, 0.057 mmol) and Na2CO3 (182 mg, 1.71 mmol) in dioxane (3.6 mL) and water (0.9 mL) was stirred for 1 hour at 100° C. The mixture was cooled down to ambient temperature and partitioned between EtOAc and water. The organic layer was washed with brine, dried over MgSO4, diluted with hexane, and filtered through silica gel pad (eluted with 50% EtOAc in hexane). The filtrate was concentrated at reduced pressure to give crude di-tert-butyl [6′-(3,6-dihydro-2H-pyran-4-yl)dispiro[1,3-oxazole-4,4′-chromene-3′,3″-oxetan]-2-yl]imidodicarbonate which was used for the next reaction without further purification.
Reaction SMILES: C(P([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])(CC)=O)C.[H-].[Na+].[CH:15]([C:17]1[CH:18]=[C:19]([CH3:36])[C:20]([N:23]2[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]2)=[N:21][CH:22]=1)=O.O>C1COCC1>[CH2:11]([O:10][C:8](=[O:9])/[CH:7]=[CH:15]/[C:17]1[CH:18]=[C:19]([CH3:36])[C:20]([N:23]2[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:34])([CH3:33])[CH3:35])=[O:30])[CH2:25][CH2:24]2)=[N:21][CH:22]=1)[CH3:12]
Reactant: CCOC(=O)CP(=O)(CC)CC
Reactant: Cc1cc(C=O)cnc1N1CCN(C(=O)OC(C)(C)C)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)/C=C/c1cnc(N2CCN(C(=O)OC(C)(C)C)CC2)c(C)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 50.3 %

Procedure:
Ethyl (diethylphosphoryl)acetate (471 mg) was dissolved in THF (15 ml), and NaH (98 mg) was added thereto, followed by stirring at room temperature for 30 minutes. A solution of tert-butyl 4-(5-formyl-3-methylpyridin-2-yl)piperazine-1-carboxylate (493 mg) in THF (5 ml) was added thereto, followed by stirring at room temperature for 3 hours. To the reaction mixture was added water, followed by extraction with CHCl3. The organic layer was dried over Na2SO4 and the solvent was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (CHCl3/MeOH) to obtain tert-butyl 4-{5-[(1E)-3-ethoxy-3-oxoprop-1-en-1-yl]-3-methylpyridin-2-yl}piperazine-1-carboxylate (305 mg).
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:13])[C:4]2([CH3:12])[O:10][C:7]([CH3:11])([C:8]=1Cl)[CH:6]=[CH:5]2.[CH3:14][OH:15].C[O-].[Na+]>CCCCCC.C(OCC)(=O)C>[Cl:1][C:2]1[C:3](=[O:13])[C:4]2([CH3:12])[O:10][C:7]([CH3:11])([C:8]=1[O:15][CH3:14])[CH:6]=[CH:5]2
Reactant: CO
Reactant: CC12C=CC(C)(O1)C(Cl)=C(Cl)C2=O
Agent: C[O-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COC1=C(Cl)C(=O)C2(C)C=CC1(C)O2
Temperature: 25 °C
Yield: 52.9 %

Procedure:
6.0 g (27.39 mmol) of 3,4-dichloro-1,5-dimethyl-8-oxa-bicyclo[3.2.1]octa-3,6-dien-2-one is introduced into 39 ml of anhydrous methanol. At a temperature of 0° C., the reaction mixture is further diluted dropwise with a solution of 15.2 ml of 5.4M sodium methanolate (82.17 mmol) and treated with 10 ml of absolute methanol. The reaction mixture is then heated to ambient temperature with 35 minutes' stirring. Using thin-layer chromatography (hexane/ethyl acetate 8:2) it can be established that reaction of the starting material is complete. The reaction solution is then concentrated under reduced pressure. The residue is then extracted by means of carbon tetrachloride against water. The aqueous phase is extracted a further three times using fresh carbon tetrachloride. The combined organic extracts are dried over sodium sulfate and concentrated by evaporation under reduced pressure; with ice-cooling, the oily product that remains behind crystallises out in the form of a ˜1:1 mixture. The mixture is separated by means of column chromatography on silica gel (eluant: gradient from 1-5% ethyl acetate/hexane). 3.1 g (52.9%) of pure 3-chloro-1,5-dimethyl-4-methoxy-8-oxa-bicyclo[3.2.1]octa-3,6-dien-2-one are isolated.
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2]([CH3:4])=[O:3].[CH2:7]([O:14][C:15](=[O:18])[CH2:16][NH2:17])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>>[CH2:7]([O:14][C:15](=[O:18])[CH2:16][NH:17][C:1](=[O:5])[C:2]([CH3:4])=[O:3])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: NCC(=O)OCc1ccccc1
Reactant: CC(=O)C(=O)Cl
Product: CC(=O)C(=O)NCC(=O)OCc1ccccc1

Procedure:
More preferably the thionyl chloride or oxalyl chloride is added to a mechanically stirred suspension of sodium pyruvate in dichloromethane whereby a gas is evolved and pyruvyl chloride is yielded. The pyruvyl chloride is cooled during the dropwise addition of glycine benzyl ester solution to yield pyruvyl-glycine benzyl ester following the warming to room temperature, the addition of water, separation, washing with diluted hydrochloric acid and brine, drying with magnesium sulfate, evaporation of the dichloromethane, precipitation, filtering and drying again. The pyruvyl-glycine benzyl ester is then charged in a hydrogen pressure vessel with ethyl acetate and 4% to 20% palladium on carbon, with the hydrogen pressure being approximately 40-150 psi, such that hydrogen is digested whereby following warming, filtering, concentration, precipitation, filtering and drying there is yielded pyruvyl-glycine.
Reaction SMILES: [C:1]1([C:8]2[C:9]([OH:14])=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:2]([OH:7])=[CH:3][CH:4]=[CH:5][CH:6]=1.Cl[C:16]([O:18][CH2:19][CH3:20])=[O:17]>N1C=CC=CC=1>[C:16](=[O:17])([O:18][CH2:19][CH3:20])[O:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[O:7][C:16](=[O:17])[O:18][CH2:19][CH3:20]
Reactant: Oc1ccccc1-c1ccccc1O
Reactant: CCOC(=O)Cl
Solvent: c1ccncc1
Product: CCOC(=O)Oc1ccccc1-c1ccccc1OC(=O)OCC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a round-bottom flask is charged biphenyl-2,2′-diol (7.45 g, 40 mmol) and pyridine (50 mL). The flask is immersed in an ice-water bath and ethyl chloroformate (9.48 mL, 100 mmol) is added dropwise. After gradually warming to room temperature, the mixture is stirred overnight. The volatiles are removed in vacuo, and the residue is suspended in 100 mL of ethyl acetate. After filtration, the filtrate is concentrated and purified by flash chromatography. The product is obtained as a colorless oil. Yield: 5.0 g; 1H NMR (500 MHz, CDCl3, ppm) δ 7.23-7.44 (m, 8H), 4.13 (q, 4H), 1.19 (t, 6H).
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[CH2:3][OH:4].[H-].[Na+].[F:9][C:10]([F:38])([F:37])[C:11]1[CH:12]=[C:13]([CH:34]=[CH:35][CH:36]=1)[CH2:14][NH:15][C:16](=[O:33])[C:17]1[CH:22]=[CH:21][N:20]=[C:19]([C:23]2[CH:28]=[C:27](F)[CH:26]=[CH:25][C:24]=2[N+:30]([O-:32])=[O:31])[CH:18]=1>O1CCCC1.O>[F:37][C:10]([F:9])([F:38])[C:11]1[CH:12]=[C:13]([CH:34]=[CH:35][CH:36]=1)[CH2:14][NH:15][C:16](=[O:33])[C:17]1[CH:22]=[CH:21][N:20]=[C:19]([C:23]2[CH:28]=[C:27]([O:4][CH2:3][C:2]([F:6])([F:5])[F:1])[CH:26]=[CH:25][C:24]=2[N+:30]([O-:32])=[O:31])[CH:18]=1
Reactant: O=C(NCc1cccc(C(F)(F)F)c1)c1ccnc(-c2cc(F)ccc2[N+](=O)[O-])c1
Reactant: OCC(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(NCc1cccc(C(F)(F)F)c1)c1ccnc(-c2cc(OCC(F)(F)F)ccc2[N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of 2,2,2-trifluoroethanol (150 mg, 1.50 mmol, 2.00 equiv) in tetrahydrofuran (10 mL). This was followed by the addition of sodium hydride (180 mg, 7.50 mmol, 10.00 equiv), in portions at 0° C. The resulting solution was stirred for 20 min at 0° C. in an ice/salt bath. To this was added N-(3-(trifluoromethyl)benzyl)-2-(5-fluoro-2-nitrophenyl)isonicotinamide 14d (300 mg, 0.72 mmol, 1.00 equiv). The resulting solution was stirred overnight at room temperature. The resulting solution was diluted with 20 mL of water. The resulting solution was extracted with 3×20 mL of dichloromethane and the organic layers combined and dried over sodium sulfate and concentrated under vacuum. This resulted in 200 mg (crude) of N-(3-(trifluoromethyl)benzyl)-2-(2-nitro-5-(2,2,2-trifluoroethoxy)phenyl)isonicotinamide as a yellow solid.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[C:5]2[S:10][C:9]([NH:11][C:12](=[O:16])[CH:13]([CH3:15])[CH3:14])=[CH:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:31]2[CH:39]=[CH:38][CH:37]=[C:36]3[C:32]=2[CH:33]=[N:34][NH:35]3)O1>>[NH:35]1[C:36]2[C:32](=[C:31]([C:2]3[N:3]=[C:4]([N:17]4[CH2:22][CH2:21][O:20][CH2:19][CH2:18]4)[C:5]4[S:10][C:9]([NH:11][C:12](=[O:16])[CH:13]([CH3:15])[CH3:14])=[CH:8][C:6]=4[N:7]=3)[CH:39]=[CH:38][CH:37]=2)[CH:33]=[N:34]1
Reactant: CC(C)C(=O)Nc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Reactant: CC1(C)OB(c2cccc3[nH]ncc23)OC1(C)C
Product: CC(C)C(=O)Nc1cc2nc(-c3cccc4[nH]ncc34)nc(N3CCOCC3)c2s1

Procedure:
The crude N-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)isobutyramide (45 mg) was coupled to 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole 7 via General Procedure A. The product was purified by reverse phase HPLC to yield 1.9 mg of 164. MS (Q1) 423 (M)+
Reaction SMILES: [F:1][C:2]1[C:3](=[O:9])[NH:4][C:5](=[O:8])[NH:6][CH:7]=1.[H-].[Na+].[CH2:12]([N:14]([CH2:18][CH3:19])[C:15](Cl)=[O:16])[CH3:13]>CC(N(C)C)=O>[CH2:12]([N:14]([CH2:18][CH3:19])[C:15]([N:6]1[CH:7]=[C:2]([F:1])[C:3](=[O:9])[NH:4][C:5]1=[O:8])=[O:16])[CH3:13]
Reactant: O=c1[nH]cc(F)c(=O)[nH]1
Reactant: CCN(CC)C(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CCN(CC)C(=O)n1cc(F)c(=O)[nH]c1=O
Temperature: 30 °C
Reaction time: 5 h
Yield: 75.5 %

Procedure:
1.3 g. (0.01 mole) of 5-fluorouracil was dissolved in 20 ml. of dimethyl acetamide and then 0.48 g. (0.01 mole) of 50% sodium hydride was added thereto. Subsequently, 1.36 g. (0.01 mole) of N,N-diethylcarbamoyl chloride in 5 ml. of dimethyl acetamide was added dropwise at 30° C. After stirring at 30° C. for 5 hours, the reaction mixture was allowed to stand overnight at room temperature. The reaction mixture was filtered and the resultant filtrate was evaporated under reduced pressure. The residue obtained was extracted with 30 ml. of chloroform and the extract was concentrated to dryness to give 2.14 g. of crude product. The product was washed with diethyl ether and 1.73 g. (75.5% yield) of 1-(N,N-diethylcarbamoyl)-5-fluorouracil melting at 157°-160° C. was obtained.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9][CH2:10][C:11](=[CH2:14])[CH2:12][OH:13])=[O:8].[CH2:15]([N:28]=[C:29]=[O:30])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH2:15]([NH:28][C:29]([O:13][CH2:12][C:11](=[CH2:14])[CH2:10][O:9][C:7](=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][Br:1])=[O:30])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: C=C(CO)COC(=O)CCCCCBr
Reactant: CCCCCCCCCCCCCN=C=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: C=C(COC(=O)CCCCCBr)COC(=O)NCCCCCCCCCCCCC
Temperature: 22 °C
Reaction time: 23 h

Procedure:
3-(6-Bromohexanoyloxy)-2-methylenepropan-1-ol (from Preparation 44) (0.58 g), tridecyl isocyanate (0.55 g) and 4-dimethylaminopyridine (0.05 g) were mixed in methylene chloride (3 ml). After stirring for 23 hours at 22° C. the mixture was filtered, and the filtrate was purified through a column of silica gel 60 (70-230 mesh, 4 g) eluting with ether/chloroform 1:1. Further purification was achieved by chromatography on Waters PrepLC®/System 500A using a prepPAK®-500/SILICA cartridge with ether/chloroform/pentane 1:1:4 as eluent.
Reaction SMILES: C[O:2][C:3](=[O:22])[CH2:4][CH2:5][NH:6][C:7](=[O:21])[C:8]1[CH:13]=[CH:12][C:11]([C:14](=O)[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:10][CH:9]=1.[NH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][C:33]([C:36]#[N:37])=[CH:32][CH:31]=2)=[CH:26][CH:25]=1>>[C:36]([C:33]1[CH:32]=[CH:31][C:30]([C:27]2[CH:28]=[CH:29][C:24]([NH:23][CH:14]([C:11]3[CH:12]=[CH:13][C:8]([C:7]([NH:6][CH2:5][CH2:4][C:3]([OH:2])=[O:22])=[O:21])=[CH:9][CH:10]=3)[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:25][CH:26]=2)=[CH:35][CH:34]=1)#[N:37]
Reactant: CCCCCC(=O)c1ccc(C(=O)NCCC(=O)OC)cc1
Reactant: N#Cc1ccc(-c2ccc(N)cc2)cc1
Product: CCCCCC(Nc1ccc(-c2ccc(C#N)cc2)cc1)c1ccc(C(=O)NCCC(=O)O)cc1

Procedure:
The title compound is prepared by the general method exemplified in Example 1 using 3-(4-hexanoyl-benzoylamino)-propionic acid methyl ester (Preparation 5) and 4′-amino-biphenyl-4-carbonitrile as starting materials. MS (ES): 470.2 [M+H]+.
Reaction SMILES: [NH2:1][C@H:2]1[C@@H:7]([CH3:8])[CH2:6][N:5]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][C:10]=2[NH:15][C:16](=[O:32])[C:17]2[CH:22]=[CH:21][C:20]([F:23])=[C:19]([C:24]3[C:29]([F:30])=[CH:28][CH:27]=[CH:26][C:25]=3[F:31])[N:18]=2)[CH2:4][C@H:3]1[NH:33]C(=O)OC(C)(C)C.[CH3:41][S:42](Cl)(=[O:44])=[O:43]>>[NH2:33][C@H:3]1[C@@H:2]([NH:1][S:42]([CH3:41])(=[O:44])=[O:43])[C@@H:7]([CH3:8])[CH2:6][N:5]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][C:10]=2[NH:15][C:16](=[O:32])[C:17]2[CH:22]=[CH:21][C:20]([F:23])=[C:19]([C:24]3[C:29]([F:30])=[CH:28][CH:27]=[CH:26][C:25]=3[F:31])[N:18]=2)[CH2:4]1
Reactant: CS(=O)(=O)Cl
Reactant: C[C@H]1CN(c2ccncc2NC(=O)c2ccc(F)c(-c3c(F)cccc3F)n2)C[C@@H](NC(=O)OC(C)(C)C)[C@H]1N
Product: C[C@H]1CN(c2ccncc2NC(=O)c2ccc(F)c(-c3c(F)cccc3F)n2)C[C@@H](N)[C@H]1NS(C)(=O)=O
Yield: 28 %

Procedure:
Method 4 was followed using tert-butyl ((3R,4S,5S)-4-amino-1-(3-(6-(2,6-difluorophenyl)-5-fluoropicolinamido)pyridin-4-yl)-5-methylpiperidin-3-yl)carbamate and methanesulfonyl chloride to give N-(4-((3R,4S,5S)-3-amino-5-methyl-4-(methylsulfonamido)piperidin-1-yl)pyridin-3-yl)-6-(2,6-difluorophenyl)-5-fluoropicolinamide in 28% yield. LC/MS (m/z)=535.0 (MH+), Rt=0.58 min.