Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([CH2:7][CH2:8][C:9](OCC)=[O:10])=[CH:4][CH:3]=1.[H-].C([Al+]CC(C)C)C(C)C>C1COCC1.O.[Cl-].[Na+].O>[CH3:1][C:2]1[O:6][C:5]([CH2:7][CH2:8][CH2:9][OH:10])=[CH:4][CH:3]=1
Reactant: CCOC(=O)CCc1ccc(C)o1
Agent: CC(C)C[Al+]CC(C)C
Agent: [Cl-]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(CCCO)o1
Temperature: 25 °C
Yield: 39.6 %

Procedure:
To a solution of ethyl 3-(5-methyl-2-furanyl)propionate (3.6 g, 20 mmol) in 50 mL of THF at 0° C. was added dropwise under nitrogen 8 mL of diisobutylaluminum hydride (1M in hexane), and the mixture was stirred at room temperature over-night. The resulting solution was diluted with 2 mL of water in 10 mL of THF and brine, and the mixture was stirred for 30 min. The solid was removed by filtration, and the filtrate was diluted with 20 mL of water, extracted with methylene chloride. The organic layer was washed with water, dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by passing through MPLC column (ethyl acetate/hexane) to afford 1.11 g of the desired product.
Reaction SMILES: Cl.C(OC([N:9]1[CH2:14][CH2:13][CH:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[S:21][C:22]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[NH:24][CH:23]=2)[CH2:11][CH2:10]1)=O)(C)(C)C.C([O-])(O)=O.[Na+]>C(OCC)C>[NH:9]1[CH2:14][CH2:13][CH:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[S:21][C:22]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[NH:24][CH:23]=2)[CH2:11][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccccc2Sc2c[nH]c3ccccc23)CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Product: c1ccc(C2CCNCC2)c(Sc2c[nH]c3ccccc23)c1
Temperature: 25 °C

Procedure:
1.58 g 4-(2-Triisopropylsilanylsulfanyl-phenyl)-piperidine-1-carboxylic acid tert-butyl ester (3.51 mmol) in 10 mL THF was added to 1.21 g tetrabutylammonium fluoride dihydrate (3.85 mmol) in 5 mL THF at 0° C. The reaction mixture was stirred 1 hour at 0° C., filtered through a plug of silica (eluted with EtOAc/heptane 1:1) and concentrated in vacuo. The residue was redissolved in 14 mL THF. 2 mL of this solution (≈0.5 mmol) was added to 67 mg N-chloro succinimide (0.50 mmol) in 2 mL 1,2-dichloro-ethane at 0° C. The reaction mixture was stirred 30 minutes at room temperature. The resulting solution was added to 90 mg indole (0.75 mmol) in 2 mL THF at 0° C. The reaction mixture was stirred 2 hour at 0° C., poured into 20 mL saturated NaHCO3 and extracted with ethyl acetate (2×50 mL). The combined organic phases were washed with brine (20 mL), dried with MgSO4 and concentrated in vacuo. The residue was purified by flash chromatography (silica gel; ethyl acetate/heptane) to give 89 mg 4-[2-(1H-indol-3-ylsulfanyl)-phenyl]-piperidine-1-carboxylic acid tert-butyl ester (0.22 mmol, ≈44%). 2 mL diethyl ether saturated with HCl was added to 4-[2-(1H-indol-3-ylsulfanyl)-phenyl]-piperidine-1-carboxylic acid tert-butyl ester and stirred over night at room temperature. The reaction mixture was neutralized with saturated NaHCO3 and extracted with ethyl acetate (2×50 mL). The combined organic phases were washed with brine (20 mL), dried with MgSO4 and concentrated in vacuo. 3-(2-piperidin-4-yl-phenylsulfanyl)-1H-indole was isolated after preparative HPLC.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH:11][C:12]2[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=2)[CH:15]=[O:16])[CH2:9][CH3:10])=[CH:4][C:3]=1[CH3:20].[CH3:21][Mg]Br>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH:11][C:12]2[CH:13]=[C:14]([CH:15]([OH:16])[CH3:21])[CH:17]=[CH:18][CH:19]=2)[CH2:9][CH3:10])=[CH:4][C:3]=1[CH3:20]
Reactant: CC[C@@H](Nc1cccc(C=O)c1)c1ccc(Cl)c(C)c1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: CC[C@@H](Nc1cccc(C(C)O)c1)c1ccc(Cl)c(C)c1
Temperature: -20 °C
Reaction time: 1 h

Procedure:
To a solution of INT 7 (600 mg, 2.09 mmol) in THF (7 mL) at −20° C. was added methylmagnesium bromide (3 M in Et2O, 0.83 mL, 2.50 mmol) dropwise. The reaction mixture was stirred at −20° C. for 1 hour. The mixture was quenched with saturated aqueous NH4Cl and extracted with Et2O (3×). The combined organic layers were washed with brine (2×), dried over MgSO4, filtered and concentrated. The residue was purified by chromatography on silica gel (heptane/EtOAc) to give INT 10.
Reaction SMILES: I[CH2:2][CH:3]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4]1.[C-:12]#[N:13].[K+].C(=O)(O)[O-].[Na+]>CN(C=O)C>[C:12]([CH2:2][CH:3]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4]1)#[N:13]
Reactant: [C-]#N
Reactant: ICC1Cc2ccccc2N1
Agent: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CCC1Cc2ccccc2N1
Temperature: 80 °C
Reaction time: 5 h
Yield: 37 %

Procedure:
To a mixture of 2-hydroxymethylindoline (7.77 g, 52.08 mmol), imidazole (8.86g, 130.2 mmol), triphenylphosphine (34.15 g, 130.2 mmol)in toluene (500 mL) was added iodine (26.44 g, 104.16 mmol) in acetonitrile (100 mL) at 0° C. The mixture was stirred for 10 min and water was added. The organic layer was separated, washed with brine, dried over magnesium sulfate, and concentrated. The residue was triturated with diethyl ether and insoluble solids were removed by filtration. The filtrate was concentrated to give crude 2-iodomethylindoline. The crude 2-iodomethylindoline was dissolved in DMF (130 mL) and KCN (4.07 g, 62.5 mmol) was added. The mixture was heated at 80° C. for 12 h and after addition of KCN (4.07 g), the heating was further continued for 5 h. The mixture was poured into saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography with 3:1 to 2:1 hexane/ethyl acetate to give 3.04 g of 2-cyanomethylindoline (37%): 1H NMR (270 MHz, CDCl3) δ7.03 (m, 2 H), 6.77 (t, 1H, J=7 Hz), 6.54 (t, 1H, J=7 Hz), 4.42 (m, 1H), 4.13 (bs, 1H), 3.07 (m, 1H), 2.81 (dt, 1H, J=16, 4 Hz), 2.22 (m, 2H).
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[K+].[NH2:30][C:31]1[C:36]([CH:37]=O)=[C:35]([Cl:39])[N:34]=[CH:33][N:32]=1>C1COCC1>[Cl:39][C:35]1[N:34]=[CH:33][N:32]=[C:31]([NH2:30])[C:36]=1[CH:37]=[CH:2][O:3][CH3:4]
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Nc1ncnc(Cl)c1C=O
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC=Cc1c(N)ncnc1Cl
Temperature: -2 °C
Reaction time: 1 h
Yield: 1.2 %

Procedure:
A suspension of (methoxymethyl)triphenylphosphonium chloride (276.0 g, 0.807 mol, 1.1 equiv) in THF (1.5 L) was cooled in an ice/salt bath to −2° C. and 1 M potassium tert-butoxide (KOtBu) in THF (807 mL, 0.807 mol, 1.1 equiv) was added over 1.5 h at −2 to −3° C. The deep red-orange mixture was stirred at −2 to −3° C. for 1 h. 4-Amino-6-chloropyrimidine-5-carbaldehyde (115.2 g, 0.7338 mol, 1.0 equiv) was then added portion wise to the reaction mixture as a solid form using THF (200 mL) to rinse the container and funnel. During the addition the reaction temperature increased from −3 to 13° C. and a brown color developed. When the reaction temperature dropped to 10° C., the cooling bath was removed and the reaction mixture was allowed to warm to ambient temperature and stirred at ambient temperature for 42 h. The reaction mixture was cooled to −2° C. before being quenched by the slow addition of saturated NH4Cl aqueous solution (750 mL). The mixture was concentrated under reduced pressure to remove most of the THF. The residue was partitioned between EtOAc (3 L) and H2O (1 L). The organic phase was filtered to remove insoluble material at the interface, then extracted with 2 N HCl (4×250 mL) followed by 3 N HCl (2×250 mL). The combined HCl extracts were back-extracted with EtOAc (500 mL) then filtered through Celite to remove insoluble material. The filtrate was cooled in an ice/brine bath, adjusted to pH 8 with a 6 N aqueous NaOH solution and extracted with EtOAc (3×1 L). The combined EtOAc extracts were washed with brine (1 L), dried over Na2SO4, stirred with charcoal (10 g) and silica gel (10 g) for 1 h. The mixture was filtered through Celite, washing the Celite pad with EtOAc (1 L). The filtrate was concentrated, co-evaporating residual EtOAc with n-heptane (500 mL). The resulting tan solid was pumped under high vacuum for 2 h to afford crude 6-chloro-5-(2-methoxyvinyl)pyrimidin-4-ylamine (72.3 g, 136.2 g theoretical, 53.1%). The crude desired product was used in the following reaction without further purification. A sample of crude product (2.3 g) was purified by silica gel column chromatography on, eluting with 0-35% EtOAc/n-heptane to give 1.7 g of pure 6-chloro-5-(2-methoxyvinyl)pyrimidin-4-ylamine as a white solid, which was found to be a 1 to 2 mixture of E/Z isomers. 1H NMR (300 MHz, DMSO-d6) for E-isomer: δ 8.02 (s, 1H), 7.08 (bs, 2H), 6.92 (d, 1H, J=13.1), 5.35 (d, 1H, J=13.0 Hz), 3.68 (s, 3H) ppm and for Z-isomer: δ 8.06 (s, 1H), 7.08 (bs, 2H), 6.37 (d, 1H, J=6.8 Hz), 5.02 (d, 1H, J=6.7 Hz), 3.69 (s, 3H) ppm; C7H8ClN3O (MW, 185.61), LCMS (EI) m/e 186/188 (M++H).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:6]=1[OH:15])([CH3:4])([CH3:3])[CH3:2].[CH:16](=O)[CH:17]([CH3:19])[CH3:18].CNC>C(O)(C)C>[CH3:18][C:17]([CH3:19])=[CH:16][C:9]1[CH:10]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:6]([OH:15])=[C:7]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=1
Reactant: CC(C)C=O
Reactant: CC(C)(C)c1cccc(C(C)(C)C)c1O
Agent: CNC
Solvent: CC(C)O
Product: CC(C)=Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Temperature: 25 °C
Yield: 71 %

Procedure:
2,6-di-tertiary-butyl phenol (4.1 g; 20 mmol), isobutyraldehyde (3 ml; 33 mmol), dimethylamine (1.5 g; 34 mmol) dissolved in isopropanol (7.5 g) were charged to a 100 ml glass vessel and refluxed at ambient pressure under nitrogen for 48 hours. The resultant reaction mixture was allowed to cool to ambient temperature and concentrated to a yellow oil which was recrystallized from a mixture of ethanol and water (90:10) to give yellow crystals (3.7 g; 71% yield) of 1,1-dimethyl-2-(3',5'-di-t-butyl-4'-hydroxyphenyl)ethene as characterized by VPC, mass spectroscopy and NMR.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][NH:9][OH:10].C(N(CC)CC)C.[CH3:18][C:19]([CH3:26])([C:23](Cl)=[O:24])[C:20](Cl)=[O:21]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][N:9]1[C:20](=[O:21])[C:19]([CH3:26])([CH3:18])[C:23](=[O:24])[O:10]1
Reactant: CC(C)(C(=O)Cl)C(=O)Cl
Reactant: ONCc1ccccc1Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC1(C)C(=O)ON(Cc2ccccc2Cl)C1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 29.8 %

Procedure:
To a stirred solution of 8.3 grams (0.053 mole) of N-(2-chlorophenylmethyl)hydroxylamine and 12.1 grams (0.12 mole) of triethylamine in 200 ml of dry toluene was added dropwise a solution of 9.0 grams (0.053 mole) of dimethylmalonyl chloride in 50 ml of dry toluene. The addition required approximately 30 minutes and caused a white precipitate to form. The reaction mixture was stirred at room temperature for about 16 hours. The white precipitate was collected by filtration and washed with toluene. The combined wash and filtrate was washed with two portions of water and one portion of an aqueous solution saturated with sodium chloride and then dried with sodium sulfate. The solution was filtered from the sodium sulfate, and the filtrate was concentrated under reduced pressure to a viscous liquid. The liquid was subjected to column chromatography on silica gel. Elution was accomplished with 15% ethyl acetate in hexane. The fractions showing product by thin layer chromatography were combined to give an oil, which was distilled under reduced pressure to give 4.0 grams of 2-[(2-chlorophenyl)methyl]-4,4-dimethylisoxazolidine-3,5-dione; bp 115° C./0.03 mm. The nmr and the ir spectra were consistent with the assigned structure.
Reaction SMILES: NC1(OC2C=CC=C(C(F)(F)F)C=2)C2N=CC=C(C)C=2C=C(OC)C1.ICCCC([N:32]1[C:36](=[O:37])[C:35]2=[CH:38][CH:39]=[CH:40][CH:41]=[C:34]2[C:33]1=[O:42])C.IC(N1C(=O)C2=CC=CC=C2C1=O)CCCC.C(N(CC)CC)C>C(OCCO)C.C(Cl)Cl>[C:36]1(=[O:37])[NH:32][C:33](=[O:42])[C:34]2=[CH:41][CH:40]=[CH:39][CH:38]=[C:35]12
Reactant: CC(CCCI)N1C(=O)c2ccccc2C1=O
Agent: CCCCC(I)N1C(=O)c2ccccc2C1=O
Agent: COC1=Cc2c(C)ccnc2C(N)(Oc2cccc(C(F)(F)F)c2)C1
Solvent: CCOCCO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1NC(=O)c2ccccc21
Reaction time: 4.5 h
Yield: 0.3 %

Procedure:
A solution of 8-amino-6-methoxy-4-methyl-8-(3-trifluoromethylphenoxy)quinoline (5.26 g, 15 mmol), 1-iodo-4-phthalimidopentane (5.26 g, 15 mol) in 2-ethoxyethanol (25 mL) was heated at 110° for 1.5 hour after which time an additional 7.5 mmol of iodophthalimidopentane and triethylamine were added. After stirring 1.5 hour an additional 7.5 mmol of each reagent was added. After stirring an additional 4.5 hours the reaction mixture was diluted with CH2Cl2 and the organic layer was washed with water (×3). After drying (K2CO3) the organic layer was concentrated to dryness and the residue was chromatographed over a silica gel column (33 mm×500 mm). Elution with chloroform afforded the intermediate phthalimide (6.65 g, 79%) which could be crystallized from EtOH to give mp 122°-124°.
Reaction SMILES: [CH2:1]([C:8]1([C:12]2[CH:13]=[C:14]([CH:28]=[CH:29][CH:30]=2)[O:15][CH2:16][CH2:17][NH:18][S:19]([C:22]2[N:23]=[CH:24][N:25]([CH3:27])[CH:26]=2)(=[O:21])=[O:20])[CH2:11][NH:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(NC(C)C)(C)C.[F:38][CH2:39][C:40](Cl)=[O:41]>ClCCl>[CH2:1]([C:8]1([C:12]2[CH:13]=[C:14]([CH:28]=[CH:29][CH:30]=2)[O:15][CH2:16][CH2:17][NH:18][S:19]([C:22]2[N:23]=[CH:24][N:25]([CH3:27])[CH:26]=2)(=[O:21])=[O:20])[CH2:11][N:10]([C:40](=[O:41])[CH2:39][F:38])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cn1cnc(S(=O)(=O)NCCOc2cccc(C3(Cc4ccccc4)CNC3)c2)c1
Reactant: O=C(Cl)CF
Solvent: CC(C)NC(C)C
Solvent: ClCCl
Product: Cn1cnc(S(=O)(=O)NCCOc2cccc(C3(Cc4ccccc4)CN(C(=O)CF)C3)c2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of N-(2-(3-(3-benzylazetidin-3-yl)phenoxy)ethyl)-1-methyl-1H-imidazole-4-sulfonamide (81 mg, 0.190 mmol) in dry dichloromethane (1.5 ml) containing diisopropylamine (0,066 ml, 0,380 mmol) under argon was added fluoroacetyl chloride (0.022 ml, 0.285 mmol) and stirred at room temperature for 1 h. Washed with 1N HCl, sodium bicarbonate and brine, dried over MgSO4, filtered, evaporated and the crude material was purified by flash silica gel chromatography on 4 g SiO2-cartridge using 5% MeOH in dichloromethane affording 68.7 mg of a white solid.
Reaction SMILES: [Br:1][C:2]1[C:3](O)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([CH3:18])(=[NH:17])=[O:16])=[CH:11][CH:10]=2)=[N:6][CH:7]=1.N.P(Cl)(Cl)([Cl:23])=O>>[Br:1][C:2]1[C:3]([Cl:23])=[N:4][C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([CH3:18])(=[NH:17])=[O:16])=[CH:11][CH:10]=2)=[N:6][CH:7]=1
Reactant: CS(=N)(=O)c1ccc(Nc2ncc(Br)c(O)n2)cc1
Reactant: O=P(Cl)(Cl)Cl
Agent: N
Product: CS(=N)(=O)c1ccc(Nc2ncc(Br)c(Cl)n2)cc1
Temperature: 106 °C
Reaction time: 16 h

Procedure:
255 mg of (RS)—S-{4-[(5-bromo-4-hydroxypyrimidin-2-yl)amino]phenyl}-S-methyl sulfoximide is suspended in 1.5 ml of phosphorus oxychloride and stirred for 3 hours at 106° C. and for 16 hours at room temperature. The mixture is poured into ice water, made alkaline with 25% ammonia solution while being cooled intensely (temperature <5° C.) and stirred for 1 hour in an ice bath. The precipitate is suctioned off, washed with water and dried at 60° C. 220 mg (81.8% of theory) of the product with a melting point of 170-173° C. is obtained.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH:11]=O)=[CH:8][C:6]=2[N:7]=1.[CH3:19][N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.ClCCl>[Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH2:11][N:23]3[CH2:24][CH2:25][N:20]([CH3:19])[CH2:21][CH2:22]3)=[CH:8][C:6]=2[N:7]=1
Reactant: CN1CCNCC1
Reactant: O=Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Solvent: ClCCl
Product: CN1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 45 %

Procedure:
To a mixture of 2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-carbaldehyde (147 mg, 0.52 mmol), 1-methyl-piperazine (1.5 eq, 87 μL) and acetic acid (1.05 eq, 32 μL) in 1,2-dichloroethane (3 mL) was added sodium triacetoxyborohydride (1.1 eq, 121 mg) and then stirred at room temperature overnight. The reaction mixture was diluted with dichloromethane, washed with saturated solution of sodium hydrogen carbonate, brine, separated and dried (MgSO4). The crude product was evaporated in vacuo and purified by chromatography to give the title compound as an off-white crystalline solid (51 mg, 45%).
Reaction SMILES: [I:1][C:2]1[C:11]2[O:10][CH2:9][C:8](=[O:12])[NH:7][C:6]=2[CH:5]=[C:4]([C:13]([O:15][CH3:16])=[O:14])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:24][CH2:25][CH2:26][CH3:27]>CS(C)=O.O>[CH2:24]([N:7]1[C:6]2[CH:5]=[C:4]([C:13]([O:15][CH3:16])=[O:14])[CH:3]=[C:2]([I:1])[C:11]=2[O:10][CH2:9][C:8]1=[O:12])[CH2:25][CH2:26][CH3:27]
Reactant: COC(=O)c1cc(I)c2c(c1)NC(=O)CO2
Reactant: CCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CCCCN1C(=O)COc2c(I)cc(C(=O)OC)cc21
Temperature: 80 °C
Reaction time: 1 h
Yield: 72.6 %

Procedure:
To a solution of Methyl 8-iodo-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylate (2.64 g) and potassium carbonate (5 g) in DMSO (20 mL) was added bromobutane (5 g), and the reaction mixture was stirred for 1 h at 80° C. The mixture was cooled to room temperature, diluted with 1:1 ethyl acetate/hexanes (100 mL) and water (160 mL), and separated. The organic layer was washed with water, and brine, dried (magnesium sulfate), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica, 1:10 ethyl acetate/hexanes) afforded 2.24 g of the title compound: 1H NMR (300 MHz, CDCl3) δ 8.13, 7.63, 4.74, 3.96, 3.92, 1.64, 1.42, 0.97.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][N:5]=[CH:4]1.[CH3:8][Si:9]([CH3:16])([CH3:15])[CH2:10][CH2:11][O:12][CH2:13]Cl>O1CCCC1>[CH3:8][Si:9]([CH3:16])([CH3:15])[CH2:10][CH2:11][O:12][CH2:13][N:3]1[CH:7]=[CH:6][N:5]=[CH:4]1
Reactant: c1c[nH]cn1
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1ccnc1
Temperature: 25 °C
Yield: 89.1 %

Procedure:
A suspension of sodium hydride (3.08 g of 60% in oil, 1.85 g, 77 mmol) in dry tetrahydrofuran (80 mL) at 0° C. was treated dropwise with a solution of imidazole (5.00 g, 73.4 mmol) in dry tetrahydrofuran (20 mL) over 15 minutes. The mixture was warmed at room temperature for 30 minutes, followed by cooling again to 0° C. and addition of 2-trimethylsilylethyoxymethyl chloride (13.7 mL, 12.86 g, 77 mmol) dropwise. The mixture was allowed to warm to room temperature for 18 hours, and was quenched by addition of saturated ammonium chloride solution. The mixture was diluted with water and concentrated in vacuo to remove tetrahydrofuran. The residue was extracted with ethyl acetate and the organic layer was extracted with saturated sodium chloride solution. Drying (Na2SO4), filtration, and concentration in vacuo afforded an orange oil, which was distilled (93-94° C./0.2 mm Hg) to afford the title compound (12.97 g, 89%) as a colorless liquid. MS (ESI+) m/z (rel abundance) 199 (100, M+H)+.
Reaction SMILES: [CH2:1]([C@@H:4]([C@@:9]([NH:15][C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17])([CH2:11][CH:12]([CH3:14])[CH3:13])[CH3:10])[C:5]([O:7]C)=[O:6])[CH:2]=[CH2:3].[OH-].[K+].Cl>CO>[CH2:1]([C@@H:4]([C@@:9]([NH:15][C:16]([O:18][CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)=[O:17])([CH2:11][CH:12]([CH3:14])[CH3:13])[CH3:10])[C:5]([OH:7])=[O:6])[CH:2]=[CH2:3]
Reactant: C=CC[C@H](C(=O)OC)[C@](C)(CC(C)C)NC(=O)OCc1ccccc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: C=CC[C@H](C(=O)O)[C@](C)(CC(C)C)NC(=O)OCc1ccccc1

Procedure:
221 mg of the methyl ester from Step 1 are hydrolyzed by treatment with 5 mL of 1N KOH and 5 mL of MeOH for 4 hours at room temperature. The solution is made acidic with 1N HCl. Most of the MeOH is removed and the product is extracted into EtOAC. The product is purified by flash chromatography on silica gel using 70% hexanes/28% EtOAc/2% HOAc to give the title compound.
Reaction SMILES: [CH:1]1([CH2:4][CH2:5][NH:6][C:7]2[CH:8]=[C:9]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=3)[CH:10]=[CH:11][CH:12]=2)[CH2:3][CH2:2]1.Cl[S:24]([C:27]1[CH:39]=[CH:38][C:30]([O:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])=[C:29]([CH3:40])[CH:28]=1)(=[O:26])=[O:25].C(N(CC)CC)C>C(Cl)Cl.O>[CH:1]1([CH2:4][CH2:5][N:6]([C:7]2[CH:8]=[C:9]([C:13]3[CH:14]=[CH:15][C:16]([C:19]([F:20])([F:21])[F:22])=[CH:17][CH:18]=3)[CH:10]=[CH:11][CH:12]=2)[S:24]([C:27]2[CH:39]=[CH:38][C:30]([O:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])=[C:29]([CH3:40])[CH:28]=2)(=[O:26])=[O:25])[CH2:3][CH2:2]1
Reactant: CCOC(=O)COc1ccc(S(=O)(=O)Cl)cc1C
Reactant: FC(F)(F)c1ccc(-c2cccc(NCCC3CC3)c2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)COc1ccc(S(=O)(=O)N(CCC2CC2)c2cccc(-c3ccc(C(F)(F)F)cc3)c2)cc1C
Yield: 54.5 %

Procedure:
To a solution of N-(2-cyclopropylethyl)-N-[4′-(trifluoromethyl)-1,1′-biphenyl-3-yl]amine (155 mg, 0.51 mmol) in anhydrous CH2Cl2 (10 mL) under nitrogen at room temperature was added ethyl [4-(chlorosulfonyl)-2-methylphenoxy]acetate (223 mg, 0.76 mmol) and triethylamine (0.213 mL, 1.53 mmol). The resultant mixture was stirred for 40 h at room temperature. The reaction mixture was diluted with water (15 mL) and extracted with CH2Cl2 (30 mL). The organic solution was passed through a hydrophobic frit and the solvent was removed in vacuo. Purification by Biotage™ chromatography (40 g Silica column) eluted with 1:19–1:9 EtOAc:cyclohexane afforded the title compound as a white crystalline solid (156 mg).
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:32][C:33]1[C:42]2[C:37](=[CH:38][C:39]([OH:45])=[C:40]([O:43][CH3:44])[CH:41]=2)[N:36]=[CH:35][CH:34]=1.[O:46]1[CH2:51][CH2:50][N:49]([CH2:52][CH2:53][CH2:54]O)[CH2:48][CH2:47]1>C(Cl)Cl>[Cl:32][C:33]1[C:42]2[C:37](=[CH:38][C:39]([O:45][CH2:54][CH2:53][CH2:52][N:49]3[CH2:50][CH2:51][O:46][CH2:47][CH2:48]3)=[C:40]([O:43][CH3:44])[CH:41]=2)[N:36]=[CH:35][CH:34]=1
Reactant: OCCCN1CCOCC1
Reactant: COc1cc2c(Cl)ccnc2cc1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1cc2c(Cl)ccnc2cc1OCCCN1CCOCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 66.3 %

Procedure:
Diethyl azodicarboxylate (120 μl, 0.76 mmol) was added dropwise to a solution of triphenylphosphine (200 mg, 0.76 mmol), 4-chloro-7-hydroxy-6-methoxyquinoline (100 mg, 0.47 mmol), 3-morpholino-1-propanol (75 mg, 0.52 mmol), (Tet. Lett. 1994, 35, 1715), in methylene chloride (5 ml). The mixture was stirred for 4 hours at ambient temperature, the solvent was removed by evaporation to dryness and purified by column chromatography eluting with methylene chloride/methanol (9/1) to give 4-chloro-6-methoxy-7-(3-morpholinopropoxy)quinoline (105 mg, 66%).