Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]([C:11]2[S:12][C:13]([S:19][C:20]3[CH:25]=[CH:24][C:23]([NH2:26])=[CH:22][CH:21]=3)=[C:14]([N+:16]([O-])=O)[CH:15]=2)=[O:10])[CH:5]=[CH:6][CH:7]=1.N1C=CC=CC=1.Cl[C:34]([O:36][CH2:37][C:38]([Cl:41])([Cl:40])[Cl:39])=[O:35]>ClCCl>[Cl:39][C:38]([Cl:41])([Cl:40])[CH2:37][O:36][C:34](=[O:35])[NH:26][C:23]1[CH:24]=[CH:25][C:20]([S:19][C:13]2[S:12][C:11]([C:9](=[O:10])[NH:8][C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=3)=[CH:15][C:14]=2[NH2:16])=[CH:21][CH:22]=1
Reactant: Nc1ccc(Sc2sc(C(=O)Nc3cccc(Br)c3)cc2[N+](=O)[O-])cc1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: Nc1cc(C(=O)Nc2cccc(Br)c2)sc1Sc1ccc(NC(=O)OCC(Cl)(Cl)Cl)cc1
Reaction time: 0.5 h

Procedure:
To the product from Example 356C dissolved in dichloromethane was added pyridine followed by the dropwise addition of 2,2,2-trichloroethyl chloroformate. The resultant solution was stirred for 4 hours and then concentrated under vacuum. The mixture was then poured into water, the pH of the solution adjusted to 5 with 1N aqueous hydrochloric acid, the resultant solution stirred for 30 minutes and the resultant solid collected and dried followed by reduction of the nitro group according to the procedure described in Example 356E to provide the title product.
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10](F)[C:9]([Cl:14])=[C:8]2[C:3]=1[C:4](=[O:21])[C:5]([C:18]([OH:20])=[O:19])=[CH:6][N:7]2[CH:15]1[CH2:17][CH2:16]1.C(OC([NH:29][CH:30]1[CH2:34][CH2:33][NH:32][CH2:31]1)=O)(C)(C)C.C(N(CC)CC)C>C(#N)C>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([N:32]2[CH2:33][CH2:34][CH:30]([NH2:29])[CH2:31]2)[C:9]([Cl:14])=[C:8]2[C:3]=1[C:4](=[O:21])[C:5]([C:18]([OH:20])=[O:19])=[CH:6][N:7]2[CH:15]1[CH2:17][CH2:16]1
Reactant: Nc1c(F)c(F)c(Cl)c2c1c(=O)c(C(=O)O)cn2C1CC1
Reactant: CC(C)(C)OC(=O)NC1CCNC1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Nc1c(F)c(N2CCC(N)C2)c(Cl)c2c1c(=O)c(C(=O)O)cn2C1CC1
Temperature: 100 °C
Yield: 63 %

Procedure:
To 1.57 g (5 mmol) of 5-amino-8-chloro-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinoline carboxylic acid in 20 ml of acetonitrile was added 0.93 g (5 mmol) of 3-[(t-butoxycarbonyl)amino]pyrrolidine and 1.0 g (10 mmol) of triethylamine. The mixture was refluxed for three hours, cooled, and filtered. The solids were washed with acetonitrile and ether, then dissolved in 10 ml of acetic acid and 2 ml of 3N hydrochloric acid. The mixture was heated at 100° C. for four hours, concentrated, and triturated with 2-propanol. The solid that formed was filtered and washed with ether to give 1.2 g of the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:3](Cl)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([CH3:12])=[CH:7][CH:6]=2.[CH3:14][O-:15].[Na+]>O1CCCC1.CO>[NH2:1][C:2]1[C:3]([O:15][CH3:14])=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([CH3:12])=[CH:7][CH:6]=2
Reactant: Cc1ccc2nc(Cl)c(N)nc2c1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: COc1nc2ccc(C)cc2nc1N
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.9 %

Procedure:
To 3-amino-2-chloro-6-methylquinoxaline (550 mg, 2.84 mmol) dissolved in tetrahydrofuran (30 ml), 25 wt % sodium methoxide (6.14 g, 28.4 mmol) in methanol was added at room temperature and stirred further at room temperature for 60 minutes. The resulting mixture was concentrated under the reduced pressure to remove the solvent. The product was extracted with dichloromethane and the organic layer was washed with water and dried over MgSO4. After concentration under the reduced pressure, the crude product was purified by SiO2 column chromatography. Extraction of the residue with n-hexane:ethyl acetate (2:1) mixture and concentration gave 467 mg of the titled compound (yield, 87%).
Reaction SMILES: CC(N(C)C)=O.[SH:7][C:8]1[N:13]2[N:14]=[C:15]([C:17]([OH:19])=O)[N:16]=[C:12]2[N:11]=[C:10]([CH3:20])[CH:9]=1.ClC(N(C)C)=C(C)C.Cl.[CH3:30][NH:31][OH:32].C(N(C(C)C)C(C)C)C>CC(N(C)C)=O>[OH:32][N:31]([CH3:30])[C:17]([C:15]1[N:16]=[C:12]2[N:11]=[C:10]([CH3:20])[CH:9]=[C:8]([SH:7])[N:13]2[N:14]=1)=[O:19]
Reactant: CNO
Reactant: Cc1cc(S)n2nc(C(=O)O)nc2n1
Agent: CC(C)=C(Cl)N(C)C
Agent: Cl
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(S)n2nc(C(=O)N(C)O)nc2n1
Temperature: -10 °C
Reaction time: 18 h
Yield: 62.8 %

Procedure:
7-Mercapto-5-methyl-s-triazolo[1,5-a]pyrimidine-2-carboxylic acid dimethylacetamide (0.99 g) (3.33 mmol) is suspended in 15 ml of absolute dimethylacetamide and treated while stirring with 530 mg (3.96 mmol) of 1-chloro-N,N,2-trimethyl-1-propenamine. After 4 hours the solution is cooled to -10° C. and treated while stirring with 550 mg (6.6 mmol) of N-methylhydroxylamine hydrochloride and 860 mg (6.6 mmol) of ethyl-diisopropylamine. The reaction mixture is stirred at room temperature for 18 hours and subsequently concentrated in a high vacuum. The residue is crystallized using water and recrystallized from dimethylformamide/diethyl ether. There is obtained 0.50 g of N-hydroxy-7-mercapto-N,5-dimethyl-s-triazolo[1,5-a]pyrimidine-2-carboxamide as yellow crystals of melting point 215° C. (dec.).
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([SH:10])[CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:4].CI.[C:20]([O-])(O)=O.[Na+]>CO>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10][CH3:20])[CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:4]
Reactant: O=C([O-])O
Reactant: COC(=O)[C@@H]1C[C@@H](S)CN1C(=O)OC(C)(C)C
Agent: [Na+]
Solvent: CI
Solvent: CO
Product: COC(=O)[C@@H]1C[C@@H](SC)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 12 h
Yield: 68.9 %

Procedure:
To a solution of (2S,4R)-4-mercapto-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (9.5 g, 35.4 mmol) in MeOH (300 ml) were added methyl iodide (24 ml, 363.5 mmol) and NaHCO3 (3.4 g, 39.98 mmol). The reaction mixture was stirred for 12 h at 25° C. After complete consumption of the starting material, the solvent was removed under reduced pressure to get the crude material that was purified by column chromatography over silica gel (25-40% EtOAc/hexane) to obtain the title compound as white solid (6.9 g, 24.4 mmol; 69%). MS (ESI): m/z=276.4 [M+H]+.
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([C:9]2[C:10]([C:15]#[N:16])=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:5]=[CH:6][C:7]=1[F:8].N([O-])=O.[Na+].[BrH:21]>O1CCOCC1.O.[Cu]Br>[Br:21][C:2]1[CH:3]=[C:4]([C:9]2[C:10]([C:15]#[N:16])=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: Br
Reactant: N#Cc1ccccc1-c1ccc(F)c(N)c1
Agent: [Cu]Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: N#Cc1ccccc1-c1ccc(F)c(Br)c1
Temperature: 3 °C
Reaction time: 2 h
Yield: 45 %

Procedure:
A warm solution of 3′-amino-4′-fluorobiphenyl-2-carbonitrile (4.24 g, 20 mmol) in 1,4-dioxane (30 ml) was treated with 48% hydrobromic acid (100 ml) and the resulting suspension stirred and cooled to 3° C. (internal temp). A solution of sodium nitrite (1.59 g, 23 mmol) in water (4 ml) was then added dropwise over 20 min keeping the internal temperature <5° C. Stirring at <5° C. was continued for 2 h before adding a cooled (5° C.) solution of copper(I) bromide in 48% hydrobromic acid (30 ml). The resulting purple reaction mixture was stirred at 5° C. for 10 min then warmed to 50° C. for 20 min. The reaction was diluted with ice-cold water (500 ml) and extracted with ethyl acetate (2×200 ml). The organics were combined, washed with 5% aqueous sodium sulfite and saturated aqueous ammonium chloride, dried over anhydrous magnesium sulfate, filtered and pre-adsorbed onto silica. Purification on silica, eluting with isohexane on a gradient of ethyl acetate (2-12%) afforded 3′-bromo-4′-fluorobiphenyl-2-carbonitrile as a white solid (2.5 g, 45%): δH (400 MHz, CDCl3) 7.22-7.27 (1H, m), 7.45-7.53 (4H, m), 7.66 (1H, td, J 8 and 2), 7.73 (1H, dd, J 8 and 2), 7.77 (1H, dd, J 8 and 2).
Reaction SMILES: Cl[CH2:2]/[CH:3]=[CH:4]/[C:5]#[C:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH2:13]([O:15][C:16](=[O:29])[C@@H:17]([O:26][CH2:27][CH3:28])[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=1)[CH3:14].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(C)=O.O>[CH2:13]([O:15][C:16](=[O:29])[C@@H:17]([O:26][CH2:27][CH3:28])[CH2:18][C:19]1[CH:20]=[CH:21][C:22]([O:25][CH2:2]/[CH:3]=[CH:4]/[C:5]#[C:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[CH:23][CH:24]=1)[CH3:14]
Reactant: ClC/C=C/C#Cc1ccccc1
Reactant: CCOC(=O)[C@H](Cc1ccc(O)cc1)OCC
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CCOC(=O)[C@H](Cc1ccc(OC/C=C/C#Cc2ccccc2)cc1)OCC

Procedure:
To a solution of (E)-(5-chloro-pent-3-en-1-ynyl)-benzene (177 mg, 1.0 mmol) and (S)-2-ethoxy-3-(4-hydroxy-phenyl)-propionic acid ethyl ester (238 mg, 1.0 mmol) in acetone (15 mL) was added potassium carbonate (700 mg, 5.0 mmol) and potassium iodide (17 mg, 0.1 mmol). The mixture was heated to reflux over night with stirring. Water was added and the product extracted with tert-butyl methyl ether (×3) The combined organic phases were dried (MgSO4), filtered and concentrated in vacuo, to give the title compound as a crude product.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[N:10]=[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19](=O)[CH3:20])[N:14]=1)[CH3:12].[C-:22]1([NH2:27])[CH:26]=[CH:25][CH:24]=[CH:23]1.[CH-:28]1[CH:32]=[CH:31][CH:30]=[CH:29]1.[Fe+2:33]>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[N:10]=[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19](=[N:27][C-:22]2[CH:26]=[CH:25][CH:24]=[CH:23]2)[CH3:20])[N:14]=1)[CH3:12].[CH-:28]1[CH:32]=[CH:31][CH:30]=[CH:29]1.[Fe+2:33]
Reactant: CC(=O)c1cccc(C(C)=Nc2c(C)cc(C)cc2C)n1
Reactant: N[c-]1cccc1
Agent: [Fe+2]
Agent: c1cc[cH-]c1
Solvent: Cc1ccccc1
Product: CC(=Nc1c(C)cc(C)cc1C)c1cccc(C(C)=N[c-]2cccc2)n1
Reaction time: 16 h

Procedure:
Monoimine 2-[1-(2,4,6-trimethylphenylimino)ethyl]-6-acetylpyridine (1, 263 mg, 0.94 mmol) and ferrocenylamine (280 mg, 1.03 mmol) were dissolved in 40 ml of toluene. To this solution, molecular sieves (4 Å) were added. After standing for 16 hours the mixture was filtered. The solvent was removed in vacuo. The residue was recrystallised from ethanol. Yield 180 mg (41%) of mixed diimine 6.
Reaction SMILES: C[N:2]([CH3:19])[CH:3]=[CH:4][C:5]([C:7]1[CH:8]=[C:9]([N:13]([CH2:17][CH3:18])[C:14](=[O:16])[CH3:15])[CH:10]=[CH:11][CH:12]=1)=O.N[C:21]1[C:25]([C:26]#[N:27])=C[NH:23][N:22]=1.P(=O)(O)(O)O>O.CO>[CH3:18][CH2:17][N:13]([C:14]([CH3:15])=[O:16])[C:9]1[CH:10]=[CH:11][CH:12]=[C:7]([C:5]2[N:23]3[N:22]=[CH:21][C:25]([C:26]#[N:27])=[C:19]3[N:2]=[CH:3][CH:4]=2)[CH:8]=1
Reactant: CCN(C(C)=O)c1cccc(C(=O)C=CN(C)C)c1
Reactant: N#Cc1c[nH]nc1N
Agent: O=P(O)(O)O
Solvent: CO
Solvent: O
Product: CCN(C(C)=O)c1cccc(-c2ccnc3c(C#N)cnn23)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 91.4 %

Procedure:
N-[3-[3-(dimethylamino)-1-oxo-2-propenyl]phenyl]-N-ethylacetamide (2.6 g, 0.01 mol) and 3-amino-4-cyanopyrazole (1.08 g, 0.01 mol) were dissolved in the mixture of water (35 cm3) and methanol (20 cm3). Phosphoric acid (85%) (0.67 cm3, 0.01 mol) was then added and the mixture was stirred at room temperature for about 4 hours. The reaction mixture was then cooled to about 5° C. and the crystalline product that formed was collected, washed with water and dried at about 60° C. to yield zaleplon (2.79 g, 91.5%) in 98.83% purity as determined by HPLC.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][NH:4][CH2:3]1.Cl[CH2:9][CH2:10][CH2:11][C:12]#[N:13]>C1C=CC=CC=1>[CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][N:4]([CH2:9][CH2:10][CH2:11][C:12]#[N:13])[CH2:3]1
Reactant: N#CCCCCl
Reactant: CC1CCCNC1
Solvent: c1ccccc1
Product: CC1CCCN(CCCC#N)C1
Reaction time: 0.42 h
Yield: 70.3 %

Procedure:
In a solution under reflux of 58.6 ml (0.50 mole) of 3-methylpiperidine in 65 ml of benzene, were run in 25 minutes 27.2 g (0.25 mole) of 4-chlorobutyronitrile Reflux was continued for 2h, the precipitate was removed by filtration and the filtrate brought to dryness under reduced pressure. The residue from the evaporation was purified by distillation under reduced pressure to give 29.2 g (yields=70.3%) of 4-(3-methylpiperidino)-butyronitrile which was in the form of a colourless oil. Boiling point 5-6 mmHg =100° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:16])=[CH:4][C:5]2[O:10][CH2:9][C:8](=[O:11])[N:7]([CH2:12][C:13]#[CH:14])[C:6]=2[CH:15]=1.C(N(CC)C1C=CC=CC=1)C.Cl[C:29]([O:31][CH3:32])=[O:30]>ClCCCl>[F:16][C:3]1[C:2]([NH:1][C:29]([O:31][CH3:32])=[O:30])=[CH:15][C:6]2[N:7]([CH2:12][C:13]#[CH:14])[C:8](=[O:11])[CH2:9][O:10][C:5]=2[CH:4]=1
Reactant: C#CCN1C(=O)COc2cc(F)c(N)cc21
Reactant: COC(=O)Cl
Solvent: ClCCCl
Solvent: CCN(CC)c1ccccc1
Product: C#CCN1C(=O)COc2cc(F)c(NC(=O)OC)cc21
Yield: 75.4 %

Procedure:
A mixture of 6-amino-7-fluoro-4-propargyl-2H-1,4-benzoxazin-3(4H)-one (2.1 g), N,N-diethylaniline (1.5 g) and methyl chloroformate (1.0 g) was dissolved in 1,2-dichloroethane (10 g), and the resultant mixture was heated under reflux for 3 hours. After cooling, the reaction mixture was washed with water, and the organic layer was concentrated. The residue was washed with methanol to give 7-fluoro-6-methoxycarbonylamino-4-propargyl-2H-1,4-benzoxazin-3(4H)-one (2.0 g).
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[CH3:13][C:14]1[CH:23]=[CH:22][C:21]2[CH2:20][CH2:19][CH2:18][N:17]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C:16]=2[N:15]=1.[C:31](=O)([O:35]CC)[O:32][CH2:33][CH3:34]>C1COCC1>[C:27]([O:26][C:24]([N:17]1[C:16]2[N:15]=[C:14]([CH2:13][C:31]([O:32][CH2:33][CH3:34])=[O:35])[CH:23]=[CH:22][C:21]=2[CH2:20][CH2:19][CH2:18]1)=[O:25])([CH3:30])([CH3:29])[CH3:28]
Reactant: Cc1ccc2c(n1)N(C(=O)OC(C)(C)C)CCC2
Reactant: CCOC(=O)OCC
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCOC(=O)Cc1ccc2c(n1)N(C(=O)OC(C)(C)C)CCC2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 102.1 %

Procedure:
To a solution of diisopropylamine (47.7 mL, 364 mmole) in dry THF (250 mL) at 0° C. was added n-BuLi (2.5 M in hexanes, 145.6 mL, 364 mmole) dropwise. After 15 min, this solution was added dropwise to a solution of 2-methyl-8-(tert-butoxycarbonyl)-5,6,7,8-tetrahydro-1,8-naphthyridine (32.3 g, 130 mmole) and diethyl carbonate (56.8 mL, 481 mmole) in dry THF (400 mL) at −78° C. After 30 min, the mixture was quenched with saturated NH4Cl (500 mL), warmed to RT, and extracted with EtOAc (3×500 mL). The combined organic extracts were dried (MgSO4), filtered, and concentrated under reduced pressure. Drying under high vacuum overnight gave the title compound (42.52 g, 102%) as a light yellow oil: 1H NMR (300 MHz, CDCl3) δ 7.35 (d, J=7.5 Hz, 1 H), 6.96 (d, J=7.5 Hz, 1 H), 4.18 (t, 2H), 3.75 (m, 4 H), 2.72 (t, 2 H), 1.91 (m, 2 H), 1.52 (s, 9 H), 1.24 (m, 3 H); MS (ES) m/e 321 (M+H)+.
Reaction SMILES: [H-].[K+].[NH2:3][C:4]1[N:8]([C:9]2[C:14]([Cl:15])=[CH:13][C:12]([C:16]([F:19])([F:18])[F:17])=[CH:11][C:10]=2[Cl:20])[N:7]=[C:6]([C:21]#[N:22])[C:5]=1[S:23]([CH3:25])=[O:24].[CH2:26]([S:28]([CH:31]=[CH2:32])(=[O:30])=[O:29])[CH3:27].[Cl-]>CN(C)C=O>[Cl:20][C:10]1[CH:11]=[C:12]([C:16]([F:17])([F:18])[F:19])[CH:13]=[C:14]([Cl:15])[C:9]=1[N:8]1[C:4]([NH:3][CH2:27][CH2:26][S:28]([CH2:31][CH3:32])(=[O:30])=[O:29])=[C:5]([S:23]([CH3:25])=[O:24])[C:6]([C:21]#[N:22])=[N:7]1
Reactant: C=CS(=O)(=O)CC
Reactant: CS(=O)c1c(C#N)nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1N
Agent: [Cl-]
Agent: [H-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCS(=O)(=O)CCNc1c(S(C)=O)c(C#N)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Temperature: 20 °C
Reaction time: 0.33 h
Yield: 31.1 %

Procedure:
To a suspension of 35% potassium hydride in oil (0.7 g) in dry N,N-dimethylformamide (DMF) was added a solution of 5-amino-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-4-(methylsulfinyl)-1H-pyrazole-3-carbonitrile (10.0 g) in dry DMF dropwise at 4° C. over 10 minutes. After stirring for 20 minutes, vinyl ethyl sulfone (3.13 g) in dry DMF was added during 5 hours at 4° C. The mixture was stirred overnight under nitrogen with warming to 20° C. Ammnonium chloride was added at 4° C., and the mixture extracted (ethyl acetate), washed twice with water, dried (sodium sulfate) and evaporated. Crystallization from ethyl acetate/methanol/hexane gave 1-[2,6-dichlor-4-(trifluoromethyl)phenyl]-5-[2-(ethylsulfonyl)ethylamino]-4-(methylsulfinyl)-1H-pyrazole-3-carbonitrile (4.08 g), m.p.131-132° C. By proceeding in a similar manner the following compounds were prepared:
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][CH2:3]1.[N+:13]([O-])([OH:15])=[O:14]>S(=O)(=O)(O)O>[N+:13]([C:7]1[CH:6]=[C:5]2[C:10]([CH2:11][C:2]([CH3:12])([CH3:1])[CH2:3][NH:4]2)=[CH:9][CH:8]=1)([O-:15])=[O:14]
Reactant: CC1(C)CNc2ccccc2C1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: CC1(C)CNc2cc([N+](=O)[O-])ccc2C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 59.1 %

Procedure:
1,2,3,4-Tetrahydro-3,3-dimethylquinoline (51 mg, 0.32 mmol) was dissolved in sulfuric acid (0.5 mL) and the temperature lowered to 0° C. To this solution 90% fuming nitric acid (14 mL, 0.32 mol) was added slowly and the mixture stirred at 0° C. for 1 h, then warmed to rt. The reaction mixture was then poured onto 1 g of ice and extracted with dichloromethane (2×5 mL). The organic phase was washed with saturated aqueous NaHCO3 (3 mL) and concentrated in vacuo to a reddish residue that was subjected to chromatography (silica gel, hexanes/ethyl acetate, 85:15) which afforded 39 mg (58%) of 7-nitro-1,2,3,4-tetrahydro-3,3-dimethylquinoline. Data for 7-nitro-1,2,3,4-tetrahydro-3,3-dimethylquinoline: 1H NMR (400 MHz, CDCl3) 7.40 (dd, J=8.3, 2.1, 1H), 7.29 (d, J=1.8, 1H), 7.01 (d, J=8.3H, 1H), 4.25 (s, 1H), 2.98 (s, 2H), 2.54 (s, 2H), 1.01 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[CH:4][CH:3]=1.[NH2:11][C:12]1[CH:25]=[CH:24][C:15]([O:16][CH2:17][CH2:18][N:19]2[CH2:22][CH:21]([OH:23])[CH2:20]2)=[C:14]([C:26]2[N:27]([CH3:32])[N:28]=[CH:29][C:30]=2[Cl:31])[CH:13]=1>ClCCl.CN(C=O)C>[Cl:31][C:30]1[CH:29]=[N:28][N:27]([CH3:32])[C:26]=1[C:14]1[CH:13]=[C:12]([NH:11][C:9]([NH:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)=[O:10])[CH:25]=[CH:24][C:15]=1[O:16][CH2:17][CH2:18][N:19]1[CH2:22][CH:21]([OH:23])[CH2:20]1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: Cn1ncc(Cl)c1-c1cc(N)ccc1OCCN1CC(O)C1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cn1ncc(Cl)c1-c1cc(NC(=O)Nc2ccc(Cl)cc2)ccc1OCCN1CC(O)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.4 %

Procedure:
4-Chlorophenylisocyanate (19.0 mg, 0.124 mmol) was added to a solution of 1-{2-[4-amino-2-(4-chloro-2-methyl-2H-pyrazol-3-yl)-phenoxy]-ethyl}-azetidin-3-ol (40.0 mg, 0.124 mmol) in dichloromethane (2.0 mL) and DMF (0.1 mL), and the mixture stirred at room temperature overnight. The solution was concentrated and purified by RP-HPLC. The collected fractions were concentrated and 12% sodium hydroxide (aq) (0.2 mL) was added to give pH 9. The solution was extracted into ethyl acetate and the organic layer was dried over sodium sulfate, filtered, and evaporated to dryness to give a white solid (28 mg, 47%). LCMS m/z (%)=476 (M+H35Cl, 100), 478 (M+H37Cl, 67). 1H NMR (400 MHz, DMSO-d6) δ: 8.81 (bs, 1H), 8.71 (bs, 1H), 7.60 (s, 1H), 7.53-7.50 (m, 1H), 7.47 (d, J=2.08 Hz, 1H), 7.46 (d, J=2.10 Hz, 1H), 7.36 (d, J=2.71 Hz, 1H), 7.32 (d, J=2.11 Hz, 1H), 7.30 (d, J=2.04 Hz, 1H), 7.11 (d, J=9.06 Hz, 1H), 5.19 (d, J=8.00 Hz, 1H), 4.10-4.00 (m, 1H), 3.99-3.85 (m, 2H), 3.65 (s, 3H), 3.40-3.30 (m, 2H), 2.70-2.55 (m, 4H).
Reaction SMILES: [OH:1][N:2]=[C:3]([C:19]1[CH:28]=[CH:27][C:26]2[C:25]([CH3:30])([CH3:29])[CH2:24][CH2:23][C:22]([CH3:32])([CH3:31])[C:21]=2[CH:20]=1)[C:4]([NH:6][C:7]1[CH:18]=[CH:17][C:10]([C:11]([O:13][CH2:14][CH:15]=[CH2:16])=[O:12])=[CH:9][CH:8]=1)=[O:5].Br[CH2:34][CH2:35][CH2:36][OH:37]>>[OH:37][CH:36]([O:1][N:2]=[C:3]([C:19]1[CH:28]=[CH:27][C:26]2[C:25]([CH3:30])([CH3:29])[CH2:24][CH2:23][C:22]([CH3:32])([CH3:31])[C:21]=2[CH:20]=1)[C:4]([NH:6][C:7]1[CH:18]=[CH:17][C:10]([C:11]([O:13][CH2:14][CH:15]=[CH2:16])=[O:12])=[CH:9][CH:8]=1)=[O:5])[CH2:35][CH3:34]
Reactant: C=CCOC(=O)c1ccc(NC(=O)C(=NO)c2ccc3c(c2)C(C)(C)CCC3(C)C)cc1
Reactant: OCCCBr
Product: C=CCOC(=O)c1ccc(NC(=O)C(=NOC(O)CC)c2ccc3c(c2)C(C)(C)CCC3(C)C)cc1

Procedure:
Following the basic procedure of Example 1 (f), 3.4 g (7.8 mmol) of allyl 4-[α-hydroxyimino-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)acetamido]benzoate were reacted with 710 μl (7.8 mmol) of 3-bromo-1-propanol. 1.4 g (36%) of the syn allyl ester and 710 mg (18%) of the trans allyl ester were recovered after purification by chromatography on a silica column, eluted with dichloromethane.
Reaction SMILES: [CH3:1][Si:2]([C:5]#[CH:6])([CH3:4])[CH3:3].[CH2:7]([NH:9][C:10](=[O:20])[CH:11]([C:13]1[CH:18]=[CH:17][C:16](I)=[CH:15][CH:14]=1)[CH3:12])[CH3:8].CCOC(C)=O>C(#N)C.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.[Cu]I>[CH2:7]([NH:9][C:10](=[O:20])[CH:11]([C:13]1[CH:18]=[CH:17][C:16]([C:6]#[C:5][Si:2]([CH3:4])([CH3:3])[CH3:1])=[CH:15][CH:14]=1)[CH3:12])[CH3:8]
Reactant: CCNC(=O)C(C)c1ccc(I)cc1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCNC(=O)C(C)c1ccc(C#C[Si](C)(C)C)cc1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To 4.90 g (49.9 mmol) trimethylsilylacetylene in 450 mL acetonitrile are added 12.1 g (39.9 mmol) N-ethyl-2-(4-iodo-phenyl)-propionamide (IV.1) under argon, followed by 1.68 g (2.40 mmol) Pd(PPh3)2Cl2 as catalyst, 0.23 g (1.20 mmol) copper(I)iodide and 11.1 mL (80 mmol) TEA as base. The mixture is stirred at rt for 2.5 h. After that time, EtOAc is added and the organic layer is washed with saturated ammonium chloride solution and brine. The organic layer is separated, dried over sodium sulphate and the solvent is evaporated. The residue is purified by column chromatography (silicia gel; EtOAc/heptane, gradient 50% to 80%) to yield the desired product.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:37])[CH:10]([NH:19][C:20]([O:22]CC1C2C=CC=CC=2C2C1=CC=CC=2)=O)[CH2:11][CH2:12][C:13]([O:15][CH2:16][CH:17]=[CH2:18])=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:38](Cl)(=O)[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46]C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH2:1]([O:8][C:9](=[O:37])[CH:10]([NH:19][C:20](=[O:22])[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])[CH2:11][CH2:12][C:13]([O:15][CH2:16][CH:17]=[CH2:18])=[O:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=CCOC(=O)CCC(NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)OCc1ccccc1
Reactant: CCCCCCCCCC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: C=CCOC(=O)CCC(NC(=O)CCCCCCCCC)C(=O)OCc1ccccc1
Temperature: 22 °C
Reaction time: 24 h
Yield: 63.5 %

Procedure:
The Fmoc protective group was subsequently removed by exposure to DMAP and the free amine was acylated in situ with decanoyl chloride to give 2-Decanoylamino-pentanedioic acid 5-allyl ester 1-benzyl ester (7) in 63% yield as follows. To a suspension of 1 g (2.0 mmol) of 6 in 10 mL of CH2Cl2 was added 1 g (8.2 mmol) of DMAP. The reaction mixture was stirred at 22° C. for 24 h, treated with 0.62 mL (3.0 mmol) of decanoyl chloride, stirred for 2 h at 22° C., and extracted with saturated sodium bicarbonate solution (2×10 mL). The organic layer was dried (Na2SO4), evaporated to dryness, and the residue was chromatographed on SiO2 (Hexanes/EtOAc, 5:1) to give 548 mg (63%) of 7 as a viscous oil: IR (neat) 3293, 3063, 2924, 2855, 1740, 1649, 1534, 1453, 1379, 1175, 986, 930 cm-1 ; 1H NMR δ 7.26 (s, 5 H), 6.68 (d, I H, J=7.8 Hz), 5.85-5.75 (m, 1 H), 5.22 (d, 1 H, J=17.3 Hz), 5.14 (d, 1 H, J=10.4 Hz), 5.08 (s, 2 H), 4.63-4.57 (m, 1 H), 4.48 (d, 2 H, J=5.6 Hz), 2.38-2.28 (m, 2 H), 2.2-2.1 (m, 3 H), 2.0-1.9 (m, 1 H), 1.55 (t, 2 H, J=6.9 Hz), 1.20 (bs, 12 H), 0.82 (t, 3 H, J=5.9 Hz); 13C NMR δ 173.0, 172.1, 171.6, 135.0, 131.7, 128.2, 128.1, 127.8, 117.9, 66.8, 64.9, 51.3, 36.0, 31.6, 29.9, 29.1, 29.0, 26.8, 25.3, 22.3, 13.8; MS (El) m/z (relative intensity) 431 (12), 319 (21), 296 (51), 142 (100), 124 (31), 91 (91); HRMS (El) m/z calculated for C25H37NO5 : 431.2672, found: 431.2673.