Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH2:13])(=[O:12])[CH:2]=[CH:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[C:14]([O-:17])(=O)[CH3:15].[Na+].[C:19](OO)(=O)[CH3:20].S(=O)(O)[O-].[Na+]>C(Cl)Cl.O>[CH2:1]([NH:13][C:14](=[O:17])[CH2:15][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:19]=[CH2:20])[CH2:2][NH:13][C:1](=[O:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]=[CH2:11]
Reactant: CCCCCCCCC=CC(N)=O
Reactant: CC(=O)[O-]
Reactant: CC(=O)OO
Agent: O=S([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: C=CCCCCCCCCC(=O)NCCNC(=O)CCCCCCCCC=C
Temperature: 15 °C

Procedure:
To a 500 mL, three-necked round bottom flask (fitted with a reflux condenser, addition funnel, and stir bar) was added undecenamide according to the above formula (8) (8.90 g, 22.7 mmol, 45.3 mmol double bonds), sodium acetate (0.63 g), and methylene chloride (170 mL). To the addition funnel was added 32 wt % peracetic acid (19.1 mL of 32 wt %, 21.6 g of 32 wt %, 6.91 g of peracetic acid, and 90.9 mmol of peracetic acid). The peracetic acid solution was added dropwise over 20 minutes to the suspension of formula (8) in methylene chloride, which had been cooled to 15° C. The reaction mixture was stirred at 25° C. for one hour, during which time the amide dissolved/reacted. The reaction mixture was then heated at reflux for 16 hours. The reaction mixture was then cooled to 15° C. in an ice bath, after which a solution of 60% (w/v) sodium bisulfite (9.44 g, 90.8 mmol) in water (200 mL) was added dropwise to the reaction mixture. A white solid/gel precipitated from solution. The solid was collected via suction filtration. The aqueous and organic phases were discarded. The crude product was recrystallized from a 2:1 mixture of acetone/ethanol (400 mL), then dried in vacuo at 25° C. for 16 hours. The thus obtained polyepoxy amide is represented by formula (9) shown below. Yield: 5.93 g (61%). Epoxide equivalent weight (EEW): 218.8 g/mol epoxide (calculated EEW=212.3).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH2:9])=[CH:5][CH:6]=[CH:7][CH:8]=1>CC(O)=O.[Rh]>[CH3:1][O:2][CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH:4]1[NH2:9]
Reactant: COc1ccccc1N
Agent: [Rh]
Solvent: CC(=O)O
Product: COC1CCCCC1N
Yield: 22.7 %

Procedure:
Shake a mixture of o-anisidine (5.0 g, 41 mmol) and rhodium on carbon (5% Rh; 5.0 g) in AcOH (65 mL) under H2 (60 psig) at 60° C. for 6 h. Filter the reaction mixture and rotary evaporate the filtrate (75° C.). Dissolve this material in CHCl3 (100 mL) and basify with satd aq NaHCO3 (50 mL). Dry the organic layer (Na2SO4) and rotary evaporate (40° C.) to yield 1.20 g of 2-methoxy-cyclohexylamine as a yellow oil.
Reaction SMILES: N([C:3]1[C:8]([Cl:9])=[C:7]([C:10](Cl)([Cl:12])[Cl:11])[N:6]=[C:5]([Cl:14])[C:4]=1[Cl:15])N.[OH-].[Na+]>CO>[Cl:9][C:8]1[C:7]([CH:10]([Cl:11])[Cl:12])=[N:6][C:5]([Cl:14])=[C:4]([Cl:15])[CH:3]=1
Reactant: NNc1c(Cl)c(Cl)nc(C(Cl)(Cl)Cl)c1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Clc1cc(Cl)c(C(Cl)Cl)nc1Cl
Yield: 59 %

Procedure:
In procedures as noted in Example 1, a reaction mixture of 4-hydrazino-2,3,5-trichloro-6-(trichloromethyl)pyridine (9.9 grams; 0.03 mole) and sodium hydroxide (1/N, 37.5 ml, 0.0375 mole) in methanol (100 ml) was heated under reflux conditions for a period of about 4 hours and the product similarly recovered as a brown oil. Examination of GLC, PMR and mass spectral analysis indicated a product yield of 59% of 3,5,6-trichloro-2-(dichloromethyl)pyridine. A portion of the crude product was distilled over at 168°-73° C./21 mmHg as a colorless oil which crystallized as large colorless prisms from hexane, m.p. 61°-62° C.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7].[OH:16][C:17]1[C:18](=[O:28])[C:19]2[C:24]([C:25](=[O:27])[CH:26]=1)=[CH:23][CH:22]=[CH:21][CH:20]=2>C1C=CC=CC=1.[Ag]>[O:28]=[C:18]1[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:25]([O:27][CH2:2][CH2:3][CH2:4][CH2:5][C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])=[CH:26][C:17]1=[O:16]
Reactant: O=C(CCCCBr)OCc1ccccc1
Reactant: O=C1C=C(O)C(=O)c2ccccc21
Agent: [Ag]
Solvent: c1ccccc1
Product: O=C(CCCCOC1=CC(=O)C(=O)c2ccccc21)OCc1ccccc1

Procedure:
A mixture of benzyl 5-bromovalerate (2.27 g, 8.4 mmol) and the silver salt of 2-hydroxy-1,4-naphthoquinone (1.63 g, 5.81 mmol) in benzene (8 mL) was stirred for 48 h at 55° C. and filtered through celite. The filtrate was diluted with diethyl ether, extracted with a 20% aqueous solution of NaHSO3 then basified to pH 10-11 with Na2CO3, and extracted with CH2Cl2. Yellow solid (1.334 g, 63%). 1H NMR (CDCl3) 8.12 (d, J=7.5 Hz, 1H), 7.85 (d, J=7.7 Hz, 1H), 7.68 (t, J=7.5, 1H), 7.58 (t, J=7.7 Hz, 1H), 7.25-7.50 (m, 5H), 5.93 (s, 1H), 5.14 (s, 2H), 4.15 (t, J=5.7 Hz, 2H), 2.50 (t, J=7.0 Hz, 2H), 1.8-2.2 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([NH:11][C:12](=[O:17])[CH2:13][C:14](=O)[CH3:15])[CH:9]=2)[NH:4][N:3]=1.[NH2:18][C:19]([NH2:21])=[O:20].FC(F)(F)S([O-])(=O)=O.[Yb+3].FC(F)(F)S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O.[F:47][C:48]1[CH:55]=[CH:54][C:51]([CH:52]=O)=[CH:50][CH:49]=1>C(#N)C.O>[Cl:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([NH:11][C:12]([C:13]3[CH:52]([C:51]4[CH:54]=[CH:55][C:48]([F:47])=[CH:49][CH:50]=4)[NH:18][C:19](=[O:20])[NH:21][C:14]=3[CH3:15])=[O:17])[CH:9]=2)[NH:4][N:3]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: NC(N)=O
Reactant: CC(=O)CC(=O)Nc1ccc2[nH]nc(Cl)c2c1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: CC#N
Solvent: O
Product: CC1=C(C(=O)Nc2ccc3[nH]nc(Cl)c3c2)C(c2ccc(F)cc2)NC(=O)N1
Temperature: 100 °C
Yield: 85 %

Procedure:
The product from Step (c) (0.25 g, 1.0 mmol), urea (90 mg, 1.5 mmol) and Ytterbium trifluoromethanesulfonate (62 mg, 0.1 mmol) were combined in acetonitrile (5 ml) and 4-Fluorobenzaldehyde (0.11 ml, 1.0 mmol) was added to the mixture. The reaction mixture was sealed and heated to 100° C. for 3 hours. The reaction was diluted with water (1 ml) and the solid product was collected by filtration. The solid was washed three times with 1:1 Et2O/CH3CN to afford the title compound, (0.34 g, 85%); MS (ES+) m/e 401 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([O:8][C:9]2[CH:10]=[C:11]([NH:15][C:16](=[O:26])/[CH:17]=[CH:18]/[CH2:19][N:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[CH:12]=[CH:13][CH:14]=2)[C:3]=1[C:27]1[CH:32]=[CH:31][C:30]([O:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[CH:29][CH:28]=1.[O:40]=[C:41]1[NH:45][CH:44]2[CH2:46][S:47][C@@H:48]([CH2:49][CH2:50][CH2:51][CH2:52][C:53](OC3C(F)=C(F)C(F)=C(F)C=3F)=[O:54])[CH:43]2[NH:42]1>>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([O:8][C:9]2[CH:10]=[C:11]([NH:15][C:16](=[O:26])/[CH:17]=[CH:18]/[CH2:19][N:20]3[CH2:25][CH2:24][N:23]([C:53](=[O:54])[CH2:52][CH2:51][CH2:50][CH2:49][C@H:48]4[CH:43]5[CH:44]([NH:45][C:41](=[O:40])[NH:42]5)[CH2:46][S:47]4)[CH2:22][CH2:21]3)[CH:12]=[CH:13][CH:14]=2)[C:3]=1[C:27]1[CH:28]=[CH:29][C:30]([O:33][C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)=[CH:31][CH:32]=1
Reactant: O=C1NC2CS[C@@H](CCCCC(=O)Oc3c(F)c(F)c(F)c(F)c3F)C2N1
Reactant: Nc1ncnc(Oc2cccc(NC(=O)/C=C/CN3CCNCC3)c2)c1-c1ccc(Oc2ccccc2)cc1
Product: Nc1ncnc(Oc2cccc(NC(=O)/C=C/CN3CCN(C(=O)CCCC[C@@H]4SCC5NC(=O)NC54)CC3)c2)c1-c1ccc(Oc2ccccc2)cc1
Yield: 45 %

Procedure:
((E)-N-(3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)phenyl)-4-(4-(5-((4S)-2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl)pentanoyl)piperazin-1-yl)but-2-enamide was prepared from (E)-N-(3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)phenyl)-4-(piperazin-1-yl)but-2-enamide and perfluorophenyl 5-((4S)-2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl)pentanoate using Method F (45% yield). HPLC: 100%, RT=3.635 min. MS: m/z=750 [M+H]+, RT=1.84 min.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].I[CH2:8][CH3:9].[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][C:12]=1[I:18]>CN(C=O)C.CCOCC.O>[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:8][CH3:9])=[CH:13][C:12]=1[I:18]
Reactant: Oc1ccc(Cl)c(I)c1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1ccc(Cl)c(I)c1
Temperature: 50 °C
Reaction time: 3 h
Yield: 87.8 %

Procedure:
Add 2 g (14.5 mmol) of K2CO3 and 1.16 mL (14.5 mmol) of iodoethane to a solution of 2.45 g (9.6 mmol) of 4-chloro-3-iodophenol in 30 mL of DMF. Heat the reaction mixture at 50° C. while stirring for 3 h, then distribute in 200 mL of ether/water 1:1 mixture. Wash the organic phase with 3×50 mL of water then dry over Na2SO4 and concentrate under reduced pressure. We obtain 2.38 g of 1-chloro-2-iodo-4-ethoxybenzene in the form of oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:11]=[C:10]([CH2:19][CH2:20][CH:21]=O)[CH:9]=2)=[CH:4][CH:3]=1.[CH3:23][CH:24]1[CH2:29][NH:28][CH2:27][CH2:26][N:25]1[C:30]1[CH:31]=[C:32]([CH3:36])[CH:33]=[CH:34][CH:35]=1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:11]=[C:10]([CH2:19][CH2:20][CH2:21][N:28]3[CH2:27][CH2:26][N:25]([C:30]4[CH:31]=[C:32]([CH3:36])[CH:33]=[CH:34][CH:35]=4)[CH:24]([CH3:23])[CH2:29]3)[CH:9]=2)=[CH:4][CH:3]=1
Reactant: O=CCCc1cc(-c2ccc(Cl)cc2)n(-c2ccccc2)n1
Reactant: Cc1cccc(N2CCNCC2C)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccc(N2CCN(CCCc3cc(-c4ccc(Cl)cc4)n(-c4ccccc4)n3)CC2C)c1

Procedure:
114 mg (85%) of target compound was obtained by using a method same as in Example 1 by using 3-(5-(4-chlorophenyl)-1-phenyl-1H-pyrazol-3-yl)-propanal (80 mg, 0.257 mmol), 2-methyl-1-m-tolylpiperazine (49 mg, 0.257 mmol), DIPEA (0.070 mL, 0.386 mmol) and NaBH(OAc)3 (163 mg, 0.771 mmol).
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:10])=[CH:4][C:5](I)=[C:6]([NH2:8])[CH:7]=1.[CH2:11]([Sn](CCCC)(CCCC)C=C)[CH2:12]CC>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:1][C:2]1[C:3]([Cl:10])=[CH:4][C:5]([CH:11]=[CH2:12])=[C:6]([NH2:8])[CH:7]=1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: Nc1cc(Br)c(Cl)cc1I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C=Cc1cc(Cl)c(Br)cc1N
Temperature: 25 °C
Yield: 57.3 %

Procedure:
A mixture of 5-bromo-4-chloro-2-iodobenzenamine (2.5 g, 7.51 mmol), tributyl(vinyl)stannane (2.4 g, 7.51 mmol), Pd(PPh3)4 (867 mg, 0.75 mmol) in toluene (25 mL) was stirred at reflux under argon for 16 h. The reaction mixture was allowed to cool to room temperature and quenched with aqueous KF solution. The mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over Na2SO4 and concentrated. The residue was purified by flash column chromatography on silica gel (petroleum ether/ethyl acetate=20:1) to afford the desired product (1.0 g, 57.4% yield). ESI-MS m/z: 232.2[M+H]+.
Reaction SMILES: F[C:2]1[CH:19]=[CH:18][C:5]([C:6]([N:8]2[CH2:12][CH2:11][C@H:10]([N:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)[CH2:9]2)=[O:7])=[CH:4][CH:3]=1.[CH:20]1[C:25]([OH:26])=[CH:24][CH:23]=[CH:22][C:21]=1[CH3:27].C(=O)([O-])[O-].[K+].[K+].[Cl:34]CCl>CN(C)C=O>[ClH:34].[CH3:27][C:21]1[CH:20]=[C:25]([CH:24]=[CH:23][CH:22]=1)[O:26][C:2]1[CH:19]=[CH:18][C:5]([C:6]([N:8]2[CH2:12][CH2:11][C@H:10]([N:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)[CH2:9]2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(c1ccc(F)cc1)N1CC[C@H](N2CCCC2)C1
Reactant: ClCCl
Reactant: Cc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cccc(Oc2ccc(C(=O)N3CC[C@H](N4CCCC4)C3)cc2)c1
Product: Cl
Temperature: 150 °C

Procedure:
A solution of (3′S)-1′-(4-fluorobenzoyl)-1,3′-bipyrrolidine (0.011 g, 0.381 mmol in dimethylformamide was treated with m-cresol (0.127 g, 1.14 mmol) and potassium carbonate (0.105 g, 0.762 mmol), heated to 150° C. via microwave radiation for 20 minutes and cooled to room temperature. The reaction mixture was diluted with dichloromethane, washed sequentially with water and saturated aqueous sodium chloride, dried over magnesium sulfate and concentrated in vacuo. The resultant residue was purified by flash column chromatography (silica, methanol:dichloromethane 5:95) to give the free amine of the title product as a yellow oil. This oil was dissolved in isopropanol and diethyl ether (1:10), treated with 1.0N HCl in diethyl ether and filtered. The filter cake was dried to afford the title product as a yellow solid, 0.021 g (16%), identified by NMR and mass spectral analyses. MS [351.3 m/e (M+H)].
Reaction SMILES: C[O:2][C:3]([CH2:5][S:6][C@@H:7]1[NH:10][C:9](=[O:11])[C@H:8]1[NH:12][C:13]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=O.[NH3:32]>C(O)C>[NH2:32][C:3]([CH2:5][S:6][C@@H:7]1[NH:10][C:9](=[O:11])[C@H:8]1[NH:12][C:13]([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:2]
Reactant: COC(=O)CS[C@@H]1NC(=O)[C@H]1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: N
Solvent: CCO
Product: NC(=O)CS[C@@H]1NC(=O)[C@H]1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 48 h

Procedure:
To a solution of 0.477 g of (3R,4S)-4-[[(methoxycarbonyl)methyl]thio]-3-tritylamino-2-azetidinone in 5 ml of ethanol is added 1 ml of 25 to 28% aqueous ammonia and the reaction mixture is allowed to stand at room temperature for 2 days. The solvent is then distilled off under reduced pressure and 20 ml of ethyl acetate is added to the residue. The mixture is washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is purified by silica gel column chromatography using ethyl acetate-chloroform-methanol (8:8:1) to give 0.173 g of (3R,4S)-4-[[(aminocarbonyl)methyl]thio]-3-tritylamino-2-azetidinone.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14]([OH:16])=O)[CH:11]=[CH:10][C:9]=2[CH:17]2[CH2:21][CH2:20][O:19][CH2:18]2)[CH:5]=[CH:6][CH:7]=1.[CH3:22][C:23]([CH3:30])([C:25]1[S:26][CH:27]=[CH:28][N:29]=1)[NH2:24]>>[CH3:22][C:23]([NH:24][C:14]([C:12]1[CH:11]=[CH:10][C:9]([CH:17]2[CH2:21][CH2:20][O:19][CH2:18]2)=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[N:13]=1)=[O:16])([C:25]1[S:26][CH:27]=[CH:28][N:29]=1)[CH3:30]
Reactant: CC(C)(N)c1nccs1
Reactant: O=C(O)c1ccc(C2CCOC2)c(-c2cccc(Cl)c2)n1
Product: CC(C)(NC(=O)c1ccc(C2CCOC2)c(-c2cccc(Cl)c2)n1)c1nccs1

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-(3-chloro-phenyl)-5-(tetrahydro-furan-3-yl)-pyridine-2-carboxylic acid and α,α-dimethyl-2-thiazolemethanamine (CAN 1082393-38-1) as starting materials, MS (EI): m/e=428.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1.[CH3:13][O:14][C:15]([CH:17]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:16]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:9]=[CH:8][C:5](/[CH:6]=[CH:17]/[C:15]([O:14][CH3:13])=[O:16])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1
Reactant: O=Cc1ccc(Cl)cc1[N+](=O)[O-]
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: COC(=O)/C=C/c1ccc(Cl)cc1[N+](=O)[O-]
Yield: 98.3 %

Procedure:
4-Chloro-2-nitrobenzaldehyde (5 g, 0.027M) was dissolved in toluene (150 ml) with methyl (triphenylphosphoranylidene) acetate (9.91 g, 1.1 molar equivalents) and heated under reflux for 1h. The reaction mixture was concentrated under vacuum and the residue was purified by chromatography on silica gel using dichloromethane as eluent to give the required compound (6.4 g, 98%) as a solid. δ(360MHz, CDCl3) 3.83 (3H, s, CH3), 6.36 (1H, d, J=15.9Hz, CHA =CHB), 7.58 (1H, d, J=8.4Hz, 6H), 7.63 (1H, dd, J=8.4 and 2.0Hz, 5-H), 8.04 (1H, d, J=2.0Hz, 3-H), 8.05 (1H, d, J=8.4Hz, CHA =CHB); MS (EI) m/e 241 [M+ ].
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:19]=[CH:18][C:6]2=[N:7][N:8]([C:10]3[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][C:11]=3[OH:17])[N:9]=[C:5]2[CH:4]=1.[CH2:22]([O:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH:23]1[O:25][CH2:24]1.O.C(OCC)(=O)C>[Br-].C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)C.C1(C)C(C)=CC=CC=1>[F:21][C:2]([F:1])([F:20])[C:3]1[CH:19]=[CH:18][C:6]2=[N:7][N:8]([C:10]3[CH:15]=[CH:14][C:13]([O:16][CH2:24][CH:23]([OH:25])[CH2:22][O:26][CH2:27][CH2:28][CH2:29][CH3:30])=[CH:12][C:11]=3[OH:17])[N:9]=[C:5]2[CH:4]=1
Reactant: CCCCOCC1CO1
Reactant: Oc1ccc(-n2nc3ccc(C(F)(F)F)cc3n2)c(O)c1
Agent: CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: Cc1ccccc1C
Solvent: CCOC(C)=O
Solvent: O
Product: CCCCOCC(O)COc1ccc(-n2nc3ccc(C(F)(F)F)cc3n2)c(O)c1

Procedure:
A mixture of 2.3 g of 5-trifluoromethyl-2-(2,4-dihydroxyphenyl)-2H-benzotriazole prepared in Example 31, 1.3 mL of butyl glycidyl ether and 100 mg of ethyl triphenylphosphonium bromide in 50 mL of xylene is heated to reflux under nitrogen for 14 hours. Water (25 mL) and 25 mL of ethyl acetate are added and 3 g of the crude product is isolated. Recrystallization from heptane give 2.1 g of the title compound whose structure is confirmed by nmr.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6]([O:8][CH3:9])=[O:7].[C:13]1(B(O)O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[Na+].[Na+]>O.C(COC)OC.ClCCl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:2]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6]([O:8][CH3:9])=[O:7])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: COC(=O)c1cccc(CBr)c1
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Solvent: ClCCl
Product: COC(=O)c1cccc(Cc2ccccc2)c1
Yield: 84.2 %

Procedure:
A mixture of methyl 3-(bromomethyl)benzoate (1.50 g; 6.35 mmol), phenylboronic acid (0.790 g; 6.35 mmol), sodium carbonate (1.35 g; 12.70 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.074 g; 0.063 mmol) in water (4 mL) and dimethoxyethane (12 mL) was irradiated in a microwave oven at 130° C. for 10 minutes. The mixture was diluted with dichloromethane and washed with a saturated aqueous solution of sodium bicarbonate. The organic layer was concentrated under reduced pressure and the crude material was purified by flash chromatography on silica gel (eluent 15 to 100% dichloromethane in heptane) to afford 1.21 g (84%) of methyl 3-benzylbenzoate.
Reaction SMILES: C([C:4]1[C:13]([CH2:14][O:15][C:16](=[O:18])[CH3:17])=[N+:12]([O-:19])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N+:5]=1[O-:20])(=O)C.[OH-].[Na+]>C(Cl)Cl>[OH:18][C:16]1([CH3:17])[C:4]2=[N+:5]([O-:20])[C:6]3[C:11]([N+:12]([O-:19])=[C:13]2[CH2:14][O:15]1)=[CH:10][CH:9]=[CH:8][CH:7]=3
Reactant: CC(=O)OCc1c(C(C)=O)[n+]([O-])c2ccccc2[n+]1[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CC1(O)OCc2c1[n+]([O-])c1ccccc1[n+]2[O-]
Temperature: 25 °C
Reaction time: 3 h
Yield: 18 %

Procedure:
2-Acetyl-3-acetoxymethylquinoxaline 1,4-dioxide (2.0 g., 7.24 mmol.) was dissolved in ice-cold concentrated hydrochloric acid (9 ml.). The reaction mixture was allowed to warm to room temperature and was stirred for 3 hours. Methylene chloride (20 ml.) was added, and the two-phase system was cooled in an ice-bath and made slightly basic (pH 8) with 50% sodium hydroxide solution. The methylene chloride layer was separated and the aqueous layer was extracted with more methylene chloride (two 20-ml. portions). The combined methylene chloride extracts were treated with activated carbon and evaporated under reduced pressure leaving a yellow solid. Recrystallization from methanol gave a 310 mg. (18% yield) of 1-hydroxy-1-methyl-1,3-dihydrofuro[3,4-b]quinoxaline 4,9-dioxide having m.p. 163°-165° C.
Reaction SMILES: [OH-].[Li+].C[O:4][C:5](=[O:37])[C:6]1[CH:11]=[C:10]([C:12]2[CH:17]=[C:16]([O:18][CH:19]3[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]3)[N:15]=[N:14][C:13]=2[CH2:26][CH2:27][CH2:28][CH3:29])[CH:9]=[CH:8][C:7]=1[O:30][CH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1.Cl>C1COCC1.CO>[CH2:26]([C:13]1[N:14]=[N:15][C:16]([O:18][CH:19]2[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]2)=[CH:17][C:12]=1[C:10]1[CH:9]=[CH:8][C:7]([O:30][CH:31]2[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]2)=[C:6]([CH:11]=1)[C:5]([OH:37])=[O:4])[CH2:27][CH2:28][CH3:29]
Reactant: CCCCc1nnc(OC2CCN(C)CC2)cc1-c1ccc(OC2CCCCC2)c(C(=O)OC)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCCCc1nnc(OC2CCN(C)CC2)cc1-c1ccc(OC2CCCCC2)c(C(=O)O)c1
Reaction time: 8 h

Procedure:
2 N aq. lithium hydroxide solution (2.5 mmol, 1.25 mL) was added to a solution of 5-[3-butyl-6-(1-methyl-piperidin-4-yloxy)-pyridazin-4-yl]-2-cyclohexyloxy-benzoic acid methyl ester (Example 71, 0.615 mmol, 296 mg) in THF (5 mL) and MeOH (1.25 mL). It was stirred overnight. Aq. HCl solution was added to adjust pH to neutral. The reaction mixture was partitioned between DCM (20 mL) and water (20 mL). The DCM layer was separated and dried over sodium sulfate. The organic solvents were removed in vacuo to give 5-[3-butyl-6-(1-methyl-piperidin-4-yloxy)-pyridazin-4-yl]-2-cyclohexyloxy-benzoic acid.
Reaction SMILES: [CH2:1]([CH:5]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:2][CH2:3][CH3:4].OC1[CH2:22][C:21]([CH3:24])([CH3:23])[N:20]([O:25][CH3:26])[C:19]([CH3:28])([CH3:27])C1>[NH2-].[Li+].C1(C)C(C)=CC=CC=1>[CH2:1]([CH:5]([C:11]([O:13][CH:14]1[CH2:24][C:21]([CH3:22])([CH3:23])[N:20]([O:25][CH3:26])[C:19]([CH3:27])([CH3:28])[CH2:15]1)=[O:12])[C:6]([O:8][CH:9]1[CH2:22][C:21]([CH3:24])([CH3:23])[N:20]([O:25][CH3:26])[C:19]([CH3:28])([CH3:27])[CH2:10]1)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CON1C(C)(C)CC(O)CC1(C)C
Reactant: CCCCC(C(=O)OCC)C(=O)OCC
Agent: [Li+]
Agent: [NH2-]
Solvent: Cc1ccccc1C
Product: CCCCC(C(=O)OC1CC(C)(C)N(OC)C(C)(C)C1)C(=O)OC1CC(C)(C)N(OC)C(C)(C)C1
Yield: 98.4 %

Procedure:
A mixture of diethyl n-butylmalonate (11.55 g, 53.4 mmol), 4-hydroxy-1-methoxy-2,2,6,6-tetramethylpiperidine (20.0 g, 107 mmol), lithium amide (120 mg), and xylene (100 ml) is distilled until the distillate reaches a constant temperature of 137° C. Xylene is evaporated and the residue is dissolved in heptane. Acetic acid is added and the resulting precipitate is filtered. The filtrate is concentrated to obtain 26.2 g (98% yield) of a light yellow oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Si:8]([CH3:11])([CH3:10])[CH3:9])=[CH:4][CH:3]=1.C([Li])CCC.CCCCCC.CN([CH:26]=[O:27])C>C1COCC1>[CH3:9][Si:8]([CH3:11])([CH3:10])[C:5]1[CH:6]=[CH:7][C:2]([CH:26]=[O:27])=[CH:3][CH:4]=1
Reactant: C[Si](C)(C)c1ccc(Br)cc1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: C[Si](C)(C)c1ccc(C=O)cc1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 103.2 %

Procedure:
Bromo-4-(trimethylsilyl)benzene (1.15 g, 5 mmol) was dissolved in THF (30 ml) and cooled to −78° C. Under argon a 1.6 M solution of n-butyl lithium in hexane (3.13 ml, 5 mmol) was added dropwise keeping the temperature below −70° C. The clear colorless solution was stirred at −78° C. for 15 min and DMF (1.156 ml, 15 mmol) was added quickly. The reaction temperature increased to −68° C. The reaction was stirred for additional 15 min at −78° C., quenched with 1N aqueous hydrogen chloride solution and extracted twice with diethyl ether. The combined organic layers were washed twice with water and once with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and the solvent was evaporated to afford the product as a colorless oil (920 mg, 100%). The product was pure enough to be used directly in the next step. MS (ISP) 179.2 (M+H+). 1HNMR (CDCl3, 300 MHz): δ 10.02 (s, 1H) 7.84 (d, 2H), 7.69 (d, 2H), 0.31 (s, 9H).