Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[S:8][C:9]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:10][C:11]=2[OH:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH3:21][O:22][CH2:23]Cl.CCOCC.O>CN(C)C=O>[C:1]1([C:7]2[S:8][C:9]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)=[CH:10][C:11]=2[O:12][CH2:21][O:22][CH3:23])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COCCl
Reactant: Oc1cc(-c2ccccc2)sc1-c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COCOc1cc(-c2ccccc2)sc1-c1ccccc1
Reaction time: 0.33 h
Yield: 87.7 %

Procedure:
To a stirred, ice cooled solution of 2,5-diphenyl-3-hydroxythiophene (0.12 g, 0.5 mmol) in dried N,N-dimethylformamide (2 ml) was added sodium hydride (30 mg of a 60% suspension in mineral oil). When the initial vigorous reaction subsides (ca. 4 minutes), the mixture was allowed to stir at ambient temperatures for 20 minutes and then recooled. Chloromethyl methyl ether (0.055 ml, 0.7 mmol) was then added all at once. After stirring cold for ca. 30 minutes, the mixture was allowed to stir at ambient temperatures for ca. 4 hours and then added to a stirred ether/water mixture. The ether layer was washed 3 times with water, dried over sodium sulfate, filtered, concentrated to a residue, and chromatographed on silica gel (methylene chloride/hexane), to yield 0.13 g of (II). M.S.: M+ =296; NMR: consistent. ##STR27##
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1.[F:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[N:30]=[C:31]=[O:32]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:31]([NH:30][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[F:23])=[O:32])=[CH:18][CH:17]=1
Reactant: COc1cc2ncnc(Oc3ccc(N)cc3)c2cc1OC
Reactant: O=C=Nc1ccccc1F
Solvent: Cc1ccccc1
Product: COc1cc2ncnc(Oc3ccc(NC(=O)Nc4ccccc4F)cc3)c2cc1OC
Yield: 66 %

Procedure:
6,7-Dimethoxy-4-(4-aminophenoxy)quinazoline (100 mg) was dissolved in toluene (10 ml) with heat, 2-fluorophenyl isocyanate (0.30 ml) was added, and the admixture was refluxed with heat for 40 minutes. The separated solid was filtered and washed with toluene to obtain 96 mg of the title compound (yield: 66%).
Reaction SMILES: [C:1]1([CH:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:8]2[CH2:11][CH:10](OS(C)(=O)=O)[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:23][S:24]([N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)(=[O:26])=[O:25]>C(#N)C>[NH2:23][S:24]([N:27]1[CH2:32][CH2:31][N:30]([CH:10]2[CH2:9][N:8]([CH:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:11]2)[CH2:29][CH2:28]1)(=[O:26])=[O:25]
Reactant: NS(=O)(=O)N1CCNCC1
Reactant: CS(=O)(=O)OC1CN(C(c2ccccc2)c2ccccc2)C1
Solvent: CC#N
Product: NS(=O)(=O)N1CCN(C2CN(C(c3ccccc3)c3ccccc3)C2)CC1
Yield: 8.1 %

Procedure:
A solution of 1-diphenylmethyl-3-methanesulphonyloxyazetidine (see Preparation 54) (4.8 g, 15.1 mmol) and 1-aminosulphonylpiperazine (see Example 123(f)) (5 g) in acetonitrile (50 ml) was heated under reflux for 4 hours. The reaction was cooled and the solid filtered off and washed with acetonitrile (50 ml). The filtrate was concentrated under reduced pressure and the residue slurried in hot toluene (50 ml), cooled, the solid filtered off and washed with toluene (50 ml). The product was then further purified by slurrying in hot ethyl acetate (3 ml), cooling and filtering to give the title compound (0.47 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]23[CH:17]4[CH2:18][CH:14]([CH2:15][CH2:16]4)[CH:13]2[CH2:12][N:11](C)[CH2:10]3)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl[C:21]([O:23][CH2:24][CH3:25])=[O:22]>C1(C)C=CC=CC=1.ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]23[CH:17]4[CH2:18][CH:14]([CH2:15][CH2:16]4)[CH:13]2[CH2:12][N:11]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:10]3)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CN1CC2C3CCC(C3)C2(c2ccc(Cl)c(Cl)c2)C1
Reactant: CCOC(=O)Cl
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CCOC(=O)N1CC2C3CCC(C3)C2(c2ccc(Cl)c(Cl)c2)C1

Procedure:
To a solution of 5.0 g of 3a-(3,4-dichlorophenyl)octahydro-2-methyl-4,7-methano-1H-isoindole in 200 ml of toluene was added, dropwise over a 30 minute period, at room temperature, 30 ml of a solution of freshly distilled ethyl chloroformate in toluene. The reaction mixture was heated under reflux for 16 hours, then was concentrated in vacuo to give a colorless, viscous liquid. This liquid was dissolved in dichloromethane and chromatographed by preparative liquid chromatography on a silica gel column, eluting with 10% ethyl acetate/hexane and gave 1.9 g of 3a-(3,4-dichlorophenyl)octahydro-4,7-methano-2H-isoindole-2-carboxylic acid, ethyl ester as a slightly yellow, viscous liquid.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[OH:8][CH:9]([CH:14]([CH3:16])[CH3:15])[C:10](=[CH2:13])[C:11]#[N:12].[OH-].[Na+]>CN(C)C1C=CN=CC=1.O1CCCC1.C(OC)(C)(C)C.O>[C:11]([C:10](=[CH2:13])[CH:9]([O:8][C:1](=[O:3])[CH3:2])[CH:14]([CH3:16])[CH3:15])#[N:12]
Reactant: C=C(C#N)C(O)C(C)C
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: COC(C)(C)C
Solvent: C1CCOC1
Product: C=C(C#N)C(OC(C)=O)C(C)C
Temperature: 50 °C
Yield: 95.2 %

Procedure:
To a 500 mL, four-necked, round-bottom flask equipped with an overhead stirrer, a temperature probe, a reflux condenser, and a nitrogen inlet is charged acetic anhydride (40 mL, 0.45 mol). This solution is heated to 50° C. and a solution of 3-hydroxy-4-methyl-2-methylenepentanenitrile (50 g, 0.40 mol) and 4-(dimethylamino)pyridine (1.5 g) in tetrahydrofuran (25 mL) is added over 35 minutes. A temperature of 50° C. to 63° C. is maintained without external heating. After the addition is complete, the reaction mixture is heated at 60° C. for 75 minutes. The solution is cooled to 30° C. and the cooled reaction mixture is diluted with 30 mL of tert-butylmethyl ether (MTBE) and 25 mL of water. This mixture is cooled to 10° C. and a solution of 50% aqueous sodium hydroxide (37 g, 0.46 mol) diluted with 45 mL of water is added with cooling, such that the temperature is maintained at about 15° C. For the final pH adjustment, 50% aqueous sodium hydroxide 9.8 g (0.12 mol) is added dropwise to a final pH of 9.4. After adding 10 mL of water and 10 to 15 mL of MTBE, the reaction mixture is phased and separated. The upper organic product layer is separated and washed with 25 mL of brine, dried over magnesium sulfate, and concentrated in vacuo to provide 63.7 g (95%) of acetic acid 2-cyano-1-isopropyl-allyl ester as a pale yellow oil. Ethyl 3-cyano-5-methyl hex-3-enoate
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH:5]([O:17][CH2:18][CH3:19])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][C:8]=1[O:14][CH2:15][CH3:16])[CH3:2].Cl[CH2:22][C:23]1[N:24]=[C:25]([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[CH:30]=2)[O:26][C:27]=1[CH3:28].ClC1C=C(C=CC=1)C=O.O=P(Cl)(Cl)Cl.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:1]([O:3][C:4](=[O:20])[CH:5]([O:17][CH2:18][CH3:19])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:22][C:23]2[N:24]=[C:25]([C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[CH:30]=3)[O:26][C:27]=2[CH3:28])=[CH:9][C:8]=1[O:14][CH2:15][CH3:16])[CH3:2]
Reactant: CCOC(=O)C(Cc1ccc(O)cc1OCC)OCC
Reactant: Cc1oc(-c2cccc(Cl)c2)nc1CCl
Agent: O=C([O-])[O-]
Agent: O=Cc1cccc(Cl)c1
Agent: [K+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: CCOC(=O)C(Cc1ccc(OCc2nc(-c3cccc(Cl)c3)oc2C)cc1OCC)OCC

Procedure:
In analogy to the procedure described in example 1 f], [rac]-2-ethoxy-3-(2-ethoxy-4-hydroxy-phenyl)-propionic acid ethyl ester (example 47 c]) was reacted with 4-chloromethyl-2-(3-chloro-phenyl)-5-methyl-oxazole (prepared from 3-chloro-benzaldehyde and diacetyl monoxyme followed by treatment with POCl3 in analogy to the procedures described in examples 5 a] and 2 b]) in N,N-dimethylformamide in the presence of potassium carbonate to yield [rac]-3-{4-[2-(3-chloro-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2-ethoxy-phenyl}-2-ethoxy-propionic acid ethyl ester, which was further saponified in analogy to the procedure described in example 1 g], to yield [rac]-3-{4-[2-(3-chloro-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2-ethoxy-phenyl}-2-ethoxy-propionic acid as colorless solid, which can be separated into its antipodes by methods known in the art, such as separation of the antipodes via diastereomeric salts by crystallization with optically pure amines such as e.g. (R) or (S)-1-phenyl-ethylamine, (R) or (S)-1-naphthalen-1-yl-ethylamine, brucine, quinine and quinidine or by separation of the antipodes by specific chromatographic methods using either a chiral adsorbens or a chiral eluent to give the title compound.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[C:12]([Si:16]([CH3:28])([CH3:27])[O:17][CH:18]1[CH2:25][CH2:24][CH2:23][CH:22]([NH2:26])[CH2:21][CH2:20][CH2:19]1)([CH3:15])([CH3:14])[CH3:13].C(N(C(C)C)CC)(C)C>ClCCl>[CH2:5]([O:4][C:2](=[O:3])[NH:26][CH:22]1[CH2:23][CH2:24][CH2:25][CH:18]([O:17][Si:16]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:27])[CH3:28])[CH2:19][CH2:20][CH2:21]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CC(C)(C)[Si](C)(C)OC1CCCC(N)CCC1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)[Si](C)(C)OC1CCCC(NC(=O)OCc2ccccc2)CCC1
Temperature: 25 °C

Procedure:
Benzyl chloroformate (4 mL, 28.02 mmol) was added to a stirred and cooled (0° C.) solution of the product of Example 5C (14.01 mmol) and diisopropylethyl amine (7.5 mL, 42.03 mmol) in dry dichloromethane (50 mL). After the addition, the solution was warmed to room temperature and stirred for another three hours. It was quenched with NaHCO3 solution. The phases were separated and the organic phase was washed with NaHSO4 solution brine, dried (Na2SO4), filtered, and evaporated. The crude [5-(tert-Butyl-dimethyl-silanyloxy)-cyclooctyl]-carbamic acid benzyl ester was isolated as an oil and was used without further purification. Tetrabutyl ammonium fluoride (42 mL, 1 M in tetrahydrofuran, 42.03 mmol) was added to a solution of crude [5-(tert-Butyl-dimethyl-silanyloxy)-cyclooctyl]-carbamic acid benzyl ester (about 14.01 mmol) in tetrahydrofuran (35 mL). The resulting solution was stirred for two hours at 23° C. before it was partitioned with diethyl ether and water. The organic layer was washed with brine, dried (MgSO4), filtered, and evaporated. The residue was purified over silica gel using 5-50% ethyl acetate in hexanes to give (5-Hydroxy-cyclooctyl)-carbamic acid benzyl ester as an oil. (5-Hydroxy-cyclooctyl)-carbamic acid benzyl ester (2.68 g, 9.66 mmol) was stirred in the presence of Pd(OH)2/C (0.5 g) in methanol under H2 (balloon) for two hours at 23° C. before it was filtered through a pad of Celite and the solvent was evaporated. The title compound was isolated as an oil and used without further purification.
Reaction SMILES: [F:1][C:2]1[C:3]([C:11]2[C:15]([Cl:16])=[C:14]([O:17][CH:18]([F:20])[F:19])[N:13]([CH3:21])[N:12]=2)=[N:4][C:5]([CH:9]=C)=[C:6]([Cl:8])[CH:7]=1.[O:22]1CCOCC1.O.[O-]I(=O)(=O)=O.[Na+]>C(OCC)(=O)C.[Os](=O)(=O)(=O)=O>[F:1][C:2]1[C:3]([C:11]2[C:15]([Cl:16])=[C:14]([O:17][CH:18]([F:20])[F:19])[N:13]([CH3:21])[N:12]=2)=[N:4][C:5]([CH:9]=[O:22])=[C:6]([Cl:8])[CH:7]=1
Reactant: C=Cc1nc(-c2nn(C)c(OC(F)F)c2Cl)c(F)cc1Cl
Reactant: C1COCCO1
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Solvent: CCOC(C)=O
Product: Cn1nc(-c2nc(C=O)c(Cl)cc2F)c(Cl)c1OC(F)F
Reaction time: 8 h

Procedure:
13.2 g of 3-(3-fluoro-5-chloro-6-vinyl-2-pyridyl)-4-chloro-5-difluoromethoxy-1-methyl-[1 H]-pyrazole (Example H35) are initially introduced into a mixture of 120 ml of dioxane and 40 ml of water. 16.7 g of sodium (meta)periodate (NalO4) and a spatula-tip of osmium tetroxide are added, while stirring, and the mixture is subsequently stirred overnight at 22° C. The following day, the resulting mixture is taken up in ethyl acetate and washed first with dilute hydrochloric acid and then with brine. After drying over sodium sulfate, the mixture is filtered and the filtrate is concentrated in vacuo. After purification over a silica gel flash column (eluting agent: n-hexane/ethyl acetate 2/1), 9.4 g of the desired title compound are obtained as a white solid of melting point 120-121° C.
Reaction SMILES: C([O:5][C:6](=[O:36])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][N:18]([C:26]2[C:31]([Cl:32])=[CH:30][C:29]([C:33](=[O:35])[NH2:34])=[CH:28][N:27]=2)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[N:15]=1)([CH3:9])[CH3:8])(C)(C)C>FC(F)(F)C(O)=O>[ClH:32].[C:33]([C:29]1[CH:30]=[C:31]([Cl:32])[C:26]([N:18]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:17][CH2:16][C:14]2[N:15]=[C:11]([S:10][C:7]([CH3:9])([CH3:8])[C:6]([OH:36])=[O:5])[S:12][CH:13]=2)=[N:27][CH:28]=1)(=[O:35])[NH2:34]
Reactant: CCCCCCCN(CCc1csc(SC(C)(C)C(=O)OC(C)(C)C)n1)c1ncc(C(N)=O)cc1Cl
Solvent: O=C(O)C(F)(F)F
Product: CCCCCCCN(CCc1csc(SC(C)(C)C(=O)O)n1)c1ncc(C(N)=O)cc1Cl
Product: Cl
Temperature: 25 °C
Reaction time: 12 h
Yield: 167.9 %

Procedure:
2-[(4-{2-[(5-Carbamoyl-3-chloropyridin-2-yl)(heptyl)amino]ethyl}-1,3-thiazol-2-yl)thio]-2-methylpropionic acid tert-butyl ester (300 mg) obtained in Example 281-2 was dissolved in trifluoroacetic acid (5 mL), and the mixture was stirred at room temperature for 12 hr. The reaction mixture was concentrated under reduced pressure, dissolved in ether, and 4N hydrochloric acid/ethyl acetate was added. The precipitated crystals were collected by filtration to give the title compound (243 mg) as white crystals.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:12]1([CH:18]=[CH:19][CH2:20]O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.P(=O)(O)(O)O>>[C:12]1([CH:18]=[CH:19][CH2:20][O:5][C:4](=[O:6])[C:3]2[CH:7]=[CH:8][C:9]([CH3:11])=[CH:10][C:2]=2[OH:1])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: OCC=Cc1ccccc1
Reactant: Cc1ccc(C(=O)O)c(O)c1
Agent: O=P(O)(O)O
Product: Cc1ccc(C(=O)OCC=Cc2ccccc2)c(O)c1
Yield: 89.1 %

Procedure:
Using the method of example 1, 15.24 g of 2-hydroxy-4-methylbenzoic acid (0.1 moles), 40.251 g of 3-phenyl-2-propen-1-ol (0.3 moles) and 4.9 g of anhydrous phosphoric acid (0.05 moles) give 23.9 g (89% yield) of (3-phenyl-2-propenyl)-2-hydroxy-4-methylbenzoate, m.p. 196°14 196.5° C.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([S:14][CH3:15])[N:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O.O>[CH3:15][S:14][C:10]1[N:9]=[C:8]([C:7]2[C:2]([O:23][C:20]3[CH:21]=[CH:22][C:17]([NH2:16])=[CH:18][CH:19]=3)=[N:3][CH:4]=[CH:5][CH:6]=2)[CH:13]=[CH:12][N:11]=1
Reactant: CSc1nccc(-c2cccnc2Cl)n1
Reactant: Nc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: CSc1nccc(-c2cccnc2Oc2ccc(N)cc2)n1
Temperature: 130 °C

Procedure:
A resealable pressure bottle was charged with 4-(2-chloropyridin-3-yl)-2-(methylthio)pyrimidine (6.00 g, 25.2 mmol), 4-aminophenol (2.89 g, 26.5 mmol), and cesium carbonate (16.4 g, 50.5 mmol). These reagents were suspended in DMSO (50.5 ml, 0.50 M). The vessel was sealed and heated to 130° C. for 48 hrs. Reaction mixture was allowed to cool to RT, diluted with water and extracted with EtOAc. The organic layer was collected, dried with Na2SO4, filtered, and concentrated to give a light brown residue, which was purified by silica gel chromatography (ISCO, 10% to 50% Ethyl Acetate/Hexanes) to afford clean material as light yellow solid. MS m/z=311 [N+H]+. Calc'd for C16H14N4OS: 310.37.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][CH:10]([CH2:14][OH:15])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(=O)C.[Na+].[Cl:21][CH2:22][C:23](Cl)=[O:24]>CC(C)=O.O.CCOC(C)=O>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:23](=[O:24])[CH2:22][Cl:21])[CH:10]([CH2:14][OH:15])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCC1CN(Cc2ccccc2)CCN1
Reactant: O=C(Cl)CCl
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: O=C(CCl)N1CCN(Cc2ccccc2)CC1CO
Temperature: 0 °C
Reaction time: 1 h
Yield: 99.4 %

Procedure:
To a stirred solution of (4-benzyl-piperazin-2-yl)methanol (500 mg, 2.42 mmol) and sodium acetate (397.6 mg, 4.85 mmol, 2.0 eq) in acetone (9.7 mL) and water (24.2 mL) under N2 at 0° C. was added dropwise chloroacetyl chloride (0.20 mL, 2.54 mmol, 1.05 eq) over 5 minutes. The mixture was stirred at 0° C. for 5 min and at rt for 1 h. The mixture was diluted with EtOAc (150 mL) and the organic phase was washed with water, aqueous saturated NaHCO3 solution, and brine. The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo to give 680 mg (99%) of the desired product as an oil. 1H-NMR (300 MHz, CD3OD) δ 7.32 to 7.23 (m, 5H), 4.51 (d, 1H), 4.32 to 3.98 (m, 4H), 3.82 to 3.73 (m, 1H), 3.62 to 3.42 (m, 3H), 3.06 to 3.00 (m, 1H), 2.91 to 2.82 (m, 2H), 2.25 to 1.98 (m, 2H).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[N:7][NH:8][CH:9]=1.Cl[C:11]1[N:12]=[N+:13]([O-:22])[C:14]2[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:15]=2[N:16]=1>CN(C)C=O>[CH3:3][O:4][C:5]1[CH:6]=[N:7][N:8]([C:11]2[N:12]=[N+:13]([O-:22])[C:14]3[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:15]=3[N:16]=2)[CH:9]=1
Reactant: [O-][n+]1nc(Cl)nc2ccc(Cl)cc21
Reactant: COc1cn[nH]c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cnn(-c2nc3ccc(Cl)cc3[n+]([O-])n2)c1
Temperature: 60 °C
Reaction time: 3 h
Yield: 62.3 %

Procedure:
3.45 g (0.115 mol) of sodium hydride (80% pure) were introduced into a solution of 12.6 g (0.13 mol) of 4-methoxy-pyrazole in 100 ml of absolute dimethylformamide at room temperature and the mixture was subsequently warmed briefly to 60° C. 21.6 g (0.1 mol) of 3,7-dichloro-benzo-1,2,4-triazine 1-oxide were added in portions to the mixture, which had been cooled to room temperature. After the exothermic reaction had subsided, the mixture was subsequently stirred at 30° to 40° C. for a further 3 hours and the reaction product was then precipitated with water. This product was filtered off, stirred in 150 ml of methanol, filtered off again and dried. 17.3 g of 3-(4-methoxypyrazol-1-yl)-7-chloro-benzo-1,2,4-triazine 1-oxide of melting point 253°-255° C. (with decomposition) were obtained, that is to say 62.3% of theory. The compound could be recrystallized from dimethylformamide.
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:28]([O:30][CH3:31])=[O:29])=[CH:12][C:13]=3[N:14]3[C:21]=2[C:20]2[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=2[O:18][CH2:17][CH:16]([CH2:26][OH:27])[CH2:15]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>C(Cl)Cl.CCOC(C)=O>[CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:28]([O:30][CH3:31])=[O:29])=[CH:12][C:13]=3[N:14]3[C:21]=2[C:20]2[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=2[O:18][CH2:17][CH:16]([CH:26]=[O:27])[CH2:15]3)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(CO)COc1ccccc1-3
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(C=O)COc1ccccc1-3
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of methyl 14-cyclohexyl-7-(hydroxymethyl)-7,8-dihydro-6H-indolo[1,2-e][1,5]benzoxazocine-11-carboxylate (from step 2) in dry DCM (0.1 M) was treated with DMP (1.2 eq.) and the resulting solution was stirred for 2 h at RT. The reaction mixture was diluted with EtOAc and washed with a 1:1 (v/v) mixture of sodium thiosulfate and NaHCO3 (both aqueous saturated solutions), then with brine. Drying over Na2SO4, filtration and concentration i. vac. gave the crude methyl 14-cyclohexyl-7-formyl-7,8-dihydro-6H-indolo[1,2-e][1,5]benzoxazocine-11-carboxylate, which without further purification.
Reaction SMILES: [CH3:1][N:2]([CH2:10]C1CCNCC1)[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6].Cl.Cl[C:19]1C=C[N:22]=[CH:21][N:20]=1.[CH3:25][CH2:26][N:27]([CH:31]([CH3:33])C)[CH:28]([CH3:30])C>CC(O)C.C(OCC)(=O)C.C(=O)([O-])O.[Na+]>[CH3:10][N:2]([CH:1]1[CH2:25][CH2:26][N:27]([C:28]2[CH:30]=[CH:19][N:20]=[CH:21][N:22]=2)[CH2:31][CH2:33]1)[C:3](=[O:9])[O:4][C:5]([CH3:6])([CH3:7])[CH3:8]
Reactant: CCN(C(C)C)C(C)C
Reactant: Clc1ccncn1
Reactant: CN(CC1CCNCC1)C(=O)OC(C)(C)C
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: CN(C(=O)OC(C)(C)C)C1CCN(c2ccncn2)CC1
Yield: 78 %

Procedure:
tert-Butyl methyl(piperidin-4-ylmethyl)carbamate (4.67 mmol, 1.0 eq) and 4-chloropyrimidine hydrochloride (14.0 mmol, 3.0 eq) were dissolved in 2-propanol (18 ml) and DIPEA (23.33 mmol. 5.0 eq) and refluxed for 16 hours. After monitoring by TLC, the reaction solution was diluted with ethyl acetate and sat. sodium hydrogen carbonate solution, and the phases were separated. The aqueous phase was washed with ethyl acetate. The combined organic phases were washed 1× with sat. NaCl solution, dried over magnesium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, ethyl acetate:ethanol 10:1+ammonia solution). Yield: 78%
Reaction SMILES: N1(C[CH2:9][N:10]2[CH2:15][CH2:14][CH:13]([NH:16][C:17]([C:19]3[NH:20][C:21]4[C:26]([CH:27]=3)=[C:25]([O:28][C:29]3[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=3)[CH:24]=[CH:23][CH:22]=4)=[O:18])[CH2:12][CH2:11]2)CCCCCC1.NC1CCN(C[C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)CC1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)C(C)C)C>CN(C=O)C>[CH2:9]([N:10]1[CH2:15][CH2:14][CH:13]([NH:16][C:17]([C:19]2[NH:20][C:21]3[C:26]([CH:27]=2)=[C:25]([O:28][C:29]2[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=2)[CH:24]=[CH:23][CH:22]=3)=[O:18])[CH2:12][CH2:11]1)[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1
Reactant: Cc1ccc(Oc2cccc3[nH]c(C(=O)NC4CCN(CCN5CCCCCC5)CC4)cc23)cc1
Reactant: NC1CCN(Cc2ccccc2)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(Oc2cccc3[nH]c(C(=O)NC4CCN(Cc5ccccc5)CC4)cc23)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-p-tolyloxy-1H-indole-2-carboxylic acid (137) (850 mg, 3.2 mmol) and 4-amino-N-benzylpiperidine (605 mg, 3.2 mmol) are dissolved in 5 ml of DMF and after addition of TBTU (1.2 g, 3.5 mmol) and ethyldiisopropylamine (2.2 ml, 12.8 mmol) the mixture is stirred at room temperature for 2 h. Then the mixture is evaporated at high vacuum. The residue is dissolved in ethyl acetate and washed with saturated NaHCO3-solution and brine. The organic layers are dried over Na2SO4, filtrated and evaporated under reduced pressure. Yield: 1.47 g (100%) of a yellow foam. MS (ESI): 438 [M−H]−.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11]/[C:12](=[CH:17]\[C:18]1SC=[CH:21][CH:22]=1)/[C:13]([O:15][CH3:16])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:23]1C=CC(C=O)=[CH:24]1>>[CH2:1]([O:8][C:9]([NH:11]/[C:12](=[CH:17]\[C:18]1[CH:22]=[CH:21][S:23][CH:24]=1)/[C:13]([O:15][CH3:16])=[O:14])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1ccsc1
Reactant: COC(=O)/C(=C/c1cccs1)NC(=O)OCc1ccccc1
Product: COC(=O)/C(=C/c1ccsc1)NC(=O)OCc1ccccc1

Procedure:
A method similar to that used for the preparation of (99a) was used except that 3-thiophenecarboxaldehyde (762 mg) was used as the aldehyde component to afforded the desired product (549 mg). 1H NMR (300 MHz, CDCl3) δ 3.795 (s, 3H), 5.19 (s, 2H), 5.99 (br., 1H), 7.07 (m, 1H), 7.34 (m, 7H), 7.49 (d, 111, J=5 Hz), 7.77 (s, 1H). LC/MS: 2.32 min.