Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[N+:11]([O-:13])=[O:12])[N:4]([CH2:14][C:15]([O:17]CC)=O)[N:3]=1.[NH2:20][NH2:21]>CCO>[Br:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[N+:11]([O-:13])=[O:12])[N:4]([CH2:14][C:15]([NH:20][NH2:21])=[O:17])[N:3]=1
Reactant: CCOC(=O)Cn1nc(Br)c2c([N+](=O)[O-])cccc21
Reactant: NN
Solvent: CCO
Product: NNC(=O)Cn1nc(Br)c2c([N+](=O)[O-])cccc21
Temperature: 25 °C
Yield: 61.1 %

Procedure:
A solution of ethyl 2-(3-bromo-4-nitro-1H-indazol-1-yl)acetate (1.48 g, 4.51 mmol) in absolute EtOH (20 mL) was treated at ambient temperature with hydrazine (1.45 g, 45.1 mmol) and was heated at reflux for 16 hours under a nitrogen atmosphere. The reaction mixture was cooled to ambient temperature, and the precipitate was isolated by filtration. The solids were dried under vacuum to afford the product (0.865 g) as a tan powder.
Reaction SMILES: COC[O:4][C@H:5]1[CH2:18][C@H:17]2[C@@H:8]([C@@H:9]3[C@@H:14]([CH2:15][CH2:16]2)[CH2:13][C@@:12]2([CH3:24])[C@H:19]([C:22]#[N:23])[CH2:20][CH2:21][C@H:11]2[CH2:10]3)[CH2:7][CH2:6]1.COCO[C@H]1C[C@H]2[C@@H]([C@@H]3[C@@H](CC2)C[C@@]2(C)C(OS(C(F)(F)F)(=O)=O)=CC[C@@H]2C3)CC1.Cl>CO>[OH:4][C@H:5]1[CH2:18][C@H:17]2[C@@H:8]([C@@H:9]3[C@@H:14]([CH2:15][CH2:16]2)[CH2:13][C@@:12]2([CH3:24])[C@H:19]([C:22]#[N:23])[CH2:20][CH2:21][C@@H:11]2[CH2:10]3)[CH2:7][CH2:6]1
Reactant: COCO[C@@H]1CC[C@H]2[C@@H](CC[C@H]3C[C@]4(C)[C@@H](CC[C@H]4C#N)C[C@@H]32)C1
Agent: COCO[C@@H]1CC[C@H]2[C@@H](CC[C@H]3C[C@@]4(C)C(OS(=O)(=O)C(F)(F)F)=CC[C@@H]4C[C@@H]32)C1
Agent: Cl
Solvent: CO
Product: C[C@@]12C[C@@H]3CC[C@H]4C[C@H](O)CC[C@@H]4[C@H]3C[C@H]1CC[C@H]2C#N
Reaction time: 4 h

Procedure:
To a solution of compound 50 (250 mg containing the aromatic impurity carried over from compound 48) in methanol (30 mL) was added 6 N HCl (15 mL) at room temperature. After 4 h, the product was extracted into dichloromethane (50 mL×3), and the combined extracts were dried, filtered, and concentrated. The residue was purified by flash column chromatography (silica gel eluted with 25% EtOAc in hexanes) to give compound 51 (84 mg): mp. 163-165° C.; [α]D25 −33.9 (c 0.18, CHCl3); 1H NMR (CDCl3) δ 4.06-4.00 (m, 1H), 0.88 (s, 3H); 13C NMR (CDCl3) δ 121.4, 66.2, 48.4, 48.0, 47.0, 45.0, 44.2, 40.3, 39.8, 38.1, 36.0, 33.9, 33.8, 32.7, 28.4, 26.4 (2×C), 23.2, 14.2; IR νmax 3456, 2235 cm−1. Anal. Calcd for (C19H29NO): C, 79.39; H, 10.17. Found: C, 79.16; H, 10.14.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH3:9])[N:5]=[C:4]([N:10]2[CH2:15][CH2:14][CH:13]([C:16]([O:18]CC)=[O:17])[CH2:12][CH2:11]2)[N:3]=1.O.[OH-].[Li+].O.CO>O1CCCC1.C(OCC)(=O)C>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH3:9])[N:5]=[C:4]([N:10]2[CH2:15][CH2:14][CH:13]([C:16]([OH:18])=[O:17])[CH2:12][CH2:11]2)[N:3]=1
Reactant: CCOC(=O)C1CCN(c2nc(Cl)nc(NC)n2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: O
Product: CNc1nc(Cl)nc(N2CCC(C(=O)O)CC2)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.3 %

Procedure:
To a solution of ethyl 1-[4-chloro-6-(methylamino)-1,3,5-triazin-2-yl]-4-piperidinecarboxylate (983 mg, 3.28 mmol, 1.00 equiv) in tetrahydrofuran (21 ml) at 0° C., a premixed solution of lithium hydroxide monohydrate (275 mg, 6.56 mmol, 2.00 equiv) and water (7 ml) was added dropwise. Methanol (7 ml) was added. The reaction was allowed to warm to room temperature over 1 h and stirring was continued for 3 h. The solvent was removed under reduced pressure, yielding a colorless oil. Ethyl acetate was added to the oil, and the desired product precipitated as a white solid. The solid was filtered and dried under reduced pressure to provide 885 mg (99%) of the title compound. MS (ES+): m/e 272.0 [M+H]+.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[OH:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:19]([O:21][CH3:22])=[O:20])=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C>[N+:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[O:11][C:12]1[CH:13]=[CH:14][C:15]([CH2:18][C:19]([O:21][CH3:22])=[O:20])=[CH:16][CH:17]=1)([O-:10])=[O:9]
Reactant: COC(=O)Cc1ccc(O)cc1
Reactant: O=[N+]([O-])c1ccccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: COC(=O)Cc1ccc(Oc2ccccc2[N+](=O)[O-])cc1
Temperature: 140 °C
Reaction time: 1 h
Yield: 96.8 %

Procedure:
A mixture of 2-fluoronitrobenzene (1.1 g, 10 mmols), methyl p-hydroxyphenylacetate (1.7 g, 10 mmols) and potassium carbonate (1.4 g, 10 mmols) was stirred at 140° C. for 1 hour. The reaction mixture was diluted with ethyl acetate, then washed with water, and thereafter dried with anhydrous magnesium sulfate. This was concentrated under reduced pressure to give an oil of methyl 4-(2-nitrophenoxy)phenylacetate (2.78 g, 96.9%).
Reaction SMILES: [F:1][CH:2]([F:12])[C:3]1[CH:10]=[C:9](F)[CH:8]=[CH:7][C:4]=1[CH:5]=[O:6].[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.C([O-])([O-])=O.[K+].[K+]>CS(C)=O.O>[F:1][CH:2]([F:12])[C:3]1[CH:10]=[C:9]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[CH:8]=[CH:7][C:4]=1[CH:5]=[O:6]
Reactant: C1COCCN1
Reactant: O=Cc1ccc(F)cc1C(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: O=Cc1ccc(N2CCOCC2)cc1C(F)F
Temperature: 100 °C
Reaction time: 4 h
Yield: 51.6 %

Procedure:
A mixture containing 2-(difluoromethyl)-4-fluorobenzaldehyde (47; 3.50 g, 20.1 mmol), morpholine (48; 1.9 g, 22.1 mmol) and K2CO3 (5.5 g, 40.2 mmol) in 50 mL of DMSO was stirred at 100° C. for 4 h. The resulting reaction mixture was cooled to room temperature and diluted with water (200 mL). The precipitated solids were collected by filtration and dried to afford 2-(difluoromethyl)-4-morpholinobenzaldehyde 49 (2.5 g, 52%).
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][CH:12]=2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[NH2:48][C:49]1[S:50][CH:51]=[CH:52][N:53]=1>C(Cl)Cl>[CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][CH:12]=2)[C:8]([NH:48][C:49]2[S:50][CH:51]=[CH:52][N:53]=2)=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Nc1nccs1
Reactant: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)O)cc1
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)Nc2nccs2)cc1
Temperature: 25 °C
Reaction time: 19 h
Yield: 71.6 %

Procedure:
A solution of 3-cyclopentyl-2-(4-methanesulfonyl-phenyl)propionic acid (4.91 g, 16.56 mmol) and triphenylphosphine (6.52 g, 24.85 mmol) in methylene chloride (41 mL) was cooled to 0° C. and then treated with N-bromosuccinimide (5.01 g, 28.16 mmol) in small portions. The reaction mixture color changed from light yellow to a darker yellow then to brown. After the complete addition of N-bromosuccinimide, the reaction mixture was allowed to warm to 25° C. over 30 min. The brown reaction mixture was then treated with 2-aminothiazole (4.98 g, 49.69 mmol). The resulting reaction mixture was stirred at 25° C. for 19 h. The reaction mixture was then concentrated in vacuo to remove methylene chloride. The remaining black residue was diluted with a 10% aqueous hydrochloric acid solution (400 mL) and then extracted with ethyl acetate (3×200 mL). The combined organic layers were washed with a saturated aqueous sodium chloride solution (1×200 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70–230 mesh, 3/1 hexanes/ethyl acetate then 1/1 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(4-methanesulfonyl-phenyl)-N-thiazol-2-yl-propionamide (4.49 g, 72%) as a white solid: mp 216–217° C.; EI-HRMS m/e calcd for C18H22N2O3S2 (M+) 378.1072, found 378.1071.
Reaction SMILES: [CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([NH:15][C:16]4[CH:24]=[CH:23][C:19]([C:20]([OH:22])=O)=[CH:18][N:17]=4)[N:13]=[CH:14][C:9]=3[CH:8]=[C:7]2[C:25](=[O:29])[N:26]([CH3:28])[CH3:27])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:30]([O:34][C:35]([N:37]1[CH:42]2[CH2:43][CH2:44][CH:38]1[CH2:39][NH:40][CH2:41]2)=[O:36])([CH3:33])([CH3:32])[CH3:31]>>[C:30]([O:34][C:35]([N:37]1[CH:38]2[CH2:44][CH2:43][CH:42]1[CH2:41][N:40]([C:20]([C:19]1[CH:18]=[N:17][C:16]([NH:15][C:12]3[N:13]=[CH:14][C:9]4[CH:8]=[C:7]([C:25](=[O:29])[N:26]([CH3:27])[CH3:28])[N:6]([CH:1]5[CH2:5][CH2:4][CH2:3][CH2:2]5)[C:10]=4[N:11]=3)=[CH:24][CH:23]=1)=[O:22])[CH2:39]2)=[O:36])([CH3:33])([CH3:31])[CH3:32]
Reactant: CC(C)(C)OC(=O)N1C2CCC1CNC2
Reactant: CN(C)C(=O)c1cc2cnc(Nc3ccc(C(=O)O)cn3)nc2n1C1CCCC1
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(C(=O)N4CC5CCC(C4)N5C(=O)OC(C)(C)C)cn3)nc2n1C1CCCC1

Procedure:
Following general amide formation method 1, 6-(7-cyclopentyl-6-(dimethylcarbamoyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)nicotinic acid (400 mg, 1.01 mmol) was combined with 3,8-Diaza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (250 mg, 1.18 mmol. 1.1 eq) which yielded 3-[6-(7-Cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridine-3-carbonyl]-3,8-diaza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester after work up and was immediately used in next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([O:8][C:9]2[CH:31]=[N:30][C:12]3[N:13]([CH3:29])[C:14](=[O:28])[N:15]([CH2:18][CH2:19][CH2:20][O:21][CH:22]4[CH2:27][CH2:26][CH2:25][CH2:24][O:23]4)[C:16](=[O:17])[C:11]=3[CH:10]=2)[CH:5]=[N:6][CH:7]=1.[Li+].CC([N-]C(C)C)C.[Cl:40][C:41]1[CH:48]=[CH:47][C:44]([CH:45]=[O:46])=[CH:43][CH:42]=1>C1COCC1.CC(=O)OCC.O>[Cl:40][C:41]1[CH:48]=[CH:47][C:44]([CH:45]([OH:46])[C:10]2[C:11]3[C:16](=[O:17])[N:15]([CH2:18][CH2:19][CH2:20][O:21][CH:22]4[CH2:27][CH2:26][CH2:25][CH2:24][O:23]4)[C:14](=[O:28])[N:13]([CH3:29])[C:12]=3[N:30]=[CH:31][C:9]=2[O:8][C:4]2[CH:5]=[N:6][CH:7]=[C:2]([F:1])[CH:3]=2)=[CH:43][CH:42]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: Cn1c(=O)n(CCCOC2CCCCO2)c(=O)c2cc(Oc3cncc(F)c3)cnc21
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: Cn1c(=O)n(CCCOC2CCCCO2)c(=O)c2c(C(O)c3ccc(Cl)cc3)c(Oc3cncc(F)c3)cnc21
Temperature: -78 °C
Reaction time: 1 h
Yield: 25 %

Procedure:
To a solution of 6-((5-fluoropyridin-3-yl)oxy)-1-methyl-3-(3-((tetrahydro-2H-pyran-2-yl)oxy) propyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (150 mg, 0.35 mmol) in THF (8 mL) at −78° C. was added LDA (2M in THF, 0.7 mL, 1.40 mmol) dropwise. The reaction was stirred at −78° C. for 1 h then 4-chlorobenzaldehyde (98 mg, 0.70 mmol) in THF (2 mL) was added. The reaction was stirred for 30 min at −78° C. then diluted with EA (10 mL) and water (10 mL). The organic layer was dried over Na2SO4 and concentrated to a residue which was purified by Prep TLC eluted with PE/EA (1:1) to give 5-((4-chlorophenyl)(hydroxy)methyl)-6-((5-fluoropyridin-3-yl)oxy)-1-methyl-3-(3-((tetrahydro-2H-pyran-2-yl)oxy)propyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (50 mg, 25.1% yield) as an oil. LCMS: [MH+-THP] 487 and TR=1.423 min. Used without further purification.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[CH2:3][CH2:4][C:5](O)=[O:6].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[C:43]1([CH3:59])[CH:48]=[CH:47][C:46]([C:49]2[O:50][C:51]3[CH:57]=[CH:56][C:55]([NH2:58])=[CH:54][C:52]=3[N:53]=2)=[CH:45][CH:44]=1>CN(C)C=O.C(OCC)(=O)C>[F:1][C:2]([F:9])([F:8])[CH2:3][CH2:4][C:5]([NH:58][C:55]1[CH:56]=[CH:57][C:51]2[O:50][C:49]([C:46]3[CH:47]=[CH:48][C:43]([CH3:59])=[CH:44][CH:45]=3)=[N:53][C:52]=2[CH:54]=1)=[O:6]
Reactant: O=C(O)CCC(F)(F)F
Reactant: Cc1ccc(-c2nc3cc(N)ccc3o2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1ccc(-c2nc3cc(NC(=O)CCC(F)(F)F)ccc3o2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 8.5 %

Procedure:
To 4,4,4-trifluorobutanoic acid (128 mg, 0.90 mmol) in dry dimethylformamide (5 mL) was added HATU (397 mg, 1.05 mmol) and diisopropylethylamine (494 μL, 2.85 mmol). The mixture was then stirred at room temperature for 10 min. 2-p-Tolylbenzo[d]oxazol-5-amine (200 mg, 0.95 mmol) was then added and the resulting mixture was stirred at room temperature for 16 h. Ethyl acetate was added and the organic layer was washed once with saturated aqueous Na2CO3, followed by another wash with brine. The combined organic layers were dried over anhydrous MgSO4 and evaporated. The resulting solid was purified by column chromatography eluting with ethyl acetate/hexanes 40:60 v/v to afford 26.7 mg (8%) of the title compound (LCMS RT=6.77 min, MH+ 348.9)
Reaction SMILES: [F:1][CH:2]([C:8]([O:10]CC)=[O:9])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[OH-].[K+]>C(O)C>[CH2:6]([O:5][C:3](=[O:4])[CH:2]([F:1])[C:8]([OH:10])=[O:9])[CH3:7]
Reactant: CCOC(=O)C(F)C(=O)OCC
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)C(F)C(=O)O
Temperature: 25 °C
Reaction time: 14 h
Yield: 114.1 %

Procedure:
Diethyl fluoromalonate (15.0 g, 84.19 mmol) was suspended in ethanol (50 ml), a solution of potassium hydroxide (5.56 g, 84.19 mmol) in ethanol (50 ml) was added dropwise under cooling on ice and the mixture was stirred at room temperature for 14 hours. The solvent was removed under reduced pressure, the residue was dissolved in water and acidified by adding a 6N hydrochloric acid aqueous solution under cooling on ice. The mixture was extracted with diethyl ether and the extract was dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to yield 14.42 g of a crude product of the title compound in the form of a colorless clear oily product.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.[C:14]1([O:24][CH2:25][CH:26]2[O:28][CH2:27]2)[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1.Cl>C(O)(C)C>[OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:13][CH2:12][N:11]([CH2:27][CH:26]([OH:28])[CH2:25][O:24][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=[CH:16][CH:15]=2)[CH2:10][CH2:9]1
Reactant: c1ccc2c(OCC3CO3)cccc2c1
Reactant: Oc1ccccc1N1CCNCC1
Agent: Cl
Solvent: CC(C)O
Product: Oc1ccccc1N1CCN(CC(O)COc2cccc3ccccc23)CC1

Procedure:
4.56 g. (0.025 mole) 1-(2-hydroxyphenyl)-piperazine and 5.6 g. (0.028 mole) 2,3-epoxypropyl naphthyl ether are dissolved in 50 ml. isopropanol and the solution obtained is heated under reflux for 5 hours, while stirring. Thereafter, the reaction mixture is diluted with a further 50 ml. isopropanol and acidified isopropanolic hydrochloric acid. A voluminous product precipitates out which is filtered off with suction, washed several times with isopropanol and recrystallised from methanol. Yield 8.8 g. (77% of theory); m.p. 249°-250° C.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:16](=[N:30][OH:31])[CH2:17][O:18][C:19]2[CH:28]=[CH:27][C:22]([C:23]([O:25]C)=[O:24])=[C:21]([OH:29])[CH:20]=2)[CH:8]=[CH:9][C:10]=1[N:11]([CH2:14][CH3:15])[CH2:12][CH3:13])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>>[C:1]([C:5]1[CH:6]=[C:7]([C:16](=[N:30][OH:31])[CH2:17][O:18][C:19]2[CH:28]=[CH:27][C:22]([C:23]([OH:25])=[O:24])=[C:21]([OH:29])[CH:20]=2)[CH:8]=[CH:9][C:10]=1[N:11]([CH2:14][CH3:15])[CH2:12][CH3:13])([CH3:3])([CH3:4])[CH3:2]
Reactant: CCN(CC)c1ccc(C(COc2ccc(C(=O)OC)c(O)c2)=NO)cc1C(C)(C)C
Agent: [Na+]
Agent: [OH-]
Product: CCN(CC)c1ccc(C(COc2ccc(C(=O)O)c(O)c2)=NO)cc1C(C)(C)C

Procedure:
In a manner similar to that of Example 1.g, by reaction of 120 mg (0.3 mmol) of methyl 4-[2-(3-tert-butyl-4-diethylaminophenyl)-2-hydroxyiminoethoxy]-2-hydroxybenzoate with 46 mg (1.4 mmol) of powdered sodium hydroxide. The final product is then recrystallized from a heptane/ethyl ether system. A white crystalline solid is obtained (m.p.=210° C., m=60 mg, yield=48%); (1H NMR (DMSO): 0.96-1.00 (t, 6H); 1.38 (s, 9H); 2.7-3 (m, 4H); 5.26 (s, 2H); 6.46-6.49 (dd, J=6.4 Hz, J′=2.4 Hz, 1H); 6.55 (d, J=2.4 Hz, 1H); 7.26-7.28 (d, J=8.3 Hz, 1H); 7.46-7.48 (dd, J=6.2 Hz, J′=2.03 Hz,1H); 7.65-7.67 (d, J=8.8 Hz, 1H); 7.69 (d, J=2.03 Hz, 1H); 11.9 (s, 1H); 13-14 (s, 1H)).
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[F:23][C:24]([F:41])([F:40])[C:25]1[N:30]=[C:29]([N:31]2[CH2:35][C@@H:34]3[C@H:36]([OH:39])[CH2:37][CH2:38][C@@H:33]3[CH2:32]2)[CH:28]=[CH:27][CH:26]=1>ClCCl>[F:41][C:24]([F:23])([F:40])[C:25]1[N:30]=[C:29]([N:31]2[CH2:35][C@@H:34]3[C:36](=[O:39])[CH2:37][CH2:38][C@@H:33]3[CH2:32]2)[CH:28]=[CH:27][CH:26]=1
Reactant: O[C@@H]1CC[C@@H]2CN(c3cccc(C(F)(F)F)n3)C[C@@H]21
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: O=C1CC[C@@H]2CN(c3cccc(C(F)(F)F)n3)C[C@H]12
Reaction time: 7 h

Procedure:
Dess-Martin periodinane (2.181 g, 5.14 mmol) was added to a solution of (3aR,4R,6aS)-2-[6-(trifluoromethyl)pyridin-2-yl]octahydrocyclopenta[c]pyrrol-4-ol (1 g, 3.67 mmol) from Example 30 in dichloromethane (24.49 mL). The mixture was stirred for 7 hours and then quenched with 1 N sodium thiosulfate (18 mL) and saturated NaHCO3 solution (12 mL). The mixture was stirred for 1 hour. The organic layer was separated, and concentrated. The crude product was purified by silica gel chromatography using 100% dichloromethane as eluent to give the title compound: 1H NMR (500 MHz, pyridine-d5) δ ppm 7.51 (t, J=7.9, 1H), 6.99 (d, J=7.3, 1H), 6.48 (d, J=8.6, 1H), 3.84 (dd, J=10.7, 2.8, 1H), 3.65 (dd, J=10.9, 8.6, 1H), 3.52 (dd, J=10.6, 8.7, 1H), 3.17 (dd, J=11.1, 6.3, 1H), 3.00-2.89 (m, 1H), 2.83 (td, J=8.4, 2.9, 1H), 2.39-2.21 (m, 2H), 1.96 (dtd, J=13.4, 8.9, 6.9, 1H), 1.75-1.62 (m, 1H); MS (ESI+) m/z 271 (M+H)+.
Reaction SMILES: CN([CH2:4][C:5]1[CH:10]=[C:9]([CH3:11])[C:8]([OH:12])=[C:7]([CH3:13])[CH:6]=1)C.[CH2:14]=[CH:15][CH:16]=[CH2:17]>C1(C)C=CC=CC=1>[CH3:13][C:7]1[C:8](=[O:12])[C:9]([CH3:11])=[CH:10][C:5]2([CH2:17][CH2:16][CH:15]=[CH:14][CH2:4]2)[CH:6]=1
Reactant: C=CC=C
Reactant: Cc1cc(CN(C)C)cc(C)c1O
Solvent: Cc1ccccc1
Product: CC1=CC2(C=C(C)C1=O)CC=CCC2
Yield: 78 %

Procedure:
Following the same general procedure as in Example I, 5 mmols of N,N-dimethyl-4-aminomethyl-2,6-dimethylphenol were reacted with 20 mmols of 1,3-butadiene in 40 g of toluene at 189°-205° C. for six hours. GC analysis showed a 78% yield of 2,4-dimethylspiro[5.5]undeca-1,4,8-trien-3-one.
Reaction SMILES: [C:1]([S:14]([NH:17][CH3:18])(=[O:16])=[O:15])([C:4]([C:7]([C:10]([F:13])([F:12])[F:11])([F:9])[F:8])([F:6])[F:5])([F:3])[F:2].[CH2:19]([CH:21]1[O:23][CH2:22]1)Cl>>[CH3:18][N:17]([CH2:19][CH:21]1[CH2:22][O:23]1)[S:14]([C:1]([F:3])([F:2])[C:4]([F:6])([F:5])[C:7]([F:9])([F:8])[C:10]([F:13])([F:11])[F:12])(=[O:15])=[O:16]
Reactant: ClCC1CO1
Reactant: CNS(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Product: CN(CC1CO1)S(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 64 °C
Yield: 42 %

Procedure:
A mixture of C4F9SO2NHCH3 (313 g, 1.00 mol), generally made as described in U.S. Pat. No. 6,664,354, Example 1, Part A, and sodium methoxide (216 g of a 25% solution in methanol) was concentrated to a solid, which was dissolved in dry THF (500 mL). Epichlorohydrin (120.2 g, 1.3 mol) was rapidly added to the resulting solution, and the mixture was stirred at reflux (64° C.) for 20 hours. The cooled mixture was washed with about 1 L of water, and dichloromethane was used to help transfer the organic fraction. The organic fraction was dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by one-plate distillation [bp 90° C./0.06 mmHg (8 Pa)] to provide 155.2 g of N-methyl-N-(oxiran-2-ylmethyl)perfluorobutane-1-sulfonamide, which was 98% pure by GLC.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH:8]([CH3:18])[CH2:9][C:10]1[O:14][N:13]=[C:12]([C:15]([OH:17])=O)[CH:11]=1.[NH2:19][C@@H:20]([CH3:36])[CH2:21][N:22]1[CH:26]=[CH:25][C:24]([C:27]2[CH:34]=[CH:33][C:30]([C:31]#[N:32])=[C:29]([Cl:35])[CH:28]=2)=[N:23]1>>[Cl:35][C:29]1[CH:28]=[C:27]([C:24]2[CH:25]=[CH:26][N:22]([CH2:21][C@@H:20]([NH:19][C:15]([C:12]3[CH:11]=[C:10]([CH2:9][CH:8]([O:7][CH:2]4[CH2:3][CH2:4][CH2:5][CH2:6][O:1]4)[CH3:18])[O:14][N:13]=3)=[O:17])[CH3:36])[N:23]=2)[CH:34]=[CH:33][C:30]=1[C:31]#[N:32]
Reactant: CC(Cc1cc(C(=O)O)no1)OC1CCCCO1
Reactant: C[C@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Product: CC(Cc1cc(C(=O)N[C@@H](C)Cn2ccc(-c3ccc(C#N)c(Cl)c3)n2)no1)OC1CCCCO1

Procedure:
The title compound was prepared using the method of Example 34(d) starting from 5-(2-(tetrahydro-2H-pyran-2-yloxy)propyl)isoxazole-3-carboxylic acid (0.392 g, 1.534 mmol) and (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (0.2 g, 0.767 mmol). The product was purified by reverse phase flash chromatography. LC-MS: [M+1]=498.97.
Reaction SMILES: [Cl:1][C:2]1[C:7]([S:8]([N:11]([O:13][CH3:14])[CH3:12])(=[O:10])=[O:9])=[C:6]([OH:15])[C:5]([NH:16][C:17]2[C:20](=[O:21])[C:19](=[O:22])[C:18]=2OCC)=[CH:4][CH:3]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH3:37][C@H:38]1[O:42][C@@H:41]([C@H:43]([NH2:46])[CH2:44][CH3:45])[CH2:40][CH2:39]1>CC#N.CCO>[Cl:1][C:2]1[C:7]([S:8]([N:11]([O:13][CH3:14])[CH3:12])(=[O:9])=[O:10])=[C:6]([OH:15])[C:5]([NH:16][C:17]2[C:20](=[O:21])[C:19](=[O:22])[C:18]=2[NH:46][C@@H:43]([C@H:41]2[CH2:40][CH2:39][C@@H:38]([CH3:37])[O:42]2)[CH2:44][CH3:45])=[CH:4][CH:3]=1
Reactant: CC[C@@H](N)[C@H]1CC[C@@H](C)O1
Reactant: CCOc1c(Nc2ccc(Cl)c(S(=O)(=O)N(C)OC)c2O)c(=O)c1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC#N
Solvent: CCO
Product: CC[C@@H](Nc1c(Nc2ccc(Cl)c(S(=O)(=O)N(C)OC)c2O)c(=O)c1=O)[C@H]1CC[C@@H](C)O1
Temperature: 50 °C
Reaction time: 20 h

Procedure:
To a stirred suspension of 6-chloro-3-(2-ethoxy-3,4-dioxo-cyclobut-1-enylamino)-2-hydroxy-N-methoxy-N-methyl-benzenesulfonamide (Intermediate A) (7 g, 17.91 mmol) in MeCN (2 ml) and EtOH (1 ml) under N2 at RT was added ((R)-1-((2R,5R)-5-methyl-tetrahydro-furan-2-yl)-propylamine para-toluenesulfonate salt (Intermediate E) (5.67 g, 17.91 mmol) and TEA (0.999 ml, 7.16 mmol) and the reaction mixture was heated at 50° C. for 16 hours. Further TEA was added (2.48 ml, 17.91 mmol) and the reaction was heated at 50° C. for 1 hour then 60° C. for 20 hours. Further TEA (2.48 ml, 17.91 mmol) and Intermediate E (1.13 g, 3.58 mmol) was added and the reaction was heated at 60° C. for 17.5 hours. The reaction mixture was concentrated in vacuo and partitioned between EtOAc and 1M HCl (aq). The aqueous layer was adjusted to pH 5 using 2M NaOH (aq) and extracted using EtOAc. The EtOAc layers were combined and washed with saturated sodium bicarbonate (aq), water and brine. The organic layer was dried (MgSO4) and concentrated in vacuo. The resulting residue was recrystallised from toluene to give a light brown solid; [M+H]+ 488.2. 1H NMR (DMSO) 0.9 (3H, t, CH3), 1.2 (3H, d, CH3), 1.3 (1H, m) 1.6 (3H, m) 1.9 (2H, m) 3.6 (3H, s, CH3), 3.6 (3H, s, CH3), 3.9 (2H, m) 4.0 (1H, m), 7.2 (1H, d), 8.1 (1H, d), 8.2 (1H, d), 9.5 (1H, s), 10.1 (1H, s).
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[O:6][C:5](=[CH:7][C:8](Cl)=[O:9])[C:4](=[O:11])[O:3]1.[CH2:13]([NH:20][O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH2:13]([N:20]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:8](=[O:9])[CH:7]=[C:5]1[C:4](=[O:11])[O:3][C:2]([CH3:12])([CH3:1])[O:6]1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: c1ccc(CNOCc2ccccc2)cc1
Reactant: CC1(C)OC(=O)C(=CC(=O)Cl)O1
Product: CC1(C)OC(=O)C(=CC(=O)N(Cc2ccccc2)OCc2ccccc2)O1
Yield: 92 %

Procedure:
Reaction of (2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-acetyl chloride with N,O-dibenzyl-hydroxylamine (Bhat, J. I., Clegg, W.; Maskill, H.; Elsegood, M. R. J.; Menner, I. D.; Miatt, P. C. J. Chem. Soc. Perkin Trans. 2, 2000, 1435-1446) as described in the preparation of compound 1-A gave the title amide as white crystals (92% yield): mp 107-108° C. (ethyl acetate-hexane). 1HNMR 400 MHz (CDCl3) δ (ppm): 1.72 (6H, s), 4.76 (2H, s), 4.84 (2H, s), 6.36 (1H, s), 7.28-7.38 (10H, m). HRMS (MAB N2) calculated for C21H21NO5[M+]: 367.141973: Found: 367.140292.