Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]([O:8]CC)=[CH:4][CH2:5][CH:6]=[CH2:7]>S(=O)(=O)(O)O>[F:1][C:2]([F:12])([F:11])[C:3](=[O:8])[CH2:4][CH2:5][CH:6]=[CH2:7]
Reactant: C=CCC=C(OCC)C(F)(F)F
Agent: O=S(=O)(O)O
Product: C=CCCC(=O)C(F)(F)F
Reaction time: 0.33 h

Procedure:
A mixture of 20 ml of 1-bromo-3-butyne and 25 mmole of tirphenylphosphine in 50 ml of benzene is heated at reflux for 3 days. The solid which separates upon cooling is filtered, washed with benzene and dried under reduced pressure is afford triphenyl-3-butenylphosphonium bromide. To a solution of 100 ml of liquid ammonia is added 0.26 g of finely divided sodium and a catalytic amount of ferric nitrate. When the blue solution turns gray finely powdered triphenyl-3-butenylphosphonium bromide (2.10-2 mole) is added. The reaction mixture is stirred for 15 minutes after which the ammonia is evaporated under a stream of nitrogen. To the resulting residue is added 100 ml of benzene, and the heterogeneous mixture is heated at reflux temperature for 10 minutes. The solid residue is filtered off and the filtrate is evaporated to dryness to give 3-butenylidenephosphorane. To a solution of salt free 3-butenylidenephosphorane (2.10-2 mole) in 100 ml of benzene is added 6.6 g (5.10-2 mole) of ethyl trifluoroacetate. The reaction mixture is heated at reflux temperature for 12 hours under nitrogen. Concentration of the solvent leaves an oily residue which is purified by distillation to give 1-trifluoromethyl-1-ethoxy-1,4-pentadiene. A suspension of 10 g of 1-trifluoromethyl-1-ethoxy-1,4-pentadiene in 20 ml of 1 N aqueous sulfuric acid is stirred for 20 minutes. Continuous extraction of the mixture with ether affords 1-trifluoromethylpent-4-ene-1-one.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]#[N:9])=[N:6][CH:7]=1.[CH:10]1([CH:16]=[CH:17]B(O)O)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.C(Cl)Cl.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1>[CH:10]1(/[CH:16]=[CH:17]/[C:2]2[CH:3]=[CH:4][C:5]([C:8]#[N:9])=[N:6][CH:7]=2)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: N#Cc1ccc(Br)cn1
Reactant: OB(O)C=CC1CCCCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: ClCCl
Product: N#Cc1ccc(/C=C/C2CCCCC2)cn1
Temperature: 90 °C
Yield: 75.9 %

Procedure:
Combine a mixture of 5-bromo-2-cyano-pyridine (2 g, 10.93 mmol), 2-cyclohexylvinyl boronic acid (2.52 g, 16.39 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with DCM (446 mg, 0.546 mmol) and 2M aqueous Na2CO3 (18.2 mL, 36.07 mmol) in 1,4-dioxane (110 mL). Purge with nitrogen and heat at 90° C. overnight. Cool the reaction to room temperature and partition between EtOAc and water. Separate the aqueous phase and extract with EtOAc. Dry the combined organic extracts over MgSO4, filter and concentrate in vacuo. Purify by chromatography on silica gel (120 g, pre-packed cartridge) eluting stepwise with hexane/EtOAc (1:0 over 5 min, 49:1 over 5 min and 19:1 over 5 min; 50 mL/min) to obtain the desired intermediate (1.76 g, 76%). MS (APCI+) m/z: 213 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]([O:10]CC)=O)=[CH:6][N:5]=[C:4]2[C:13]([CH3:18])=[C:14]([CH2:16][OH:17])[S:15][C:3]=12.[Cl:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][NH2:25])=[CH:22][CH:21]=1>Cl>[Cl:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][NH:25][C:8]([C:7]2[C:2]([OH:1])=[C:3]3[S:15][C:14]([CH2:16][OH:17])=[C:13]([CH3:18])[C:4]3=[N:5][CH:6]=2)=[O:10])=[CH:22][CH:21]=1
Reactant: CCOC(=O)c1cnc2c(C)c(CO)sc2c1O
Reactant: NCc1ccc(Cl)cc1
Agent: Cl
Product: Cc1c(CO)sc2c(O)c(C(=O)NCc3ccc(Cl)cc3)cnc12
Temperature: 80 °C
Yield: 92.4 %

Procedure:
Ethyl 7-hydroxy-2-(hydroxymethyl)-3-methylthieno[3,2-b]pyridine-6-carboxylate (1.27 g, 4.77 mmol) was dissolved in 4-chlorobenzylamine (11.6 mL, 95.4 mmol) and heated to 80° C. for 18 hours. After cooling to room temperature, the mixture was treated with 1 N HCl (100 mL). After chilling in the refrigerator for 2 hrs, the resulting thick precipitate was collected and washed with copious amounts of 1 N HCl until all unreacted 4-chlorobenzylamine had been washed away. The resulting off-white solid was dried in vacuo to give the title compound (1.60 g). 1H NMR (DMSO-d6) δ 2.27 (3 H), 4.53 (2 H), 4.72 (2 H), 5.06 (1 H), 7.38 (4 H), 8.52 (1 H), 10.49 (1 H), 12.95 (1 H). HPLC retention time: 2.73 minutes; MS (ESI−) for C17H15ClN2O3S m/z 361, 363.
Reaction SMILES: Br[C:2]([F:9])([F:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[N+:10]([C:13]1[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=1[CH:15]=[O:16])([O-:12])=[O:11]>C1COCC1.CCOC(C)=O.[Zn]>[CH2:6]([O:5][C:3](=[O:4])[C:2]([F:9])([F:8])[CH:15]([C:14]1[CH:17]=[CH:18][CH:19]=[CH:20][C:13]=1[N+:10]([O-:12])=[O:11])[OH:16])[CH3:7]
Reactant: CCOC(=O)C(F)(F)Br
Reactant: O=Cc1ccccc1[N+](=O)[O-]
Agent: [Zn]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)C(F)(F)C(O)c1ccccc1[N+](=O)[O-]
Temperature: 23 °C
Reaction time: 3 h
Yield: 90.9 %

Procedure:
To a slurry of activated zinc (6.25 g, 99.2 mmol) in 75 mL anhydrous THF, was added ethyl bromodifluoroacetate (11.0 mL, 85.8 mmol) and the mixture was heated to reflux. After a visible reaction had occurred, 2-nitrobenzaldehyde (5.0 g, 33.1 mmol) in 30 mL anhydrous THF, was added dropwise to maintain reflux. After 3 h, the solution was cooled to 23° C., diluted with EtOAc (50 mL), washed with 1M KHSO4 (2×50 mL) and brine (1×50 mL), and dried (Na2SO4). Concentration in vacuo yielded a residue which was purified by flash chromatography (chloroform:EtOH, 99:1) to afford 2-(3-ethoxy-3-oxo-2,2-difluoro-1-hydroxypropyl)nitrobenzene (8.28 g, 91%) as an orange oil, which was taken on to the next step without further characterization.
Reaction SMILES: C[O:2][C:3](=[O:31])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([CH:16]2[CH2:21][CH2:20][N:19]([S:22]([N:25]3[CH2:29][CH2:28][CH2:27][CH2:26]3)(=[O:24])=[O:23])[CH2:18][CH2:17]2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:30])[CH:11]=2)[CH:6]=1.O.[OH-].[Li+]>C1COCC1.O>[F:30][C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][CH:9]=1)[CH:6]=[C:5]([CH2:4][C:3]([OH:31])=[O:2])[C:14]([CH3:15])=[C:13]2[CH:16]1[CH2:21][CH2:20][N:19]([S:22]([N:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)(=[O:23])=[O:24])[CH2:18][CH2:17]1
Reactant: COC(=O)Cc1cc2ccc(F)cc2c(C2CCN(S(=O)(=O)N3CCCC3)CC2)c1C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(CC(=O)O)cc2ccc(F)cc2c1C1CCN(S(=O)(=O)N2CCCC2)CC1
Reaction time: 8 h
Yield: 66.4 %

Procedure:
To a solution of {6-fluoro-3-methyl-4-[1-(pyrrolidine-1-sulfonyl)-piperidin-4-yl]-naphthalen-2-yl}-acetic acid methyl ester (86.5 mg, 0.193 mmol) in THF (8.0 mL) was added a solution of lithium hydroxide monohydrate (92.4 mg, 2.2 mmol) in water (2.0 mL) at room temperature. The resulting solution was stirred overnight under a nitrogen atmosphere. The solvent was evaporated. Water (20 mL) was added and the mixture was acidified with 1.0 N aqueous HCl (4 mL). The resulting white precipitate was collected by filtration, washed with water and hexanes, and dried under high vacuum to give {6-fluoro-3-methyl-4-[1-(pyrrolidine-1-sulfonyl)-piperidin-4-yl]-naphthalen-2-yl}-acetic acid (55.7 mg, 66%) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ 12.44 (br. s., 1H), 8.07 (br. s, 1H), 7.90 (dd, J=9.0, 6.5 Hz, 1H), 7.69 (s, 1H), 7.35 (td, J=8.5, 2.0 Hz, 1H), 3.78 (br. s., 4H), 3.22-3.43 (m, 5H), 3.09 (br. s., 2H), 2.42 (br. s., 3H), 1.81-1.97 (m, 4H), 1.67 (bd, 2H). MS cald. for C22H28FN2O4S [(M+H)+]: 434, obsd. 434.2.
Reaction SMILES: [CH3:1][CH:2]([CH2:9][CH:10]([CH3:12])[CH3:11])[CH:3]([OH:8])[CH2:4][N+:5]([O-:7])=[O:6].[C:13](OCC)(=[O:15])[CH3:14]>N1C=CC=CC=1.C(OC(=O)C)(=O)C>[C:13]([O:8][CH:3]([CH:2]([CH3:1])[CH2:9][CH:10]([CH3:12])[CH3:11])[CH2:4][N+:5]([O-:7])=[O:6])(=[O:15])[CH3:14]
Reactant: CCOC(C)=O
Reactant: CC(C)CC(C)C(O)C[N+](=O)[O-]
Solvent: c1ccncc1
Solvent: CC(=O)OC(C)=O
Product: CC(=O)OC(C[N+](=O)[O-])C(C)CC(C)C
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 87.3 %

Procedure:
After dissolving 7.8 g of 3,5-dimethyl-1-nitro-2-hexanol in 30 ml of pyridine, 10 ml of acetic anhydride were added thereto, and the solution was stirred at room temperature for 2.5 hours. Ethyl acetate was added to the solution, and the organic layer was washed with 1 mol/l of aqueous hydrochloric acid and saturated saline. The organic layer was dried with magnesium sulfate and concentrated, and then purified by silica gel chromatography (hexane/ethyl acetate=10/1), thereby obtaining 8.4 g of 3,5-dimethyl-1-nitrohex-2-yl acetate (yield: 87.3%).
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])[CH2:2][C:3]([O:5][CH3:6])=[O:4].[H-].[Na+].[C:12]([O:16][CH2:17][CH3:18])(=[O:15])[CH:13]=[CH2:14]>C1COCC1>[CH:2]([C:1]([O:8][CH3:9])=[O:7])([C:3]([O:5][CH3:6])=[O:4])[CH2:14][CH2:13][C:12]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: C=CC(=O)OCC
Reactant: COC(=O)CC(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)CCC(C(=O)OC)C(=O)OC
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 77 %

Procedure:
To a solution of dimethyl malonate (2.5 g, 18.9 mmol) in anhydrous THF (20 mL) was added NaH (0.038 g, 0.95 mmol, 60% in mineral oil). The reaction was stirred at ambient temperature for 15 minutes. In a separate flask, ethyl acrylate was dissolved in anhydrous THF (1 mL) and then added dropwise over 30 minutes to the dimethyl malonate solution. The reaction was stirred at ambient temperature for 16 h and then concentrated under vacuum. The residue was dissolved in EtOAc (ethyl acetate) and washed with saturated NH4Cl solution and brine. The organic phase was dried over Na2SO4, filtered, and concentrated under vacuum. The crude residue was purified by column chromatography (silica gel) using an EtOAc/hexanes gradient to yield the desired compound as a colorless oil (1.68 g, 77%).
Reaction SMILES: [H-].[Na+].[N:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:13][CH2:12][NH:11][C:10]2=[O:14])=[CH:5][CH:4]=1.CN(C=O)C.Br[CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23]>O>[O:14]=[C:10]1[N:9]([C:6]2[CH:5]=[CH:4][N:3]=[CH:8][CH:7]=2)[CH2:13][CH2:12][N:11]1[CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23]
Reactant: O=C1NCCN1c1ccncc1
Reactant: CC(C)(C)OC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CN1CCN(c2ccncc2)C1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66.6 %

Procedure:
Sodium hydride (60% in oil, 0.40 g, 10.1 mmol) was added to a mixture of 1-(4-pyridyl)-2-imidazolidinone (1.5 g, 9.2 mmol) and DMF (20 ml) at 0° C., and the mixture was stirred at room temperature for 30 minutes. Successively, tert-butyl bromoacetate (2.2 g, 11.2 mmol) was added to the mixture, and the mixture was stirred at room temperature for 2 hrs. The reaction mixture was combined with water and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was evaporated, and the residue was subjected to a silica gel column chromatography. The fractions eluted with ethyl acetate-methanol (5:1, v/v) were collected, concentrated and recrystallized from tetrahydrofuran-hexane to give the titled compound (1.7 g, 68%) as white crystals.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[H-].[Na+].[C:13](Cl)(=[O:22])[CH:14]=[CH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.Cl>O1CCCC1>[C:13]([NH:6][C:4](=[O:5])[C:3]1[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=1[F:1])(=[O:22])/[CH:14]=[CH:15]/[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(Cl)C=Cc1ccccc1
Reactant: NC(=O)c1ccccc1F
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(/C=C/c1ccccc1)NC(=O)c1ccccc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.9 %

Procedure:
Under an argon atmosphere, 2-fluorobenzamide (1.41 g, 10.0 mmol), sodium hydride (60% dispersion in mineral oil, 1.04 g, 25.0 mmol) and tetrahydrofuran (3 mL) were stirred under ice-cooling. A solution of cinnamoyl chloride (1.68 g, 10.0 mmol) in tetrahydrofuran (3 mL) was added thereto, and the mixture was warmed to room temperature. After stirring for 1 hr, to the mixture was added diluted hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with aqueous sodium hydrogencarbonate, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was crystallized from ethyl acetate/n-hexane to give the title compound (1.91 g) as a white solid. The yield was 70%.
Reaction SMILES: [CH:1]([CH:21]1[CH2:26][C:25](=[O:27])O[C:22]1=[O:23])=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].[NH3:28]>>[CH:1]([CH:21]1[CH2:26][C:25](=[O:27])[NH:28][C:22]1=[O:23])=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: N
Reactant: CCCCCCCCCCCCCCCCCCC=CC1CC(=O)OC1=O
Product: CCCCCCCCCCCCCCCCCCC=CC1CC(=O)NC1=O
Temperature: 160 °C

Procedure:
In another reaction vessel was placed 570 grams of the above isomerized eicosenyl succinic anhydride. This was heated to 160° C. and ammonia injection started. The temperature rose to 175° C. Ammonia injection was continued at 175° C. until the temperature dropped. Then 30" Hg vacuum was slowly applied to distill out water and ammonia. Additional ammonia was injected to be sure no anhydride remained. There was no further reaction so this ammonia was stripped out at 30" Hg vacuum at 170° C. yielding isomerized eicosenyl succinimide.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:10])[C:5]([NH2:9])=[CH:6][C:7]=1[CH3:8].[F:11][C:12]([F:19])([F:18])[CH:13]([OH:17])[C:14](O)=O.Cl.C(=O)(O)[O-].[Na+]>O.C(OCC)(=O)C>[Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]2[NH:9][C:14]([CH:13]([OH:17])[C:12]([F:19])([F:18])[F:11])=[N:10][C:4]=2[CH:3]=1
Reactant: O=C(O)C(O)C(F)(F)F
Reactant: Cc1cc(N)c(N)cc1Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1cc2[nH]c(C(O)C(F)(F)F)nc2cc1Cl
Temperature: 108 °C

Procedure:
4-Chloro-5-methyl-benzene-1,2-diamine (5.06 g; 32.3 mmoles) and 3,3,3-trifluoro-2-hydroxy-propionic acid (7.11 g; 49.4 mmoles) were suspended in 6N HCl (12 mL; 72 mmoles) under a nitrogen atmosphere. The reaction was stirred vigorously and heated to 108° C. for 18 hrs, then cooled to room temperature. The reaction was diluted with water (100 mL) and with ethyl acetate (100 mL), then sodium bicarbonate (9.12 g; 109 mmoles) was added slowly and in portions to quench the reaction. The aqueous layer was separated and extracted with ethyl acetate (3×40 mL). The extracts were combined, washed with water (30 mL) and brine (30 mL), then dried over Na2SO4. The filtrate was concentrated in vacuo to yield a crude brown solid which was then purified by column chromatography (SiO2; 30% ethyl acetate/CH2Cl2) to yield the title compound as a purple/brown solid.
Reaction SMILES: C1(N[C:7]2[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]=[C:9]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[N:8]=2)CCCC1.[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][CH:25]=1>>[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][C:7]2[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]=[C:9]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[N:8]=2)=[CH:26][CH:25]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: Cc1nc(NCc2ccccn2)nc(NC2CCCC2)c1C
Product: Cc1nc(NCc2ccccn2)nc(Nc2ccc(Cl)cc2)c1C

Procedure:
The titled compound was synthesized according to the procedure described for preparation of N4-cyclopentyl-5,6-dimethyl-N2-(pyridin-2-ylmethyl)pyrimidine-2,4-diamine (Example 29) using (4-chlorophenyl)amine instead of cyclopentanamine. The crude material was purified by column chromatography eluting with mixture of chloroform/ethanol/20% water solution of ammonia (200:10:1), and then the final product was washed with diethyl ether to afford the titled compound as a white solid. 1H NMR (300 MHz, CDCl3) δ ppm 2.06 (s, 3H), 2.33 (s, 3H), 4.60 (d, J=3.0 Hz, 2H), 5.77 (bs, 1H), 6.30 (bs, 1H), 7.13-7.20 (m, 3H), 7.32 (d, J=6.8 Hz, 1H), 7.43 (d, J=7.8 Hz, 2H), 7.61 (t, J=7.6 Hz, 1H), 8.58 (d, J=3.4 Hz, 1H); MS (ESI) m/z 340.6 (M+1)+.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4](=[O:18])[C:5]([C:16]#[N:17])=[C:6]2[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[C:8](=[O:15])[C:7]=12.S(=O)(=O)(O)[OH:20]>O>[CH3:1][C:2]1[NH:3][C:4](=[O:18])[C:5]([C:16]([NH2:17])=[O:20])=[C:6]2[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[C:8](=[O:15])[C:7]=12
Reactant: O=S(=O)(O)O
Reactant: Cc1[nH]c(=O)c(C#N)c2c1C(=O)c1ccccc1-2
Solvent: O
Product: Cc1[nH]c(=O)c(C(N)=O)c2c1C(=O)c1ccccc1-2

Procedure:
A mixture of approximately 2 parts of 3,9-dihydro-1-methyl-3,9-dioxo-2H-indeno[2,1-c]pyridine-4-carbonitrile, 37 parts of concentrated sulfuric acid, and 1 part of water is heated at 90°-95° for 2 hours, then slowly diluted with 175 parts of water. The precipitate which forms is filtered off, washed with methanol, dried in vacuo, and crystallized from aqueous N,N-dimethylformamide to give 3,9-dihydro-1-methyl-3,9-dioxo-2H-indeno[2,1-c]pyridine-4-carboxamide as a pale yellow solid melting above 300°. The product has the formula ##STR17##
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([C@@H:13]([CH2:23][C@H:24]3[CH2:28][CH2:27][NH:26][CH2:25]3)[C:14]([NH:16][C:17]3[S:18][C:19]([F:22])=[CH:20][N:21]=3)=[O:15])=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.[CH3:29][NH:30][C:31](=O)[O:32]C1C=CC=CC=1.[OH-].[Na+].O>O1CCCC1>[CH:1]1([S:4]([C:7]2[CH:8]=[CH:9][C:10]([C@H:13]([C:14]([NH:16][C:17]3[S:18][C:19]([F:22])=[CH:20][N:21]=3)=[O:15])[CH2:23][C@H:24]3[CH2:28][CH2:27][N:26]([C:31]([NH:30][CH3:29])=[O:32])[CH2:25]3)=[CH:11][CH:12]=2)(=[O:5])=[O:6])[CH2:3][CH2:2]1
Reactant: CNC(=O)Oc1ccccc1
Reactant: O=C(Nc1ncc(F)s1)[C@H](C[C@H]1CCNC1)c1ccc(S(=O)(=O)C2CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CNC(=O)N1CC[C@H](C[C@@H](C(=O)Nc2ncc(F)s2)c2ccc(S(=O)(=O)C3CC3)cc2)C1
Reaction time: 1.5 h
Yield: 74.7 %

Procedure:
(R)-2-(4-(Cyclopropylsulfonyl)phenyl)-N-(5-fluorothiazol-2-yl)-3-((S)-pyrrolidin-3-yl)propanamide (500 mg, 1.05 mmol) was dissolved in tetrahydrofuran (40 mL), and thereafter, phenyl N-methylcarbamate (636 mg, 4.21 mmol) and an aqueous solution of sodium hydroxide (2 M, 2 mL) were added to the above obtained solution under ice-cold condition. The obtained mixture was stirred for 1.5 hours. Thereafter, water was added to the reaction solution, and the mixed solution was then extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and was then concentrated in vacuo. The obtained residue was purified by silica gel chromatography (chloroform/methanol=1%→15%) to obtain the captioned compound (377 mg, 75%) in the form of a white solid.
Reaction SMILES: Cl.[C:2]1([CH:8]([CH3:23])[CH2:9][CH2:10][CH2:11][C:12]2[N:13]=[C:14]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[S:15][CH:16]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:24][C:25]1[N:29]([CH2:30][C:31](O)=[O:32])[N:28]=[C:27]([C:34]([F:37])([F:36])[F:35])[CH:26]=1>>[CH3:24][C:25]1[N:29]([CH2:30][C:31]([N:20]2[CH2:19][CH2:18][CH:17]([C:14]3[S:15][CH:16]=[C:12]([CH2:11][CH2:10][CH2:9][CH:8]([C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[CH3:23])[N:13]=3)[CH2:22][CH2:21]2)=[O:32])[N:28]=[C:27]([C:34]([F:36])([F:35])[F:37])[CH:26]=1
Reactant: CC(CCCc1csc(C2CCNCC2)n1)c1ccccc1
Reactant: Cc1cc(C(F)(F)F)nn1CC(=O)O
Agent: Cl
Product: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCC(c2nc(CCCC(C)c3ccccc3)cs2)CC1

Procedure:
tert-Butyl 4-{4-[(1Z)-4-phenylpent-1-en-1-yl]-1,3-thiazol-2-yl}piperidine-1-carboxylate (IV-4, 1.00 g) is dissolved in methanol and, at 40° C., hydrogenated under an H2-pressure of 10 bar in the presence of Pd/C (10%) for 5 hours. Filtration and removal of the solvent under reduced pressure gives tert-butyl 4-[4-(4-phenylpentyl)-1,3-thiazol-2-yl]piperidine-1-carboxylate (1.00 g) as a colourless oil. This is deprotected analogously to Example II-2. This gives 850 mg of 4-[4-(4-phenylpentyl)-1,3-thiazol-2-yl]piperidine hydrochloride. 169 mg are then reacted analogously to Example I-81 with [5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetic acid (100 mg). After chromatographic purification, this gives 2-[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]-1-{4-[4-(4-phenylpentyl)-1,3-thiazol-2-yl]piperidin-1-yl}ethanone (180 mg) as a colourless oil.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:11]([O:13][CH3:14])=[O:12])[C:7](=[O:10])[NH:8][CH:9]=1)([O-:3])=[O:2].[F:15][C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=1>N1C=CC=CC=1.O1CCOCC1.N.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[F:15][C:16]1[CH:21]=[CH:20][C:19]([N:8]2[CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[C:6]([C:11]([O:13][CH3:14])=[O:12])[C:7]2=[O:10])=[CH:18][CH:17]=1
Reactant: COC(=O)c1cc([N+](=O)[O-])c[nH]c1=O
Reactant: OB(O)c1ccc(F)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: N
Solvent: c1ccncc1
Solvent: C1COCCO1
Product: COC(=O)c1cc([N+](=O)[O-])cn(-c2ccc(F)cc2)c1=O
Temperature: 80 °C
Reaction time: 4 h
Yield: 52.3 %

Procedure:
A mixture of methyl 5-nitro-2-oxo-1,2-dihydropyridine-3-carboxylate (850 mg, 4.29 mmol), 4-fluorophenylboronic acid (1.40 g, 10 mmol, Combi-Blocks) and copper acetate (200 mg, 1.1 mmol) in pyridine (1 mL) and dioxane (20 mL) was stirred at 80° C. for 4 h. The reaction mixture was cooled to room temperature and diluted with a solution of ammonia. The solid was collected, washed with water and dried to afford the title compound (656 mg, 52%). 1H NMR (DMSO-d6) δ 8.95 (d, 1H, J=3.2 Hz), 8.80 (d, 1H, J=3.2 Hz), 7.40 (m, 2H), 7.25 (m, 2H), 3.95 (s, 3H); MS(ESI+) m/z 293 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:9]([O:20][CH3:21])=[CH:8][C:5]=1[C:6]#[N:7])([O-])=O.[Na]>C(Cl)Cl.O.S(S([O-])=O)([O-])=O.[Na+].[Na+]>[NH2:1][C:4]1[CH:11]=[C:10]([O:12][CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:9]([O:20][CH3:21])=[CH:8][C:5]=1[C:6]#[N:7]
Reactant: COc1cc(C#N)c([N+](=O)[O-])cc1OCc1ccccc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Agent: [Na]
Solvent: ClCCl
Solvent: O
Product: COc1cc(C#N)c(N)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.6 %

Procedure:
2-nitro-4-benzyloxy-5-methoxybenzonitrile (40 g, 125 mmol) tetrabutylammonium chloride (21 g, 75 mmol) in methylenechloride (500 ml) was treated with Na2S2O4 (180 g, 87.9 mmol) in H2O (700 ml), sodium hydrosulfite was added over 45 minutes, and the mixture was stirred for 2 hours at room temperature. Sodium hydroxyde was added (pH 8.2) the mixture was extracted with methylene chloride. The organic phase was made acidic with HCl-ether (2.3N, 250 ml), the solid was recovered, suspended in methanol (250 ml) and treated with a saturated solution of sodium bicarbonate (pH 8.1). The solid was recovered, washed with water, ether to give title compound (30.7 g, 97%).
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][C@H:11]([OH:23])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].ClC(Cl)(Cl)C(=N)O[CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.ClCCl.C(=O)(O)[O-].[Na+]>FC(F)(F)S(O)(=O)=O.C1CCCCC1>[CH2:28]([O:23][C@H:11]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:10][CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: N=C(OCc1ccccc1)C(Cl)(Cl)Cl
Reactant: CCCCCCCCCCC[C@@H](O)CCO[Si](C)(C)C(C)(C)C
Agent: O=C([O-])O
Agent: O=S(=O)(O)C(F)(F)F
Agent: [Na+]
Solvent: C1CCCCC1
Solvent: ClCCl
Product: CCCCCCCCCCC[C@H](CCO[Si](C)(C)C(C)(C)C)OCc1ccccc1
Yield: 88.6 %

Procedure:
Trifluoromethanesulphonic acid (0.14 mL, 1.6 mmol) was added to a mixture of alcohol 10 (6.9 g, 20 mmol) and benzyl trichloroacetimidate (12.3 g, 49 mmol) in a 1:1 mixture of dichloromethane and cyclohexane (320 mL) at room temperature. After completion of the reaction (5 h) a saturated solution of sodium bicarbonate (50 mL) was added and the phases were separated. The aqueous phase was extracted with ethyl acetate (2×50 mL) and the organic phases were washed with brine (50 mL), dried (MgSO4), and concentrated in vacuo. The product was purified by flash chromatography to afford compound 45 as an oil (Rf 0.18, silica, 2% ethyl acetate in hexane, 7.7 g, 88%).