Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@@:2]12[C@@H:10]([C:11]([CH2:13][OH:14])=[O:12])[CH2:9][CH2:8][C@H:7]1[C@@H:6]1[CH2:15][CH2:16][C:17]3[C@@:23]([CH3:24])([C@H:5]1[CH2:4][CH2:3]2)[CH2:22][CH2:21][C:19](=[O:20])[CH:18]=3.[Br:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]Br.[OH-].[K+].[OH-].C([N+](CCCC)(CCCC)CCCC)CCC>ClCCl>[Br:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][O:14][CH2:13][C:11]([CH:10]1[C:2]2([CH3:1])[CH:7]([CH:6]3[CH:5]([CH2:4][CH2:3]2)[C:23]2([CH3:24])[C:17](=[CH:18][C:19](=[O:20])[CH2:21][CH2:22]2)[CH2:16][CH2:15]3)[CH2:8][CH2:9]1)=[O:12]
Reactant: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@]43C)[C@@H]1CC[C@@H]2C(=O)CO
Reactant: BrCCCCCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Product: CC12CCC(=O)C=C1CCC1C2CCC2(C)C(C(=O)COCCCCCBr)CCC12
Temperature: 25 °C
Reaction time: 16 h
Yield: 43.1 %

Procedure:
A mixture of 21-hydroxyprogesterone (200 mg, 0.605 mmol), 1,5-dibromopentane (1.65 mL, 12.1 mmol), 40% KOH (300 μL), and tetrabutylammonium hydroxide (60 μL) was stirred for 16 h at room temperature. The reaction mixture was diluted in dichloromethane and washed with water three times. The organic layer was dried over sodium sulfate and concentrated by rotary evaporation. The crude residue was purified by flash chromatography with hexanes/ethyl acetate (2:1) as the eluent to afford 7 as a colorless oil (125 mg, 43%). 1H NMR (500 MHz, CDCl3) δ 5.67 (s, 1H), 3.96 (q, J=17.2 Hz, 2H), 3.41 (t, J=6.4 Hz, 2H), 3.38-3.31 (m, 2H), 2.56 (t, J=9.1 Hz, 1H), 2.40-2.09 (m, 6H), 1.96 (m, 1H), 1.90-1.74 (m, 5H), 1.72-1.16 (m, 14H), 1.12 (s, 3H), 1.05-0.86 (m, 2H), 0.65-0.58 (m, 3H). 13C NMR (125 MHz, CDCl3) δ 207.55, 198.50, 169.94, 122.92, 75.79, 70.34, 61.56, 57.43, 55.12, 52.51, 43.53, 37.54, 34.61, 32.85, 31.74, 31.47, 30.82, 28.69, 27.74, 23.77, 23.47, 21.81, 19.97, 16.34, 12.55. ESI-MS m/z [M+H]+ observed: 481.1, calculated: 481.2.
Reaction SMILES: [CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.[CH:7]([OH:9])=[O:8]>S(=O)(=O)(O)O>[CH3:1][C:6]1([C:7]([OH:9])=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: C1=CCCCC1
Reactant: O=CO
Agent: O=S(=O)(O)O
Product: CC1(C(=O)O)CCCC1
Yield: 2.7 %

Procedure:
Cyclohexene (25 ml, 0.246 mol) was treated with conc. sulphuric acid (100 ml) and formic acid (18.9 ml, 0.5 mol) at 5° C. for two hours. The mixture was poured onto ice and extracted twice with EtOAc. The organic extracts were washed with brine, then extracted with 2M KOH. The basic extract was acidified with 2M HCl and extracted with CHCl3, filtered (Whatman® 1 PS phase separator) and evaporated. The resultant brown oil was purified by bulb-to-bulb distillation (125° C./oil pump) to give the title compound as a colourless oil (860 mg, 2%).
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([OH:16])=[CH:13][CH:14]=3)[C:9]([CH3:17])=[C:8]2[CH2:18][CH2:19][C:20]([OH:22])=[O:21])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:31](Br)[CH:32]=[CH2:33]>CC(C)=O.O>[Cl:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH2:33][CH:32]=[CH2:31])=[CH:13][CH:14]=3)[C:9]([CH3:17])=[C:8]2[CH2:18][CH2:19][C:20]([OH:22])=[O:21])=[CH:4][CH:3]=1
Reactant: Cc1c(CCC(=O)O)n(Cc2ccc(Cl)cc2)c2ccc(O)cc12
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: C=CCOc1ccc2c(c1)c(C)c(CCC(=O)O)n2Cc1ccc(Cl)cc1

Procedure:
Using 845 mg of the product of Example 23 as starting material, diluted in 23 ml of dimethyl ketone, 476 mg of potassium carbonate and 225 μl of allyl bromine was added. The reaction was refluxed overnight. The reaction was then diluted with water and the acetone removed in vacuo. Then the reaction was extracted with CH3CO2Et and the organic phase was dried and concentrated to yield after flash chromatography (hexane 8, ethyl acetate 2) 790 mg of the compound, which was then hydrolyzed following the procedure of Example 2.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[CH3:5][O:6][C:7](=[O:22])[C:8]([C@H:11]1[CH2:16][CH2:15][C@@H:14](OS(C)(=O)=O)[CH2:13][CH2:12]1)([CH3:10])[CH3:9]>CN(C)C=O.O>[CH3:5][O:6][C:7](=[O:22])[C:8]([C@H:11]1[CH2:12][CH2:13][C@H:14]([N:1]=[N+:2]=[N-:3])[CH2:15][CH2:16]1)([CH3:10])[CH3:9]
Reactant: COC(=O)C(C)(C)[C@H]1CC[C@@H](OS(C)(=O)=O)CC1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C(C)(C)[C@H]1CC[C@H](N=[N+]=[N-])CC1
Temperature: 100 °C

Procedure:
Sodium azide (0.761 g) is added to a solution of 0.898 g of cis-2-(4-methanesulfonyloxy-cyclohexyl)-2-methyl-propionic acid methyl ester in 7 ml of N,N-dimethylformamide. The reaction mixture is warmed to 100° C. for 16 hours. The mixture is cooled to room temperature, diluted with 20 ml of water and extracted with tert-butyl methyl ether (3×30 ml). The combined organic phases are washed with brine (20 ml), dried over sodium sulphate and concentrated by evaporation. The title compound is identified from the residue by means of flash chromatography (SiO2 60F) based on its Rf value.
Reaction SMILES: [CH2:1](O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1>>[CH2:1]([C:14]1[CH:15]=[C:10]([Cl:9])[CH:11]=[CH:12][C:13]=1[OH:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1ccccc1
Reactant: Oc1ccc(Cl)cc1
Product: Oc1ccc(Cl)cc1Cc1ccccc1
Temperature: 200 °C
Yield: 25.4 %

Procedure:
A German patent, Ger.Offen 2,547,030 (1977), disclosed the preparation of o-benzyl toluenes by the reaction of o-methylbenzyl halides with substituted benzenes in the presence of Al-silicate. The 2-CH3C6H4CH2Cl was stirred with toluene and Al-silicate (25% Al2O3) at 110° C. to give 81% 2-methylbenzyltoluene. According to a Japanese patent, JP 59,186,937 (1984), o-benzylphenol was prepared by the liquid phase reaction of benzyl alcohol with phenol in the presence of γ-Al2O3. For example 7.5 g γ-Al2O3 was added to a mixture of 32.5 g benzyl alcohol and 47 g phenol at 190° C. under stirring to give a product-containing 49.9% o-benzylphenol. A German Patent, Ger. Offen DE 3,700,917 (1988), disclosed the preparation of p-substituted o-benzylphenols by alkylation of p-substituted phenols with benzylalcohol in the presence of Na—Y type zeolite. A mixture of 0.5 mole 4-ClC6H4OH, 0.1 mole C6H5CH2OH and 0.6 g of Na—Y type zeolite was heated at 200° C. for 3 hrs to give 25.4% 2-benzyl-4-chlorophenol.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][N:12]3[N:15]=[CH:16][C:17]([C:18]([OH:20])=O)=[C:11]3[N:10]=2)=[CH:5][CH:4]=1.[CH3:23][S:24]([C:27]1[CH:28]=[C:29]([NH2:33])[CH:30]=[CH:31][CH:32]=1)(=[O:26])=[O:25]>>[CH3:23][S:24]([C:27]1[CH:28]=[C:29]([NH:33][C:18]([C:17]2[CH:16]=[N:15][N:12]3[CH:13]=[CH:14][C:9]([C:6]4[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:22])[F:21])=[CH:8][CH:7]=4)=[N:10][C:11]=23)=[O:20])[CH:30]=[CH:31][CH:32]=1)(=[O:25])=[O:26]
Reactant: O=C(O)c1cnn2ccc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: CS(=O)(=O)c1cccc(N)c1
Product: CS(=O)(=O)c1cccc(NC(=O)c2cnn3ccc(-c4ccc(C(F)(F)F)cc4)nc23)c1

Procedure:
The title compound was prepared from 5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.23) and 3-methanesulfonyl-phenylamine according to general procedure II. Pale-yellow solid. MS (ISP) 461.3 [(M+H)+]; mp 254-255° C.
Reaction SMILES: [N:1]([C:4]1[CH:55]=[CH:54][C:7]([CH2:8][O:9][CH2:10][C@H:11]2[O:23][C@@H:15]([S:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C@H:14]([O:24]CC3C=CC(OC)=CC=3)[C@@H:13]([O:34]CC3C=CC(OC)=CC=3)[C@@H:12]2[O:44]CC2C=CC(OC)=CC=2)=[CH:6][C:5]=1[Cl:56])=[N+:2]=[N-:3].O.C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N.O=C1O[C@H]([C@H](CO)O)C(O)=C1O>ClCCl>[N:1]([C:4]1[CH:55]=[CH:54][C:7]([CH2:8][O:9][CH2:10][C@H:11]2[O:23][C@@H:15]([S:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C@H:14]([OH:24])[C@@H:13]([OH:34])[C@@H:12]2[OH:44])=[CH:6][C:5]=1[Cl:56])=[N+:2]=[N-:3]
Reactant: COc1ccc(CO[C@@H]2[C@@H](OCc3ccc(OC)cc3)[C@H](Sc3ccccc3)O[C@H](COCc3ccc(N=[N+]=[N-])c(Cl)c3)[C@H]2OCc2ccc(OC)cc2)cc1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Solvent: ClCCl
Solvent: O
Product: [N-]=[N+]=Nc1ccc(COC[C@H]2O[C@@H](Sc3ccccc3)[C@H](O)[C@@H](O)[C@@H]2O)cc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 86 %

Procedure:
To a solution of phenyl 6-O-(4-azido-3-chlorobenzyl)-2,3,4-tri-O-(4-methoxybenzyl)-1-thio-β-D-glucopyranoside (9) (1.24 g, 1.55 mmol) in dichloromethane (10 ml) were added water (0.5 ml) and DDQ (1.41 g, 6.21 mmol), and the resulting mixture was stirred at room temperature for 3 hr. Thereto was added 5% aqueous L-ascorbic acid solution, and the mixture was stirred for a while, and extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous sodium hydrogencarbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue obtained was purified by silica gel column chromatography (eluent; dichloromethane:ethyl acetate=1:3) to give phenyl 6-O-(4-azido-3-chlorobenzyl)-1-thio-β-D-glucopyranoside (10) (584 mg, yield 86%) as yellow crystals.
Reaction SMILES: Cl.[CH:2]1([N:5]([CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[C:6](=[O:18])[C:7]2[CH:12]=[CH:11][C:10]([C:13]3[O:17][CH:16]=[N:15][CH:14]=3)=[CH:9][CH:8]=2)[CH2:4][CH2:3]1.Cl[C:26]1[N:31]=[CH:30][C:29]([CH:32]2[CH2:34][CH2:33]2)=[CH:28][N:27]=1.C(N=P1(N(CC)CC)N(C)CCCN1C)(C)(C)C.CN1CCCC1=O>>[CH:2]1([N:5]([CH:19]2[CH2:24][CH2:23][N:22]([C:26]3[N:31]=[CH:30][C:29]([CH:32]4[CH2:34][CH2:33]4)=[CH:28][N:27]=3)[CH2:21][CH2:20]2)[C:6](=[O:18])[C:7]2[CH:8]=[CH:9][C:10]([C:13]3[O:17][CH:16]=[N:15][CH:14]=3)=[CH:11][CH:12]=2)[CH2:4][CH2:3]1
Reactant: O=C(c1ccc(-c2cnco2)cc1)N(C1CCNCC1)C1CC1
Reactant: Clc1ncc(C2CC2)cn1
Agent: CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1C
Agent: Cl
Solvent: CN1CCCC1=O
Product: O=C(c1ccc(-c2cnco2)cc1)N(C1CC1)C1CCN(c2ncc(C3CC3)cn2)CC1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
A mixture of N-cyclopropyl-4-oxazol-5-yl-N-piperidin-4-yl-benzamide hydrochloride (35 mg), 2-chloro-5-cyclopropyl-pyrimidine (46 mg), and 2-tert-butylimino-2-diethylamino-1,3-dimethyl-perhydro-1,3,2-diazaphosphorine (82 mg) in N-methylpyrrolidinone (1.5 mol) is stirred at 70° C. overnight. The crude product is purified by preparative HPLC to give the title compound. LC (method 18): tR=1.41 min; Mass spectrum (ESI+): m/z=430 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]([OH:20])[CH2:9][CH2:10][CH:11]([C:13]2[CH:14]=[N:15][C:16]([Cl:19])=[CH:17][CH:18]=2)[OH:12])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:28][S:29](Cl)(=[O:31])=[O:30]>ClCCl>[CH3:28][S:29]([O:20][CH:8]([C:5]1[CH:6]=[N:7][C:2]([Cl:1])=[CH:3][CH:4]=1)[CH2:9][CH2:10][CH:11]([O:12][S:29]([CH3:28])(=[O:31])=[O:30])[C:13]1[CH:14]=[N:15][C:16]([Cl:19])=[CH:17][CH:18]=1)(=[O:31])=[O:30]
Reactant: CS(=O)(=O)Cl
Reactant: OC(CCC(O)c1ccc(Cl)nc1)c1ccc(Cl)nc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OC(CCC(OS(C)(=O)=O)c1ccc(Cl)nc1)c1ccc(Cl)nc1
Temperature: -20 °C
Reaction time: 1 h
Yield: 99.9 %

Procedure:
The product from Example 207B (2.23 g, 7.12 mmol) and triethylamine (2.98 mL, 21.36 mmol) were combined in dichloromethane (50 mL). The mixture was cooled to −20° C. and methanesulfonyl chloride (1.383 mL, 17.80 mmol) was added. The mixture was stirred at room temperature for 1 hour. The solvent was evaporated to give the title product (approx 3.34 g) which was directly used for the next reaction.
Reaction SMILES: C(O[C@@:5]([CH3:21])([C:19]#[CH:20])[CH2:6][CH2:7][C:8]1[C:9](=[O:18])[C:10]([CH3:17])=[C:11]([CH3:16])[C:12](=[O:15])[C:13]=1[CH3:14])(=O)C.C(O)(=O)C>C(Cl)Cl.[Zn]>[C:19]([C@:5]1([CH3:21])[CH2:6][CH2:7][C:8]2[C:13]([CH3:14])=[C:12]([OH:15])[C:11]([CH3:16])=[C:10]([CH3:17])[C:9]=2[O:18]1)#[CH:20]
Reactant: C#C[C@@](C)(CCC1=C(C)C(=O)C(C)=C(C)C1=O)OC(C)=O
Agent: [Zn]
Solvent: CC(=O)O
Solvent: ClCCl
Product: C#C[C@]1(C)CCc2c(C)c(O)c(C)c(C)c2O1
Temperature: 4 °C
Reaction time: 0.83 h
Yield: 25 %

Procedure:
A solution of 285 mg (0.99 mmol) of (R)-2-[3-(acetyloxy)-3-methyl-4-pentynyl]-3,5,6-trimethyl-2,5-cyclohexadiene-1,4-dione in 4 mL of CH2Cl2 was stirred with 250 mg of Zn dust, and 250 mg of glacial acetic acid. The reaction mixture was stirred at 4° C. under argon for 50 min, then filtered. It was worked up with CH2Cl2 as described above. The crude hydroquinone acetate was taken into 6 mL of CH2Cl2 and treated with 20 mg of AgClO4.H2O as described above to give 124 mg of crude product after workup, and purification by flash chromatography. Crystallization of this material from toluene-hexane (1:1) at -15° C. gave 57 mg of (S)-2-ethynyl-3,4-dihydro-2,5,7,8-tetramethyl-2H-1-benzopyran-6-ol: [α]D25 +20.20°, (c 1.3, CHCl3).
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:7][CH2:6][CH2:5][C:4]1([CH3:9])[OH:8].N1C=CC=CC=1.[C:16]1([CH3:26])[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:9][C:4]1([OH:8])[CH2:5][CH2:6][CH2:7][CH:3]1[CH2:2][O:1][S:22]([C:19]1[CH:20]=[CH:21][C:16]([CH3:26])=[CH:17][CH:18]=1)(=[O:24])=[O:23]
Reactant: CC1(O)CCCC1CO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCC2CCCC2(C)O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.3 %

Procedure:
To a mixture of 7a (1.78 g, crude), pyridine (5.5 mL, 68.0 mmol) and 4-dimethylaminopyridine (0.17 g, 1.37 mmol) in CH2Cl2 (40 mL) was added p-toluenesulfonyl chloride (3.13 g, 16.4 mmol) in one portion, and the mixture was left to stand at 4° C. overnight. The mixture was stirred at ambient temperature for 100 min. To the mixture was added ice and the mixture was stirred at ambient temperature and the organic layer was separated. The aqueous layer was extracted with EtOAc and ,he combined organic layers were washed with water, CuSO4 solution, water, NaHCO3 solution and NaCl solution, and dried over Na2SO4. Filtration and concentration gave 3.86 g of 8a, which was used in the next reaction without further purification.
Reaction SMILES: [CH:1]1([NH:7][C:8](=[O:18])[C@H:9]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[NH2:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:19]1[CH2:25][S:22](=[O:24])(=[O:23])[O:21][CH2:20]1>O1CCCC1>[CH2:11]([C@H:9]([NH:10][CH2:20][CH2:19][CH2:25][S:22]([OH:24])(=[O:23])=[O:21])[C:8]([NH:7][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)=[O:18])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: N[C@@H](Cc1ccccc1)C(=O)NC1CCCCC1
Reactant: O=S1(=O)CCCO1
Solvent: C1CCOC1
Product: O=C(NC1CCCCC1)[C@H](Cc1ccccc1)NCCCS(=O)(=O)O
Temperature: 25 °C
Yield: 38.9 %

Procedure:
To a solution of L-Phenylalanine cyclohexylamide (2.5 g, 10.1 mmol) in tetrahydrofuran (25 mL) was added 1,3-propanesultone (1.17 g, 9.7 mmol). The solution was stirred at reflux for 2 hours. It was cooled to room temperature. The solid was collected by filtration, washed with acetone (2×25 mL) and dried in the vacuum oven (50° C.), affording the title compound (1.39 g, 39%). 1H NMR (D2O, 500 MHz) δ ppm 7.21 (m, 3H), 7.08 (m, 2H), 4.42 (m, 0.5H), 3.83 (m, 1H). 3.29 (m, 1H), 3.15 (m, 1H), 3.02 (m, 2H), 2.86 (m, 3H), 2.49 (m, 0.5H), 2.01 (m, 2H), 1.54 (m, 1H), 1.45 (m, 1H), 1.33 (m, 2H), 1.02 (m, 4H), 0.55 (m, 1H). 13C (D2O, 125 MHz) δ ppm 133.71, 129.54, 129.18, 128.03, 62.08, 49.25, 47.97, 45.41, 36.29, 31.73, 31.46, 24.86, 24.28, 24.20, 21.39. [α]D=+36.4° (c=0.0019 in water), ES-MS 369 (M+1).
Reaction SMILES: Cl.[O:2]([CH2:9][C:10](=[NH:12])[NH2:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Cl:13][C:14]([SH:17])(Cl)Cl.[OH-].[Na+]>ClCCl.O>[Cl:13][C:14]1[S:17][N:11]=[C:10]([CH2:9][O:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[N:12]=1
Reactant: SC(Cl)(Cl)Cl
Reactant: N=C(N)COc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: Clc1nc(COc2ccccc2)ns1
Temperature: 25 °C
Yield: 68.4 %

Procedure:
To a solution of 2-phenoxyethanimidamide hydrochloride (2.00 g, 10.7 mmol) and perchloromethyl mercaptan (1.15 ml, 10.7 mmol) in dichloromethane (40 ml) was added dropwise a solution of sodium hydroxide (2.15 g, 53.7 mmol) in water (6 ml) under ice-cooling. Then, the reaction mixture was stirred under ice-cooling for 1 hour and at room temperature for 1 hour. The organic layer was separated, washed with water, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by a silica gel column chromatography (hexane:ethyl acetate=9:1) to give 1.66 g (68.3%) of the desired product as an oil.
Reaction SMILES: Cl[C:2]1[C:3]2[N:10]=[N:9][N:8]([CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[F:18])[C:4]=2[N:5]=[CH:6][N:7]=1.C(O)C.[CH3:22][NH2:23]>C1(C)C=CC=CC=1>[F:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[CH2:11][N:8]1[C:4]2[N:5]=[CH:6][N:7]=[C:2]([NH:23][CH3:22])[C:3]=2[N:10]=[N:9]1
Reactant: CN
Reactant: Fc1ccccc1Cn1nnc2c(Cl)ncnc21
Solvent: Cc1ccccc1
Solvent: CCO
Product: CNc1ncnc2c1nnn2Cc1ccccc1F
Reaction time: 15 h

Procedure:
A solution of 9.22 g (35 mmol) of crude 7-chloro-3-(2-fluorobenzyl)-3H-1,2,3-triazolo[4,5-d]pyrimidine in 150 ml of toluene is added dropwise, while stirring, to a mixture of 750 ml of ethanol and 200 ml of 40% aqueous methylamine solution. The whole is left to stand for 15 hours at room temperature and then the solvent is distilled off under reduced pressure. 500 ml of water are added to the residue. The precipitated product is filtered off with suction and recrystallised from methanol. In this manner 3-(2-fluorobenzyl)-7-(N-methylamino)-3H-1,2,3-triazolo[4,5-d]pyrimidine having a melting point of 180°-182° is obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][CH:14]=1)[O:5][CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8].C([Sn](CCCC)(CCCC)[C:20]1[CH:24]=[CH:23][S:22][CH:21]=1)CCC.[F-].[K+]>C1(C)C(C)=CC=CC=1.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>[S:22]1[CH:23]=[CH:24][C:20]([C:2]2[CH:3]=[C:4]([CH:12]=[CH:13][CH:14]=2)[O:5][CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:21]1
Reactant: CCOC(=O)COc1cccc(Br)c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccsc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [F-]
Agent: [K+]
Solvent: Cc1ccccc1C
Product: CCOC(=O)COc1cccc(-c2ccsc2)c1
Yield: 64.6 %

Procedure:
2.6 g of the resulting ether compound, 5.3 g of tri-n-butyl(3-thienyl)tin and 20 mg of tetrakis(triphenylphosphine)palladium were dissolved in 10 ml of xylene, and the mixture was refluxed for 5.5 hours. A 25% aqueous solution of potassium fluoride was added to the solution, and then the precipitate was removed by filtration. The organic layer separated was worked up in a customary manner, and the product was purified by silica gel column chromatography [hexane/ethyl acetate=20/1→15/1] to give 1.7 g of ethyl 3-(3thienyl)phenoxyacetate as a white powder.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[CH:6]2.[Br:15]Br.N1C=CC=CC=1>ClC(Cl)(Cl)Cl>[Br:15][C:7]1[CH:8]=[N:9][C:10]2[C:5]([CH:6]=1)=[CH:4][C:3]([C:2]([F:1])([F:13])[F:14])=[CH:12][CH:11]=2
Reactant: BrBr
Reactant: FC(F)(F)c1ccc2ncccc2c1
Solvent: c1ccncc1
Solvent: ClC(Cl)(Cl)Cl
Product: FC(F)(F)c1ccc2ncc(Br)cc2c1
Reaction time: 1 h

Procedure:
19.7 g of 6-trifluoromethyl-quinoline is introduced into 200 ml of tetrachloromethane. 5.2 ml of bromine is instilled and the solution is refluxed for one hour. Within twenty minutes, 7.9 g of pyridine in 8 ml of tetrachloromethane is instilled in the boiling solution. After one hour, it is allowed to cool, decanted from the precipitated salt and the solution is concentrated by evaporation. After column chromatography, 14.6 g of 3-bromo-6-trifluoromethyl-quinoline of melting point 79° C. is obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Cl:11])[CH:10]=1)[C:5](O)=[O:6].C(Cl)(=O)C(Cl)=O.C[N:19](C=O)C.[OH-].[NH4+]>C(Cl)Cl.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Cl:11])[CH:10]=1)[C:5]([NH2:19])=[O:6]
Reactant: O=C(O)c1cc(Cl)cc(Br)c1
Reactant: CN(C)C=O
Agent: O=C(Cl)C(=O)Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: NC(=O)c1cc(Cl)cc(Br)c1
Temperature: 25 °C

Procedure:
3-Bromo-5-chlorobenzoic acid (2.35 g, 10 mmol) was suspended in CH2Cl2 (50 mL) and stirred under argon at room temperature. Oxalyl chloride (2.53 g, 20 mmol) was added followed by DMF (10 μL), and the mixture stirred overnight. The solvents were pumped off. The residue was taken up in EtOAc and added to concentrated ammonium hydroxide (10 mL). This was stirred for thirty min. The phases were separated and the organic layer was washed 1× with brine, dried over anhydrous Na2SO4, filtered, and concentrated. The residue was crystallized from EtOAc/hexane to give the title compound as a white crystalline solid. LC-MS m/z 233.7 (M+H)+, 1.57 min (ret time); analytical HPLC shows 96.5% purity, (ret time 12.131 min).
Reaction SMILES: [H-].[Na+].[CH3:3][CH:4]1[CH:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:7][NH:6][C:5]1=[O:14].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>O1CCOCC1>[CH2:15]([N:6]1[CH2:7][CH:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:4]([CH3:3])[C:5]1=[O:14])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)C1CNC(=O)C1C
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCOC(=O)C1CN(Cc2ccccc2)C(=O)C1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.7 %

Procedure:
To a suspension of sodium hydride (2.30 g) in absolute dioxane (100 ml) was added dropwise ethyl 3-methyl-2-oxo-4-pyrrolidinecarboxylate (13.68 g) with stirring at room temperature. After stirring for 30 minutes, to a reaction mixture was added benzylbromide (16.42 g) during 20 minutes, then stirred for 2 hours and allowed to stand overnight at room temperature. The reaction mixture was poured into ice-water (100 ml) and extracted with chloroform, washed with water, dried over anhydrous sodium sulfate and concentrated. The residue was purified by vacuum distillation to give ethyl 1-benzyl-3-methyl-2-oxo-4-pyrrolidinecarboxylate (16.86 g), bp 155°-185° C./2 mmHg.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:22])=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[C:16]([S:18]([CH3:21])(=[O:20])=[O:19])[CH:17]=2)[C:5]([OH:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.[CH2:23](O)[CH3:24].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[Cl:1][C:2]1[C:3]([F:22])=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[C:16]([S:18]([CH3:21])(=[O:20])=[O:19])[CH:17]=2)[C:5]([O:11][CH2:23][CH3:24])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1
Reactant: CCO
Reactant: CC(=O)c1cc(Cl)c(F)c(-c2cncc(S(C)(=O)=O)c2)c1O
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOc1c(C(C)=O)cc(Cl)c(F)c1-c1cncc(S(C)(=O)=O)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 89.7 %

Procedure:
A solution of 1-{5-chloro-4-fluoro-2-hydroxy-3-[5-(methylsulfonyl)pyridin-3-yl]phenyl}ethanone (1.3 g, 3.6 mmol) in THF (32 mL) was treated with ethanol (0.28 mL, 4.73 mmol) and triphenylphosphine (1.3 g, 5.1 mmol). The reaction mixture was cooled to 0° C., treated with diisopropyl azodicarboxylate (1.1 mL, 5.5 mmol) dropwise, and stirred at 20° C. for 1 hour. The reaction mixture was concentrated to remove most of the THF, diluted with EtOAc, washed with saturated sodium bicarbonate, water, brine, dried over sodium sulfate, filtered and concentrated to a crude residue which was purified by flash column chromatography using EtOAc in hexanes (15%-65%) to give the desired product (1.2 g, 87%). LCMS for C16H16ClFNO4S (M+H)+: m/z=372.0. Found: 372.1.