Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10]/[N:11]=[CH:12]/[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[N+]([C:21]([CH2:48][CH2:49][CH2:50][CH3:51])=[CH:22][C:23]1[CH:35]=[CH:34][C:26]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])=[CH:25][C:24]=1[C:36]([N:38]1[CH2:47][CH2:46][C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH2:39]1)=[O:37])([O-])=O>>[C:30]([O:29][C:27]([C:26]1[CH:34]=[CH:35][C:23]([C:22]2[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[N:11][N:10]([C:7]3[CH:6]=[CH:5][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:9][CH:8]=3)[C:21]=2[CH2:48][CH2:49][CH2:50][CH3:51])=[C:24]([C:36]([N:38]2[CH2:47][CH2:46][C:45]3[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=3)[CH2:39]2)=[O:37])[CH:25]=1)=[O:28])([CH3:31])([CH3:32])[CH3:33]
Reactant: CCOC(=O)/C=N/Nc1ccc(C(C)C)cc1
Reactant: CCCCC(=Cc1ccc(C(=O)OC(C)(C)C)cc1C(=O)N1CCc2ccccc2C1)[N+](=O)[O-]
Product: CCCCc1c(-c2ccc(C(=O)OC(C)(C)C)cc2C(=O)N2CCc3ccccc3C2)c(C(=O)OCC)nn1-c1ccc(C(C)C)cc1
Yield: 51.3 %

Procedure:
Following a procedure analogous to that for the synthesis of Intermediate 223E, (E)-ethyl 2-(2-(4-isopropylphenyl)hydrazono)acetate (25.2 mg, 0.108 mmol) and tert-butyl 4-(2-nitrohex-1-enyl)-3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)benzoate (50 mg, 0.108 mmol) were converted to the title compound (36 mg, 52%) as a pale yellow oil. 1H NMR (CDCl3, 1:1 mixture of amide rotamers) δ 8.08 (dd, J=8, 2 Hz, 1H), 8.04-8.03 (m, 1H), 7.43-6.81 (m, 9H), 5.02-4.98 (m, 1H), 4.46-4.38 (m, 1H), 4.30-4.27 (m, 2H), 4.15-3.98 (m, 1H), 3.54-3.33 (m, 1H), 2.98-2.50 (m, 5H), 1.61 (s, 9H), 1.29-1.24 (m, 7.5H), 1.22 (t, J=8 Hz, 1.5H), 1.18-0.95 (m, 4H), 0.60-0.56 (m, 3H); MS (ESI+) m/z 650.4 (M+H)+.
Reaction SMILES: [Cl:1][C:2]([F:9])([F:8])[CH2:3][CH2:4][C:5](Cl)=[O:6].[NH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1.N1C=CC=CC=1>C1(C)C=CC=CC=1.C(OCC)C>[Cl:1][C:2]([F:9])([F:8])[CH2:3][CH2:4][C:5]([NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1)=[O:6]
Reactant: O=C(Cl)CCC(F)(F)Cl
Reactant: Nc1ccccn1
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Solvent: CCOCC
Product: O=C(CCC(F)(F)Cl)Nc1ccccn1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
4.0 g of 4-chloro-4,4-difluoro-butyric acid chloride are added dropwise at 0° over a period of half an hour to a solution of 2.13 g of 2-aminopyridine and 4.47 g of pyridine in 50 ml of toluene. The reaction mixture is stirred for 16 hours at room temperature, diluted with 150 ml of diethyl ether, washed in succession with saturated NaHCO3 solution and saturated NaCl solution, dried over MgSO4, and concentrated by evaporation. The residue is recrystallised from toluene/hexane to give the title compound which melts at 64°-65°.
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[S:10][C:11]([Si:14]([CH3:17])([CH3:16])[CH3:15])=[CH:12][CH:13]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.[F:23][C:24]([F:31])([F:30])[C:25]([F:29])=[C:26](F)[F:27].Cl>CCOCC.CCCCCC.O>[C:1]([NH:5][S:6]([C:9]1[S:10][C:11]([Si:14]([CH3:17])([CH3:15])[CH3:16])=[CH:12][C:13]=1[C:26]([F:27])=[C:25]([F:29])[C:24]([F:31])([F:30])[F:23])(=[O:7])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: FC(F)=C(F)C(F)(F)F
Reactant: CC(C)(C)NS(=O)(=O)c1ccc([Si](C)(C)C)s1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: O
Solvent: CCOCC
Product: CC(C)(C)NS(=O)(=O)c1sc([Si](C)(C)C)cc1C(F)=C(F)C(F)(F)F
Temperature: 25 °C
Reaction time: 4 h
Yield: 55.3 %

Procedure:
Two grams of the N-tert-butyl-5-trimethylsilyl-2-thiophenesulfonamide prepared in (1) above was dissolved in 100 ml of dry ether under nitrogen stream. To the solution, 15 ml of a 1.6M solution of n-butyllithium in n-hexane was added dropwise at 10° to 15° C., followed by stirring at room temperature for 4 hours. Subsequently, a dry ice condenser was attached to the reactor, and then 10 g of hexafluoropropene was charged at 0° to 10° C. under nitrogen stream. Reaction was performed under stirring for 3 hours. After completion of the reaction, the resulting product was poured into water, acidified with hydrochloric acid and extracted with ether. The ether layer was washed with water and dried. After distilling off ether under vacuum, the residue was purified by column chromatography on silica gel (eluent: methylene chloride) to provide 1.6 g of N-tert-butyl-3-(1,2,3,3,3-pentafluoropropen-1-yl)-5-trimethylsilyl-2-thiophenesulfonamide having a melting point of 92° to 94° C.
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]([OH:14])=[O:13])[C:3]1=[O:15].C(Cl)(=O)C(Cl)=O.[C:22]1(=O)[CH2:27][CH2:26][CH2:25][C:24](=[O:28])[CH2:23]1.C(N(CC)CC)C>ClCCl.CN(C)C=O>[CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]([O:14][C:22]2[CH2:27][CH2:26][CH2:25][C:24](=[O:28])[CH:23]=2)=[O:13])[C:3]1=[O:15]
Reactant: Cn1c(=O)c(C(=O)O)nc2ccccc21
Reactant: O=C1CCCC(=O)C1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cn1c(=O)c(C(=O)OC2=CC(=O)CCC2)nc2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.9 %

Procedure:
4.6 g (22.5 mmol) of 1-methyl-2-oxo-1,2-dihydroquinoxaline-3-carboxylic acid was dissolved in dichloromethane (200 mL), and N,N-dimethylformamide (0.5 mL) and 4.3 g (33.9 mmol) of oxalyl chloride were added thereto. The mixture was stirred for 1 hour at room temperature. The reaction mixture was concentrated under reduced pressure, and the obtained residue was dissolved in dichloromethane (100 mL). This solution was added dropwise at room temperature to a solution prepared by dissolving 2.8 g (25.0 mmol) of 1,3-cyclohexanedione and 2.7 g (26.7 mmol) of triethylamine in dichloromethane (100 mL). The mixture was stirred for 1 hour at room temperature, and then, the reaction mixture was washed with water, and dried over anhydrous sodium sulfate. The inorganic matter was separated by filtration, and then the solvent was distilled off under reduced pressure, to obtain 6.3 g (yield 94%) of 3-oxo-1-cyclohexenyl 1-methyl-2-oxo-1,2-dihydroquinoxaline-3-carboxylate as a yellow solid.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH3:12][C:13]1([CH3:27])[CH2:22][C:21](=[N:23][OH:24])[C:20]2[C:15](=[CH:16][C:17]([O:25][CH3:26])=[CH:18][CH:19]=2)[O:14]1>N1C=CC=CC=1>[S:7]([C:4]1[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=1)([OH:14])(=[O:9])=[O:8].[CH3:12][C:13]1([CH3:27])[CH2:22][C:21](=[N:23][OH:24])[C:20]2[C:15](=[CH:16][C:17]([O:25][CH3:26])=[CH:18][CH:19]=2)[O:14]1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: COc1ccc2c(c1)OC(C)(C)CC2=NO
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)O)cc1
Temperature: 0 °C

Procedure:
85.8 g (0.45 mol) of p-toluenesulfonyl chloride were introduced into a solution of 88.5 g (0.4 mol) of 2,2-dimethyl-7-methoxy-4-chromanone oxime (Heterocycles 38 (1994), 305-318) in 550 ml of pyridine at 0° C. The mixture was allowed to come to room temperature and was subsequently stirred for several hours, stirred into ice/water and extracted with methylene chloride. The organic solution was washed twice with 2N hydrochloric acid and then several times with water, dried and evaporated, and the residue was recrystallized from ethanol. The 2,2-dimethyl-7-methoxy-4-chromanone oxime tosylate had a melting point of 113° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:8])/[CH:4]=[CH:5]/[O:6][CH3:7].[CH:9](OC)([O:12][CH3:13])[O:10][CH3:11].[C:16](=O)([O-])[O-:17].[Na+].[Na+]>C1([Sn](Cl)(Cl)Cl)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:8])[CH:4]([CH:9]([O:12][CH3:13])[O:10][CH3:11])[CH:5]([O:17][CH3:16])[O:6][CH3:7]
Reactant: CO/C=C/C(=O)OC
Reactant: COC(OC)OC
Reactant: O=C([O-])[O-]
Agent: Cl[Sn](Cl)(Cl)c1ccccc1
Agent: [Na+]
Product: COC(=O)C(C(OC)OC)C(OC)OC
Temperature: 60 °C
Reaction time: 2 h
Yield: 110.6 %

Procedure:
To a stirred mixture of 17.7 g methyl-trans-3-methoxyacrylate and 32.3 g trimethyl ortho formate was added 1.0 g PhSnCl3. The mixture was heated to 60° C. for 24 hours, cooled to room temperature and 5.00 g anhydrous sodium carbonate were added. After stirring for 2 hours, the mixture was filtered and the filter-cake washed with trimethyl ortho formate. Fractional distillation gave 11.6 g colorless liquid (69% of theoretical based on converted methyl-trans-3-methoxyacrylate) of boiling point 1000° C./4 mm Hg, A GC-analysis of the liquid revealed an assay of >99% (FID-detection).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:19]3=[N:20][CH:21]=[CH:22][C:23]([CH3:24])=[C:18]3[NH:17][C:16]2=[O:25])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I[CH:27]([CH3:29])[CH3:28].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([N:15]2[C:19]3=[N:20][CH:21]=[CH:22][C:23]([CH3:24])=[C:18]3[N:17]([CH:27]([CH3:29])[CH3:28])[C:16]2=[O:25])=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)I
Reactant: Cc1ccnc2c1[nH]c(=O)n2-c1ccc(OCc2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccnc2c1n(C(C)C)c(=O)n2-c1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A suspension of 3-[4-(benzyloxy)phenyl]-7-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (360 mg), 2-iodopropane (0.217 mL) and potassium carbonate (180 mg) in DMF (10 mL) was stirred overnight at room temperature. The reaction mixture was poured into water, and the mixture was extracted with AcOEt. The extract was washed with water and brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, eluted with 15%-20% AcOEt in hexane) to give the title compound (218 mg) as colorless oil.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][CH:18]=1)[C:6]([CH2:8][C:9](=O)[C:10]([O:12]CC)=[O:11])=O.[CH3:21][NH:22][NH2:23].O>C(O)C>[CH3:21][N:22]1[C:9]([C:10]([OH:12])=[O:11])=[CH:8][C:6]([C:5]2[CH:16]=[CH:17][CH:18]=[C:3]([C:2]([F:20])([F:19])[F:1])[CH:4]=2)=[N:23]1
Reactant: CCOC(=O)C(=O)CC(=O)c1cccc(C(F)(F)F)c1
Reactant: CNN
Solvent: O
Solvent: CCO
Product: Cn1nc(-c2cccc(C(F)(F)F)c2)cc1C(=O)O
Reaction time: 2 h

Procedure:
Following the procedure of Example 1, 5.8 g. of ethyl 3-trifluoromethylbenzoylpyruvate and 0.92 g. of methyl hydrazine were heated in ethanol solution for about one hour at about 80° C. The reaction mixture was cooled and water added. The aqueous mixture was extracted with two 100 ml. portions of ether followed by one 100 ml. portion of chloroform. The combined extracts were dried with phase separation paper. The solvents were removed from the filtrate. NMR indicated that the residue comprised the isomeric pair ethyl 1-methyl-3-(3-trifluoromethylphenyl)pyrazole-5-carboxylate and ethyl 1-methyl-5-(3-trifluoromethylphenyl)pyrazole-3-carboxylate in about a 60-40 mixture. Following the procedure of Example 2, the isomers were separated by chromatography over silica gel using dichloromethane. The faster moving fraction, comprising the desired ethyl 1-methyl-3-(3-trifluoromethylphenyl)pyrazole-5-carboxylate, was collected and the solvent removed therefrom; weight=2.0 g. The desired ethyl ester was hydrolyzed without further purification according to the following procedure. A solution of 2.0 g. of ethyl 1-methyl-3-(3-trifluoromethylphenyl)pyrazole-5-carboxylate in 40 ml. of ethanol was refluxed with a solution of 0.3 g. of sodium hydroxide in 120 ml. of water for about 2 hours. The hydrolysis mixture was cooled and then acidified with 1N aqueous hydrochloric acid. The free acid, being insoluble in the acidic aqueous solution, precipitated and was collected by filtration. Recrystallization of the filer cake yielded 1-methyl-3-(3-trifluoromethylphenyl)pyrazole-5-carboxylic acid melting at 198°-9° C. after recrystallization from ethanol.
Reaction SMILES: [BH4-].[Na+].[C:3]([C:6]1[N:7]=[C:8]([CH2:33][CH2:34][CH2:35][CH3:36])[N:9]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[CH:16][CH:15]=2)[C:10]=1[C:11]#[N:12])(=[O:5])[CH3:4].CC(C)=O>C(O)C>[C:29]([O:28][C:26]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[C:17]1[CH:18]=[CH:19][C:14]([CH2:13][N:9]2[C:10]([C:11]#[N:12])=[C:6]([CH:3]([OH:5])[CH3:4])[N:7]=[C:8]2[CH2:33][CH2:34][CH2:35][CH3:36])=[CH:15][CH:16]=1)=[O:27])([CH3:32])([CH3:31])[CH3:30]
Reactant: CCCCc1nc(C(C)=O)c(C#N)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CC(C)=O
Product: CCCCc1nc(C(C)O)c(C#N)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.6 %

Procedure:
0.098 g of sodium borohydride was added to a solution of 1.18 g of 4-acetyl-1-[(2'-t-butoxycarbonylbiphenyl-4-yl)methyl]-2-butylimidazole-5-carbonitrile [prepared as described in step (a) above] in 30 ml of ethanol, and the resulting mixture was stirred at room temperature for 1 hour. The excess sodium borohydride was decomposed by adding acetone, and then the reaction mixture was concentrated by evaporation under reduced pressure. The residue was diluted with an aqueous solution of sodium chloride and extracted with ethyl acetate. The extract was dried and concentrated by evaporation under reduced pressure. The oily residue was purified by column chromatography through silica gel, using a 3:2 by volume mixture of ethyl acetate and hexane as the eluent, to afford 1.18 g of the title compound as a viscous oil.
Reaction SMILES: Cl[C:2]1[CH:7]=CC=[C:4]([C:8]([O:10]O)=[O:9])[CH:3]=1.C(OC([NH:19][C@@H:20]([CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C@H:21]([OH:38])/C=C/CCCNC(=O)OCC1C=CC=CC=1)=O)(C)(C)C.C([C@H](NC(=O)OC(C)(C)C)[C@H](O)[C@@H](O)[C@@H]1CCC[NH:57]1)C1C=CC=CC=1.C([C@H](NC(=O)OC(C)(C)C)[C@H](O)[C@H](O)[C@H]1CCCN1)C1C=CC=CC=1>>[NH2:19][C@H:20]([C:21]([N:57]1[CH2:7][CH2:2][CH2:3][C@H:4]1[C:8]([OH:10])=[O:9])=[O:38])[CH2:39][C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@H](O)/C=C/CCCNC(=O)OCc1ccccc1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@H](O)[C@@H](O)[C@@H]1CCCN1
Agent: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@H](O)[C@H](O)[C@H]1CCCN1
Product: N[C@@H](Cc1ccccc1)C(=O)N1CCC[C@H]1C(=O)O

Procedure:
Eventually, using the benzyl 3-((2S,3S)-3-{[(1S,2S)-1-hydroxy-2-[(tert-butoxycarbonyl)amino]-3-phenylpropyl}oxiran-2-yl)propylcarbamate, recoverable as a by-product from the epoxidation with m-chloroperbenzoic acid of the allylic alcohol (4E,6R,7S)-7-[(tert-butoxycarbonyl)amino]-6-hydroxy-8-phenyl-oct-4-enylcarbamate (8), and following an approach similar to the one already described for the synthesis of tert-butyl (1S,2S,3S)-1-benzyl-2,3-dihydroxy-3-[(2S)-pyrrolidin-2-yl]propylcarbamate (10), tert-butyl (1S,2S,3R)-1-benzyl-2,3-dihydroxy-3-[(2R)-pyrrolidin-2-yl]propylcarbamate can be obtained as a possible fourth diaminodiol (S,S,R,R) Phe-Pro isostere.
Reaction SMILES: [N+](C1C=CC(C([O:10][C@H:11]2[C:17]3=[N:18][CH:19]=[CH:20][CH:21]=[C:16]3[CH2:15][C@@:14]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:24]=3[F:30])([OH:22])[CH2:13][CH2:12]2)=O)=CC=1)([O-])=O.[OH-].[Li+]>O1CCCC1.C(OCC)(=O)C.O>[F:30][C:24]1[C:25]([F:29])=[CH:26][CH:27]=[CH:28][C:23]=1[C@:14]1([OH:22])[CH2:13][CH2:12][C@@H:11]([OH:10])[C:17]2=[N:18][CH:19]=[CH:20][CH:21]=[C:16]2[CH2:15]1
Reactant: O=C(O[C@@H]1CC[C@@](O)(c2cccc(F)c2F)Cc2cccnc21)c1ccc([N+](=O)[O-])cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: O[C@@H]1CC[C@@](O)(c2cccc(F)c2F)Cc2cccnc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.8 %

Procedure:
In a 250 mL round-bottom flask was dissolved (6S,9R)-6-(2,3-difluorophenyl)-6-hydroxy-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl 4-nitrobenzoate (125 mg, 0.284 mmol) in tetrahydrofuran (2 mL) to give a colorless solution. Lithium hydroxide (0.568 mmol) was added, and the mixture was stirred at room temperature for 2 h. LCMS indicated complete conversion. It was diluted with ethyl acetate and water. The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried, and concentrated to a white solid. Purification by FCC up to 6% methanol/methylene chloride afforded the desired product as a white crystalline solid (71 mg, 86%). A few crystals were picked out and an x-ray structure was obtained to confirm the cis-diol stereochemistry. MS(ESI)[M+H+]=292.21; 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 8.44 (d, J=4.58 Hz, 1H) 7.38-7.51 (m, 2H) 7.19 (dd, J=7.48, 5.04 Hz, 1H) 7.04-7.16 (m, 2H) 5.99 (br. s., 1H) 4.90 (dd, J=11.29, 2.14 Hz, 1H) 3.80-3.91 (m, 1H) 2.92 (dd, J=14.65, 2.14 Hz, 1H) 2.57-2.70 (m, 1H) 2.37 (br. s., 1H) 2.11 (ddd, J=14.19, 5.95, 3.97 Hz, 1H) 1.96-2.06 (m, 1H) 1.74-1.91 (m, 1H); 19F NMR (470 MHz, CHLOROFORM-d) δ ppm −138.91-−138.74 (m, 1F) −139.22-−139.06 (m, 1F); 13C NMR (126 MHz, CHLOROFORM-d) δ ppm 160.64 (s, 1C) 152.00-150.10 (dd, J=21.42 and 254.52 Hz, 1C) 148.75-146.71 (dd, J=11.52 and 244.44 Hz, 1C) 145.55 (s, 3C) 139.91 (s, 3C) 138.44 (d, J=8.64 Hz, 1C) 129.37 (s, 1C) 123.89-124.57 (m, 2C) 122.48 (s, 3C) 120.84 (s, 1C) 116.22 (d, J=17.28 Hz, 2C) 71.79 (m, 3C) 71.70 (m, 4C) 44.30 (d, J=4.80 Hz, 2C) 39.65 (s, 1C) 31.29 (s, 2C).
Reaction SMILES: [CH2:1]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([O:19][CH3:20])=[C:13]([O:17][CH3:18])[CH:14]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:21][I:22]>CC(C)=O>[I-:22].[CH2:1]([N+:8]1([CH3:21])[CH2:9][C:10]2[C:15](=[CH:14][C:13]([O:17][CH3:18])=[C:12]([O:19][CH3:20])[CH:11]=2)[CH2:16]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc2c(cc1OC)CN(Cc1ccccc1)C2
Reactant: CI
Solvent: CC(C)=O
Product: COc1cc2c(cc1OC)C[N+](C)(Cc1ccccc1)C2
Product: [I-]
Reaction time: 6 h
Yield: 14.4 %

Procedure:
500 mg (1.86 mmol) of N-benzyl-5,6-dimethoxyisoindoline was dissolved in 10 ml of acetone, and 316 mg (2.27 mmol) of methyl iodide was added thereto at room temperature. The mixture was left to stand for 6 hours. Then, the precipitated crystals were collected by filtration and washed with 10 ml of acetone to obtain 640 mg of the above identified compound. The filtrate was distilled off under reduced pressure, and the crystal residue was washed with 10 ml of ethyl acetate to obtain 110 mg of the secondary crystals. The total yield was 750 mg.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH2:12][OH:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH:12]=[O:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: OCc1ccc2ncnc(Cl)c2c1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: O=Cc1ccc2ncnc(Cl)c2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86.5 %

Procedure:
To a solution of 4-chloroquinazoline-6-yl-methanol (3.5 g, 0.018 mol) in dry CH2Cl2 (100 mL) was added Dess-Martin periodinane (8.4 g, 0.019 mol) and stirred at RT for 30 min. The reaction mixture was washed with 10% aqueous NaHCO3 (75 mL), water, brine and dried. The solvent was removed under vacuum to give 4-chloroquinazoline-6-carboxaldehyde (3 g, 88%) as pale yellow solid.
Reaction SMILES: CO[C:3]([C:5]1[N:6]([CH3:26])[N:7]=[C:8]([O:10][CH2:11][C:12]2[C:13]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)=[N:14][O:15][C:16]=2[CH2:17][OH:18])[CH:9]=1)=[O:4].[F:27][C:28]([F:35])([C:31]([F:34])([F:33])[F:32])[CH2:29][NH2:30]>>[F:27][C:28]([F:35])([C:31]([F:34])([F:33])[F:32])[CH2:29][NH:30][C:3]([C:5]1[N:6]([CH3:26])[N:7]=[C:8]([O:10][CH2:11][C:12]2[C:13]([C:19]3[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=3)=[N:14][O:15][C:16]=2[CH2:17][OH:18])[CH:9]=1)=[O:4]
Reactant: NCC(F)(F)C(F)(F)F
Reactant: COC(=O)c1cc(OCc2c(-c3ccc(F)cc3)noc2CO)nn1C
Product: Cn1nc(OCc2c(-c3ccc(F)cc3)noc2CO)cc1C(=O)NCC(F)(F)C(F)(F)F
Yield: 87 %

Procedure:
As described for example 91h, 5-[3-(4-fluoro-phenyl)-5-hydroxymethyl-isoxazol-4-ylmethoxy]-2-methyl-2H-pyrazole-3-carboxylic acid methyl ester (100 mg, 0.28 mmol) was converted, using 2,2,3,3,3-pentafluoropropylamine instead of 4-aminotetrahydropyran, to the title compound (115 mg, 87%) which was obtained as a brown oil. MS: m/e=477.0 [M−]−.
Reaction SMILES: FC(F)(F)C(O)=O.CC([NH:16][S:17]([C:20]1[CH:21]=[N:22][C:23]([C:26]2[C:31]([O:32][CH3:33])=[CH:30][CH:29]=[CH:28][C:27]=2[O:34][CH3:35])=[CH:24][CH:25]=1)(=[O:19])=[O:18])(C)CC(C)(C)C>ClCCl>[CH3:33][O:32][C:31]1[CH:30]=[CH:29][CH:28]=[C:27]([O:34][CH3:35])[C:26]=1[C:23]1[N:22]=[CH:21][C:20]([S:17]([NH2:16])(=[O:19])=[O:18])=[CH:25][CH:24]=1
Reactant: COc1cccc(OC)c1-c1ccc(S(=O)(=O)NC(C)(C)CC(C)(C)C)cn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cccc(OC)c1-c1ccc(S(N)(=O)=O)cn1
Temperature: 25 °C

Procedure:
Trifluoroacetic acid (3.6 ml, 47 mmol) was added to a solution of 6-(2,6-Dimethoxy-phenyl)-pyridine-3-sulfonic acid (1,1,3,3-tetramethyl-butyl)-amide (1.90 g, 4.7 mmol) in 40 ml dichloromethane and stirred at room temperature (monitored by TLC). The mixture was evaporated to dryness, taken up in 10 ml ethyl acetate and washed with aqueous sodium bicarbonate. The organic layer was evaporated to dryness and the residue was purified by flash chromatography (SiO2, heptane-ethyl acetate gradient) to return 1.28 g of the title compound as an off-white solid, m/z=295 (ES+), 293 (ES−).
Reaction SMILES: [C:1]([C:5]1([CH2:8][O:9][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][O:11]2)[CH2:7][O:6]1)([CH3:4])([CH3:3])[CH3:2].[NH:16]1[CH:20]=[CH:19][N:18]=[CH:17]1>C(#N)C.C(OCC)(=O)C>[C:1]([C:5]([OH:6])([CH2:7][N:16]1[CH:20]=[CH:19][N:18]=[CH:17]1)[CH2:8][O:9][CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][O:11]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)C1(COC2CCCCO2)CO1
Reactant: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC(C)(C)C(O)(COC1CCCCO1)Cn1ccnc1
Yield: 71.2 %

Procedure:
A solution of 59 g (0.28 mol of 2-tert.-butyl-2-(tetrahydro-2H-pyran-2-yloxy-methyl)-oxirane in 100 ml of acetonitrile is added dropwise to a mixture of 119 g 1.75 mol of imidazole, 1 g 9 mols) of potassium tert.-butylate and 500 ml of acetonitrile under a nitrogen atmosphere, the reaction mixture being boiled under reflux. When the addition has ended, the mixture is boiled under reflux for a further 10 hours, the solvent is then stripped off under reduced pressure and the residue which remains is taken up in ethyl acetate. The organic phase is washed with water, dried over sodium sulphate and concentrated under reduced pressure. The product thus obtained is purified chromatographically over silica gel with chloroform as the mobile phase. 56.3 g (72% of theory) of 2-tert.-butyl-3-(imidazol-1-yl)-1-(tetrahydro-2H-pyran-2-yloxy)-propan-2-ol are obtained in this manner in the form of a solid substance of melting point 107° C.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[NH2:6][C:7]1[N:8]=[C:9]([Cl:24])[C:10]2[CH2:19][C@H:18]3[C@@H:13]([CH2:14][CH2:15][CH2:16][N:17]3[CH2:20][CH2:21][CH3:22])[CH2:12][C:11]=2[N:23]=1>>[ClH:3].[NH2:6][C:7]1[N:8]=[C:9]([Cl:24])[C:10]2[CH2:19][C@H:18]3[C@@H:13]([CH2:14][CH2:15][CH2:16][N:17]3[CH2:20][CH2:21][CH3:22])[CH2:12][C:11]=2[N:23]=1
Reactant: O=P(Cl)(Cl)Cl
Agent: CCCN1CCC[C@H]2Cc3nc(N)nc(Cl)c3C[C@@H]21
Product: Cl

Procedure:
The 4-hydroxy product thus obtained was refluxed with 4 ml. of phosphorous oxychloride. The reaction mixture, containing trans-(±)-2-amino-4-chloro-6-n-propyl-5,5a,6,7,8,9,9a,10-octahydropyrimido[4,5-g]quinoline formed in the above reaction, was poured onto ice and the resulting aqueous mixture made basic. The basic mixture was filtered and the insoluble material dissolved in 0.1N aqueous hydrochloric acid. The hydrochloride salt thus prepared was recrystallized from ethanol to yield trans-(±)-2-amino-4-chloro-6-n-propyl-5,5a,6,7,8,9,9a,10-octahydropyrimido[4,5-g]quinoline hydrochloride having the following physical characteristics. Mass spectrum, molecular ion at 280, smaller peak at 282.