Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:3]([CH:19]([F:21])[F:20])=[CH:4][C:5]2[C:14]3[C:9](=[C:10]([CH3:15])[N:11]=[CH:12][CH:13]=3)[C:8](=[O:16])[N:7]([CH3:17])[C:6]=2[CH:18]=1.[OH:22][CH2:23][C@@H:24]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:25][CH:26]([CH3:28])[CH3:27].C(P(C(C)(C)C)C1C=CC=CC=1C1C(C(C)C)=CC(C(C)C)=CC=1C(C)C)(C)(C)C.C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1>[F:20][CH:19]([F:21])[C:3]1[C:2]([O:22][CH2:23][C@@H:24]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:33])([CH3:35])[CH3:34])[CH2:25][CH:26]([CH3:28])[CH3:27])=[CH:18][C:6]2[N:7]([CH3:17])[C:8](=[O:16])[C:9]3[C:14]([C:5]=2[CH:4]=1)=[CH:13][CH:12]=[N:11][C:10]=3[CH3:15]
Reactant: Cc1nccc2c1c(=O)n(C)c1cc(Cl)c(C(F)F)cc21
Reactant: CC(C)C[C@@H](CO)NC(=O)OC(C)(C)C
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C(C)(C)C)C(C)(C)C)c(C(C)C)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Product: Cc1nccc2c1c(=O)n(C)c1cc(OC[C@H](CC(C)C)NC(=O)OC(C)(C)C)c(C(F)F)cc21
Temperature: 25 °C
Yield: 38.2 %

Procedure:
A solution of 8-chloro-9-(difluoromethyl)-4,6-dimethylbenzo[c][2,7]naphthyridin-5(6H)-one (700 mg, 1.519 mmol), (S)-tert-butyl (1-hydroxy-4-methylpentan-2-yl)carbamate (660 mg, 3.04 mmol), 2-di-t-butylphosphino-2′,4′,6′-tri-i-propyl-1,1′-biphenyl (387 mg, 0.912 mmol), PdOAc2 (34.1 mg, 0.152 mmol) and Cs2CO3 (990 mg, 3.04 mmol) in toluene (20 mL) was heated at 80° C. for 16 h. After cooling to room temperature, the mixture was concentrated under reduced pressure. The residue was taken up in ethyl acetate and filtered through diatomaceous earth (Celite®). The organic layer was washed with brine and water; dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography using EtOAc-hexane as the eluent to afford (S)-tert-butyl (1-((9-(difluoromethyl)-4,6-dimethyl-5-oxo-5,6-dihydrobenzo[c][2,7]naphthyridin-8-yl)oxy)-4-methylpentan-2-yl)carbamate (0.6 g, 0.58 mmol, 54% yield) as a brown gummy solid. LC/MS (ESI) m/e 490.2 [(M+H)+, calcd for C26H34F2N3O4, 490.2]; LC/MS retention time (method B): tR=2.72 min.
Reaction SMILES: ClC1C=C(C=CC=1I)N.[C:10]([NH:17][C:18]1[CH:23]=[CH:22][C:21]([I:24])=[C:20]([Cl:25])[CH:19]=1)([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].[H-].[Na+].Br[CH:29]([CH3:37])[C:30]([O:32][CH2:33][CH:34]([CH3:36])[CH3:35])=[O:31]>CN(C=O)C.ClCCl>[CH2:33]([O:32][C:30](=[O:31])[C@H:29]([CH3:37])[N:17]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C:18]1[CH:23]=[CH:22][C:21]([I:24])=[C:20]([Cl:25])[CH:19]=1)[CH:34]([CH3:36])[CH3:35]
Reactant: CC(C)(C)OC(=O)Nc1ccc(I)c(Cl)c1
Reactant: CC(C)COC(=O)C(C)Br
Agent: Nc1ccc(I)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)COC(=O)[C@H](C)N(C(=O)OC(C)(C)C)c1ccc(I)c(Cl)c1
Temperature: 100 °C

Procedure:
Following General Procedure R above and using 3-chloro-4-iodoaniline (Aldrich), N-BOC-3-chloro-4-iodoaniline was prepared. To a stirred slurry of 5.0 equivalents of sodium hydride in DMF was added 1.0 equivalent of N-BOC-3-chloro-4-iodoaniline and then 1.1 equivalents of iso-butyl 2-bromopropionate (from Example D above) were slowly added. The reaction was heated to 100° C. for 10 hours, cooled, diluted with dichloromethane and washed with cold 1N HCl, water and brine. The solvents were removed at reduced pressure and the residue was chromatographed to provide N-BOC-N-(3-chloro-4-iodophenyl)alanine iso-butyl ester as a clear oil. Following General Procedure N above, the BOC group was removed from N-BOC-N-(3-chloro-4-iodophenyl)alanine iso-butyl ester to provide the title compound. The BOC-removal reaction was monitored by tlc on silica gel (Rf=0.58 in 30% EtOAc/hexanes) and purification was by preparative plate chromatography (silica gel using 30% EtOAc/hexanes as the eluant). The compound was further purified by chromatography on an HPLC chiral column (Chiralcel OD).
Reaction SMILES: [CH:1]1[CH:6]=[C:5]([S:7]([F:12])([F:11])([F:10])([F:9])[F:8])[CH:4]=[C:3]([C:13]([OH:15])=O)[CH:2]=1.O=S(Cl)[Cl:18]>>[F:8][S:7]([F:12])([F:11])([F:10])([F:9])[C:5]1[CH:4]=[C:3]([CH:2]=[CH:1][CH:6]=1)[C:13]([Cl:18])=[O:15]
Reactant: O=C(O)c1cccc(S(F)(F)(F)(F)F)c1
Reactant: O=S(Cl)Cl
Product: O=C(Cl)c1cccc(S(F)(F)(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 3-(pentafluorothio)benzoic acid (Apollo Scientific, 0.42 g, 1.7 mmol) and SOCl2 (1.2 mL, 16.9 mmol) was warmed to reflux and was allowed to stir for 2 h. The mixture was cooled to ambient temperature and concentrated under reduced pressure. The residue was dissolved in toluene (5 mL) and was concentrated under reduced pressure. This dilution with toluene and concentration was repeated two additional times to remove residual thionyl chloride and afford 3-(pentafluoro-λ6-sulfanyl)benzoyl chloride, that was used directly below.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)[N:9]=[CH:8][N:7]=[C:6]2[O:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[NH:27][C:26]([CH3:31])=[CH:25]2.Cl[CH2:33][C:34]#[N:35].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C=O)C.O>[C:34]([CH2:33][CH:14]([CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)[O:13][C:12]1[CH:11]=[C:10]2[C:5]([C:6]([O:21][C:22]3[CH:23]=[C:24]4[C:28](=[CH:29][CH:30]=3)[NH:27][C:26]([CH3:31])=[CH:25]4)=[N:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:2][CH3:1])#[N:35]
Reactant: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3)ncnc2cc1OCC1CCNCC1
Reactant: N#CCCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3)ncnc2cc1OC(CC#N)C1CCNCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.4 %

Procedure:
A mixture of 6-methoxy-4-(2-methylindol-5-yloxy)-7-(piperidin-4-ylmethoxy)quinazoline (419 mg, 1 mmol), (prepared as described in Example 70), in DMF (6 ml) containing chloroacetonitrile (114 mg, 1.5 mmol), potassium carbonate (346 mg, 2.5 mmol) and potassium iodide (50 mg, 0.3 mmol) was stirred at ambient temperature overnight. The mixture was poured into water and the precipitate was filtered, washed with water and dried under vacuum. The residue was purified by column chromatography, eluting with methylene chloride, followed by methylene chloride/methanol (98/2 and 95/5). After removal of the solvent under vacuum, the residue was triturated with ether, filtered, washed with ether and dried under vacuum to give 7-((1-cyanomethyl)piperidin-4-ylmethoxy)-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline (304 mg, 66%).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH3:5][O:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=1.[Cl-].[C:18]([O:27][CH3:28])(=[O:26])[CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O-])=[O:24].C(Cl)(=O)C(Cl)=O.C(OC)(=O)CCCCC([O-])=O>[N+](C1C=CC=CC=1)([O-])=O.C(Cl)Cl>[CH3:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[CH:13]=[C:12]([C:23](=[O:24])[CH2:22][CH2:21][CH2:20][CH2:19][C:18]([O:27][CH3:28])=[O:26])[CH:11]=[CH:10]2
Reactant: COC(=O)CCCCC(=O)[O-]
Reactant: COc1ccc2ccccc2c1
Agent: O=C(Cl)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O=[N+]([O-])c1ccccc1
Product: COC(=O)CCCCC(=O)c1ccc2cc(OC)ccc2c1
Reaction time: 8 h

Procedure:
Into a solution of 6.32 g (47.4 mmol) of anhydrous aluminum chloride in 60 ml of dry nitrobenzene was added 5.03 g (31.7 mmol) of 2-methoxynaphthalene chilled with an ice bath, followed by stirring. Subsequently, under an ice bath, monomethyl adipate chloride (synthesized by adding 5.0 ml (57.3 mmol) of oxalyl chloride under an ice bath to a solution of 5.85 ml (39.5 mmol) monomethyl adipate in 50 ml of dry methylene chloride) to carry out the reaction for 6 hours, and evaporating methylene chloride and excessive oxalyl chloride under a reduced pressure) was gradually added, and the reaction was carried out at 0° C. to room temperature overnight (for 15 hours). The reaction mixture was poured into ice-water, extracted with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate. After evaporation of the organic solvent and nitrobenzene under a reduced pressure, the desired product was obtained by silica gel chromatography. Yield: 3.82 g (40%).
Reaction SMILES: [CH:1]1([CH:4]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][NH:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]4[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:26]=4[F:33])=[C:21]([CH2:34][C:35]([CH3:38])([CH3:37])[CH3:36])[CH:20]=3)[CH:12]=2)[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:3][CH2:2]1.C(N(C(C)C)C(C)C)C.[C:48](Cl)(=[O:50])[CH3:49]>C1COCC1>[CH:1]1([CH:4]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][N:18]([C:19]3[CH:24]=[CH:23][C:22]([C:25]4[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:26]=4[F:33])=[C:21]([CH2:34][C:35]([CH3:37])([CH3:36])[CH3:38])[CH:20]=3)[C:48](=[O:50])[CH3:49])[CH:12]=2)[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:3][CH2:2]1
Reactant: CC(=O)Cl
Reactant: CCOC(=O)CC(c1cccc(CNc2ccc(-c3cc(OC)ccc3F)c(CC(C)(C)C)c2)c1)C1CC1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CC(c1cccc(CN(C(C)=O)c2ccc(-c3cc(OC)ccc3F)c(CC(C)(C)C)c2)c1)C1CC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of ethyl 3-cyclopropyl-3-(3-(((2′-fluoro-5′-methoxy-2-neopentyl-[1,1′-biphenyl]-4-yl)amino)methyl)phenyl)propanoate (104 mg) in THF (2.0 mL) were added N-ethyldiisopropylamine (52 μL) and acetyl chloride (17 μL) at 0° C., and the mixture was stirred at room temperature for 1.5 hr. Ice water was added at 0° C., and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate. The is solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (104 mg) as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([CH2:12][N:13]([CH3:15])[CH3:14])[CH:11]=1)[N:8]=[CH:7][C:6]([C:16]#[N:17])=[C:5]2[NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([Br:25])[CH:20]=1.C(N(CC)C(C)C)(C)C.[C:35](Cl)(=[O:38])[CH:36]=[CH2:37]>C1COCC1.C(=O)(O)[O-].[Na+]>[Br:25][C:21]1[CH:20]=[C:19]([NH:18][C:5]2[C:4]3[C:9](=[C:10]([CH2:12][N:13]([CH3:14])[CH3:15])[CH:11]=[C:2]([NH:1][C:35](=[O:38])[CH:36]=[CH2:37])[CH:3]=3)[N:8]=[CH:7][C:6]=2[C:16]#[N:17])[CH:24]=[CH:23][CH:22]=1
Reactant: CN(C)Cc1cc(N)cc2c(Nc3cccc(Br)c3)c(C#N)cnc12
Reactant: C=CC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: C=CC(=O)Nc1cc(CN(C)C)c2ncc(C#N)c(Nc3cccc(Br)c3)c2c1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a stirred solution of 6-amino-4-[(3-bromophenyl)amino]-8-dimethylaminomethyl-3-quinolinecarbonitrile (0.20 g, 0.50 mmol) and N,N-diisopropylethylamine (0.13 ml, 0.75 mmol) in 3.4 ml of THF at 0° C. was added acryloyl chloride (0.045 ml, 0.55 mmol) during 5 m. After stirring for 3 h at 0° C. the mixture was diluted with sodium bicarbonate solution. The resulting solid was filtered off, washed with water, dried, and subjected to chromatography on silica gel with methylene chloride-ethyl acetate-methanol-triethylamine to give a yellow solid; mass spectrum (electrospray, m/e) M+H 449.9, 452.0.
Reaction SMILES: [CH3:1][N:2]1[C:6]([N+:7]([O-:9])=[O:8])=[CH:5][N:4]=[C:3]1[C:10](=[NH:14])OCC.C(O)C.[NH2:18][NH:19][C:20]([NH2:22])=[S:21]>C(O)(=O)C>[CH3:1][N:2]1[C:6]([N+:7]([O-:9])=[O:8])=[CH:5][N:4]=[C:3]1[C:10]([NH:18][NH:19][C:20]([NH2:22])=[S:21])=[NH:14]
Reactant: CCOC(=N)c1ncc([N+](=O)[O-])n1C
Reactant: NNC(N)=S
Solvent: CC(=O)O
Solvent: CCO
Product: Cn1c([N+](=O)[O-])cnc1C(=N)NNC(N)=S

Procedure:
To a stirred solution of ethyl 1-methyl-5-nitro-2-imidazolecarboximidate (0.198 g., 0.001 mole) in 10 ml. of absolute ethanol is added thiosemicarbazide (0.091 g., 0.001 mole) and 1 ml. of glacial acetic acid. The mixture is heated at reflux for 11/4 hours and is cooled in an ice bath. The orange-red solid is filtered washed and dried affording 0.173 g. of the title compound, melting point 210°-214°, dec.
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[C:8]([C:24]3[CH:29]=[CH:28][C:27]([O:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[CH:26][CH:25]=3)[N:9]=[C:10]([C@H:11]3[CH2:16][CH2:15][C@H:14]([CH2:17][NH:18][CH2:19]CN(C)C)[CH2:13][CH2:12]3)[N:6]2[N:5]=[CH:4][N:3]=1.[CH3:37]NC>>[CH3:37][N:18]([CH2:17][C@H:14]1[CH2:13][CH2:12][C@H:11]([C:10]2[N:6]3[C:7]([C:2]([NH2:1])=[N:3][CH:4]=[N:5]3)=[C:8]([C:24]3[CH:29]=[CH:28][C:27]([O:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[CH:26][CH:25]=3)[N:9]=2)[CH2:16][CH2:15]1)[CH3:19]
Reactant: CNC
Reactant: CN(C)CCNC[C@H]1CC[C@H](c2nc(-c3ccc(Oc4ccccc4)cc3)c3c(N)ncnn32)CC1
Product: CN(C)C[C@H]1CC[C@H](c2nc(-c3ccc(Oc4ccccc4)cc3)c3c(N)ncnn32)CC1

Procedure:
Prepared according to the procedure analogous to that described above for trans-N-{4-[4-Amino-5-(4-phenoxy-phenyl)-imidazo[5,1-f][1,2,4]triazin-7-yl]-cyclohexylmethyl}-N′,N′-dimethyl-ethane-1,2-diamine, except using dimethylamine.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][NH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][OH:19])=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].C1([O:26][C:27](=O)[NH:28][C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][C:30]=2[F:36])C=CC=CC=1>C1(C)C=CC=CC=1>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([CH2:11][N:12]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][OH:19])[C:27]([NH:28][C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][C:30]=2[F:36])=[O:26])=[CH:9][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(Nc1ccc(F)cc1F)Oc1ccccc1
Reactant: CCCCc1ccc(CNCCCCCCO)cc1
Solvent: Cc1ccccc1
Product: CCCCc1ccc(CN(CCCCCCO)C(=O)Nc2ccc(F)cc2F)cc1
Reaction time: 16 h
Yield: 37 %

Procedure:
A mixture of 1.58 g of 6-[[(4-butylphenyl)methyl]amino]-1-hexanol and 1.5 g of phenyl-N-(2,4-difluorophenyl)carbamate in 40 ml of toluene was heated at reflux for 5 hours. The reaction mixture was cooled and allowed to stand at room temperature for 16 hours. The solution was washed with 3N aqueous hydrochloric acid, brine, 1N aqueous sodium hydroxide and brine again, then was dried over anhydrous magnesium sulfate and filtered. The filtrate was evaporated in vacuo and gave a yellow oil. The oil was treated by preparative high pressure liquid chromatography and gave 0.93 g (37%) of the desired product as a colorless oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[C:14]([CH2:18][CH3:19])=[N:15][C:16](I)=[C:10]2[CH:9]1[CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([CH3:28])=[C:24]([CH3:29])[CH:23]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.[C:44](=O)([O-])[O-:45].[Cs+].[Cs+]>CO.[Cu]I>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[C:14]([CH2:18][CH3:19])=[N:15][C:16]([O:45][CH3:44])=[C:10]2[CH:9]1[CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([CH3:28])=[C:24]([CH3:29])[CH:23]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCc1nc(I)c2n1CCN(C(=O)OC(C)(C)C)C2CCc1ccc(C)c(C)c1
Reactant: O=C([O-])[O-]
Agent: [Cu]I
Agent: [Cs+]
Agent: c1cnc2c(c1)ccc1cccnc12
Solvent: CO
Product: CCc1nc(OC)c2n1CCN(C(=O)OC(C)(C)C)C2CCc1ccc(C)c(C)c1

Procedure:
A solution of 8-[2-(3,4-dimethyl-phenyl)-ethyl]-3-ethyl-1-iodo-5,6-dihydro-8H-imidazo[1,5-a]pyrazine-7-carboxylic acid tert-butyl ester (1.500 g; 2.944 mmol) in anhydrous MeOH (30 ml) was treated successively with copper(I) iodide (56 mg; 0.294 mmol), 1,10-phenanthroline (116.7 mg; 0.589 mmol), and cesium carbonate (1.535 g; 4.711 mmol). The resulting brown suspension was sealed and put in the microwave oven (150 W; 150° C.; 13 bars; 1h30). The resulting brown suspension was concentrated to dryness under reduced pressure and the crude was purified by FC (EA/heptane: 2/3 to 3/2]. The expected product 8-[2-(3,4-dimethyl-phenyl)-ethyl]-3-ethyl-1-methoxy-5,6-dihydro-8H-imidazo[1,5-a]pyrazine-7-carboxylic acid tert-butyl ester was obtained as a yellow oil (260.6 mg; 21%). LC-MS: tR=0.91 min.; [M+H]+=414.35 g/mol.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH2:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1.[Br:15][CH2:16][CH2:17]Br.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH3:1][O:2][C:3](=[O:14])[CH2:4][CH2:5][CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:17][CH2:16][Br:15])=[CH:11][CH:12]=1
Reactant: COC(=O)CCCc1ccc(O)cc1
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CCCc1ccc(OCCBr)cc1
Temperature: 80 °C
Reaction time: 48 h
Yield: 16.8 %

Procedure:
4-(4-hydroxyphenyl)butanoic acid methyl ester (2) (2.6 g) from the previous step was dissolved in N,N′-dimethylformamide (30 mL), 1,2-dibromoethane (12.6 g) and potassium carbonate (3.7 g) were added, and stirred at 80° C. for two days. The reaction solution was poured into water, and extracted with ethyl acetate (100 mL). The organic layer was washed with water (50 mL) and saturated sodium chloride solution (50 mL). After drying on anhydrous sodium sulfate, filtration and vacuum concentration, the residue was purified by silica gel flash column chromatography (developing solvent: n-hexane:ethyl acetate=8:1) to give the above-identified compound (676 mg, yield 17%).
Reaction SMILES: [CH:1]1([CH2:4][O:5][NH2:6])[CH2:3][CH2:2]1.C([O:9][C:10]([C:12]1[C:17]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][C:20]=2[F:26])=[C:16]([CH3:27])[C:15](=[O:28])[N:14]([CH3:29])[C:13]=1[CH3:30])=O)C.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1>[CH:1]1([CH2:4][O:5][NH:6][C:10]([C:12]2[C:17]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][C:20]=3[F:26])=[C:16]([CH3:27])[C:15](=[O:28])[N:14]([CH3:29])[C:13]=2[CH3:30])=[O:9])[CH2:3][CH2:2]1
Reactant: NOCC1CC1
Reactant: CCOC(=O)c1c(Nc2ccc(C)cc2F)c(C)c(=O)n(C)c1C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1ccc(Nc2c(C(=O)NOCC3CC3)c(C)n(C)c(=O)c2C)c(F)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 40.6 %

Procedure:
O-cyclopropylmethyl-hydroxylamine (0.046 g, 0.527 mmol) was added to a solution of 4-(2-fluoro-4-methylphenylamino)-1,2,5-trimethyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid ethyl ester (0.070 g, 0.211 mmol) in THF (2 mL). The solution was cooled to 0° C. and lithium bis(trimethylsilyl)amide (1.05 mL, 1 M solution in hexanes) was added dropwise. The reaction mixture was warmed to room temperature. After stirring for 1 hour, the reaction was quenched by addition of a saturated aqueous solution of NaHCO3 and partitioned between EtOAc and brine. The aqueous layer was reextracted with EtOAc. The combined organic extracts were dried (Na2SO4) and concentrated. Purification by flash column chromatography (30:1 methylene chloride/MeOH) gave 0.032 g (40%) desired product as a yellow solid; MS ESI (+) m/z 374 (M+1) detected; 1H NMR (400 MHz, CD3OD) δ 6.91 (d,1H), 6.83 (d, 1H), 6.63 (t, 1H), 3.59 (s, 3H), 3.47 (d, 2H), 2.41 (s, 3H), 2.27 (s, 3H), 1.86 (s, 3H) 0.99 (m, 1H) 0.48 (m, 2H) 0.18 (m, 2H). 19F (376 MHz, CD3OD)-132.1 (s, 1F).
Reaction SMILES: [CH:1]([NH:4][C:5]([C:7]1[CH:16]=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[C:9]([S:17](=[O:20])(=[O:19])[NH2:18])[CH:8]=1)=[O:6])([CH3:3])[CH3:2].[CH3:21][O:22][C:23]1[CH:28]=[C:27]([O:29][CH3:30])[N:26]=[C:25]([NH:31][C:32](=O)[O:33]C2C=CC=CC=2)[N:24]=1.N12CCCN=C1CCCCC2.Cl>C(#N)C>[CH3:30][O:29][C:27]1[CH:28]=[C:23]([O:22][CH3:21])[N:24]=[C:25]([NH:31][C:32](=[O:33])[NH:18][S:17]([C:9]2[CH:8]=[C:7]([C:5](=[O:6])[NH:4][CH:1]([CH3:3])[CH3:2])[CH:16]=[CH:15][C:10]=2[C:11]([O:13][CH3:14])=[O:12])(=[O:20])=[O:19])[N:26]=1
Reactant: COC(=O)c1ccc(C(=O)NC(C)C)cc1S(N)(=O)=O
Reactant: COc1cc(OC)nc(NC(=O)Oc2ccccc2)n1
Agent: Cl
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: COC(=O)c1ccc(C(=O)NC(C)C)cc1S(=O)(=O)NC(=O)Nc1nc(OC)cc(OC)n1
Temperature: 0 °C
Reaction time: 3 h
Yield: 94.2 %

Procedure:
2.6 g (8.6 mmol) of methyl 4-isopropylcarbamoyl-2-sulfamoylbenzoate and 2.8 g (10.3 mmol) of phenyl N-(4,6-dimethoxypyrimidin-2-yl)carbamate were initially charged in 50 ml of acetonitrile. At room temperature, 2.9 g (19 mmol) of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) were added dropwise, and the mixture was stirred at this temperature for 3 h. The mixture was poured into ice-water and the pH was adjusted to 1 using 2N hydrochloric acid. The precipitated solid was filtered off with suction and washed with water. After drying, 3.9 g (94% of theory) of methyl 2-[3-(4,6-dimethoxypyrimidin-2-yl)ureidosulfonyl]-4-isopropylcarbamoylbenzoate of m.p. 149-151° C. (decomp.) were obtained.
Reaction SMILES: [NH2:1][NH:2][C:3]([NH:5][NH2:6])=[O:4].[C:7]([N:11]=[N:12][C:13]1([N:19]=[C:20]=[S:21])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)([CH3:10])([CH3:9])[CH3:8].O>CO>[C:7]([N:11]=[N:12][C:13]1([NH:19][C:20]([NH:1][NH:2][C:3]([NH:5][NH:6][C:20]([NH:19][C:13]2([N:12]=[N:11][C:7]([CH3:10])([CH3:9])[CH3:8])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)=[S:21])=[O:4])=[S:21])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]1)([CH3:10])([CH3:8])[CH3:9]
Reactant: NNC(=O)NN
Reactant: CC(C)(C)N=NC1(N=C=S)CCCCC1
Solvent: O
Solvent: CO
Product: CC(C)(C)N=NC1(NC(=S)NNC(=O)NNC(=S)NC2(N=NC(C)(C)C)CCCCC2)CCCCC1
Reaction time: 8 h

Procedure:
To a slurry of 2.25 grams (.025 moles) of carbohydrazide in 30 ml of methanol stirred by a magnetic stirrer in a 50 ml erlenmeyer flask was added 11.3 grams (.05 moles) of 1-t-butylazo-1-isothiocyanatocyclohexane (from Example I). The reaction was stirred overnight, during which time complete solution was obtained. The next morning the solution was poured into 200 ml water and the product extracted with methylene chloride. The methylene chloride extract was washed with water, dried over anhydrous Na2SO4, filtered and the methylene chloride evaporated under reduced pressure to leave 11.9 grams (87.5% crude yield) of a yellow viscous liquid that slowly crystallized.
Reaction SMILES: [CH3:1][O:2][CH:3]([CH3:8])[C:4]([O:6][CH3:7])=[O:5].[Li+].CC([N-]C(C)C)C.C(NC(C)C)(C)C.C([Li])CCC.[C:29]([Si:33](Cl)([CH3:35])[CH3:34])([CH3:32])([CH3:31])[CH3:30]>C1COCC1>[C:29]([Si:33]([O:5][C:4]([O:6][CH3:7])=[C:3]([O:2][CH3:1])[CH3:8])([CH3:35])[CH3:34])([CH3:32])([CH3:31])[CH3:30]
Reactant: COC(=O)C(C)OC
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COC(C)=C(OC)O[Si](C)(C)C(C)(C)C
Temperature: -20 °C
Reaction time: 8 h

Procedure:
A solution of methyl 2-methoxypropionate (177 mg, 1.5 mmol) in THF (1 mL) was added to a solution of LDA prepared from diisopropylamine (0.212 mL, 1.50 mmol) and butyllithium (0.60 mL, 1.50 mmol) in THF (2 mL) at −78° C. under nitrogen. The mixture was gradually allowed to warm to −20° C. over 1 h, re-cooled to −78° C. and then a solution of tert-butylchlorodimethylsilane (233 mg, 1.50 mmol) in THF (1 mL) was added. The mixture was allowed to warm to rt over 2 h and stirred overnight. The reaction was quenched with satd. NaHCO3 (5 mL), diluted with DCM (10 mL). The organic layer was separated, washed with water, brine and dried (MgSO4). Evaporation of solvents afforded tert-butyl((1,2-dimethoxyprop-1-en-1-yl)oxy)dimethylsilane as a clear oil and used in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([F:10])[C:7]([O:11][CH3:12])=[CH:6][C:3]=1[CH:4]=[O:5].[C-:13]#[N:14].[K+].OS([O-])=O.[Na+]>C(OCC)(=O)C.O>[F:1][C:2]1[CH:9]=[C:8]([F:10])[C:7]([O:11][CH3:12])=[CH:6][C:3]=1[CH:4]([OH:5])[C:13]#[N:14]
Reactant: [C-]#N
Reactant: COc1cc(C=O)c(F)cc1F
Agent: O=S([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: COc1cc(C(O)C#N)c(F)cc1F
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To 98A (506 mg, 2.94 mmol) in ethyl acetate (10 mL) was added a solution of KCN (574 mg, 8.82 mmol) and NaHSO3 (917 mg, 8.82 mmol) dissolved in H2O (10 mL). The reaction was stirred at rt for 48 h. It was extracted with ethyl acetate (2×50 mL). The combined organic extracts were dried and concentrated to give 98B as an oil. It was used for next step without purification.