Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([OH:8])[CH:7]=1.[CH2:9](O)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[CH2:9]([O:8][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Br:1])[CH:7]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Oc1cncc(Br)c1
Reactant: OCc1ccccc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Brc1cncc(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 31.9 %

Procedure:
To a vial is added 3-bromo-5-hydroxypyridine (200 mg, 1.15 mmol), benzyl alcohol (137 mg, 1.27 mmol) and triphenylphosphine (332 mg, 1.27 mmol) in THF (5 ml) at 0° C., followed by the addition of diisopropyl azodicarboxylate (256 mg, 1.27 mmol). The reaction mixture is stirred at room temperature for 18 hours. The reaction mixture is concentrated in vacuo. The residue is diluted with EtOAc, washed with sat NaHCO3, water, brine, dried under anhy. Na2SO4, filtered and concentrated. The residue is purified by flash chromatography (SiO2, 0-5% MeOH/CH2Cl2) to afford title compound (97 mg); m/z 264.0, 266.0 [M, M+2H]
Reaction SMILES: [C:1]1([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][CH:9]([OH:31])[CH:10]([CH2:18][CH2:19][N:20]2[C:25](=[O:26])[C:24]3[CH:27]=[CH:28][CH:29]=[CH:30][C:23]=3[N:22]=[N:21]2)[C:11]([O:13]C(C)(C)C)=[O:12])=[CH:3][CH:2]=1.FC(F)(F)C(O)=O>ClCCl>[C:1]1([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:2]=[CH:3][C:4]([CH2:7][CH2:8][CH:9]([OH:31])[CH:10]([CH2:18][CH2:19][N:20]2[C:25](=[O:26])[C:24]3[CH:27]=[CH:28][CH:29]=[CH:30][C:23]=3[N:22]=[N:21]2)[C:11]([OH:13])=[O:12])=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)C(CCn1nnc2ccccc2c1=O)C(O)CCc1ccc(-c2ccccc2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)C(CCn1nnc2ccccc2c1=O)C(O)CCc1ccc(-c2ccccc2)cc1
Reaction time: 2.5 h
Yield: 45.1 %

Procedure:
To a solution of the compound (100 mg) obtained from step 3 above in dichloromethane (2 ml) at 0° C. was added trifluoroacetic acid (8 ml) and stirred the reaction mixture for about 2-3 hours and then at room temperature for 3 hours. The solvent and excess reagents were evaporated under reduced pressure and the residue thus obtained was purified by preparative thin layer chromatography (eluant-ethyl acetate) to furnish the title compound (40 mg).
Reaction SMILES: C([Si](C)(C)[O:6][CH2:7][C:8]([N:11]1[C:19]2[CH:18]=[CH:17][N:16]=[CH:15][C:14]=2[C:13]([C:20]([C:22]2[CH:23]=[C:24]([NH:28][C:29](=[O:38])[CH2:30][C:31]3[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][N:32]=3)[CH:25]=[N:26][CH:27]=2)=[O:21])=[CH:12]1)([CH3:10])[CH3:9])(C)(C)C>C1COCC1.Cl.O1CCOCC1>[Cl:37][C:34]1[CH:35]=[CH:36][C:31]([CH2:30][C:29]([NH:28][C:24]2[CH:25]=[N:26][CH:27]=[C:22]([C:20]([C:13]3[C:14]4[CH:15]=[N:16][CH:17]=[CH:18][C:19]=4[N:11]([C:8]([CH3:10])([CH3:9])[CH2:7][OH:6])[CH:12]=3)=[O:21])[CH:23]=2)=[O:38])=[N:32][CH:33]=1
Reactant: CC(C)(CO[Si](C)(C)C(C)(C)C)n1cc(C(=O)c2cncc(NC(=O)Cc3ccc(Cl)cn3)c2)c2cnccc21
Agent: Cl
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: CC(C)(CO)n1cc(C(=O)c2cncc(NC(=O)Cc3ccc(Cl)cn3)c2)c2cnccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 69 %

Procedure:
To a solution of N-(5-{1-[2-(tert-Butyl-dimethyl-silanyloxy)-1,1-dimethyl-ethyl]-1H-pyrrolo[3,2-c]pyridine-3-carbonyl}-pyridin-3-yl)-2-(5-chloro-pyridin-2-yl)-acetamide (Preparation 8, 45 mg, 0.077 mmol) in THF (3 mL), 4M dioxane-HCl (0.4 mL) was added and stirred at room temperature for 18 hours. The reaction was evaporated in vacuo and purified by column chromatography on silica gel (gradient of MeOH: DCM 0:100 to 3:100) to afford the title compound as a yellow solid in 69% yield, 25 mg.
Reaction SMILES: C([O:8][C:9]([C:11]1[CH:23]=[CH:22][C:21]2[C:20]3[C:15](=[CH:16][C:17]([C:24]([O:26]CC4C=CC=CC=4)=[O:25])=[CH:18][CH:19]=3)[CH:14]([CH:34]=[O:35])[C:13]=2[CH:12]=1)=[O:10])C1C=CC=CC=1.[H][H]>C1COCC1.[Pd]>[CH:34]([CH:14]1[C:15]2[CH:16]=[C:17]([C:24]([OH:26])=[O:25])[CH:18]=[CH:19][C:20]=2[C:21]2[C:13]1=[CH:12][C:11]([C:9]([OH:10])=[O:8])=[CH:23][CH:22]=2)=[O:35]
Reactant: O=CC1c2cc(C(=O)OCc3ccccc3)ccc2-c2ccc(C(=O)OCc3ccccc3)cc21
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: O=CC1c2cc(C(=O)O)ccc2-c2ccc(C(=O)O)cc21

Procedure:
In a Parr hydrogenation bottle (Parr Instrument Company, Moline Ill.) was dissolved 9-formyl-2,7-fluorenedicarboxylic acid dibenzyl ester (3.0 g, 0.0061 mol) in THF anh. (350 mL). After careful addition of 20% Pd/C (wet with 50% water) 20% by weight (600 mg), the Parr bottle was evacuated/filled 3 times on a Parr apparatus to ensure hydrogen atmosphere. The suspension was shaken under 20-30 psi hydrogen gas for approximately 60 hours and then the remaining hydrogen was removed at reduced pressure. The suspension was filtered over a bed of celite, rinsed with additional THF and evaporated. 1H-NMR (d6-DMSO): δ (ppm) 9.0 (s, 1H, Ar); 8.5-8.1 (m, 6H, Ar).
Reaction SMILES: Br[C:2]1[N:6]2[N:7]=[C:8]([NH:11][CH2:12][CH2:13][N:14]3[CH2:18][CH2:17][N:16]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:15]3=[O:23])[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.Cl.[NH2:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1.C([O-])([O-])=O.[K+].[K+]>CC#N.O.CC#N.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([C:2]2[N:6]3[N:7]=[C:8]([NH:11][CH2:12][CH2:13][N:14]4[CH2:18][CH2:17][N:16]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:15]4=[O:23])[CH:9]=[CH:10][C:5]3=[N:4][CH:3]=2)=[CH:29][CH:28]=1
Reactant: NCc1ccc(B(O)O)cc1
Reactant: CC(C)(C)N1CCN(CCNc2ccc3ncc(Br)n3n2)C1=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CC#N
Solvent: O
Product: CC(C)(C)N1CCN(CCNc2ccc3ncc(-c4ccc(CN)cc4)n3n2)C1=O
Temperature: 150 °C
Yield: 79.5 %

Procedure:
A mixture of 1-[2-(3-bromo-imidazo[1,2-b]pyridazin-6-ylamino)-ethyl]-3-tert-butyl-imidazolidin-2-one (75 mg, 0.2 mmol), (4-aminomethylphenyl)boronic acid hydrochloride (49 mg, 0.26 mmol), K2CO3 (83 mg, 0.6 mmol) and dichlorobis(triphenylphosphine)palladium(II) (7 mg, 0.01 mmol) in MeCN/water (2.8 ml/0.7 ml) was heated in a microwave at 150° C. for 15 min. The reaction mixture was diluted with MeCN and filtered. The filtrate was subjected to preparative HPLC to give the titled compound (64.8 mg). 1H NMR (400 MHz, METHANOL-d4) δ ppm 1.26 (s, 9H) 3.24-3.31 (m, 4H) 3.40 (t, J=5.95 Hz, 2H) 3.52 (t, J=5.95 Hz, 2H) 4.17 (s, 2H) 6.70 (d, J=9.70 Hz, 1H) 7.54-7.63 (m, 3H) 7.77 (s, 1H) 8.19-8.23 (m, 2H) 8.56 (s, 1H). LRMS (ESI) m/z 408.4 [(M+H)]+, calc'd for C22H29N7O: 407.52.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[C:7]([C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([OH:14])=O)#[N:8].[NH2:18][C:19]1[CH:31]=[C:30]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:29]=[CH:28][C:20]=1[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22].Cl>O1CCCC1.C(OCC)(=O)C.C(N(CC)CC)C.C(Cl)Cl.CN(C)C=O>[C:7]([C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([NH:18][C:19]1[CH:31]=[C:30]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:29]=[CH:28][C:20]=1[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[O:14])#[N:8]
Reactant: N#Cc1cccc(C(=O)O)c1
Reactant: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1N
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cccc(C#N)c1
Reaction time: 0.5 h

Procedure:
2.5 mL of methylene chloride, 0.015 mL of N,N-dimethylformamide and 0.095 mL of oxalyl chloride were added to 0.17 g of 3-cyanobenzoic acid at room temperature sequentially and stirred at the same temperature for 30 minutes. The reaction mixture was added to a mixed solution of 2.0 mL of methylene chloride and 0.35 mL of triethylamine containing 0.25 g of tert-butyl 2-amino-4-phenylbenzoate at room temperature and stirred at the same temperature for 10 minutes. Ethyl acetate, 1.0 mol/L hydrochloric acid and tetrahydrofuran were added to the reaction mixture. The organic layer was separated and dried over anhydrous magnesium sulfate after washed with a saturated sodium chloride aqueous solution, and the solvent was evaporated under reduced pressure. The obtained residue was purified with silica gel column chromatography [PSQ100B (spherical) manufactured by Fuji Silysia Chemical Ltd., eluent; chloroform] to obtain 0.29 g of tert-butyl 2-(3-cyanobenzamido)-4-phenylbenzoate as white solid.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]2[N:11]=[CH:10][NH:9][C:7](=O)[C:5]=2[CH:6]=1.P(Cl)(Cl)([Cl:14])=O.C(=O)(O)[O-].[Na+]>C1C=CC=CC=1>[Cl:14][C:7]1[C:5]2[C:4](=[CH:3][CH:2]=[CH:1][CH:6]=2)[N:11]=[CH:10][N:9]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]cnc2ccccc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccccc1
Product: Clc1ncnc2ccccc12
Temperature: 25 °C
Yield: 153.2 %

Procedure:
Quinazolinone 2 (20.0 g, 79.3 mmol) was suspended in 500 mL dry benzene in a 1 L round-bottomed flask equipped with a reflux condenser. N,N-Dimethylanaline (14.4 g, 119 mmol) was added and the reaction was refluxed for 30 minutes under nitrogen. Upon cooling to room temperature, phosphorus oxychloride (12.2 g, 79.3 mmol) was added and the reaction mixture was then refluxed for an additional 3 hours under nitrogen. The mixture was cooled to room temperature, poured over ice, and neutralized with saturated aqueous sodium bicarbonate. The solution was then extracted four times with toluene and the combined organic layers dried over magnesium sulfate, filtered, and concentrated in vacuo to a reddish-brown solid. The resulting 4-chloroquinazoline 3 was purified via flash chromatography (40% hexanes, 60% dichloromethane) to afford 20 g (93%) 3 as a yellow solid.
Reaction SMILES: [C:1]([C:3]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[F:22])([CH2:10][CH2:11][C:12]([O:14]C)=O)[CH2:4][CH2:5][C:6]([O:8][CH3:9])=[O:7])#[N:2].[H-].[Na+].CO>C1(C)C=CC=CC=1>[C:1]([C:3]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[F:22])[CH2:4][CH:5]([C:6]([O:8][CH3:9])=[O:7])[C:12](=[O:14])[CH2:11][CH2:10]1)#[N:2]
Reactant: COC(=O)CCC(C#N)(CCC(=O)OC)c1ccccc1F
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Product: COC(=O)C1CC(C#N)(c2ccccc2F)CCC1=O
Yield: 92.8 %

Procedure:
Dimethyl 4-cyano-4-(2-fluorophenyl)heptanedioate (D18, 35.86 g, 0.12 mol) was stirred under Ar in toluene (500 ml) as sodium hydride (80% in mineral oil, 3.5 g, 0.12 mol) was added. Methanol (10 ml) was added dropwise, and the mixture was then stirred at reflux for 16 h, partitioned between ethyl acetate and dilute HCl, and separated. The organic portion was washed with brine, dried (Na2SO4) and evaporated to an oil. This was dissolved in dichloromethane (500 ml), filtered, and evaporated to give the title compound (30.66 g, 95%) as a cream solid.
Reaction SMILES: [OH-].[Na+].[N:3]([O:5][CH2:6]CCC)=O.[CH3:10][C:11]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][C:12]=1[O:13][CH2:14][C:15]1[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=1[CH2:17][C:18]#[N:19].S(OC)(OC)(=O)=O>O.C1(C)C=CC=CC=1.CC(C)=O>[CH3:10][C:11]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][C:12]=1[O:13][CH2:14][C:15]1[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=1[C:17]([C:18]#[N:19])=[N:3][O:5][CH3:6]
Reactant: CCCCON=O
Reactant: Cc1ccc(C)c(OCc2ccccc2CC#N)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: Cc1ccccc1
Solvent: COS(=O)(=O)OC
Product: CON=C(C#N)c1ccccc1COc1cc(C)ccc1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.7 %

Procedure:
95% Sodium hydroxide (0.32 g, 7.5 mmol), acetone (5 ml) and butyl nitrite (0.62 g, 6 mmol) were added to 2-(2,5-dimethylphenoxymethyl)benzyl cyanide (1.26 g, 5 mmol). The mixture was stirred at room temperature for 2 hours. Dimethyl sulfate (0.95 g, 7.5 mmol) was added, and the mixture was stirred under ice-cooling for 10 minutes and at room temperature for 1 hour. After completion of the reaction, toluene (10 ml) and 1N aqueous sodium hydroxide solution (10 ml) were added, and the mixture was stirred at room temperature for 1 hour. After stirring, water (100 ml) was added. The mixture was extracted with ether (100 ml), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (ethyl acetate/n-hexane) to give 2-(2,5-dimethylphenoxymethyl)-α-methoxyiminobenzyl cyanide (1.29 g, Yield: 87.6%, E/Z=13/87).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl.[CH2:8]([O:15][C:16](=[O:37])[C@H:17]([CH:34]([CH3:36])[CH3:35])[NH:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[C:32]#[N:33])=[CH:22][CH:21]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[C:38](Cl)(=[O:43])[CH2:39][CH2:40][CH2:41][CH3:42]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O.ClCCl>[CH2:8]([O:15][C:16](=[O:37])[C@H:17]([CH:34]([CH3:35])[CH3:36])[N:18]([CH2:19][C:20]1[CH:21]=[CH:22][C:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[C:32]#[N:33])=[CH:24][CH:25]=1)[C:38](=[O:43])[CH2:39][CH2:40][CH2:41][CH3:42])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CC(C)[C@H](NCc1ccc(-c2ccccc2C#N)cc1)C(=O)OCc1ccccc1
Reactant: CCCCC(=O)Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: O
Product: CCCCC(=O)N(Cc1ccc(-c2ccccc2C#N)cc1)[C@H](C(=O)OCc1ccccc1)C(C)C
Reaction time: 0.21 h

Procedure:
A mixture of potassium carbonate (95.3 g) and de-mineralized water (100 ml) was stirred for 10 to 15 minutes to dissolve the solid. The temperature of the mixture was maintained at 25° to 30° C. and dichloromethane (300 ml) was added to the mixture. (S)—N-[(2′-Cyanobiphenyl-4-yl)methyl]-(L)-valine benzyl ester hydrochloride (100 g) and tetrabutyl ammonium bromide (10.0 g) were added to the mixture. The reaction mixture was cooled to −10° to −8° C. and valeryl chloride (36.1 g) was added at −10° to −5° C. The reaction mixture was stirred for 60 to 90 minutes at 0° to 5° C. After the completion of the reaction, the temperature was raised to 25° to 30° C. De-mineralized water (200 ml) was added to the reaction mixture and the mixture was stirred for 1 hour at 25° to 30° C. The two phases were separated and the organic layer was washed with de-mineralized water (200 ml). The organic layer was concentrated at 40° to 45° C. to obtain a residual liquid containing the title compound.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]3[N:27](C(OCC)C)[N:26]=[N:25][N:24]=3)=[CH:13][CH:12]=2)[C:8]([C:33]([C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([CH:41]([O:44][CH3:45])[O:42][CH3:43])[N:36]=2)=[O:34])=[C:7]([Cl:46])[N:6]=1)[CH2:2][CH2:3][CH3:4].Cl.CO.C([O-])([O-])=O.[Na+].[Na+]>>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]3[NH:27][N:26]=[N:25][N:24]=3)=[CH:15][CH:16]=2)[C:8]([C:33]([C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([CH:41]([O:42][CH3:43])[O:44][CH3:45])[N:36]=2)=[O:34])=[C:7]([Cl:46])[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(Cl)c(C(=O)c2cccc(C(OC)OC)n2)n1Cc1ccc(-c2ccccc2-c2nnnn2C(C)OCC)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: CCCCc1nc(Cl)c(C(=O)c2cccc(C(OC)OC)n2)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 78.8 %

Procedure:
To 38 mg (0.059 mmole) of the compound obtained in step 2 of Example 1 was added 1 ml of 3% hydrogen chloride/methanol solution and the resulting solution was stirred for 10 minutes at room temperature. After being added with a small amount of Na2CO3, the resultant was concentrated under reduced pressure and purified with silica gel column chromatography to obtain 26.6 mg of the title compound (yield 78.9%).
Reaction SMILES: [C:1]([C@H:4]1[N:7]([CH:8]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[C:6](=[O:27])[C@@H:5]1[C@H:28]([OH:30])[CH3:29])([OH:3])=[O:2].S(=O)(=O)(O)O.[OH-].[Na+].[CH3:38]O>>[CH3:38][O:2][C:1]([C@H:4]1[N:7]([CH:8]([CH2:18][C:19]2[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=2)[CH2:9][C:10]2[CH:11]=[CH:12][C:13]([O:16][CH3:17])=[CH:14][CH:15]=2)[C:6](=[O:27])[C@@H:5]1[C@H:28]([OH:30])[CH3:29])=[O:3]
Reactant: COc1ccc(CC(Cc2ccc(OC)cc2)N2C(=O)[C@H]([C@@H](C)O)[C@H]2C(=O)O)cc1
Reactant: CO
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: COC(=O)[C@@H]1[C@@H]([C@@H](C)O)C(=O)N1C(Cc1ccc(OC)cc1)Cc1ccc(OC)cc1
Temperature: 40 °C

Procedure:
To a solution of (3S,4S)-4-carboxy-3-(1-(R)-hydroxyethyl)-1-di(p-anisyl)methyl-2-azetidinone (34 g) in methanol (310 ml), there was added 98% sulfuric acid (2.9 g). The resultant mixture was heated at 65° C. for 3 hours, cooled down to 40° C., neutralized with 8% aqueous sodium hydroxide solution (15 ml) and concentrated to make a one third volume. The concentrate was diluted with 1,2-dichloroethane (105 ml) and washed with water. The aqueous layer was separated from the organic layer and extracted with 1,2-dichloroethane (105 ml). The extract was combined with the organic layer, washed with water and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated in vacuo to give (3S,4S)-4-methoxycarbonyl-3-(1-(R)-hydroxyethyl)-1-di(p-anisyl)methyl-2-azetidinone. m.p., 102°-104° C.
Reaction SMILES: [OH:1][N:2]=[C:3]([Cl:17])[C@H:4]1[C@H:8]([CH2:9][O:10][CH3:11])[O:7][C:6]2([CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[O:5]1.[CH3:18][S:19](Cl)(=[O:21])=[O:20].C(N(CC)CC)C>>[CH3:11][O:10][CH2:9][C@@H:8]1[O:7][C:6]2([CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[O:5][C@H:4]1[C:3]([Cl:17])=[N:2][O:1][S:19]([CH3:18])(=[O:21])=[O:20]
Reactant: COC[C@@H]1OC2(CCCCC2)O[C@H]1C(Cl)=NO
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Product: COC[C@@H]1OC2(CCCCC2)O[C@H]1C(Cl)=NOS(C)(=O)=O
Reaction time: 0.5 h
Yield: 49 %

Procedure:
(2R,3S)-N-hydroxy-3-(methoxymethyl)-1,4-dioxaspiro[4.5]decane-2-carbimidoyl chloride (35.6 g, 135.0 mmol) was dissolved in Et2OH (600 mL) and cooled in an ice bath. Methanesulfonyl chloride (10.49 ml, 135.0 mmol) was added, followed by dropwise addition of triethylamine (18.82 ml, 135.0 mmol). The reaction was stirred for 30 minutes and then filtered and concentrated. The residue was purified on 1 Kg SiO2 (1 to 5% EtOAc in CH2Cl2) to afford (2R,3S)-3-(methoxymethyl)-N-(methylsulfonyloxy)-1,4-dioxaspiro[4.5]decane-2-carbimidoyl chloride (22.6 g, 66.12 mmol, 48.98% yield).
Reaction SMILES: Br[CH:2]1[CH2:6][CH2:5][CH2:4][CH2:3]1.[O:7]=[CH:8][C:9]1[CH:17]=[CH:16][C:14]([OH:15])=[C:11]([O:12][CH3:13])[CH:10]=1.C(=O)([O-])[O-].[K+].[K+]>CCO>[CH:2]1([O:15][C:14]2[CH:16]=[CH:17][C:9]([CH:8]=[O:7])=[CH:10][C:11]=2[O:12][CH3:13])[CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: BrC1CCCC1
Reactant: COc1cc(C=O)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: COc1cc(C=O)ccc1OC1CCCC1
Yield: 97.7 %

Procedure:
Bromocyclopentane (7.0 mL, 66 mmol) was added to a suspension of vanillin (5.0 g, 33 mmol) and potassium carbonate (13.6 g, 99 mmol) in EtOH (75 mL) and treated according to Procedure 3. 4-Cyclopentyloxy-3-methoxybenzaldehyde (7.1 g, 98%) was obtained as a yellow oil; δH (400 MHz, CDCl3) 1.62 (m, 2H, CH2), 1.78-2.04 (m, 6H, CH2), 3.89 (s, 3H, OCH3), 4.86 (tt, J=6.0, 3.2 Hz, 1H, OCH), 6.94 (d, J5,6=8.0 Hz, 1H, H5), 7.38 (d, J2,6=2.0 Hz, 1H, H2), 7.41 (dd, J5,6=8.0, J2,6=2.0 Hz, 1H, H6), 9.82 (s, 1H, CHO); δC (100 MHz, CDCl3) 24.1, 32.8, 56.0, 80.6, 109.4, 112.8, 126.6, 129.5, 150.2, 153.4, 190.9; vmax 977, 1260, 1504, 1580, 1680, 2869, 2956 cm−1.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[C:5]([CH2:16][C:17]([O:19]CC1C=CC=CC=1)=[O:18])([N:11]1[CH:15]=[CH:14][CH:13]=[CH:12]1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2]>O1CCOCC1.[C].[Pd]>[CH2:1]([O:3][C:4](=[O:27])[C:5]([CH2:16][C:17]([OH:19])=[O:18])([N:11]1[CH:12]=[CH:13][CH:14]=[CH:15]1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2]
Reactant: CCOC(=O)C(CC(=O)OCc1ccccc1)(C(=O)OCC)n1cccc1
Agent: [Pd]
Solvent: C1COCCO1
Product: CCOC(=O)C(CC(=O)O)(C(=O)OCC)n1cccc1
Yield: 80.2 %

Procedure:
A mixture of 2-benzyloxycarbonylmethyl-2-(pyrrol-1-yl)malonic acid diethyl ester (80.0 g) in dioxane (150 ml) was hydrogenated over 10% palladium-carbon (500 mg) at 40° C. After the calculated amount of hydrogen was absorbed, the catalyst was filtered off and the filtrate was evaporated under reduced pressure. The residue was recrystallized from ethyl acetate/n-hexane to give the title compound (48.7 g, 80.2%) as colorless crystals, mp 93°-94° C.
Reaction SMILES: N#CBr.C[N:5]1[CH2:10][CH2:9][CH2:8][CH:7]([CH2:11][C:12]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=[O:13])[CH2:6]1.C(N1CCCC(CC(C2C=CC(F)=CC=2)=O)C1)#N.Cl.[C:40]([OH:47])(=[O:46])/[CH:41]=[CH:42]\[C:43]([OH:45])=[O:44]>C(OCC)C.O.C(O)(=O)C.C1C=CC=CC=1>[C:40]([OH:47])(=[O:46])/[CH:41]=[CH:42]\[C:43]([OH:45])=[O:44].[F:20][C:17]1[CH:16]=[CH:15][C:14]([C:12](=[O:13])[CH2:11][CH:7]2[CH2:8][CH2:9][CH2:10][NH:5][CH2:6]2)=[CH:19][CH:18]=1
Reactant: CN1CCCC(CC(=O)c2ccc(F)cc2)C1
Agent: Cl
Agent: N#CBr
Agent: N#CN1CCCC(CC(=O)c2ccc(F)cc2)C1
Solvent: O
Solvent: CCOCC
Solvent: CC(=O)O
Product: O=C(CC1CCCNC1)c1ccc(F)cc1

Procedure:
The procedure of Example 19 was repeated to give 19 g of crude 1-cyano-3-(4-fluorophenacyl)piperidine, except that 5.4 g of cyanogen bromide, 10.0 g of 1-methyl-3-(4-fluorophenacyl)piperidine (Example 3), and 110 ml of benzene were employed and the addition was carried out at ambient temperature over a 45-minute period. The crude cyanopiperidine was hydrolyzed as described in Example 21, using as the hydrolysis mixture a solution consisting of 80 ml of glacial acetic acid, 40 ml of water, and 20 ml of concentrated hydrochloric acid; hydrolysis time was increased to 19 hours. The final residue was taken up in diethyl ether and combined with a solution of 2.6 g of maleic acid in 200 ml of diethyl ether. An oil separated which crystallized upon standing. The solid, 5.5 g, was recrystallized 3 times from acetone/diethyl ether to give 3-(4-fluorophenacyl)piperidine, maleate salt, mp 131°-132°. The following elemental analysis was obtained:
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]([CH:11]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12]2)[CH:8]=[CH:9][CH:10]=1)=[O:4].[OH-].[Na+]>CCO.O>[C:19]([O:18][C:16]([N:13]1[CH2:14][CH2:15][CH:11]([C:7]2[CH:6]=[C:5]([CH:10]=[CH:9][CH:8]=2)[C:3]([OH:4])=[O:2])[CH2:12]1)=[O:17])([CH3:22])([CH3:20])[CH3:21]
Reactant: COC(=O)c1cccc(C2CCN(C(=O)OC(C)(C)C)C2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(c2cccc(C(=O)O)c2)C1
Temperature: 29 °C
Reaction time: 0.5 h
Yield: 98 %

Procedure:
To a solution of tert-butyl 3-(3-(methoxycarbonyl)phenyl)pyrrolidine-1-carboxylate (210 mg, 0.7 mmol) in EtOH (4 ml) was added a solution of NaOH (56 mg, 1.4 mmol) in H2O (1 ml) at 29° C. The mixture was stirred for 30 min at 29° C. The mixture was concentrated and the residue was treated with water and extracted with EA. The water layer was treated with 2N HCl until pH=3, extracted with EA and the combined organic layers were washed with brine, dried over Na2SO4 and concentrated to give the title compound which was used in next step without further purification (200 mg, Yield 98.0%).
Reaction SMILES: F[C:2]1[N:6]([CH3:7])[N:5]=[C:4]([C:8]([F:14])([F:13])[C:9]([F:12])([F:11])[F:10])[C:3]=1[C:15]([F:18])([F:17])[F:16].[CH2:19]([SH:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(N(CC)CC)C>C(#N)C>[CH2:19]([S:26][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([C:8]([F:14])([F:13])[C:9]([F:12])([F:11])[F:10])[C:3]=1[C:15]([F:18])([F:17])[F:16])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: SCc1ccccc1
Reactant: Cn1nc(C(F)(F)C(F)(F)F)c(C(F)(F)F)c1F
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cn1nc(C(F)(F)C(F)(F)F)c(C(F)(F)F)c1SCc1ccccc1
Reaction time: 2 h
Yield: 77.8 %

Procedure:
A solution of 3.00 g (10.5 mmol) of 5-fluoro-1-methyl-3-(pentafluoroethyl)-4-(trifluoromethyl)-1H-pyrazole and 1.48 ml (12.6 mmol) of benzylmercaptan is initially introduced into 24 ml of acetonitrile at 0° C. 4.78 ml (34.3 mmol) of triethylamine are then added dropwise and the reaction mixture is stirred for two hours at between 0° C. and 10° C. Following concentration by evaporation in vacuo, the resulting oil is purified by chromatography on silica gel, giving 3.19 g of 5-(benzylsulphanyl)-1-methyl-3-(pentafluoroethyl)-4-(trifluoromethyl)-1H-pyrazole (78%).