Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C:9]1[C:10]([O:19][CH3:20])=[N:11][CH:12]=[C:13]([CH:18]=1)[C:14]([O:16]C)=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].O[Li].O>C1COCC1.O>[C:24]([O:23][C:21]([N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C:9]1[C:10]([O:19][CH3:20])=[N:11][CH:12]=[C:13]([CH:18]=1)[C:14]([OH:16])=[O:15])=[O:22])([CH3:27])([CH3:26])[CH3:25]
Reactant: COC(=O)c1cnc(OC)c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: COc1ncc(C(=O)O)cc1N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of the methyl 5-[bis(tert-butoxycarbonyl)amino]-6-methoxynicotinate (1 g, 2.61 mmol) in THF (10 mL) at 0° C. was added LiOH.H2O (275 mg, 6.54 mmol) in water (2.5 mL) and the reaction allowed to stir at room temperature for 4 hours. The reaction was diluted with water (5 mL) and extracted into DCM twice (2×10 mL). The aqueous layer was acidified to pH=5 with 10% citric acid solution and extracted into DCM (4×20 mL). The organic layers were collected, washed with brine (10 mL), dried over sodium sulphate and concentrated in vacuo to afford the title compound that was used directly in the next step.
Reaction SMILES: [CH3:1][N:2]1[C:6](=[O:7])[CH2:5][C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:3]1.[F-].[K+].Cl[CH2:17][N:18]1[C:22](=[O:23])[C:21]2[C:24]([CH:30]([CH3:32])[CH3:31])=[CH:25][C:26]([O:28][CH3:29])=[CH:27][C:20]=2[S:19]1(=[O:34])=[O:33].O>CN(C=O)C>[CH:30]([C:24]1[C:21]2[C:22](=[O:23])[N:18]([CH2:17][O:7][C:6]3[N:2]([CH3:1])[N:3]=[C:4]([C:8]4[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=4)[CH:5]=3)[S:19](=[O:34])(=[O:33])[C:20]=2[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=1)([CH3:32])[CH3:31]
Reactant: CN1N=C(c2ccccc2)CC1=O
Reactant: COc1cc(C(C)C)c2c(c1)S(=O)(=O)N(CCl)C2=O
Agent: [F-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(C(C)C)c2c(c1)S(=O)(=O)N(COc1cc(-c3ccccc3)nn1C)C2=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 27.5 %

Procedure:
To a solution of 2,4-dihydro-2-methyl-5-phenyl-3H-pyrazol-3-one (0.63 g; 3.62 mmol) in DMF (20 ml) was added 230 mg (3.96 mmol) of KF followed by 2-chloromethyl-4-isopropyl-6-methoxy-1,2-benzisothiazol-3(2H)-one 1,1-dioxide (1 g, 3.29 mmol) and the resulting mixture was stirred at room temperature for 24 hours and then poured into water. The above mixture was extracted with ethyl acetate and the organic layer was washed with water, brine, dried, and concentrated in vacuo. The residue was purified by flash chromatography to afford 0.4 g (27%) of 4-isopropyl-6-methoxy-2-(1-methyl-3-phenylpyrazol-5-yl-oxymethyl)-1,2-benzisothiazol-3(2H)-one 1,1-dioxide (Formula I: R1 =CH3 ; R2 =Ph; R3 =H; R4 =CH(CH3)2 ; R5 =6-OCH3) as a white solid, m.p. 126°-128° C.
Reaction SMILES: F[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1.S(=O)(=O)(O)O.C(OCC)(=O)C.[CH2:25]([OH:29])[CH2:26][CH2:27][CH3:28]>>[CH2:25]([O:29][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1)[CH2:26][CH2:27][CH3:28]
Reactant: O=C(O)c1ccc(F)cc1[N+](=O)[O-]
Reactant: CCCCO
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Product: CCCCOc1ccc(C(=O)O)c([N+](=O)[O-])c1
Temperature: 110 °C
Reaction time: 4 h

Procedure:
A solution of 4-fluoro-2-nitrobenzoic acid (1.81 g) in butanol (20 ml) was mixed with sulfuric acid (3 ml) and stirred at 110° C. for 4 hours. Ethyl acetate (100 ml) was added, and the mixture was washed with saturated sodium bicarbonate solution (3×50 ml), dried with sodium sulfate, filtered and concentrated in vacuo. The residue (2.2 g) was added dropwise at −10° C. to a sodium butoxylate solution prepared from butanol (20 ml) and sodium hydride (2.18 g) at −10° C. under argon and then stirred for 20 hours. Ethyl acetate (100 ml) was added, and the mixture was washed with water (2×50 ml), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by preparative HPLC. The butyl 4-butoxy-2-nitrobenzoate was hydrolyzed with sodium hydoxide (5N; 100 ml) in ethanol at room temperature for 3 hours. The mixture was acidified with hydrochloric acid (10N; 100 ml) and extracted with dichloromethane, and the organic phase was dried over sodium sulfate, filtered and concentrated. This resulted in the product with the molecular weight of 239.23 (C11H13NO5); MS (ESI): 240 (M+H+).
Reaction SMILES: [C:1]([C:4]1[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:5]=1[OH:6])(=[O:3])[CH3:2].S([O-])([O-])(=O)=O.[Ca+2]>C(OCC)(=O)C.C(#N)C.C(O)C1C=CC=CC=1>[C:1]([C:4]1[C:5](=[O:6])[CH:7]=[CH:8][C:9](=[O:11])[C:10]=1[O:3][CH2:1][C:4]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:5]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1cc(O)ccc1O
Agent: O=S(=O)([O-])[O-]
Agent: [Ca+2]
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: OCc1ccccc1
Product: CC(=O)C1=C(OCc2ccccc2)C(=O)C=CC1=O
Reaction time: 2 h
Yield: 70 %

Procedure:
To a solution of 4 g of 2-acetyl hydroquinone (I) in 90 ml of ethyl acetate, 100 ml of acetonitrile and 5 ml of benzyl alcohol (III) are added 60 g of crushed calcium sulfate oven dried at 240° C., then 8.5 g of powdered cuprous chloride. It is agitated in gaseous oxygen (at a pressure of one atmosphere) for two hours and thirty minutes at ambient temperature. Then it is diluted with toluene, filtered, the filtrate is evaporated, the residue taken up in a mixture of 120 ml of ether and 80 ml of cyclohexane; by trituration of the resulting mixture followed by a filtration separation of the insoluble matter, a solution is obtained which leads to the expected compound (Yield≃70%) after evaporation of the solvents.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:13](=O)[CH:14]=[C:15]([C:20]2[CH:25]=[C:24]([Cl:26])[C:23]([F:27])=[C:22]([Cl:28])[CH:21]=2)[C:16]([F:19])([F:18])[F:17])=[C:8]2[CH2:12][CH2:11][CH2:10][C:9]=12)=[O:4].[OH-:30].[Na+].[NH2:32]O.Cl>O.C1COCC1>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:13]2[CH2:14][C:15]([C:20]3[CH:25]=[C:24]([Cl:26])[C:23]([F:27])=[C:22]([Cl:28])[CH:21]=3)([C:16]([F:19])([F:18])[F:17])[O:30][N:32]=2)=[C:8]2[CH2:12][CH2:11][CH2:10][C:9]=12)=[O:4]
Reactant: [OH-]
Reactant: NO
Reactant: COC(=O)c1sc(C(=O)C=C(c2cc(Cl)c(F)c(Cl)c2)C(F)(F)F)c2c1CCC2
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1sc(C2=NOC(c3cc(Cl)c(F)c(Cl)c3)(C(F)(F)F)C2)c2c1CCC2
Yield: 50384.1 %

Procedure:
Stir a mixture of 3-[3-(3,5-Dichloro-4-fluoro-phenyl)-4,4,4-trifluoro-but-2-enoyl]-5,6-dihydro-4H-cyclopenta[c]thiophene-1-carboxylic acid methyl ester (25 g, 53.6 mmol), NaOH (8.6 g, 0.214 mol) and NH2OH—HCl (7.4 g, 0.107 mmol) in water (100 mL) and THF (200 mL) at room temperature for overnight. After removal of the solvent under vacuum, the solution is diluted with water and extracted with EtOAc (200 mL×3). The combined organic layer is washed with brine, dried over anhydrous Na2SO4 and concentrated by vacuum to afford 3-[5-(3,5-Dichloro-4-fluoro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-5,6-dihydro-4H-cyclopenta[c]thiophene-1-carboxylic acid methyl ester as a white solid (26 g), which is used directly in the next step without purification. MS (m/z): 483 (M+1).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][C@H:7]([NH:10][C:11](=[O:20])[O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C@H:6]([O:21][CH3:22])[CH2:5]1)(=[O:3])[NH2:2].Br[CH:24]([CH2:34][CH3:35])[C:25](=O)[C:26]([O:28][CH2:29][CH2:30]CC)=[O:27].[C:36](=O)(O)[O-].[Na+]>C1COCC1>[CH2:13]([O:12][C:11]([NH:10][C@H:7]1[CH2:8][CH2:9][N:4]([C:1]2[O:3][C:24]([CH:34]([CH3:35])[CH3:36])=[C:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[N:2]=2)[CH2:5][C@H:6]1[O:21][CH3:22])=[O:20])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CO[C@@H]1CN(C(N)=O)CC[C@@H]1NC(=O)OCc1ccccc1
Reactant: CCCCOC(=O)C(=O)C(Br)CC
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)c1nc(N2CC[C@H](NC(=O)OCc3ccccc3)[C@H](OC)C2)oc1C(C)C
Yield: 30.5 %

Procedure:
The same operation as in Example (103c) was performed using cis(±)-benzyl (1-carbamoyl-3-methoxypiperidin-4-yl)carbamate obtained in Example (103b) (0.97 g, 3.16 mmol), butyl 3-bromo-4-methyl-2-oxobutanoate obtained in Example (111a) (7.6 g, 30.2 mmol), sodium bicarbonate (0.7 g, 8.3 mmol) and THF (20 mL). The resulting residue was purified by silica gel column chromatography (elution solvent: ethyl acetate/hexane=1/4, 2/3, 1/1, 3/2, 2/1) to obtain 0.43 g of the title compound as a colorless solid (100%).
Reaction SMILES: [Li]CCCC.[CH3:6][CH:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8]1.[C:16](=[C:19]1[CH:28]=[C:27]2[C:21]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]2)=[CH:20]1)([CH3:18])[CH3:17]>CCCCCC.C(OCC)C.O>[CH3:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]([C:16]([C:19]2[CH2:28][C:27]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][C:21]=3[CH:20]=2)([CH3:18])[CH3:17])[CH:8]=1
Reactant: CC(C)=C1C=C2CCCCCC2=C1
Reactant: CC1C=Cc2ccccc21
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: O
Solvent: CCCCCC
Product: CC1=CC(C(C)(C)C2=CC3=C(CCCCC3)C2)c2ccccc21
Reaction time: 3 h
Yield: 67.3 %

Procedure:
12.4 ml of LiBu 2.5 M in hexane are added, at room temperature, to an ether solution of 4.2 g (0.032 moles) of 1-methylindene in 100 ml of ethyl ether. The mixture is left under stirring for 3 hours, then 3.8 g (0.022 moles) of 2-isopropylidene-2,4,5,6,7,8-hexahydroazulene are added at -70° C. The temperature is left to rise and the mixture is left under stirring for 48 hours. The reaction mixture is hydrolyzed in water and extracted with ethyl ether which after evaporation provides a solid which is purified on a silica gel column using petroleum ether as eluant. 4.5 g (0.0148 moles) of 2-[1-(3-methyl-1H-Inden-1-yl) -1-methyl-ethyl]-1,4,5,6,7,8-hexahydroazulene are obtained which are dissolved in 200 ml of ethyl ether, to which 18.8 ml of LiMe 1.6 M in ether ethyl are added and the mixture is left under stirring for a night. A slightly yellow precipitate is formed. The mixture is cooled to -70° C. and 3.51 g (0.015 moles) of zirconium tetrachloride are added. The temperature is brought to room temperature and the mass tends to take on a dark brownish-yellow coloring. The mixture is filtered, washed with ethyl ether which tends to become yellow, and is then extracted with methylene chloride (2×100 ml). The solution is brought to a small volume and 20 ml of ethyl ether are then added. A solid precipitates which is filtered, washed with ether and hexane and then dried. 1.0 g of complex are obtained. After two days large orange crystals separate from the yellow ether mother liquor, which when filtered and washed with hexane give 2.1 g of pure complex for a total of 3.1 g (45% yield calculated on the ligand used). 1H NMR (CDCl3, δ ppm rel. TMS): 7.55 (d, 2H); 7.25 (m, 1H); 6.95 (m, 1H); 5.65 (s, 1H); 5.43 (d, 1H); 2.8-2.5 (m, 4H); 2.45 (s, 3H); 1.9-1.6 (m, 7H); 1.40 (m, 2H).
Reaction SMILES: [C:1]([N:3]1[C:11]2[CH:10]=[CH:9][C:8]([CH3:12])=[CH:7][C:6]=2[C:5]2[CH2:13][N:14]([CH3:17])[CH2:15][CH2:16][C:4]1=2)#[CH:2].Br[C:19]1[CH:24]=[CH:23][N:22]=[CH:21][N:20]=1>C(N(CC)CC)C.[Cu](I)I>[CH3:17][N:14]1[CH2:15][CH2:16][C:4]2[N:3]([C:1]#[C:2][C:19]3[CH:24]=[CH:23][N:22]=[CH:21][N:20]=3)[C:11]3[CH:10]=[CH:9][C:8]([CH3:12])=[CH:7][C:6]=3[C:5]=2[CH2:13]1
Reactant: C#Cn1c2c(c3cc(C)ccc31)CN(C)CC2
Reactant: Brc1ccncn1
Agent: I[Cu]I
Solvent: CCN(CC)CC
Product: Cc1ccc2c(c1)c1c(n2C#Cc2ccncn2)CCN(C)C1
Temperature: 40 °C
Yield: 17.7 %

Procedure:
5-Ethynyl-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (100 mg, 0.466 mmol) and 4-bromopyrimidine (126 mg, 0.797 mmol) were dissolved in triethylamine (1.5 mL), and the solution was purged with nitrogen. Dichlorobis (triphenylphosphine) palladium (12.5 mg, 0.017 mmol) and copper iodide (6.7 mg, 0.035 mmol) were added and the reaction mixture was purged again with nitrogen. The reaction mixture was heated by microwave at 40° C. for 90 min. The reaction mixture was quenched with 30 mL water and extracted with EtOAc (3×15 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to obtain crude product. The crude product was purified with column chromatography (silica gel: 100-200 mesh, eluent 0-10% MeOH in DCM) to obtain 25 mg product. 1H NMR (CDCl3, freebase) δ (ppm): 9.17 (s, 1H_), 8.76 (d, 1H), 7.57 (d, 1H), 7.40 (d, 1H), 7.18 (m, 2H), 3.64 (s, 2H), 3.06 (d, 2H), 2.98 (d, 2H), 2.61 (s, 3H), 2.43 (s, 3H).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:4]=[C:5]([CH:17]=[CH:18][CH:19]=1)[CH2:6][CH:7]1[CH2:12][CH:11]([C:13]([O:15][CH3:16])=[O:14])[CH2:10][CH2:9][NH:8]1.CCN(C(C)C)C(C)C.[C:31](Cl)(=[O:34])[O:32][CH3:33].CCOCC>ClCCl>[F:21][C:2]([F:20])([F:1])[C:3]1[CH:4]=[C:5]([CH:17]=[CH:18][CH:19]=1)[CH2:6][CH:7]1[CH2:12][CH:11]([C:13]([O:15][CH3:16])=[O:14])[CH2:10][CH2:9][N:8]1[C:31]([O:32][CH3:33])=[O:34]
Reactant: COC(=O)C1CCNC(Cc2cccc(C(F)(F)F)c2)C1
Reactant: COC(=O)Cl
Solvent: ClCCl
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C1CCN(C(=O)OC)C(Cc2cccc(C(F)(F)F)c2)C1
Yield: 85.3 %

Procedure:
Methyl 2-(3-(trifluoromethyl)benzyl)piperidine-4-carboxylate (6.0 g, 19.91 mmol) was dissolved in DIPEA (6.94 mL, 39.83 mmol) and dichloromethane (150 mL). Methyl carbonochloridate (2.258 g, 23.90 mmol) was added dropwise. Ether was added and the reaction mixture was washed with 1 M HCl and Na2CO3 (aq). The organic layer was dried over MgSO4, filtered through celite and the solvent was evaporated to yield dimethyl 2-(3-(trifluoromethyl)benzyl)piperidine-1,4-dicarboxylate (6.1 g, 85%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[C:23]([N:24](C)[C:25](=O)C(F)(F)F)=[C:22]([I:32])[N:21]=[CH:20][N:19]=2)[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]#[N:16])[CH:10]=1.[BH4-].[Na+].C(OCC)(=O)C>C(O)(C)C.O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[C:23]([NH:24][CH3:25])=[C:22]([I:32])[N:21]=[CH:20][N:19]=2)[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:10]=[C:11]([CH:12]=[CH:13][CH:14]=1)[C:15]#[N:16]
Reactant: CN(C(=O)C(F)(F)F)c1c(I)ncnc1Nc1ccc(Oc2cccc(C#N)c2)c(Cl)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: CNc1c(I)ncnc1Nc1ccc(Oc2cccc(C#N)c2)c(Cl)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 90.7 %

Procedure:
To a solution of N-(4-{[3-chloro-4-(3-cyanophenoxy)phenyl]amino}-6-iodopyrimidin-5-yl)-2,2,2-trifluoro-N-methylacetamide (1.0 g) in isopropanol-tetrahydrofuran (5.0 mL-10 mL) was added sodium borohydride (70 mg) at room temperature. The mixture was stirred at room temperature for 1.5 hrs, and ethyl acetate was added. The mixture was washed with water and saturated brine and the organic layer was dried over magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified by silica gel column chromatography (eluent, hexane:ethyl acetate=4:1→3:2) to give the title compound (755 mg) as a white amorphous solid.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:29]([CH2:30][CH3:31])=[CH:28][C:7]2[NH:8][C:9]([C:11]3[C:15]([NH:16][C:17]([CH:19]4[CH2:21][CH2:20]4)=[O:18])=[CH:14][N:13](C4CCCCO4)[N:12]=3)=[N:10][C:6]=2[CH:5]=1)[CH3:2].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>C(O)C>[CH2:1]([O:3][C:4]1[C:29]([CH2:30][CH3:31])=[CH:28][C:7]2[NH:8][C:9]([C:11]3[C:15]([NH:16][C:17]([CH:19]4[CH2:20][CH2:21]4)=[O:18])=[CH:14][NH:13][N:12]=3)=[N:10][C:6]=2[CH:5]=1)[CH3:2]
Reactant: CCOc1cc2nc(-c3nn(C4CCCCO4)cc3NC(=O)C3CC3)[nH]c2cc1CC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOc1cc2nc(-c3n[nH]cc3NC(=O)C3CC3)[nH]c2cc1CC
Yield: 49.9 %

Procedure:
A solution of cyclopropanecarboxylic acid [3-(5-ethoxy-6-ethyl-1H-benzoimidazol-2-yl)-1-(tetrahydropyran-2-yl)-1H-pyrazol-4-yl]amide [0.3 g, Reference Example 48(a)] and p-toluenesulfonic acid hydrate (1.2 g) in ethanol (25 mL) was heated in an 80° C. in an oil bath for 1 hour, then cooled, and then poured into aqueous sodium bicarbonate solution. The aqueous mixture was extracted twice with ethyl acetate (75 mL). The combined extracts were evaporated and the residue was redissolved in a mixture of methylene chloride (100 mL) and methanol (10 mL). This solution was washed with aqueous sodium bicarbonate, to remove some residual p-toluenesulfonic acid, then evaporated to give cyclopropanecarboxylic acid[3-(5-ethoxy-6-ethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]amide (120 mg) as a white solid. LC-MS (Method E): RT=2.36 minutes, 340 (M+H)+. (b) 3-(1,5,6,7-Tetrahydro-1,3-diaza-s-indacen-2-yl)-1H-pyrazol-4-ylamine
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C@@H:10]2[CH2:15][CH:14]=[CH:13][CH2:12][C@H:11]2[N+]([O-])=O)=[CH:6][C:5]=1[O:19][CH2:20][CH3:21])[CH3:2].[O-:22]CC.[Na+].Cl.NC(N)=O>C(O)C.O>[CH2:20]([O:19][C:5]1[CH:6]=[C:7]([CH:10]2[CH2:15][CH:14]=[CH:13][CH2:12][C:11]2=[O:22])[CH:8]=[CH:9][C:4]=1[O:3][CH2:1][CH3:2])[CH3:21]
Reactant: CCOc1ccc([C@@H]2CC=CC[C@H]2[N+](=O)[O-])cc1OCC
Reactant: CC[O-]
Agent: Cl
Agent: NC(N)=O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOc1ccc(C2CC=CCC2=O)cc1OCC
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
15.0 g of (+/−)-trans-1,2-diethoxy-4-(2-nitrocyclohex-4-enyl)benzene are dissolved in 375 ml of ethanol and added dropwise to 42 ml of 20% strength sodium ethoxide solution. The mixture is stirred at RT for 20 min. and then added dropwise to an ice-cooled solution of 67.5 ml of conc. hydrochloric acid and 1.35 g of urea in 225 ml of water and 170 ml of ethanol. The solution is extracted with water/dichloromethane and the organic phase is dried with sodium sulfate and concentrated under reduced pressure. The residue is chromatographed over silica gel using petroleum ether/ethyl acetate in a ratio of 2/1. Concentration of the appropriate eluate fractions gives 10.33 g (77.1% of Th.) of the title compound as an oil.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]([CH3:31])([C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18](=[O:30])[C:19]2[C:28](=[O:29])[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[NH:21][CH:20]=2)=[CH:13][CH:12]=1)[CH3:10])(C)(C)C.C(O)(C(F)(F)F)=O.[OH-].[Na+]>C(Cl)Cl>[NH2:7][CH2:8][C:9]([C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18]([C:19]2[C:28](=[O:29])[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[NH:21][CH:20]=2)=[O:30])=[CH:13][CH:12]=1)([CH3:10])[CH3:31]
Reactant: CC(C)(C)OC(=O)NCC(C)(C)c1ccc(CC(=O)c2c[nH]c3ccccc3c2=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(CN)c1ccc(CC(=O)c2c[nH]c3ccccc3c2=O)cc1
Reaction time: 8 h
Yield: 169.3 %

Procedure:
(2-Methyl-2-{4-[2-oxo-2-(4-oxo-1,4-dihydro-quinolin-3-yl)-ethyl]-phenyl}-propyl)-carbamic acid tert-butyl ester (88) (0.50 g, 1.15 mmol), TFA (5 mL) and CH2Cl2 (5 mL) were combined and stirred at room temerpature overnight. The reaction mixture was then neutralized with 1N NaOH. The precipitate was collected via filtration to yield the product 3-(2-(4-(1-amino-2-methylpropan-2-yl)phenyl)acetyl)quinolin-4(1H)-one as a brown solid (651 mg, 91%). HPLC ret. time 2.26 min, 10-99% CH3CN, 5 min run; ESI-MS 336.5 m/z (MH+).
Reaction SMILES: [O:1]=[C:2]1[C:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:11][CH:10]=2)=[C:6]([CH2:23][CH2:24][CH3:25])[N:5]2[N:26]=[CH:27][N:28]=[C:4]2[NH:3]1.[CH3:29][C:30]1([O:33][CH2:32]1)[CH3:31].C(=O)([O-])[O-].[K+].[K+].CN(C)C(=O)C>C(OCC)(=O)C>[OH:33][C:30]([CH3:32])([CH3:31])[CH2:29][N:3]1[C:2](=[O:1])[C:7]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([C:15]3[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:13][CH:14]=2)=[C:6]([CH2:23][CH2:24][CH3:25])[N:5]2[N:26]=[CH:27][N:28]=[C:4]12
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)[nH]c2ncnn12
Reactant: CC1(C)CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(CC(C)(C)O)c2ncnn12
Temperature: 100 °C
Reaction time: 16 h
Yield: 79 %

Procedure:
A mixture of 4′-[(5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile (0.8 g), isobutylene oxide (1.9 mL), potassium carbonate (0.6 g) and N,N-dimethylacetamide (5 mL) was stirred in a sealed tube at 100° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% aqueous potassium hydrogensulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.76 g, 79%).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:16])=[N:4][S:5][C:6]=1[NH:7][C@H:8]([C:13]([OH:15])=O)[CH2:9][CH:10]([CH3:12])[CH3:11].C1CN([P+](O[N:34]2N=[N:41][C:36]3C=CC=C[C:35]2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.Cl.NCC#N.C(N(CC)CC)C>CN(C=O)C.CCOCC>[Br:1][C:2]1[C:3]([CH3:16])=[N:4][S:5][C:6]=1[NH:7][C@H:8]([C:13]([NH:41][CH2:36][C:35]#[N:34])=[O:15])[CH2:9][CH:10]([CH3:11])[CH3:12]
Reactant: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Reactant: Cc1nsc(N[C@@H](CC(C)C)C(=O)O)c1Br
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: N#CCN
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1nsc(N[C@@H](CC(C)C)C(=O)NCC#N)c1Br
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To an ice cold solution of N-(4-bromo-3-methylisothiazol-5-yl)-L-leucine (9.83 g, 32 mmol), PyBOP (18.6 g, 35.7 mmol) and 2-aminoacetonitrile hydrochloride (6.5 g, 70.3 mmol) in DMF (250 mL) was slowly added over 5 min triethylamine (15.6 mL, 112 mmol). The resulting suspension was stirred at room temperature for 18 h. The reaction mixture was partitioned between EtOAc and half-saturated NaHCO3. The organic layer was washed once with water, dried over Na2SO4 and concentrated in vacuo. The crude product was purified by flash chromatography using EtOAc in hexane to give a colorless syrup. This syrup was disolved in Et2O, washed once with 3% HCl and once with diluted NaHCO3, dried over Na2SO4 and concentrated in vacuo to give N2-(4-bromo-3-methylisothiazol-5-yl)-N1-(cyanomethyl)-L-leucinamide as a white foam.
Reaction SMILES: [Br-].O[C@@H]1CCC[N+](CC(=O)NC2C=CON=2)(C)C1.[CH3:19][N:20]1[CH2:25][CH2:24][CH:23]([OH:26])[CH2:22][CH2:21]1.[Br:27]CC(NC1C=CON=1)=O.[O:37]([CH2:44][CH2:45]Br)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>>[Br-:27].[OH:26][CH:23]1[CH2:24][CH2:25][N+:20]([CH3:19])([CH2:45][CH2:44][O:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH2:21][CH2:22]1
Reactant: CN1CCC(O)CC1
Reactant: BrCCOc1ccccc1
Reactant: O=C(CBr)Nc1ccon1
Agent: C[N+]1(CC(=O)Nc2ccon2)CCC[C@@H](O)C1
Agent: [Br-]
Product: C[N+]1(CCOc2ccccc2)CCC(O)CC1

Procedure:
This compound is prepared by an analogous method to (1R/S,3R)-3-Hydroxy-1-(isoxazol-3-ylcarbamoylmethyl)-1-methyl-piperidinium bromide (Intermediate C) by replacing (R)-1-methyl-piperidin-3-ol (step C3) with 1-methyl-piperidin-4-ol and by replacing 2-bromo-N-isoxazol-3-yl-acetamide (Intermediate A) with 2-phenoxy-ethylbromide.
Reaction SMILES: [CH:1]1([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][NH:17][CH:18]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[CH:11]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[F:25][C:26]1[CH:31]=[C:30]([F:32])[CH:29]=[C:28]([F:33])[C:27]=1[NH:34][C:35](=[O:43])OC1C=CC=CC=1>C1(C)C=CC=CC=1>[CH:18]1([N:17]([CH2:16][C:12]2[CH:13]=[CH:14][CH:15]=[C:10]([CH2:9][N:8]([CH:1]3[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[C:35]([NH:34][C:27]3[C:28]([F:33])=[CH:29][C:30]([F:32])=[CH:31][C:26]=3[F:25])=[O:43])[CH:11]=2)[C:35]([NH:34][C:27]2[C:28]([F:33])=[CH:29][C:30]([F:32])=[CH:31][C:26]=2[F:25])=[O:43])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: c1cc(CNC2CCCCCC2)cc(CNC2CCCCCC2)c1
Reactant: O=C(Nc1c(F)cc(F)cc1F)Oc1ccccc1
Solvent: Cc1ccccc1
Product: O=C(Nc1c(F)cc(F)cc1F)N(Cc1cccc(CN(C(=O)Nc2c(F)cc(F)cc2F)C2CCCCCC2)c1)C1CCCCCC1
Yield: 64.1 %

Procedure:
A mixture of 0.82 g N,N'-dicycloheptyl-m-xylylenediamine, 1.26 g phenyl 2,4,6-trifluorophenylcarbamate and 50 ml toluene was heated under reflux for one hour. After cooling, the reaction mixture was washed twice with 50 ml of 1N-NaOH solution and then with sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure from the dried solution, and the residue was recrystallized from acetone, giving 1.02 g of 1,3-bis[[1-cycloheptyl-3-(2,4,6-trifluorophenyl)ureido]methyl]benzene.