Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1([CH3:9])[CH2:7][CH2:6][CH2:5][NH:4][C:3]1=[O:8].[Na].[O:11]=[C:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[S:14](=[O:22])(=[O:21])[NH:13]1.O>CN(C)C=O>[O:21]=[S:14]1(=[O:22])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:12](=[O:11])[N:13]1[C:2]1([CH3:9])[CH2:7][CH2:6][CH2:5][NH:4][C:3]1=[O:8]
Reactant: O=C1NS(=O)(=O)c2ccccc21
Reactant: CC1(Br)CCCNC1=O
Agent: [Na]
Solvent: CN(C)C=O
Solvent: O
Product: CC1(N2C(=O)c3ccccc3S2(=O)=O)CCCNC1=O
Reaction time: 0.5 h
Yield: 24 %

Procedure:
6.8 g of 3-bromo-3-methyl-2-piperidone and 8 g of the dried sodium salt of 2,3-dihydro-3-oxo-1,2-benzisothiazol-1,1-dioxide are heated while stirring to 110°-115° in 25 ml of distilled dimethyl formamide for a period of 75 minutes. After cooling 75 ml of water are added and the stirring is continued for further 30 minutes. The precipitate is filtered off, washed with water, dried in a vacuum at 80° C. and then recrystallized from n-butanol. 3-(2,3-Dihydro-1,1-dioxido-3-oxo-1,2-benzisothiazol-2-yl)-3-methyl-2-oxo-piperidine melting at 211° to 215° C. is thus obtained in a yield of 24% of the theoretical.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:26])[CH2:6][CH2:7][NH:8][C:9]([C:11]1[C:12]([C:22]([F:25])([F:24])[F:23])=[N:13][N:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:15]=1)=[O:10]>C1COCC1.CO.O>[C:16]1([N:14]2[CH:15]=[C:11]([C:9]([NH:8][CH2:7][CH2:6][C:5]([OH:26])=[O:4])=[O:10])[C:12]([C:22]([F:24])([F:25])[F:23])=[N:13]2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: COC(=O)CCNC(=O)c1cn(-c2ccccc2)nc1C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C(O)CCNC(=O)c1cn(-c2ccccc2)nc1C(F)(F)F
Temperature: 25 °C
Reaction time: 5 h
Yield: 98 %

Procedure:
NaOH (212.1 mg, 5.3 mmol) was added to 3-[(1-phenyl-3-trifluoromethyl-1H-pyrazole-4-carbonyl)amino]propionic acid methyl ester (181 mg, 0.53 mmol) dissolved in THF/MeOH/water (25 mL, 4:2:1). The reaction mixture was stirred at 25° C. for 5 hours and concentrated under vacuum. The residue was acidified with 1M HCl up to pH 2 and extracted with ethyl acetate. The extract was washed with brine and dried with anhydrous sodium sulfate and concentrated under vacuum to obtain the desired compound (170 mg, 98%) as a white solid.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][CH2:10][C:9]([F:13])([F:12])[CH2:8][CH2:7]1)=O)C.[AlH4-].[Li+].O.[OH-].[Na+]>C1COCC1>[F:12][C:9]1([F:13])[CH2:10][CH2:11][CH:6]([CH2:4][OH:3])[CH2:7][CH2:8]1
Reactant: CCOC(=O)C1CCC(F)(F)CC1
Agent: [AlH4-]
Agent: [Li+]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: OCC1CCC(F)(F)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 100.8 %

Procedure:
To a reaction mixture of 4,4-difluorocyclohexanecarboxylic acid ethyl ester (7.1 g, 37 mmol) in THF (50 mL) cooled to 0° C. was added dropwise 2.0 M lithium tetrahydroaluminate in THF (18.5 mL) over 10 min. The reaction mixture was stirred at 0° C. for 1 h. Water (5 mL) was added dropwise, followed by 1.0N NaOH (5 mL). The reaction mixture was filtered through Celite, THF was evaporated, and the resulting aqueous solution was diluted with brine (50 mL) and extracted with ethyl acetate (50 mL). The organic layer was collected, dried over anhydrous sodium sulfate, filtered, and concentrated to give the title compound as a clear oil (5.6 g) which was used without further purification.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[N:9]=[CH:8][C:7]([CH2:10][CH:11]([C:17]2[N:18]=[CH:19][NH:20][CH:21]=2)[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:6][CH:5]=1.Br[CH2:23][C:24]#[C:25][CH3:26].O>CN(C=O)C>[NH2:3][C:4]1[N:9]=[CH:8][C:7]([CH2:10][CH:11]([C:17]2[N:18]=[CH:19][N:20]([CH2:23][C:24]#[C:25][CH3:26])[CH:21]=2)[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:6][CH:5]=1
Reactant: CC#CCBr
Reactant: CCOC(=O)C(Cc1ccc(N)nc1)c1c[nH]cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC#CCn1cnc(C(Cc2ccc(N)nc2)C(=O)OCC)c1
Reaction time: 1 h
Yield: 39 %

Procedure:
11 mg (0.23 mmol, 50%) of sodium hydride were added to a solution of 60 mg (0.23 mmol) of ethyl 3-(6-aminopyridin-3-yl)-2-(1H-imidazol-4-yl)propionate (example 1g) in 0.5 ml of DMF at RT and stirred for 1 h. Then 31 mg (37 μl, 0.23 mmol) of 1-bromo-2-butine were added, and the mixture was stirred at RT for 1 h. 1 ml of water was then added and the mixture was extracted with EA. The organic phase was dried over Na2SO4, filtered and concentrated. Chromatography of the residue on silica gel afforded 28 mg of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:15][C:16]2[N:21]=[C:20]([CH:22]=[O:23])[CH:19]=[C:18]([CH2:24][O:25][CH2:26][C:27]([F:30])([F:29])[F:28])[N:17]=2)[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1.C(=O)([O-])[O-].[K+].[K+].[F:37][C:38]([Si](C)(C)C)([F:40])[F:39]>CN(C=O)C>[F:37][C:38]([F:40])([F:39])[CH:22]([C:20]1[CH:19]=[C:18]([CH2:24][O:25][CH2:26][C:27]([F:29])([F:30])[F:28])[N:17]=[C:16]([NH:15][C:5]2[CH:6]=[CH:7][C:8]([N:9]3[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]3)=[C:3]([O:2][CH3:1])[CH:4]=2)[N:21]=1)[OH:23]
Reactant: COc1cc(Nc2nc(C=O)cc(COCC(F)(F)F)n2)ccc1-n1cnc(C)c1
Reactant: C[Si](C)(C)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(Nc2nc(COCC(F)(F)F)cc(C(O)C(F)(F)F)n2)ccc1-n1cnc(C)c1
Reaction time: 0.5 h
Yield: 10.2 %

Procedure:
Molecular sieves were added to a solution of 2-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenylamino)-6-((2,2,2-trifluoroethoxy)methyl)pyrimidine-4-carbaldehyde (60 mg, 0.14 mmol) in dry DMF (1 mL) under argon atmosphere. The mixture was stirred for 30 minutes. Potassium carbonate (2 mg, 0.01 mmol) and (trifluoromethyl)trimethylsilane (0.427 mL, 0.21 mmol) were added. The mixture was stirred at ambient temperature for 2 days. The mixture was filtered and purified by preparative HPLC to yield the title compound (7 mg, 10%).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C@H:6]2[C@H:14]([CH3:15])[O:13][C:12](=[O:16])[C@@H:11]([NH:17][C:18](=[O:28])[C:19]3[C:24]([OH:25])=[C:23]([O:26][CH3:27])[CH:22]=[CH:21][N:20]=3)[CH2:10][CH2:9][CH2:8][C@@H:7]2[CH2:29][C:30]2[CH:35]=[CH:34][C:33](F)=[CH:32][CH:31]=2)[CH2:3][CH2:2]1>C1COCC1.[Rh]>[CH:30]1([CH2:29][C@@H:7]2[C@@H:6]([O:5][CH2:4][CH:1]3[CH2:2][CH2:3]3)[C@H:14]([CH3:15])[O:13][C:12](=[O:16])[C@@H:11]([NH:17][C:18](=[O:28])[C:19]3[C:24]([OH:25])=[C:23]([O:26][CH3:27])[CH:22]=[CH:21][N:20]=3)[CH2:10][CH2:9][CH2:8]2)[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: COc1ccnc(C(=O)N[C@H]2CCC[C@H](Cc3ccc(F)cc3)[C@@H](OCC3CC3)[C@H](C)OC2=O)c1O
Agent: [Rh]
Solvent: C1CCOC1
Product: COc1ccnc(C(=O)N[C@H]2CCC[C@H](CC3CCCCC3)[C@@H](OCC3CC3)[C@H](C)OC2=O)c1O
Temperature: 70 °C
Reaction time: 29 h
Yield: 27.1 %

Procedure:
A high pressure reactor equipped with a stir bar was charged with a solution of N-((3S,7R,8R,9S)-8-(cyclopropylmethoxy)-7-(4-fluorobenzyl)-9-methyl-2-oxooxonan-3-yl)-3-hydroxy-4-methoxypicolinamide (230 mg, 0.459 mmol) in THF (7 mL) and 5% rhodium on carbon (56.8 mg, 0.028 mmol). After the reactor was sealed and purged with H2 (4×), the reaction was charged to ˜600 psi of H2 at room temperature. The reactor was warmed to 70° C. and stirred for 29 h, cooled to room temperature, and the reaction mixture was filtered through a Celite® pad. The filtrate was concentrated and purified by column chromatography on SiO2 (gradient, hexanes/ethyl acetate) to furnish the title product as a white solid (60.8 mg, 27%): 1H NMR (400 MHz, CDCl3) δ 12.11 (d, J=0.6 Hz, 1H), 8.49 (d, J=8.2 Hz, 1H), 7.99 (d, J=5.2 Hz, 1H), 6.87 (d, J=5.2 Hz, 1H), 4.95-4.84 (m, 1H), 4.55 (ddd, J=10.7, 8.2, 7.0 Hz, 1H), 3.94 (s, 3H), 3.49 (dd, J=9.6, 7.0 Hz, 1H), 3.37 (dd, J=9.6, 6.8 Hz, 1H), 3.01 (t, J=8.8 Hz, 1H), 2.39-2.28 (m, 1H), 1.78-1.46 (m, 10H), 1.45 (d, J=7.0 Hz, 3H), 1.41-0.71 (m, 10H), 0.59-0.52 (m, 2H), 0.26-0.18 (m, 2H); 13C NMR (101 MHz, CDCl3) δ 172.21, 168.62, 155.31, 148.69, 140.51, 130.42, 109.44, 84.33, 78.51, 75.66, 56.05, 51.49, 40.09, 38.30, 35.05, 34.59, 33.63, 32.34, 27.44, 26.68, 26.48, 26.15, 18.77, 18.10, 11.14, 3.16, 2.94; ESIMS m/z 489.3 ([M+H]+).
Reaction SMILES: CC(O)=O.[C:5]1([CH2:11][S:12][CH2:13][C@@H:14]([CH2:25][CH3:26])[C:15]([O:17]CC2C=CC=CC=2)=[O:16])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>Br.O>[C:5]1([CH2:11][S:12][CH2:13][C@@H:14]([CH2:25][CH3:26])[C:15]([OH:17])=[O:16])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CC[C@H](CSCc1ccccc1)C(=O)OCc1ccccc1
Agent: Br
Solvent: CC(=O)O
Solvent: O
Product: CC[C@H](CSCc1ccccc1)C(=O)O
Temperature: 70 °C
Reaction time: 8 h
Yield: 76.2 %

Procedure:
Glacial HOAc (120 ml) was added to a suspension of the product of step 8 (32.4 g, approx. 103 mmol) in 210 ml of 30-32% anhydrous HBr in glacial HOAc (approx. 1.03 mol) to complete the dissolution. The resulting solution was stirred at 70° C. for 6 h and at 50° overnight. The reaction mixture was then cooled to r.t., diluted with H2O (750 mL) and extracted with CH2Cl2 (7×). The combined organic extracts were concentrated in vacuo. The residue was diluted with toluene (500 mL) and concentrated in vacuo 5 times to remove HOAc. The residue was dissolved in 1M aq KOH (750 mL), washed with CH2Cl2 (4×), acidified to pH 1 with concentrated HCl and extracted with CH2Cl2 (6×). The combined organic extracts were dried over Na2SO4 and concentrated in vacuo to afford 17.6 g of the title compound as a pale yellow liquid which was used as such for the next step.
Reaction SMILES: [C:1]([Si:5]([CH3:28])([CH3:27])[O:6][C:7]1[C:8]([O:25][CH3:26])=[C:9]([CH:15]([C:17]2[C:18]([Cl:24])=[N:19][C:20]([Cl:23])=[N:21][CH:22]=2)[OH:16])[C:10]([F:14])=[C:11]([F:13])[CH:12]=1)([CH3:4])([CH3:3])[CH3:2].C(=O)(O)[O-].[Na+].Cl[O-].[Na+].C(OCC)(=O)C>C(Cl)Cl.O.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.CC1(C)N([O])C(C)(C)CCC1>[C:1]([Si:5]([CH3:28])([CH3:27])[O:6][C:7]1[C:8]([O:25][CH3:26])=[C:9]([C:15]([C:17]2[C:18]([Cl:24])=[N:19][C:20]([Cl:23])=[N:21][CH:22]=2)=[O:16])[C:10]([F:14])=[C:11]([F:13])[CH:12]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1c(O[Si](C)(C)C(C)(C)C)cc(F)c(F)c1C(O)c1cnc(Cl)nc1Cl
Agent: CC1(C)CCCC(C)(C)N1[O]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: O
Solvent: CCOC(C)=O
Product: COc1c(O[Si](C)(C)C(C)(C)C)cc(F)c(F)c1C(=O)c1cnc(Cl)nc1Cl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 95.7 %

Procedure:
To a solution of [3-(tert-butyl-dimethyl-silanyloxy)-5,6-difluoro-2-methoxy-phenyl]-(2,4-dichloro-pyrimidin-5-yl)-methanol (955 mg, 2.116 mmol, Example 267) in methylene chloride (6 mL) and water (1 mL) were added sodium bicarbonate (80 mg, 0.952 mmol), tetrabutylammonium bromide (21 mg, 0.0635 mmol), TEMPO (3.3 mg, 0.0212 mmol, Aldrich). The mixture was cooled to 0° C. and sodium hypochlorite (2.548 mL, 2.539 mmol, Clorox™) was added. The reaction mixture was stirred at 0° C. for 30 minutes and more sodium hypochlorite (0.5 mL) was added. Thin layer chromatography (silica gel, 10% ethyl acetate in hexanes) still showed the alcohol starting material. More sodium hypochlorite (3×0.5 mL) was added until no alcohol was seen. The reaction mixture was diluted with methylene chloride (30 mL) and water (20 mL). The layers were separated, and the organic phase was washed with water (2×10 mL), brine (1×10 mL) and dried over anhydrous magnesium sulfate. The solids were filtered off and the filtrate was concentrated in vacuo to give [3-(tert-butyl-dimethyl-silanyloxy)-5,6-difluoro-2-methoxy-phenyl]-(2,4-dichloro-pyrimidin-5-yl)-methanone as pale yellow oil (910 mg, 96%). The crude product was used without further purification.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH:15]2[O:20][CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16]2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([N:8]1[CH2:9][CH2:10][N:11]([CH2:14][CH:15]2[O:20][CH2:19][CH2:18][NH:17][CH2:16]2)[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCOC(CN2CCN(Cc3ccccc3)CC2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: c1ccc(CN2CCN(CC3CNCCO3)CC2)cc1
Yield: 225 %

Procedure:
To a solution of tert-butyl 2-((4-benzylpiperazin-1-yl)methyl)morpholine-4-carboxylate (600 mg) in CH2Cl2 (10 ml) is added trifluoroacetic acid (1.8 ml), and the mixture is stirred over night. The solvent is removed under reduced pressure to give 2-((4-benzylpiperazin-1-yl)methyl)morpholine*3 TFA (990 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([S:12](=[O:15])(=[O:14])[NH2:13])=[CH:7][C:3]=1[C:4](O)=[O:5].B.C1COCC1>C1COCC1>[Cl:1][C:2]1[C:3]([CH2:4][OH:5])=[CH:7][C:8]([S:12]([NH2:13])(=[O:14])=[O:15])=[C:9]([F:11])[CH:10]=1
Reactant: NS(=O)(=O)c1cc(C(=O)O)c(Cl)cc1F
Agent: B
Solvent: C1CCOC1
Product: NS(=O)(=O)c1cc(CO)c(Cl)cc1F
Reaction time: 12 h
Yield: 62.7 %

Procedure:
To a solution of 2-chloro-4-fluoro-5-sulfamoylbenzoic acid (3.2 g, 12.65 mmol) in THF (10 mL) was added 1M BH3.THF (38 mL, 38.0 mmol). After stirring 12 h, the reaction mixture was quenched with MeOH and concentrated in vacuo. The residue was purified by chromatography (silica, EtOAc-Hex) to afford 4-chloro-2-fluoro-5-(hydroxymethyl)benzenesulfonamide (1.9 g). To a suspension of 4-chloro-2-fluoro-5-(hydroxymethyl)benzenesulfonamide (1.78 g, 7.43 mmol) in DCM (10 mL) was added PBr3 (2.21 g, 8.17 mmol). The reaction was stirred for 24 h when it was determined to be complete by GCMS. The reaction was carefully quenched with H2O and then partitioned between THF and brine. The organic layer was dried over Na2SO4 and concentrated in vacuo to afford 5-(bromomethyl)-4-chloro-2-fluorobenzenesulfonamide (1.98 g) as an off-white solid. 1H-NMR (DMSO-d6, 400 MHz) δ 8.08 (d, J=7.8 Hz, 1H), 7.84 (s, 2H), 7.80 (d, J=9.9 Hz, 1H), 4.83 (s, 2H).
Reaction SMILES: [C:1]([C:5]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:15]=2[F:21])[N:9]=1)=[O:6])([CH3:4])([CH3:3])[CH3:2].[Br:22]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[C:1]([C:5]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][Br:22])=[CH:16][C:15]=2[F:21])[N:9]=1)=[O:6])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(-c2cccc(NC(=O)C(C)(C)C)n2)c(F)c1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)C(=O)Nc1cccc(-c2ccc(CBr)cc2F)n1
Yield: 84 %

Procedure:
To a 250 mL round-bottomed flask equipped with condenser and N2 inlet were added 5.0 g (17.48 mmol) N-t-butylcarbonyl-6-(2-fluoro-4-methylphenyl)-pyridin-2-ylamine (Example 2B), 4.36 g (24.47 mmol) N-bromosuccinimide, 10 mg azobisdi-(1,1-dimethylcyclohexyl)nitrile, and 85 mL carbon tetrachloride. The reaction was refluxed under a heat lamp for 30 min, cooled, and filtered. The filtrate was concentrated and chromatographed on silica gel using hexane/ethyl acetate as eluant to afford 5.36 g (52%) of the product as an oil, which was crystallized from isopropanol to give mp 97-100° C.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9]/[C:10](=[C:17]2\[C:18](=[O:26])[NH:19][C:20]3[C:25]\2=[CH:24][CH:23]=[CH:22][CH:21]=3)/[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:5][CH:4]=1.[C:27](OC(=O)C)(=[O:29])[CH3:28]>C(O)(=O)C>[C:27]([NH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([NH:9]/[C:10](=[C:17]2\[C:18](=[O:26])[NH:19][C:20]3[C:25]\2=[CH:24][CH:23]=[CH:22][CH:21]=3)/[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:7][CH:8]=1)(=[O:29])[CH3:28]
Reactant: CC(=O)OC(C)=O
Reactant: NCc1ccc(N/C(=C2\C(=O)Nc3ccccc32)c2ccccc2)cc1
Solvent: CC(=O)O
Product: CC(=O)NCc1ccc(N/C(=C2\C(=O)Nc3ccccc32)c2ccccc2)cc1

Procedure:
Prepared analogously to Example 31 from (Z)-3-[1-(4-aminomethyl-phenylamino)-1-phenyl-methylidene]-2-indolinone, glacial acetic acid and acetic anhydride.
Reaction SMILES: C([O:3][C:4]([C:6]1([CH3:12])[N+:10]([O-:11])=[CH:9][CH2:8][CH2:7]1)=O)C.[OH-].[NH4+].COC1C=C(C=CC=1OC)C(O)=O.[NH2:28]C(N)=O>CO.C(OCC)(=O)C>[C:4]([C:6]1([CH3:12])[N+:10]([O-:11])=[CH:9][CH2:8][CH2:7]1)(=[O:3])[NH2:28]
Reactant: NC(N)=O
Reactant: CCOC(=O)C1(C)CCC=[N+]1[O-]
Agent: COc1ccc(C(=O)O)cc1OC
Agent: [NH4+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC1(C(N)=O)CCC=[N+]1[O-]

Procedure:
AMPO was prepared from EMPO based on the procedure described previously with minor modification.2 A solution of 0.5 g of EMPO was mixed with 10 mL of concentrated ammonium hydroxide in a sealed tube for 5 days at room temperature with shaking. The mixture was rotary evaporated to yield a viscous dark oil and passed through a silica gel column (200-400 mesh 60 Å) twice using methanol-ethyl acetate (30:70) as solvent. White crystalline product was obtained (0.10 g, 24%), mp. 134-135° C. (lit. 137° C.)., (corrected using 3,4 dimethoxybenzoic acid, m.p., 180° C. and urea, m.p., 135° C.). 1H NMR (400 MHz, D2O) δ 1.64 (3 H, s, C(5)Me), 2.21-2.29 and 2.54-2.61 (2 H, m, C(4)H), 2.73-2.73 (2 H, m, C(3)H), 7.36 (1 H, t, C(2)H). 1H NMR (400 MHz, CDCl3) 1.90 (3 H, s, C(5)Me), 2.27-2.34 and 3.14-3.20 (2 H, m, C(4)H), 2.79 (2 H, m, C(3)H), 7.19 (1 H, t, C(2)H), 5.85 and 8.46 (2 H, br, NH2). 13C NMR (100 MHz, CDCl3) δ 24.2 (s, —CH3), 25.0 (s, C-3), 30.5 (s, C-4), 79.1 (C-5), 137.4 (C-2), 172.9 (—C═O). IR (Neat film) 1676 (C═O), 1585 (C═N), 1215 (N—O). ESI-MS calcd for C6H10N2O2Na+ m/z 165.0634, found 165.0637 amu. Anal. Calcd. for C6H10N2O2: C, 50.81; H, 7.23; N, 19.14. Found: C, 50.61; H, 7.25; N, 19.31.
Reaction SMILES: [I-].[CH3:2][S+](C)(C)=O.[OH-].[Na+].[F:9][C@H:10]1[CH2:29][C@@:28]2([CH3:30])[C@@H:21]([CH2:22][CH2:23][C@:24]2([OH:31])[C:25](=[O:27])[CH3:26])[C@H:20]2[C@H:11]1[C@:12]1([CH3:33])[C:17]([CH:18]=[CH:19]2)=[CH:16][C:15](=[O:32])[CH:14]=[CH:13]1>CS(C)=O>[F:9][C@H:10]1[CH2:29][C@@:28]2([CH3:30])[C@@H:21]([CH2:22][CH2:23][C@:24]2([OH:31])[C:25](=[O:27])[CH3:26])[C@H:20]2[C@H:11]1[C@:12]1([CH3:33])[C:17]([CH:18]=[CH:19]2)=[CH:16][C:15](=[O:32])[C@@H:14]2[CH2:2][C@H:13]12
Reactant: C[S+](C)(C)=O
Reactant: CC(=O)[C@@]1(O)CC[C@H]2[C@@H]3C=CC4=CC(=O)C=C[C@]4(C)[C@H]3[C@@H](F)C[C@@]21C
Agent: [I-]
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CC(=O)[C@@]1(O)CC[C@H]2[C@@H]3C=CC4=CC(=O)[C@@H]5C[C@@H]5[C@]4(C)[C@H]3[C@@H](F)C[C@@]21C
Reaction time: 4.5 h

Procedure:
One gram of trimethylsulfoxonium iodide in 30 ml. of dimethyl sulfoxide is agitated under nitrogen for 30 minutes with 200 mg. of pulverized sodium hydroxide. Then, 1.6 g. of 11β-fluoro-17-hydroxy-1,4,6-pregnatriene-3,20-dione is added to the reaction mixture. After 4.5 hours, the reaction mixture is stirred into acetic ice/water. The precipitate is vacuum-filtered, taken up in methylene chloride, and dried over sodium sulfate. After chromatographing the crude product on silica gel with acetone/hexane, 1.4 g. of 11β-fluoro-17-hydroxy-1α,2α -methylene-4,6-pregnadiene-3,20-dione is obtained. UV: ε282 = 16,900.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=1[O:29][CH3:30])[CH2:5][NH:6][C:7]1[C:12]([C:13]([NH:15][CH2:16][C:17]2[N:22]=[CH:21][CH:20]=[CH:19][N:18]=2)=[O:14])=[CH:11][N:10]=[C:9](S(C)=O)[N:8]=1.[CH3:31][N:32]1[CH2:41][CH2:40][CH2:39][C:34]2([CH2:38][NH:37][CH2:36][CH2:35]2)[CH2:33]1.C(N(CC)CC)C.O>C1COCC1.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=1[O:29][CH3:30])[CH2:5][NH:6][C:7]1[C:12]([C:13]([NH:15][CH2:16][C:17]2[N:22]=[CH:21][CH:20]=[CH:19][N:18]=2)=[O:14])=[CH:11][N:10]=[C:9]([N:37]2[CH2:36][CH2:35][C:34]3([CH2:39][CH2:40][CH2:41][N:32]([CH3:31])[CH2:33]3)[CH2:38]2)[N:8]=1
Reactant: CN1CCCC2(CCNC2)C1
Reactant: COc1ccc(CNc2nc(S(C)=O)ncc2C(=O)NCc2ncccn2)cc1Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: COc1ccc(CNc2nc(N3CCC4(CCCN(C)C4)C3)ncc2C(=O)NCc2ncccn2)cc1Cl
Reaction time: 4 h
Yield: 16.9 %

Procedure:
In THF (10 mL) were dissolved 4-((3-chloro-4-methoxybenzyl)amino)-2-(methylsulfinyl)-N-(pyrimidin-2-ylmethyl)pyrimidine-5-formamide (100 mg, 0.22 mmol) and 7-methyl-2,7-diazaspiro[4.5]decane (42 mg, 0.27 mmol). Triethylamine (68 mg, 0.67 mmol) was added dropwisely. The reaction was conducted at ambient temperature for 4 h, followed by addition of water and extraction with DCM. The organic phase was dried over sodium sulfate and purified by silica gel column chromatography (DCM/methanol=20/1) to give 4-((3-chloro-4-methoxybenzyl)amino)-2-(7-methyl-2,7-diazaspiro[4.5]decan-2-yl)-N-(pyrimidin-2-ylmethyl)pyrimidine-5-formamide as a white solid (20 mg, 17% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]([CH2:21][CH2:22][CH2:23][NH:24][C:25]([O:27][CH3:28])=[O:26])[C:9](=[O:20])[CH2:10][N:11](C)[C:12](=O)OC(C)(C)C)[CH:5]=[CH:6][CH:7]=1.C(=O)(O)[O-].[Na+]>C(O)(C(F)(F)F)=O.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]([CH2:21][CH2:22][CH2:23][NH:24][C:25](=[O:26])[O:27][CH3:28])[C:9](=[O:20])[CH2:10][NH:11][CH3:12])[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)NCCCN(C(=O)CN(C)C(=O)OC(C)(C)C)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNCC(=O)N(CCCNC(=O)OC)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.7 %

Procedure:
tert-butyl 2-((3-chlorophenyl)(3-(methoxycarbonylamino)propyl)amino)-2-oxoethyl(methyl)carbamate (130 mg, 0.31 mmol) was dissolved in a solution of 20% (V/V) TFA/CH2Cl2 (4 mL). The reaction mixture was stirred at room temperature for 1 h, a solution of saturated sodium bicarbonate was added drop wise to adjust the pH=7-8. The resulting mixture was extracted with CH2Cl2 (3×10 mL), washed with brine, dried over Na2SO4, concentrated in vacuo to afford methyl 3-(N-(3-chlorophenyl)-2-(methylamino)acetamido)propylcarbamate (95 mg, 95%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[N:8]=[C:7]([O:13][CH3:14])[C:6]([NH:15][C:16](=[O:20])OCC)=[N:5]2.[CH3:21][C:22]1[CH:23]=[C:24]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[CH:25]=[C:26]([CH3:28])[CH:27]=1>>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[N:8]=[C:7]([O:13][CH3:14])[C:6]([NH:15][C:16]([N:32]1[CH2:33][CH2:34][N:29]([C:24]3[CH:25]=[C:26]([CH3:28])[CH:27]=[C:22]([CH3:21])[CH:23]=3)[CH2:30][CH2:31]1)=[O:20])=[N:5]2
Reactant: Cc1cc(C)cc(N2CCNCC2)c1
Reactant: CCOC(=O)Nc1nc2cc(F)c(F)cc2nc1OC
Product: COc1nc2cc(F)c(F)cc2nc1NC(=O)N1CCN(c2cc(C)cc(C)c2)CC1
Yield: 70 %

Procedure:
Ethyl N-(6,7-difluoro-2-methoxyquinoxalin-3-yl)carbamate and 1-(3,5-dimethylphenyl)piperazine were reacted by the same way with the example 169 to obtain the titled compound (yield, 70%). 1H NMR (300 MHz, CDCl3) δ 2.30 (s, 6H), 3.26-3.28 (m, 4H), 3.74-3.76 (m, 4H), 4.15 (s, 3H), 6.59 (s, 3H), 7.29 (s, 1H), 7.49-7.53 (m, 1H), 7.52-7.62 (m, 1H).
Reaction SMILES: [C:1]([C:5]1[C:13]2[O:12][CH:11]([CH2:14][NH2:15])[CH2:10][C:9]=2[CH:8]=[C:7]([O:16][CH3:17])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.Cl[C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29]>>[CH2:31]([O:30][C:28](=[O:29])[NH:15][CH2:14][CH:11]1[CH2:10][C:9]2[CH:8]=[C:7]([O:16][CH3:17])[CH:6]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[C:13]=2[O:12]1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: COc1cc2c(c(C(C)(C)C)c1)OC(CN)C2
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2c(c(C(C)(C)C)c1)OC(CNC(=O)OCc1ccccc1)C2
Yield: 85.5 %

Procedure:
Treatment of (±)-(7-tert-butyl-5-methoxy-2,3-dihydro-1-benzofuran-2-yl)methylamine (1.03 g, 3.8 mmol) with diisopropylethylamine (0.735 g, 5.7 mmol) and benzyl chloroformate (0.711 g, 4.2 mmol) generally according to the procedure described for Intermediate 12 gave 1.2 g (59%) of (±)-benzyl(7-tert-butyl-5-methoxy-2,3-dihydro-1-benzofuran-2-yl)methylcarbamate as a colorless oil. Rf=0.51 (silica, ethyl acetate:hexanes 2:8); Anal. calcd. for C22H27NO4 C, 71.52; H, 7.37; N, 3.79. Found C, 71.2; H, 7.44; N, 3.77.
Reaction SMILES: [C:1]([O:5][O:6][C:7]([CH3:13])([CH3:12])[CH2:8][CH:9]([CH3:11])[OH:10])([CH3:4])([CH3:3])[CH3:2].[C:14](Cl)(=[O:18])[C:15]([Cl:17])=[O:16]>>[C:15]([Cl:17])(=[O:16])[C:14]([O:10][CH:9]([CH3:11])[CH2:8][C:7]([O:6][O:5][C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:12])[CH3:13])=[O:18]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(O)CC(C)(C)OOC(C)(C)C
Product: CC(CC(C)(C)OOC(C)(C)C)OC(=O)C(=O)Cl
Yield: 98.4 %

Procedure:
In this example the product was prepared in two synthetic steps. In the first step 3-t-butylperoxy-1,3-dimethylbutanol was reacted with 100% molar excess of oxalyl chloride. Upon completion of the reaction the excess oxalyl chloride was stripped from the product at reduced pressure to produce 3-t-butylperoxy-1,3-dimethylbutyl chlorooxalate having an assay of 98.1% and in a corrected yield of 98.4%. In the second step 3-t-butylperoxy-1,3-dimethylbutyl chlorooxalate was reacted with 3-hydroperoxy-1,3-dimethylbutanol in the presence of pyridine to yield the product as described below: