Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:4]([C@@H:17]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:18](=[O:24])[N:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1)S(C1C=CC=CC=1[N+]([O-])=O)(=O)=O)[CH:2]=[CH2:3].C(=O)([O-])[O-].[K+].[K+].C1(S)C=CC=CC=1.O>CN(C)C=O>[CH2:1]([NH:4][C@@H:17]([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[C:18]([N:19]1[CH2:20][CH2:21][CH2:22][CH2:23]1)=[O:24])[CH:2]=[CH2:3]
Reactant: C=CCN([C@H](C(=O)N1CCCC1)c1ccccc1)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: Sc1ccccc1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCN[C@H](C(=O)N1CCCC1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 84.8 %

Procedure:
To a stirred solution of N-allyl-2-nitro-N-(2-oxo-1-(S)-phenyl-2-pyrrolidin-1-yl-ethyl)-benzenesulfonamide (66.2 g, 154 mmol) in anhydrous dimethylformamide (300 cm3) was added potassium carbonate (63.9 g, 462 mmol). The mixture was stirred at ambient temperature for 10 minutes and thiophenol (22.2 cm3, 216 mmol) was added dropwise over 10 minutes. The mixture was stirred for 16 hours at ambient temperature and poured into water (2000 cm3) and extracted with ethyl acetate (3×500 cm3). The combined ethyl acetate extracts were washed with water (2×400 cm3), brine (1×300 cm3), dried over sodium sulfate, vacuum filtered and the volatile fractions removed in vacuo to a foul smelling yellow oil. The crude product was purified by column chromatography (silica, eluting with hexane-ethyl acetate 1:1 to 0:1 and then dichloromethane-methanol 19:1 to 9:1) to afford the title compound as a yellow viscous oil (31.9 g, 84.9%) with a positive ion ESI (M+H)+245.3.
Reaction SMILES: C([O:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[CH:19]=[CH:18][C:17]([CH2:20][N:21]2[C:25]([C:26]([NH2:28])=[O:27])=[C:24]([C:29]([OH:36])([CH:33]([CH3:35])[CH3:34])[CH:30]([CH3:32])[CH3:31])[N:23]=[C:22]2[CH2:37][CH2:38][CH2:39][CH3:40])=[CH:16][CH:15]=1)=[O:7])(C)(C)C.Cl>O1CCOCC1>[CH2:37]([C:22]1[N:21]([CH2:20][C:17]2[CH:16]=[CH:15][C:14]([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=3[C:6]([OH:7])=[O:5])=[CH:19][CH:18]=2)[C:25]([C:26]([NH2:28])=[O:27])=[C:24]([C:29]([OH:36])([CH:33]([CH3:34])[CH3:35])[CH:30]([CH3:32])[CH3:31])[N:23]=1)[CH2:38][CH2:39][CH3:40]
Reactant: CCCCc1nc(C(O)(C(C)C)C(C)C)c(C(N)=O)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Agent: Cl
Solvent: C1COCCO1
Product: CCCCc1nc(C(O)(C(C)C)C(C)C)c(C(N)=O)n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Following a procedure similar to that described in Example 45(d), but using 220 mg of 1-[(2'-t-butoxycarbonylbiphenyl-4-yl)methyl]-2-butyl-4-[1-hydroxy-2-methyl-1-(1-methylethyl)propyl]imidazole-5-carboxamide [prepared as described in step (b) above] and 4.5 ml of a 4N solution of hydrogen chloride in dioxane, 201 mg of the hydrochloride of the title compound were obtained as an amorphous solid, melting at 178°-181° C.
Reaction SMILES: CN([CH:4]=[C:5]1[C:11](=O)[C:10]2[CH:13]=[C:14]([F:17])[CH:15]=[CH:16][C:9]=2[NH:8][C:7](=[O:18])[CH2:6]1)C.Cl.[C:20]([NH2:23])(=[NH:22])[CH3:21]>>[F:17][C:14]1[CH:15]=[CH:16][C:9]2[NH:8][C:7](=[O:18])[CH2:6][C:5]3[CH:4]=[N:22][C:20]([CH3:21])=[N:23][C:11]=3[C:10]=2[CH:13]=1
Reactant: CN(C)C=C1CC(=O)Nc2ccc(F)cc2C1=O
Reactant: CC(=N)N
Agent: Cl
Product: Cc1ncc2c(n1)-c1cc(F)ccc1NC(=O)C2
Yield: 50 %

Procedure:
Analogous to Scheme 1, from 4-[(dimethylamino)methylene]-7-fluoro-3,4-dihydro-1H-benzazepine-2,5-dione and acetamidine hydrochloride. Yield: 50%.
Reaction SMILES: C[O:2][C:3](=[O:37])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([CH2:34][CH:35]=[CH2:36])([CH2:14][O:15][C:16]2[CH:21]=[C:20]([CH3:22])[C:19]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=3)=[C:18]([CH3:33])[CH:17]=2)[CH2:11][CH:12]=[CH2:13])=[CH:6][CH:5]=1.[Li+].[OH-].Cl>C1COCC1>[CH2:11]([C:10]([C:7]1[CH:6]=[CH:5][C:4]([C:3]([OH:37])=[O:2])=[CH:9][CH:8]=1)([CH2:14][O:15][C:16]1[CH:21]=[C:20]([CH3:22])[C:19]([C:23]2[CH:28]=[CH:27][C:26]([C:29]([F:31])([F:32])[F:30])=[CH:25][CH:24]=2)=[C:18]([CH3:33])[CH:17]=1)[CH2:34][CH:35]=[CH2:36])[CH:12]=[CH2:13]
Reactant: C=CCC(CC=C)(COc1cc(C)c(-c2ccc(C(F)(F)F)cc2)c(C)c1)c1ccc(C(=O)OC)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: C=CCC(CC=C)(COc1cc(C)c(-c2ccc(C(F)(F)F)cc2)c(C)c1)c1ccc(C(=O)O)cc1
Temperature: 70 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
A solution of 4-[1-allyl-1-(2,6-dimethyl-4′-trifluoromethyl-biphenyl-4-yloxymethyl)-but-3-enyl]-benzoic acid methyl ester (0.386 g, 0.758 mmol) in THF (8.0 mL) is treated with 1N LiOH (8.0 mL, 8.0 mmol), warmed to 70° C., and stirred overnight. The reaction mixture is cooled to room temperature, acidified with 1N HCl (9.0 mL), and extracted with EtOAc (3×20 mL). The combined extracts are dried over MgSO4, filtered, and concentrated to provide 0.356 g (95%) of the title compound as a white foam. MS (ES): 493.3 [M−H]−.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([NH2:16])[CH:12]=[CH:13][C:14]=1[F:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17]([O:23][CH2:24][CH3:25])(=[O:22])[CH2:18][C:19]([CH3:21])=O.O.C([O-])(O)=O.[Na+]>C1CCCCC1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:24]([O:23][C:17](=[O:22])[CH:18]=[C:19]([NH:16][C:11]1[CH:12]=[CH:13][C:14]([F:15])=[C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:10]=1)[CH3:21])[CH3:25]
Reactant: Nc1ccc(F)c(OCc2ccccc2)c1
Reactant: CCOC(=O)CC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCCCC1
Solvent: O
Product: CCOC(=O)C=C(C)Nc1ccc(F)c(OCc2ccccc2)c1
Temperature: 25 °C
Yield: 98.9 %

Procedure:
92.7 g (0.43 mol) of 3-Benzyloxy-4-fluoro-phenylamine, 57 ml (0.45 mol) of ethyl acetoacetate and 0.81 g (4 mmol) of p-toluenesulfonic acid monohydrate in 370 ml of cyclohexane were heated at reflux for 3 h in the presence of a water separator funnel. The reaction mixture was cooled to RT, ACOEt (1 l) and saturated aqueous NaHCO3 solution (0.5 l) were added, the layers were separated and the organic layer once extracted with AcOEt (0.3 l). The combined organic layers were dried over magnesium sulfate and concentrated in vacuo to give 140 g (100%) of the desired 3-(3-benzyloxy-4-fluoro-phenylamino)-but-2-enoic acid ethyl ester as yellow-orange crystalline solid. Melting point: 79° C.-80° C.
Reaction SMILES: [CH:1]1([NH:7][CH2:8][CH2:9][C:10]2[CH:11]=[C:12]([OH:16])[CH:13]=[CH:14][CH:15]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:17](Cl)(=[O:20])[CH:18]=[CH2:19]>C(Cl)Cl.C(=O)(O)[O-].[Na+]>[CH:1]1([N:7]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([OH:16])[CH:11]=2)[C:17](=[O:20])[CH:18]=[CH2:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Oc1cccc(CCNC2CCCCC2)c1
Reactant: C=CC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: C=CC(=O)N(CCc1cccc(O)c1)C1CCCCC1
Reaction time: 1 h

Procedure:
To a stirred solution of the oil isolated in Step E (313 mg, 1.4 mmol) in methylene chloride (10 mL) and saturated aqueous sodium bicarbonate solution (10 m) at 0° C. was added acryloyl chloride (115 μL, 1.4 mmol). The resulting mixture was stirred for 1 h and then was extracted with methylene chloride. The solution was concentrated, the resulting residue was dissolved in MeOH (3 mL) and aqueous LiOH solution (1N, 1 mL). The mixture was then stirred at room temperature for 30 minutes. The solution was acidified with 1N HCl and then extracted with methylene chloride. The solution was dried over sodium sulfate and concentrated to yield an oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5]([C:10]1[CH:15]=[CH:14][N:13]=[C:12]([Br:16])[CH:11]=1)([CH2:8][OH:9])[CH2:6][OH:7])[CH3:2].[C@@:18]12(CS(O)(=O)=O)C(C)(C)C(C[CH2:24]1)C[C:19]2=O>CN(C=O)C>[CH2:1]([O:3][C:4]([C:5]1([C:10]2[CH:15]=[CH:14][N:13]=[C:12]([Br:16])[CH:11]=2)[CH2:8][O:9][C:18]([CH3:24])([CH3:19])[O:7][CH2:6]1)=[O:17])[CH3:2]
Reactant: CC1(C)C2CC[C@]1(CS(=O)(=O)O)C(=O)C2
Reactant: CCOC(=O)C(CO)(CO)c1ccnc(Br)c1
Solvent: CN(C)C=O
Product: CCOC(=O)C1(c2ccnc(Br)c2)COC(C)(C)OC1
Temperature: 80 °C

Procedure:
A mixture of 2-(2-bromo-pyridin-4-yl)-3-hydroxy-2-hydroxymethyl-propionic acid ethyl ester (30.0 g, 98.6 mmol) 2,2-dimethoxy propane (51.11 g, [60.5 ml], 493.1 mmol) and (1R)-(−)-10-camphor sulphonic acid (5.72 g, 24.65 mmol) in DMF (100 ml) was heated at 80° C. for 10 h. Reaction mixture was cooled to rt and concentrated under reduced pressure. The residue was dissolved in ethyl acetate and worked up by washing with water, brine, followed by drying over anhy. Na2SO4. Organic layer was concentrated under reduced pressure and the crude product was purified by column chromatography using 10% ethyl acetate in Hexane to obtain title compound as a yellow solid. Yield=18.15 g (53%). TLC (30% ethyl acetate in hexane) Rf=0.52; LCMS: RtH7=1.487; [M+1]+=344.0 and 346.0; HPLC RtH9=7.6 min (74%); 1H NMR (300 MHz, CDCl3): b 8.41-8.34 (t, 1H), 7.54 (s, 1H), 7.32-7.28 (m, 1H), 4.51 (dd, 2H), 4.27-4.21 (q, 4H), 1.45 (s, 3H), 1.39 (s, 3H), 1.23 (t, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:13][NH:12][C:11](=[O:14])[CH2:10]2)=[CH:5][CH:4]=1.[I:15](O)(=O)=O.II>C(O)(=O)C.O.S(=O)(=O)(O)O>[I:15][C:4]1[CH:5]=[C:6]([CH:9]2[CH2:13][NH:12][C:11](=[O:14])[CH2:10]2)[CH:7]=[CH:8][C:3]=1[O:2][CH3:1]
Reactant: [O-][I+2]([O-])O
Reactant: COc1ccc(C2CNC(=O)C2)cc1
Agent: II
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc(C2CNC(=O)C2)cc1I
Temperature: 80 °C
Reaction time: 10 h
Yield: 414.5 %

Procedure:
A solution of 19.1 g of 4-(4-methoxyphenyl)-pyrrolidin-2-one (100 mmol) in 200 ml of glacial acetic acid, 4.8 ml of water and 1.2 ml of concentrated sulfuric acid is combined with 3.44 g (19.55 mmol) of iodic acid and 8.64 g (70 mmol) of iodine and stirred at a bath temperature of 80° C. for 10 hours. Subsequently, the mixture is concentrated on a rotary evaporator up to onset of crystallization, cooled, the crystalline precipitate is suctioned off and recrystallized from ethyl acetate, thus obtaining 25.7 g (81% of theory) of 4-(3-iodo-4-methoxyphenyl)pyrrolidin-2-one, mp 158° C.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[C:4]([C:11]2[N:12]=[C:13]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[C:14]3[S:19][C:18]([CH2:20][OH:21])=[CH:17][C:15]=3[N:16]=2)[CH:3]=1.[H-].[Na+].[C:30]1([CH3:40])[CH:35]=[CH:34][C:33]([S:36](Cl)(=[O:38])=[O:37])=[CH:32][CH:31]=1>C1COCC1.CN(C=O)C>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[S:36]([C:33]2[CH:34]=[CH:35][C:30]([CH3:40])=[CH:31][CH:32]=2)(=[O:38])=[O:37])=[C:4]([C:11]2[N:12]=[C:13]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[C:14]3[S:19][C:18]([CH2:20][O:21][S:36]([C:33]4[CH:34]=[CH:35][C:30]([CH3:40])=[CH:31][CH:32]=4)(=[O:38])=[O:37])=[CH:17][C:15]=3[N:16]=2)[CH:3]=1
Reactant: OCc1cc2nc(-c3cc(F)cc4[nH]ccc34)nc(N3CCOCC3)c2s1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)OCc2cc3nc(-c4cc(F)cc5c4ccn5S(=O)(=O)c4ccc(C)cc4)nc(N4CCOCC4)c3s2)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a suspension of [2-(6-fluoro-1H-indol-4-yl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-yl]-methanol (0.54 g, 1.41 mmol) in anhydrous THF (20 mL) and DMF (5 mL) was added sodium hydride (60% suspension in mineral oil, 0.34 g, 8.5 mmol). The resulting mixture was stirred at RT for 10 min, then p-toluenesulfonyl chloride (1.08 g, 5.66 mmol) was added and the reaction mixture was heated at 40° C. for 3 h.
Reaction SMILES: [Na].[CH3:2][O:3][C:4](=[O:15])[C:5]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH3:14])=[CH:6][OH:7].C1OCCOCCOCCOCCOC1.Cl[CH:32]([F:34])[F:33].[OH-].[Na+].Cl>CN1CCCC1=O.O>[CH3:2][O:3][C:4](=[O:15])[C:5]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH3:14])=[CH:6][O:7][CH:32]([F:34])[F:33]
Reactant: FC(F)Cl
Reactant: COC(=O)C(=CO)c1ccccc1C
Agent: C1COCCOCCOCCOCCO1
Agent: Cl
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Product: COC(=O)C(=COC(F)F)c1ccccc1C
Temperature: 5 °C

Procedure:
Preparation of ##STR8## 7.76 g of the sodium salt of 3-hydroxy-2-(o-tolyl)-acrylic acid methyl ester and 0.3 g of 15-crown-5 in 160 ml of N-methyl-2-pyrrolidone (NMP) are cooled to 5° C. with stirring. Chlorodifluoromethane is then passed in while simultaneously adding dropwise a solution of 8.5 g of sodium hydroxide in 9.3 ml of water and the reaction mixture is left to react with vigorous stirring at 5°-8° C. for 2 hours. 82 ml of 2N hydrochloric acid are then added dropwise at 0°-8° C. and the phases are separated. The aqueous phase is extracted exhaustively with ethyl acetate and the combined organic phases are washed with a saturated sodium chloride solution. After drying over sodium sulfate, the residue is filtered and concentrated to dryness by evaporation in vacuo. 3-difluoromethoxy-2-(o-tolyl)acrylic acid methyl ester is obtained in the form of a pale yellow oil.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([N:23]([CH2:25][CH:26]2[CH2:28][CH2:27]2)[CH3:24])[N:12]=[N:13][C:14]=1[O:15]CC1C=CC=CC=1)C1C=CC=CC=1>[Pd].C(OCC)(=O)C>[CH:26]1([CH2:25][N:23]([CH3:24])[C:11]2[CH:10]=[C:9]([OH:8])[C:14](=[O:15])[NH:13][N:12]=2)[CH2:27][CH2:28]1
Reactant: CN(CC1CC1)c1cc(OCc2ccccc2)c(OCc2ccccc2)nn1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CN(CC1CC1)c1cc(O)c(=O)[nH]n1
Reaction time: 2 h
Yield: 5.9 %

Procedure:
A suspension of 5,6-bis(benzyloxy)-N-(cyclopropylmethyl)-N-methylpyridazin-3-amine (Intermediate 46; 2.44 mmol) and palladium on carbon (10% wt loading, dry basis; 0.259 g, 0.244 mmol) in ethyl acetate (10 ml) was stirred under a hydrogen atmosphere for 2 hours. The reaction mixture was filtered through a diatomaceous earth cartridge commercially sold under the trade mark ‘Celite’, eluting with ethyl acetate, tetrahydrofuran and methanol. The filtrate was concentrated in vacuo to afford a brown solid, which was triturated from ethyl acetate to give the title compound as a pale brown solid (27.9 mg, 38%).
Reaction SMILES: [N+:1]([C:4]1[N:5]=[CH:6][N:7]([CH:9]2[CH2:12][CH:11]([OH:13])[CH2:10]2)[CH:8]=1)([O-:3])=[O:2].CCN(CC)CC.[C:21]1([CH3:31])[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1>C(Cl)Cl>[N+:1]([C:4]1[N:5]=[CH:6][N:7]([C@H:9]2[CH2:10][C@H:11]([O:13][S:27]([C:24]3[CH:25]=[CH:26][C:21]([CH3:31])=[CH:22][CH:23]=3)(=[O:29])=[O:28])[CH2:12]2)[CH:8]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cn(C2CC(O)C2)cn1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)O[C@H]2C[C@H](n3cnc([N+](=O)[O-])c3)C2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
3-(4-nitro-imidazol-1-yl)-cyclobutanol (Preparation 4, Step 1; 4 g, 22 mmol) was treated with Et3N (7.7 mL, 55 mmol) in methylene chloride (150 mL) followed by p-toluenesulfonyl chloride (TsCl) (5 g, 26.4 mmol) and 4-N,N-dimethylaminopyridine (DMAP) (268 mg, 2.2 mmol). The resulting mixture was stirred at room temperature for 24 h. Analysis by thin layer chromatography showed two new spots. The reaction mixture was diluted with methylene chloride and was washed with water (1×) and brine (1×). The organic layer was dried (MgSO4), filtered, and concentrated in vacuo. Purification by silica gel chromatography (1:1 to 2:1 hexanes-ethyl acetate) allowed for separation of the trans and cis diastereomers. The first spot to elute (high Rf) was the trans-isomer, trans-toluene-4-sulfonic acid 3-(4-nitro-imidazol-1-yl)-cyclobutyl ester (2.7 g, 37% yield); 1H NMR (400 MHz, CDCl3) δ7.79 (s, 1H), 7.77 (m, 2H), 7.44 (d, J=1.7 Hz, 1H), 7.36 (dd, J=0.5, 8.0 Hz, 2H), 5.034 (m, 1H), 4.94 (m, 1H), 2.9 (m, 2H), 2.7 (m, 2H); MS (AP/Cl): 338.1 (M+H)+. The second spot to elute was the cis-isomer, cis-toluene-4-sulfonic acid 3-(4-nitro-imidazol-1-yl)-cyclobutyl ester (2.9 g, 39% yield); 1H NMR (400 MHz, CDCl3) δ7.8 (m, 3H), 7.43 (d, J=1.4 Hz, 1H), 7.36 (dd, J=0.6, 8.5 Hz, 2H), 4.74 (m, 1H), 4.30 (m, 1H), 3.05 (m, 2H), 2.6-2.5 (m, 2H), 2.45 (s, 3H); MS (AP/Cl): 338.1 (M+H)+. Relative configurations were determined by the measurement of nuclear Overhauser effects.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8]/[CH:9]=[CH:10]/[CH:11]([OH:21])[CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1.[C:22](OC(=O)C)(=[O:24])[CH3:23].N1C=CC=CC=1>CCOCC>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8]/[CH:9]=[CH:10]/[CH:11]([O:21][C:22](=[O:24])[CH3:23])[CH2:12][O:13][C:14]1[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=1
Reactant: OC(/C=C/COC1CCCCO1)COc1ccc(F)cc1
Reactant: CC(=O)OC(C)=O
Solvent: CCOCC
Solvent: c1ccncc1
Product: CC(=O)OC(/C=C/COC1CCCCO1)COc1ccc(F)cc1
Reaction time: 4 h

Procedure:
A mixture of 1-(2-tetrahydropyranyloxy)-4-hydroxy-5-(4-fluorophenoxy)-trans-2-pentene (23.6 g., 0.08 mole), acetic anhydride (9.2 g., 0.09 mole), and pyridine (7.9 g., 0.1 mole) is heated at 55°-60° for 4 hours and then at 95° for an additional 4 hours. The solution is cooled, diluted with ether and washed with ice-cold saturated sodium carbonate solution, ice water (3 x) and brine, and dried over sodium sulfate. Removal of solvent under vacuum leaves the title compound as a residual orange oil.
Reaction SMILES: CC1[N:3]([C:8]2[N:9]=[C:10]([CH3:24])[C:11]3[CH:17]=[CH:16][C:15](=[O:18])[N:14]([N:19]4[CH2:23][CH2:22][CH2:21][CH2:20]4)[C:12]=3[N:13]=2)C(C)=CC=1>O>[NH2:3][C:8]1[N:9]=[C:10]([CH3:24])[C:11]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([N:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)[C:12]=2[N:13]=1
Reactant: Cc1nc(-n2c(C)ccc2C)nc2c1ccc(=O)n2N1CCCC1
Solvent: O
Product: Cc1nc(N)nc2c1ccc(=O)n2N1CCCC1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
To a microwave vial was added 2-(2,5-dimethyl-1H-pyrrol-1-yl)-4-methyl-8-(pyrrolidin-1-yl)pyrido[2,3,d]pyrimidin-7(8H)-one (530 mg, 1.64 mmol) hydroxamine hydrochloride (1.14 g, 16.4 mmol) ethanol (20 ml) and water (2.92 ml). The vial was capped and refluxed at 100° C. After 3 h, the reaction mixture was concentrated to dryness under reduced pressure and the resulting residue was purified by column chromatography eluted with 10% 7N NH3 in MeOH:CHCl3 to give the desired product weighted 296 mg 74%
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[CH2:12]([O:14][CH:15]([O:18][CH2:19][CH3:20])[CH2:16]Cl)[CH3:13].C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>CN(C)C=O>[CH2:12]([O:14][CH:15]([O:18][CH2:19][CH3:20])[CH2:16][O:8][C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1)[CH3:13]
Reactant: Cc1ccc(O)cc1[N+](=O)[O-]
Reactant: CCOC(CCl)OCC
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(COc1ccc(C)c([N+](=O)[O-])c1)OCC

Procedure:
A mixture of 15.3 g (0.1 mole) of 4-methyl-3-nitrophenol, 16.8 g (0.11 mole) of chloroacetaldehyde diethyl acetal, 20.7 g (0.15 mole) of ground potassium carbonate, 4.5 g (30 mmole) of sodium iodide and 100 ml of dimethylformamide is boiled under reflux for 12 hours. The whole is subsequently filtered with suction, the residue is washed with dimethylformamide and the solution is concentrated by evaporation in vacuo. Chromatography of the residue over silica gel (methylene chloride) and subsequent distillation of the pure fractions (105°-110°/6.10-2 torr) yields 2-(4-methyl-3-nitrophenoxy)-acetaldehyde diethyl acetal in the form of a yellowish oil.
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=O.P(Cl)(Cl)(Cl)(Cl)[Cl:11]>O>[CH2:8]([O:7][C:1](=[O:6])[CH:2]=[C:3]([Cl:11])[CH3:5])[CH3:9]
Reactant: CCOC(=O)CC(C)=O
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: O
Product: CCOC(=O)C=C(C)Cl
Reaction time: 3 h

Procedure:
To a stirred solution of ethyl acetoacetate (150.0 g, 0.86 mol) in hexanes (200 mL) was added phosphorus pentachloride (95.0 g, 0.456 mol) at 23° C. under nitrogen and stirred for 3 h. Water (300 mL) was added to the reaction mixture while cooling in an ice-bath. The organic layer was separated, washed with an aqueous solution of 20% potassium carbonate (3×200 mL) followed by a saturated sodium chloride solution (2×100 mL), dried over sodium sulfate and concentrated in vacuo to afford 3-chloro-but-2-enoic acid ethyl ester which was purified by distillation (95.8 g, 75%): boiling range 160°-170° C.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[C:10]([CH2:11][OH:12])=[CH:9][CH:8]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)[N:6]=1)[CH3:3].[CH2:23]([O:25][C:26](=[O:39])[C:27]([O:30][C:31]1[CH:36]=[CH:35][C:34](O)=[CH:33][C:32]=1[CH3:38])([CH3:29])[CH3:28])[CH3:24].C(P(CCCC)CCCC)CCC.CN(C)C(N=NC(N(C)C)=O)=O>C1COCC1>[CH2:23]([O:25][C:26](=[O:39])[C:27]([O:30][C:31]1[CH:36]=[CH:35][C:34]([O:12][CH2:11][C:10]2[C:5]([CH2:4][N:2]([CH3:1])[CH3:3])=[N:6][C:7]([C:13]3[CH:14]=[CH:15][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:17][CH:18]=3)=[CH:8][CH:9]=2)=[CH:33][C:32]=1[CH3:38])([CH3:28])[CH3:29])[CH3:24]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(O)cc1C
Reactant: CN(C)Cc1nc(-c2ccc(C(F)(F)F)cc2)ccc1CO
Agent: CCCCP(CCCC)CCCC
Agent: CN(C)C(=O)N=NC(=O)N(C)C
Solvent: C1CCOC1
Product: CCOC(=O)C(C)(C)Oc1ccc(OCc2ccc(-c3ccc(C(F)(F)F)cc3)nc2CN(C)C)cc1C
Reaction time: 6 h

Procedure:
0.170 g (0.548 mmol) of the above prepared [2-dimethylaminomethyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-methanol and 0.122 g (0.512 mmol) of 2-(4-hydroxy-2-methyl-phenoxy)-2-methyl-propionic acid ethyl ester (described in WO 02/092590) were dissolved in 6 ml of abs. THF and treated successively at 0° C. with 0.133 g (0.658 mmol) of tributylphosphine and 0.114 g (0.659 mmol) of N,N,N′,N′-tetramethylazodicarboxamide. The cooling bath was then removed and stirring continued for additional 6 h. The reaction mixture was then poured onto crashed ice, extracted twice with AcOEt, washed with water and brine, and dried over magnesium sulfate. Evaporation of the solvents i. V., followed by flash chromatography (SiO2, hexane/AcOEt=25/75) yielded 0.016 g of the title product as yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:12])[CH2:9][NH:10][CH3:11])=[CH:4][CH:3]=1.[C:13]([O:17][C:18](=[O:20])O)([CH3:16])([CH3:15])[CH3:14].O1CCCC1.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[C:13]([O:17][C:18](=[O:20])[N:10]([CH2:9][CH:8]([C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)[OH:12])[CH3:11])([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)OC(=O)O
Reactant: CNCC(O)c1ccc(F)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CN(CC(O)c1ccc(F)cc1)C(=O)OC(C)(C)C

Procedure:
A solution of 1-(4-fluorophenyl)-2-methylamino ethanol (the compound of Preparation Example 17) (9.7 g) and t-butylbicarbonate (10.0 g) in a mixed solvent of tetrahydrofuran solution (100 mL) and an aqueous solution of saturated sodium bicarbonate (50 mL) was stirred at room temperature for 1.5 hours. The solution was diluted with ethyl acetate, and washed with water and saturated sodium chloride water. After drying the organic layer with anhydrous sodium sulfate, the residue that was obtained by evaporating the solvent at reduced pressure was purified by silica gel column chromatography (hexane/ethyl acetate), and the title compound (9.5 g) was obtained as a colorless solid.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([I:12])[CH:11]=1)[C:5](OC)=[O:6].O.[NH2:14][NH2:15].O>C(O)C>[I:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([I:12])[CH:11]=1)[C:5]([NH:14][NH2:15])=[O:6]
Reactant: COC(=O)c1cc(I)cc(I)c1
Reactant: NN
Solvent: O
Solvent: CCO
Product: NNC(=O)c1cc(I)cc(I)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To Methyl 3,5-diiodobenzoate (5.0 g, 12.89 mmol) in ethanol (70.0 ml) was added hydrazine hydrate (20.0 ml) under stirring. During heating, white solid was appeared. The reaction was kept 50° C. for 1 h. Heating was stopped and then water (100.0 ml) was added. After cooling down to room temperature, the white product solid was collected by filtration. The product was washed with water and dried under vacuum. Final white product was obtained in 4.6 g (92.0%). 1H NMR (400 MHz, DMSO-d6, δ): 9.92 (s, 1H, NH), 8.22 (t, J=1.6 Hz, 1H), 8.12 (d, J=1.6 Hz, 2H), 4.53 (s, 2H, NH2).