Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[C:3]([C:5]1([O:18][CH3:19])[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1)=[O:4].[CH3:20][Si](C[Li])(C)C.[Cl-].[NH4+].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.C(OCC)C.C(OCC)(=O)C.O>[C:3]([C:5]1([O:18][CH3:19])[CH2:6][CH2:7][N:8]([C:11]([O:13][C:14]([CH3:15])([CH3:16])[CH3:17])=[O:12])[CH2:9][CH2:10]1)(=[O:4])[CH3:20]
Reactant: [Li]C[Si](C)(C)C
Reactant: COC(=O)C1(OC)CCN(C(=O)OC(C)(C)C)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: COC1(C(C)=O)CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 0.5 h
Yield: 37.1 %

Procedure:
To a solution of 1-tert-butyl 4-methoxycarbonyl-4-methoxypiperidine-1-carboxylate (2.5 g, 9.05 mmol) dissolved in 100 mL of tetrahydrofuran at −78° C. was added trimethylsilylmethyl lithium (23 mL, 23 mmol). After 30 min additional trimethylsilylmethyl lithium (2.7 mL, 2.7 mmol) was added. The reaction mixture was then diluted with diethyl ether, poured into saturated ammonium chloride, and extracted three times with diethyl ether. The organic layers were combined, washed with saturated sodium chloride, dried over sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography eluting with 10% ethyl acetate/hexanes to afford 1.7 g of silyl product which was taken up in tetrahydrofuran (50 mL) and tetrabutylammonium fluoride (6.1 mL, 6.1 mmol) was added. After 30 min at room temperature, the reaction mixture was diluted with ethyl acetate, poured into water, and extracted three times with ethyl acetate. The organic layers were combined, washed with sodium chloride solution, dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography to afford the title compound (0.863 g).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][N:3]=1.[CH2:12](OC(OCC)CBr)[CH3:13].Br>C(O)C>[F:10][C:8]([F:11])([F:9])[C:6]1[CH:5]=[CH:4][N:3]2[CH:12]=[CH:13][N:1]=[C:2]2[N:7]=1
Reactant: Nc1nccc(C(F)(F)F)n1
Reactant: CCOC(CBr)OCC
Agent: Br
Solvent: CCO
Product: FC(F)(F)c1ccn2ccnc2n1
Temperature: 70 °C
Yield: 86.2 %

Procedure:
A mixture of 2-amino-4-(trifluoromethyl)pyrimidine (prepared according to Zanatta et al. in J. Heterocyclic Chem., 1997, 34(2), 509-513) (500 mg, 3.1 mmol) and bromoacetaldehyde diethyl acetal (1.38 ml, 9.2 mmol) in ethanol (10 ml) was treated with hydrobromic acid (0.5 ml of a 48% aqueous solution) and then heated at 70° C. for 12 h. The reaction was cooled to ambient temperature then pre-adsorbed onto silica. Purification by chromatography on silica eluting with dichloromethane (containing 1% conc. ammonia) on a gradient of methanol (1-5%) afforded 7-trifluoromethylimidazo[1,2-α]pyrimidine (500 mg, 87%) as a cream-coloured solid: δH (400 MHz, CDCl3) 7.22 (1H, d, J 7), 7.74 (1H, d, J 1), 8.03 (1H, d, J 1), 8.67 (1H, d, J 7).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH2:4][CH2:5][CH2:6][C:7]1([CH2:13][C:14]([O:16]C)=O)[CH2:12][CH2:11][CH2:10][CH:9]=[CH:8]1.N([Li])(C(C)C)C(C)C.[NH4+].[Cl-]>C1COCC1>[CH3:1][O:2][C:3]([C:4]1[CH2:5][CH2:6][C:7]2([CH2:12][CH2:11][CH2:10][CH:9]=[CH:8]2)[CH2:13][C:14]=1[OH:16])=[O:18]
Reactant: COC(=O)CCCC1(CC(=O)OC)C=CCCC1
Agent: [Cl-]
Agent: [Li]N(C(C)C)C(C)C
Agent: [NH4+]
Solvent: C1CCOC1
Product: COC(=O)C1=C(O)CC2(C=CCCC2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91 %

Procedure:
To a solution of the relevant 4-(1-methoxycarbonylmethyl-cyclohex-2-enyl)-butyric acid methyl ester isomer (8) or (8′) (31.0 g, 122 mmol) in dry THF (580 mL) at −78° C. was added dropwise i-Pr2NLi (2 M solution in n-heptane; 122 mL, 244 mmol). The reaction mixture was allowed to warm to room temperature and stirred for 2 hours. A saturated NH4Cl solution (700 mL) was added and the aqueous layer repeatedly extracted with Et2O. The combined organic layers were dried over anhydrous MgSO4 and the solvents removed in vacuo. The resulting residue was purified over silica (n-pentane/Et2O, 95:5) to afford 24.7 g (91% yield) of the desired product as white crystals which were characterized as follows:
Reaction SMILES: [C:1]([C:5]1[C:6](=[O:16])[C:7](=O)[CH:8]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[SH:24]>CCOCC>[C:1]([C:5]1[C:6](=[O:16])[C:7]2[C:8](=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:10]=1)[S:24][C:19]1[C:18](=[CH:23][CH:22]=[CH:21][CH:20]=1)[N:17]=2)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)C1=CC(=O)C(=O)C(C(C)(C)C)=C1
Reactant: Nc1ccccc1S
Solvent: CCOCC
Product: CC(C)(C)c1cc(C(C)(C)C)c(=O)c2nc3ccccc3sc1-2
Reaction time: 1 h

Procedure:
To a solution of 4.4 gm of 3,5-di-t-butyl-1,2-benzoquinone in 20 ml of ether was added a solution of 1.25 g of 2-aminothiophenol in 5 ml of ether. After stirring for 1 hour at 25°, the reaction mixture was evaporated. The residue was purified by flash chromatography on silica gel using 2% ethyl acetate in benzene as eluent. There was thus obtained 860 mg of the title compound as dark blue plates, m.p. 137°-141°.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:11][C:10]([CH2:12][N:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)=[N:9][C:8]=2[CH:18]=1)([O-])=O>[Pd].CCOC(C)=O.CO>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]2[O:11][C:10]([CH2:12][N:13]3[CH2:14][CH2:15][CH2:16][CH2:17]3)=[N:9][C:8]=2[CH:18]=1
Reactant: O=[N+]([O-])c1ccc2oc(CN3CCCC3)nc2c1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: Nc1ccc2oc(CN3CCCC3)nc2c1
Reaction time: 0.5 h
Yield: 100 %

Procedure:
To a solution of 5-nitro-2-[(pyrrolidin-1-yl)methyl]benzoxazole (300 mg, 1.21 mmol) in a mixed solvent of EtOAc-MeOH (1:1, 70 mL) was added 10% Pd—C (40 mg), the flask was purged with argon, then the argon was replaced with H2, the reaction mixture was stirred under H2 atmosphere for 30 min. After filtration through Celite, washed with ethyl acetate. The solvents were evaporated to provide 263 mg (100%) of 5-amino-2-[(pyrrolidin-1-yl)methyl]benzoxazole as a yellow solid.
Reaction SMILES: C([N:4]1[C:8]2=[N:9][C:10](Br)=[CH:11][CH:12]=[C:7]2[C:6]([C:14]#[N:15])=[CH:5]1)(=O)C.C(N(CC)CC)C.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.[F:57][C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][C:59]=1B(O)O>O1CCOCC1>[F:57][C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][C:59]=1[C:10]1[N:9]=[C:8]2[NH:4][CH:5]=[C:6]([C:14]#[N:15])[C:7]2=[CH:12][CH:11]=1
Reactant: OB(O)c1ccccc1F
Reactant: CC(=O)n1cc(C#N)c2ccc(Br)nc21
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: N#Cc1c[nH]c2nc(-c3ccccc3F)ccc12
Temperature: 100 °C
Yield: 97.9 %

Procedure:
In a 100 mL round-bottomed flask, 1-acetyl-6-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile (250 mg, 947 μmol, Eq: 1.00), triethylamine (575 mg, 792 μl, 5.68 mmol, Eq: 6) and X-PHOS (181 mg, 379 μmol, Eq: 0.40) were combined with dioxane (25.0 ml) to give a colorless solution. [1,1′-bis(diphenylphosphino)ferrocene]dichloropaladium(II) (173 mg, 237 μmol, Eq: 0.25) and 2-fluorophenylboronic acid (265 mg, 1.89 mmol) were added and the resultant mixture was degassed for 5 minutes under Nitrogen. The reaction mixture was heated to 100° C. and microwaved for 1 hr. The reaction mixture was poured into 50 mL EtOAc and washed with H2O. The organic layers were dried over MgSO4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 40 g, 20% to 30% EtOAc in hexanes) to give 6-(2-fluorophenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile (220 mg, 98%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:15][C:16]2[CH:17]=[C:18]([CH:23]=[CH:24][C:25]=2[CH3:26])[C:19]([NH:21][CH3:22])=[O:20])=[N:4][CH:5]=[N:6][C:7]=1[N:8]([CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH3:9].[C:27](Cl)(=[O:29])[CH3:28].C(N(CC)CC)C>C(Cl)Cl>[C:27]([NH:1][C:2]1[C:3]([NH:15][C:16]2[CH:17]=[C:18]([CH:23]=[CH:24][C:25]=2[CH3:26])[C:19]([NH:21][CH3:22])=[O:20])=[N:4][CH:5]=[N:6][C:7]=1[N:8]([CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH3:9])(=[O:29])[CH3:28]
Reactant: CNC(=O)c1ccc(C)c(Nc2ncnc(N(C)CC(C)(C)C)c2N)c1
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CNC(=O)c1ccc(C)c(Nc2ncnc(N(C)CC(C)(C)C)c2NC(C)=O)c1

Procedure:
3-{5-Amino-6-[(2,2-dimethyl-propyl)-methyl-amino]-pyrimidin-4-ylamino}-4,N-dimethyl-benzamide (16 mg), acetyl chloride (3.5 mg), triethylamine (0.02 ml) were stirred in methylene chloride (0.2 mL) at room temperature for overnight. The product (2.8 mg) was purified by preparative thin layer chromatography. MS (m/z): 399 (M+H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8]C#N)=[CH:4][C:3]=1[CH3:11].S(=O)(=O)(O)O.[C:17](=[O:20])([O-])[O-:18].[Na+].[Na+]>O>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:17]([OH:18])=[O:20])=[CH:4][C:3]=1[CH3:11]
Reactant: O=C([O-])[O-]
Reactant: Cc1cc(CC#N)cnc1Cl
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: Cc1cc(CC(=O)O)cnc1Cl
Temperature: 100 °C
Reaction time: 4 h

Procedure:
To a flask containing 2-(6-chloro-5-methylpyridin-3-yl)acetonitrile 74-3 (1.12 g, 6.75 mmol) were added water (9.0 mL) and dropwise concentrated sulfuric acid (9.0 mL). The reaction mixture was stirred at 100° C. for 4 hours. After cooled down to room temperature, the reaction mixture was poured into water (100 mL). The resulting solution was neutralized with powder sodium carbonate to pH around 3, and extracted with ethyl acetate (50 mL×3). The combined organic layers were washed with brine, dried over Na2SO4 and then taken to dryness by rotary evaporation give 2-(6-Chloro-5-methylpyridin-3-yl)acetic acid 74-4 as pale yellow solid, which was used directly for next step. MS m/z 186.1 (M+1)
Reaction SMILES: [CH3:1][C:2]1[C:3]([O:19][CH2:20][C:21]([F:24])([F:23])[F:22])=[CH:4][CH:5]=[N:6][C:7]=1[CH2:8][S:9][C:10]1[NH:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=2[N:18]=1.C[OH:26].OO>C[Re](=O)(=O)=O.O>[CH3:1][C:2]1[C:7]([CH2:8][S:9]([C:10]2[NH:11][C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=3[N:18]=2)=[O:26])=[N:6][CH:5]=[CH:4][C:3]=1[O:19][CH2:20][C:21]([F:24])([F:22])[F:23]
Reactant: Cc1c(OCC(F)(F)F)ccnc1CSc1nc2ccccc2[nH]1
Reactant: CO
Agent: C[Re](=O)(=O)=O
Agent: OO
Solvent: O
Product: Cc1c(OCC(F)(F)F)ccnc1CS(=O)c1nc2ccccc2[nH]1
Temperature: 5 °C

Procedure:
In a 1-liter flask equipped with dropping funnel and mechanical stirring 50 g (0.142 moles) of Lansoprazole sulfide, 35.0 mg (0.00014 moles) of methyltrioxorhenium (Aldrich) and 500 ml of methanol are charged. The temperature of the solution is brought to 5° C., and then 17.8 g (0.173 moles) of a 33% (v/v) aqueous solution of hydrogen peroxide are added. The mixture is maintained at 5° C. for 4 hours, then 1000 ml of cold deionized water are added, whereby a dense precipitate forms. The mixture is stirred for 1 additional hour at 5° C. and is then filtered on a Buchner, the cake is washed with 3×100 ml of cold deionized water and is discharged. The wet solid weighs 59.5 g. A 1 g sample is collected and dried under vacuum (50 mmHg) at 40° C. for 12 hours, which loses 16.5% of its weight. The yield of crude product is thus 95%. The amount of residual water in the crystalline solid is calculated through the Karl-Fischer method and the solid is then recrystallised, talking into account the amount of residual water, from 8 volumes of a 9:1 mixture of ethanol and water. The yield of the crystallized, dried product starting from the sulfide is 75%, the purity of the product is >99.5% (HPLC).
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:32])[CH2:11][CH2:12]/[CH:13]=[CH:14]\[CH2:15]/[CH:16]=[CH:17]\[CH2:18]/[CH:19]=[CH:20]\[CH2:21]/[CH:22]=[CH:23]\[CH2:24]/[CH:25]=[CH:26]\[CH2:27]/[CH:28]=[CH:29]\[CH2:30][CH3:31])=[CH:5][CH:4]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:53]>C(Cl)Cl>[Br:53][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:32])[CH2:11][CH2:12]/[CH:13]=[CH:14]\[CH2:15]/[CH:16]=[CH:17]\[CH2:18]/[CH:19]=[CH:20]\[CH2:21]/[CH:22]=[CH:23]\[CH2:24]/[CH:25]=[CH:26]\[CH2:27]/[CH:28]=[CH:29]\[CH2:30][CH3:31])=[CH:5][CH:4]=1
Reactant: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCC(=O)Nc1ccc(CO)cc1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCC(=O)Nc1ccc(CBr)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
(4Z,7Z,10Z,13Z,16Z,19Z)—N-(4-(hydroxymethyl)phenyl)docosa-4,7,10,13,16,19-hexaenamide (0.5 mmol) was taken up in 5 mL of CH2Cl2 and cooled to 0° C. Triphenylphosphine (0.5 mmol) and carbon tetrabromide (0.5 mmol) were added and the resulting reaction mixture was slowly warmed to room temperature. After 2 h at room temperature, the reaction mixture was concentrated under reduced pressure. The resulting residue can be purified by silica gel chromatography to afford (4Z,7Z,10Z,13Z,16Z,19Z)—N-(4-(bromomethyl)phenyl)docosa-4,7,10,13,16,19-hexaenamide.
Reaction SMILES: [S:1]([C:5]1[CH:11]=[CH:10][C:8]([CH3:9])=[CH:7][CH:6]=1)([O-:4])(=[O:3])=[O:2].[O:12]1[C:16]2[CH:17]=CC=C[C:15]=2[CH:14]=N1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[S:1]([C:5]1[CH:11]=[CH:10][C:8]([CH3:9])=[CH:7][CH:6]=1)([O:4][CH2:14][CH2:15][CH:16]([OH:12])[CH3:17])(=[O:3])=[O:2]
Reactant: Cc1ccc(S(=O)(=O)[O-])cc1
Reactant: c1ccc2oncc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1ccc(S(=O)(=O)OCCC(C)O)cc1
Temperature: 25 °C

Procedure:
Racemic 3-hydroxybutyl tosylate was prepared in a manner described by Ferreira et al., Tetrahedron, 46, pp. 6311-6318, (1990). To a solution of the racemic tosylate (9.2 g, 37.7 mmol) in acetonitrile (190 ml) was added 6-fluoro-3-(4-piperidinyl)-1,2-piperidinyl)-1,2-benzisoxazole (8.3 g, 37.7 mmol) followed by milled potassium carbonate (7.8 g, 56.6 mmol) at room temperature under nitrogen. The reaction mixture was warmed to reflux for 4.5 hours and allowed to cool to room temperature. The solids were removed via filtration through a pad of Celite and were washed with EtOAc. The combined filtrates were concentrated to give the crude product. Purification via preparative HPLC (silica gel, 10% MeOH/EtOAc) afforded 6.3 g (57%), m.p.=100°-102° C.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:9]=[CH:8][C:6]([OH:7])=[CH:5][C:4]=1[OH:10].Cl.[N:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH2:18]Cl.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C(N(CC)CC)C>[N:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]1[O:10][C:4]2[CH:5]=[C:6]([OH:7])[CH:8]=[CH:9][C:3]=2[N:2]=1
Reactant: ClCc1ccccn1
Reactant: Nc1ccc(O)cc1O
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: Cl
Agent: c1cc[nH+]cc1
Solvent: CCN(CC)CC
Product: Oc1ccc2nc(-c3ccccn3)oc2c1

Procedure:
4-Aminoresorcinol hydrochloride (2.0 g, 12.4 mL), picolinyl chloride hydrochloride (2.4 g, 13.6 mM), triethylamine (2.8 g, 27.2 mM) and pyridinium-p-toluenesulfonate (PPTS, 800 mg, 3.2 mM) were refluxed in xylenes (50 mL) for about 72 hours. The reaction mixture was concentrated and the residue dissolved in ethyl acetate (200 mL) and washed with H2O (3×150 mL). The combined aqueous layer was back extracted with ethyl acetate (200 mL) and the combined organic layer was dried over MgSO4. Filtration and concentration provided 1.0 g. Filtration through a silica gel column eluted with 4% methanol/methylene chloride provided an orange solid, 0.32 g; m.p., 100-103° C.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[CH2:11][CH:12]([CH3:14])[CH3:13])=[CH:4][C:3]=1[O:15][C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=1[F:23].C[C:25]([N:27](C)C)=O>>[F:23][C:17]1[CH:18]=[C:19]([F:22])[CH:20]=[CH:21][C:16]=1[O:15][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:2]=1[C:25]#[N:27])[N:8]([CH2:11][CH:12]([CH3:14])[CH3:13])[N:7]=[CH:6]2
Reactant: CC(=O)N(C)C
Reactant: CC(C)Cn1ncc2cc(Oc3ccc(F)cc3F)c(Br)cc21
Product: CC(C)Cn1ncc2cc(Oc3ccc(F)cc3F)c(C#N)cc21
Temperature: 150 °C
Yield: 95 %

Procedure:
6-Bromo-5-(2,4-difluorophenoxy)-1-isobutyl-1H-indazole (31.2 g, 82 mmol) and Cu(I) CN (13.9 g, 156 mmol) were dissolved in DMA and degassed with nitrogen under vacuum. The reaction mixture was heated to 150° C. for 16 hours. The mixture was cooled to room temperature and diluted with ethyl acetate before washing twice with 7M NH4OH. The organics were washed with brine and degassed with nitrogen before being dried over MgSO4 and concentrated under reduced pressure. The crude product was chromatographed eluting with 10% ethyl acetate in hexanes to afford 25.1 g of product (95% yield).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([O:9][C:10](=[O:33])[C@@H:11]([CH2:18][C:19]1[C:20]([CH2:28][O:29]C(=O)C)=[C:21]2[C:25](=[CH:26][CH:27]=1)[NH:24][N:23]=[CH:22]2)[CH2:12][C:13]([O:15][CH2:16]C)=[O:14])C>CO>[CH3:7][O:9][C:10](=[O:33])[C@@H:11]([CH2:18][C:19]1[C:20]([CH2:28][OH:29])=[C:21]2[C:25](=[CH:26][CH:27]=1)[NH:24][N:23]=[CH:22]2)[CH2:12][C:13]([O:15][CH3:16])=[O:14]
Reactant: CCOC(=O)C[C@H](Cc1ccc2[nH]ncc2c1COC(C)=O)C(=O)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: COC(=O)C[C@H](Cc1ccc2[nH]ncc2c1CO)C(=O)OC
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 92 %

Procedure:
Potassium carbonate (1.6 g, 11.6 mmol) was added to a solution of 2-(S)-(4-acetoxymethyl-1H-indazol-5-ylmethyl)-succinic acid diethyl ester (2.0 g, 5.5 mmol) in methanol (60 mL). Mixture was stirred at room temperature for 1.5 hours. Reaction was quenched with the addition of 1N hydrochloric acid (30 mL). Methanol was removed from the mixture in vacuo. Remaining aqueous was basified with sodium bicarbonate. Mixture was extracted with ethyl acetate (2×40 mL). Combined organic layers were washed successively with water (30 mL) and brine (30 mL). Organic was dried (magnesium sulfate), filtered then concentrated in vacuo. Desired product was obtained in 92% yield as an amber oil. 1H NMR (300 MHz, CDCl3): δ=8.21 ((s, 1 H), 7.34 (d, J=9.2, 1H), 7.17 (d, J=8.8, 1H), 5.02 (dd, J1=12.4, J2=17.9, 1H) 3.63 (s, 6H), 3.23 (m, 1H), 2.98 (m, 1H), 2.77 (dd, J1=7.7, J2=16.8, 1H), 2.53 (dd, J1=6.4, J2=16.7, 1H). MS m/e (M+H)+=307.0.
Reaction SMILES: [C:1]([CH:6]1[C:11](=[O:12])[CH2:10][CH:9]([C:13]2[C:18]([CH3:20])([CH3:19])[CH2:17][CH2:16][CH2:15][C:14]=2[CH3:21])[CH2:8][C:7]1=[O:22])(=O)[CH2:2][CH2:3][CH3:4].[Cl-].[CH2:24]([O:27][NH3+:28])[CH:25]=[CH2:26].C([O-])(=O)C.[Na+]>C(O)C>[CH2:24]([O:27][NH:28][C:1](=[C:6]1[C:7](=[O:22])[CH2:8][CH:9]([C:13]2[C:18]([CH3:20])([CH3:19])[CH2:17][CH2:16][CH2:15][C:14]=2[CH3:21])[CH2:10][C:11]1=[O:12])[CH2:2][CH2:3][CH3:4])[CH:25]=[CH2:26]
Reactant: CCCC(=O)C1C(=O)CC(C2=C(C)CCCC2(C)C)CC1=O
Reactant: C=CCO[NH3+]
Agent: CC(=O)[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Product: C=CCONC(CCC)=C1C(=O)CC(C2=C(C)CCCC2(C)C)CC1=O

Procedure:
8.0 parts by weight of 2-butyryl-5-(1,3,3-trimethylcyclohex-1-en-2-yl)-cyclohexane-1,3-dione are reacted with 2.9 parts by weight of allyloxyammonium chloride and 2.4 parts by weight of sodium acetate in 100 parts by volume of ethanol and the mixture is worked up, by a procedure similar to that of Example 1. 9.0 parts by weight of 2-(1-allyloxyaminobutylidene)-5-(1,3,3-trimethylcyclohex-1-en-2-yl)-cyclohexane-1,3-dione are obtained as a viscous oil (active ingredient No.2).
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]1([N:16]2[CH:20]=[C:19]([C:21]([NH:23][CH2:24][C:25]([OH:27])=O)=[O:22])[N:18]=[CH:17]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[CH3:50][C:51]1[CH:58]=[CH:57][C:54]([C:55]#[N:56])=[CH:53][C:52]=1[O:59][CH:60]1[CH2:65][CH2:64][NH:63][CH2:62][CH2:61]1>CN(C=O)C.O>[C:55]([C:54]1[CH:57]=[CH:58][C:51]([CH3:50])=[C:52]([CH:53]=1)[O:59][CH:60]1[CH2:61][CH2:62][N:63]([C:25](=[O:27])[CH2:24][NH:23][C:21]([C:19]2[N:18]=[CH:17][N:16]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:20]=2)=[O:22])[CH2:64][CH2:65]1)#[N:56]
Reactant: O=C(O)CNC(=O)c1cn(-c2ccccc2)cn1
Reactant: Cc1ccc(C#N)cc1OC1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(C#N)cc1OC1CCN(C(=O)CNC(=O)c2cn(-c3ccccc3)cn2)CC1
Reaction time: 0.03 h
Yield: 82.7 %

Procedure:
DIPEA (236 mg, 1.826 mmol) was added to a stirred solution of [(1-phenyl-1H-imidazole-4-carbonyl)-amino]-acetic acid (prepared from Intermediate 68 by means of Step 3 of the General Scheme) (100 mg, 0.4 mmol) in DMF (5 mL) followed by HOBt (60.5 mg, 0.4 mmol) and EDCI (195 mg, 1.02 mmol). After 2 minutes of stirring, 4-methyl-3-(piperidin-4-yloxy)-benzonitrile hydrochloride (113 mg, 0.45 mmol) (prepared by the method used for the synthesis of Intermediate 15) was added and the resulting mixture was stirred at ambient temperature overnight. The reaction mixture was diluted with cold water, the precipitate was collected and purified by recrystallisation from a mixture of diethyl ether (15 mL) and MeOH (0.1 mL) to afford 149 mg (82.7% Yield) of 1-phenyl-1H-imidazole-4-carboxylic acid {2-[4-(5-cyano-2-methyl-phenoxy)-piperidin-1-yl]-2-oxo-ethyl}-amide. LC/MS [M+H]+: 443, 98.73%. 1H NMR (300 MHz, DMSO-d6): δ 8.4 (s, 1H), 8.3 (s, 1H), 8.08 (t, 1H), 7.8 (d, 2H), 7.6 (t, 3H), 7.4-7.18 (m, 3H), 4.85 (m, 1H), 4.2 (d, 2H), 3.85-3.6 (d, 2H), 3.5 (bs, 2H), 2.3 (s, 3H), 2.1 (d, 2H), 1.8 (d, 2H).
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[CH:15]=[CH:14][O:13][C:12]=1[NH:16][C:17](=[O:23])OC(C)(C)C)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[C:25](Cl)(=O)[CH2:26][CH2:27]C>>[CH2:1]([NH:8][C:9]([C:11]1[CH:15]=[CH:14][O:13][C:12]=1[NH:16][C:17](=[O:23])[CH2:25][CH2:26][CH3:27])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCC(=O)Cl
Reactant: CC(C)(C)OC(=O)Nc1occc1C(=O)NCc1ccccc1
Agent: Cl
Product: CCCC(=O)Nc1occc1C(=O)NCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of tert-butyl 3-[(benzylamino)carbonyl]-2-furylcarbamate (1-1, 1 equiv) is saturated with HCl gas at 0° C., and the resulting solution is stirred at 0° C. for 1 h, then allowed to warm to 23° C. and stirred for 1 h. The reaction mixture is concentrated and the residue is dissolved in pyridine. The resulting solution is cooled to 0° C., and butyryl chloride (3 equiv) is added in three equal portions over 1 h. The reaction mixture is partitioned between aqueous sodium bicarbonate solution and ethyl acetate. The organic layer is dried over sodium sulfate and concentrated. The residue is purified by flash column (hexanes initially, grading to 100% ethyl acetate) to give N-benzyl-2-(butyrylamino)-3-furamide (1-2).