Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[S:11][CH2:12][CH2:13][N:14]=2)=[N:8][CH:9]=1)([OH:3])=[O:2].C1(OC2C=CC=CC=2)C=CC=CC=1>CO.[Pd]>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[S:11][CH:12]=[CH:13][N:14]=2)=[N:8][CH:9]=1)([OH:3])=[O:2]
Reactant: O=C(O)c1ccc(C2=NCCS2)nc1
Agent: [Pd]
Solvent: CO
Solvent: c1ccc(Oc2ccccc2)cc1
Product: O=C(O)c1ccc(-c2nccs2)nc1

Procedure:
A mixture of 500 mg (2.4 mmol) of 5-carboxy-2-(4,5-dihydro-2-thiazolyl)-pyridine, 50 mg of 10% Pd on C and 5 g of diphenylether is refluxed for 4 h. The mixture is then diluted with methanol and the catalyst filtered off. The methanol is evaporated and some hexane added to the residue. The diphenylether dissolves and a solid is left, which is filtered off and washed with hexane. This residue is dissolved again in methanol and treated with charcoal. After evaporation of the methanol the title compound, m.p. >300°, is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[S:12][C:11]([C:13]([N:15]2[CH2:20][CH2:19][C:18]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)([C:21]([NH2:23])=[O:22])[CH2:17][CH2:16]2)=[O:14])=[CH:10][C:9]=1[C:30]1[CH:35]=[CH:34][C:33]([O:36]C)=[CH:32][CH:31]=1.B(Br)(Br)Br>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[S:12][C:11]([C:13]([N:15]2[CH2:16][CH2:17][C:18]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)([C:21]([NH2:23])=[O:22])[CH2:19][CH2:20]2)=[O:14])=[CH:10][C:9]=1[C:30]1[CH:31]=[CH:32][C:33]([OH:36])=[CH:34][CH:35]=1
Reactant: COc1ccc(-c2cc(C(=O)N3CCC(C(N)=O)(c4ccccc4)CC3)sc2-c2ccccc2Cl)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: NC(=O)C1(c2ccccc2)CCN(C(=O)c2cc(-c3ccc(O)cc3)c(-c3ccccc3Cl)s2)CC1
Reaction time: 8 h
Yield: 72.5 %

Procedure:
1.7 g of the compound obtained in stage 12B) and then 12.8 ml of a 1M solution of BBr3 in CH2Cl2 are added to 50 ml of CH2Cl2 at the temperature of melting ice and the temperature of the reaction medium is allowed to return to AT overnight. The reaction medium is subsequently poured onto distilled water and the expected compound is extracted with CH2Cl2. The organic phase is dried and evaporated. The compound crystallizes from ethyl ether. 1.2 g of the expected compound are obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])/[C:4](/[CH2:10]Br)=[CH:5]/[C:6]([O:8][CH3:9])=[O:7].[CH3:13][Mg]Br.Cl.[Cl-].[NH4+]>C(OCC)C.CN(C)P(=O)(N(C)C)N(C)C>[CH3:1][O:2][C:3](=[O:12])[CH:4]([CH3:10])[C:5](=[CH2:13])[C:6]([O:8][CH3:9])=[O:7]
Reactant: C[Mg]Br
Reactant: COC(=O)/C=C(\CBr)C(=O)OC
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: C=C(C(=O)OC)C(C)C(=O)OC
Reaction time: 1 h

Procedure:
To a solution of (Z)-2-bromomethyl-2-butenedioic acid dimethyl ester (19.3 g) and hexamethylphosphoric acid triamide (70 ml) in diethyl ether (200 ml) was added dropwise methyl magnesium bromide (1.12 M solution in tetrahydrofuran, 100 ml) over 1 hour at −20° C. and stirred for additional 1 hour. To this reaction mixture were added a 6M aqueous solution of hydrochloric acid (18 ml) and a saturated aqueous solution of ammonium chloride (100 ml), and then the mixture was warmed to room temperature and extracted with diethyl ether (200 ml). The resulting organic layer was washed with water twice, followed by a saturated aqueous solution of sodium chloride once, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane/chloroform=1/1 to 0/1) to give the titled compound (9.92 g).
Reaction SMILES: [C:1]1([C:7]2[O:11][N:10]=[C:9]([C:12]3[O:16][N:15]=[C:14]4[C:17]5[C:22]([CH2:23][C:13]=34)=[CH:21][C:20]([CH:24]=C)=[CH:19][CH:18]=5)[C:8]=2[C:26]([F:29])([F:28])[F:27])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[N+]1([O-])CC[O:34]CC1.I([O-])(=O)(=O)=O.[Na+]>C1COCC1.O.[Os](=O)(=O)(=O)=O>[C:1]1([C:7]2[O:11][N:10]=[C:9]([C:12]3[O:16][N:15]=[C:14]4[C:17]5[C:22]([CH2:23][C:13]=34)=[CH:21][C:20]([CH:24]=[O:34])=[CH:19][CH:18]=5)[C:8]=2[C:26]([F:27])([F:28])[F:29])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C[N+]1([O-])CCOCC1
Reactant: C=Cc1ccc2c(c1)Cc1c-2noc1-c1noc(-c2ccccc2)c1C(F)(F)F
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: C1CCOC1
Solvent: O
Product: O=Cc1ccc2c(c1)Cc1c-2noc1-c1noc(-c2ccccc2)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a clear solution of 3-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-6-vinyl-4H-indeno[1,2-c]isoxazole (Preparation 87C, 25 mg, 0.063 mmol) in THF (1 mL) were sequentially added NMO (50% in water, 0.016 mL, 0.076 mmol) and osmium tetroxide (4% in water, 0.012 mL, 1.902 μmol) at room temperature. The solution was vigorously stirred at room temperature for 1 hr before more osmium tetroxide (4% in water, 0.02 mL) was added. The mixture was stirred at room temperature overnight. Sodium periodate (17.63 mg, 0.082 mmol) in water (0.1 mL) was added. After the mixture was stirred vigorously at room temperature under nitrogen for 1 hr, water (2 mL) was added. The mixture was concentrated, the solid was filtered, washed with water (1×0.5 mL) and dried to give 3-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-4H-indeno[1,2-c]isoxazole-6-carbaldehyde as a yellow solid.
Reaction SMILES: C[O:2][C:3](=[O:28])[CH:4]([N:11]1[C:16](=[O:17])[CH:15]=[C:14]([O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[C:25](=[O:27])[CH3:26])[CH:13]=[N:12]1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1>O1CCOCC1.Cl>[C:25]([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[O:18][C:14]1[CH:13]=[N:12][N:11]([CH:4]([CH2:5][CH:6]2[CH2:7][CH2:8][CH2:9][CH2:10]2)[C:3]([OH:28])=[O:2])[C:16](=[O:17])[CH:15]=1)(=[O:27])[CH3:26]
Reactant: COC(=O)C(CC1CCCC1)n1ncc(Oc2ccccc2C(C)=O)cc1=O
Agent: Cl
Solvent: C1COCCO1
Product: CC(=O)c1ccccc1Oc1cnn(C(CC2CCCC2)C(=O)O)c(=O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 53.1 %

Procedure:
A solution of 2-[4-(2-acetyl-phenoxy)-6-oxo-6H-pyridazin-1-yl]-3-cyclopentyl-propionic acid methyl ester (23.4 g, 0.061 mol) in 1,4-dioxane (230 mL) and hydrochloric acid (230 mL) was stirred at reflux overnight. After this time, the reaction was cooled to 25° C., concentrated in vacuo, and was treated with acetone (200 mL) and stirred at 25° C. for 1 h. The resulting precipitate was collected by filtration, washed with petroleum ether, acetone, ethyl acetate, and then dried to afford 2-[4-(2-acetyl-phenoxy)-6-oxo-6H-pyridazin-1-yl]-3-cyclopentyl-propionic acid (12 g, 53%); ESI-MS 371 [M+H+]; HPLC: >98% (purity). 1H-NMR (300 MHz, DMSO-d6) δ 1.14 (m, 2H), 1.45 (m, 7H), 1.98 (m, 1H), 2.02 (m, 1H); 5.34 (m, 1H); 5.77 (s, 1H); 7.43 (m, 1H); 7.54 (m, 1H); 7.76 (m, 1H); 7.95 (m, 1H); 8.13 (m, 1H) 13.01 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[C:8]([C:15]2[N:16]=[N:17][CH:18]=[CH:19][CH:20]=2)=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].OS(O)(=O)=O.[CH3:26]O>>[CH3:26][O:5][C:4](=[O:6])[C:3]1[CH:7]=[C:8]([C:15]2[N:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[C:9]([C:11]([F:12])([F:13])[F:14])=[CH:10][C:2]=1[NH2:1]
Reactant: Nc1cc(C(F)(F)F)c(-c2cccnn2)cc1C(=O)O
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc(-c2cccnn2)c(C(F)(F)F)cc1N
Temperature: 110 °C
Yield: 46 %

Procedure:
2-Amino-5-pyridazin-3-yl-4-trifluoromethyl-benzoic acid (165 mg, 0.583 mmol) was dissolved in MeOH (15 mL). Concd H2SO4 (360 μL) was added and solution was heated to 110° C. for 11.5 h. The solution was concentrated in vacuo and the residue was dissolved in water (2 mL). The aqueous layer was neutralized with aq NaOH (2 N) and extracted with DCM. The organic phase was washed with brine, dried (Na2SO4), and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, EtOAc/hexanes (1:4 to 1:1)) to give the title compound (79 mg, 46%). API-ES: m/z 298.1 [M+H]+, rt 3.48 min
Reaction SMILES: CC1[N:3]([C@H:8]2[CH2:12][C@:11]([C:16]([N:18]3[CH2:27][CH2:26][C:25]4[N:24]=[CH:23][C:22]([C:28]([F:31])([F:30])[F:29])=[CH:21][C:20]=4[CH2:19]3)=[O:17])([CH:13]([CH3:15])[CH3:14])[CH:10]=[CH:9]2)C(C)=CC=1.NO>>[CH:13]([C@@:11]1([C:16]([N:18]2[CH2:27][CH2:26][C:25]3[N:24]=[CH:23][C:22]([C:28]([F:31])([F:30])[F:29])=[CH:21][C:20]=3[CH2:19]2)=[O:17])[CH2:12][C@H:8]([NH2:3])[CH:9]=[CH:10]1)([CH3:15])[CH3:14]
Reactant: Cc1ccc(C)n1[C@@H]1C=C[C@@](C(=O)N2CCc3ncc(C(F)(F)F)cc3C2)(C(C)C)C1
Agent: NO
Product: CC(C)[C@]1(C(=O)N2CCc3ncc(C(F)(F)F)cc3C2)C=C[C@@H](N)C1

Procedure:
treating the 6-{[(1S,4S)-4-(2,5-dimethyl-1H-pyrrol-1-yl)-1-isopropylcyclopent-2-en-1-yl]carbonyl}-3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,6-naphthyridine with hydroxylamine to form (1S,4S)-4-isopropyl-4-{[3-(trifluoromethyl)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl]carbonyl}cyclopent-2-en-1-amine; and
Reaction SMILES: C(O)(=O)C.[CH:5]([NH2:7])=[NH:6].Br[CH:9]([CH3:15])[C:10]([CH:12]1[CH2:14][CH2:13]1)=O.C(N(CC)CC)C>C(O)C>[CH:12]1([C:10]2[N:6]=[CH:5][NH:7][C:9]=2[CH3:15])[CH2:14][CH2:13]1
Reactant: N=CN
Reactant: CC(Br)C(=O)C1CC1
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Solvent: CCO
Product: Cc1[nH]cnc1C1CC1
Temperature: 60 °C

Procedure:
4-Cyclopropyl-5-methyl-1H-imidazole was synthesized according to the following procedure: Under nitrogen with stirring formamidine acetate (15.62 g, 150 mmol) was suspended in 40 ml anhydrous ethanol. 2-bromo-1-cyclopropylpropan-1-one (2.64 g, 15 mmol) was added via syringe and the mixture was heated to 60° C. for 2 hours. Triethylamine (21 ml, 155 mmol) was then added and the reaction was heated for an additional 12 hours at 60° C. The solvent was removed under reduced pressure, and the residue was dissolved in 50 ml of water. An aqueous solution of saturated sodium bicarbonate (20 ml) was added, followed by sodium chloride until the solution became saturated. The mixture was placed in a separatory funnel and extracted with ethyl acetate (3×50 ml), the organic extracts combined, dried over magnesium sulfate, filtered and then the solvent removed under reduced pressure. The oily residue was washed with hexanes (2×100 ml) to remove any residual triethylamine, leaving an oily residue which was >90% pure by 1H-NMR, which was further purified by loading onto a silica gel column in ethyl acetate and eluting with 0 to 10% methanol in ethyl acetate. Yield 0.607 g, 33%
Reaction SMILES: [S:1]1[CH2:5][CH:4]=[N:3][C:2]1=[O:6].Cl[CH2:8][CH2:9][NH:10][C:11]1[CH:26]=[CH:25][C:14]([CH:15]=[C:16]([C:21]([O:23][CH3:24])=[O:22])[C:17]([O:19][CH3:20])=[O:18])=[CH:13][CH:12]=1>>[O:6]=[C:2]1[N:3]([CH2:8][CH2:9][NH:10][C:11]2[CH:26]=[CH:25][C:14]([CH:15]=[C:16]([C:21]([O:23][CH3:24])=[O:22])[C:17]([O:19][CH3:20])=[O:18])=[CH:13][CH:12]=2)[C:4]2[CH:26]=[CH:11][CH:12]=[CH:13][C:5]=2[S:1]1
Reactant: COC(=O)C(=Cc1ccc(NCCCl)cc1)C(=O)OC
Reactant: O=C1N=CCS1
Product: COC(=O)C(=Cc1ccc(NCCn2c(=O)sc3ccccc32)cc1)C(=O)OC

Procedure:
The procedure is as in Step B of Example 37, starting from thiazolinone and with the replacement of dimethyl 2-{4-[2-chloroethoxy]benzylidene}malonate with dimethyl 2-{4-[(2-chloroethyl)amino]benzylidene}malonate.
Reaction SMILES: [OH:1][N:2]=[C:3]([C:6]1[CH:10]=[CH:9][S:8][CH:7]=1)[C:4]#[N:5].C(N(CC)CC)C.[CH3:18][S:19](Cl)(=[O:21])=[O:20]>O1CCCC1>[CH3:18][S:19]([O:1][N:2]=[C:3]([C:6]1[CH:10]=[CH:9][S:8][CH:7]=1)[C:4]#[N:5])(=[O:21])=[O:20]
Reactant: N#CC(=NO)c1ccsc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CS(=O)(=O)ON=C(C#N)c1ccsc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 48.6 %

Procedure:
In general analogy to the reaction described under 3.2, 15.2 g (0.1 mol) of α-hydroxyimino-thiophene-3-acetonitrile and 15.2 g (0.15 mol) of triethylamine are dissolved in 150 ml of tetrahydrofuran and to this is added dropwise a solution of 12.6 g (0.11 mol) of methanesulfonyl chloride at 0-5° C. After the addition is complete, the mixture is stirred for 30 minutes at 0° C. and then overnight at room temperature. The reaction mixture is filtered, the filtrate is washed with dilute hydrochloric acid and with saturated sodium chloride solution and then dried over magnesium sulfate. The solvent is distilled off on a rotary evaporator, giving a solid residue which is then recrystallised from ethyl acetate/hexane (2:1). 11.2 g (49%) of α-(methylsulfonyloxyimino)thiophene3-acetonitrile are obtained in the form of a colourless powder having an m.p. of 116-124° C. The 1H-NMR spectrum shows it to be the pure cis-isomer (Example 5a).
Reaction SMILES: [OH:1][C@H:2]([CH3:19])[CH2:3][CH2:4][C:5]1[C:10]([O:11][CH2:12][O:13][CH3:14])=[CH:9][CH:8]=[CH:7][C:6]=1[NH:15][C:16](=[O:18])[CH3:17].C(N(CC)CC)C.[CH3:27][S:28](Cl)(=[O:30])=[O:29].[Cl-].[Na+]>C(#N)C.C(OCC)(=O)C>[CH3:27][S:28]([O:1][C@@H:2]([CH2:3][CH2:4][C:5]1[C:10]([O:11][CH2:12][O:13][CH3:14])=[CH:9][CH:8]=[CH:7][C:6]=1[NH:15][C:16](=[O:18])[CH3:17])[CH3:19])(=[O:30])=[O:29]
Reactant: COCOc1cccc(NC(C)=O)c1CC[C@@H](C)O
Reactant: CS(=O)(=O)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COCOc1cccc(NC(C)=O)c1CC[C@@H](C)OS(C)(=O)=O
Temperature: 0 °C
Reaction time: 3 h
Yield: 100.1 %

Procedure:
A solution of (R)—N-(2-(3-hydroxybutyl)-3-(methoxymethoxy)phenyl)acetamide (4.0 g, 14.96 mmol) in acetonitrile (40 mL) was treated with triethylamine (3.13 mL, 22.44 mmol) and cooled to 0° C. Methanesulfonyl chloride (1.46 mL, 18.7 mmol) was slowly added and a precipitate formed immediately. The slurry was stirred at 0° C. After 3 h, the reaction mixture was diluted with ethyl acetate and poured into 5% aqueous sodium chloride solution (50 mL). The layers were separated, and the organic layer washed with additional 5% aqueous sodium chloride solution (40 mL). The combined aqueous layers were extracted with ethyl acetate, and the combined organic layers were concentrated under reduced pressure. The residue was dissolved in toluene (50-75 mL), which was then removed under reduced pressure to afford (R)-4-(2-acetamido-6-(methoxymethoxy)phenyl)butan-2-yl methanesulfonate (5.17 g, 100%) as an amber syrup. The crude was used without further purification. MS (ESI, pos. ion) m/z 250 [M−95].+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][C:13]=1[O:14][C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1)[C:7]([O:9][CH3:10])=[O:8])([O-])=O.Cl>CO.[Fe]>[NH2:1][C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][C:13]=1[O:14][C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1ccc(Oc2cccnc2)c([N+](=O)[O-])c1
Agent: [Fe]
Agent: Cl
Solvent: CO
Product: COC(=O)c1ccc(Oc2cccnc2)c(N)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 47.4 %

Procedure:
71 g of methyl 3-nitro-4-(3-pyridyloxy)benzoate and 52 g of iron powder are stirred in 500 ml of MeOH and, at RT, 500 ml of saturated aqueous HCl solution are slowly added. The mixture is then stirred at RT for 2 h and then the volatile constituents are removed in vacuo. The residue is stirred with 300 ml of saturated aqueous Na2CO3 solution (pH=11), and the precipitate is filtered off with suction. This precipitate is then extracted by boiling twice with 500 ml of EA each time, and the filtrate is extracted twice with 500 ml of EA each time. The combined EA phase is washed twice with 500 ml of water each time and dried over Na2SO4, and the solvent is removed in vacuo. 30 g of yellow-brown crystals, mp 101° C., are obtained.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]3[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=3[CH:9]=2)[C:4](O)=[CH:3][CH:2]=1.CN(C)C1C=CC=CC=1.P(Br)(Br)(Br)(Br)[Br:26]>C(#N)C>[Br:26][C:4]1[C:5]2[C:10](=[CH:9][C:8]3[CH:11]=[CH:12][CH:13]=[CH:14][C:7]=3[CH:6]=2)[N:1]=[CH:2][CH:3]=1
Reactant: Oc1ccnc2cc3ccccc3cc12
Reactant: BrP(Br)(Br)(Br)Br
Solvent: CN(C)c1ccccc1
Solvent: CC#N
Product: Brc1ccnc2cc3ccccc3cc12
Temperature: 0 °C
Yield: 56.2 %

Procedure:
Crude benzo[g]quinolin-4-ol (6) (5.07 mmol) was dissolved in 50 mL of acetonitrile (0.1 M) and cooled to 0° C. under a nitrogen atmosphere. N,N-dimethylaniline (3.2 mL, 5 equivalents) was added followed by 3.3 g of phosphorus pentabromide (1.5 equivalents). After removal of the bath, the mixture was heated to reflux and followed by TLC until complete. Upon cooling to rt, the mixture was slowly poured onto ice water and extracted with methylene chloride three times. The organic layers were combined, washed with brine, dried with magnesium sulfate, and concentrated in vacuo. Flash chromatography (gradient: 9:1 to 8:2 to 7:3 hexanes:EtOAc) afforded 736 mg of clean 4-bromobenzo[g]quinoline (7a) in 55% yield for the 2 steps.
Reaction SMILES: [CH:1]([CH:19]1[CH2:24][C:23](=[O:25])O[C:20]1=[O:21])=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[NH2:26]CCNCCNCCNCCN>O>[CH:1]([CH:19]1[CH2:24][C:23](=[O:25])[NH:26][C:20]1=[O:21])=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: NCCNCCNCCNCCN
Reactant: CCCCCCCCCCCCCCCCC=CC1CC(=O)OC1=O
Solvent: O
Product: CCCCCCCCCCCCCCCCC=CC1CC(=O)NC1=O

Procedure:
Into a 189 liter (50 gallon) stainless steel reactor, charge 62.6 kg. (137.8 lbs.) of double-bond isomerized-octadecenyl succinic anhydride (Dixie Chemical Company, Inc.) and 13.1 kg. (28.8 lbs.) of 150 solvent neutral (S150N) mineral oil. Heat the contents of the reactor to 130° C.±10° C. under a nitrogen atmosphere and stir at a speed of 150 rpm. Charge 15 kg. (33 lbs.) of tetraethylene pentamine (Union Carbide "Ultra High Purity" grade) below the surface of the reactor contents and heat the contents to 160° C.±5° C. Strip with nitrogen for approximately 21/2 hours or until water no longer evolves.
Reaction SMILES: C(NC(C)C)(C)C.[Cl:8][C:9]1[CH:17]=[C:16](I)[C:12]2[O:13][CH2:14][O:15][C:11]=2[C:10]=1[NH2:19].[CH2:20]([O:23][CH3:24])[C:21]#[CH:22]>C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu](I)I>[Cl:8][C:9]1[CH:17]=[C:16]([C:22]#[C:21][CH2:20][O:23][CH3:24])[C:12]2[O:13][CH2:14][O:15][C:11]=2[C:10]=1[NH2:19]
Reactant: C#CCOC
Reactant: Nc1c(Cl)cc(I)c2c1OCO2
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CC(C)NC(C)C
Solvent: CCOC(C)=O
Product: COCC#Cc1cc(Cl)c(N)c2c1OCO2
Temperature: 25 °C

Procedure:
Bis(Triphenyl-phosphine)palladium(II) chloride (472 mg), copper iodide (192 mg) and diisopropylamine (680 mg) were added to a stirred solution of 5-chloro-7-iodo-1,3-benzodioxol-4-amine (1000 mg) and methyl propargyl ether (471 mg) in ethyl acetate (10 mls) at −20° C. The reaction was allowed to warm to ambient temperature over 16 hours. The reaction mixture was partitioned between Ethyl acetate and saturated NaHCO3. The organics were washed with water and saturated brine and dried over magnesium sulfate. The product was purified by column chromatography on silica using a gradient of 80-100% Dichloromethane/isohexane as eluent. The 5-chloro-7-(3-methoxyprop-1-ynyl)-1,3-benzodioxol-4-amine product was thus obtained as a tan crystalline solid (200 mg); NMR Spectrum: (DMSOd6) 3.28 (s, 3H), 4.26 (s, 2H), 5.52 (s, 2H), 6.05 (s, 2H), 6.93 (s, 1H).
Reaction SMILES: C[O:2][C:3]1[C:4]([CH3:36])=[C:5]([C:27]([O:34]C)=[C:28]([O:32][CH3:33])[C:29]=1[O:30][CH3:31])[CH2:6][C:7]1[C:8]([C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)=[C:9]([CH:18]=[CH:19][CH:20]=1)[C:10]([N:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)=[O:11].O=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+].C(=O)([O-])O.[Na+]>C(#N)C.O>[CH3:31][O:30][C:29]1[C:3](=[O:2])[C:4]([CH3:36])=[C:5]([CH2:6][C:7]2[C:8]([C:21]3[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=3)=[C:9]([CH:18]=[CH:19][CH:20]=2)[C:10]([N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[O:11])[C:27](=[O:34])[C:28]=1[O:32][CH3:33]
Reactant: COc1c(C)c(Cc2cccc(C(=O)N3CCCCC3)c2-c2cccnc2)c(OC)c(OC)c1OC
Agent: O=C([O-])O
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Solvent: O
Solvent: CC#N
Product: COC1=C(OC)C(=O)C(Cc2cccc(C(=O)N3CCCCC3)c2-c2cccnc2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.9 %

Procedure:
N-[3-(3,4,5,6-Tetramethoxy-2-methylbenzyl)-2-(3-pyridyl)benzoyl]piperidine (80 mg, 0.1632 mmol) was dissolved in a mixed solvent of acetonitrile (9 ml) and water (3 ml), then CAN (128 mg, 0.2335 mmol) was added thereto at room temperature and the mixture was stirred for 1 hour. The reaction solution poured into water, neutralized with a saturated aqueous solution of sodium hydrogen carbonate and extracted with ethyl acetate. The extract was washed with water and dried and the solvent was evaporated therefrom. The residue was purified by preparative thin layer silica gel (hexane:ethyl acetate=1:3) to give the title compound (51 mg, 0.1108 mmol, 68%). This compound was converted to a methanesulfonate by the method according to Example 58.
Reaction SMILES: C(OCC)(=O)C(C)=C.ON1C(=O)C2=CC=CC=C2C1=O.O=O.[OH:23][C:24]([CH3:35])([CH2:30][C:31]([OH:34])([CH3:33])[CH3:32])[C:25](OCC)=[O:26]>C([O-])(=O)C.[Co+2].C([O-])(=O)C.C(#N)C.CC(O)C>[OH:23][C:24]1([CH3:35])[CH2:30][C:31]([CH3:33])([CH3:32])[O:34][C:25]1=[O:26]
Reactant: CCOC(=O)C(C)(O)CC(C)(C)O
Agent: [Co+2]
Agent: C=C(C)C(=O)OCC
Agent: CC(=O)[O-]
Solvent: CC(C)O
Solvent: CC#N
Product: CC1(C)CC(C)(O)C(=O)O1

Procedure:
A mixture of 3 mmol of ethyl methacrylate, 4 ml of 2-propanol, 0.6 mmol of N-hydroxyphthalimide, 0.015 mmol of cobalt(II) acetate, and 0.045 mmol of acetylacetonatocobalt(III), and 1 ml of acetonitrile was stirred at 70° C. in an oxygen atmosphere (1 atm) for 5 hours. A gas chromatographic analysis of products in a reaction mixture revealed that ethyl 2,4-dihydroxy-2,4-dimethylpentanoate and α-hydroxy-α,γ,γ-trimethyl-γ-butyrolactone were formed in yields of 1% and 65%, respectively. The conversion rate from ethyl methacrylate was 85%.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]([C@@:7]1([NH:12][C:13]([C@@H:15]2[CH2:19][C@@H:18]([OH:20])[CH2:17][NH:16]2)=[O:14])[CH2:9][C@H:8]1[CH:10]=[CH2:11])=[O:6])[CH3:3].[CH2:21]([O:25][CH2:26][CH2:27][C@H:28]([NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[C:29](O)=[O:30])[CH2:22][CH:23]=[CH2:24].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C1(C)C=CC=CC=1.C(#N)C.O.C(OCC)(=O)C>[CH:21]([O:25][CH2:26][CH2:27][C@H:28]([NH:32][C:33]([O:35][C:36]([CH3:37])([CH3:39])[CH3:38])=[O:34])[C:29]([N:16]1[CH2:17][C@H:18]([OH:20])[CH2:19][C@H:15]1[C:13]([NH:12][C@:7]1([C:5]([O:4][CH2:2][CH3:3])=[O:6])[CH2:9][C@H:8]1[CH:10]=[CH2:11])=[O:14])=[O:30])=[CH:22][CH2:23][CH3:24]
Reactant: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@H](O)CN1)C(=O)OCC
Reactant: C=CCCOCC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@H](O)CN1C(=O)[C@H](CCOC=CCC)NC(=O)OC(C)(C)C)C(=O)OCC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(1R,2S)-ethyl-1-((2S,4R)-4-hydroxypyrrolidine-2-carboxamido)-2-vinylcyclopropanecarboxylate hydrochloride salt (WO2005095403) (1.21 g, 3.84 mmol), (S)-4-(but-3-enyloxy)-2-(tert-butoxycarbonylamino)-butanoic acid (1.00 g, 3.66 mmol) and HATU (1.53 g, 4.03 mmol) in toluene (18 mL) and ACN (2 mL) was added DIEA (1.28 mL, 4.03 mmol) at 0° C. The reaction warmed to rt and stirred at rt for 1 hr. Ethyl acetate (30 mL) and water (20 mL) was added. The organic layer was separated and washed with brine, dried over sodium sulfate. After removal of solvent, the residue was purified by chromatography (Ethyl acetate) to give (1R,2S)-ethyl 1-((2S,4R)-1-((S)-4-(but-enyloxy)-2-(tert-butoxycarbonylamino)butanoyl)-4-hydroxypyrrolidine-2-carboxamido)-2-vinylcyclopropanecarboxylate as white wax solid (1.7 g, 89%). MS: Calcd.: 523; Found: [M+H]+ 524.