Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC(Cl)(O[C:5](=[O:11])OC(Cl)(Cl)Cl)Cl.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[C:24]([C:25]([F:28])([F:27])[F:26])=[C:23]([NH2:29])[CH:22]=[N:21]2)=[CH:16][CH:15]=1.C([O-])([O-])=O.[Na+].[Na+].Cl.[CH3:37][S:38]([C:41]1[CH:42]=[C:43]([NH2:47])[CH:44]=[CH:45][CH:46]=1)(=[O:40])=[O:39]>C(Cl)Cl.O>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([N:20]2[C:24]([C:25]([F:27])([F:26])[F:28])=[C:23]([NH:29][C:5]([NH:47][C:43]3[CH:44]=[CH:45][CH:46]=[C:41]([S:38]([CH3:37])(=[O:40])=[O:39])[CH:42]=3)=[O:11])[CH:22]=[N:21]2)=[CH:18][CH:19]=1
Reactant: CS(=O)(=O)c1cccc(N)c1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Nc1cnn(-c2ccc(Cl)cc2)c1C(F)(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CS(=O)(=O)c1cccc(NC(=O)Nc2cnn(-c3ccc(Cl)cc3)c2C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 62.3 %

Procedure:
Triphosgene (0.042 g, 0.140 mmol) was added to a solution of 1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazol-4-ylamine (0.100 g, 0.382 mmol) and Na2CO3 (0.405 g, 3.82 mmol) in CH2Cl2/H2O (50 mL, 1:1) and stirred at room temperature for 30 min. 3-Methanesulfonyl-phenylamine HCl (0.095 g, 0.458 mmol) was added to the reaction mixture, stirred at room temperature for 2 hrs, organic layer collected and aqueous layer extracted with EtOAc (3×25 mL). Organic layers were collected, concentrated and crude product purified by column chromatography to give 1-[1-(4-chloro-phenyl)-5-trifluoromethyl-1H-pyrazol-4-yl]-3-(3-methanesulfonyl-phenyl)-urea (0.040 g, 22%).
Reaction SMILES: [C:1]([C:3]1[C:4]([F:14])=[C:5]([CH:9]=[C:10]([F:13])[C:11]=1[F:12])[C:6](O)=[O:7])#[N:2].C(Cl)(=O)C([Cl:18])=O>C(Cl)Cl.CN(C)C=O>[C:1]([C:3]1[C:4]([F:14])=[C:5]([CH:9]=[C:10]([F:13])[C:11]=1[F:12])[C:6]([Cl:18])=[O:7])#[N:2]
Reactant: N#Cc1c(F)c(F)cc(C(=O)O)c1F
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: N#Cc1c(F)c(F)cc(C(=O)Cl)c1F
Yield: 97 %

Procedure:
111 g of 3-cyano-2,4,5-trifluoro-benzoic acid and 84 g of oxalyl chloride are stirred at room temperature for 5 hours in 930 ml of dry methylene chloride with addition of a few drops of dimethylformamide. The methylene chloride is then stripped off and the residue is distilled in vacuo. 117.6 g of 3-cyano-2,4,5-trifluoro-benzoyl chloride are obtained as a yellow oil.
Reaction SMILES: CNC[CH2:4][CH2:5][CH2:6][C:7]([O:9][CH2:10][C@H:11]1[O:15][N:14]=[C:13]([C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][C:25]([N:28]4[CH2:32][C@H:31]([CH2:33][N:34]5[CH:38]=[CH:37][N:36]=[N:35]5)[O:30][C:29]4=[O:39])=[CH:24][C:23]=3[F:40])=[CH:18][N:17]=2)[CH2:12]1)=[O:8].[CH3:41][N:42]([CH3:47])[CH2:43]C(O)=O.C(N=C=NC(C)C)(C)C.[CH3:57][N:58]([CH:60]=[O:61])[CH3:59]>CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[CH3:41][N:42]([CH3:47])[CH2:43][C:60]([N:58]([CH3:59])[CH2:57][CH2:4][CH2:5][CH2:6][C:7]([O:9][CH2:10][C@H:11]1[O:15][N:14]=[C:13]([C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][C:25]([N:28]4[CH2:32][C@H:31]([CH2:33][N:34]5[CH:38]=[CH:37][N:36]=[N:35]5)[O:30][C:29]4=[O:39])=[CH:24][C:23]=3[F:40])=[CH:18][N:17]=2)[CH2:12]1)=[O:8])=[O:61]
Reactant: CN(C)C=O
Reactant: CNCCCCC(=O)OC[C@@H]1CC(c2ccc(-c3ccc(N4C[C@H](Cn5ccnn5)OC4=O)cc3F)cn2)=NO1
Reactant: CN(C)CC(=O)O
Agent: CC(C)N=C=NC(C)C
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Product: CN(C)CC(=O)N(C)CCCCC(=O)OC[C@@H]1CC(c2ccc(-c3ccc(N4C[C@H](Cn5ccnn5)OC4=O)cc3F)cn2)=NO1
Reaction time: 24 h

Procedure:
[(5S)-3-(5-{2-fluoro-4[(5R)-2-oxo-5-(1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-3-yl]phenyl}pyridin-2-yl)-4,5-dihydroisoxazol-5-yl]methyl 5-(methylamino)pentanoate (Example 37: 134 mg, 0.23 mMol), N,N-dimethylglycine (140 mg, 1.36 mMol), 1,3-diisopropylcarbodiimide (121 mg, 0.96 mMol), and 4-dimethylaminopyridine (5 mg, 0.04 mMol) were suspended in 2 ml of DMF at room temperature. The mixture was stirred one day, diluted with ethyl acetate, washed with saturated aqueous sodium bicarbonate, dried over sodium sulfate and evaporated. The residue was purified by chromatography (silica gel; elution with 1 to 10% methanol in dichloromethane) to give the title compound as the free base. The sample was dissolved in methylene chloride (0.5 ml), treated with HCl (4M solution in dioxane, 0.05 ml) and diluted with diethyl ether (10 ml). The suspension was sonicated and triturated, the solution was decanted from the solids which were resuspended in diethyl ether followed by further sonication then filtration. The solid was dried in vacuo to yield the hydrochloride salt of the title compound as a light yellow solid (95 mg), melting point: 133° C.
Reaction SMILES: O[C@@H:2]([C@@:9](C)([N:13]1[C:17](=[O:18])[C:16]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:15]2[C:14]1=[O:23])CCC)[C:3]1[CH:8]=CC=C[CH:4]=1.C1(C)C=CC(S([O:34][CH3:35])(=O)=O)=CC=1.[H-].[Na+].[C:39]1([CH3:45])[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>>[CH3:35][O:34][C@@H:45]([C@@H:9]([N:13]1[C:14](=[O:23])[C:15]2=[CH:22][CH:21]=[CH:20][CH:19]=[C:16]2[C:17]1=[O:18])[CH2:2][CH:3]([CH3:4])[CH3:8])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: CCC[C@@](C)([C@H](O)c1ccccc1)N1C(=O)c2ccccc2C1=O
Reactant: COS(=O)(=O)c1ccc(C)cc1
Reactant: Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Product: CO[C@H](c1ccccc1)[C@H](CC(C)C)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C

Procedure:
To a solution of N-[1-(S)-[α-(R)-hydroxybenzyl-]-methylbutyl]phthalimide]30.4 g, 94.0 mmol.) in toluene (380 mL) were successively added methyl p-toluene-sulfonate (19.2 g, 103 mmol) and 60% sodium hydride (4.13 g, 103 mmol.). The resulting mixture was heated under reflux for 18 hours under stirring, cooled to room temperature, successively washed with water and aqueous saturated sodium chloride solution, dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by middle pressure column chromatography (n-hexane/ethyl acetate=5/1), to give N-[1-(S)-[α-(R)-methoxybenzyl)-3-methyl-butyl]phthalimide as a white crystalline product (25.6 g, yield: 81%)
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH2:7]Br)=[CH:5][CH:4]=1)#[N:2].[CH3:11][NH:12][CH2:13][CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16]>>[C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH2:7][N:12]([CH3:11])[CH2:13][CH2:14][C:15]([O:17][C:18]([CH3:20])([CH3:19])[CH3:21])=[O:16])=[CH:5][CH:4]=1)#[N:2]
Reactant: CNCCC(=O)OC(C)(C)C
Reactant: N#Cc1ccc(CBr)cc1
Product: CN(CCC(=O)OC(C)(C)C)Cc1ccc(C#N)cc1

Procedure:
The title compound was prepared following the general procedure 10, starting from 4-cyanobenzyl bromide (1.5 g, 7.7 mmol) and tert-butyl N-methyl-beta-alaninate (1.5 g, 9.2 mmol, prepared as described in Biorg. Med. Chem. (11) 2003, 3083-3099). It was isolated as a yellow oil (1.9 g, 89%). 1H NMR (DMSO-d6, 300 MHz) δ 7.78 (d, J=8.3 Hz, 2H), 7.49 (d, J=8.3 Hz, 2H), 3.55 (s, 2H), 2.60 (t, J=6.9 Hz, 2H), 2.38 (t, J=6.9 Hz, 2H), 2.11 (s, 3H), 1.39 (s, 9H). LC/MS (Method B): 275.0 (M+H)+. HPLC (Method A) Rt 2.40 min (Purity: 82.5%).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[C:12]1[CH:13]=[C:14]([OH:22])[C:15]([CH3:21])=[C:16]([CH:20]=1)[C:17]([OH:19])=[O:18].[N+:23]([C:26]1[CH:33]=[CH:32][C:29]([CH2:30]Br)=[CH:28][CH:27]=1)([O-:25])=[O:24].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[C:12]1[CH:13]=[C:14]([OH:22])[C:15]([CH3:21])=[C:16]([CH:20]=1)[C:17]([O:19][CH2:30][C:29]1[CH:32]=[CH:33][C:26]([N+:23]([O-:25])=[O:24])=[CH:27][CH:28]=1)=[O:18]
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: Cc1c(O)cc(N2C(=O)c3ccccc3C2=O)cc1C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1c(O)cc(N2C(=O)c3ccccc3C2=O)cc1C(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 4 h
Yield: 109.1 %

Procedure:
A mixture of 120 mg of 5-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-3-hydroxy-2-methylbenzoic acid, 87 mg of 4-nitrobenzyl bromide and 139 mg of potassium carbonate in 3 ml of dimethylformamide was stirred at 0° C. for 4 hours. The solvent was evaporated in vacuo, and the residue was triturated with a mixture of methylene chloride and saturated sodium bicarbonate solution. The unsoluble material was isolated by filtration to yield 190 mg of p-nitrobenzyl 5-(1,3-dioxo-1,3-dihydroisoindol-2-yl)-3-hydroxy-2-methylbenzoate, m.p. 210°-244° C.
Reaction SMILES: [OH-].[K+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]([C:13]([C:15]2[CH:23]=[C:22]3[C:18]([CH:19]=[CH:20][NH:21]3)=[CH:17][CH:16]=2)=[O:14])[CH:8]=[C:9]([O:11][CH3:12])[CH:10]=1.I[CH3:25]>CN(C=O)C.CCOCC>[CH3:3][O:4][C:5]1[CH:6]=[C:7]([C:13]([C:15]2[CH:23]=[C:22]3[C:18]([CH:19]=[CH:20][N:21]3[CH3:25])=[CH:17][CH:16]=2)=[O:14])[CH:8]=[C:9]([O:11][CH3:12])[CH:10]=1
Reactant: COc1cc(OC)cc(C(=O)c2ccc3cc[nH]c3c2)c1
Reactant: CI
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: COc1cc(OC)cc(C(=O)c2ccc3ccn(C)c3c2)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 73.1 %

Procedure:
Potassium hydroxide (0.21 g, 3.7 mmol) was added to a mixture of (3,5-dimethoxy-phenyl)-(1H-indol-6-yl)-methanone (0.69 g, 2.5 mmol) in DMF (7 mL) at 0° C. followed by addtion of iodomethane (0.2 mL, 2.7 mmol) and stirred at 0° C. for 2 hours. The mixture was diluted with ether (15 mL) and washed with brine (2×10 mL). The organic phase was dried over MgSO4, concentrated and purified via flash column chromatography (EtOAc/Hexane) to give (3,5-dimethoxy-phenyl)-(1-methyl-1H-indol-6-yl)-methanone as an off-white solid (0.54 g, 75% yield): 1H NMR (DMSO-d6) δ 3.80 (s, 6H, 20CH3), 3.85 (s, 3H, NCH3), 6.55 (d, J=3 Hz, 1H, Ar), 6.78 (t, J=2 Hz, 1H, Ar), 6.83 (d, J=2 Hz, 2H, Ar), 7.47 (d, J=2 Hz, 1H, Ar), 7.61 (d, J=3 Hz, 1H, Ar), 7.68 (d, J=8 Hz, 1H, Ar), 7.90 (brs, 1H, Ar). The product was used in the next step without further purification.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[F:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][C:27]=1[F:28])[CH:23]=[O:24].[F:29][C:30]([Si](C)(C)C)([F:32])[F:31].Cl>C1COCC1>[F:19][C:20]1[CH:21]=[C:22]([CH:23]([OH:24])[C:30]([F:32])([F:31])[F:29])[CH:25]=[CH:26][C:27]=1[F:28]
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: O=Cc1ccc(F)c(F)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: C1CCOC1
Product: OC(c1ccc(F)c(F)c1)C(F)(F)F
Temperature: 25 °C
Reaction time: 4 h
Yield: 89.6 %

Procedure:
Tetrabutylammonium fluoride (TBAF: 0.1 ml, 1M) in THF was added to a solution of 3,4-difluoro-benzaldehyde (1.42 g, 10 mmol) and (trifluoromethyl)trimethylsilane (1.70 g, 12 mmol) in 10 ml THF at 0° C. The mixture was warmed up to room temperature and stirred for 4 hours. The reaction mixture was treated with 12 ml of 1M HCl and stirred overnight. The product was extracted with dichloromethane (3×20 ml), the organic layer was combined and passed through a pad of silica gel. The organic solvent was evaporated to give 1.9 g of 1-(3,4-difluoro-phenyl)-2,2,2-trifluoro-ethanol, yield 90%.
Reaction SMILES: CO.[F:3][C:4]1[CH:28]=[CH:27][C:7]([NH:8][C:9]2[CH:18]=[C:17](/[CH:19]=[CH:20]/[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:16]=[CH:15][C:10]=2[C:11]([O:13]C)=[O:12])=[CH:6][CH:5]=1.[OH-].[Na+]>O1CCCC1>[F:3][C:4]1[CH:28]=[CH:27][C:7]([NH:8][C:9]2[CH:18]=[C:17](/[CH:19]=[CH:20]/[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:16]=[CH:15][C:10]=2[C:11]([OH:13])=[O:12])=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(/C=C/c2ccccc2)cc1Nc1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1ccc(/C=C/c2ccccc2)cc1Nc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a mixed solution of methanol 2 mL and tetrahydrofuran 2 mL of the obtained methyl 2-(4-fluoroanilino)-4-((E)-2-phenylvinyl)benzoate was added 2.0 mol/L sodium hydroxide aqueous solution 2.5 mL at room temperature, and it was stirred at room temperature for 4 hours. The solvent was removed under reduced pressure, water was added to it, and it was adjusted to pH4.0 with 1.0 mol/L hydrochloric acid. Solid matter was filtrated, and it was refined by silica gel column chromatography [eluent; hexane:ethyl acetate=2:1] to give 2-(4-fluoroanilino)-4-((E)-2-phenylvinyl)benzoic acid 58 mg.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10](=O)[O:11]C1C=CC=CC=1.O.[NH2:22][NH2:23]>C(O)C>[F:1][C:2]([F:20])([F:19])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10]([NH:22][NH2:23])=[O:11]
Reactant: NN
Reactant: O=C(Nc1ccccc1C(F)(F)F)Oc1ccccc1
Solvent: O
Solvent: CCO
Product: NNC(=O)Nc1ccccc1C(F)(F)F

Procedure:
Phenyl (2-trifluoromethylphenyl)carbamate (12.1 g) was dissolved in ethanol (150 mL). Hydrazine monohydrate (16.7 mL) was added and the mixture was heated under reflux for 2.25 hours. The reaction solution was concentrated under reduced pressure and the residue was purified by silica gel column chromatography to obtain the title compound (7.5 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=2)=[CH:4][C:3]=1[CH2:15][NH:16][C:17]1[C:18]([F:25])=[C:19]([OH:24])[CH:20]=[CH:21][C:22]=1[F:23].C([O-])([O-])=O.[Cs+].[Cs+].[CH2:32]([O:34][C:35](=[O:38])[CH2:36]Br)[CH3:33].O>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=2)=[CH:4][C:3]=1[CH2:15][NH:16][C:17]1[C:18]([F:25])=[C:19]([CH:20]=[CH:21][C:22]=1[F:23])[O:24][CH2:36][C:35]([O:34][CH2:32][CH3:33])=[O:38]
Reactant: CCOC(=O)CBr
Reactant: Oc1ccc(F)c(NCc2cc(-c3cccc(F)c3)ccc2Cl)c1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)COc1ccc(F)c(NCc2cc(-c3cccc(F)c3)ccc2Cl)c1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.2 %

Procedure:
To a solution of 3-[[2-chloro-5-(3-fluorophenyl)phenyl]methylamino]-2,4-difluoro-phenol (128 mg, 0.35 mmol, 1.0 eq) in DMF (10 mL) was added Cs2CO3 (172 mg, 0.53 mmol, 1.5 eq). The reaction was stirred at room temperature for 30 min then ethylbromoacetate (70.5 mg, 0.42 mmol, 1.2 eq) was added dropwise. The reaction was stirred at room temperature for further 3 h then water was added and the aqueous layer extracted with EtOAc. The organic extract was washed with water and brine, dried (Na2SO4), filtered, evaporated in vacuo and the residue obtained purified by chromatography (petroleum ether:EtOAc, 100:1 to 20:1) to give the title compound as a colourless oil (120 mg, 76%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][N:3]=[CH:2]1.Cl[CH2:8][CH:9]=[O:10]>CC(C)=O>[N:3]1([CH2:8][CH:9]=[O:10])[CH2:4][CH2:5][CH2:6][N:1]=[CH:2]1
Reactant: C1=NCCCN1
Reactant: O=CCCl
Solvent: CC(C)=O
Product: O=CCN1C=NCCC1

Procedure:
A mixture of 8.4 g. of 1,4,5,6-tetrahydropyrimidine and 7.8 g. of chloroacetaldehyde is refluxed in 100 ml. of acetone for two hours. The solvent is removed in vacuo and the residue is taken up in water and neutralized with 1N sodium hydroxide. Extracting with chloroform, drying and removing the solvent in vacuo gives 1,4,5,6-tetrahydropyrimidine-1-acetaldehyde.
Reaction SMILES: CC(C)([O-])C.[K+].C(OP([CH2:15][C:16]#[N:17])(=O)OCC)C.[CH3:18][C:19]1([CH3:28])[CH2:24][C:23](=O)[CH2:22][C:21]([CH3:27])([CH3:26])[NH:20]1>C1COCC1>[CH3:18][C:19]1([CH3:28])[CH2:24][C:23](=[CH:15][C:16]#[N:17])[CH2:22][C:21]([CH3:27])([CH3:26])[NH:20]1
Reactant: CC1(C)CC(=O)CC(C)(C)N1
Reactant: CCOP(=O)(CC#N)OCC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC1(C)CC(=CC#N)CC(C)(C)N1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 32.8 %

Procedure:
Potassium tert-butoxide (9.40 g, 83.7 mmol) is suspended in THF (175 mL), then cooled to 0° C. Cyanomethyl-phosphonic acid diethyl ester (16.0 g, 90.2 mmol) is added over five minutes. After stirring for 20 minutes, 2,2,6,6-tetramethylpiperidin-4-one (10.0 g, 64.4 mmol) dissolved in THF (50 mL) is added to the reaction mixture at −78° C. After the addition is complete the cold bath is removed. The reaction is stirred overnight, then enough water is added to dissolve any suspended salts. The organic layer is separated and the aqueous layer is extracted with EtOAc. The organic layers are combined, concentrated, then the residue is chromatographed on silica gel, eluting with 0-3% 2M NH3/MeOH in dichloromethane to give 3.77 g of (2,2,6,6-tetramethylpiperidin-4-ylidene)-acetonitrile (33% yield).
Reaction SMILES: [C:1]([O:6][CH2:7][CH3:8])(=[O:5])[C:2]([CH3:4])=[O:3].N1C=CC=CC=1.[C:15](Cl)(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])O.[Na+]>C(OCC)C>[C:15]([O:3][C:2](=[CH2:4])[C:1]([O:6][CH2:7][CH3:8])=[O:5])(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CCOC(=O)C(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CCOCC
Product: C=C(OC(=O)c1ccccc1)C(=O)OCC
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 54.5 %

Procedure:
While ethyl pyruvate (174 g, 1.5 mol) was being stirred at 0° C., pyridine (120 g, 1.5 mol) was dropped into the ethyl pyruvate. After it was stirred at 0° C. for 10 minutes, benzoyl chloride (210 g, 1.5 mol) was slowly dropped into this mixture. After the temperature of the reaction solution reached room temperature, the reaction solution was stirred for 48 hours. An aqueous solution of saturated sodium hydrogencarbonate and diethyl ether were added to the reaction solution, and an organic layer was separated by use of a separating funnel. Diethyl ether was again added to the aqueous layer and an organic compound was extracted. The obtained organic layer was then mixed with the organic compound, and sodium sulfate was added for dehydration. Thereafter, the sodium sulfate was removed by filtration and the solvent was removed by use of an evaporator under a reduced pressure. The concentrate was distilled under a reduced pressure (1 mmHg, 92 to 102° C.) to give ethyl α-benzoyloxyacrylate (180 g, yield: 54%).
Reaction SMILES: Cl.C[O:3][C:4]1[C:9]([NH2:10])=[C:8]([NH2:11])[CH:7]=[CH:6][N:5]=1.[CH3:12][O:13][C:14]1[CH:22]=[C:21]([S:23][CH3:24])[CH:20]=[CH:19][C:15]=1[C:16](Cl)=O.N>O>[CH3:12][O:13][C:14]1[CH:22]=[C:21]([S:23][CH3:24])[CH:20]=[CH:19][C:15]=1[C:16]1[N:10]=[C:9]2[C:4](=[O:3])[NH:5][CH2:6][CH:7]=[C:8]2[N:11]=1
Reactant: COc1cc(SC)ccc1C(=O)Cl
Reactant: COc1nccc(N)c1N
Agent: Cl
Agent: N
Solvent: O
Product: COc1cc(SC)ccc1C1=NC2=CCNC(=O)C2=N1

Procedure:
0.88 g of 2-methoxy-3,4-diamino-pyridine hydrochloride and 1.08 g of 2-methoxy-4-methylmercapto-benzoyl chloride were intimately mixed, and the mixture was stirred into warm polyphosphoric acid at 120° C. The mixture was kept at this temperature for an hour and was then poured into water, the aqueous mixture was made alkaline with ammonia, and the precipitate thus obtained was purified on a silica gel column (eluant: methylene chloride/methanol=100:10).
Reaction SMILES: C(Cl)CCl.Cl.[CH3:6][O:7][C:8](=[O:26])[C@H:9]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:14][CH:13]=1)[NH2:10].[CH3:27][O:28][C:29]1[CH:37]=[CH:36][CH:35]=[C:34]([O:38][CH3:39])[C:30]=1[C:31](O)=[O:32].C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1>C(Cl)Cl>[CH3:6][O:7][C:8](=[O:26])[C@H:9]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[CH:14][CH:13]=1)[NH:10][C:31](=[O:32])[C:30]1[C:34]([O:38][CH3:39])=[CH:35][CH:36]=[CH:37][C:29]=1[O:28][CH3:27]
Reactant: COc1cccc(OC)c1C(=O)O
Reactant: COC(=O)[C@@H](N)Cc1ccc(OCc2ccccc2)cc1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Solvent: ClCCCl
Product: COC(=O)[C@H](Cc1ccc(OCc2ccccc2)cc1)NC(=O)c1c(OC)cccc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.2 %

Procedure:
EDC (212 mg, 1.1 mmol) was added to a solution of (O-benzyl)tyrosine methyl ester hydrochloride (322 mg, 1 mmol), 2,6-dimethoxybenzoic acid (182 mg, 1 mmol), HOBT (149 mg, 1.1 mmol) and NMM (242 μl, 2.2 mmol) in DCM (10 ml). The mixture was stirred at room temperature overnight, then diluted with DCM (100 ml), washed with 10% citric acid (20 ml), saturated sodium bicarbonate solution (20 ml) and brine (20 ml), dried (Na2SO4) and evaporated under reduced pressure. The residue was purified by column chromatography (SiO2; EtOAc/hexane, 60:40) to give the title compound as a colourless gum (392 mg, 87%). δH (CDCl3) 7.44-7.31 (5H, m, OCH2Ph), 7.29 (1H, t, 18.4 Hz, Ar(OMe)H), 7.14 (2H, d, 18.7 Hz, CH2Ar(O)H), 6.88 (2H, d, J 8.7 Hz, CH2Ar(O)H), 6.55 (2H, d, J 8.4 Hz, Ar(OMe)H), 6.36 (1H, br d, 17.4 Hz, CONH), 5.11 (1H, dt, J 7.5, 5.2 Hz, CHαtyr) 5.02 (2H, s, OCH2Ph), 3.80 (6H, s, 2×ArOMe), 3.72 (3H, s, CO2Me), 3.29 (1H, dd, J 5.5, 14.0 Hz. CHCHAHBAr) and 3.16 (1H, dd, J 4.9, 14.0 Hz, CHCHAHBAr); m/z (ESI, 15V) 450 (Mh+).
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]2[C@H:8]3[C@H:19]([CH2:20][CH2:21][C@:3]12[CH3:4])[C@:16]1([CH2:17][OH:18])[C:11](=[CH:12][C:13](=O)[CH2:14][CH2:15]1)[CH2:10][CH2:9]3.O[C@H]1CC[C@H]2[C@H]3[C@H](CC[C@]12C)[C@]1(CO)C(=CC(=O)C[C@@H]1C)CC3>>[CH3:4][C@:3]12[CH2:21][CH2:20][C@H:19]3[C@@H:8]([CH2:9][CH2:10][C:11]4[C@:16]3([CH2:17][OH:18])[CH2:15][CH2:14][CH2:13][CH:12]=4)[C@@H:5]1[CH2:6][CH2:7][C@@H:2]2[OH:1]
Reactant: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@]43CO)[C@@H]1CC[C@@H]2O
Agent: C[C@H]1CC(=O)C=C2CC[C@H]3[C@@H]4CC[C@H](O)[C@@]4(C)CC[C@@H]3[C@]21CO
Product: C[C@]12CC[C@H]3[C@@H](CCC4=CCCC[C@@]43CO)[C@@H]1CC[C@@H]2O

Procedure:
Substituting 17β,19-dihydroxy-4-androsten-3-one for the 17β,19-dihydroxy-1α-methyl-4-androsten-3-one above results in the preparation of 4-androstene-17β,19-diol.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]#[N:9].O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[CH3:24][C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1>>[C:8]([C:7]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:28]1[CH:29]=[CH:30][C:25]([CH3:24])=[CH:26][CH:27]=1)#[N:9]
Reactant: Cc1ccc(B(O)O)cc1
Reactant: N#Cc1ccncc1Br
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Product: Cc1ccc(-c2cnccc2C#N)cc1

Procedure:
Synthetic Scheme XXVI shows the 6-step preparation of the alkylating reagent 3-(4bromomethylphenyl)-4-cyanopyridine (66) from 4-picoline (67) (Aldrich). In step 1, 4-picoline was brominated with bromine in fuming sulfuric acid at high temperatures to give 3-bromo-4-picoline (68). In step 2, the picoline 68 was oxidized to the corresponding carboxylic acid 69 with KMnO4. In step 3, the acid 69 was first converted to its acid chloride with oxalyl chloride and subsequently treated with condensed ammonia to give the amide 70. In step 4, the amide 70 was converted to 3-bromo-4-cyanopyridine (71) by treatment with P2O5 at high temperatures. In step 5, the nitrile 71 was coupled with 4-methylphenylboronic acid (56) (Scheme XXIV) using Snieckus conditions (Scheme XIII) to give 4-cyano-3-(4-methylphenyl)pyridine (72). In step 6, 72 was brominated with NBS/AIBN in carbon tetrachloride at reflux to give the desired alkylating reagent 66.