Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[N:7]2[CH:8]=[CH:9][CH:10]=[C:11]([O:12][C@@H:13]3[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[CH2:15][C@H:14]3[O:22]S(C)(=O)=O)[C:6]2=[N:5][C:4]=1[CH3:27])=[O:2].C([O-])(=O)C.[K+].O1CCOCCOCCOCCOCCOCC1.C(#N)C>ClCCl>[CH:1]([C:3]1[N:7]2[CH:8]=[CH:9][CH:10]=[C:11]([O:12][C@@H:13]3[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[CH2:15][C@@H:14]3[OH:22])[C:6]2=[N:5][C:4]=1[CH3:27])=[O:2]
Reactant: Cc1nc2c(O[C@@H]3c4ccccc4C[C@H]3OS(C)(=O)=O)cccn2c1C=O
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC#N
Product: Cc1nc2c(O[C@@H]3c4ccccc4C[C@@H]3O)cccn2c1C=O
Temperature: 70 °C
Reaction time: 1 h
Yield: 14.4 %

Procedure:
1 g of 3-formyl-2-methyl-8-(2-(trans)-methylsulfonyloxy-2,3-dihydro-1-indenyloxy)-imidazo[1,2-a]pyridine is added to a mixture of 5.1 g of anhydrous potassium acetate, 13.8 g of 1,4,7,10,13,16-hexaoxacyclooctadecan ("18-crown-6) and 100 ml of anhydrous acetonitrile, while stirring and excluding any moisture. The brownish suspension is warmed for 18 hours at 70° C. and heated for a further 10 hours under reflux. After cooling, it is poured onto water and extraction carried out several times with dichloromethane. The organic phases are washed with water, dried and the solvent stripped off in vacuo. The dark brown residue is assayed by chromotography with the mobile phase ethyl acetate/methanol=95:5 (V/V) over silica gel. After stripping off of the solvent, the residue (0.18 g) is dissolved in 3.6 ml methanol and this solution is added dropwise with stirring to a solution of 0.072 g potassium hydroxide in 1.2 ml water. Stirring continues for one hour at room temperature, water is added, the pH is adjusted with diluted acetic acid to 6 and extraction is carried out several times with dichloromethane. The organic phases are washed with water, dried and the solvent is stripped off in vacuo. 115 mg of the title compound as a yellowish residue of m.p. 171°-173° C. is obtained.
Reaction SMILES: [N+](C1C=C(S(O[CH2:14][C@:15]2([CH3:18])[CH2:17][O:16]2)(=O)=O)C=CC=1)([O-])=O.[C:19]1(=[O:29])[NH:23][C:22](=[O:24])[C:21]2=[CH:25][CH:26]=[CH:27][CH:28]=[C:20]12.[K]>CN(C)C=O>[CH3:14][C@@:15]1([CH2:18][N:23]2[C:19](=[O:29])[C:20]3[C:21](=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:22]2=[O:24])[CH2:17][O:16]1
Reactant: C[C@@]1(COS(=O)(=O)c2cccc([N+](=O)[O-])c2)CO1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Product: C[C@@]1(CN2C(=O)c3ccccc3C2=O)CO1
Temperature: 50 °C
Reaction time: 5 h
Yield: 56.8 %

Procedure:
To a solution of (2S)-(2-methyloxiran-2-yl)methyl 3-nitrobenzenesulphonate (1.913 g, 7 mmoles) in dry dimethylformamide (15 ml), was added potassium phthalimide (1.304 g, 7 mmoles). The mixture was stirred at 50° C. for 5 h and then cooled to room temperature. The resulting mixture was partitioned between ethyl acetate and water. The aqueous phase was washed with ethyl acetate (2×100 ml) and the combined organic extracts were washed with water (3×100 ml), saturated brine solution, dried over sodium sulfate and concentrated in vacuo to leave a crude orange wax. Purification by chromatography (silica, 20% ethyl acetate in iso-hexane) afforded the subtitle compound as a white solid (0.864 g).
Reaction SMILES: [OH-].[Na+].[NH2:3][C:4]([CH3:8])([CH3:7])[C:5]#[N:6]>CCCCCCCCCCCCCCCC[N+](C)(C)C.[Cl-]>[N:3]([C:4]([CH3:8])([CH3:7])[C:5]#[N:6])=[N:3][C:4]([CH3:8])([CH3:7])[C:5]#[N:6]
Reactant: CC(C)(N)C#N
Agent: CCCCCCCCCCCCCCCC[N+](C)(C)C
Agent: [Cl-]
Agent: [Na+]
Product: CC(C)(C#N)N=NC(C)(C)C#N
Reaction time: 0.67 h

Procedure:
The resulting aqueous dispersion of N,N'-dichloro-2-amino -2-methylpropanenitrile was adjusted to pH7 with caustic soda and 3 ml of "Arquad 16-29%" was added. A further 24.1 gm of 2-amino-2-methylpropanenitrile was then added, concurrently with sufficient caustic soda to maintain a pH of greater than 12, over 40 minutes and the resulting title compound was filtered off to yield 39.4 g (91.8% yield).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7](Br)[N:8]([CH2:10][O:11][CH2:12][CH2:13][Si:14]([CH3:17])([CH3:16])[CH3:15])[CH:9]=1)=[O:4].C([Sn](CCCC)(CCCC)[C:24]([O:26][CH2:27][CH3:28])=[CH2:25])CCC>O1CCOCC1.O.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>[CH2:27]([O:26][C:24]([C:7]1[N:8]([CH2:10][O:11][CH2:12][CH2:13][Si:14]([CH3:17])([CH3:16])[CH3:15])[CH:9]=[C:5]([C:3]([O:2][CH3:1])=[O:4])[N:6]=1)=[CH2:25])[CH3:28]
Reactant: COC(=O)c1cn(COCC[Si](C)(C)C)c(Br)n1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1COCCO1
Product: C=C(OCC)c1nc(C(=O)OC)cn1COCC[Si](C)(C)C
Temperature: 25 °C

Procedure:
Methyl-2-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-carboxylate (10 g, 29.9 mmol) was dissolved in dioxane (200 ml). Tributyl(1-ethoxy-vinyl)stannane (16.2 g, 44.8 mmol) was added to the solution. The resulting mixture was degassed and purged with argon for 20 min. Then Pd(PPh3)4 (3.45 g, 2.99 mmol) was added and the mixture was refluxed overnight. The reaction mixture was cooled to RT and diluted with cold water. The mixture was extracted with EtOAc and washed with aqueous KF solution. The organic layer was concentrated to give the desired product. Yield 12.1 g. LC-MS: [M+1]=327.78.
Reaction SMILES: [CH2:1]([N:3]([CH2:29][CH3:30])[CH2:4][CH2:5][N:6]1[C:14]2[C:9](=[C:10]([C:16]([F:19])([F:18])[F:17])[CH:11]=[C:12](I)[CH:13]=2)[C:8]([OH:27])([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[Cl:26])[C:7]1=[O:28])[CH3:2].[O:31]1[CH2:36][CH2:35][N:34]([C:37]([CH2:39][CH2:40][C:41]#[CH:42])=[O:38])[CH2:33][CH2:32]1>>[CH2:1]([N:3]([CH2:29][CH3:30])[CH2:4][CH2:5][N:6]1[C:14]2[C:9](=[C:10]([C:16]([F:19])([F:18])[F:17])[CH:11]=[C:12]([C:42]#[C:41][CH2:40][CH2:39][C:37]([N:34]3[CH2:35][CH2:36][O:31][CH2:32][CH2:33]3)=[O:38])[CH:13]=2)[C:8]([OH:27])([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[Cl:26])[C:7]1=[O:28])[CH3:2]
Reactant: CCN(CC)CCN1C(=O)C(O)(c2ccccc2Cl)c2c1cc(I)cc2C(F)(F)F
Reactant: C#CCCC(=O)N1CCOCC1
Product: CCN(CC)CCN1C(=O)C(O)(c2ccccc2Cl)c2c1cc(C#CCCC(=O)N1CCOCC1)cc2C(F)(F)F

Procedure:
The title compound (246 mg) was prepared from (+)-1-(2-diethylaminoethyl)-4-trifluoromethyl-6-iodo-3-hydroxy-3-(2-chlorophenyl)oxindole (300 mg, 0.543 mmol) and 4-morpholinocarbonyl-1-butyne by the procedure similar to that described in Reference Example 21. The hydrochloride of the title compound was obtained by treating with 4 N HCl in dioxane followed by concentration to dryness. The NMR spectra of the title compound exhibited the same as in Example 70. [α]D +58.3° (c=0.252, MeOH).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[OH:12])[O:8][CH2:7][CH2:6]C2(O[Si](C)(C)C)C#N.[C:20]([OH:23])(=[O:22])[CH3:21]>Cl.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[OH:12])[O:8][CH2:7][CH2:6][CH:21]2[C:20]([OH:23])=[O:22]
Reactant: CC(=O)O
Reactant: C[Si](C)(C)OC1(C#N)CCOc2cc(O)c(Cl)cc21
Agent: Cl
Solvent: CCOC(C)=O
Product: O=C(O)C1CCOc2cc(O)c(Cl)cc21
Reaction time: 12 h
Yield: 100 %

Procedure:
A solution of 6-chloro-7-hydroxy-4-(trimethylsilyloxy)chroman-4-carbonitrile (129 g, 433 mmol) and SnCl2 dihydrate (293 g, 1299 mmol) in concentrated HCl (435 ml) and glacial acetic acid (435 ml) was heated to 125° C. and stirred for 12 hours. The reaction was taken up in ethyl acetate (500 ml) and washed with water (3×500 ml), dried over magnesium sulfate, filtered and concentrated to give the desired compound (99 g, 100%).
Reaction SMILES: [N+:1]([C:4]1[O:8][C:7]([C:9](Cl)=[O:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH:12]([C:14]1[S:15][C:16]2[CH:22]=[C:21]([O:23][CH2:24][Cl:25])[CH:20]=[CH:19][C:17]=2[N:18]=1)[NH2:13]>>[Cl:25][CH2:24][O:23][C:21]1[CH:20]=[CH:19][C:17]2[N:18]=[C:14]([NH:12][NH:13][C:9]([C:7]3[O:8][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=3)=[O:10])[S:15][C:16]=2[CH:22]=1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])o1
Reactant: NNc1nc2ccc(OCCl)cc2s1
Product: O=C(NNc1nc2ccc(OCCl)cc2s1)c1ccc([N+](=O)[O-])o1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
The compound 4g was prepared according to above described method by using 5-nitro-2-furancarboxylic acid chloride (430 mg, 1 mmol) and 2-hydrazino-6-chloromethoxybenzothiazole (298 mg, 1.5 mmol) which stirred for 1 h at 0° C. and stirring continued at 25° C. for 11 h (yield 237 mg, 70%).
Reaction SMILES: [NH2:1][C:2]1[CH:20]=[CH:19][CH:18]=[CH:17][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]([CH2:15][CH3:16])[CH3:14])=[CH:9][CH:8]=1)=[O:5].[OH:21][C:22]1[CH:29]=[CH:28][C:25]([CH:26]=O)=[CH:24][CH:23]=1.II.[OH-].[K+]>CN(C)C=O>[CH:13]([C:10]1[CH:11]=[CH:12][C:7]([N:6]2[C:4](=[O:5])[C:3]3[C:2](=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:1]=[C:26]2[C:25]2[CH:28]=[CH:29][C:22]([OH:21])=[CH:23][CH:24]=2)=[CH:8][CH:9]=1)([CH2:15][CH3:16])[CH3:14]
Reactant: O=Cc1ccc(O)cc1
Reactant: CCC(C)c1ccc(NC(=O)c2ccccc2N)cc1
Agent: II
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CCC(C)c1ccc(-n2c(-c3ccc(O)cc3)nc3ccccc3c2=O)cc1
Temperature: 110 °C

Procedure:
To a solution of 2-amino-N-(4-sec-butylphenyl)-benzamide (0.500 g, 1.86 mmol) in N,N-dimethylformamide (9 mL) under nitrogen atmosphere was added 4-hydroxy-benzaldehyde (0.450 g, 3.73 mmol) followed by iodine (0.560 g, 2.23 mmol) and potassium hydroxide (0.120 g, 2.23 mmol). The resulting mixture was heated at 110° C. overnight, then the solvent was removed under reduced pressure, the residue was diluted with ethyl acetate, washed with water and dried over sodium sulfate. The crude oil (0.97 g) was purified by column chromatography (silica gel 230-400 mesh; 1/1 hexanes/EtOAc as eluent) to give pure 3-(4-sec-butylphenyl)-2-(4-hydroxyphenyl)-3H-quinazolin-4-one as a yellow solid. Yield: 0.33 g (47.8%). To a mixture of 3-(4-sec-butylphenyl)-2-(4-hydroxyphenyl)-3H-quinazolin-4-one (0.11 g, 0.31 mmol) and potassium carbonate (0.13 g, 0.93 mmol) in N,N-dimethylformamide (3.5 mL) under nitrogen atmosphere was added 2-chloroethanol (0.032 mL, 46 mmol). The reaction mixture was heated at reflux for 14 hours, then the solvent was removed under reduced pressure and the residue was diluted with ethyl acetate, washed with 5% aqueous solution of sodium hydroxide, brine, and dried over sodium sulfate. The crude solid (0.13 g) was purified by column chromatography (silica gel 230-400 mesh; 10/0 to 1/1 hexanes/EtOAc, then 10/0 to 9.4/0.6 methylene chloride/MeOH as eluent) and triturated with Et2O to give the pure title compound as a light brown solid. Yield: 60 mg, (46.3%). MP 172.8-174.9° C. 1H-NMR (400 MHz, CDCl3): δ 8.35 (d, 1H), 7.80 (d, 2H), 7.50 (m, 1H), 7.28 (d, 2H), 7.14 (d, 2H), 7.05 (d, 2H), 6.72 (d, 2H), 4.00 (m, 2H), 3.95 (m, 2H), 2.58 (m, 1H), 1.95 (s, OH), 1.65-1.48 (m, 2H), 1.20 (d, 3H), 0.75 (t, 3H). MS (ES+) m/z: 415.09 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:28]=[CH:27][C:6]([C:7]([N:9]([CH2:21][C:22]([O:24]CC)=O)[CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][CH:13]=2)=[O:8])=[C:5]([N+:29]([O-])=O)[C:4]=1[O:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37].C(O)C.[H][H].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[C].[Pd].C1(C)C=CC=CC=1>[NH2:18][C:15]1[CH:16]=[CH:17][C:12]([CH2:11][CH2:10][N:9]2[C:7](=[O:8])[C:6]3[CH:27]=[CH:28][C:3]([O:2][CH3:1])=[C:4]([O:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[C:5]=3[NH:29][C:22](=[O:24])[CH2:21]2)=[CH:13][CH:14]=1
Reactant: [H][H]
Reactant: CCCCCOc1c(OC)ccc(C(=O)N(CCc2ccc([N+](=O)[O-])cc2)CC(=O)OCC)c1[N+](=O)[O-]
Agent: [Pd]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: CCCCCOc1c(OC)ccc2c1NC(=O)CN(CCc1ccc(N)cc1)C2=O
Yield: 63 %

Procedure:
Ethyl {(4-Methoxy-2-nitro-3-pentyloxybenzoyl)-[2-(4-nitrophenyl)-ethyl]amino}acetate (70.0 mg, 0.135 mmol) and ethanol (2 ml) were mixed, and 10% palladium-carbon catalyst was added. The reaction mixture was stirred in a stream of hydrogen at room temperature for 10.5 hours, and then filtered. The filtrate was concentrated under reduced pressure. Toluene (10 ml) and p-toluene sulfonate monohydrate (1 mg, 0.0053 mmol) were added to the precipitated crude crystals, and the mixture was refluxed under heating for 3.5 hours. Ethyl acetate (20 ml) was added to this reaction mixture, and the organic layer was washed with saturated aqueous sodium hydrogencarbonate solution (5 ml) and saturated brine (5 ml) and dried over anhydrous magnesium sulfate. The drying agent was filtered off and the filtrate was concentrated under reduced pressure. The obtained residue was purified by column chromatography on silica gel (chloroform/methanol=10/1) to give 4-[2-(4-aminophenyl)ethyl]-8-methoxy-9-pentyloxy-3,4-dihydro-1H-benzo[e][1,4]diazepine-2,5-dione (35 mg, 63% in 2 steps) as colorless crystals.
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Al+3].[C:5]([N:13]1[CH2:20][C@@H:19](F)[CH2:18][C@H:14]1[C:15]([OH:17])=[O:16])(=[O:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.Cl>C1C=CC=CC=1>[C:5]([N:13]1[CH2:20][C@H:19]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH2:18][C@H:14]1[C:15]([OH:17])=[O:16])(=[O:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C(O)[C@@H]1C[C@H](F)CN1C(=O)c1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: c1ccccc1
Product: O=C(O)[C@@H]1C[C@@H](c2ccccc2)CN1C(=O)c1ccccc1

Procedure:
A suspension of aluminum trichloride (191 mg, 1.43 mmole) in benzene (5 ml) was stirred under argon and treated with Part B (cis)-N-benzoyl-4-fluoro-L-proline (100 mg, 0.42 mmole). The reaction was stirred at room temperature for 20 hours, cooled to 0° C. and hydrolyzed with 1N HCl. The layers were separated and the aqueous layer was extracted with ethyl acetate. The organic extracts were combined, washed with brine, dried and concentrated. The residue consisted of
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][C@H:15]([NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][C@H:13]([C:25]([OH:27])=[O:26])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.[CH2:30](Cl)CCl.CC1C=CN=C(N)C=1C>ClCCl>[C:21]([O:20][C:18]([NH:17][C@H:15]1[CH2:16][N:11]([C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:10])[CH2:12][C@@H:13]([C:25]([O:27][CH3:30])=[O:26])[CH2:14]1)=[O:19])([CH3:23])([CH3:24])[CH3:22]
Reactant: CC(C)(C)OC(=O)N[C@@H]1C[C@H](C(=O)O)CN(C(=O)OCc2ccccc2)C1
Reactant: ClCCCl
Agent: Cc1ccnc(N)c1C
Solvent: CO
Solvent: ClCCl
Product: COC(=O)[C@H]1C[C@@H](NC(=O)OC(C)(C)C)CN(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of cis (+/−)-1-(benzyloxycarbonyl)-5-(tert-butoxy-carbonylamino)piperidine-3-carboxylic acid (1.0 eq), methanol (20 eq.) and EDC (1.3 eq) in dichloromethane at a concentration of 0.25 M at 0° C. was added dimethyl-aminopyridine (0.1 eq). After stirring for 48 hours as the reaction was allowed to warm to rt the volatiles were removed in vacuo. Upon addition of ethyl acetate and washing with H2O (3×), 1N HCl, NaHCO3 (sat.) and brine, the solution was dried over MgSO4, filtered, concentrated and purified by column chromatography (25% ethyl acetate/hexanes) to yield cis (+/−)-1-benzyl 3-methyl 5-(tert-butoxycarbonylamino)-piperidine-1,3-dicarboxylate. LCMS (m/z): 293.1 (MH-Boc+); LC Rt=4.09 min
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[NH2:10][C:11]1[C:16](Br)=[N:15][C:14]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)=[CH:13][N:12]=1>CN(C=O)C>[NH2:10][C:11]1[C:16]([S:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[N:15][C:14]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)=[CH:13][N:12]=1
Reactant: Sc1ccccc1
Reactant: COc1ccc(-c2cnc(N)c(Br)n2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(-c2cnc(N)c(Sc3ccccc3)n2)cc1
Temperature: 7.5 °C
Reaction time: 0.25 h
Yield: 69.3 %

Procedure:
To a cooled solution of thiophenol (0.08 mL, 0.7 mmol) in dry DMF (10 mL), sodium hydride (NaH) (0.025 g, 1.00 mmol) was added and the resulting mixture was stirred for 15 min at 5-10° C. After this time 2-amino-3-bromo-5-(4-methoxyphenyl)pyrazine 17a (0.20 g, 0.71 mmol) was added and the mixture refluxed for 6 h, cooled and extracted with EtOAc. The organic layer was washed with water, dried over Na2SO4, filtered and the solvent removed under reduced pressure to get a crude that was purified by flash chromatography using petroleum ether-EtOAc (65:45 v/v) as eluent, to obtain 0.15 g of the title compound 18a as an orange solid (mp 89-90° C., 70% yield). 1H-NMR (CDCl3): 3.81 (s, 3H), 4.90 (br s, 2H), 6.89 (d, J=8.7, 2H), 7.33-7.39 (m, 7.45-7.50 (m, 2H), 7.69 (d, J=8.7, 2H), 8.28 (s, 1H). MS (ESI): m/z 310 (M+H+).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([NH:16]C(=O)C(F)(F)F)[CH:7]=[C:8]([S:10]([F:15])([F:14])([F:13])([F:12])[F:11])[CH:9]=1)(=[O:3])[CH3:2].S(=O)(=O)(O)O>C(Cl)Cl>[NH2:16][C:6]1[CH:5]=[C:4]([C:1](=[O:3])[CH3:2])[CH:9]=[C:8]([S:10]([F:15])([F:11])([F:12])([F:13])[F:14])[CH:7]=1
Reactant: CC(=O)c1cc(NC(=O)C(F)(F)F)cc(S(F)(F)(F)(F)F)c1
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: CC(=O)c1cc(N)cc(S(F)(F)(F)(F)F)c1
Temperature: 100 °C
Reaction time: 7 h
Yield: 92.5 %

Procedure:
N-(3-Acetyl-5-pentafluorosulfanylphenyl)-2,2,2-trifluoroacetamide (O3.075; 9.4 g) was admixed with semiconcentrated sulfuric acid (200 ml), and DCM (15 ml) was added. After stirring at 100° C. for 7 h, the mixture was left to stand overnight. Then the mixture was added to ice-water and extracted with EA. The combined EA phases were washed with saturated sodium hydrogencarbonate solution, dried over magnesium sulfate, filtered and concentrated by rotary evaporation. 6.36 g of the title compound were obtained. LC-MS rt: 1.38 min [M+H]+: 262.0 (met. a)
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:12]=1)[C:7]([OH:9])=O)([O-:3])=[O:2].OC1C2N=NNC=2C=CC=1.CCN=C=NCCCN(C)C.[NH:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1>CN(C=O)C>[N:38]1([C:7]([C:6]2[CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)=[O:9])[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1
Reactant: O=C(O)c1cc([N+](=O)[O-])cc(C(F)(F)F)c1
Reactant: C1COCCN1
Agent: CCN=C=NCCCN(C)C
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Product: O=C(c1cc([N+](=O)[O-])cc(C(F)(F)F)c1)N1CCOCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 27.8 %

Procedure:
In a round bottomed flask, 3-nitro-5-trifluoromethylbenzoic acid (5.0 g, 21.3 mmoles) was dissolved in 40 mL of dry DMF, to this solution was added hydroxybenzotriazole (5.8 g, 42.5 mmoles) and EDCI (8.2 g, 42.5 mmoles) and the solution stirred for 1 hour at room temperature. At the end of this time morpholine (2.2 g. 25.5 mmoles) was added and the reaction stirred overnight. The solution was then concentrated to dryness, and partitioned between water and ethyl acetate. The aqueous layer was extracted with ethyl acetate and the combined extracts dried with magnesium sulfate, filtered and concentrated. Chromatography with silica gel and eluting with a ethyl acetate/hexane gradient of 0-35% over 80 minutes gave morpholin-4-yl-(3-nitro-5-trifluoromethyl-phenyl)-methanone (1.8 g). 1H NMR (300 MHz, DMSO-d6) δ 8.6 (d, 2H), 8.3 (s, 1H), 3.8-3.6 (bm, 4H), 3.56 (b, 2H), 3.33 (bs, 2H).
Reaction SMILES: C(OC(N1C=C([CH2:13][CH:14]([C:25]2[CH:30]=[CH:29][C:28]3[O:31][CH2:32][O:33][C:27]=3[CH:26]=2)[C:15]([O:17]CC2C=CC=CC=2)=[O:16])N=C1CCCC)=O)(C)(C)C>[Pd].CO.O>[CH2:32]1[O:31][C:28]2[CH:29]=[CH:30][C:25]([CH:14]([CH3:13])[C:15]([OH:17])=[O:16])=[CH:26][C:27]=2[O:33]1
Reactant: CCCCc1nc(CC(C(=O)OCc2ccccc2)c2ccc3c(c2)OCO3)cn1C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: O
Solvent: CO
Product: CC(C(=O)O)c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 1 h
Yield: 188 %

Procedure:
The mixture of benzyl (2RS)-3-(1-tert-butoxycarbonyl-2-n-butylimidazol-4-yl)-2-(3,4-methylenedioxyphenyl)propionate (2R:2S=1:4, 3.65 g) and 10% palladium on activated carbon (1.0 g) in methanol (50 ml) and water (5 ml) was shaken under hydrogen atmosphere (3 atmospheric pressure) at ambient temperature for 1 hour. The catalyst was filtered through a bed of celite and the filtrate was evaporated in vacuo. The residue was diluted with AcOEt (ethyl acetate) and the organic layer was washed with brine. Drying, filtering and removal of the solvents afforded (2RS)-3-(1-tert-butoxycarbonyl)-2-n-butylimidazol-4-yl)-2-(3,4-methylenedioxyphenyl)propionic acid (2R:2S=1:4) (2.63 g) as a white solid.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[NH:15][C:14](=[O:16])[O:13][C:12]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C:11]=2[CH:29]=1.[CH:30]1([C:36]2[CH:41]=[CH:40][C:39]([SH:42])=[CH:38][CH:37]=2)[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1>>[CH:30]1([C:36]2[CH:37]=[CH:38][C:39]([S:42][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]3[CH:8]=[CH:9][C:10]4[NH:15][C:14](=[O:16])[O:13][C:12]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C:11]=4[CH:29]=3)=[CH:40][CH:41]=2)[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]1
Reactant: CCCCCCC1(CCCCCC)OC(=O)Nc2ccc(OCCCCCl)cc21
Reactant: Sc1ccc(C2CCCCC2)cc1
Product: CCCCCCC1(CCCCCC)OC(=O)Nc2ccc(OCCCCSc3ccc(C4CCCCC4)cc3)cc21

Procedure:
Prepared analogously to Example 1 from 6-(4-chlorobutoxy)-4,4-di-n-hexyl-4H-3,1-benzoxazin-2-one [oil, RF value: 0.7; silica gel plate; chloroform/acetone (19:1)] and 4-cyclohexyl-thiophenol.
Reaction SMILES: Cl.[CH2:2]1[O:12][C:6]2([CH2:11][CH2:10][NH:9][CH2:8][CH2:7]2)[O:5][CH2:4][CH2:3]1.Cl[C:14]1[C:23]2[C:18](=[CH:19][C:20]([O:26][CH3:27])=[C:21]([O:24][CH3:25])[CH:22]=2)[CH:17]=[N:16][N:15]=1.C(N(CC)CC)C>C(O)C>[CH2:4]1[O:5][C:6]2([CH2:11][CH2:10][N:9]([C:17]3[C:18]4[C:23](=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH3:27])[CH:19]=4)[CH:14]=[N:15][N:16]=3)[CH2:8][CH2:7]2)[O:12][CH2:2][CH2:3]1
Reactant: C1COC2(CCNCC2)OC1
Reactant: COc1cc2cnnc(Cl)c2cc1OC
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: COc1cc2cnnc(N3CCC4(CC3)OCCCO4)c2cc1OC
Yield: 71.5 %

Procedure:
4-Piperidone trimethylene ketal hydrochloride (20 g), 1-chloro-6,7-dimethoxyphthalazine (10 g), triethylamine (50 ml) and ethanol (300 ml) were heated together under reflux for 70 hours. The resulting mixture was evaporated in vacuo and the residue was partitioned between chloroform (2×100 ml) and water (60 ml). The chloroform extracts were combined, dried (MgSO4) and evaporated in vacuo to give a crude brown oil which on trituration with ethyl acetate (100 ml) at boiling point gave 1-[6,7-dimethoxyphthalazin-1-yl]piperid-4-one trimethylene ketal (11 g), m.p. 194°-6°. A second crop of the product (3 g) was obtained by evaporating the ethyl acetate trituration liquors.
Reaction SMILES: [CH2:1]([NH:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[C:16]([CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[C:15]([C:25]([OH:27])=O)[N:14]=[N:13]2)=[CH:8][CH:7]=1)=[O:5])[CH3:2].C1C=C[C:31]2N(O)N=[N:34][C:32]=2[CH:33]=1.C1(N)CC1.CCN=C=NCCCN(C)C>C(#N)C.CN(C=O)C>[CH:32]1([NH:34][C:25]([C:15]2[N:14]=[N:13][N:12]([C:9]3[CH:10]=[CH:11][C:6]([C:4]([NH:3][CH2:1][CH3:2])=[O:5])=[CH:7][CH:8]=3)[C:16]=2[CH2:17][CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[O:27])[CH2:33][CH2:31]1
Reactant: CCNC(=O)c1ccc(-n2nnc(C(=O)O)c2CCc2ccccc2)cc1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: NC1CC1
Solvent: CN(C)C=O
Solvent: CC#N
Product: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2CCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 189.2 %

Procedure:
1-{4-[(Ethylamino)carbonyl]phenyl}-5-(2-phenylethyl)-1H-1,2,3-triazole-4-carboxylic acid (501 mg, 1.37 mmol) obtained in Example 98b), HOBt (93.8 mg, 0.687 mmol, 0.5 eq.) and cyclopropylamine (0.128 ml, 1.79 mmol, 1.3 eq.) were dissolved in acetonitrile-DMF (2:1, 7.5 ml), WSC (323 mg, 1.65 mmol, 1.2 eq.) was added, and the mixture was stirred at room temperature for 1.5 hr. The reaction mixture was concentrated, and the residue was diluted with ethyl acetate (40 ml) and washed with 2% aqueous sodium carbonate solution (×2), 10% aqueous ammonium chloride solution and saturated brine. The aqueous layer was each extracted with ethyl acetate-hexane (2:1, 30 ml). The organic layers were combined, dried over anhydrous sodium sulfate and concentrated, and diethyl ether was added to the residue. The precipitate was collected by filtration, washed with diethyl ether and dried to give the title compound as a white powder (526 mg, 1.30 mmol, 95.2%).