Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:17][CH2:16][C@@H:15]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:14][C@H:13]1[CH2:26][OH:27])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:35]1([N:41]=[C:42]=[O:43])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>ClCCl.CN(C)C=O>[CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:17][CH2:16][C@@H:15]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:22])([CH3:23])[CH3:24])[CH2:14][C@H:13]1[CH2:26][O:27][C:42](=[O:43])[NH:41][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C=Nc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@H](NC(=O)OCc2ccccc2)[C@H](CO)C1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H]1CC[C@H](NC(=O)OCc2ccccc2)[C@H](COC(=O)Nc2ccccc2)C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of tert-butyl(1R,3R,4S)-4-benzyloxycarbonylamino-3-(hydroxymethyl)cyclohexylcarbamate (75 mg) in dichloromethane (1 mL) and N,N-dimethylformamide (0.1 mL) was-treated with triethylamine (3 μL) and phenyl isocyanate (33 μL), and the mixture was and stirred at rt for 18 h. Additional phenyl isocyanate (22 μL) was added and stirring was continued for 96 h. The mixture was concentrated, and the residue was purified by flash column chromatography on silica gel, eluting with 4:6 v/v ethyl acetate/hexane, to provide tert-butyl(1R,3R,4S)-(4-benzyloxycarbonylamino-3-phenylcarbamoyloxymethylcyclohexyl)carbamate as a white glassy foam (85 mg). MS found: (M+H)+=498.3.
Reaction SMILES: [SH:1][C:2]1[S:3][C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)=[N:5][N:6]=1.[OH-].[K+].[F:15][CH2:16][F:17]>O1CCOCC1.O.[I-].[K+].[Br-].C([NH+](CCCC)CCCC)CCC>[F:15][CH:16]([F:17])[S:1][C:2]1[S:3][C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)=[N:5][N:6]=1
Reactant: FCF
Reactant: Sc1nnc(-c2ccccn2)s1
Agent: CCCC[NH+](CCCC)CCCC
Agent: [Br-]
Agent: [I-]
Solvent: O
Solvent: C1COCCO1
Product: FC(F)Sc1nnc(-c2ccccn2)s1
Yield: 15.3 %

Procedure:
A suspension of 341.5 g (l.75 mol) of 2-mercapto-5-pyrid-2-yl-1,3,4-thiadiazole in 4000 ml of dioxane is added to a solution of 230.5 g of 85% potassium hydroxide in 800 ml of water. Then 10 g of potassium iodide and 6 g of tributylammonium bromide are added to the reaction mixture and 750 g (~8.6 mol) of gaseous difluoromethane are introduced over 41/2 hours at 22°-37° C. After evaporating off the dioxane, the reaction mixture is diluted with ethyl acetate, the aqueous phase is separated and the organic solution is washed cold with 1N sodium hydroxide and water, dried over sodium sulfate and clarified with activated carbon. They ethyl acetate is removed under vacuum and the residue is crystallised from ethyl acetate/hexane, affording 321.9 g (75.1%) of the title compound with a melting point of 90°-92° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([NH:8][C:9]2[CH:26]=[CH:25][C:12]([CH2:13][CH2:14][N:15]3[CH2:20][CH2:19][CH:18]([C:21]([O:23]C)=[O:22])[CH2:17][CH2:16]3)=[CH:11][CH:10]=2)=[N:6][CH:7]=1.[Li+].[OH-].Cl.[O-]S([O-])(=O)=O.[Na+].[Na+]>C1COCC1.CO.O.C1COCC1>[Br:1][C:2]1[CH:3]=[N:4][C:5]([NH:8][C:9]2[CH:26]=[CH:25][C:12]([CH2:13][CH2:14][N:15]3[CH2:20][CH2:19][CH:18]([C:21]([OH:23])=[O:22])[CH2:17][CH2:16]3)=[CH:11][CH:10]=2)=[N:6][CH:7]=1
Reactant: COC(=O)C1CCN(CCc2ccc(Nc3ncc(Br)cn3)cc2)CC1
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)C1CCN(CCc2ccc(Nc3ncc(Br)cn3)cc2)CC1

Procedure:
Crude methyl 1-(4-(5-bromopyrimidin-2-ylamino)phenethyl)piperidine-4-carboxylate 20 is suspended in THF/MeOH/H2O (3:2:1, 10 mL) and 6N LiOH (9.3 mmol) and stirred at rt for 2 h. After neutralization to pH 6 by addition of HCl (1N), the solvent is removed under vacuum to give a solid which is dissolved in THF (20 mL). To the above suspension, excess Na2SO4 is added and filtered. The filtrate is concentrated to yield 1-(4-(5-bromopyrimidin-2-ylamino)phenethyl)piperidine-4-carboxylic acid 21. 1H NMR (400 MHz, d6-DMSO) δ 9.87 (s, 1H), 9.39 (bs, 1H), 8.59 (s, 2H), 7.66 (d, J=8.4 Hz, 2H), 7.20 (d, J=8.4 Hz, 2H), 3.58-3.64 (m, 2H), 3.48-3.28 (m, 1H), 3.22-3.27 (m, 2H), 2.88-3.03 (m, 4H), 2.05-2.15 (m, 2H), 1.66-1.80 (m, 2H). MS (m/z) (M+1)+: 405.1, 407.1.
Reaction SMILES: [CH3:1][S:2]([O:5][C:6](=[O:8])C)(=[O:4])=[O:3].[O:9]1[CH2:14]COOO1.C(OCOCOC(=O)C)(=O)C>>[CH3:1][S:2]([O:5][CH2:6][O:8][CH2:14][O:9][S:2]([CH3:1])(=[O:4])=[O:3])(=[O:4])=[O:3]
Reactant: CC(=O)OS(C)(=O)=O
Reactant: C1COOOO1
Agent: CC(=O)OCOCOC(C)=O
Product: CS(=O)(=O)OCOCOS(C)(=O)=O
Yield: 67 %

Procedure:
Using the procedure of Example 2, acetyl methanesulfonate and tetroxane, in a molar ratio of 2:1, were reacted for 18-24 hours at 90° C. and 0.5 mm. pressure allowing the bis(acetoxymethyl) ether to distill. The residual oil was recrystallized from a small volume of dry tetrahydrofuran to give a 67% yield of CH3SO3CH2OCH2OSO2CH3.
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]([O:10]C(C)C)=[O:9])=[C:6]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=2)[C:5]([C:23]([O:25][CH:26]([CH3:28])[CH3:27])=[O:24])=[C:4]([CH3:29])[N:3]=1.[OH-].[K+]>C(O)C.O>[CH:26]([O:25][C:23]([C:5]1[C:4]([CH3:29])=[N:3][C:2]([CH3:1])=[C:7]([C:8]([OH:10])=[O:9])[C:6]=1[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=1)=[O:24])([CH3:28])[CH3:27]
Reactant: Cc1nc(C)c(C(=O)OC(C)C)c(-c2cccc([N+](=O)[O-])c2)c1C(=O)OC(C)C
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1nc(C)c(C(=O)OC(C)C)c(-c2cccc([N+](=O)[O-])c2)c1C(=O)O

Procedure:
1 g (2.5 mmols) of diisopropyl 2,6-dimethyl-4-(3-nitrophenyl)pyridine-3,5-dicarboxylate was heated under reflux for 5 hours in a solution of 140 mg (2.5 mmols) of potassium hydroxide in 10 ml of ethanol and 1 ml of water. After cooling down, the mixture was evaporated to dryness, the residue was taken up in water and extracted several times with chloroform. The aqueous phase was adjusted to pH 3 to 4 with dilute hydrochloric acid, the precipitated product was filtered off with suction and dissolved again with saturated sodium bicarbonate solution. After adding a little animal charcoal, the mixture was filtered and the filtrate was adjusted to pH 3 to 4 with dilute hydrochloric acid. The precipitated product was filtered off with suction and dried in vacuo.
Reaction SMILES: Cl[CH: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:21]=[CH:20][C:19]2[C:14](=[N:15][C:16]([Cl:22])=[CH:17][CH:18]=2)[N:13]=1.Cl.[CH3:24][N:25]1[CH2:30][CH2:29][CH:28]([C:31]([OH:33])=[O:32])[CH2:27][CH2:26]1.N12CCCN=C1CCCCC2>CN(C)C=O>[CH3:24][N:25]1[CH2:30][CH2:29][CH:28]([C:31]([O:33][CH:2]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[C:4](=[O:11])[N:3]2[C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[N:15][C:16]([Cl:22])=[CH:17][CH:18]=3)[N:13]=2)=[O:32])[CH2:27][CH2:26]1
Reactant: CN1CCC(C(=O)O)CC1
Reactant: O=C1c2ccccc2C(Cl)N1c1ccc2ccc(Cl)nc2n1
Agent: Cl
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: CN1CCC(C(=O)OC2c3ccccc3C(=O)N2c2ccc3ccc(Cl)nc3n2)CC1
Yield: 42.7 %

Procedure:
Working as in Example 1, but starting with 3-chloro-2-(7-chloro-1,8-naphthyridin-2-yl)-1-isoindolinone (9.9 g) in anhydrous dimethylformamide (100 cc), 1methyl-4-piperidinecarboxylic acid hydrochloride (5.4 g) and 1,8-diazabicyclo[5.4.0]undec-7-ene (10.7g), and after the residue obtained has been recrystallized twice successively in ethanol and then in acetonitrile, 2-(7-chloro-1,8-naphthyridin-2-yl)-1-oxo-3-isoindolinyl 1-methyl-4-piperidinecarboxylate (5.6 g), m.p. 136° C. and then 157° C., is obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:25]=[CH:24][C:6]([O:7][C:8]2[C:16]([S:17](=[O:20])(=[O:19])[NH2:18])=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]=2[N+:21]([O-])=O)=[CH:5][CH:4]=1.[N+](C1C=C(C=C(S(=O)(=O)N)C=1OC1C=CC=CC=1)C(O)=O)([O-])=O>>[NH2:21][C:9]1[CH:10]=[C:11]([CH:15]=[C:16]([S:17](=[O:20])(=[O:19])[NH2:18])[C:8]=1[O:7][C:6]1[CH:24]=[CH:25][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[C:12]([OH:14])=[O:13]
Reactant: COc1ccc(Oc2c([N+](=O)[O-])cc(C(=O)O)cc2S(N)(=O)=O)cc1
Agent: NS(=O)(=O)c1cc(C(=O)O)cc([N+](=O)[O-])c1Oc1ccccc1
Product: COc1ccc(Oc2c(N)cc(C(=O)O)cc2S(N)(=O)=O)cc1

Procedure:
By substituting 4-(p-methoxyphenoxy)-3-nitro-5-sulphamyl-benzoic acid (7 g) for the 3-nitro-4-phenoxy-5-sulphamyl-benzoic acid of Example 1 B, the above compound was obtained with a melting point of 260°-261°C.
Reaction SMILES: [CH2:1]([O:8][NH:9][C:10](=O)[CH:11]=[CH:12][S:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Br)(Br)(Br)[Br:22].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(#N)C>[CH2:1]([O:8][N:9]=[C:10]([Br:22])[CH:11]=[CH:12][S:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrC(Br)(Br)Br
Reactant: O=C(C=CSc1ccccc1)NOCc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: BrC(C=CSc1ccccc1)=NOCc1ccccc1
Yield: 90.1 %

Procedure:
Pyridine (2.7 ml) was added to THF (80 ml) solution of 3-(phenylthio)acryloyl chloride (3.0 g) and hydrochloric acid salt of O-benzylhydroxylamine (2.6 g) under ice-cooling and stirred at the same temperature for one hour and at room temperature for three hours. The reaction mixture was concentrated under reduced pressure. Chloroform (150 ml) was added to the residue, washed successively with 1N hydrochloric acid, pure water and aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane:ethyl acetate 2:1) to obtain N-benzyloxy-3-(phenylthio)acrylamide (3.5 g) as colorless oil. N-benzyloxy-3-(phenylthio)acrylamide (1.0 g) was dissolved to acetonitrile (70 ml), carbon tetrabromide (2.3 g) and triphenylphosphine (1.8 g) were added thereto under ice-cooling, then heat refluxing for four hours. The reaction mixture was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane:ethyl acetate20:1) to obtain N-benzyloxy-3-(phenylthio)acrylimidoyl bromide (1.1 g) as light yellow oil.
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH:4]([OH:6])[CH2:3]1.C(N(C(C)C)CC)(C)C.[CH2:16]([S:19](Cl)(=[O:21])=[O:20])[CH2:17][CH3:18].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>ClCCl>[CH2:16]([S:19]([N:2]1[CH2:5][CH:4]([OH:6])[CH2:3]1)(=[O:21])=[O:20])[CH2:17][CH3:18]
Reactant: CCCS(=O)(=O)Cl
Reactant: OC1CNC1
Agent: Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCS(=O)(=O)N1CC(O)C1
Temperature: 25 °C
Yield: 36.5 %

Procedure:
To a cooled solution (0-5° C.) of azetidin-3-ol hydrochloride (1 g, 9.13 mmol) in 10 ml dichloromethane containing diisopropyl ethyl amine (2,391 ml, 13.69 mmol) was added dropwise a solution of propane-1-sulfonyl chloride (1,126 ml, 10.04 mmol) dissolved in 5 ml dichloromethane over an 1 h period. The mixture was allowed to warm up to room temperature and was stirred over night. Citric acid (10%) was added, extracted with dichloromethane, dried over MgSO4, filtered and the solvent was evaporated to obtain 597 mg of a yellow oil, which was purified by chromatography (yield 470 mg)
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[C:7]1[CH:12]=[C:11]([Cl:13])[N:10]=[C:9](Cl)[CH:8]=1)([CH3:4])([CH3:3])[CH3:2].CN1C(=O)CCC1.[CH2:23]([Mg]Cl)[CH:24]([CH3:26])[CH3:25]>C1COCC1>[C:1]([O:5][C:6](=[O:15])[C:7]1[CH:8]=[C:9]([CH2:23][CH:24]([CH3:26])[CH3:25])[N:10]=[C:11]([Cl:13])[CH:12]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)C[Mg]Cl
Reactant: CC(C)(C)OC(=O)c1cc(Cl)nc(Cl)c1
Solvent: CN1CCCC1=O
Solvent: C1CCOC1
Product: CC(C)Cc1cc(C(=O)OC(C)(C)C)cc(Cl)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
To a solution of 2,6-dichloro-isonicotinic acid tert.-butyl ester (1.74 g, 7.0 mmol), Fe(acac)3 (706 mg, 2.0 mmol) and NMP (1.0 g, 10 mmol) in THF (250 mL), a solution of isobutylmagnesium chloride (1.15 g, 9.8 mmol) in THF is slowly added at −77° C. The brown solution turns turbid and black. Stirring is continued for 1 h at −72° C. before it is warmed to rt. The mixture is again cooled to −40° C. and then stirred for 16 h. The reaction is carefully quenched with 0.5 N aq. HCl (100 mL) and diluted with ether. The org. layer is separated and the aq. phase is extracted five more times with ether. The combined org. extracts are dried over MgSO4, filtered and evaporated. The crude product is purified by MPLC on silica gel to give 2-chloro-6-isobutylisonicotinic acid tert.-butyl ester as a pale yellow oil (1.70 g) which contains 2,6-di-isobutylisonicotinic acid tert.-butyl ester as an impurity; LC-MS: tR=1.12 min, [M+1]+=270.07.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[C:6]([OH:8])=O.[CH3:9][C:10]1[N:11]=[C:12]([NH2:21])[S:13][C:14]=1[CH2:15][CH2:16][O:17][N+:18]([O-:20])=[O:19]>>[CH3:9][C:10]1[N:11]=[C:12]([NH:21][C:6]([CH:2]2[CH2:3][CH2:4][CH2:5][NH:1]2)=[O:8])[S:13][C:14]=1[CH2:15][CH2:16][O:17][N+:18]([O-:20])=[O:19]
Reactant: O=C(O)C1CCCN1
Reactant: Cc1nc(N)sc1CCO[N+](=O)[O-]
Product: Cc1nc(NC(=O)C2CCCN2)sc1CCO[N+](=O)[O-]
Yield: 55 %

Procedure:
Pet-160 was prepared according to the general procedure described hereinabove and the procedure described above for the preparation of Pet-154, using pyrrolidine-2-carboxylic acid and 4-methyl-5-(2-nitrooxy-ethyl)-thiazol-2-ylamine (Pet-10) as the starting materials, in an overall yield of 55%.
Reaction SMILES: F[CH:2]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]2[NH:34][N:33]=[N:32][N:31]=2)[CH:25]=1)[C:3]1[CH:23]=[CH:22][C:6]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15](=[O:17])[CH3:16])=[C:11]([OH:18])[C:10]=2[CH2:19][CH2:20][CH3:21])=[CH:5][CH:4]=1.[C:35](C1C=CC(OCC2C=CC(C(OC)C3C=C(C=CC=3)C#N)=CC=2)=C(CCC)C=1O)(=[O:37])C>>[OH:18][C:11]1[C:10]([CH2:19][CH2:20][CH3:21])=[C:9]([O:8][CH2:7][C:6]2[CH:22]=[CH:23][C:3]([CH:2]([O:37][CH3:35])[C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]4[NH:31][N:32]=[N:33][N:34]=4)[CH:25]=3)=[CH:4][CH:5]=2)[CH:14]=[CH:13][C:12]=1[C:15](=[O:17])[CH3:16]
Reactant: CCCc1c(OCc2ccc(C(OC)c3cccc(C#N)c3)cc2)ccc(C(C)=O)c1O
Reactant: CCCc1c(OCc2ccc(C(F)c3cccc(-c4nnn[nH]4)c3)cc2)ccc(C(C)=O)c1O
Product: CCCc1c(OCc2ccc(C(OC)c3cccc(-c4nnn[nH]4)c3)cc2)ccc(C(C)=O)c1O
Yield: 47 %

Procedure:
The title compound is prepared essentially as described for 1-[4-(4-{fluoro-[3-(1H-tetrazol-5-yl)-phenyl]-methyl}-benzyloxy)-2-hydroxy-3-propyl-phenyl]-ethanone, employing 3-{[4-(4-acetyl-3-hydroxy-2-propyl-phenoxymethyl)-phenyl]-methoxy-methyl}-benzonitrile to give (129 mg, 47%) of the title compound as a lavender foam. 1H NMR (DMSO-d6) δ 12.85 (s, 1H), 8.12 (s, 1H), 7.93 (m, 1H), 7.80 (d, 1H), 7.59 (d, 2H), 7.42-7.49 (m, 4H), 6.71 (d, 1H), 5.50 (s, 1H), 5.25 (s, 2H), 2.57-2.61 (m, 5H), 2.09 (s, 3H), 1.47-1.56 (m, 2H), 0.84-0.92 (m, 3H). LCMS M−1 471.
Reaction SMILES: [C:1]([O:5][C:6](=[O:39])[CH:7]([CH2:28][N:29](CC1C=CC=CC=1)[CH2:30][CH3:31])[CH2:8][C:9]1([C:14](=[O:27])[NH:15][C@H:16]2[CH2:21][CH2:20][C@@H:19]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:18][CH2:17]2)[CH2:13][CH2:12][CH2:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2]>[OH-].[OH-].[Pd+2].C(O)C>[C:1]([O:5][C:6](=[O:39])[CH:7]([CH2:28][NH:29][CH2:30][CH3:31])[CH2:8][C:9]1([C:14](=[O:27])[NH:15][C@H:16]2[CH2:17][CH2:18][C@@H:19]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:20][CH2:21]2)[CH2:13][CH2:12][CH2:11][CH2:10]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)[C@H]1CC[C@@H](NC(=O)C2(CC(CN(CC)Cc3ccccc3)C(=O)OC(C)(C)C)CCCC2)CC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CCNCC(CC1(C(=O)N[C@H]2CC[C@@H](C(=O)OCC)CC2)CCCC1)C(=O)OC(C)(C)C
Yield: 83.7 %

Procedure:
2-(N-Benzyl-N-ethylaminomethyl)-3-{1-[(cis-4-ethoxycarbonylcyclohexyl)carbamoyl]cyclopentyl}-propanoic acid t-butyl ester (3.38 g, 6.2 mmole) was dissolved in, ethanol (70 ml) and hydrogenated at 30 p.s.i. (2 bar) over 20% palladium hydroxide on carbon at room temperature for 16 hours. The catalyst was removed by filtration through an Arbacell pad and the filtrate evaporated under vacuum. The residue was chromatographed on silica eluting with methanol-dichloromethane mixtures to give the title compound as an oil (2.35 g, 83%). Found: C,65.51; H,9.57; N,6.14. C25H44N2O5.0.1 CH2Cl2 requires C,65.37; H,9.66; N,6.08%.
Reaction SMILES: [O:1]1[CH:5]2[C:6]([O:8][C:9](=[O:10])[CH:2]1[CH2:3][CH2:4]2)=O.[NH2:11][CH2:12][CH2:13][CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][N:19]([C:22]2[N:27]=[CH:26][CH:25]=[CH:24][N:23]=2)[CH2:18][CH2:17]1>C1(C)C=CC=CC=1>[N:23]1[CH:24]=[CH:25][CH:26]=[N:27][C:22]=1[N:19]1[CH2:20][CH2:21][N:16]([CH2:15][CH2:14][CH2:13][CH2:12][N:11]2[C:6](=[O:8])[CH:5]3[O:1][CH:2]([CH2:3][CH2:4]3)[C:9]2=[O:10])[CH2:17][CH2:18]1
Reactant: NCCCCN1CCN(c2ncccn2)CC1
Reactant: O=C1OC(=O)C2CCC1O2
Solvent: Cc1ccccc1
Product: O=C1C2CCC(O2)C(=O)N1CCCCN1CCN(c2ncccn2)CC1

Procedure:
Tetrahydrofuran-2,5-dicarboxylic anhydride (1.5 g., 10 mmole) was dissolved in 150 ml. of toluene in a 500 ml. round bottom flask equipped with a Dean-Stark trap and condenser. 1-(4-Aminobutyl)-4-(2-pyrimidinyl)piperazine (2.59 g., 11 mmole) was added and the mixture was refluxed for 24 hours. When the analysis failed to detect the expected product, the solvent was removed in vacuum and replaced with xylene. Reflux was continued for 48 hours. The solvent was then removed in vacuum and the residue column chromatographed on 100 g. of silica gel using a gradient elution from pure chloroform to 5% ethanol/chloroform. The relevant fractions were combined and concentrated in vacuum and the product crystallized from isopropanol with the addition of 4N HCl/isopropanol. 1.2 Grams of the title compound was obtained as the dihydrochloride; m.p. 221°-222° C.
Reaction SMILES: [C:1]([N:4]([CH2:17][C:18]1[O:19][C:20]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[C:21]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:22]=1)[C:5]1[CH:6]=[C:7]([CH:14]=[CH:15][CH:16]=1)[O:8][CH2:9][C:10]([O:12]C)=[O:11])(=[O:3])[CH3:2].O[Li].O>CO>[C:1]([N:4]([CH2:17][C:18]1[O:19][C:20]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[C:21]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:22]=1)[C:5]1[CH:6]=[C:7]([CH:14]=[CH:15][CH:16]=1)[O:8][CH2:9][C:10]([OH:12])=[O:11])(=[O:3])[CH3:2]
Reactant: COC(=O)COc1cccc(N(Cc2nc(-c3ccccc3)c(-c3ccccc3)o2)C(C)=O)c1
Agent: [Li]O
Solvent: O
Solvent: CO
Product: CC(=O)N(Cc1nc(-c2ccccc2)c(-c2ccccc2)o1)c1cccc(OCC(=O)O)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 88.7 %

Procedure:
A mixture of methyl [3-[N-acetyl-[(4,5-diphenyl-2-oxazolyl)methyl]amino]phenoxy]acetate (0.58 g, 1.3 mmol), LiOH.H2O (0.05 g, 1.3 mmol) and MeOH (30 mL) was stirred at room temperature for about 15 hours before adding LiOH.H2O (0.05 g, 1.3 mmol). After about 1 hour, the solvent was evaporated, the residue diluted with 1N HC1 solution and extracted with CH2Cl2. The combined extracts were washed with saturated NaCl solution, dried over MgSO4 and concentrated in vacuo to leave [3-[N-acetyl-[(4,5-diphenyl-2-oxazolyl) methyl]amino]phenoxy]acetic acid (0.51 g, 91%), mp 75-80° C. IR (KBr) 2500 (CO2H), 1740 (CO2H), 1660 (NCOCH3) cm-1 ; 1H NMR (CDCl3) δ1.95 (3H, s, COCH3), 4.55 (2H, s, OCH2), 5.11 (2H, s, NCH2) 6.70-6.95 (3H, m, aromatic H) , 7.25-7.40 (7H, m, aromatic H) , 7.45-7.65 (4H, m, aromatic H); MS m/z 443 (MH+).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[C:14]2[C:9](=[C:10]([F:16])[C:11]([F:15])=[CH:12][CH:13]=2)[NH:8][N:7]=1)=[O:4].[NH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1>C(#N)C>[F:15][C:11]1[C:10]([F:16])=[C:9]2[C:14]([C:6]([NH:5][C:3](=[O:4])[CH2:2][N:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)=[N:7][NH:8]2)=[CH:13][CH:12]=1
Reactant: O=C(CCl)Nc1n[nH]c2c(F)c(F)ccc12
Reactant: C1CCNCC1
Solvent: CC#N
Product: O=C(CN1CCCCC1)Nc1n[nH]c2c(F)c(F)ccc12

Procedure:
The process is performed as in Example 75, starting with 8.5 g of 2-chloro-N-(6,7-difluoro-1H-indazol-3-yl)acetamide, 200 cm3 of acetonitrile and 8.8 cm3 of piperidine. The reaction medium is refluxed for 1 hour, the precipitate formed is then filtered off on a sinter funnel and the crystals are taken up in 200 cm3 of ethyl acetate and 100 cm3 of water. The organic phase is separated out after settling of the phases has taken place, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2 kPa; 50° C.). The crude product is purified by chromatography under an argon pressure of 50 kPa, on a column of silica gel (particle size 40-60 μm; diameter 3.5 cm), eluting with ethyl acetate. The fractions containing the expected product are combined and evaporated under reduced pressure (2 kPa; 50° C.); the residue is recristallized from a mixture of 50 cm3 of cyclohexane and 16 cm3 of ethyl acetate, filtered off and dried (90 Pa; 45° C.) to give 3.2 g of N-(6,7-difluoro-1H-indazol-3-yl)-1-piperidineacetamide in the form of white crystals melting at 158° C.
Reaction SMILES: [C:1]([CH2:9][C:10]([O:12]CC)=O)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:15]1([NH:21][NH2:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(O)C>[C:15]1([N:21]2[C:10](=[O:12])[CH2:9][C:1]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[N:22]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CCOC(=O)CC(=O)c1ccccc1
Reactant: NNc1ccccc1
Solvent: CCO
Product: O=C1CC(c2ccccc2)=NN1c1ccccc1
Yield: 40.2 %

Procedure:
According to General Procedure A; ethyl benzoylacetate (12.2 mL, 71.2 mmol, 1.1 equ.) in ethanol (130 mL) was treated at 0° C. with phenylhydrazine (7.00 g, 71.2 mmol, 1.0 equ.) to give 1,3-diphenyl-1H-pyrazol-5(4H)-one (6.75 g, 28.6 mmol, 44%) after purification by column chromatography on silica gel (hexanes:ethyl acetate; 4:1) and crystallization (ethanol) as a white off solid. 1H-NMR (400 MHz) DMSO: 11.84 (s, 1H), 7.84-7.82 (d, 4H), 7.50-7.40 (m, 4H), 7.34-7.27 (m, 2H), 6.02 (s, 1H), 13C-NMR (100 MHz) DMSO: 154.2, 150.0, 139.3, 133.8, 129.3, 129.0, 128.2, 126.1, 125.5, 121.5, 85.5; LC/MS-MS: 237.0→77.1 m/z; GS1 and GS2 at 30, DP=81, CE=68, CXP=4, tR=4.15 min.
Reaction SMILES: Br[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1)=[O:4].C(=O)([O-])[O-].[K+].[K+].[CH3:18][O:19][C:20]1[CH:21]=[C:22]2[C:27](=[CH:28][CH:29]=1)[N:26]=[CH:25][N:24]=[C:23]2[O:30][CH2:31][CH:32]1[CH2:37][CH2:36][CH:35]([NH2:38])[CH2:34][CH2:33]1>CN(C=O)C>[CH3:18][O:19][C:20]1[CH:21]=[C:22]2[C:27](=[CH:28][CH:29]=1)[N:26]=[CH:25][N:24]=[C:23]2[O:30][CH2:31][CH:32]1[CH2:37][CH2:36][CH:35]([NH:38][CH2:2][C:3]([NH:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=2)=[O:4])[CH2:34][CH2:33]1
Reactant: COc1ccc2ncnc(OCC3CCC(N)CC3)c2c1
Reactant: O=C(CBr)Nc1ccccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc2ncnc(OCC3CCC(NCC(=O)Nc4ccccn4)CC3)c2c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
2-Bromo-N-pyridin-2-yl-acetamide (0.075 g, 0.35 mmol) and potassium carbonate (0.054 g, 0.39 mmol) were added to a solution of 4-(6-methoxy-quinazolin-4-yloxymethyl)-cyclohexylamine (0.1 g, 0.35 mmol) in DMF (3.5 ml). The reaction mixture was stirred at room temperature for 2 days and then concentrated to dryness by rotary evaporation. The residue was purified by column chromatography on silica gel (dichloromethane/MeOH 19/1 1% NH4OH).
Reaction SMILES: CC(O[C:6](=O)[N:7]([CH2:9][CH2:10][NH:11][C:12]1[CH:21]=[N:20][C:19]2[C:14](=[CH:15][C:16]([F:23])=[C:17]([F:22])[CH:18]=2)[N:13]=1)C)(C)C.[ClH:25]>CO.O1CCOCC1>[ClH:25].[ClH:25].[F:22][C:17]1[CH:18]=[C:19]2[C:14](=[CH:15][C:16]=1[F:23])[N:13]=[C:12]([NH:11][CH2:10][CH2:9][NH:7][CH3:6])[CH:21]=[N:20]2
Reactant: CN(CCNc1cnc2cc(F)c(F)cc2n1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CNCCNc1cnc2cc(F)c(F)cc2n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 100 %

Procedure:
An ice-cooled solution of [2-(6,7-difluoro-quinoxalin-2-ylamino)-ethyl]-methyl-carbamic acid dimethyl-ethyl ester, D1 (500 mg, 1.48 mmol) in methanol (20 ml) was treated with HCl in dioxane (4M solution, 4 ml). After stirring under argon at room temperature for 4 h the volatiles were removed in vacuo and the residue was triturated with diethyl ether to afford the title compound as a beige powder (100%).
Reaction SMILES: [O:1]=[CH:2][C@H:3]([C@@H:5]([C@@H:7]([C@H:9]([CH3:11])[OH:10])[OH:8])[OH:6])[OH:4].O=C[C@H]([C@@H]([C@@H](CO)O)O)O>>[OH:1][CH2:2][C:3]([C@@H:5]([C@@H:7]([C@H:9]([CH3:11])[OH:10])[OH:8])[OH:6])=[O:4]
Reactant: C[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)C=O
Agent: O=C[C@@H](O)[C@H](O)[C@H](O)CO
Product: C[C@H](O)[C@@H](O)[C@@H](O)C(=O)CO

Procedure:
Under the following reaction conditions, L-fucose (6-deoxy L-galactose) was isomerized with D-arabinose isomerase, to produce 6-deoxy L-tagatose.