Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([I:17])=[CH:13][C:12]=2[F:18])[C:5]([C:8]#[N:9])=[N:6][CH:7]=1.C[Si](C)(C)[O-:21].[K+]>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([I:17])=[CH:13][C:12]=2[F:18])[C:5]([C:8]([NH2:9])=[O:21])=[N:6][CH:7]=1
Reactant: C[Si](C)(C)[O-]
Reactant: N#Cc1ncc(F)cc1Nc1ccc(I)cc1F
Agent: [K+]
Solvent: C1CCOC1
Product: NC(=O)c1ncc(F)cc1Nc1ccc(I)cc1F
Temperature: 100 °C

Procedure:
To 5-fluoro-3-(2-fluoro-4-iodo-phenylamino)-pyridine-2-carbonitrile (50 mg, 0.14 mmol) in THF (0.7 mL) was added potassium trimethylsilanolate (40 mg, 0.28 mmol). The mixture was heated in sealed tube at 100° C. overnight. The mixture was then concentrated and purified by HPLC to afford the pure product. LC/MS [6.90 min; 376 (M+1)].
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[NH:12]C(=O)C.O.S(=O)(=O)(O)O>C(O)C>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[NH2:12]
Reactant: CC(=O)Nc1cc([N+](=O)[O-])c(C)cc1C
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CCO
Product: Cc1cc(C)c([N+](=O)[O-])cc1N

Procedure:
A mixture of N-(2,4-dimethyl-5-nitrophenyl)acetamide, water (24 mL), concentrated sulfuric acid (12 mL), and ethanol (120 mL) was heated at reflux under an atmosphere of nitrogen for 4 hours. The ethanol was evaporated under reduced pressure and the residue partitioned between ethyl acetate (250 mL) and brine (150 mL). The brine solution was reextracted with ethyl acetate. The combined ethyl acetate extracts were then dried over magnesium sulfate. Evaporation afforded a crude product which was flash chromatographed on silica and eluted with ethyl acetate:hexane (1:4) to afford 4.63 g as a pale yellow solid.
Reaction SMILES: C([O:3][C:4](=[O:24])[CH2:5][CH:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([O:17][C:18]3[CH:23]=[CH:22][N:21]=[CH:20][N:19]=3)[CH:14]=[C:15]([CH3:16])[C:7]1=2)C.[Li+].[OH-].Cl>C1COCC1.O.O>[OH:11][B:9]1[C:8]2[CH:12]=[C:13]([O:17][C:18]3[CH:23]=[CH:22][N:21]=[CH:20][N:19]=3)[CH:14]=[C:15]([CH3:16])[C:7]=2[CH:6]([CH2:5][C:4]([OH:24])=[O:3])[O:10]1
Reactant: CCOC(=O)CC1OB(O)c2cc(Oc3ccncn3)cc(C)c21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(Oc2ccncn2)cc2c1C(CC(=O)O)OB2O
Temperature: 25 °C
Yield: 82.6 %

Procedure:
To a solution of [1-hydroxy-4-methyl-6-(pyrimidin-4-yloxy)-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl]-acetic acid ethyl ester (0.4 g, 1.21 mmol) in THF:H2O (1:1, 10 mL) at 0° C. was added LiOH (0.087 g, 3.65 mmol) in water (1 mL). The solution was allowed to warm to room temperature over 6 hours then acidified to pH 2 with 1N HCl at 0° C. and extracted with EtOAc (2×10 mL). The organic extracts were dried and concentrated in vacuo. The residue was purified by preparative HPLC to give [1-hydroxy-4-methyl-6-(pyrimidin-4-yloxy)-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl]-acetic acid (0.3 g, 82%). 1H NMR (400 MHz, DMSO): δ 9.25 (s, 1H), 8.73 (s, 1H), 8.65 (d, J=5.6 Hz, 1H), 7.26 (d, J=2.0 Hz, 1H), 7.12 (d, J=7.2 Hz, 2H), 5.51 (dd, J=2.4, 9.6 Hz, 1H), 3.07 (dd, J=2.0, 15.2 Hz, 1H), 2.29 (s, 3H), 2.17-2.11 (m, 1H). MS (ESI) m/z=301 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].O.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]([C:25](Br)([CH3:27])[CH3:26])=[O:24])=[CH:19][CH:18]=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:25]([C:23]([C:20]2[CH:19]=[CH:18][C:17]([Cl:16])=[CH:22][CH:21]=2)=[O:24])([CH3:27])[CH3:26])=[CH:4][CH:3]=1
Reactant: Oc1ccc(Cl)cc1
Reactant: CC(C)(Br)C(=O)c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(Oc1ccc(Cl)cc1)C(=O)c1ccc(Cl)cc1
Temperature: 40 °C
Reaction time: 5 h
Yield: 85 %

Procedure:
A solution of 59.2 g (0.47 mol) of dimethyl sulphate and 32 g (0.517 mol) of dimethyl sulphide in 270 ml of acetonitrile is stirred at room temperature for 5 days. A solution of 87 g of 4-chlorophenyl 2-(p-chlorophenoxy)-prop-2-yl ketone in 80 ml of acetonitrile is then added dropwise at 20° to 25° C., in the course of approx. 2 hours. 28.7 g (0.53 mol) of sodium methylate are introduced at the same temperature, and the mixture is stirred for a further 12 hours and then concentrated. The residue is stirred overnight with a mixture of 200 ml of ethyl acetate and 150 ml of water. The organic phase is separated off, dried over sodium sulphate and concentrated in vacuo. 49 g (76% of theory) of crude 2-(4 chlorophenyl)-2-[2-(p-chlorophenoxy)-prop-2-yl]-oxirane are obtained, and this compound is directly reacted further. ##STR158## 52 g (0.3982 mol) of p-chlorophenol and 55 g (0.3982 mol) of potassium carbonate in 400 ml of toluene are heated under reflux for 2 hours in a water separator. The mixture is cooled to 40° C., and a solution of 2-bromo-prop-2-yl 4-chlorophenyl ketone in 170 ml of toluene is added dropwise. This reaction mixture is stirred for a further 5 hours at 100° C. and then cooled, water is added and the organic phase is separated off. This is washed with dilute sodium hydroxide solution and water, dried over sodium sulphate and concentrated. 87 g (85% of theory) of crude 4-chlorophenyl 2-(p-chlorophenoxy)-prop-2-yl ketone are obtained, and this compound is directly reacted further. ##STR159## 1 ml of hydrogen bromide/glacial acetic acid is added to 65.5 g (0.36 mol) of 4-chlorophenyl isopropyl ketone in 200 ml of chloroform, and 57.5 g (0.36 mol) of bromine are then added dropwise at 30° C. The mixture is stirred for a further 30 minutes at room temperature, and thereafter concentrated in vacuo. 86.6 g (92% of theory) of crude 2-bromo-prop-2-yl 4-chlorophenyl ketone are obtained, and this compound is directly reacted further.
Reaction SMILES: C(O[CH2:5][CH:6]=[CH2:7])(=O)C.C(N(CC)CC)C.CN(C)C(=NC)N(C)C.[CH2:24]([CH:31]1[C:35](=[O:36])[O:34][C:33]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[N:32]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(#N)C>[CH2:7]([C:31]1([CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:35](=[O:36])[O:34][C:33]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[N:32]1)[CH:6]=[CH2:5]
Reactant: C=CCOC(C)=O
Reactant: O=C1OC(c2ccccc2)=NC1Cc1ccccc1
Agent: CN=C(N(C)C)N(C)C
Solvent: CC#N
Solvent: CCN(CC)CC
Product: C=CCC1(Cc2ccccc2)N=C(c2ccccc2)OC1=O

Procedure:
Allyl acetate (21.6 μL, 200 μmol) was added to a solution of triethylamine (56 μL, 400 μmol) or pentamethylguanidine (51.7 mg, 400 μmol) and 4-benzyl-2-phenyl-2-oxazolin-5-one (450 μmol) in acetonitrile (1 mL). Then a preformed solution of bis(η3 -allyl)di-,μ-chlorodipalladium (II) (1.8 mg, 4.9 μmol) and ligand 1 (10.4 mg, 15.1 μmol) in acetonitrile (1 mL) was added via cannula. The reaction mixture was quenched with aqueous phosphate buffer (pH 7, 40 ml) and extracted with CH2Cl2 (3×30 mL). The combined organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with petroleum ether-AcOEt (95:5) to give 4-allyl-4-benzyl-2-phenyl-2-oxazolin-5-one. ##STR15##
Reaction SMILES: [CH3:1][CH:2]([CH3:10])[C:3](=[O:9])[CH2:4][C:5]([O:7][CH3:8])=[O:6].[CH2:11](O)[CH2:12][OH:13]>C1(C)C=CC=CC=1.CC1C=CC(S(O)(=O)=O)=CC=1>[CH:2]([C:3]1([CH2:4][C:5]([O:7][CH3:8])=[O:6])[O:13][CH2:12][CH2:11][O:9]1)([CH3:10])[CH3:1]
Reactant: COC(=O)CC(=O)C(C)C
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: COC(=O)CC1(C(C)C)OCCO1
Yield: 71.2 %

Procedure:
To a solution of methyl 4-methyl-3-oxopentanoate (72 g, 0.5 mol), and ethylene glycol (56 g, 1 mol) in toluene (500 mL) was added 4-methylbenzenesulfonic acid (1.9 g, 0.01 mol). The mixture was stirred at reflux with a Dean-Stark trap to remove water. The reaction mixture was washed with a small amount of water and brine, dried over anhydrous Na2SO4, and concentrated in vacuum to give the crude methyl 2-(2-isopropyl-1,3-dioxolan-2-yl)-acetate (67 g 71% yield), which was used for the next step without further purification.
Reaction SMILES: [CH2:1]=C1CCC2(OCCO2)CC1.[CH2:12]1[C:16]2([CH2:21][CH2:20][C:19](=O)[CH2:18][CH2:17]2)[CH2:15][CH2:14][CH2:13]1.O1C2(CCC(=O)CC2)OCC1>>[CH2:1]=[C:19]1[CH2:20][CH2:21][C:16]2([CH2:15][CH2:14][CH2:13][CH2:12]2)[CH2:17][CH2:18]1
Reactant: C=C1CCC2(CC1)OCCO2
Reactant: O=C1CCC2(CCCC2)CC1
Agent: O=C1CCC2(CC1)OCCO2
Product: C=C1CCC2(CCCC2)CC1

Procedure:
The title compound was prepared following the method reported here for Compound 31a. As starting material spiro[4.5]decan-8-one replaced 1,4-dioxaspiro[4.5]decan-8-one. After the usual work-up procedure, the residue was purified by means of automated flash chromatography (SP01®M-Biotage; CH2Cl2) to give the title compound as a colorless oil. Yield: 98.5%.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH:10]=[CH:9][N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[C:6]=2[N:7]=1.[OH:20][C:21]1[CH:22]=[C:23]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH:24]=[CH:25][CH:26]=1.C([O-])([O-])=O.[K+].[K+].CCOC(C)=O>C(#N)C>[Cl:1][C:2]1[N:3]=[C:4]([O:20][C:21]2[CH:22]=[C:23]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:32])([CH3:31])[CH3:33])[CH:24]=[CH:25][CH:26]=2)[C:5]2[CH:10]=[CH:9][N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[C:6]=2[N:7]=1
Reactant: C[Si](C)(C)CCOCn1ccc2c(Cl)nc(Cl)nc21
Reactant: CC(C)(C)OC(=O)Nc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)Nc1cccc(Oc2nc(Cl)nc3c2ccn3COCC[Si](C)(C)C)c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 90.4 %

Procedure:
To a solution of 2,4-dichloro-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine (1470 mg, 4.62 mmol) in acetonitrile (10 mL) was added tert-butyl (3-hydroxyphenyl)carbamate (966 mg, 4.62 mmol) and K2CO3 (1280 mg, 9.24 mmol) and the mixture heated at 80° C. with stirring overnight. The reaction was then cooled to rt, EtOAc (20 mL) added, washed with water (50 mL), the aqueous layer extracted with EtOAc (three×20 mL), dried with MgSO4, filtered and stripped to a light oil. Upon standing, the light oil solidified to give the title compound (2052 mg, 90% yield) as a tan solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.38-9.83 (m, 1H) 7.73 (d, J=3.78 Hz, 1H) 7.41-7.46 (m, 2H) 7.51 (s, 1H) 6.97 (dt, J=5.98, 2.68 Hz, 1H) 6.58 (d, J=3.78 Hz, 1H) 5.64 (s, 2H) 3.54-3.67 (m, 2H) 1.54 (s, 9H) 0.91-0.96 (m, 2H) 0.00 (s, 9H). LCMS (ESI, pos): m/z (ESI+) for C23H31ClN4O4Si 491.20 (M+H)+.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:11]2[C:12]([O:16][CH3:17])=[N:13][CH:14]=[CH:15][C:10]=2[N:9]([CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)[N:8]=1)(=O)=O.[C:25]([C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][CH:33]=1)(=[O:27])[NH2:26].C(=O)([O-])[O-].[Na+].[Na+].O>COCCOC.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>[CH:18]1([N:9]2[C:10]3[CH:15]=[CH:14][N:13]=[C:12]([O:16][CH3:17])[C:11]=3[C:7]([C:32]3[CH:33]=[C:28]([CH:29]=[CH:30][CH:31]=3)[C:25]([NH2:26])=[O:27])=[N:8]2)[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: COc1nccc2c1c(OS(=O)(=O)C(F)(F)F)nn2C1CCCC1
Reactant: NC(=O)c1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COc1nccc2c1c(-c1cccc(C(N)=O)c1)nn2C1CCCC1
Yield: 93.2 %

Procedure:
A solution of 1-cyclopentyl-4-methoxy-1H-pyrazolo[4,3-c]pyridin-3-yl trifluoromethanesulfonate (120 mg) obtained in Step C of Example 12, (3-carbamoyl phenyl)boronic acid (81.0 mg), tetrakis(triphenylphosphine)palladium(0) (38.0 mg) and 2M aqueous sodium carbonate solution (0.821 mL) in DME (10 mL) was heated overnight with reflux under nitrogen atmosphere. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (103 mg).
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[C:6]([C:10]1[O:14][N:13]=[C:12]([NH2:15])[CH:11]=1)([CH3:9])([CH3:8])[CH3:7].N1C=CC=CC=1>ClCCl>[C:6]([C:10]1[O:14][N:13]=[C:12]([NH:15][C:3](=[O:4])[CH2:2][Cl:1])[CH:11]=1)([CH3:9])([CH3:8])[CH3:7]
Reactant: O=C(Cl)CCl
Reactant: CC(C)(C)c1cc(N)no1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)c1cc(NC(=O)CCl)no1
Temperature: 0 °C
Reaction time: 2 h
Yield: 132.4 %

Procedure:
Chloroacetic acid chloride (0.93 ml; II.42 mmol) is dropped slowly into a stirred solution of 5-t-Butyl-3-amino isoxazole (1.5 g; 7.67 mmol) in pyridine (1.09 ml; 13.49 mmol) and dichloromethane (20 ml), cooled to 0° C. Stirring is continued for 2 h at room temperature. The reaction mixture is diluted with dichloromethane, washed twice with 1N aqueous hydrochloric acid, twice with an aqueous solution of NaHCO3 and with water. The reaction mixture is then dried over Na2SO4, filtered and evaporated to yield 2.2 g (98%) brownish solid of 10.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[CH:7]=[CH:8][N:9]=[CH:10][C:11]=3[NH:12]2)=[CH:4][CH:3]=1.O.[N+:16]([O-])([OH:18])=[O:17]>>[Cl:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[CH:7]=[CH:8][N:9]=[CH:10][C:11]=3[N:12]2[N+:16]([O-:18])=[O:17])=[CH:4][CH:3]=1
Reactant: Clc1ccc2c(c1)[nH]c1cnccc12
Reactant: O=[N+]([O-])O
Solvent: O
Product: O=[N+]([O-])n1c2cnccc2c2ccc(Cl)cc21
Reaction time: 2 h

Procedure:
A mixture 7-chloro-β-carboline (500 mg, 2.48 mmol) in concentrated nitric acid (20 ml) was stirred at RT for 22 h. The reaction mixture was carefully poured into cold (3° C. to 5° C.) water (50 ml), and after stirring for 2 h the precipitate was collected. The solid was suspended in saturated aqueous NaHCO3 (50 ml) and stirred at RT for 12 h. The product was filtered and washed with water to provide 550 mg of 7-chloro-9-nitro-β-carboline.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8](I)[C:7]([C:11]([F:14])([F:13])[F:12])=[CH:6][C:5]=1[NH2:15].[CH3:17][C:18]1[CH:22]=[C:21]([Sn](CCCC)(CCCC)CCCC)[N:20]([CH2:36][CH2:37][O:38][CH2:39][Si:40]([CH3:43])([CH3:42])[CH3:41])[N:19]=1>O1CCOCC1>[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([C:21]2[N:20]([CH2:36][CH2:37][O:38][CH2:39][Si:40]([CH3:41])([CH3:43])[CH3:42])[N:19]=[C:18]([CH3:17])[CH:22]=2)[C:7]([C:11]([F:14])([F:13])[F:12])=[CH:6][C:5]=1[NH2:15]
Reactant: COC(=O)c1cc(I)c(C(F)(F)F)cc1N
Reactant: CCCC[Sn](CCCC)(CCCC)c1cc(C)nn1CCOC[Si](C)(C)C
Solvent: C1COCCO1
Product: COC(=O)c1cc(-c2cc(C)nn2CCOC[Si](C)(C)C)c(C(F)(F)F)cc1N
Temperature: 90 °C
Reaction time: 18 h
Yield: 58.7 %

Procedure:
2-Amino-5-iodo-4-trifluoromethyl-benzoic acid methyl ester (583 mg, 1.69 mmol) and 3-methyl-5-tributylstannanyl-1-(2-trimethylsilanylmethoxy-ethyl)-1H-pyrazole (847 mg, 1 equiv) were weighed in air and added to a flame-dried flask. Bistriphenylphosphinedichloropalladium (119 mg, 0.1 equiv) was added. Dioxane (15 mL) was added and the mixture was stirred for 18 h at 90° C. The mixture was evaporated to dryness. The crude product was purified by flash chromatography (hexanes to EtOAc/hexanes (1:4)) to furnish 2-amino-5-[5-methyl-2-(2-trimethylsilanylmethoxy-ethyl)-2H-pyrazol-3-yl]-4-trifluoromethyl-benzoic acid methyl ester (426 mg, 59%) as a yellow paste (ESI-MS: m/z 430.5 [M+H]+, rt 6.54 min).
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][C:5]([O:6][C:7]2[CH:8]=[C:9]([CH:13]3[CH2:16][CH:15]([NH:17][OH:18])[CH2:14]3)[CH:10]=[CH:11][CH:12]=2)=[CH:4][CH:3]=1.C[Si]([N:25]=[C:26]=[O:27])(C)C>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C:7]2[CH:8]=[C:9]([CH:13]3[CH2:16][CH:15]([N:17]([OH:18])[C:26]([NH2:25])=[O:27])[CH2:14]3)[CH:10]=[CH:11][CH:12]=2)=[CH:19][CH:20]=1
Reactant: C[Si](C)(C)N=C=O
Reactant: ONC1CC(c2cccc(Oc3ccc(F)cc3)c2)C1
Solvent: C1CCOC1
Product: NC(=O)N(O)C1CC(c2cccc(Oc3ccc(F)cc3)c2)C1
Reaction time: 0.17 h
Yield: 50 %

Procedure:
To a solution of 3-(3-(4-fluorophenoxy)phenyl)-1-cyclobutylhydroxylamine from above in THF (50 mL) was added trimethylsilylisocyanate (1.64 g of 85% purity, 12.12 mmol) and the reaction was stirred for 10 min. It was then concentrated in vacuo. The resulting residue was chromatographed (silica gel; ether, methanol 96:4 to 90:10) to afford 1.60 g (50% over three steps) of N-[3-(3-(4-fluorophenoxy)phenyl)-cyclobutyl]-N-hydroxyurea as a 1:1 mixture of diastereomers.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@H:11]1[C@@H:15]2[O:16][C:17]([CH3:20])([CH3:19])[O:18][C@@H:14]2[C@:13]([CH2:24][OH:25])([N:21]=[N+:22]=[N-:23])[O:12]1.C[Si](Cl)(C)C.[C:31](Cl)([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:32].CO>N1C=CC=CC=1>[N:21]([C@@:13]1([CH2:24][OH:25])[C@H:14]2[O:18][C:17]([CH3:20])([CH3:19])[O:16][C@H:15]2[C@H:11]([N:6]2[CH:5]=[N:4][C:3]3[C:7]2=[N:8][CH:9]=[N:10][C:2]=3[NH:1][C:31](=[O:32])[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[O:12]1)=[N+:22]=[N-:23]
Reactant: O=C(Cl)c1ccccc1
Reactant: CC1(C)O[C@H]2[C@H](n3cnc4c(N)ncnc43)O[C@@](CO)(N=[N+]=[N-])[C@H]2O1
Agent: C[Si](C)(C)Cl
Solvent: CO
Solvent: c1ccncc1
Product: CC1(C)O[C@H]2[C@H](n3cnc4c(NC(=O)c5ccccc5)ncnc43)O[C@@](CO)(N=[N+]=[N-])[C@H]2O1
Reaction time: 1 h
Yield: 91.8 %

Procedure:
Compound 36.2 (300 mg, 0.86 mmol) was dissolved in 8.6 mL anhydrous pyridine, and treated with TMSCl (1.09 mL, 8.6 mmol). The mixture was stirred for 1 h, and then treated with BzCl (1.0 mL, 8.6 mmol), stirred for overnight. MeOH was added to the mixture after the reaction was completed. The mixture was stirred for another 5 min and then concentrated under reduced pressure. The residue was dissolved in EtOAc, washed with sat. NaHCO3 twice and the organic layer was dried over MgSO4, filtered and concentrated under reduced pressure. The residue was subjected to a silica gel column chromatography eluting with 50% EtOAc in hexane to give compound 36.3 (357 mg, 74% yield).
Reaction SMILES: C(N(CC)CC)C.B([C:11]1[CH:16]=[CH:15][C:14]([N:17]([C:34](=[O:43])/[CH:35]=[CH:36]/[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH2:18][C:19]([N:21]2[CH2:25][CH2:24][C@H:23]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:22]2)=[O:20])=[CH:13][CH:12]=1)(O)O.[C:44]1([OH:50])[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>ClCCl>[O:50]([C:11]1[CH:16]=[CH:15][C:14]([N:17]([C:34](=[O:43])/[CH:35]=[CH:36]/[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH2:18][C:19]([N:21]2[CH2:25][CH2:24][C@H:23]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:22]2)=[O:20])=[CH:13][CH:12]=1)[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN(C(=O)CN(C(=O)/C=C/c2ccccc2)c2ccc(B(O)O)cc2)C1
Reactant: Oc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H]1CCN(C(=O)CN(C(=O)/C=C/c2ccccc2)c2ccc(Oc3ccccc3)cc2)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 61.5 %

Procedure:
Triethylamine (0.13 mL, 0.91 mmol) was added to [(S)-1-(2-{(4-borono-phenyl)-[(E)-(3-phenylacryloyl)]amino}acetyl)pyrrolidin-3-yl]carbamic acid, tert-butyl ester 5 (90 mg, 0.18 mmol), copper[II]acetate, 4 Å sieve (powdered) and phenol (26 mg, 0.27 mmol) in dichloromethane (4 mL). The reaction mixture was stirred at room temperature for 16 h and then diluted with dichloromethane and washed with 10% hydrochloric acid, 1M NaOH (×2) and brine, dried (Na2SO4) and evaporated to dryness. The residue was purified by column chromatography on silica gel, eluting with ethyl acetate/petrol (2:1), to give the title compound as a white powder (60 mg) which was used directly in the next stage.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([I:16])=[CH:12][C:11]=2[F:17])[C:5]([NH2:18])=[CH:4][CH:3]=1.[Br:19][C:20]1[C:21]([S:25](Cl)(=[O:27])=[O:26])=[CH:22][S:23][CH:24]=1>>[Br:19][C:20]1[C:21]([S:25]([NH:18][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[C:7]([F:8])[C:6]=2[NH:9][C:10]2[CH:15]=[CH:14][C:13]([I:16])=[CH:12][C:11]=2[F:17])(=[O:27])=[O:26])=[CH:22][S:23][CH:24]=1
Reactant: O=S(=O)(Cl)c1cscc1Br
Reactant: Nc1ccc(F)c(F)c1Nc1ccc(I)cc1F
Product: O=S(=O)(Nc1ccc(F)c(F)c1Nc1ccc(I)cc1F)c1cscc1Br

Procedure:
According to the general procedure B, 5,6-difluoro-N1-(2-fluoro-4-iodophenyl)benzene-1,2-diamine was reacted with 4-bromothiophene-3-sulfonyl chloride to obtain the title compound. 1H NMR (300 MHz, CDCl3): δ 7.48 (br m, 2H), 7.39 (dd, J=1.8 & 10.5 Hz, 1H), 7.28 (ddd, J=2.4, 4.8 & 9.0 Hz, 1H), 7.17 (d, J=8.4 Hz, 1H), 7.02 (m, 1H), 6.02 (dt, J=2.4, 8.7 & 17.4 Hz, 1H), 5.68 (br s, 1H).
Reaction SMILES: [C:1]([OH:5])(C)([CH3:3])[CH3:2].[Cl:6][C:7]1[C:12](CC#C)=[C:11](Cl)[N:10]=[C:9]([NH2:17])[N:8]=1.[OH-].[Na+]>O>[Cl:6][C:7]1[C:12]2[CH:2]=[C:1]([CH3:3])[O:5][C:11]=2[N:10]=[C:9]([NH2:17])[N:8]=1
Reactant: CC(C)(C)O
Reactant: C#CCc1c(Cl)nc(N)nc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1cc2c(Cl)nc(N)nc2o1

Procedure:
To a mixture of 80 ml t-butanol and 60 ml water was added 6.0 g of 4,6-dichloro-5-(2-propynyl)-2-pyrimidinamine followed by 30 ml of 2N sodium hydroxide. After heating to reflux (ca 70°) for 20 hours, the mixture was cooled and the solid product was collected by filtration. The yield of product was 1.8 g, m.p. 255°-257°. An NMR (60 MHz) spectrum in trifluoroacetic acid solution exhibited absorptions at 2.8 (doublet) and 6.6 (triplet) ppm in a 3 to 1 ratio indicating the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([CH3:12])[C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1.[Br:13]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:13][CH2:12][C:10]1[C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=[C:2]([Cl:1])[CH:11]=1
Reactant: COC(=O)c1cnc(Cl)cc1C
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1cnc(Cl)cc1CBr
Temperature: 25 °C

Procedure:
A mixture of methyl 6-chloro-4-methylnicotinate (2.50 g, 13.5 mmol), N-bromosuccinimide (2.88 g, 16.2 mmol) and benzoyl peroxide (0.14 g, 0.56 mmol) in carbon tetrachloride (100 mL) was refluxed under an atmosphere of nitrogen overnight. The mixture was cooled to room temperature, and filtered through a pad of celite. The mixture was concentrated. The residue was purified by combi-flash chromatography (ethyl acetate in hexanes: 30%) to afford the desired product.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:2]1.[C:11](Cl)(=[O:24])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].C(O)(=O)CCCCCCCCCCCC.Cl>C1C=CC=CC=1>[C:11]([C:5]1[NH:1][CH:2]=[C:3]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH:4]=1)(=[O:24])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CCOC(=O)c1cc[nH]c1
Reactant: CCCCCCCCCCCCC(=O)Cl
Agent: CCCCCCCCCCCCC(=O)O
Agent: Cl
Solvent: c1ccccc1
Product: CCCCCCCCCCCCC(=O)c1cc(C(=O)OCC)c[nH]1
Temperature: 25 °C
Reaction time: 15 h
Yield: 72 %

Procedure:
To a solution (20 ml) of 2.78 g (20 mmol) of ethyl pyrrole-3-carboxylate in benzene was added tridecanoyl chloride prepared from 4.28 g (20 mml) of tridecanoic acid in a conventional manner, followed by further dropwise addition of 3.5 ml (30 mmol) of stannic chloride. After the addition, the mixture was stirred for 15 hours at room temperature, treated with diluted hydrochloric acid and extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate. After removing the solvent under reduced pressure, the residue was purified by subjecting it to silica gel column chromatography (eluent: ethyl acetate/hexane=1/7) to obtain 4.85 g (72% yield) of ethyl 5-tridecanoylpyrrole-3-carboxylate.