Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[C:12]([NH:14][CH2:15][C@H:16]([OH:23])[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:11]=[CH:10][N:9]=2)[CH:5]=[CH:4][C:3]=1[C:24](=O)[CH3:25].Cl.[NH2:28][OH:29].[OH-].[K+].C(O)(C)C>O>[CH3:25][C:24]1[C:3]2[CH:4]=[CH:5][C:6]([C:8]3[N:9]=[CH:10][N:11]=[C:12]([NH:14][CH2:15][C@@H:16]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[OH:23])[CH:13]=3)=[CH:7][C:2]=2[O:29][N:28]=1
Reactant: CC(=O)c1ccc(-c2cc(NC[C@H](O)c3ccccc3)ncn2)cc1F
Reactant: NO
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: Cc1noc2cc(-c3cc(NC[C@H](O)c4ccccc4)ncn3)ccc12
Temperature: 90 °C
Yield: 27.7 %

Procedure:
A mixture of 1-[2-fluoro-4-(6-{[(2R)-2-hydroxy-2-phenyl-ethyl]amino}-pyrimidin-4-yl)-phenyl]ethanone (88 mg, 0.25 mmol), hydroxylamine hydrochloride (41 mg, 0.60 mmol), KOH (85% aq., 0.158 mL), isopropanol (0.5 mL) and water (0.5 mL) was heated in a sealed tube at 90° C. for 10 h. An additional amount of KOH (85% aq., 2.38 mmol) was added and the temperature increased to 120° C. for an additional 21 h. The reaction mixture was diluted with water (5 mL) and extracted with DCM (5 mL×3). The combined extracts were dried (Na2SO4), concentrated, and the crude product purified (FCC) to yield the title compound (24 mg, 28%). MS (ESI): mass calcd. for C20H18N4O2, 346.14; m/z found, 347.2 [M+H]+. 1H NMR (CDCl3): 8.70 (d, J=0.8 Hz, 1H), 8.13 (dd, J=1.3, 0.8 Hz, 1H), 7.93 (dd, J=8.3, 1.3 Hz, 1H), 7.70 (dd, J=8.3, 0.8 Hz, 1H), 7.45-7.37 (m, 4H), 7.34-7.30 (m, 1H), 6.80 (d, J=1.0 Hz, 1H), 5.35-5.30 (m, 1H), 5.03-4.99 (m, 1H), 3.94-3.87 (m, 1H), 3.67-3.60 (m, 1H), 2.62 (s, 3H).
Reaction SMILES: [C:1]([NH:4][CH:5]([CH2:11][C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:3])[CH3:2].[Cl-].[K+].C(#N)C.[OH-].[K+]>O.C(OCC)(=O)C>[C:1]([NH:4][C@H:5]([CH2:11][C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:3])[CH3:2]
Reactant: CCOC(=O)C(Cc1cccnc1)NC(C)=O
Agent: [Cl-]
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: O
Product: CCOC(=O)[C@@H](Cc1cccnc1)NC(C)=O
Reaction time: 0.5 h

Procedure:
A suspension of 54.7 g of ethyl 2-(acetylamino)-3-(3-pyridyl)propanoate in 420 cm3 of water, to which has been added 18.5 g of potassium chloride, is dissolved by adding 100 cm3 of acetonitrile. An orange-colored solution of neutral pH is obtained, 0.168 g of α-chymotrypsin is then added and the pH falls. Aqueous 2N potassium hydroxide solution is added dropwise, with stirring, to remain at a constant pH of 7.2. After 1 hour 30 min, with the pH showing little change, the mixture is stirred for 48 hours at room temperature. The pH of the solution is then approximately 5.6 and, on adding aqueous 2N potassium hydroxide solution, it is thereby adjusted to about 7. 0.084 g of α-chymotrypsin is introduced and the pH is adjusted to 7.2 by a further addition of aqueous 2N potassium hydroxide solution, and the mixture is left stirring for 1 hour 30 min. The pH of the reaction medium does not change. 400 cm3 of ethyl acetate are added and the mixture is stirred for 30 min and then filtered through Celite. The filtrate is separated out after settling has taken place and the aqueous phase is extracted with 3 times 400 cm3 of ethyl acetate. The organic phases are combined, washed with 400 cm3 of saturated sodium chloride solution and dried over magnesium sulfate. After filtration and concentration under reduced pressure (2 kPa) at a temperature in the region of 40° C., 20.77 g of ethyl (2R)-2-(acetylamino)-3-(3-pyridyl)propanoate are obtained in the form of a beige-colored solid melting at 80° C. [1H NMR spectrum (400 MHz, (CD3)2SO-d6, δ in ppm): 1.13 (t, J=7 Hz: 3H); 1.81 (s: 3H); 2.92 (dd, J=14 and 9.5 Hz: 1H); 3.05 (dd, J=14 and 5.5 Hz: 1H); 4.07 (q, J=7 Hz: 2H); 4.48 (mt: 1H); 7.33 (dd, J=8 and 5 Hz: 1H); 7.66 (dt, J=8 and 2 Hz: 1H); 8.36 (d, J=8 Hz: 1H); 8.44 (mt: 2H)].
Reaction SMILES: [C:1]([C:3]1[CH:25]=[CH:24][C:6]2[O:7][C:8]([CH3:23])([CH3:22])[C@@H:9](OS(C)(=O)=O)[C@H:10]([NH:11][C:12](=[N:14][C:15]#[N:16])[CH3:13])[C:5]=2[CH:4]=1)#[N:2].C(=O)([O-])[O-].[K+].[K+].[I-].[K+].Br[CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37]>C(#N)C>[C:1]([C:3]1[CH:25]=[CH:24][C:6]2[O:7][C:8]([CH3:23])([CH3:22])[CH:9]=[C:10]([N:11]([C:12](=[N:14][C:15]#[N:16])[CH3:13])[CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])[C:5]=2[CH:4]=1)#[N:2]
Reactant: CCOC(=O)CBr
Reactant: CC(=NC#N)N[C@@H]1c2cc(C#N)ccc2OC(C)(C)[C@H]1OS(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)CN(C1=CC(C)(C)Oc2ccc(C#N)cc21)C(C)=NC#N

Procedure:
6.0 g of 6-cyano-2,2-dimethyl-4-[(N-cyano-acetimidoyl)amino]-2H-benzo[b]pyran obtained in Example 34 was suspended in 200 ml of acetonitrile, and 6.12 g of potassium carbonate, 0.75 g of potassium iodide and 7.53 g of ethyl bromoacetate were added thereto. The mixture was stirred under reflux for 2 hours. Then, the reaction mixture was cooled and then filtered to remove insoluble potassium carbonate and potassium bromide The filtrate was distilled to remove acetonitrile under reduced pressure. The residue was dissolved in 250 ml of ethyl acetate, washed with a saturated sodium chloride aqueous solution, and then dried over anhydrous sodium sulfate. Then, ethyl acetate was distilled off under reduced pressure. The residual solid was recrystallized from ethyl acetate/n-hexane to obtain 4.8 g of the above identified compound in the form of crystals.
Reaction SMILES: C1(S[C:8]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:15]=2)([CH3:13])[C:9]([O:11][CH3:12])=[O:10])C=CC=CC=1>C(O)C.[Ni]>[O:20]([C:16]1[CH:15]=[C:14]([CH:8]([CH3:13])[C:9]([O:11][CH3:12])=[O:10])[CH:19]=[CH:18][CH:17]=1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: COC(=O)C(C)(Sc1ccccc1)c1cccc(Oc2ccccc2)c1
Agent: [Ni]
Solvent: CCO
Product: COC(=O)C(C)c1cccc(Oc2ccccc2)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 90.7 %

Procedure:
Methyl α-phenylthio-α-(m-phenoxyphenyl)propionate (210 mg) was dissolved in 1 ml of ethanol. An ethanol suspension (5 ml) of 2 cc of Raney nickel (W-II) was added, and the mixture was stirred at room temperature for 5 hours. The reaction mixture was filtered, and the insoluble matter was washed with 50 ml of methanol. The filtrate and the washing were combined, and concentrated under reduced pressure. Methylene chloride (30 ml) was added to the residue, and the insoluble matter was separated by filtration. The filtrate was concentrated under reduced pressure, and the residue was chromatographed on a column of silica gel using benzene as an eluent to afford 134 mg of methyl α-(m-phenoxyphenyl)propionate in a yield of 90%.
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C:3]1[CH:4]=[C:5]([CH2:13][O:14][C@H:15]2[CH2:20][CH2:19][CH2:18][NH:17][C@H:16]2[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.Cl.FC(F)(F)C1C=[C:34]([CH2:42][O:43][C@H]2CCCN[C@H]2C2C=CC=CC=2)C=C(C(F)(F)F)C=1>>[C:42]([N:17]1[CH2:18][CH2:19][CH2:20][C@H:15]([O:14][CH2:13][C:5]2[CH:4]=[C:3]([C:2]([F:27])([F:1])[F:28])[CH:8]=[C:7]([C:9]([F:12])([F:10])[F:11])[CH:6]=2)[C@@H:16]1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(=[O:43])[CH3:34]
Reactant: FC(F)(F)c1cc(CO[C@H]2CCCN[C@H]2c2ccccc2)cc(C(F)(F)F)c1
Agent: Cl
Product: CC(=O)N1CCC[C@H](OCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1c1ccccc1
Temperature: 23 °C
Reaction time: 3 h

Procedure:
To a solution of (+)-cis-3-((3,5-bis(trifluoromethyl) phenyl)methyloxy)-2-phenyl piperidine prepared from hydrochloride salt (Example 5, 1.0 g) by partitioning between aqueous sodium carbonate and dichloromethane) in dry dichloromethane (5 ml) was added pyridine (0.67 ml), acetic anhydride (0.79 ml) and 4,4-dimethylamine pyridine (10 mg). After the solution had been stirred for 3 h at 23° C., saturated sodium bicarbonate solution was added and the organic phase dried (MgSO4), evaporated in vacuo and chromatographed on silica gel to give the title compound as an oil. Found: C, 59.51; H, 4.90; N, 3.09. Calcd for C22H21NO2F6 ; C, 59.33; H, 4.75; N, 3.14%.
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH:14]([CH3:16])[CH3:15])=[C:9]([Cl:17])[CH:8]=2)=[N:4][CH:3]=1.[CH2:18]([C:20]1[C:27](B2OC(C)(C)C(C)(C)O2)=[CH:26][CH:25]=[CH:24][C:21]=1[CH:22]=[O:23])[CH3:19].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C)C=O.O.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>[Cl:17][C:9]1[CH:8]=[C:7]([C:5]2[S:6][C:2]([C:27]3[C:20]([CH2:18][CH3:19])=[C:21]([CH:24]=[CH:25][CH:26]=3)[CH:22]=[O:23])=[CH:3][N:4]=2)[CH:12]=[CH:11][C:10]=1[O:13][CH:14]([CH3:16])[CH3:15]
Reactant: CC(C)Oc1ccc(-c2ncc(Br)s2)cc1Cl
Reactant: CCc1c(C=O)cccc1B1OC(C)(C)C(C)(C)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCc1c(C=O)cccc1-c1cnc(-c2ccc(OC(C)C)c(Cl)c2)s1
Temperature: 120 °C
Yield: 86.2 %

Procedure:
To a solution of 5-bromo-2-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,3-thiazole (D71) (500 mg), 2-ethyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (430 mg) and tripotassium phosphate (638 mg) in N,N-dimethylformamide (DMF) (12 mL) and water (2 mL) stirred under nitrogen at room temperature was added Pd(Ph3P)4 (174 mg) in one charge. The reaction vessel was sealed and heated under microwave at 120° C. for 15 min. After cooling the reaction, the reaction mixture was filtered and the filtrate was partitioned between ethyl acetate (250 mL) and saturated brine (50 mL). The organic phase was dried over sodium sulphate and evaporated in vacuo. The crude product was purified by column chromatography to give 3-(2-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,3-thiazol-5-yl)-2-ethylbenzaldehyde (D74) (500 mg) as a brown oil. MS (ES): C21H20ClNO2S requires 385. found 386.0 (M+H+).
Reaction SMILES: [F:1][CH:2]([F:23])[O:3][C:4]1[C:9]2[O:10][C:11]3[C:12](=[O:19])[N:13]([CH2:17][CH3:18])[N:14]=[CH:15][C:16]=3[C:8]=2[C:7]([C:20]([OH:22])=[O:21])=[CH:6][CH:5]=1.C(N(CC)CC)C.[CH:31]1[C:36]([N+:37]([O-:39])=[O:38])=[CH:35][CH:34]=[C:33](O)[CH:32]=1.CCN=C=NCCCN(C)C>O1CCCC1>[F:23][CH:2]([F:1])[O:3][C:4]1[C:9]2[O:10][C:11]3[C:12](=[O:19])[N:13]([CH2:17][CH3:18])[N:14]=[CH:15][C:16]=3[C:8]=2[C:7]([C:20]([O:22][C:33]2[CH:32]=[CH:31][C:36]([N+:37]([O-:39])=[O:38])=[CH:35][CH:34]=2)=[O:21])=[CH:6][CH:5]=1
Reactant: CCn1ncc2c(oc3c(OC(F)F)ccc(C(=O)O)c32)c1=O
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: CCN=C=NCCCN(C)C
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCn1ncc2c(oc3c(OC(F)F)ccc(C(=O)Oc4ccc([N+](=O)[O-])cc4)c32)c1=O
Temperature: 25 °C
Reaction time: 16.5 h

Procedure:
A mixture of 6-difluoromethoxy-3-ethyl-4-oxo-3,4-dihydrobenzo[4,5]furo[2,3-d]pyridazine-9-carboxylic acid (form step II) (90 mg, 0.276 mmol), triethyl amine (41 mg, 0.415 mmol), p-nitro phenol (43 mg, 0.304 mmol) and EDCI (79 mg, 0.415 mmol) in tetrahydrofuran (3 ml) was stirred at room temp for 16-17 hrs. Progress of reaction was monitored by TLC. At the end, reaction mixture was concentrated under vacuum. Then water (50 ml) was added to reaction mixture and acidified with dilute HCl. The precipitate obtained was filtered and dried in oven. 87 mg buff colored solid was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:13](=[O:14])[C:12]([O:15][CH2:16][CH:17]([CH3:19])[CH3:18])=[C:11]([C:20]3[CH:25]=[CH:24][C:23]([S:26](C)(=[O:28])=[O:27])=[CH:22][CH:21]=3)[CH:10]=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[NH3:30]>>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:13](=[O:14])[C:12]([O:15][CH2:16][CH:17]([CH3:19])[CH3:18])=[C:11]([C:20]3[CH:25]=[CH:24][C:23]([S:26]([NH2:30])(=[O:28])=[O:27])=[CH:22][CH:21]=3)[CH:10]=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)COc1c(-c2ccc(S(C)(=O)=O)cc2)cnn(-c2cccc(Cl)c2)c1=O
Reactant: N
Product: CC(C)COc1c(-c2ccc(S(N)(=O)=O)cc2)cnn(-c2cccc(Cl)c2)c1=O

Procedure:
The title compound was prepared according to the method of Example 384, substituting 2-(3-chlorophenyl)-4-(2-methylpropoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (Example 335) in place of 2-benzyl-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (yield: 0.0458 g, 25%). mp 80–85° C. 1H NMR (300 MHz, DMSO d6) δ 0.80 (d, J=6 Hz, 6H), 1.74–1.92 (m, 3H), 4.20 (d, J=6 Hz, 2H), 7.49–7.64 (m, 5H), 7.76 (m, 1H), 7.85 (m, 2H), 7.95 (m, 2H), 8.21 (m, 1H). MS (DCI/NH3) m/z 434 (M+H)+, 451 (M+NH4)+. Anal. calc. for C20H20ClN3O4S: C, 55.36; H, 4.65; N, 9.68. Found: C, 55.12; H, 4.58; N, 9.42.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([NH:11][C:12]([S:14][CH3:15])=[S:13])=[C:6]([CH:10]=1)[C:7](O)=[O:8]>C(OC(=O)C)(=O)C>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:12]([S:14][CH3:15])[S:13][C:7](=[O:8])[C:6]=2[CH:10]=1
Reactant: CSC(=S)Nc1ccc(C)cc1C(=O)O
Solvent: CC(=O)OC(C)=O
Product: CSc1nc2ccc(C)cc2c(=O)s1
Temperature: 25 °C
Yield: 82.3 %

Procedure:
Compound 3 (2.85 g, 11.8 mmol) was dissolved in 50 mL of acetic anhydride and heated at reflux for 1 hour. The mixture was cooled to room temperature and the precipitate was filtered off. The crude product was recrystallized from ethyl alcohol to give 5 as white needle-shaped crystals (2.17 g, 83%). mp: 113.6° C.
Reaction SMILES: [Cl:1][CH:2]([Cl:5])[C:3]#[N:4].C[O-].[Na+].Cl.N[C@H:11]([C:14]([O:16][CH2:17]C)=[O:15])[CH2:12][OH:13].ClCCl>CO.O>[Cl:1][CH:2]([Cl:5])[C:3]1[O:13][CH2:12][CH:11]([C:14]([O:16][CH3:17])=[O:15])[N:4]=1
Reactant: N#CC(Cl)Cl
Reactant: CCOC(=O)[C@@H](N)CO
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Solvent: O
Product: COC(=O)C1COC(C(Cl)Cl)=N1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of dichloroacetonitrile (215 g, 1.96 mol) in methanol (200 mL) was added drop-wise to a −5° C. solution of sodium methoxide (15.4 g, 0.285 mol) in methanol (500 mL). A solution of ethyl serinate, hydrochloride salt (382 g, 2.45 mol) in methanol (300 mL) was then added to the −5° C. reaction mixture, which was subsequently allowed to stir at room temperature for 16 hours. Dichloromethane (1 L) and water (800 mL) were added, and the aqueous layer was extracted with dichloromethane (1 L); the combined organic layers were concentrated in vacuo to provide the product as a yellow oil, which was used in the next step without additional purification. Yield: 300 g, 1.4 mol, 71%. 1H NMR (400 MHz, CDCl3) 6.29 (s, 1H), 4.90 (dd, J=10.8, 8.3 Hz, 1H), 4.74 (dd, J=8.8, 8.3 Hz, 1H), 4.66 (dd, J=10.8, 8.9 Hz, 1H), 3.82 (s, 3H).
Reaction SMILES: [CH:1]1([C:4]#[C:5][C:6]2[CH:7]=[C:8]3[C:13](=[N:14][CH:15]=2)[N:12]([CH3:16])[C:11](=[O:17])[C:10]([C:18]([NH:20][CH2:21][C:22]([O:24]C(C)(C)C)=[O:23])=[O:19])=[C:9]3[OH:29])[CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O>>[CH:1]1([C:4]#[C:5][C:6]2[CH:7]=[C:8]3[C:13](=[N:14][CH:15]=2)[N:12]([CH3:16])[C:11](=[O:17])[C:10]([C:18]([NH:20][CH2:21][C:22]([OH:24])=[O:23])=[O:19])=[C:9]3[OH:29])[CH2:2][CH2:3]1
Reactant: Cn1c(=O)c(C(=O)NCC(=O)OC(C)(C)C)c(O)c2cc(C#CC3CC3)cnc21
Solvent: O=C(O)C(F)(F)F
Product: Cn1c(=O)c(C(=O)NCC(=O)O)c(O)c2cc(C#CC3CC3)cnc21

Procedure:
The title compound was prepared similarly to the procedure described for Example 1 (g) by treatment of tert-butyl 2-(6-(2-cyclopropylethynyl)-4-hydroxy-1-methyl-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamido)acetate (Example 81 (a)) with TFA. MS (ESI, pos. ion) m/z: 342 (M+1). 1H NMR (300 MHz, DMSO-d6) δ ppm: 10.40 (t, J=5.6 Hz, 1 H), 8.80 (d, J=2.2 Hz, 1 H), 8.31 (d, J=2.2 Hz, 1 H), 4.14 (d, J=5.6 Hz, 2 H), 3.67 (s, 3 H), 1.53-1.67 (m, 1 H), 0.86-0.99 (m, 2 H), 0.74-0.87 (m, 2 H).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[N:13]=[C:12]([NH:14][C:15](OC)=[O:16])[N+:11]([O-:19])=[C:10]([NH:20][C:21]([O:23][CH3:24])=[O:22])[CH:9]=2)[CH2:4][CH2:3]1.C(Cl)Cl.[OH-].[Na+]>O>[OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[C:10]([NH:20][C:21]([O:23][CH3:24])=[O:22])[N:11]3[O:19][C:15](=[O:16])[N:14]=[C:12]3[N:13]=2)[CH2:4][CH2:3]1
Reactant: COC(=O)Nc1cc(N2CCC(O)CC2)nc(NC(=O)OC)[n+]1[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: COC(=O)Nc1cc(N2CCC(O)CC2)nc2nc(=O)on12
Reaction time: 3.5 h

Procedure:
3.1 G. of dimethyl racemic-6-(4-hydroxy-1-piperidinyl)-2,4-pyrimidine-dicarbamate-3-oxide are suspended in 100 ml. of methylene chloride and 100 ml. of water. The suspension is adjusted with concentrated sodium hydroxide to pH 12.6 and stirred at this pH for 3.5 hours. The two phases are then separated and the aqueous phase is adjusted to pH 3.2 with concentrated hydrochloric acid solution. The separated white precipitate is filtered off, pre-dried and recrystallized from methylene chloride and methanol, there being obtained pure methyl racemic-5-(4-hydroxy-1-piperidinyl)-2-oxo-2H-[1,2,4]-oxadiazolo[2,3-a]pyrimidine-7-carbamate, having a melting point of 250°-260° C. (decomposition).
Reaction SMILES: [ClH:1].Cl.[OH:3][C:4]1[C:5]([CH2:19]O)=[C:6]2[C:11](=[CH:12][CH:13]=1)[C:10](=[O:14])[CH:9]([NH:15][CH:16]([CH3:18])[CH3:17])[CH2:8][CH2:7]2>[H][H].[Pd]>[ClH:1].[OH:14][CH:10]1[C:11]2[C:6](=[C:5]([CH3:19])[C:4]([OH:3])=[CH:13][CH:12]=2)[CH2:7][CH2:8][CH:9]1[NH:15][CH:16]([CH3:18])[CH3:17]
Reactant: CC(C)NC1CCc2c(ccc(O)c2CO)C1=O
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Product: Cc1c(O)ccc2c1CCC(NC(C)C)C2O

Procedure:
In 20 ml. of 2N hydrochloric acid is dissolved 200 mg. of 6-hydroxy-5-hydroxymethyl-2-isopropylamino-3,4-dihydro-1(2H)-naphthalenone hydrochloride and with the addition of 100 mg. of 5 % palladium-on-carbon, the solution is agitated in hydrogen streams for 4 hours. After the hydrogen has ceased to be absorbed, the catalyst is filtered off and the filtrate is concentrated under reduced pressure and at a temperature not exceeding 40° C. The residue is then recrystallized from ethanol-ether. The procedure yields 1,6-dihydroxy-2-isopropylamino-5-methyl-1,2,3,4-tetrahydronaphthalene hydrochloride as colorless powders. Yield 152 mg.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[S:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[N:17]([CH3:19])[CH3:18].ClC1C=CC=C(C(OO)=[O:28])C=1>C(OCC)(=O)C>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[S:10]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[N:17]([CH3:19])[CH3:18])=[O:28]
Reactant: CN(C)c1ccccc1Sc1nc2ccccc2[nH]1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CCOC(C)=O
Product: CN(C)c1ccccc1S(=O)c1nc2ccccc2[nH]1
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 73.2 %

Procedure:
The product of step (b) (4.1 g) was dissolved in ethyl acetate (130 ml) and the stirred solution cooled to -10°. An ice cold solution of m-chloroperbenzoic acid (2.77 g of 95%) in ethyl acetate (20 ml) was added. The resulting solution was stirred for 40 minutes, and then washed with sodium bicarbonate solution, water and brine, dried and evaporated. The residue was purified by flash chromatography to produce a colourless foam. The foam was subjected to high vacuum which afforded 3.18 g of the title compound.
Reaction SMILES: O=C[C@H]([C@H]([C@H](CO)O)O)O.S(=O)(=O)(O)O.C(=O)([O-])[O-].[Li+].[Li+].[C:22]([O:25][CH:26]1[O:38][C@@H:37]([CH2:39][O:40][C:41](=[O:43])[CH3:42])[C@H:32]([O:33][C:34](=[O:36])[CH3:35])[C@@H:27]1[O:28][C:29](=[O:31])[CH3:30])(=[O:24])[CH3:23]>CO.C(O)(=O)C.C(OC(=O)C)(=O)C.C(O)(C)C.O>[C:22]([O:25][C@H:26]1[O:38][C@@H:37]([CH2:39][O:40][C:41](=[O:43])[CH3:42])[C@H:32]([O:33][C:34](=[O:36])[CH3:35])[C@@H:27]1[O:28][C:29](=[O:31])[CH3:30])(=[O:24])[CH3:23]
Reactant: CC(=O)OC[C@@H]1OC(OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Agent: O=C([O-])[O-]
Agent: O=C[C@@H](O)[C@@H](O)[C@@H](O)CO
Agent: O=S(=O)(O)O
Solvent: CC(=O)OC(C)=O
Solvent: CO
Solvent: O
Product: CC(=O)OC[C@@H]1O[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Yield: 60 %

Procedure:
In Non-Patent Document 6, L-ribose is used as a starting material, the methylation of the hydroxyl group at 1-position is carried out in methanol in the presence of sulfuric acid, the resultant mixture is then treated with lithium carbonate, the acetylation is then carried out in acetic acid and acetic anhydride, and concentrated sulfuric acid and acetic anhydride are further added thereto to carry out the acetolysis. A crude product is a mixture of α/β-anomers of 1,2,3,5-tetra-O-acetyl-L-ribofuranose. The crude product is treated with water and isopropyl alcohol to obtain 1,2,3,5-tetra-O-acetyl-β-L-ribofuranose at a total yield of 60%.
Reaction SMILES: [Br:1][C:2]1[C:15]([F:16])=[C:14]([F:17])[C:13]([F:18])=[C:12]([F:19])[C:3]=1[C:4]([CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5].[C:20]([O:23][C:24](=O)C)(=O)[CH3:21].C(OCC)(OCC)OCC>>[Br:1][C:2]1[C:15]([F:16])=[C:14]([F:17])[C:13]([F:18])=[C:12]([F:19])[C:3]=1[C:4]([C:6](=[CH:24][O:23][CH2:20][CH3:21])[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5]
Reactant: CCOC(=O)CC(=O)c1c(F)c(F)c(F)c(F)c1Br
Reactant: CC(=O)OC(C)=O
Solvent: CCOC(OCC)OCC
Product: CCOC=C(C(=O)OCC)C(=O)c1c(F)c(F)c(F)c(F)c1Br

Procedure:
45 g of crude ethyl (2-bromo-3,4,5,6-tetrafluorobenzoyl)-acetate are introduced into 32.2 g (0.31 mol) of acetic anhydride and 28.4 g (0.19 mol) of triethyl orthoformate and the mixture is heated under reflux for 2 hours. Excess reagent is stripped off, first in vacuo and then under a high vacuum (bath up to 120°-130° C.), and the crude product is reacted for the next stage.
Reaction SMILES: [C:1]1(C)C=CC=CC=1.C1(C)C(C)=CC=CC=1.[CH2:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1C)[CH3:17]>>[CH2:16]([C:18]1[CH:19]=[CH:20][C:21]([CH3:1])=[CH:22][CH:23]=1)[CH3:17]
Reactant: CCc1ccccc1C
Reactant: Cc1ccccc1
Solvent: Cc1ccccc1C
Product: CCc1ccc(C)cc1
Yield: 90.1 %

Procedure:
STDP and ethylation of toluene were carried out in the same manner as Examples 5 and 6. STDP gave a toluene conversion rate of 5.7% with a xylene product having 65.9% of the para isomer. Ethylation of toluene yielded 90.1% para-ethyltoluene in the ethyltoluene product at a toluene conversion of 20.0%.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7](O)[N:6]=[CH:5]2.O=P(Cl)(Cl)[Cl:15]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([Cl:15])[N:6]=[CH:5]2
Reactant: Oc1ncc2cc(Br)ccc2n1
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1ncc2cc(Br)ccc2n1

Procedure:
A solution of 6-bromoquinazolin-2-ol (31) (6.0 g, 26.7 mmol) in POCl3 (80 mL) was refluxed at 110° C. for 5 hours. An aliquot of the reaction mixture was analyzed by LCMS and indicated that the reaction had proceeded to completion. Most of POCl3 was removed under reduced pressure, and the residue was added dropwise to ice water (500 mL). The resulting precipitate was collected via filtration as a yellow solid (3.5 g, 54%). MS (ES+) C8H4BrClN2 requires: 242. found: 243, 245 [M+H]+.
Reaction SMILES: [Mg].[Cl:2][C:3]1[CH:8]=[CH:7][C:6](I)=[C:5]([Cl:10])[CH:4]=1.I/[C:12](=[CH:18]\[C:19]([O:21][CH2:22][CH3:23])=[O:20])/[C:13]([O:15][CH2:16][CH3:17])=[O:14]>C(OCC)C.CN(C=O)C.[Cl-].[Zn+2].[Cl-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd](Cl)Cl.C(Br)C>[CH2:16]([O:15][C:13](=[O:14])/[C:12](/[C:6]1[CH:7]=[CH:8][C:3]([Cl:2])=[CH:4][C:5]=1[Cl:10])=[CH:18]/[C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH3:17]
Reactant: CCOC(=O)/C=C(\I)C(=O)OCC
Reactant: Clc1ccc(I)c(Cl)c1
Agent: Cl[Pd]Cl
Agent: [Cl-]
Agent: [Mg]
Solvent: CCBr
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCOC(=O)/C=C(/C(=O)OCC)c1ccc(Cl)cc1Cl
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 47.3 %

Procedure:
A suspension of magnesium (0.73 g, 0.03 moles) in ethyl ether (20 ml) under nitrogen flow was added with ethyl bromide (50 mg). The solution was stirred for 15 minutes then added with a solution of 1,3-dichloro-4-iodobenzene (5.45 g, 0.02 moles) in ethyl ether (10 ml) in 1 hour keeping the temperature at 18-22° C. At the end of the addition the suspension was kept under stirring for 90 minutes at 18-22° C., then decanted and the surnatant added in 10 minutes to a suspension of dry zinc chloride (5.4 g, 0.04 moles) in ethyl ether (8 ml). At the end of the addition the stirring was kept on at 20° C. for further 90 minutes, then cooled to 0° C. DMF (10 ml) and palladium dichloride triphenylphosphine (351 mg, 0.0005 moles), then a solution of diethyl iodo-fumarate (4.18 g, 0.014 moles) in DMF (4 ml) were added. The mixture was kept under stirring for 15 hours at 25° C. and after a work-up similar to the one of point a) 2.1 g of (E)-2-(2,4-dichlorophenyl)-butendioic acid diethyl ester were yielded (yield: 63% calculated with respect to the iodo-furmarate).