Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][N:6]=[C:5]2[NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([Br:19])[CH:14]=1.[C:20]1(=[O:26])[O:25][C:23](=[O:24])[CH:22]=[CH:21]1>CN(C=O)C.O>[Br:19][C:15]1[CH:14]=[C:13]([NH:12][C:5]2[C:4]3[C:9](=[CH:10][CH:11]=[C:2]([NH:1][C:20]([CH:21]=[CH:22][C:23]([OH:25])=[O:24])=[O:26])[CH:3]=3)[N:8]=[CH:7][N:6]=2)[CH:18]=[CH:17][CH:16]=1
Reactant: O=C1C=CC(=O)O1
Reactant: Nc1ccc2ncnc(Nc3cccc(Br)c3)c2c1
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)C=CC(=O)Nc1ccc2ncnc(Nc3cccc(Br)c3)c2c1
Temperature: 70 °C
Reaction time: 2.5 h
Yield: 84.2 %

Procedure:
To a solution of 6-amino-4-[(3-bromophenyl)amino]-quinazoline (0.78 g, 2.5 mmol) in 8 mL of DMF was added maleic anhydride (0.266 g, 2.7 mmol), and the mixture was heated with stirring in a 70° C. oil bath for 2.5 hours. The resulting suspension was cooled to room temperature and then diluted with water. The solid was collected, washed sequentially with a mixture of toluene/DMF (1:1), water, and IPA. The solid was dried in vacuo at 60° C. for 16 hours to afford 3-[4-(3-bromo-phenylamino)-quinazolin-6-ylcarbamoyl]-acrylic acid (Z) (0.87 g, 86%) as a pale yellow powder, mp 224-225° C. (decomposition with gas evolution).
Reaction SMILES: [O:1]1[C:6]2=[CH:7][C:8]3[C:9](=[O:15])[C:10](=[O:14])[NH:11][C:12]=3[CH:13]=[C:5]2[O:4][CH2:3][CH2:2]1.[H-].[Na+].Br[CH2:19][C:20]1[O:21][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:23][CH:24]=1>CN(C)C=O>[F:26][C:25]([F:28])([F:27])[C:22]1[O:21][C:20]([CH2:19][N:11]2[C:12]3[CH:13]=[C:5]4[O:4][CH2:3][CH2:2][O:1][C:6]4=[CH:7][C:8]=3[C:9](=[O:15])[C:10]2=[O:14])=[CH:24][CH:23]=1
Reactant: O=C1Nc2cc3c(cc2C1=O)OCCO3
Reactant: FC(F)(F)c1ccc(CBr)o1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1C(=O)N(Cc2ccc(C(F)(F)F)o2)c2cc3c(cc21)OCCO3
Reaction time: 0.33 h
Yield: 77.9 %

Procedure:
To a stirred solution of 2,3-dihydro-6H-[1,4]dioxino[2,3-f]indole-7,8-dione (Lackey and Sternbach, Synthesis 1993:993-997) (3.08 g, 15.0 mmol) in dry N,N-dimethylformamide (150 mL) was added sodium hydride (0.9 g, 60% in mineral oil, 22.5 mmol) at ambient temperature. The deep purple mixture was stirred for 20 min followed by the addition of 2-(bromomethyl)-5-(trifluoromethyl)furan (3.80 g, 16.5 mmol) in one portion. The dark solution was stirred at ambient temperature for 1 h and concentrated in vacuo to dryness. The residue was mixed with water (150 mL) and stirred. The fine orange precipitation was filtered off and dried to afford 6-{[5-(trifluoromethyl)furan-2-yl]methyl}-2,3-dihydro-6H-[1,4]dioxino[2,3-f]indole-7,8-dione (4.13 g, 78%): 1H NMR (300 MHz, CDCl3) δ7.18 (s, 1H), 6.76-6.73 (m, 1H), 6.48 (s, 1H), 6.45-6.40 (m, 1H), 4.85 (s, 2H), 4.42-4.32 (m, 2H), 4.28-4.20 (m, 2H).
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([CH2:14][C:15]#[N:16])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si]([N:21]=[N+:22]=[N-:23])(C)C.C([Sn](=O)CCCC)CCC.[OH-].[Na+]>C1(C)C=CC=CC=1>[O:1]([C:8]1[CH:9]=[CH:10][C:11]([CH2:14][C:15]2[NH:23][N:22]=[N:21][N:16]=2)=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: N#CCc1ccc(Oc2ccccc2)cc1
Agent: CCCC[Sn](=O)CCCC
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: c1ccc(Oc2ccc(Cc3nnn[nH]3)cc2)cc1
Temperature: 25 °C

Procedure:
To a solution of 4-phenoxyphenylacetonitrile (1.16 g) in anhydrous toluene (30 ml) was added trimethylsilylazide (1.1 ml) and dibutyltin oxide (0.19 g). The mixture was heated to reflux for 19 hours then allowed to cool to room temperature. The reaction mixture was then added to 1M sodium hydroxide (100 ml) and washed with diethyl ether (3×50 ml). The aqueous layer was acidified with concentrated hydrochloric acid (30 ml) then washed with 5:1 ethyl acetate/tetrahydrofuran (60 ml) and ethyl acetate (2×50 ml). The combined organic layer was dried over anhydrous sodium sulfate, filtered and evaporated to give 5-(4-phenoxyphenylmethyl)-1H-tetrazole as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][N:13]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[CH2:12][C@@H:11]([C:25](OC)=[O:26])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].[Cl-].[BH4-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1>[C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:10][C@@H:11]([CH2:25][OH:26])[CH2:12][N:13]([C:15]([O:17][CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[O:16])[CH2:14]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)[C@H]1C[C@@H](NC(=O)OC(C)(C)C)CN(C(=O)OCc2ccccc2)C1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [BH4-]
Agent: [Cl-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H]1C[C@@H](CO)CN(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of cis (+/−)-1-benzyl 3-methyl 5-(tert-butoxycarbonylamino)piperidine-1,3-dicarboxylate (1.0 eq.) in THF at a concentration of 0.08 M was cooled at 0*C and then LiCl (2.3 eq.) and sodium borohydride (2.3 eq.) were added. After stirring for 20 hours as the reaction warmed to rt, the pH was adjusted with 1M citric acid to pH 4-5. After removal of the volatiles in vacuo, the product was extracted in dichloromethane, washed with H2O and brine, dried over MgSO4. Upon filtering and removal of the volatiles in vacuo, cis (+/−)-benzyl 3-(tert-butoxy-carbonylamino)-5-(hydroxymethyl)piperidine-1-carboxylate was obtained as a white foamy solid. LCMS (m/z): 265.0 (MH-Boc+); LC Rt=3.37 min.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:12]2[CH:17]=[C:16]([CH3:18])[C:15](N)=[CH:14][N:13]=2)[C:10]=1[CH3:11])=[O:5])[CH3:2].N([O-])=O.[Na+].[I-:24].[K+].C(=O)([O-])[O-].[Na+].[Na+]>S(=O)(=O)(O)O.O>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:12]2[CH:17]=[C:16]([CH3:18])[C:15]([I:24])=[CH:14][N:13]=2)[C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnn(-c2cc(C)c(N)cn2)c1C
Reactant: [I-]
Agent: O=C([O-])[O-]
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Solvent: O
Product: CCOC(=O)c1cnn(-c2cc(C)c(I)cn2)c1C
Temperature: 25 °C
Yield: 81.3 %

Procedure:
1-(5-Amino-4-methylpyridin-2-yl)-5-methyl-1H-pyrazole-4-carboxylic acid ethyl ester (1.0 g) was suspended in 20% (v/v) sulfuric acid aqueous solution (75 ml), sodium nitrite (318 mg) was added thereto little by little under ice-cooling with stirring, and then stirred for 40 minutes under ice-cooling. Then, potassium iodide (1.27 g) was dissolved in water (12 ml), and the obtained aqueous solution was slowly added dropwise to the reaction solution under ice-cooling with stirring. After the completion of adding dropwise, the solution was stirred for 3 hours under ice-cooling, and then gradually warmed to room temperature. The reaction solution was poured into 10% sodium carbonate aqueous solution, the precipitated solid was collected by filtration, and dissolved in ethyl acetate. The organic layer was sequentially washed with sodium thiosulfate aqueous solution, water, and saturated brine, dried over anhydrous sodium sulfate, and then the solvent was evaporated to give 1-(5-iodo-4-methylpyridin-2-yl)-5-methyl-1H-pyrazole-4-carboxylic acid ethyl ester (1.16 g) as a brown solid.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:11]([NH:15][CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])=[N:12][O:13][N:14]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:28][C:29]1[CH:38]=[CH:37][C:32]([C:33](=[O:36])[CH2:34]Br)=[CH:31][CH:30]=1>CN(C=O)C.C(OCC)(=O)C>[Cl:28][C:29]1[CH:38]=[CH:37][C:32]([C:33](=[O:36])[CH2:34][N:3]2[C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:1]=[C:2]2[C:10]2[C:11]([NH:15][CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])=[N:12][O:13][N:14]=2)=[CH:31][CH:30]=1
Reactant: O=C(CBr)c1ccc(Cl)cc1
Reactant: COC(=O)CCNc1nonc1-c1nc2ccccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)CCNc1nonc1-c1nc2ccccc2n1CC(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A suspension of 4-(1H-benzimidazol-2-yl)-furazan-3-yl-N-(2-methoxycarbonylethyl)-amine (0.052 g, 0.181 mmol), potassium carbonate (0.062 g, 0.452 mmol) and 4-chlorophenacyl bromide (0.047 g, 0.199 mmol) in DMF (5 ml) is stirred at room temperature for 16 hours. The reaction mixture is diluted with ethyl acetate, washed with water and dried over sodium sulphate. Filtration of the sodium sulphate, concentration of the filtrate under reduced pressure and chromatography of the residue on silicagel using hexane-ethyl acetate as eluent gives the title compound as hygroscopic solid of undefined melting point. 1H-NMR (400 MHz, d6-DMSO): 8.14 (d, 2H); 7.87 (m, 2H); 7.41 (m, 2H); 7.32 (d, 2H); 7.29 (t, 1H); 6.37 (s, 2H); 3.63 (m, 2H); 3.61 (s, 3H); 2.76 (t, 2H).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]([CH3:32])([CH3:31])[C:11]([O:13][C:14]1[C:15]([F:30])=[C:16]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:17]([CH3:23])=[C:18]([C:21]#[N:22])[C:19]=1[NH2:20])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>C(OCC)(=O)C>[CH2:1]([O:8][CH2:9][C:10]([C:11]1[O:13][C:14]2[C:19](=[C:18]([C:21]#[N:22])[C:17]([CH3:23])=[C:16]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:15]=2[F:30])[N:20]=1)([CH3:32])[CH3:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1c(C#N)c(N)c(OC(=O)C(C)(C)COCc2ccccc2)c(F)c1-c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1c(-c2ccccc2)c(F)c2oc(C(C)(C)COCc3ccccc3)nc2c1C#N
Yield: 90.1 %

Procedure:
A mixture of 4-amino-5-cyano-2-fluoro-6-methylbiphenyl-3-yl 3-benzyloxy-2,2-dimethylpropionate (I-64) (390 mg, 0.902 mmol), p-toluenesulfonic acid monohydrate (17 mg, 0.09 mmol) and toluene (16 ml) was heated under reflux for 3 hours. After cooling, the reaction liquid was diluted with ethyl acetate, successively washed with an aqueous saturated sodium hydrogencarbonate solution and saturated brine, dried on anhydrous magnesium sulfate, then the solvent was evaporated away to obtain a pale brown residue. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=20:1→10:1) to obtain the entitled compound (337 mg, 90%) as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[CH2:6][C:7]3[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=3[CH:9]=[CH:10][C:4]=2[CH:3]=1.Cl.Cl.CC([OH:22])C>C(OCC)C>[F:1][C:2]1[CH:16]=[CH:15][C:5]2[CH2:6][C:7]3[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=3[CH:9]3[O:22][CH:10]3[C:4]=2[CH:3]=1
Reactant: Fc1ccc2c(c1)C=Cc1ccccc1C2
Reactant: CC(C)O
Agent: Cl
Solvent: CCOCC
Product: Fc1ccc2c(c1)C1OC1c1ccccc1C2
Yield: 43 %

Procedure:
Compound 1 was dissolved in diethyl ether (20 ml) and converted into the hydrochloric acid salt (1:1) by dropwise addition of 6 N HCl/2-propanol. The solvent was evaporated. The residue was triturated under boiling 2-propanone, filtered off and dried, yielding 2.17 g (43%) of (±)-(2α,3aβ,12bα)-11-fluoro-3,3a,8,12b-tetrahydro N,N-dimethyl-2H-dibenzo[3,4:6,7]cyclohepta[1,2-b]furan-2-methanamine hydrochloride (compound 2; mp. 239. 1° C.).
Reaction SMILES: [F:1][C:2]1[C:3]([CH2:25][N:26](C)[C:27](=O)OC(C)(C)C)=[CH:4][N:5]([S:14]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][OH:24])[CH:18]=2)(=[O:16])=[O:15])[C:6]=1[C:7]1[C:8]([F:13])=[N:9][CH:10]=[CH:11][CH:12]=1.C(OCC)(=O)C.Cl>C(OCC)(=O)C.CC(O)C>[F:1][C:2]1[C:3]([CH2:25][NH:26][CH3:27])=[CH:4][N:5]([S:14]([C:17]2[CH:18]=[C:19]([CH2:23][OH:24])[CH:20]=[CH:21][CH:22]=2)(=[O:16])=[O:15])[C:6]=1[C:7]1[C:8]([F:13])=[N:9][CH:10]=[CH:11][CH:12]=1
Reactant: CN(Cc1cn(S(=O)(=O)c2cccc(CO)c2)c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: CNCc1cn(S(=O)(=O)c2cccc(CO)c2)c(-c2cccnc2F)c1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 50.1 %

Procedure:
To a solution of tert-butyl [(4-fluoro-5-(2-fluoropyridin-3-yl)-1-{[3-(hydroxymethyl)phenyl]sulfonyl}-1H-pyrrol-3-yl)methyl]methylcarbamate (207 mg) in ethyl acetate (3 mL) and 2-propanol (2 mL) was added 4 mol/L hydrogen chloride-ethyl acetate solution (6 mL), and the mixture was stirred at room temperature for 2 hr. The solvent was concentrated under reduced pressure, diluted with ethyl acetate, and washed with saturated aqueous sodium hydrogen carbonate solution. The separated aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluent: hexane-ethyl acetate=4:1→ethyl acetate:methanol=32:1) (basic TLC:Rf=0.1 (ethyl acetate)) to give a free base of the title compound as a pale-yellow oil (yield 82.6 mg). A solution of the obtained free base in ethyl acetate (1 mL) was added dropwise to a solution of fumaric acid (24 mg) in ethanol (1 mL) and the mixture was concentrated under reduced pressure. The residue was recrystallized from ethanol to give the title compound as a white solid (yield 69 mg, 36%).
Reaction SMILES: C=O.[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[CH:12][C:13]([C:16]#[C:17][C:18]3[CH:19]=[C:20]4[C:25](=[CH:26][CH:27]=3)[NH:24][CH:23]([CH2:28][N:29]3[CH2:33][CH2:32][CH2:31][CH2:30]3)[CH2:22][CH2:21]4)=[N:14][CH:15]=2)=[CH:6][CH:5]=1.[C:34]([BH3-])#N.C1(C)C(S(O)(=O)=O)=CC=CC=1>C1COCC1.C(O)(=O)C>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[CH:12][C:13]([C:16]#[C:17][C:18]3[CH:19]=[C:20]4[C:25](=[CH:26][CH:27]=3)[N:24]([CH3:34])[CH:23]([CH2:28][N:29]3[CH2:30][CH2:31][CH2:32][CH2:33]3)[CH2:22][CH2:21]4)=[N:14][CH:15]=2)=[CH:6][CH:5]=1
Reactant: [BH3-]C#N
Reactant: Clc1ccc(-c2ccc(C#Cc3ccc4c(c3)CCC(CN3CCCC3)N4)nc2)cc1
Agent: C=O
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CN1c2ccc(C#Cc3ccc(-c4ccc(Cl)cc4)cn3)cc2CCC1CN1CCCC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
37 mg (1.23 mmol) paraformaldehyde in 1.8 mL THF are added to a solution of 350 mg (0.82 mmol) 6-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-2-pyrrolidin-1-ylmethyl-1,2,3,4-tetrahydro-quinoline (see Example 3.46) in 1.6 mL THF. 0.24 mL acetic acid and 1.2 mL THF are added to this mixture. Finally, 1.00 g (2.05 mmol) cyanoborohydride resin (macroporous polystyrene, load: 2.04 mmol/g) are added and the mixture is stirred for 16 h at RT. After filtration the filtrate is combined with 1.50 g (2.15 mmol) toluenesulphonic acid resin (macroporous polystyrene, load: 1.43 mmol/g), shaken for 30 min and suction filtered. The solvent is eliminated i.vac. and purification is carried out by column chromatography using HPLC-MS.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([C:15]([CH3:20])=[CH:16][C:17]([OH:19])=[O:18])=[CH:11][CH:10]=1>O=[Pt]=O.O1CCOCC1>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([CH:15]([CH3:20])[CH2:16][C:17]([OH:19])=[O:18])=[CH:11][CH:10]=1
Reactant: CC(=CC(=O)O)c1ccc(-c2ccc(F)cc2F)cc1
Agent: O=[Pt]=O
Solvent: C1COCCO1
Product: CC(CC(=O)O)c1ccc(-c2ccc(F)cc2F)cc1

Procedure:
1 g. of 3-(2',4'-difluoro-4-biphenylyl)-2-butenoic acid is dissolved in 25 ml. of dioxane. 0.1 g. of PtO2 is added and the hydrogenation is carried out at 20° under normal pressure until hydrogen absorption has ceased. The mixture is filtered and the filtrate is evaporated to give 3-(2',4'-difluoro-4-biphenylyl)butyric acid, m.p. 109°-110°.
Reaction SMILES: [C:1]([CH2:3][CH2:4][CH:5]1[CH2:9][C:8]2[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=2[O:6]1)#[N:2].[N+:14]([O-])([O-:16])=[O:15].[Na+]>FC(F)(F)C(O)=O>[C:1]([CH2:3][CH2:4][CH:5]1[CH2:9][C:8]2[CH:10]=[C:11]([N+:14]([O-:16])=[O:15])[CH:12]=[CH:13][C:7]=2[O:6]1)#[N:2]
Reactant: O=[N+]([O-])[O-]
Reactant: N#CCCC1Cc2ccccc2O1
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: N#CCCC1Cc2cc([N+](=O)[O-])ccc2O1
Yield: 36.2 %

Procedure:
Starting from 7.5 g (43 mmol) of 2-cyanoethyl-2,3-dihydrobenzofuran in 120 ml of trifluoroacetic acid and 11 g (130 mmol) of sodium nitrate treated under the conditions described in step 6 of Example 7, 3.4 g of product were obtained.
Reaction SMILES: [CH2:1](Br)[C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:3].[C:11]([NH:19][CH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>C(O)(C)C>[CH2:1]([N:23]1[CH2:24][CH2:25][CH:20]([NH:19][C:11](=[O:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:21][CH2:22]1)[C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:3]
Reactant: O=C(NC1CCNCC1)c1ccccc1
Reactant: O=C(CBr)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Product: O=C(CN1CCC(NC(=O)c2ccccc2)CC1)c1ccccc1

Procedure:
Phenacyl bromide (2 g.), 4-benzamidopiperidine (2 g.) and potassium carbonate (2 g.) in isopropanol (25 ml.) were heated under reflux for 2 hours. The resulting solid was filtered, suspended in water and re-filtered to give the product (1.57 g.), m.p. 168° C. (Found: C, 74.4; H, 6.8; N, 8.8. C20H22N2O2 requires C, 74.5; H, 6.9; N, 8.7%).
Reaction SMILES: [O:1]=[C:2]1[C:6](=[CH:7][C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]3)=[CH:10][CH:9]=2)[S:5][C:4]([N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[N:3]1.[NH2:27][CH2:28][C@@H:29]([C:31]1[CH:32]=[CH:33][C:34]([OH:42])=[C:35]([NH:37][S:38]([CH3:41])(=[O:40])=[O:39])[CH:36]=1)[OH:30]>>[OH:42][C:34]1[CH:33]=[CH:32][C:31]([C@@H:29]([OH:30])[CH2:28][NH:27][CH:17]2[CH2:18][CH2:19][N:14]([C:11]3[CH:10]=[CH:9][C:8]([CH:7]=[C:6]4[S:5][C:4]([N:21]5[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]5)=[N:3][C:2]4=[O:1])=[CH:13][CH:12]=3)[CH2:15][CH2:16]2)=[CH:36][C:35]=1[NH:37][S:38]([CH3:41])(=[O:40])=[O:39]
Reactant: CS(=O)(=O)Nc1cc([C@@H](O)CN)ccc1O
Reactant: O=C1CCN(c2ccc(C=C3SC(N4CCCCC4)=NC3=O)cc2)CC1
Product: CS(=O)(=O)Nc1cc([C@@H](O)CNC2CCN(c3ccc(C=C4SC(N5CCCCC5)=NC4=O)cc3)CC2)ccc1O

Procedure:
The title compound was prepared from 1-[4-(4-oxo-2-piperidin-1-yl-4H-thiazol-5-ylidenemethyl)-phenyl]-piperidin-4-one (which was obtained in Intermediate 25) and N-[5-(2-amino-(1R)-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulfonamide (which was obtained in Intermediate 10) according to the procedure of Example 1 as a pale yellowish solid; mp>120° C. (dec.); 1H NMR (300 MHz, DMSO-d6) δ 1.20-1.40 (m, 2 H), 1.55-1.75 (m, 6 H), 1.80-2.00 (m, 2 H), 2.60-3.00 (m, 5 H), 2.92 (s, 3 H), 3.50-3.90 (m, 6 H), 4.49 (dd, J=8.0, 4.2 Hz, 1 H), 6.82 (d, J=8.5 Hz, 1 H), 6.95-7.07 (m, 3 H), 7.18 (d, J=2.0 Hz, 1 H), 7.45 (d, J=8.9 Hz, 2 H),7.50 (s, 1 H); MS (ES) m/z: 300.6 ((M+2H)2+, 100%), 600.1 (MH+, 50%); HRMS Calcd. for C29H37N5O5S2 (MH+): 600.2314. Found: 600.2330.
Reaction SMILES: [C:1]1([C:7]2([C:13]3[CH:33]=[CH:32][C:16]([O:17][C:18]([CH:20]([NH:24]C(=O)OC(C)(C)C)[CH:21]([CH3:23])[CH3:22])=[O:19])=[CH:15][CH:14]=3)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:24][CH:20]([CH:21]([CH3:23])[CH3:22])[C:18]([O:17][C:16]1[CH:32]=[CH:33][C:13]([C:7]2([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]2)=[CH:14][CH:15]=1)=[O:19]
Reactant: CC(C)C(NC(=O)OC(C)(C)C)C(=O)Oc1ccc(C2(c3ccccc3)CCCCC2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)C(N)C(=O)Oc1ccc(C2(c3ccccc3)CCCCC2)cc1

Procedure:
To a stirred solution at room temperature of tert-butyl 1-((4-(1-phenylcyclohexyl)phenoxy)carbonyl)-2-methylpropylcarbamate (142 mg, 0.31 mmol) in dry DCM (3 mL) was added TFA (300 μL), which caused gas evolution. Stirring was continued. After 1 h the reaction mixture was concentrated in vacuo to afford 96 mg (0.21 mmol; 67%) of colourless oil. LC-MS purity (UV/MS): 92/97%, Rt 5.45 min, M+1: 352.49. 1H NMR (400 MHz, CDCl3): 11.12 (br s), 7.76 (br s), 7.29 (d, 2H, J=8.8 Hz), 7.27 (d, 4H, J=4.8 Hz), 7.13-7.16 (m, 1H), 6.95 (d, 2H, J=8.8 Hz), 6.16 (d, 1H, J=4.0 Hz), 2.40-2.48 (m, 1H), 2.18-2.33 (m, 4H), 1.50-1.58 (m, 6H), 1.05-1.08 (m, 6H).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH3:7][N:8]1[C:12]([NH:13][C:14](=O)[C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:11][C:10]([CH3:20])=[N:9]1.O.[OH-].[Na+]>C1COCC1>[CH3:16][C:15]([CH3:18])([CH3:17])[CH2:14][NH:13][C:12]1[N:8]([CH3:7])[N:9]=[C:10]([CH3:20])[CH:11]=1
Reactant: Cc1cc(NC(=O)C(C)(C)C)n(C)n1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(NCC(C)(C)C)n(C)n1
Temperature: 67 °C
Yield: 85 %

Procedure:
To 4.7 g (123 mmol) of LiAlH4 in 150 mL of THF at 0° C. was added a solution of 12.0 g (61.45 mmol) of N-(2,5-dimethyl-2H-pyrazol-3-yl)-2,2-dimethyl-propionamide and 100 mL THF in drops over 60 min. After addition is complete, the reaction mixture was heated to 67° C. for 42 h. After cooling to 23° C., 5 mL H2O was carefully added, followed by 5 mL 5N NaOH and 5 mL H2O. The resulting mixture was filtered through Celite, evaporated to a yellow oil, dissolved in 300 mL EtOAc, washed with 1×100 mL brine, 1×100 mL H2O, 1×100 mL brine, dried over MgSO4, filtered and evaporated to give 9.45 g (52.1 mmol, an 85% yield) of the title compound as a light yellow oil. 1H NMR (300 MHz, CDCl3): δ 0.98 (s, 9H), 2.17 (s, 3H), 2.81 (m, 2H), 3.56 (s, 3H), 5.24 (s, 1H); IR (KBr, cm-−1): 3261m, 2956m, 2866m, 1568s, 1476m, 1367m, 1362m, 1267m, 1200m, 729m; MS (ES) m/z (relative intensity): 182 (M++H, 100). Anal. Calcd. for C10H19N3: C, 66.26; H, 10.56; N, 23.18. Found: C, 64.75; H, 10.23; N, 24.67.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][N:6]([CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[C:7]([CH:9]([CH2:15][S:16]([C:19]1[CH:28]=[CH:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=1)(=[O:18])=[O:17])[CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[O:8].[OH-].[Na+:35]>C(O)C>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][N:6]([CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[C:7]([CH:9]([CH2:15][S:16]([C:19]1[CH:28]=[CH:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=1)(=[O:17])=[O:18])[CH2:10][CH2:11][C:12]([O-:14])=[O:13])=[O:8].[Na+:35]
Reactant: CCCCCN(CCCOC)C(=O)C(CCC(=O)O)CS(=O)(=O)c1ccc2ccccc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCCN(CCCOC)C(=O)C(CCC(=O)[O-])CS(=O)(=O)c1ccc2ccccc2c1
Temperature: 0 °C

Procedure:
Into a solution of (-)-4-[N-(3-methoxypropyl)-N-pentylcarbamoyl]-5-(2-naphthylsulfonyl)pentanoic acid (4.00 g) in ethanol (40 ml) was added dropwise a 1N sodium hydroxide solution (8.39 ml) with stirring at 0° C. The reaction mixture was concentrated in vacuo at 35° C., and water-ethanol (1:1, 40 ml) was added and concentrated again in vacuo to the residue. The residue was recrystallized from isopropyl ether (40 ml) to give 3.90 g of sodium (-)-4-[N-(3-methoxypropyl)-N-pentylcarbamoyl]-5-(2-naphthylsulfonyl)pentanoate as a hygroscopic amorphous solid.
Reaction SMILES: N1C=CC=C(CN)C=1.[N:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][NH2:16].[F:17][C:18]1[CH:40]=[CH:39][C:21]([CH2:22][N:23]2[C@@H:27]([CH3:28])[CH2:26][N:25]([C:29]3[S:30][C:31]([C:35](O)=[O:36])=[C:32]([CH3:34])[N:33]=3)[C:24]2=[O:38])=[CH:20][CH:19]=1.FC1C=CC(CN2[C@H](C)CN(C3SC(C(O)=O)=C(C)N=3)C2=O)=CC=1>>[F:17][C:18]1[CH:40]=[CH:39][C:21]([CH2:22][N:23]2[C@H:27]([CH3:28])[CH2:26][N:25]([C:29]3[S:30][C:31]([C:35]([NH:16][CH2:15][C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][N:9]=4)=[O:36])=[C:32]([CH3:34])[N:33]=3)[C:24]2=[O:38])=[CH:20][CH:19]=1
Reactant: NCc1ccccn1
Reactant: Cc1nc(N2C[C@H](C)N(Cc3ccc(F)cc3)C2=O)sc1C(=O)O
Agent: Cc1nc(N2C[C@@H](C)N(Cc3ccc(F)cc3)C2=O)sc1C(=O)O
Agent: NCc1cccnc1
Product: Cc1nc(N2C[C@@H](C)N(Cc3ccc(F)cc3)C2=O)sc1C(=O)NCc1ccccn1

Procedure:
Following the procedure as described in Example 2, making variations as required to replace pyridin-3-ylmethanamine with pyridin-2-ylmethanamine and replace (S)-2-(3-(4-fluorobenzyl)-4-methyl-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid with (R)-2-(3-(4-fluorobenzyl)-4-methyl-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid, the title compound was obtained as a white solid (48%): mp 118-119° C. (ethanol/water); 1H NMR (300 MHz, DMSO-d6) δ 8.54-8.50 (m, 2H), 7.79-7.75 (m, 1H), 7.40-7.16 (m, 6H), 4.60 (d, J=15.6 Hz, 1H), 4.49 (d, J=5.8 Hz, 2H), 4.31 (d, J=15.6 Hz, 1H), 4.20 (dd, J=10.0, 9.2 Hz, 1H), 3.79-3.72 (m, 1H), 3.56 (dd, J=10.0, 6.8 Hz, 1H), 2.49 (s, 3H), 1.23 (d, J=6.1 Hz, 3H); MS (ES+) m/z 439.9 (M+1).