Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:9])=[CH:4][C:3]=1[N+:16]([O-:18])=[O:17].[CH3:19][C:20]([CH3:25])([CH2:23]O)[CH2:21][OH:22].CC1C=CC(S(O)(=O)=O)=CC=1.C(O)CCC>O.CC1C=CC=CC=1>[CH3:19][C:20]1([CH3:25])[CH2:21][O:22][C:8]([C:5]2[CH:6]=[CH:7][C:2]([NH2:1])=[C:3]([N+:16]([O-:18])=[O:17])[CH:4]=2)([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[O:9][CH2:23]1
Reactant: CC(C)(CO)CO
Reactant: Nc1ccc(C(=O)c2ccccc2)cc1[N+](=O)[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCCCO
Product: CC1(C)COC(c2ccccc2)(c2ccc(N)c([N+](=O)[O-])c2)OC1
Yield: 55 %

Procedure:
A mixture of 31.5 parts of (4-amino-3-nitrophenyl)phenylmethanone, 21 parts of 2,2-dimethyl-1,3-propanediol, 2 parts of 4-methylbenzenesulfonic acid, 40 parts of butanol and 450 parts of methylbenzene is stirred and refluxed for 16 hours with water-separator. The reaction mixture is cooled and washed with ammonium hydroxide. The organic phase is dried, filtered and evaporated. The residue is crystallized from 2,2'-oxybispropane, yielding 27.5 parts (55%) of 4-(5,5-dimethyl-2-phenyl-1,3-dioxan-2-yl)-2-nitrobenzenamine; mp. 139.8° C.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1)([CH3:3])[CH3:2].Cl[C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][N:12]=1>C(Cl)Cl.O>[CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][N:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)N1CCNCC1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Solvent: ClCCl
Solvent: O
Product: CC(C)N1CCN(c2ccc([N+](=O)[O-])cn2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
1-Isopropylpiperazine (1.8 mL, 12.7 mmol, 2 equiv) was added to a cold (5° C.) solution of 2-chloro-5-nitropyridine (1 g, 6.3 mmol,) in DCM (5 mL). The reaction mixture was allowed to warm to rt, stirred for 16 h, diluted with DCM and H2O. The aqueous layer was separated and extracted with DCM. The organic phase was washed with brine, dried (Na2SO4), filtered and concentrated to provide 1.58 g of he title compound as a yellow solid: ESI-MS: 251.2 [M+H]+; tR=2.20 min.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH:7]([S:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:6]=2[N:5]=[CH:4][CH:3]=1.ClC1C=C(C=CC=1)C(OO)=[O:24]>ClCCl>[CH3:1][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH:7]([S:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[O:24])[C:6]=2[N:5]=[CH:4][CH:3]=1
Reactant: Cc1ccnc2c1CCCC2Sc1ccccc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Cc1ccnc2c1CCCC2S(=O)c1ccccc1
Reaction time: 0.5 h
Yield: 101.5 %

Procedure:
A solution of the product of Step 4 (10.0 g, 39.2 mmol) in dichloromethane (200 ml) was treated portionwise with 86% 3-chloroperoxybenzoic acid (8.0 g, 40 mmol) at <10° , stirred for 30 min, washed with 0.1N-NaOH, dried (Na2SO4), and evaporated in vacuo to give the crude product (10.8 g) as a solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][C@@H:9]([OH:12])[C@H:8]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:7]1)=[O:5])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:38][C:39]1[CH:40]=[C:41](O)[CH:42]=[CH:43][CH:44]=1.N(C(OCC)=O)=NC(OCC)=O>C1C=CC=CC=1.CCOCC>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][C@H:9]([O:12][C:43]2[CH:42]=[CH:41][CH:40]=[C:39]([F:38])[CH:44]=2)[C@H:8]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:7]1)=[O:5])[CH3:2]
Reactant: Oc1cccc(F)c1
Reactant: CCOC(=O)N1CC[C@@H](O)[C@H](c2ccccc2)C1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Solvent: CCOCC
Product: CCOC(=O)N1CC[C@H](Oc2cccc(F)c2)[C@H](c2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 6.23 g of trans-1-ethoxycarbonyl-3-phenyl-4-piperidinol, 7.21 g of triphenylphosphine and 2.49 ml of m-fluorophenol in 250 ml of anhydrous benzene is added dropwise under nitrogen at 5° C. over a 90 minute period a solution of 4.79 g of diethyl azodicarboxylate in 250 ml of benzene. After the addition is complete the mixture is stirred overnight at room temperature. The solid is filtered, washed with benzene, and the filtrate is concentrated in vacuo to a gum. The gum is triturated overnight in a stoppered flask with 250 ml of hexane. The solid is filtered and washed with hexane. The filtrate is washed with 10% aqueous sodium hydroxide solution (3×75 ml), water (2×100 ml), saturated sodium chloride solution (100 ml) and dried overnight over anhydrous sodium sulfate. Filtration and concentration in vacuo affords a light yellow oil. Chromatography of the oil on 430 g of silica gel, using 2:1 (petroleum ether:ether), affords a colorless, cloudy gum. Trituration of the gum with petroleum ether yields product as a colorless crystalline solid, mp 74°-76.5° C.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]([F:22])([CH2:7][CH2:8][C:9]([F:21])([F:20])[C:10]([F:19])([F:18])[C:11]([F:17])([F:16])[C:12]([F:15])([F:14])[F:13])[C:4]([O-:6])=[O:5].[Na+].Cl.CCOCC>O>[F:1][C:2]([F:23])([F:24])[C:3]([F:22])([CH2:7][CH2:8][C:9]([F:20])([F:21])[C:10]([F:18])([F:19])[C:11]([F:16])([F:17])[C:12]([F:13])([F:14])[F:15])[C:4]([OH:6])=[O:5]
Reactant: O=C([O-])C(F)(CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)C(F)(F)F
Agent: Cl
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: O=C(O)C(F)(CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)C(F)(F)F

Procedure:
Sodium 2-trifluoromethyl-2,5,5,6,6,7,7,8,8,8-decafluorooctanoate was dissolved in water with vigorous stirring and 6N aqueous hydrochloric acid was added slowly to adjust the pH of the solution to about 1.0, and then ether was added to extract the product. The organic layer was separated, washed with water, and dried over magnesium sulfate. After removal of the solvent in vacuo, the residue was dried under high vacuum to give quantitative yield of 2-trifluoromethyl-2,5,5,6,6,7,7,8,8,8-decafluorooctanoic acid, formula above, as a white solid having a melting point of 45°-46° C.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][S:10][C@H:9]1[C:13](=[O:32])[NH:14][C:15]1[S:16][CH:17]=[C:18]([C:20]2[CH:25]=[CH:24][C:23]([C:26](=[O:31])[NH:27][CH:28]3[CH2:30][CH2:29]3)=[CH:22][CH:21]=2)[N:19]=1)=O)(C)(C)C>ClCCl.FC(F)(F)C(O)=O>[CH:28]1([NH:27][C:26]([C:23]2[CH:22]=[CH:21][C:20]([C:18]3[N:19]=[C:15]([NH:14][C:13]([C@H:9]4[NH:8][CH2:12][CH2:11][S:10]4)=[O:32])[S:16][CH:17]=3)=[CH:25][CH:24]=2)=[O:31])[CH2:30][CH2:29]1
Reactant: CC(C)(C)OC(=O)N1CCS[C@H]1C(=O)Nc1nc(-c2ccc(C(=O)NC3CC3)cc2)cs1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(NC1CC1)c1ccc(-c2csc(NC(=O)[C@H]3NCCS3)n2)cc1

Procedure:
A solution of (S)-2-[4-(4-cyclopropylcarbamoyl-phenyl)-thiazol-2-ylcarbamoyl]-thiazolidine-3-carboxylic acid tert-butyl ester (341.6 mg, 0.72 mmol) in dichloromethane (3 mL) and trifluoroacetic acid (3 mL) was stirred at ambient temperature overnight. The reaction was filtered and purified by reverse phase HPLC to give the desired product.
Reaction SMILES: [F:1][C:2]1[C:29]([F:30])=[CH:28][CH:27]=[CH:26][C:3]=1[C:4]([N:6]([CH2:22][CH2:23][CH2:24][CH3:25])[CH:7](CC=CCCl)[C:8]1[NH:12][C:11]2[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=2[N:9]=1)=[O:5].[NH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1>C1(C)C=CC=CC=1.C1(C)C=CC=CC=1.CN1CCOCC1>[CH2:22]([N:6]([CH2:7][C:8]1[N:9]([CH2:29][CH:2]=[CH:3][CH2:4][N:31]2[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]2)[C:10]2[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=2[N:12]=1)[C:4](=[O:5])[C:3]1[CH:26]=[CH:27][CH:28]=[C:29]([F:30])[C:2]=1[F:1])[CH2:23][CH2:24][CH3:25]
Reactant: C1CCNCC1
Reactant: CCCCN(C(=O)c1cccc(F)c1F)C(CC=CCCl)c1nc2ccccc2[nH]1
Solvent: Cc1ccccc1
Solvent: CN1CCOCC1
Product: CCCCN(Cc1nc2ccccc2n1CC=CCN1CCCCC1)C(=O)c1cccc(F)c1F
Temperature: 90 °C
Yield: 166.5 %

Procedure:
2,3-Difluoro-N-butyl-N-[(4-chlorobut-2-enyl)-1H-benzoimidazol-2-ylmethyl)-benzamide (26 mg, 0.06 mmol) was dissolved in 0.3 mL toluene. Piperidine (10 μL, 0.1 mmol) dissolved in 0.5 mL 95/5 toluene/4-methylmorpholine was added and the reaction mixture was heated at 90° C. for 15 hours. The reaction mixture was cooled to room temperature and deposited on a 1 g silica SPE column. The column was washed with 4 mL ethyl acetate to remove impurities followed by 4 mL 10/2/1 ethyl acetate/methanol/triethylamine to elute the product to afford 24 mg N-butyl-2,3-difluoro-N-[1-(4-piperidin-1-yl-but-2-enyl)-1H-benzoimidazol-2-ylmethyl]-benzamide.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([F:13])[CH2:10][C@@H:9]1[C@@H:14]([OH:26])[C@@H:15]([N+:23]([O-])=O)[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+]>CO.O.O.O.O.O.O.[Ni](Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([F:13])[CH2:10][C@@H:9]1[C@@H:14]([OH:26])[C@@H:15]([NH2:23])[CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1C[C@@H](F)C[C@@H]1[C@@H](O)[C@H](Cc1ccccc1)[N+](=O)[O-]
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N1C[C@@H](F)C[C@@H]1[C@@H](O)[C@@H](N)Cc1ccccc1
Reaction time: 0.17 h

Procedure:
Dissolve nickel chloride hexahydrate (0.021 g, 0.09 mmol) and 4-(S)-fluoro-2-(R)-(1-(R)-hydroxy-2-(S)-nitro-3-phenylpropyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (0.33 g, 0.897 mmol) in methanol (5 mL). Cool in an ice bath and add sodium borohydride (0.17 g, 4.485 mmol) portionwise over 1 min. Stir 10 min, then concentrate. Partition in water and ethyl acetate and filter through filter agent. Separate layers and wash organic layer with saturated aqueous sodium chloride, dry (magnesium sulfate), and concentrate to give the title compound as a white foam.
Reaction SMILES: CC1(C)[O:6][C:5](=[CH:7][C:8]([N:10]([O:22][CH3:23])[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)=[O:9])[C:4](=[O:24])O1.C=O.[CH3:28][NH2:29].[CH3:30]O>>[CH3:23][O:22][N:10]([CH2:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]([F:19])([F:20])[F:21])=[CH:16][CH:17]=1)[C:8]([C:7]1[CH2:28][N:29]([CH3:30])[C:4](=[O:24])[C:5]=1[OH:6])=[O:9]
Reactant: CON(Cc1ccc(C(F)(F)F)cc1)C(=O)C=C1OC(C)(C)OC1=O
Reactant: CN
Reactant: CO
Agent: C=O
Product: CON(Cc1ccc(C(F)(F)F)cc1)C(=O)C1=C(O)C(=O)N(C)C1
Yield: 52 %

Procedure:
Reaction of 2-(2,2-dimethyl-5-oxo-[1,3]-dioxolan-4-ylidene)-N-methoxy-N-(4-trifluoromethylbenzyl)-acetamide (0.20 g, 0.56 mmol) with the paraformaldehyde-methylamine adduct in methanol using a procedure similar to the one described in the preparation of compound 44 (method 44B) gave 0.10 g (52% yield) of the title compound as white crystals; mp 145° C. (dec) (ethyl acetate-hexane). 1HNMR 400 MHz (CDCl3) δ (ppm); 3.11 (3H, s, NCH3), 3.75 (3H, s, OCH3), 4.17 (2H, s, NCH2), 4.94 (2H, s, NCH2), 7.45 (2H, d, J=8.1 Hz, aromatics), 7.61 (2H, d, J=8.1 Hz, aromatics). Anal. Calcd for C15H15F3N2O4: C, 52.33; H, 4.39; N, 8.13. Found: C, 52.17; H, 4.34; N, 7.98.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH2:10][CH:11]=[CH:12][CH:13]=[CH2:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.Br[CH2:23][CH:24]=[CH:25][C:26]([O:28][CH2:29][CH3:30])=[O:27].O>C(#N)C>[CH2:1]([N:8]1[CH2:9][CH2:10][CH:11]2[CH:24]([CH:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:14][CH:13]=[CH:12]2)[CH2:23]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CC=CCCNCc1ccccc1
Reactant: CCOC(=O)C=CCBr
Solvent: CCN(CC)CC
Solvent: O
Solvent: CC#N
Product: CCOC(=O)C1CC=CC2CCN(Cc3ccccc3)CC21
Temperature: 25 °C
Reaction time: 72 h
Yield: 30.4 %

Procedure:
A solution of N-benzylhexa-3,5-dien-1-amine (338 mg, 1.81 mmol) and triethylamine (0.378 mL, 2.72 mmol) in acetonitrile (15 mL) was treated with ethyl 4-bromobut-2-enoate (0.249 mL, 1.81 mmol). The mixture was stirred at room temperature for 72 hours, then heated to reflux for 6 hours. The mixture was cooled to room temperature and treated with water (15 mL), then extracted with ethyl acetate (3×15 mL). The combined organic phases were dried over magnesium sulfate and concentrated to provide a pale yellow oil. The pale yellow oil was purified by radial thin-layer chromatography, eluting with 10% ethyl acetate/hexane, to provide an oil (165 mg, 30%). 1H NMR (300 MHz, CDCl3) δ7.4-7.2 (m, 5H), 5.62 (m, 2H), 4.1-3.9 (m, 2H), 3.6-3.3 (m, 2H), 2.95 (m, 1H), 2.65 (m, 2H), 2.3-2.1 (m, 6H), 1.78 (m, 1H), 1.57 (m, 1H), 1.19 (t, J=7 Hz, 3H). Mass spec (ES+) m/z 300.3 (M+H+, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([C:15]2(O)[C:19]([CH3:21])([CH3:20])[CH2:18][CH2:17][O:16]2)[N:10]2[CH:14]=[N:13][CH:12]=[N:11]2)=[CH:4][CH:3]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](=[C:15]2[C:19]([CH3:21])([CH3:20])[CH2:18][CH2:17][O:16]2)[N:10]2[CH:14]=[N:13][CH:12]=[N:11]2)=[CH:4][CH:3]=1
Reactant: CC1(C)CCOC1(O)C(Cc1ccc(Cl)cc1)n1cncn1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CC1(C)CCOC1=C(Cc1ccc(Cl)cc1)n1cncn1
Yield: 8.5 %

Procedure:
5 g (0.0155 mole) of 1-(4-chlorophenyl)-2-(3,3-dimethyl-2-hydroxy-tetrahydrofuran-2-yl)-2-(1,2,4-triazol-1-yl)-ethane are dissolved in 100 ml of toluene, 0.5 g of p-toluenesulphonic acid are added and the mixture is heated under reflux for 2 hours, using a water separator. The reaction mixture is cooled, washed with water, dried over sodium sulphate and concentrated in vacuo. The residue is purified by column chromatography (silica gel; ethyl acetate/cyclohexane=3:1). 2.8 g (59.6% of theory) of 1-(4-chlorophenyl-2-(3,3-dimethyl-tetrahydrofuran-2-ylidene)-2-(1,2,4-triazol-1-yl)-ethane are obtained as form A of melting point 89° C. and 0.4 g (8.5% of theory) of 1-(4-chlorophenyl)-2-(3,3-dimethyl-tetrahydrofuran-2-ylidene)-2-(1,2,4-triazol-1-yl)-ethane are obtained as form B of melting point 175°-177° C.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]3[C:18](=[CH:19][CH:20]=2)[N:17]=[C:16]2[N:11]3[C:12](=[O:24])[NH:13][C:14]3[C:15]2=[N:21][NH:22][CH:23]=3)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(O)CCC.[C:30](#[N:34])[CH2:31][CH2:32]C.C1(N)CC1>C1(C)C=CC=CC=1>[CH:30]1([NH:34][C:12]([NH:13][C:14]2[C:15]([C:16]3[NH:17][C:18]4[CH:19]=[CH:20][C:8]([CH2:7][N:1]5[CH2:2][CH2:3][O:4][CH2:5][CH2:6]5)=[CH:9][C:10]=4[N:11]=3)=[N:21][NH:22][CH:23]=2)=[O:24])[CH2:32][CH2:31]1
Reactant: O=c1[nH]c2c[nH]nc2c2nc3ccc(CN4CCOCC4)cc3n12
Reactant: CCCC#N
Agent: NC1CC1
Solvent: CCCCO
Solvent: Cc1ccccc1
Product: O=C(Nc1c[nH]nc1-c1nc2cc(CN3CCOCC3)ccc2[nH]1)NC1CC1
Temperature: 60 °C
Reaction time: 20 h

Procedure:
7-Morpholin-4-ylmethyl-2,4-dihydro-1,2,4,5a,10-pentaaza-cyclopenta[α]fluoren-5-one (1.0 wt, prepared as outlined above in Example 66A) and a solvent such as n-butanol, butyronitrile, glycol or toluene (3.0 vol) can be charged to a flange flask equipped with a mechanical stirrer, condenser and thermometer. Cyclopropylamine (0.351 wt) can be added at temperature such as 15 to 30° C. under an inert atmosphere e.g. nitrogen. The contents can be heated to 40 to 105° C., in particular 40-80° C. and stirred at this temperature for 16 to 24 hours. Reaction completion can be determined by 1H NMR analysis. The reaction mixture can then be cooled to 10 to 20° C. The product can then be isolated by organic-aqueous extraction method as outlined above in Example 66A, or an alternative method of isolation may be employed such as the addition of an anti-solvent, for example n-heptanes, to the reaction mixture. This could allow the reaction product to precipitate with subsequent isolation by filtration. The solid can then be dried under vacuum at 35 to 45° C. to yield 1-cyclopropyl-3-[3-(5-morpholin-4-ylmethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-urea. At this stage the solid can be purified by recrystallisation from an appropriate solvent, preferably a Class 2 or 3 solvent1. In addition, alternative methods of purification aside from recrystallisation may be employed for purification of the product such as flash column chromatography or filtration through a plug of silica gel or reverse-phase silica gel. 1 Class 3 and Class 2 solvents are as outlined Q3C—Tables and List in Guidance for Industry Q3C Impurities: Residual Solvents (November 2003, CDER, CBER, FDA, ICH) and as further outlined in Impurities: Guideline for Residual Solvents (1997, ICH).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:14])[C:11]([CH3:13])=[CH2:12])=[CH:5][C:4]=1[C:15]([F:18])([F:17])[F:16])#[N:2].ClC1C=CC=C(C(OO)=[O:27])C=1>ClCCl>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([C:11]2([CH3:13])[CH2:12][O:27]2)=[O:14])=[CH:5][C:4]=1[C:15]([F:17])([F:16])[F:18])#[N:2]
Reactant: C=C(C)C(=O)Nc1ccc(C#N)c(C(F)(F)F)c1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CC1(C(=O)Nc2ccc(C#N)c(C(F)(F)F)c2)CO1
Reaction time: 8 h

Procedure:
460 mg of the amide (7) from the Example 1 was dissolved in 30 ml of dichloromethane. 560 mg of m-chloroperbenzoic acid (purity 70-75%) was added. The reaction mixture was stirred overnight at reflux. The reaction was monitored with HPLC. The reaction mixture was washed successively with 2×20 ml of a sodium sulfite solution, 2×20 ml of saturated aqueous NaHCO3 and 20 ml of brine. The organic layer was dried (Na2SO4), filtrated and evaporated under reduced pressure yielding the epoxide (5A) as yellow solid material. Isolated yield: 400 mg (82%). 1H- and 13C-NMR confirmed the expected structure. HPLC: 96% purity.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N+:4]([O-:9])[CH:5]=[C:6]([CH3:8])[CH:7]=1.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Tl+3].[Br:23]Br>C(O)(=O)C>[Br:23][C:7]1[C:6]([CH3:8])=[CH:5][N+:4]([O-:9])=[CH:3][C:2]=1[CH3:1]
Reactant: Cc1cc(C)c[n+]([O-])c1
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Tl+3]
Solvent: CC(=O)O
Product: Cc1c[n+]([O-])cc(C)c1Br
Temperature: 60 °C
Yield: 53.5 %

Procedure:
To a solution of 3,5-dimethylpyridine 1-oxide (6.1 g, 50 mmol) in acetic acid (30 mL) was added thallium(III) triacetate (5.0 g, 13 mmol) and bromine (2.6 mL, 50 mmol). The resulting solution was heated at 60° C. overnight. The reaction was concentrated in vacuo, diluted with water and ethyl acetate. The organic layer was concentrated and residue was purified by silica gel chromatography to afford the desired product (5.40 g, 54%). 1H NMR (400 MHz, CDCl3): δ 7.96 (s, 2H), 2.38 (s, 6H).
Reaction SMILES: C([NH:4]C(C)C)(C)C.[Li]CCCC.[CH3:13][O:14][C:15]1[C:23]([CH3:24])=[C:22]2[C:18]([C:19](=[O:25])[O:20][CH2:21]2)=[C:17]([O:26][CH2:27][O:28][CH2:29][CH2:30][O:31][CH3:32])[C:16]=1[CH2:33]/[CH:34]=[C:35](\[CH3:38])/[CH2:36]Br.[NH4+].[Cl-].[C:41]([O:44][CH2:45][CH3:46])(=[O:43])[CH3:42]>C1COCC1.CN(P(N(C)C)(N(C)C)=O)C>[CH3:32][O:31][CH2:30][CH2:29][O:28][CH2:27][O:26][C:17]1[C:16]([CH2:33]/[CH:34]=[C:35](\[CH3:38])/[CH2:36][CH:42]([NH2:4])[C:41]([O:44][CH2:45][CH3:46])=[O:43])=[C:15]([O:14][CH3:13])[C:23]([CH3:24])=[C:22]2[C:18]=1[C:19](=[O:25])[O:20][CH2:21]2
Reactant: CC(C)NC(C)C
Reactant: CCOC(C)=O
Reactant: COCCOCOc1c(C/C=C(\C)CBr)c(OC)c(C)c2c1C(=O)OC2
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCOC(=O)C(N)C/C(C)=C/Cc1c(OC)c(C)c2c(c1OCOCCOC)C(=O)OC2
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 63 %

Procedure:
Freshly distilled diisopropylamine (0.435 ml) was dissolved in THF (10 ml). The solution was cooled to 0° C. and n-BuLi (1.3 ml, 2.38M) was added. The mixture was stirred at 0° C. for 20 minutes. The ice-bath was replaced by a dry ice-acetone bath and a solution of ethyl benzylidine glycinate (0.445 g) in THF (2 ml) was added slowly at -78°. The resulting red solution was stirred at -78° C. for 40 minutes. This solution was then transferred via cannula to a solution of (E)-4-(1,3-dihydro-6-methoxy -4-methoxyethoxymethoxy-7-methyl-3-oxoisobenzofuran-5-yl)-2-methylbut2-enyl bromide (0.667 g) dissolved in THF (20 ml) and HMPA (2 ml). After stirring the mixture at -78° C. for 90 minutes, the reaction mixture was poured into a concentrated solution of NH4Cl, extracted with ethyl acetate (3×30 ml), and the combined organic layers were dried over Na2SO4 and evaporated to give a dark oil, which was passed through a column (silica gel, ethyl acetate) giving 0.443 g (63%) of ethyl (E)-6-(4-methoxyethoxymethoxy -1,3-dihydro-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl)-2-amino-4-methyl -4-hexenoate the product as a light yellow oil.
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:11].I[CH2:13][CH3:14].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:13]([O:11][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]=1[CH3:1])[CH3:14]
Reactant: CCI
Reactant: Cc1c(O)cccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOc1cccc([N+](=O)[O-])c1C
Temperature: 25 °C
Yield: 100.7 %

Procedure:
A mixture of 2-methyl-3-nitrophenol 33.5 g, iodoethane 41 g and potassium carbonate 90 g in acetone 400 mL was stirred with heating under reflux for ten hours. The mixtures were cooled to room temperature and filtered and the resulting filtrates were concentrated. The resulting mixtures were extracted with ethyl acetate and the organic layers were washed with water and saturated saline, and were dried over anhydrous magnesium sulfate and were then concentrated under reduced pressure. The resulting residues were subjected to a silica gel column chromatography to give 1-ethoxy-2-methyl-3-nitrobenzene 39.9 g.
Reaction SMILES: [C:1]([C:3]1[N:11]2[C:6]([C:7]3([CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]3)[O:8][C:9]3[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][C:10]=32)=[CH:5][CH:4]=1)#[N:2].[Br:29]N1C(=O)CCC1=O.C(C(N=NC(C)(C)C#N)(C)C)#N>C(Cl)(Cl)(Cl)Cl>[Br:29][CH2:16][C:14]1[CH:13]=[CH:12][C:10]2[N:11]3[C:3]([C:1]#[N:2])=[CH:4][CH:5]=[C:6]3[C:7]3([CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]3)[O:8][C:9]=2[CH:15]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc2c(c1)OC1(CCN(C(=O)OC(C)(C)C)CC1)c1ccc(C#N)n1-2
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)OC(=O)N1CCC2(CC1)Oc1cc(CBr)ccc1-n1c(C#N)ccc12
Temperature: 80 °C
Yield: 47.6 %

Procedure:
tert-Butyl 1′-cyano-7′-methyl-spiro[piperidine-4,4′-pyrrolo[2,1-c][1,4]benzoxazine]-1-carboxylate (200 mg, 0.527 mmol), 1-bromopyrrolidine-2,5-dione (93.8 mg, 0.527 mmol), and 2-(1-cyano-1-methyl-ethyl)azo-2-methyl-propanenitrile (8.66 mg, 0.0527 mmol) were combined in carbon tetrachloride (10 mL) and the mixture was heated at 80° C. for 4 hours. The mixture was washed with water, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (50-100% CH2Cl2/hexanes) to yield tert-butyl 7′-(bromomethyl)-1′-cyano-spiro[piperidine-4,4′-pyrrolo[2,1-c][1,4]benzoxazine]-1-carboxylate (115 mg, 47%). ESI-MS m/z calc. 457.1. found 458.5 (M+1)+; Retention time 2.43 minutes (3 min run).
Reaction SMILES: C([O:4][CH2:5][CH2:6][CH:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:37])[CH2:14][CH2:15][CH2:16][N:17]2[CH2:22][CH2:21][CH:20]([C:23]([OH:36])([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:19][CH2:18]2)=[CH:9][C:8]1([CH3:39])[CH3:38])(=O)C.[OH-].[Na+]>CO>[OH:36][C:23]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[CH:20]1[CH2:21][CH2:22][N:17]([CH2:16][CH2:15][CH2:14][C:13]([C:10]2[CH:11]=[CH:12][CH:7]([CH2:6][CH2:5][OH:4])[C:8]([CH3:39])([CH3:38])[CH:9]=2)=[O:37])[CH2:18][CH2:19]1
Reactant: CC(=O)OCCC1C=CC(C(=O)CCCN2CCC(C(O)(c3ccccc3)c3ccccc3)CC2)=CC1(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC1(C)C=C(C(=O)CCCN2CCC(C(O)(c3ccccc3)c3ccccc3)CC2)C=CC1CCO
Temperature: 68 °C

Procedure:
Dissolve 4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-oxobutyl]-2,2-dimethylphenethyl acetate (69.0 g, 0.131 mol) in methanol (2.5L) and add 10% aqueous sodium hydroxide (769 mL, 1.92 mol). Stir at reflux for 1.5 hours, cool to 68° C. and evaporate the solvent in vacuo to a residue (700 mL). Add chloroform (1L) and stir until solids are dissolved. Separate the organic phase and extract the aqueous phase with chloroform (3×300 mL). Combine the organic phases, dry (MgSO4) and evaporate the solvent in vacuo and recrystallize (toluene) to give the title compound as a cream-colored powder; mp 135°-137° C.