Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[CH:8]=[CH:9][C:10]([CH3:34])=[C:11]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[C:19](=[O:23])[N:18]([CH2:24][C:25]3[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=3)[CH:17]=[C:16]4[C:31](O)=[O:32])[CH:12]=2)=[O:6])[CH2:3][CH2:2]1.[NH2:35][CH:36]1[CH2:41][CH2:40][N:39]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:38][CH2:37]1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>O1CCCC1>[C:45]([O:44][C:42]([N:39]1[CH2:40][CH2:41][CH:36]([NH:35][C:31]([C:16]2[C:15]3[C:20](=[CH:21][CH:22]=[C:13]([C:11]4[CH:12]=[C:7]([C:5](=[O:6])[NH:4][CH:1]5[CH2:2][CH2:3]5)[CH:8]=[CH:9][C:10]=4[CH3:34])[CH:14]=3)[C:19](=[O:23])[N:18]([CH2:24][C:25]3[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=3)[CH:17]=2)=[O:32])[CH2:37][CH2:38]1)=[O:43])([CH3:48])([CH3:46])[CH3:47]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(Cc3ccncc3)cc(C(=O)O)c2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(Cc3ccncc3)cc(C(=O)NC3CCN(C(=O)OC(C)(C)C)CC3)c2c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of the product of Example 54 step iii) (0.1 g), 4-amino-N-boc-piperadine (0.05 g) and N,N-diisopropylethylamine (0.25 mL) in tetrahydrofuran (10 mL) was added HATU (0.16 g) and the mixture stirred at room temperature for 3 hours. The reaction mixture was then concentrated to dryness and the crude product purified HPLC to give the sub-title compound (0.09 g).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([S:10]([NH2:13])(=[O:12])=[O:11])[CH:6]=[C:7]([I:9])[CH:8]=1)#[N:2].[H-].[Na+].[C:16](OC(=O)C)(=[O:18])[CH3:17]>CN(C)C=O>[C:16]([NH:13][S:10]([C:5]1[CH:6]=[C:7]([I:9])[CH:8]=[C:3]([C:1]#[N:2])[CH:4]=1)(=[O:12])=[O:11])(=[O:18])[CH3:17]
Reactant: N#Cc1cc(I)cc(S(N)(=O)=O)c1
Reactant: CC(=O)OC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)NS(=O)(=O)c1cc(I)cc(C#N)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 3.08 g. (10 mmoles) of 3-cyano-5-iodobenzenesulfonamide in 30 ml. of dimethylformamide is treated with 420 mg. (10 mmoles) of 57% sodium hydride emulsion. When the initial reaction subsides, the mixture is heated in a warm water bath for one hour. 2.8 Ml. (30 mmoles) of acetic anhydride is added and the solution becomes cloudy. The mixture is stirred for one hour and poured into an ice water mixture. After 30 minutes of stirring, the precipitate is filtered, washed with water, methanol and ether affording 2.97 g. (85%) of N-acetyl-3-cyano-5-iodobenzenesulfonamide melting point 249° to 251°C.
Reaction SMILES: [CH2:1]([O:8][C:9]([CH2:11][CH2:12][CH2:13][C@H:14]([N:41]=[C:42]=[O:43])[C:15]([O:17][C@@H:18]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[CH2:19][C:20]([O:22][CH2:23][C:24]([Cl:27])([Cl:26])[Cl:25])=[O:21])=[O:16])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:44][NH:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][N:47]=1.C(OCC)(=O)C>ClCCl>[CH2:1]([O:8][C:9]([CH2:11][CH2:12][CH2:13][C@H:14]([NH:41][C:42]([N:45]([CH3:44])[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][N:47]=1)=[O:43])[C:15]([O:17][C@@H:18]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[CH2:19][C:20]([O:22][CH2:23][C:24]([Cl:26])([Cl:25])[Cl:27])=[O:21])=[O:16])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CNc1ccccn1
Reactant: CCCCCCCCCCCCC[C@@H](CC(=O)OCC(Cl)(Cl)Cl)OC(=O)[C@H](CCCC(=O)OCc1ccccc1)N=C=O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCCCCCCCCCCCC[C@@H](CC(=O)OCC(Cl)(Cl)Cl)OC(=O)[C@H](CCCC(=O)OCc1ccccc1)NC(=O)N(C)c1ccccn1
Yield: 65.1 %

Procedure:
A solution of (3S)-(2,2,2-trichloroethyl) 3-[(2S)-5-benzyloxycarbonyl-2-isocyanatopentanoyl]oxyhexadecanoate (0.33 g) and 2-(methylamino)pyridine (113 mg) in dichloromethane (5 ml) was stirred at room temperature overnight. The mixture was poured into ethyl acetate (20 ml), and washed with aqueous 1 N-hydrochloric acid (20 ml×2), saturated sodium bicarbonate (20 ml), and brine (20 ml). Then, the solution was dried over magnesium sulfate, and evaporated to dryness. The residue was chromatographed on a silica gel to give (3S)-(2,2,2-trichloroethyl) 3-[(2S)-5-benzyloxycarbonyl-2-{3-methyl-3-(2-pyridyl)ureido}pentanoyl]oxyhexadecanoate (0.25 g).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[N:8][C:7]=12)#[CH:2].Br[C:27]1[CH:32]=[CH:31][C:30]([S:33]([NH:36][CH2:37][CH2:38][O:39][CH3:40])(=[O:35])=[O:34])=[CH:29][CH:28]=1>>[CH3:40][O:39][CH2:38][CH2:37][NH:36][S:33]([C:30]1[CH:31]=[CH:32][C:27]([C:2]#[C:1][C:3]2[CH:4]=[N:5][N:6]3[C:11]([C:12]([F:14])([F:13])[F:15])=[CH:10][C:9]([C:16]4[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=4)=[N:8][C:7]=23)=[CH:28][CH:29]=1)(=[O:34])=[O:35]
Reactant: COCCNS(=O)(=O)c1ccc(Br)cc1
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: COCCNS(=O)(=O)c1ccc(C#Cc2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)cc1

Procedure:
The title compound was prepared from 3-ethynyl-7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.1) (355 mg, 1.0 mmol) and 4-bromo-N-(2-methoxy-ethyl)-benzenesulfonamide (example B.28) (276 mg, 1.0 mmol) according to general procedure II. Obtained as a yellow solid (400 mg, 70%). MS (ISP) 569.1 [(M+H)+]; mp 185-187° C.
Reaction SMILES: CCCCCC.C([Li])CCC.[CH2:12]([O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[F:27][C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][C:35]=1[O:36][CH3:37])[CH:31]=[O:32].[Cl-].[NH4+]>C1COCC1>[CH2:12]([O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH:31]([C:30]1[CH:33]=[CH:34][C:35]([O:36][CH3:37])=[C:28]([F:27])[CH:29]=1)[OH:32])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: COc1ccc(C=O)cc1F
Reactant: Brc1ccccc1OCc1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1ccc(C(O)c2ccccc2OCc2ccccc2)cc1F
Reaction time: 0.5 h
Yield: 96.3 %

Procedure:
In a nitrogen stream, an n-butyllithium hexane solution (1.54 M, 6.79 mL) was added dropwise to a solution of 1-benzyloxy-2-bromobenzene (2.5 g, 9.50 mmol) in THF (30 mL) at −78° C. and the mixture was stirred at the same temperature for 30 minutes. To this solution, a solution of 3-fluoro-4-methoxybenzaldehyde (1.32 g, 8.56 mmol) in THF (8 mL) was added dropwise at −78° C. The mixture was stirred at the same temperature for one hour, and then a saturated ammonium chloride aqueous solution was added thereto and the mixture was extracted with ethyl acetate, and the organic layer was washed with a saturated sodium chloride aqueous solution and dried (anhydrous magnesium sulfate), and then the solvent was distilled under reduced pressure. The obtained residue was purified by silica gel column chromatography [developing solution=ethyl acetate:n-hexane (1:5)] to obtain the title compound (2.79 g, 96%).
Reaction SMILES: Cl.C(O[C:5](=[O:9])[CH2:6][NH:7][CH3:8])C.[Cl:10][C:11]1[CH:16]=[C:15]([N:17]=[C:18]=[O:19])[CH:14]=[C:13]([Cl:20])[N:12]=1>C(Cl)Cl>[Cl:10][C:11]1[CH:16]=[C:15]([N:17]2[C:5](=[O:9])[CH2:6][N:7]([CH3:8])[C:18]2=[O:19])[CH:14]=[C:13]([Cl:20])[N:12]=1
Reactant: O=C=Nc1cc(Cl)nc(Cl)c1
Reactant: CCOC(=O)CNC
Agent: Cl
Solvent: ClCCl
Product: CN1CC(=O)N(c2cc(Cl)nc(Cl)c2)C1=O
Temperature: 5 °C
Reaction time: 96 h
Yield: 155.4 %

Procedure:
TEA (7.2 ml, 51 mmol) was added to a suspension of the HCl salt of sarcosine ethyl ester (3.4 g, 24.5 mmol) in dry DCM (80 ml). The formed triethylamine hydrochloride was filtered off and rinsed with DCM (20 ml). The filtrate was transferred into a 3-necked round bottom flask and cooled to 5° C. A solution of 2,6-dichloropyridin-4-yl isocyanate (10 g, 53 mmol) in DCM (25 ml) was added dropwise over 10 min while keeping the inner temperature below 10° C. After 96 h at RT, the reaction mixture was refluxed for 10 h. After cooling to RT, the solution was washed with brine, dried over MgSO4 and concentrated. The obtained amorphous solid was chromatographed over silica gel (eluent: cyclohexane/EtOAc 80/20 to 50/50) to yield the above titled compound as a white solid (9.9 g). mp=134° C. 1H NMR (CDCl3): 7.75 (2H, s), 4.07 (2H, s), 3.10 (3H, s).
Reaction SMILES: [CH2:1]([NH:6][C:7]1[CH:8]=[C:9]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)[CH:10]=[CH:11][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH3:5].Cl[S:24]([C:27]1[CH:39]=[CH:38][C:30]([O:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])=[C:29]([CH3:40])[CH:28]=1)(=[O:26])=[O:25].C(N(CC)CC)C>C(Cl)Cl>[CH3:40][C:29]1[CH:28]=[C:27]([S:24]([N:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[C:7]2[CH:8]=[C:9]([C:13]3[CH:14]=[CH:15][C:16]([C:19]([F:20])([F:21])[F:22])=[CH:17][CH:18]=3)[CH:10]=[CH:11][CH:12]=2)(=[O:25])=[O:26])[CH:39]=[CH:38][C:30]=1[O:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34]
Reactant: CCCCCNc1cccc(-c2ccc(C(F)(F)F)cc2)c1
Reactant: CCOC(=O)COc1ccc(S(=O)(=O)Cl)cc1C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCN(c1cccc(-c2ccc(C(F)(F)F)cc2)c1)S(=O)(=O)c1ccc(OCC(=O)OCC)c(C)c1
Yield: 58.6 %

Procedure:
To a solution of N-pentyl-N-[4′-(trifluoromethyl)-1,1′-biphenyl-3-yl]amine (70.6 mg, 0.23 mmol) in CH2Cl2 (5 mL) under nitrogen at room temperature was added ethyl [4-(chlorosulfonyl)-2-methylphenoxy]acetate (101 mg, 0.35 mmol) and triethylamine (96 μL, 0.69 mmol). The resultant mixture was stirred for 24 h at room temperature. The reaction mixture was extracted with CH2Cl2 (15 mL) and water (10 mL). The organic solution was passed through a hydrophobic frit and the solvent was removed in vacuo. Purification by SPE (5 g Silica cartridge) eluted with 1:49–1:19 EtOAc:cyclohexane afforded the title compound as a white crystalline solid (76 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[F:20])[C:11](=[O:21])[N:10]([CH2:22][C:23]([OH:25])=O)[N:9]=2)=[CH:4][CH:3]=1.[C:26]1([CH:36]([NH2:38])[CH3:37])[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:29]=[CH:28][N:27]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[F:20])[C:11](=[O:21])[N:10]([CH2:22][C:23]([NH:38][CH:36]([C:26]3[C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[CH:29]=[CH:28][N:27]=3)[CH3:37])=[O:25])[N:9]=2)=[CH:4][CH:3]=1
Reactant: O=C(O)Cn1nc(-c2ccc(Cl)cc2)n(Cc2ccccc2F)c1=O
Reactant: CC(N)c1nccc2ccccc12
Product: CC(NC(=O)Cn1nc(-c2ccc(Cl)cc2)n(Cc2ccccc2F)c1=O)c1nccc2ccccc12
Yield: 70 %

Procedure:
The title compound is prepared analogously to Example 264 from the carboxylic acid from Example 156A (40 mg, 0.11 mmol) and 26.7 mg (0.16 mmol) of 1-isoquinolin-1-ylethylamine [preparation: see Chem. Ber. 108, 3771-3778 (1975)]. Yield: 70% of theory
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH2:5][NH:6][C:7]1[C:12]([N+:13]([O-])=O)=[CH:11][CH:10]=[C:9]([Cl:16])[N:8]=1)[CH3:2].C(N(CC)CC)C.[Cl:25][C:26]1[CH:34]=[CH:33][C:29]([C:30](Cl)=[O:31])=[CH:28][CH:27]=1>O1CCCC1.[Pt](=O)=O>[CH2:1]([O:3][C:4](=[O:17])[CH2:5][NH:6][C:7]1[C:12]([NH:13][C:30](=[O:31])[C:29]2[CH:33]=[CH:34][C:26]([Cl:25])=[CH:27][CH:28]=2)=[CH:11][CH:10]=[C:9]([Cl:16])[N:8]=1)[CH3:2]
Reactant: CCOC(=O)CNc1nc(Cl)ccc1[N+](=O)[O-]
Reactant: O=C(Cl)c1ccc(Cl)cc1
Agent: O=[Pt]=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)CNc1nc(Cl)ccc1NC(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Yield: 31 %

Procedure:
A solution of N-(6-chloro-3-nitro-2-pyridinyl) glycine ethyl ester (5.0 g, 0.0193 mole) in tetrahydrofuran (100 ml) was hydrogenated over platinum dioxide (0.5 g) at room temperature. After 2/3 of the theoretical amount of hydrogen had been absorbed, the mixture was filtered and a fresh portion of platinum dioxide (0.5 g) was added. The hydrogenation was continued until the theoretical amount of hydrogen was absorbed. The reaction mixture was cooled in ice, dried over magnesium sulfate and filtered. Triethylamine (2.05 g, 0.0203 mole) and 4-chlorobenzoyl chloride (3.55 g, 0.0203 mole) were added simultaneously, dropwise, to the cooled and stirred solution. After stirring at room temperature for 1.75 hours, the mixture was evaporated under reduced pressure and partitioned between water (100 ml) and ethyl acetate (100 ml). The layers were separated and the aqueous layer was re-extracted with ethyl acetate. The combined ethyl acetate layers were washed three times with saturated sodium chloride solution, dried over magnesium sulfate, charcoaled, filtered, and evaporated under reduced pressure. The resulting solid was dissolved in hot isopropyl alcohol, filtered hot and cooled to room temperature to give a solid which was collected by filtration and rinsed with isopropyl ether to give 2.2 g of title compound (31% yield). A 0.5% g portion was dissolved in hot isopropyl alcohol, filtered hot, isopropyl ether was added, and the mixture was cooled. The resulting suspension was filtered, the filtrate was evaporated under reduced pressure, and the residue was recrystallized from isopropyl alcohol/water and dried under high vacuum at 60° C. to give 0.37 g of the title compound, mp 157°-158.5° C.
Reaction SMILES: [C:1]1([C:7]2[CH2:8][CH2:9][N:10]([CH2:13][CH2:14][CH2:15][N:16]3[CH:24]([OH:25])[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:17]3=O)[CH2:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1>C1(C)C(C)=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[N:29]1[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=1[NH:27][CH:17]1[C:18]2[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:24](=[O:25])[N:16]1[CH2:15][CH2:14][CH2:13][N:10]1[CH2:11][CH:12]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:8][CH2:9]1
Reactant: Nc1ccccn1
Reactant: O=C1c2ccccc2C(O)N1CCCN1CC=C(c2ccccc2)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1C
Product: O=C1c2ccccc2C(Nc2ccccn2)N1CCCN1CC=C(c2ccccc2)CC1
Reaction time: 5 h
Yield: 50.6 %

Procedure:
Para-toluenesulphonic acid (50 mg) is added to an agitated solution of 2-[3-(4-phenyl-1,2,3,6-tetrahydro-1-pyridyl)propyl]-3-hydroxy1-isoindolinone (6 g) and 2-aminopyridine (2 g) in xylene (150 cc) at a temperature close to 20° C. in a Dean Stark apparatus. Agitation is continued for 5 hours at a temperature close to 135° C. After cooling to a temperature close to 20° C., the solution is washed with aqueous sodium bicarbonate solution (2×100 cc) then with distilled water (2×50 cc). The organic extracts are combined, dried over anhydrous magnesium sulphate, filtered and concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at 80° C. The precipitate is recrystallized from boiling acetonitrile (45 cc). 3.7 g of 3-(2-pyridylamino)-2-[3-(4-phenyl-1,2,3,6-tetrahydro-1-pyridyl)propyl]-1-isoindolinone are obtained, melting at 153° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][OH:5].[F:6][C:7]1[CH:8]=[C:9]([C:13]2([OH:23])[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[NH:15][C:14]2=O)[CH:10]=[CH:11][CH:12]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[F:6][C:7]1[CH:8]=[C:9]([C:13]2([OH:23])[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]=[C:14]2[NH:1][CH2:2][CH2:3][CH2:4][OH:5])[CH:10]=[CH:11][CH:12]=1
Reactant: NCCCO
Reactant: O=C1Nc2ccccc2C1(O)c1cccc(F)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: OCCCNC1=Nc2ccccc2C1(O)c1cccc(F)c1

Procedure:
Reaction of 3-aminopropanol with 3-(m-fluorophenyl)-3-hydroxy-3H-indol-2-one in presence of toluene-p-sulphonic acid by a procedure analogous to that of Example 1 gives 3-(m-fluorophenyl)-2-(3-hydroxypropylamino)-3H-indol-3-ol.
Reaction SMILES: COCCOC.Br[C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH:11]=[O:12].[CH3:16][C:17]1[C:18](B(O)O)=[CH:19][C:20]2[C:21]([CH3:30])([CH3:29])[CH2:22][CH2:23][C:24]([CH3:28])([CH3:27])[C:25]=2[CH:26]=1.C(=O)([O-])[O-].[K+].[K+]>C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:16][C:17]1[C:18]([C:8]2[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=2)[CH:11]=[O:12])=[CH:19][C:20]2[C:21]([CH3:30])([CH3:29])[CH2:22][CH2:23][C:24]([CH3:28])([CH3:27])[C:25]=2[CH:26]=1
Reactant: O=Cc1cccc(Br)c1
Reactant: Cc1cc2c(cc1B(O)O)C(C)(C)CCC2(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: COCCOC
Product: Cc1cc2c(cc1-c1cccc(C=O)c1)C(C)(C)CCC2(C)C
Reaction time: 0.17 h

Procedure:
700 ml of DME, 2.4 g (2 mmol) of tetrakistriphenylphosphinepalladium(0) and 8.44 g (45.6 mmol) of 3-bromobenzaldehyde are introduced into a three-necked flask under a stream of nitrogen and the mixture is stirred for 10 minutes. A solution of 17 g (69.1 mmol) of 3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthylboronic acid in 25 ml of ethanol are then added, followed by 46 ml (91 mmol) of potassium carbonate solution (2 M) and the mixture is refluxed for four hours. The reaction medium is cooled and filtered and the solid is washed with bicarbonate solution and then with ethyl acetate. The solid obtained is recrystallized from ethanol and 7 g (50%) of the expected aldehyde are collected, with a melting point of 104-5° C.
Reaction SMILES: [Cl-].C1([PH+](C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:21]([O:24][C@H:25]1[CH2:30][CH2:29][C@H:28]([CH:31]=O)[CH2:27][CH2:26]1)[CH2:22][CH3:23].C[CH2:34][O:35][CH2:36]C>>[CH3:34][O:35][CH:36]=[CH:31][C@H:28]1[CH2:27][CH2:26][C@H:25]([O:24][CH2:21][CH2:22][CH3:23])[CH2:30][CH2:29]1
Reactant: CCOCC
Reactant: CCCO[C@H]1CC[C@H](C=O)CC1
Agent: [Cl-]
Agent: c1ccc([PH+](c2ccccc2)c2ccccc2)cc1
Product: CCCO[C@H]1CC[C@H](C=COC)CC1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
A suspension of 94.6 g. of (methoxymethyl)(triphenylphosphonium chloride in 1000 ml. of dry ether is treated with 33.0 g. of potassium tert.butylate. After stirring for 45 minutes, a solution of 31.4 g. of trans-4-n-propyloxycyclohexane carboxaldehyde in 200 ml. of ether is added dropwise. The mixture is stirred for a further 2.5 hours and then poured into 1.2 liters of ice-water. The organic phase is separated, washed neutral with water, dried over sodium sulfate and evaporated. The crude trans-2-(4-n-propyloxycyclohexyl)vinyl methyl ether obtained is distilled at 82°-85° C./0.6 mmHg in order to separate the residual triphenylphosphine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@:8]2([C@@H:15]3[CH2:20][CH2:19][CH2:18][N:17]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:16]3)[CH2:13][CH2:12][CH2:11][C:10](=[O:14])[O:9]2)[CH:5]=[CH:6][CH:7]=1.[CH3:28][NH2:29]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([C@:8]([C@@H:15]2[CH2:20][CH2:19][CH2:18][N:17]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:16]2)([OH:9])[CH2:13][CH2:12][CH2:11][C:10]([NH:29][CH3:28])=[O:14])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]([C@]2(c3cccc(Cl)c3)CCCC(=O)O2)C1
Reactant: CN
Solvent: CO
Product: CNC(=O)CCC[C@@](O)(c1cccc(Cl)c1)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Reaction time: 2 h
Yield: 93 %

Procedure:
(R)-tert-butyl 3-((S)-2-(3-chlorophenyl)-6-oxotetrahydro-2H-pyran-2-yl)piperidine-1-carboxylate (60 mg, 0.153 mmol) was dissolved in a ca 30% solution of methylamine in methanol (3 mL). The mixture was stirred at it for 2 h then concentrated under reduced pressure to give (R)-tert-butyl 3-((S)-1-(3-chlorophenyl)-1-hydroxy-5-(methylamino)-5-oxopentyl)piperidine-1-carboxylate (60 mg, 93%), which was used directly without purification. 1H NMR (400 MHz, CDCl3): 1.12-1.45 (m, 3H), 1.46 (s, 9H), 1.58-1.81 (m, 6H), 2.05-2.17 (m, 2H), 2.50-2.58 (m, 2H), 2.69 (m, 3H), 4.06 (m, 1H), 4.12-4.28 (m, 2H), 7.22-7.32 (m, 3H), 7.43 (s, 1H). MS (E/Z): 425 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][CH:10]=[CH:9][C:8]=2[Cl:14])[N:5]=[C:4]([CH:15]([CH3:17])[CH3:16])[C:3]=1[C:18]([NH2:20])=[O:19].[OH:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][C:29](OCC)=O)=[CH:24][CH:23]=1.CC[O-].[Na+].CC(O)=O>CCO>[Cl:14][C:8]1[CH:9]=[CH:10][CH:11]=[C:12]([Cl:13])[C:7]=1[N:6]1[C:2]2[N:1]=[C:29]([CH2:28][C:25]3[CH:26]=[CH:27][C:22]([OH:21])=[CH:23][CH:24]=3)[NH:20][C:18](=[O:19])[C:3]=2[C:4]([CH:15]([CH3:16])[CH3:17])=[N:5]1
Reactant: CCOC(=O)Cc1ccc(O)cc1
Reactant: CC(C)c1nn(-c2c(Cl)cccc2Cl)c(N)c1C(N)=O
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: CC(C)c1nn(-c2c(Cl)cccc2Cl)c2nc(Cc3ccc(O)cc3)[nH]c(=O)c12
Temperature: 25 °C
Yield: 75.7 %

Procedure:
To a suspension of 5-amino-1-(2,6-dichlorophenyl)-3-isopropyl-1H-pyrazole-4-carboxylic acid amide (5.0 g, 16 mmol) in EtOH (20 mL) was added ethyl 4-hydroxyphenylacetate (8.6 g, 48 mmol) followed by NaOEt (2.66M in EtOH, 36 mL, 96 mmol). The reaction was then heated to reflux for 3 h. The reaction was then cooled to room temp and poured onto 10% aq. HOAc (100 mL). The resulting suspension was then cooled to 0° C. and filtered. The precipitate was then washed with 1:1 MeOH/H2O (100 mL) and 1:1 Et2O/hexane (75 mL). The solid was then dried under vacuum to yield the desired product (5.2 g, 76%).
Reaction SMILES: [CH2:1]([S:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[CH3:16][N:17]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:18](Cl)=[O:19]>>[CH2:1]([S:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][C:18](=[O:19])[N:17]([CH3:16])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CN(C(=O)Cl)c1ccccc1
Reactant: CCCCCCCSc1ccc(O)cc1
Product: CCCCCCCSc1ccc(OC(=O)N(C)c2ccccc2)cc1

Procedure:
The title compound was prepared from 4-heptylsulfanyl-phenol and N-methyl-N-phenylcarbamoyl chloride. The crude product was subjected to preparative HPLC (74%, colourless oil, HPLC-MS m/z=358.2 (M+1), Rt: 6.21 min.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:15]([C:17]2[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[C:19]([O:25][CH3:26])[CH:18]=2)=O)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OP([CH2:35][C:36]#[N:37])(=O)OCC)C.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].O1C2C=CC(C(C3C=C(OC)C=C(OC)C=3)=CC#N)=CC=2OCC1>C1COCC1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:15]([C:17]2[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[C:19]([O:25][CH3:26])[CH:18]=2)=[CH:35][C:36]#[N:37])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc(OC)cc(C(=O)c2cccc(OCc3ccccc3)c2)c1
Reactant: CCOP(=O)(CC#N)OCC
Agent: COc1cc(OC)cc(C(=CC#N)c2ccc3c(c2)OCCO3)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cc(OC)cc(C(=CC#N)c2cccc(OCc3ccccc3)c2)c1
Yield: 86.4 %

Procedure:
(3-Benzyloxyphenyl)-(3,5-dimethoxyphenyl)methanone (10.66 g, 30.60 mmol), cyanomethylphosphonic acid diethyl ester (9.63 ml, 61.19 mmol) in anhydrous THF (10 ml), and lithium bis (trimethylsilyl)amide (1.0 M solution in THF, 61.20 ml, 61.19 mmol) were treated in the same manner as described above for the synthesis of 3-(2,3-dihydrobenzo[1,4]dioxin-6-yl)-3-(3,5-dimethoxyphenyl)acrylonitrile. The crude material was purified via flash column chromatography (5% EtOAc in hexane gradient to 30% EtOAc in hexane in about 40 min.) to give 3-(3-benzyloxy-phenyl)-3-(3,5-dimethoxy-phenyl)-acrylonitrile as a white solid (9.82 g, 86%): 1HNMR (DMSO-d6) 7.47-7.31 (m, 6H, Ar), 7.20-6.88 (m, 3H, Ar), 6.66-6.62 (2ts, 1H, Ar), 6.46 (d, J=2 Hz, 2H, Ar), 6.40 (s, 0.5H, double bond proton of one isomer), 6.38 (s, 0.5H, double bond proton of the other isomer), 5.12 (s, 1H, half CH2), 5.11 (s, 1H, half CH2), 3.76 (s, 3H, OCH3), 3.73 (s, 3H, OCH3); 13C NMR(DMSO-d6) δ 161.2, 160.4, 158.4, 158.2, 139.6, 138.9, 138.8, 138.3, 136.7, 129.8, 128.4, 127.9, 127.8, 121.5, 120.8, 117.9, 117.9, 116.8, 116.0, 115.5, 114.4, 107.1, 106.5, 101.9, 101.1, 96.8, 96.5, 69.4, 55.4,53.6; Anal. Calcd. For C24H21NO3: C, 77.61; H, 5.70; N, 3.77. Found: C, 77.39; H, 5.70; N, 3.69.