Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([OH:7])[CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:15][S:16](Cl)(=[O:18])=[O:17]>ClCCl>[CH3:15][S:16]([O:7][CH:4]1[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1)(=[O:18])=[O:17]
Reactant: CS(=O)(=O)Cl
Reactant: OC1CCOCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OC1CCOCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of tetrahydro-2H-pyran-4-ol (10.0 g) and triethylamine (19.1 mL) in dichloromethane (100 mL) was added dropwise methanesulfonyl chloride (10.7 mL) under ice-cooling. The reaction mixture was stirred at room temperature for 1 hr, and dichloromethane was added. The organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (16.2 g).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[C:12](C(Cl)(Cl)Cl)=[CH:11][C:10]([CH2:17][OH:18])=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.OS(O)(=O)=O.[C:24]([O-:27])(O)=[O:25].[Na+]>>[Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:24]([OH:27])=[O:25])=[CH:11][C:10]([CH2:17][OH:18])=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C([O-])O
Reactant: OCc1cc(C(Cl)(Cl)Cl)n(-c2ncccc2Cl)n1
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: O=C(O)c1cc(CO)nn1-c1ncccc1Cl
Temperature: 0 °C
Yield: 90 %

Procedure:
38.7 g (0.1 mol) of [1-(3-chloropyridin-2-yl)-5-(trichloromethyl)-1H-pyrazol-3-yl]methanol and 10 g of H2SO4 (as 10% solution in water) were stirred for 3 hours at 80° C. The mixture was cooled to 0° C., made neutral with NaHCO3 solution and the precipitate was filtered off, washed with acetonitrile and dried. Yield 90%. M.p. 178-180° C.
Reaction SMILES: [CH2:1]([NH2:5])[CH:2]([CH3:4])[CH3:3].[CH:6](=O)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C1C=CC=CC=1>[CH:6](=[N:5][CH2:1][CH:2]([CH3:4])[CH3:3])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=Cc1ccccc1
Reactant: CC(C)CN
Solvent: c1ccccc1
Product: CC(C)CN=Cc1ccccc1
Reaction time: 3 h
Yield: 89.4 %

Procedure:
To a stirred solution of isobutylamine (49.7 ml, 500 mmol) in dry benzene (50 ml) was added benzaldehyde (50.8 ml, 500 mmol) over a period of 20 minutes. After three hours, the water layer was separated and the stirring of the benzene solution continued overnight. Again the separated water layer was discarded. The benzene layer after further dilution with dry benzene (150 ml) was dried over a minimum amount of magnesium sulfate. After concentrating the dried benzene solution, the residue was distilled in vacuo, yielding 72.1 g of compound, boiling point 46°-48° C. at 0.1 mm of Hg.
Reaction SMILES: [Cl-].[NH4+].[N+:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[S:12][C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1)([O-])=O>C(O)C.O.[Fe]>[N:16]1[CH:15]=[CH:14][C:13]([S:12][C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH2:3])=[CH:18][CH:17]=1
Reactant: O=[N+]([O-])c1ccccc1Sc1ccncc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: Nc1ccccc1Sc1ccncc1
Yield: 81.4 %

Procedure:
To a refluxing mixture of iron powder (3.15 g, 56.82 mmol) and ammonium chloride (380 mg, 7.1 mmol) in ethanol (45 mL) and water (8 mL) was added 4-(2-nitrophenylsulfanyl)-pyridine (AMR01105, 2.4 g, 10.33 mmol) and the resulting mixture was stirred at reflux for 2 h. After removal of the solvent, the residue was diluted in aqueous sodium hydrogen carbonate (40 mL) and extracted with DCM (3×20 mL). The organic layer was dried (MgSO4), filtered and evaporated to give 2-(pyridin-4-ylsulfanyl)-phenylamine (1.7 g, 81%) as a yellow solid, mp 103-107° C., which was used in the next step without further purification.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[NH2:7][CH:8]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH3:22])=[CH:15][CH:14]=1)[CH2:9][C:10]([OH:12])=[O:11].C(N1[C:32](=[O:33])[C:31]2=[CH:34][CH:35]=[CH:36][CH:37]=[C:30]2[C:29]1=[O:38])(OCC)=O>O.C(#N)C>[C:29]1(=[O:38])[N:7]([CH:8]([C:13]2[CH:14]=[CH:15][C:16]([O:19][CH2:20][CH2:21][CH3:22])=[CH:17][CH:18]=2)[CH2:9][C:10]([OH:12])=[O:11])[C:32](=[O:33])[C:31]2=[CH:34][CH:35]=[CH:36][CH:37]=[C:30]12
Reactant: CCCOc1ccc(C(N)CC(=O)O)cc1
Reactant: CCOC(=O)N1C(=O)c2ccccc2C1=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CCCOc1ccc(C(CC(=O)O)N2C(=O)c3ccccc3C2=O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.2 %

Procedure:
To a stirred solution of sodium carbonate (1.45 g, 13.7 mmol) in 500 mL of water-acetonitrile (1:1, v/v) was added 3-amino-3-(4-propoxyphenyl)propionic acid (3.05 g, 13.7 mmol) as a solid. The mixture was warmed to 30°-40° C. to dissolve the solids. The reaction mixture was allowed to cool to room temperature and N-carboethoxyphthalimide (3.00 g, 13.7 mmol) was added and the reaction mixture was stirred for one hour at room temperature. The reaction mixture was then partially concentrated to remove the acetonitrile and the pH of the resulting solution was adjusted to approximately 3 with 4N hydrochloric acid. The resulting slurry was stirred overnight and then filtered and the solid was washed with copious amounts of water. The solid was dried in vacuo (60° C., <1 mm) to afford 3.64 g (75%) of 3-phthalimido-3-(4-propoxyphenyl)propionic acid as a white powder: mp 142.5°-143.6° C., 1H NMR(DMSO-d6, 250 MHz) δ 12.43 (br s, 1 H), 7.80-7.95 (m, 4 H), 7.34 (d, 2 H, J=9 Hz), 6.89 (d, 2 H, J=9 Hz), 5.63 (overlapping dd, 1 H), 3.88 (t, 2 H, J=7 Hz), 3.45 (dd, 1 H, J1=9 Hz, J2=16.5 Hz), 3.30 (dd, 1 H, J1=7 Hz, J2=16.5 Hz), 1.60-1.85 (m, 2 H), 0.95 (t, 3 H, J=7 Hz); 13C (DMSO-d6) δ 171.8, 167.6, 158.6, 134.7, 131.1, 130.8, 128.3, 123.2, 114.4, 68.9, 49.7, 36.0, 22.0, 10.3; Anal. Calcd. for C20H19NO5. Theoretical: C, 67.98; H, 5.42; N, 3.96. Found: C, 67.90; H, 5.40; N, 4.00.
Reaction SMILES: C(OCCCC)CCC.[C:10]1([Li])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(OCC)C.[CH3:22][C:23]1[CH:28]=[N:27][CH:26]=[CH:25][N:24]=1>O>[CH3:22][C:23]1[C:28]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:27][CH:26]=[CH:25][N:24]=1
Reactant: [Li]c1ccccc1
Reactant: Cc1cnccn1
Solvent: CCOCC
Solvent: O
Solvent: CCCCOCCCC
Product: Cc1nccnc1-c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 22 %

Procedure:
First, in a nitrogen atmosphere, 50 mL of a dibutyl ether solution containing phenyl lithium (produced by Wako Pure Chemical Industries, Ltd, 2.1 mol/L) and 250 mL of diethylether were mixed. Then, 8.98 g of 2-methylpyrazine (produced by Tokyo Chemical Industries Co., Ltd) was dropped into this solution while the solution was being cooled with ice, and stirred at a room temperature for three hours. Water was added into the reacted solution and an organic layer was extracted with diethylether. The obtained organic layer was washed with water and dried with magnesium sulfate. After the solvent was distilled off, the obtained residue was purified by column chromatography using dichloromethane as a developing solvent, thereby obtaining a pyrazine derivative Hmppr (yellow oily matter, yield: 22%). A synthesis scheme of Step 1 is shown by the following (a-1).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([CH3:19])([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:8](OCC)=[O:9].[Li+].[BH4-].CO>C(Cl)Cl>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([CH3:19])([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[CH2:8][OH:9]
Reactant: CCOC(=O)C(C)(CCCCCBr)c1ccccc1
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Solvent: ClCCl
Product: CC(CO)(CCCCCBr)c1ccccc1
Yield: 97.7 %

Procedure:
According to the procedure given for the synthesis of 206e, 205h (60.0 g, 183 mmol) was reduced with LiBH4(5.96 g, 274 mmol) and methanol (8.55 g, 269 mmol) in anhydrous CH2Cl2 (390 mL). After the typical workup, crude 206h (51.0 g, 98%) was obtained as a yellowish oil, which was used without further purification for the next step. 1H NMR (CDCl3): δ 7.25-7.08 (m, 5H), 3.64 (d, 1H, J=7.2), 3.50 (d, 1H, J=7.2), 3.35 (t, 2H, J=6 Hz), 1.92-0.95 (m, 9H), 1.28 (s, 3H). 13C NMR (CDCl3): δ 144.77, 128.51, 126.76, 126.21, 72.63, 43.45, 38.37, 34.06, 32.73, 28.96, 23.12, 21.59. HRMS (EI): Calcd for C14H21BrO (M+): 284.0776, found: 284.0787.
Reaction SMILES: [CH3:1][C:2]([CH3:12])([O:4][C:5]([NH:7][CH2:8][C:9]([OH:11])=O)=[O:6])[CH3:3].[CH:13]1([N:19]=C=NC2CCCCC2)CCCC[CH2:14]1.[C:28]1([CH2:34][O:35][C:36]2[CH:41]=[CH:40][C:39](CCN)=[CH:38][CH:37]=2)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>O1CCCC1>[C:28]1([CH2:34][O:35][C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][C:41]=2[CH2:14][CH2:13][NH:19][C:9](=[O:11])[CH2:8][NH:7][C:5]([O:4][C:2]([CH3:1])([CH3:3])[CH3:12])=[O:6])[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: NCCc1ccc(OCc2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCC(=O)NCCc1ccccc1OCc1ccccc1
Yield: 97.5 %

Procedure:
N-(1,1-Dimethylethoxycarbonyl)glycine N-(2-(4-phenyl-methoxy)phenyl)ethyl)amide. N-(1,1-Dimethylethoxycarbonyl)glycine (850 mg, 4.85 mmol) was stirred with dicyclohexylcarbodiimide (1.00 g, 4.85 mmol) and 2-(4-(phenylmethoxy)phenyl)ethylamine (Intermediate C) (1.00 g, 4.4 mmol) in dry tetrahydrofuran (30 mL) for 16 h. The suspension was filtered and the solvent was evaporated from the filtrate under reduced pressure. The residue was dissolved in ethyl acetate and was washed with aqueous sulphuric acid (10%) and with saturated brine. The solution was dried with anhydrous magnesium sulphate and the solvent was evaporated under reduced pressure to give N-(1,1-dimethylethoxycarbonyl)glycine N-(2-(-(phenylmethoxy)phenyl)ethyl)amide (1.65 g, 98%).
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[CH:4]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:3]1[C:11]#N.[OH-:14].[K+].[OH2:16]>C(O)CO.[Cl-].[Na+].O>[CH3:1][C:2]1([CH3:13])[C@@H:4]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[C@@H:3]1[C:11]([OH:16])=[O:14]
Reactant: O
Reactant: [OH-]
Reactant: CC1(C)C(C#N)C1c1ccccc1
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Solvent: OCCO
Product: CC1(C)[C@@H](C(=O)O)[C@@H]1c1ccccc1
Temperature: 165 °C
Yield: 95 %

Procedure:
A mixture of 2,2-dimethyl-3-phenyl-cyclopropanecarbonitrile (cis/trans mixture, 3.2 g, 18.7 mmol) and freshly ground KOH (3.143 g, 56.1 mmol) in ethylene glycol was heated at 165° C. for 28 hours. The reaction mixture was then cooled and poured into a mixture of water and brine (300 mL). The resulting mixture was extracted 3 times with ethyl ether, the combined organic extracts were dried over Na2SO4, filtered and evaporated under reduced pressure to give 3.36 g (95% yield) of trans-2,2-dimethyl-3-phenyl-cyclopropanecarboxylic acid.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[CH:9][CH:10]=[N:11]2)=[CH:6][C:5]=1[CH:14]=O)([O-:3])=[O:2].[CH3:16][O:17][C:18]([CH:20]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:19]>C1(C)C=CC=CC=1>[CH3:16][O:17][C:18](=[O:19])/[CH:20]=[CH:14]/[C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:4]=1[N+:1]([O-:3])=[O:2])[N:11]=[CH:10][CH:9]=[CH:8]2
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1cc2cccnc2cc1[N+](=O)[O-]
Solvent: Cc1ccccc1
Product: COC(=O)/C=C/c1cc2cccnc2cc1[N+](=O)[O-]

Procedure:
7-Nitroquinoline-6-carbaldehyde (370 mg; 1.83 mmol) in toluene (10 ml) was treated with (methoxycarbonylmethylen)triphenylphosphoran (672 mg; 2.0 mmol) for 1 h at reflux temperature. The pure title compound crystallised after cooling the reaction mixture and adding TBME (470 mg; 78%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[C:4]([CH2:9][N+:10]([O-:12])=[O:11])[CH:3]=1.[CH2:13]=[O:14].CCN(CC)CC.[O:22]1CCOC[CH2:23]1>[Cl-].[Na+].O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[C:4]([C:9]([N+:10]([O-:12])=[O:11])([CH2:13][OH:14])[CH2:23][OH:22])[CH:3]=1
Reactant: C1COCCO1
Reactant: O=[N+]([O-])Cc1cc(Br)ccc1F
Reactant: C=O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCN(CC)CC
Product: O=[N+]([O-])C(CO)(CO)c1cc(Br)ccc1F

Procedure:
A solution of 4-bromo-1-fluoro-2-nitromethyl-benzene (7.75 g, 33.1 mmol), formaldehyde (35%, aqueous) (5.47 ml, 69.5 mmol) and Et3N (2.3 ml, 16.56 mmol) were stirred in 66 ml dioxane for 3 h. The solution was diluted with brine and extracted with TBME. The organic layer was washed with brine, dried with Na2SO4 and evaporated. The crude product was purified by chromatography on silica gel (heptane/EtOAc 3/1) to provide the title compound as a white solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][OH:8].C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[CH:19]1([NH:22][C:23]([C:25]2[CH:26]=[CH:27][C:28]([CH3:44])=[C:29]([NH:31][C:32]([C:34]3[CH:35]=[N:36][C:37](S(C)(=O)=O)=[N:38][CH:39]=3)=[O:33])[CH:30]=2)=[O:24])[CH2:21][CH2:20]1>C1COCC1>[CH:19]1([NH:22][C:23]([C:25]2[CH:26]=[CH:27][C:28]([CH3:44])=[C:29]([NH:31][C:32]([C:34]3[CH:35]=[N:36][C:37]([O:8][CH2:7][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=4)=[N:38][CH:39]=3)=[O:33])[CH:30]=2)=[O:24])[CH2:21][CH2:20]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1cnc(S(C)(=O)=O)nc1
Reactant: OCc1ccccn1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1cnc(OCc2ccccn2)nc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 12.3 %

Procedure:
To a solution of 2-pyridinylmethanol (258 μl, 2.67 mmol) in THF (50 mL) cooled in ice bath to 0° C. was added dropwise lithium hexamethyldisilazide (1M solution in THF, 2.67 mL, 2.67 mmol) and the resulting mixture stirred for 30 minutes at 0° C. N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-2-(methylsulfonyl)pyrimidine-5-carboxamide (1 g, 2.67 mmol) was added and the resulting mixture stirred for 16 h at room temperature. The reaction mixture was concentrated under reduced pressure and the residue partitioned between water and DCM. Concentration of the organic phase under reduced pressure and crystallisation from acetonitrile gave the title compound as a colourless solid (132 mg, 12%); NMR Spectrum: (DMSOd6) 0.57 (m, 2H), 0.69 (m, 2H), 2.30 (s, 3H), 2.86 (m, 1H), 5.61 (s, 2H), 7.36 (m, 2H), 7.49 (m, 1H), 7.66 (m, 1H), 7.85 (m, 2H), 8.38 (m, 1H), 8.58 (m, 1H), 9.16 (s, 2H), 10.16 (s, 1H); Mass Spectrum: M+H+ 404.
Reaction SMILES: [Cl-].[NH2:2][C:3]1[CH:8]=[C:7]([NH:9][CH3:10])[C:6]([C:11]#[N:12])=[C:5]([Cl:13])[N+:4]=1[CH3:14].[C:15](#[N:19])[CH2:16][C:17]#[N:18].C(N(CC)CC)C>O>[Cl-:13].[NH2:2][C:3]1[CH:8]=[C:7]([NH:9][CH3:10])[C:6]([C:11]#[N:12])=[C:5]([CH:16]([C:15]#[N:19])[C:17]#[N:18])[N+:4]=1[CH3:14]
Reactant: CNc1cc(N)[n+](C)c(Cl)c1C#N
Reactant: N#CCC#N
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: O
Product: CNc1cc(N)[n+](C)c(C(C#N)C#N)c1C#N
Yield: 75 %

Procedure:
2.3 gms (.01 mole) of 2-amino-6-chloro-5-cyano-1-methyl-4-methylamino pyridinium chloride (compound 1 - Table 1) was dissolved in water and 0.66 gms (.01 mole) of malononitrile and 2.0 gms (.02 mole) of triethylamine added. After a few minutes 1.7 gms (75% yield of 2-amino-5-cyano-1-methyl-4-methylamino-6-dicyanomethyl pyridinium chloride (compound 83 - Table 6) (MPt>240°C) crystallised out.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:9][NH2:10])=[C:6]([OH:8])[CH:7]=1.C[C:12]1[CH:17]=[CH:16]C(S([O-])(=O)=O)=[CH:14][CH:13]=1.C(CC(=O)C)(=O)C>C(O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:9]2[C:17]([CH3:16])=[CH:12][C:13]([CH3:14])=[N:10]2)=[C:6]([OH:8])[CH:7]=1
Reactant: NNc1ccc(Br)cc1O
Reactant: Cc1ccc(S(=O)(=O)[O-])cc1
Solvent: CCO
Solvent: CC(=O)CC(C)=O
Product: Cc1cc(C)n(-c2ccc(Br)cc2O)n1
Temperature: 25 °C
Yield: 101.2 %

Procedure:
5-bromo-2-hydrazinylphenol 4-methylbenzenesulfonate (0.9 g) and acetylacetone (0.8 g) were added to ethanol (25 mL) refluxed for 1 h. Then the reaction mixture was cooled to room temperature and the solvent was evaporated under reduced pressure. The residue was dissolved in ethyl acetate (50 mL) and washed with saturated sodium bicarbonate solution (20 mL×2). The organic layer was dried over anhydrous Na2SO4, and concentrated under reduced pressure. The resulting residue was chromatographed over silica gel column eluted with hexane/ethyl acetate (4:1) to yield the title compound (650 mg).
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:18]([NH2:20])=[O:19])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[C:21](OC(=O)C)(=[O:23])[CH3:22]>N1C=CC=CC=1>[C:4]([O:3][C:1]([NH:8][C@H:9]([C:18](=[O:19])[NH2:20])[CH2:10][C:11]1[CH:12]=[CH:13][C:14]([O:17][C:21](=[O:23])[CH3:22])=[CH:15][CH:16]=1)=[O:2])([CH3:5])([CH3:7])[CH3:6]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(O)cc1)C(N)=O
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)Oc1ccc(C[C@H](NC(=O)OC(C)(C)C)C(N)=O)cc1
Reaction time: 18 h
Yield: 86.6 %

Procedure:
To a solution of Boc-tyrosine amide (0.960 g, 3.4 mmol) in pyridine (10 mL) stirred under argon was added acetic anhydride (808 μL, 8.56 mmol). After 18 hrs of stirring the solvent was evaporated, the residue taken in EtOAc (30 mL) washed with 5% aqueous citric acid (3×20 mL) and brine. The solution was dried (MgSO4) and the solvent evaporated to yield 949 mg (86%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N:8]2C(=O)C3C(=CC=CC=3)C2=O)=[CH:6][C:5]([S:19](Cl)(=[O:21])=[O:20])=[C:4]([O:23][CH3:24])[CH:3]=1.[NH2:25][C:26]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)([CH3:28])[CH3:27].[CH2:35](N(CC)CC)C.Cl>C(Cl)Cl.CN(C)C1C=CN=CC=1>[NH2:8][C:7]1[C:2]([Cl:1])=[CH:3][C:4]([O:23][CH3:24])=[C:5]([S:19]([N:25]([CH3:35])[C:26]([CH3:28])([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH3:27])(=[O:20])=[O:21])[CH:6]=1
Reactant: COc1cc(Cl)c(N2C(=O)c3ccccc3C2=O)cc1S(=O)(=O)Cl
Reactant: CCN(CC)CC
Reactant: CC(C)(N)c1ccccc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: COc1cc(Cl)c(N)cc1S(=O)(=O)N(C)C(C)(C)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-chloro-5-(1,3-dioxo-1,3-dihydroisoindol-2-yl)-2-methoxybenzene-sulfonyl chloride (0.2 g) in methylene chloride (6 mL) were added 2-amino-2-phenylpropane (70 mg), triethylamine (0.11 mL) and 4-dimethylaminopyridine (6 mg), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into 1 mol/L hydrochloric acid, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was dissolved in N,N-dimethylformamide (6 mL). To the solution were added methyl iodide (0.057 mL) and sodium hydride (55%, 22 mg) under ice-cooling, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into 1 mol/L hydrochloric acid, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was dissolved in tetrahydrofuran (10 mL). To the solution was added hydrazine monohydrate (0.11 mL), and the mixture was heated at reflux for 2 hours. The reaction mixture was cooled to room temperature, and the insoluble material was removed by filtration. To the filtrate were added water and ethyl acetate, and the organic layer was separated. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=2/1) to give the title compound (97 mg).
Reaction SMILES: [CH2:1]=O.[O:3]=[C:4]1[NH:7][C@H:6]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:5]1.[C:18](=[O:21])([OH:20])[O-:19].[Na+]>C(O)=O>[OH:19][CH2:18][N:7]1[C:4](=[O:3])[CH2:5][C@H:6]1[C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9].[CH:18]([O:20][CH2:1][N:7]1[C:4](=[O:3])[CH2:5][C@H:6]1[C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9])=[O:21]
Reactant: O=C([O-])O
Reactant: C=O
Reactant: O=C1C[C@@H](C(=O)OCc2ccccc2)N1
Agent: [Na+]
Solvent: O=CO
Product: O=C(OCc1ccccc1)[C@@H]1CC(=O)N1CO
Product: O=COCN1C(=O)C[C@H]1C(=O)OCc1ccccc1
Reaction time: 0.25 h

Procedure:
To a mixture of 10 ml of formic acid and 20 ml of formalin was added 3 g of (S)-benzyl 4-oxo-2-azetidine-carboxylate (14). The resulting mixture was kept at 50° C. for 15 minutes. After cooling, the mixture was made alkaline with a saturated sodium bicarbonate aqueous solution and extracted twice with 50 ml of ether. The ethereal extracts were washed with a saturated sodium chloride aqueous solution and then dried. The solvent was removed by distillation under reduced pressure and the residue thus obtained was purified by column chromatography using silica gel. Thus, 970 mg of (S)-benzyl 1-hydroxymethyl-4-oxo-2-azetidinecarboxylate (15) and 1.78 g of (S)-benzyl 1-formyloxymethyl-4-oxo-2-azetidinecarboxylate (16) were obtained.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Br:7][C:8]1[CH:27]=[CH:26][C:11]([NH:12][C:13]2[C:22]3[C:17](=[CH:18][C:19]([OH:25])=[C:20]([O:23][CH3:24])[CH:21]=3)[N:16]=[CH:15][N:14]=2)=[C:10]([F:28])[CH:9]=1.[C:29]([O:33][C:34]([N:36]1[CH2:41][CH2:40][CH:39]([CH2:42]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:38][CH2:37]1)=[O:35])([CH3:32])([CH3:31])[CH3:30].O>CN(C=O)C>[Br:7][C:8]1[CH:27]=[CH:26][C:11]([NH:12][C:13]2[C:22]3[C:17](=[CH:18][C:19]([O:25][CH2:42][CH:39]4[CH2:40][CH2:41][N:36]([C:34]([O:33][C:29]([CH3:30])([CH3:32])[CH3:31])=[O:35])[CH2:37][CH2:38]4)=[C:20]([O:23][CH3:24])[CH:21]=3)[N:16]=[CH:15][N:14]=2)=[C:10]([F:28])[CH:9]=1
Reactant: COc1cc2c(Nc3ccc(Br)cc3F)ncnc2cc1O
Reactant: Cc1ccc(S(=O)(=O)OCC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2c(Nc3ccc(Br)cc3F)ncnc2cc1OCC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 79 %

Procedure:
Potassium carbonate (414 mg, 3 mmol) was added to a suspension of 4-(4-bromo-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (546 mg, 1.5 mmol) in DMF (5 ml). After stirring for 10 minutes at ambient temperature, 1-(tert-butoxycarbonyl)-4-(4-methylphenylsulphonyloxymethyl)piperidine (636 mg, 1.72 mmol) was added and the mixture was heated at 95° C. for 2 hours. After cooling, the mixture was poured onto cooled water (20 ml). The precipitate was collected by filtration, washed with water, and dried under vacuum to give 4-(4-bromo-2-fluoroanilino)-7-(1-(tert-butoxycarbonyl)piperidin-4-ylmethoxy)-6-methoxyquinazoline (665 mg, 79%).
Reaction SMILES: S([C:5]1C=CC(C)=C[CH:6]=1)(O)(=O)=O.[OH:12][CH2:13][C@@H:14]1[C@@H:20]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([Cl:28])[CH:22]=2)[CH2:19][C@H:18]2[N:29]([CH3:30])[C@@H:15]1[CH2:16][CH2:17]2.[O-]CC.[Na+]>C(O)C>[CH2:5]([O:12][CH2:13][C@@H:14]1[C@@H:20]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([Cl:28])[CH:22]=2)[CH2:19][C@H:18]2[N:29]([CH3:30])[C@@H:15]1[CH2:16][CH2:17]2)[CH3:6]
Reactant: CN1[C@H]2CC[C@@H]1[C@H](CO)[C@@H](c1ccc(Cl)c(Cl)c1)C2
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC[C@@H]1[C@@H](c2ccc(Cl)c(Cl)c2)C[C@@H]2CC[C@H]1N2C
Yield: 96.9 %

Procedure:
(1R, 2R, 3S)-2-hydroxymethyl-3-(3,4-dichlorophenyl)tropane tosylate (2.5 g, 5.5 mmol) was dissolved in anhydrous ethanol (20 ml). Sodium ethoxide in ethanol (2.4 ml, 2.5M, 6 mmol) was added and the reaction mixture was refluxed for 72 hours. The solvent was evaporated off. The residue was stirred with water and ether and extracted three times with ether (3×50 ml) and dried over MgSO4. Evaporation of the solvent yields 1.75 g of the title compound. The product was purified by column chromatography on silica using EtOAc:Et3N (99:1). Yield 1.24 g.