Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C@H:6]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH:28]([CH2:34][CH2:35][CH2:36][C:37]([F:43])([F:42])[C:38]([F:41])([F:40])[F:39])[C:29]([O:31]CC)=[O:30])[C@@:7]([C:13]3[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=3)([CH3:12])[CH2:8][S:9]2)=[CH:4][CH:3]=1.[OH-].[Na+].Cl>C(O)C.O>[OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C@H:6]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH:28]([CH2:34][CH2:35][CH2:36][C:37]([F:43])([F:42])[C:38]([F:39])([F:40])[F:41])[C:29]([OH:31])=[O:30])[C@@:7]([C:13]3[CH:14]=[CH:15][C:16]([OH:19])=[CH:17][CH:18]=3)([CH3:12])[CH2:8][S:9]2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(CCCCCCCC[C@H]1c2ccc(O)cc2SC[C@@]1(C)c1ccc(O)cc1)CCCC(F)(F)C(F)(F)F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: C[C@@]1(c2ccc(O)cc2)CSc2cc(O)ccc2[C@@H]1CCCCCCCCC(CCCC(F)(F)C(F)(F)F)C(=O)O
Yield: 90.6 %

Procedure:
Ethyl 10-[(3R,4R)-7-hydroxy-3-(4-hydroxyphenyl)-3-methylthiochroman-4-yl]-2-(4,4,5,5,5-pentafluoropentyl)decanoate (2.08 g, 3.297 mmol) and sodium hydroxide (527 mg, 13.19 mmol) were added to an ethanol/water mixture (40/10 ml), followed by heating under reflux for 4 hours. The reaction mixture was acidified with 2N hydrochloric acid and then extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. After distilling off the solvent, the residue was purified by silica gel column chromatography (eluent: ethyl acetate/hexane/dichloromethane=1/4/1) to give 10-[(3R,4R)-7-hydroxy-3-(4-hydroxyphenyl)-3-methythiochroman-4-yl]-2-(4,4,5,5,5-pentafluoropentyl)decanoic acid (1.8 g, Yield 91%) as a foam.
Reaction SMILES: [C:1]1([C:7]2([NH2:10])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:12]1[N:17]=[C:16]([S:18][C:19]#[N:20])[C:15]([N+:21]([O-:23])=[O:22])=[CH:14][N:13]=1>>[N+:21]([C:15]1[C:16]([S:18][C:19]#[N:20])=[N:17][C:12]([NH:10][C:7]2([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:9][CH2:8]2)=[N:13][CH:14]=1)([O-:23])=[O:22]
Reactant: N#CSc1nc(Cl)ncc1[N+](=O)[O-]
Reactant: NC1(c2ccccc2)CC1
Product: N#CSc1nc(NC2(c3ccccc3)CC2)ncc1[N+](=O)[O-]

Procedure:
(5-Nitro-4-thiocyanato-pyrimidin-2-yl)-(1-phenyl-cyclopropyl)-amine was prepared by addition of the above amine to 2-chloro-5-nitro-4-thiocyanato-pyrimidine using the procedure described in Example 17. m/z calcd. C14H10N5O2S [M−H]−: 312.33. Found: 312.10.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][O:11][CH2:10][C@@:9]1([CH3:24])[C:14]([O:16]CC1C=CC=CC=1)=[O:15])C1C=CC=CC=1>[Pd]>[CH3:24][C@@:9]1([C:14]([OH:16])=[O:15])[CH2:10][O:11][CH2:12][CH2:13][NH:8]1
Reactant: C[C@@]1(C(=O)OCc2ccccc2)COCCN1Cc1ccccc1
Agent: [Pd]
Product: C[C@@]1(C(=O)O)COCCN1
Yield: 66.8 %

Procedure:
(S)-benzyl 4-benzyl-3-methylmorpholine-3-carboxylate (3.26 g, 10 mmol) was reacted with H2 by Pd/C catalysis (10%, 0.33 g) according to the procedure as described in Example 34, Step C to give the title compound as a gray solid (0.97 g, 67%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]2[C:5]([C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[CH:8][N:9]2[CH:12]2[CH2:14][CH2:13]2)=[CH:4][C:3]=1[F:19].CN(C)C=O.[C:25](Cl)(=O)[C:26](Cl)=O>C(O)C.ClCCl>[CH2:25]([O:16][C:15]([C:7]1[C:6](=[O:18])[C:5]2[C:10](=[N:11][C:2]([Cl:1])=[C:3]([F:19])[CH:4]=2)[N:9]([CH:12]2[CH2:14][CH2:13]2)[CH:8]=1)=[O:17])[CH3:26]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1cn(C2CC2)c2nc(Cl)c(F)cc2c1=O
Solvent: CCO
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(C2CC2)c2nc(Cl)c(F)cc2c1=O
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 50 %

Procedure:
7-Chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-napthyridine-3-carboxylic acid, (U.S. Pat. No. 4,663,457) (20.0 g, 71 mmol) and dimethylformamide (0.5 ml) were added to dichloromethane (750 ml) to give a tan slurry. Oxalyl chloride (7.4 ml, 85 mmol) was added to this slurry over one minute and the reaction mixture stirred for 90 minutes, then an additional 2.0 ml of oxalyl chloride was added and stirring continued for 60 minutes. To the resulting brown solution was added absolute ethanol (4.3 ml, 78 mmol) and the mixture stirred for four hours and then cooled to 0° C. and stored overnight. The reaction was warmed to room temperature and an additional 2 ml of absolute ethanol was added and the stirring continued for three hours. The reaction was evaporated to a brown solid. The solid was heated in THF, filtered, and cooled to 0° C. The crystals formed were collected and dried to give the title compound, (11.1 g, 50%).
Reaction SMILES: NC1C=C(C=CC=1)OC1C(F)=C(O[C:14]2[CH:24]=[CH:23][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:16][C:15]=2OC)C(F)=C(OC2C=C(C#N)C=C(OC)C=2C2C=CC=CC=2)N=1.N#CN.Cl>C(O)C>[C:18]([O:20][CH2:21][CH3:22])(=[O:19])[C:17]1[CH:23]=[CH:24][CH:14]=[CH:15][CH:16]=1
Reactant: CCOC(=O)c1ccc(Oc2c(F)c(Oc3cccc(N)c3)nc(Oc3cc(C#N)cc(OC)c3-c3ccccc3)c2F)c(OC)c1
Agent: Cl
Agent: N#CN
Solvent: CCO
Product: CCOC(=O)c1ccccc1
Reaction time: 4 h

Procedure:
To ethanol (15 mL) was added 4-[[2-(3-aminophenoxy)-6-(5-cyano-2-phenyl-methoxyphenoxy)-3,5-difluoropyridin-4-yl]oxy]-3-methoxybenzoic acid, ethyl ester (0.50 g, 0.80 mmol), cyanamide (0.60 g, 14 mmol), and 6 M hydrochloric acid (0.7 mL). After refluxing for 19 hours, cyanamide (0.60 g, 14 mmol) and 6 M hydrochloric acid (0.7 mL) was added and refluxing was continued for 4 hours. The reaction mixture was concentrated in vacuo and purified by HPLC to give 4-[[2-[3-(guanidino)phenoxy)-6-(5-cyano-2-benzyloxyphenoxy)-3,5-difluoro-pyridin-4-yl)oxy]-3-methoxy]benzoic acid, ethyl ester.
Reaction SMILES: [C:1]([C:5]1[N:9]([CH3:10])[N:8]([CH2:11][C@H:12]2[CH2:16][CH2:15][CH2:14][O:13]2)/[C:7](=[N:17]/[C:18](=[O:36])[C:19]2[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[CH:21][C:20]=2[O:29][CH2:30][CH2:31][C:32](O)([CH3:34])[CH3:33])/[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].CCN(S(F)(F)[F:43])CC>C(Cl)Cl>[C:1]([C:5]1[N:9]([CH3:10])[N:8]([CH2:11][C@H:12]2[CH2:16][CH2:15][CH2:14][O:13]2)/[C:7](=[N:17]/[C:18](=[O:36])[C:19]2[CH:24]=[C:23]([C:25]([F:26])([F:27])[F:28])[CH:22]=[CH:21][C:20]=2[O:29][CH2:30][CH2:31][C:32]([F:43])([CH3:33])[CH3:34])/[CH:6]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: Cn1c(C(C)(C)C)c/c(=N\C(=O)c2cc(C(F)(F)F)ccc2OCCC(C)(C)O)n1C[C@H]1CCCO1
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: Cn1c(C(C)(C)C)c/c(=N\C(=O)c2cc(C(F)(F)F)ccc2OCCC(C)(C)F)n1C[C@H]1CCCO1
Temperature: 25 °C
Yield: 22.3 %

Procedure:
The product from Example 43A (215 mg, 0.42 mmol) in CH2Cl2 (10 mL) was treated dropwise with DAST (66 μL, 0.504 mmol) at −78° C. The reaction mixture was allowed to warm up to room temperature for 4 hrs. The mixture was quenched with saturated NaHCO3 and extracted with EtOAc (2×). The organic layer was dried over MgSO4, filtered and concentrated. The residue was purified by column chromatography using an Analogix® Intelliflash280™ (SiO2, 50% hexanes/EtOAc to 100% EtOAc to 9:1:0.1 EtOAc:MeOH:Et3N) to afford 48 mg (22%) of the title compound. 1H NMR (400 MHz, CDCl3) δ ppm 1.45 (d, J=21.48 Hz, 6H) 1.50 (s, 9H) 1.82-1.99 (m, 3H) 2.19-2.37 (m, 3 H) 3.67-3.83 (m, 2H) 4.14-4.23 (m, 1H) 4.24 (s, 3H) 4.48 (t, J=7.36 Hz, 2 H) 4.80-4.97 (m, 1H) 5.48 (d, J=17.18 Hz, 1H) 6.97 (s, 1H) 7.13 (d, J=8.59 Hz, 1H) 7.74 (dd, J=7.98, 1.84 Hz, 1H) 8.08 (d, J=2.15 Hz, 1H); MS (DCI/NH3) m/z 514 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[CH2:3][OH:4].CC(C)([O-])C.[K+].Cl[C:14]1[N:18]([CH3:19])[N:17]=[C:16]([CH3:20])[C:15]=1[CH:21]=[O:22]>C1COCC1.ClCCl>[CH3:19][N:18]1[C:14]([O:4][CH2:3][C:2]([F:6])([F:5])[F:1])=[C:15]([CH:21]=[O:22])[C:16]([CH3:20])=[N:17]1
Reactant: OCC(F)(F)F
Reactant: Cc1nn(C)c(Cl)c1C=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: Cc1nn(C)c(OCC(F)(F)F)c1C=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 109.4 %

Procedure:
2,2,2-Trifluoroethanol (7.11 ml, 97.6 mmol) was added dropwise to potassium tert-butoxide (1M in THF) (97.6 ml, 97.6 mmol) at 0° C. A solution of 5-chloro-1,3-dimethyl-1H-pyrazole-4-carbaldehyde (10.3 g, 65.1 mmol) in THF (28 ml) was added slowly to the solution at 0° C. The solution was allowed to warn to room temperature and stirred at room temperature for 3 hours. The mixture was diluted with dichloromethane, washed with water and brine, dried over magnesium sulfate and concentrated to give the product as a yellow oil (15.82 g, 109% yield) which was used without further purification. 1H NMR (400 MHz, CDCl3): 2.42 (s, 3H, Me), 3.65 (s, 3H, Me), 4.93 (q, 2H, CH2), 9.72 (s, 1H, CH).
Reaction SMILES: [N+:1]([C:4]1[CH:30]=[CH:29][C:7]([CH2:8][O:9][C:10]([N:12]2[CH2:16][C@H:15]([O:17]C(=O)C3C=CC=CC=3)[CH2:14][C@H:13]2CC#N)=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:31]([OH:34])(=[O:33])[CH3:32]>Cl>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][O:9][C:10]([N:12]2[CH2:16][C@H:15]([OH:17])[CH2:14][C@H:13]2[CH2:32][C:31]([OH:34])=[O:33])=[O:11])=[CH:29][CH:30]=1)([O-:3])=[O:2]
Reactant: CC(=O)O
Reactant: N#CC[C@@H]1C[C@@H](OC(=O)c2ccccc2)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Agent: Cl
Product: O=C(O)C[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
(2R,4R)-1-(p-Nitrobenzyloxycarbonyl)-2-cyanomethyl-4-benzoyloxypyrrolidine (3.0 g) was dissolved in 10 ml of acetic acid and 10 ml of conc. hydrochloric acid. After refluxing for 3 hours, the reaction mixture was cooled down to room temperature and distilled to remove the solvent. The residue was diluted with 4 ml of water and 25 ml of 1N sodium hydroxide solution. A solution of 1.53 g of p-nitrobenzyl chloroformate in 6 ml of diethyl ether and 2 ml of tetrahydrofuran was added to the above mixture at 0° C., followed by stirring at the same temperature for 30 minutes. The reaction mixture was separated. The aqueous layer was acidified with 6N hydrochloric acid to pH 1.0 and extracted with ethyl acetate. The extract was washed with water and dried over anhydrous sodium sulfate. The solvent was removed by distillation to give (2S,4R)-1-(p-nitrobenzyloxycarbonyl)-2-carboxymethyl-4-hydroxypyrrolidine.
Reaction SMILES: [O:1]=[C:2]([CH2:6][CH3:7])[CH2:3][C:4]#[N:5].CO[CH:10](OC)[N:11]([CH3:13])[CH3:12]>C1COCC1>[CH3:13][N:11]([CH:10]=[C:3]([C:2](=[O:1])[CH2:6][CH3:7])[C:4]#[N:5])[CH3:12]
Reactant: CCC(=O)CC#N
Reactant: COC(OC)N(C)C
Solvent: C1CCOC1
Product: CCC(=O)C(C#N)=CN(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 3-oxopentanenitrile (1.0 equiv.) and 1,1-dimethoxy-N,N-dimethylmethanamine (4.3 M) in THF (1.6 M) was stirred at room temperature overnight. After reaction completion, the solvent was removed under vacuum to give the crude 2-((dimethylamino)methylene)-3-oxopentanenitrile (0.98 equiv.), which was used for the next step without further purification. MS (ESI) m/z 152.1 [M+H]+.
Reaction SMILES: Br[C:2]1[N:3]([CH3:23])[C:4]([C:13]2[S:14][C:15]3[N:16]=[CH:17][N:18]=[C:19]([NH2:22])[C:20]=3[N:21]=2)=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1.C(N(CC)CC)C.[C:31]([C:33]1([NH2:39])[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1)#[CH:32]>[Cu]I.CN(C=O)C>[NH2:39][C:33]1([C:31]#[C:32][C:2]2[N:3]([CH3:23])[C:4]([C:13]3[S:14][C:15]4[N:16]=[CH:17][N:18]=[C:19]([NH2:22])[C:20]=4[N:21]=3)=[C:5]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)[N:6]=2)[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1
Reactant: C#CC1(N)CCCCC1
Reactant: Cn1c(Br)nc(-c2ccccc2)c1-c1nc2c(N)ncnc2s1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cn1c(C#CC2(N)CCCCC2)nc(-c2ccccc2)c1-c1nc2c(N)ncnc2s1
Temperature: 90 °C
Yield: 41 %

Procedure:
A mixture of 2-(2-bromo-1-methyl-4-phenyl-1H-imidazol-5-yl)[1,3]thiazolo[5,4-d]pyrimidin-7-amine (Example 26) (0.02 g), PdCl2dppf (3.5 mg), triethylamine (0.1 mL), DMF (5 mL), copper(I) iodide (1 mg) and 1-ethynylcyclohexylamine (0.034 mL) was heated at 90° C., under an inert atmosphere, for 1.5 hours. The solvent was evaporated in vacuo then purification by flash chromatography on silica eluting with DCM:MeOH (9:1) gave the title compound as a beige solid (9 mg, 41%).
Reaction SMILES: C[O:2][C:3](=[O:23])[C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[C:6]([S:14]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)(=[O:16])=[O:15])[CH:5]=1.O.O.[OH-].[Li+].Cl>O1CCOCC1.C(OCC)(=O)C>[N:17]1([S:14]([C:6]2[CH:5]=[C:4]([CH:9]=[C:8]([C:10]([F:13])([F:11])[F:12])[CH:7]=2)[C:3]([OH:23])=[O:2])(=[O:15])=[O:16])[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1
Reactant: COC(=O)c1cc(C(F)(F)F)cc(S(=O)(=O)N2CCOCC2)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(O)c1cc(C(F)(F)F)cc(S(=O)(=O)N2CCOCC2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.3 %

Procedure:
To a solution of 3-(morpholine-4-sulfonyl)-5-trifluoromethyl-benzoic acid methyl ester (1.04 g, 2.94 mmol) in dioxane (10 mL) was added water (10 mL) and lithium hydroxide monohydrate (154 mg, 3.68 mmol) and the resulting clear solution was stirred at room temperature for 2 hours. The reaction mixture was poured on 1M aqueous hydrochloric acid (100 mL) and 100 mL ethyl acetate and the layers were separated. The aqueous layer was extracted a second time with ethyl acetate (100 mL). The organic layers were washed with brine (100 mL), dried over magnesium sulfate, filtered and concentrated under vacuum to give the desired compound as a colorless solid (1 g, 100%) which was pure for the next step without further purification. MS (ESI−): m/z=338.033 ([M−H]−).
Reaction SMILES: [N:1]([CH2:4][C:5]1[O:9][C:8]([C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:21]([CH3:22])=[CH:20][CH:19]=[C:18]([C:23]([NH:25][CH:26]4[CH2:28][CH2:27]4)=[O:24])[CH:17]=3)=[CH:12][CH:11]=2)=[N:7][N:6]=1)=[N+]=[N-].[H][H]>[Pd].C(O)C>[NH2:1][CH2:4][C:5]1[O:9][C:8]([C:10]2[CH:11]=[CH:12][C:13]([C:16]3[C:21]([CH3:22])=[CH:20][CH:19]=[C:18]([C:23]([NH:25][CH:26]4[CH2:28][CH2:27]4)=[O:24])[CH:17]=3)=[CH:14][CH:15]=2)=[N:7][N:6]=1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc(-c2nnc(CN=[N+]=[N-])o2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc(-c2nnc(CN)o2)cc1

Procedure:
4′-[5-(Azidomethyl)-1,3,4-oxadiazol-2-yl]-N-cyclopropyl-6-methyl-1,1′-biphenyl-3-carboxamide (Intermediate 44) (27.8 mg) and palladium on carbon (10% w/w, 5 mg) in ethanol (5 ml) were hydrogenated under 1 Atm. of hydrogen for 2 hours. The reaction was filtered through celite, the filtrate reduced to dryness under vacuum and the residue applied to a bond-elut (silica, 4 g). The column was eluted with chloroform, ether, ethyl acetate, and methanol. The methanol fraction was reduced to dryness under vacuum to give 4′-[5-(aminomethyl)-1,3,4-oxadiazol-2-yl]-N-cyclopropyl-6-methyl-1,1′-biphenyl-3-carboxamide.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:3]=1[C:4]([OH:6])=O.[NH2:12][CH2:13][CH2:14][CH2:15][C@H:16]1[O:20][C:19](=[O:21])[N:18]([C:22]2[CH:23]=[CH:24][C:25]3[S:30][CH2:29][C:28](=[O:31])[NH:27][C:26]=3[CH:32]=2)[CH2:17]1>>[NH2:1][C:2]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:3]=1[C:4]([NH:12][CH2:13][CH2:14][CH2:15][C@H:16]1[O:20][C:19](=[O:21])[N:18]([C:22]2[CH:23]=[CH:24][C:25]3[S:30][CH2:29][C:28](=[O:31])[NH:27][C:26]=3[CH:32]=2)[CH2:17]1)=[O:6]
Reactant: NCCC[C@@H]1CN(c2ccc3c(c2)NC(=O)CS3)C(=O)O1
Reactant: Nc1ccc(F)cc1C(=O)O
Product: Nc1ccc(F)cc1C(=O)NCCC[C@@H]1CN(c2ccc3c(c2)NC(=O)CS3)C(=O)O1
Yield: 70 %

Procedure:
Starting from 2-amino-5-fluorobenzoic acid and 6-[(R)-5-(3-amino-propyl)-2-oxo-oxazolidin-3-yl]-4H-benzo[1,4]thiazin-3-one (described in WO 2010/041219) and using Procedure D, the title compound was obtained as a beige solid (160 mg; 70% yield).
Reaction SMILES: [C:1]1([OH:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[OH-].[K+].O.[Cl:15][C:16]1[CH:17]=[C:18]([N+:23]([O-:25])=[O:24])[CH:19]=[CH:20][C:21]=1Cl>C1(C)C(C)=CC=CC=1.[Cu]>[C:1]1([O:11][C:21]2[CH:20]=[CH:19][C:18]([N+:23]([O-:25])=[O:24])=[CH:17][C:16]=2[Cl:15])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=[N+]([O-])c1ccc(Cl)c(Cl)c1
Reactant: Oc1cccc2ccccc12
Agent: [Cu]
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1C
Product: O=[N+]([O-])c1ccc(Oc2cccc3ccccc23)c(Cl)c1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
To a solution of 144 g (1 mol) of α-naphthol in 1 liter of xylene were added 65 g (1 mol) of finely powdered 88% potassium hydroxide. The mixture thus obtained was boiled under N2 -atmosphere in an apparatus equipped with an effective water trap under constant stirring until no water was separating any more and the head temperature had risen to 137° C. Then, 500 ml of dimethylformamide were added, The solution thus obtained was boiled for a further two hours under nitrogen in the apparatus equippped with an effective water trap; then, 500 ml of solvent were distilled therefrom. The residue was allowed to cool off under nitrogen to 100° C., and 211 g (1 mol) of 3,4-dichloronitrobenzene and 1 g of copper powder were added. Then it was refluxed under nitrogen while stirring for 8 hours (approx. 140° C. bottom temperature). Afterwards it was allowed to cool off to ~50° C., approx. 30 g of kieselguhr were added, the mixture thus obtained was stirred, and the undissolved substance was removed by suction filtration and washed with xylene. The filtrate united with the wash liquid was evaporated in vacuo to dryness. The residue was dissolved in warm toluene. The obtained solution was extracted thrice with separate portions of 500 ml of 1 N sodium hydroxide solution and, subsequently, twice with separate portions of 500 ml of water. Then, the toluene phase was evaporated to dryness in vacuo (crude yield: 290 g, 96% of theory). The residue was stirred with 1.7 liter of gasoline (boiling range 80°-110° C.) at approx. 85° C. Most of the crude product dissolved; some resin remain undissolved. The solution decanted therefrom was allowed to cool off slowly. First, the product precipitated oily; however, by trituration at approx. 50° C., crystals were obtained. Then it was cooled for several hours to 5° C. and the crystalline product was removed by suction filtration.
Reaction SMILES: C(=O)C1OC=CC=1.CC(C)[O-].[Al+3].CC(C)[O-].CC(C)[O-].C([O:23][CH2:24]/[CH:25]=[C:26](/[CH2:28][CH2:29][CH:30]=[C:31]([CH3:33])[CH3:32])\[CH3:27])=O>>[CH3:33][C:31](=[CH:30][CH2:29][CH2:28][C:26](=[CH:25][CH:24]=[O:23])[CH3:27])[CH3:32]
Reactant: CC(C)=CCC/C(C)=C/COC=O
Agent: CC(C)[O-]
Agent: [Al+3]
Solvent: O=Cc1ccco1
Product: CC(C)=CCCC(C)=CC=O
Yield: 86 %

Procedure:
According to the same procedure of Example 1, using 19.5 g (200 mmol) of furfural, and 642 mg (3 mmol) of aluminum isopropoxide, 18.2 g (100 mmol) of geranyl formate was oxidized to obtain citral at a yield of 86%.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH:15]=[O:16])=[N:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.S(=O)(=O)([OH:20])N.Cl([O-])=O.[Na+]>CC(C)=O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]([OH:20])=[O:16])=[N:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1ccc(OCc2ccccc2)cn1
Reactant: NS(=O)(=O)O
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: O
Solvent: CC(C)=O
Product: O=C(O)c1ccc(OCc2ccccc2)cn1
Temperature: 25 °C
Reaction time: 6 h
Yield: 73.4 %

Procedure:
To a solution of 5-benzyloxypyridine-2-carbaldehyde (3.8 g) in acetone (50 ml) was added water (50 ml), sulfamic acid (2.4 g) and sodium chlorite (2.2 g) were sequentially added thereto on an ice bath, and the solution was stirred for 6 hours at room temperature. The solid that was precipitated was filtered and rinsed with water to provide the title compound (3.0 g).
Reaction SMILES: [CH2:1]([S:3][C:4]1[N:8]=[CH:7][NH:6][N:5]=1)[CH3:2].[CH2:9]([N:11]([CH2:15][CH3:16])[C:12](Cl)=[O:13])[CH3:10].O1CCCC1.C(N(CC)CC)C>CCOCC>[CH2:9]([N:11]([CH2:15][CH3:16])[C:12]([N:6]1[CH:7]=[N:8][C:4]([S:3][CH2:1][CH3:2])=[N:5]1)=[O:13])[CH3:10]
Reactant: CCN(CC)C(=O)Cl
Reactant: CCSc1nc[nH]n1
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCSc1ncn(C(=O)N(CC)CC)n1

Procedure:
A mixture of 6.45 g. 3-ethylthio-1,2,4-triazole, 7.5 g. diethylcarbamoyl chloride, 40 ml. dry tetrahydrofuran and 7.75 ml. dry triethylamine was refluxed under anhydrous conditions for 22 hours. The reaction mixture was worked up as described in Example 1, using ether in place of methylene dichloride, to give a residual oil. This oil was distilled under reduced pressure to give 1-diethylcarbamoyl-3-ethylthio-1,2,4-triazole, b.p. 110° - 111°C./0.2 mm. (93.6% 1-isomer by GLC assay). Elemental analysis satisfactory.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[C:12]([Br:17])[CH:11]=1)([CH3:4])([CH3:3])[CH3:2].Br[C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][N:21]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.O.CCOC(C)=O>[C:1]([O:5][C:6](=[O:18])[NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][N:21]=2)=[C:12]([Br:17])[CH:11]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: FC(F)(F)c1ccc(Br)nc1
Reactant: CC(C)(C)OC(=O)NCCc1ccc(O)c(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NCCc1ccc(Oc2ccc(C(F)(F)F)cn2)c(Br)c1
Temperature: 60 °C
Reaction time: 8 h
Yield: 78.4 %

Procedure:
[2-(3-bromo-4-hydroxy-phenyl)-ethyl]-carbamic acid tert-butyl ester (2.212 mmol, 1 eq), 2-bromo-5-(trifluoromethyl)-pyridine (2.212 mmol, 1 eq) and potassium carbonate (5.531 mmol, 1.5 eq) were suspended in dimethylsulfoxide (25 ml). The reaction mixture was stirred at 60° C. overnight. Reaction mixture was diluted with water (150 ml) and extraction with EtOAc followed (7×15 ml). Organic layers were combined, washed with brine, dried over MgSO4, filtered and evaporated giving {2-[3-bromo-4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl]-ethyl}-carbamic acid tert-butyl ester (1.734 mmol, yield=78%, purity=93%). [M+H]+=461.29 1H NMR (300 MHz, CDCl3) δ/ppm 1.43 (s, 9H), 2.74-2.84 (m, 2H), 3.29-3.45 (m, 2H), 4.51-4.65 (m, 1H), 7.02-7.15 (m, 2H), 7.16-7.23 (m, 1H), 7.45-7.50 (m, 1H), 7.86-7.95 (m, 1H), 8.35-8.41 (m, 1H)
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5](=[O:15])[C:6](=[O:14])[C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1.Cl[CH2:17][C:18]([C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][CH:21]=1)=[O:19]>CN(C)C=O>[CH3:3][O:4][C:5](=[O:15])[C:6](=[O:14])[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:17][C:18]([C:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:23]=[CH:22][CH:21]=2)=[O:19])=[CH:9][CH:8]=1
Reactant: COC(=O)C(=O)c1ccc(O)cc1
Reactant: O=C(CCl)c1cccc2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(=O)c1ccc(OCC(=O)c2cccc3ccccc23)cc1
Temperature: 60 °C
Reaction time: 8 h
Yield: 16.3 %

Procedure:
Sodium hydride (55%; 0.238 g) and 4-hydroxy-alpha-oxobenzeneacetic acid methyl ester (0.978 g) in dimethylformamide (12 mL) were stirred at room temperature for 30 minutes and then 2-chloro-1-(1-naphthalenyl)ethanone (1 g) in dimethylformamide (6 mL) was added. The reaction mixture was stirred at 60° C. overnight and worked up as in Example 20. The crude product (1.7 g) was purified by flash chromatography over silica gel (ethyl acetate-hexane-dichloromethane; 2.5:37.5:60) to afford of 0.277 g of 4-[2-(1 -naphthalenyl)-2-oxoethoxy]-alpha-oxobenzeneacetic acid methyl ester. Crystallization of the ester from ethyl acetate-hexane gave the analytical specimen, mp 99°-100.5° C.
Reaction SMILES: [CH:1]([C:3]1[CH:12]=[CH:11][CH:10]=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6])=[O:2].S([CH2:23][N+:24]#[C-:25])(C1C=CC(C)=CC=1)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>CO>[O:2]1[C:1]([C:3]2[CH:12]=[CH:11][CH:10]=[CH:9][C:4]=2[C:5]([O:7][CH3:8])=[O:6])=[CH:25][N:24]=[CH:23]1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: COC(=O)c1ccccc1C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: COC(=O)c1ccccc1-c1cnco1
Yield: 21.5 %

Procedure:
To a solution of methyl 2-formylbenzoate (15 g) and tosylmethyl isocyanide (18 g) in methanol (250 mL) was added potassium carbonate (15 g), and the mixture was heated under reflux for 16 hr. The reaction mixture was concentrated under reduced pressure, the residue was diluted with ethyl acetate, and the mixture was washed with water and saturated brine. The extract was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/petroleum ether) to give the title compound (4.0 g).