Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(=[O:4])[CH2:2][CH3:3].[CH2:6]([CH:9]1[CH2:14][CH2:13][CH:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:21]2[CH:22]=[C:23]([OH:27])[CH:24]=[CH:25][CH:26]=2)[CH2:11][CH2:10]1)[CH2:7][CH3:8].O.Cl>N1C=CC=CC=1>[C:1]([O:27][C:23]1[CH:24]=[CH:25][CH:26]=[C:21]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[CH:12]2[CH2:13][CH2:14][CH:9]([CH2:6][CH2:7][CH3:8])[CH2:10][CH2:11]2)[CH:22]=1)(=[O:4])[CH2:2][CH3:3]
Reactant: CCC(=O)Cl
Reactant: CCCC1CCC(c2ccccc2-c2cccc(O)c2)CC1
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: CCCC1CCC(c2ccccc2-c2cccc(OC(=O)CC)c2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 107.9 %

Procedure:
Under a nitrogen atmosphere, 1.6 g of propanoyl chloride was added to 5.0 g of 3-((4-propylcyclohexyl)phenyl)phenol (1) dissolved in 10 mL (mili-litter) of pyridine under cooling with iced water, and after completing dropwise addition, the mixture was stirred at ambient temperature for 2 hours. The resulting solution was added to 20 mL of 3N hydrochloric acid. The aqueous layer was extracted with diethyl ether, which was added to the organic layer, and the organic layer was washed with a saturated salt solution and then dried over anhydrous magnesium sulfate. The solvent was distilled off to obtain 6.42 g of 3-((4-propylcyclohexyl)phenyl)phenyl propanoate (2).
Reaction SMILES: Cl.C(OC([N:9]1[CH2:13][CH2:12][CH:11]([N:14]2[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)=[C:15]2[C:26]2[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=2)[CH2:10]1)=O)(C)(C)C>O1CCOCC1.C(O)C>[F:25][C:22]1[CH:21]=[CH:20][C:19]([C:16]2[CH:17]=[CH:18][N:14]([CH:11]3[CH2:12][CH2:13][NH:9][CH2:10]3)[C:15]=2[C:26]2[CH:27]=[CH:28][N:29]=[CH:30][CH:31]=2)=[CH:24][CH:23]=1
Reactant: CC(C)(C)OC(=O)N1CCC(n2ccc(-c3ccc(F)cc3)c2-c2ccncc2)C1
Agent: Cl
Solvent: CCO
Solvent: C1COCCO1
Product: Fc1ccc(-c2ccn(C3CCNC3)c2-c2ccncc2)cc1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 87.3 %

Procedure:
6.01 ml (24.05 mmol) of a 4N solution of hydrogen chloride in dioxane were added to a solution of 1.96 g (4.81 mmol) of (±)-1-[1-(t-butoxycarbonyl)pyrrolidin-3-yl]-3-(4-fluorophenyl)-2-(pyridin-4-yl)-1H-pyrrole [prepared as described in step 18(i) above] in 10 ml of ethanol. The resulting mixture was stirred at 50° C. for 30 minutes, after which the solvent was distilled off under reduced pressure. A saturated aqueous solution of sodium hydrogencarbonate was added to the residue thus obtained, and then this was extracted with ethyl acetate. The organic extract was washed with water, dried over anhydrous magnesium sulfate and then concentrated by evaporation under reduced pressure to give 1.29 g (yield 87%) of the title compound as a pale yellow powder.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH2:13][CH2:14][N:15]1[N:19]=[CH:18][CH:17]=[N:16]1)[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.Cl.[N:22]1[CH:27]=[CH:26][CH:25]=[N:24][C:23]=1[C:28]1([NH2:31])[CH2:30][CH2:29]1.CCN(CC)CC.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O.CCOC(C)=O>[C:1]([O:5][C:6](=[O:7])[NH:8][CH:9]([C:10](=[O:12])[NH:31][C:28]1([C:23]2[N:24]=[CH:25][CH:26]=[CH:27][N:22]=2)[CH2:30][CH2:29]1)[CH2:13][CH2:14][N:15]1[N:19]=[CH:18][CH:17]=[N:16]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: NC1(c2ncccn2)CC1
Reactant: CC(C)(C)OC(=O)NC(CCn1nccn1)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NC(CCn1nccn1)C(=O)NC1(c2ncccn2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of the 2-tert-butoxycarbonylamino-4-1,2,3-triazol-2-yl-butyric acid (0.1 g, 0.37 mmol) in DMF (2 mL) was added 1-pyrimidin-2-yl-cyclopropylamine dihydrochloride (50 mg, 0.24 mmol) followed by Et3N (0.1 ml, 0.74 mmol) and HATU (211 mg, 0.55 mmol). The mixture was stirred at room temperature for 1 h. The mixture was diluted with water and EtOAc. The layers were separated and the organic layer was washed with water (3×30 mL), brine (2×30 mL), dried over MgSO4, filtered, and concentrated in vacuo to yield crude [1-(1-pyrimidin-2-yl-cyclopropyl-carbamoyl)-3-1,2,3-triazol-2-yl-propyl]-carbamic acid tert-butyl ester. The product was not purified and was used in subsequent reactions.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([F:31])([F:30])[C:12]3[N:17]=[N:16][C:15]([NH:18]CC4C=CC(OC)=CC=4OC)=[CH:14][CH:13]=3)=[N:9][N:10]=2)[CH:7]=1.C1(OC)C=CC=CC=1>C(O)(C(F)(F)F)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([F:31])([F:30])[C:12]3[N:17]=[N:16][C:15]([NH2:18])=[CH:14][CH:13]=3)=[N:9][N:10]=2)[CH:7]=1
Reactant: COc1ccc(CNc2ccc(C(F)(F)c3nnc4ccc(Br)cn34)nn2)c(OC)c1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: Nc1ccc(C(F)(F)c2nnc3ccc(Br)cn23)nn1
Yield: 95.8 %

Procedure:
A solution of 6-((6-bromo-[1,2,4]triazolo[4,3-a]pyridin-3-yl)difluoromethyl)-N-(2,4-dimethoxybenzyl)pyridazin-3-amine (16.5 g, 33.6 mmol) and anisole (5.45 g, 50.4 mmol) in TFA (150 mL) was stirred at 70° C. for 30 min. The reaction was concentrated to dryness via rotary evaporation and the resulting residue was sonicated in a solution of Et2O/NaHCO3 (pH=7). The resulting solid was collected by filtration, rinsed with water and then Et2O, and dried in vacuum over P2O5 to provide the title compound, 6-((6-bromo-[1,2,4]triazolo[4,3-a]pyridin-3-yl)difluoromethyl)pyridazin-3-amine 45H (11.0 g, 32.2 mmol, 96%). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.14 (d, J=9.35 Hz, 1 H) 7.71 (dd, J=9.85, 1.77 Hz, 1 H) 7.92 (d, J=9.35 Hz, 1 H) 7.92 (d, J=10.20 Hz, 1 H) 8.02 (d, J=10.20, 1 H) 8.74 (s, 1 H). ESI-MS:m/z 340.9 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:9][CH2:10][C:11]([NH:13][C:14]2[C:15]([CH3:23])=[C:16]([CH:20]=[CH:21][CH:22]=2)[C:17]([OH:19])=O)=[O:12])[CH:5]=[CH:6][C:7]=1[F:8].[CH3:24][N:25]([CH3:29])[CH2:26][CH2:27][NH2:28].F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1.CN(C1C=CC=CN=1)C.C(N(CC)C(C)C)(C)C>CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]([NH:9][CH2:10][C:11]([NH:13][C:14]2[C:15]([CH3:23])=[C:16]([CH:20]=[CH:21][CH:22]=2)[C:17]([NH:28][CH2:27][CH2:26][N:25]([CH3:29])[CH3:24])=[O:19])=[O:12])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CN(C)CCN
Reactant: Cc1c(NC(=O)CNc2ccc(F)c(F)c2)cccc1C(=O)O
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: CN(C)c1ccccn1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(NC(=O)CNc2ccc(F)c(F)c2)cccc1C(=O)NCCN(C)C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 3-[2-(3,4-difluorophenylamino)acetylamino]-2-methylbenzoic acid (0.2 g), N,N-dimethylethylenediamine (0.08 ml), bromotripyrrolidinophosphonium hexafluorophosphate (PyBroP®) (0.34 g), dimethylaminopyridine (0.07 g) and N,N-diisopropylethylamine (0.31 ml) in dimethylformamide (5 ml) was stirred at room temperature under N2 for 18 hours. The reaction mixture was partitioned between ethyl acetate and water and the organic phase was washed with water and brine, dried (MgSO4) and evaporated. The crude product was triturated with diethyl ether. The resultant solid was triturated with ethyl acetate and filtered. Yield 70 mg.
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:5]2[O:6][CH2:7][C:8]([CH3:10])([CH3:9])[C:4]=2[CH:3]=1.CN(C1C=CC=CN=1)C.[C:26](Cl)(=[O:29])[CH2:27][CH3:28].CCCCCC>C(Cl)Cl.CCOCC.CCOC(C)=O>[C:13]([C:11]1[C:5]2[O:6][CH2:7][C:8]([CH3:10])([CH3:9])[C:4]=2[CH:3]=[C:2]([NH:1][C:26](=[O:29])[CH2:27][CH3:28])[CH:12]=1)([CH3:16])([CH3:15])[CH3:14]
Reactant: CCC(=O)Cl
Reactant: CC(C)(C)c1cc(N)cc2c1OCC2(C)C
Agent: CN(C)c1ccccn1
Solvent: CCOC(C)=O
Solvent: CCOCC
Solvent: CCCCCC
Product: CCC(=O)Nc1cc(C(C)(C)C)c2c(c1)C(C)(C)CO2
Reaction time: 1 h

Procedure:
To a solution of 5-amino-7-tert-butyl-3,3-dimethyl-2,3-dihydrobenzo[b]furan (400 mg, 1.84 mmol) and dimethylaminopyridine (61 mg, 0.50 mmol) in CH2Cl2 (5 mL) is added at 24° C. propionyl chloride (160 μL, 1.84 mmol) in a single portion. The reaction is stirred for 1 h, and monitored by TLC (hexane:EtOAc, 9:1). The mixture is diluted with Et2O (5 mL), and a fine precipitate is filtered off. The filtrate is evaporated to an orange solid which is purified by preparative TLC (hexane:EtOAc, 9:1) to yield N-(7-tert-butyl-3,3-dimethyl-2,3-dihydrobenzo[b]-furan-5-yl)propanamide as a white solid.
Reaction SMILES: ClCCl.[OH:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]1[C:19]([OH:20])=[C:18]([O:21][CH3:22])[C:17]([O:23][CH3:24])=[CH:16][C:15]=1[CH3:25].N1C=CC=CC=1.[O:32]=O>C1C=C(C=NCCN=CC2C([O-])=CC=CC=2)C([O-])=CC=1.[Co+2]>[OH:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]1[C:19](=[O:20])[C:18]([O:21][CH3:22])=[C:17]([O:23][CH3:24])[C:16](=[O:32])[C:15]=1[CH3:25]
Reactant: O=O
Reactant: COc1cc(C)c(CCCCCCCCCO)c(O)c1OC
Agent: [Co+2]
Agent: [O-]c1ccccc1C=NCCN=Cc1ccccc1[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC1=C(OC)C(=O)C(CCCCCCCCCO)=C(C)C1=O

Procedure:
To a dichloromethane solution (30 ml) of 6-(9-hydroxynonyl)-2,3-dimethoxy-5-methylphenol (1.8 g) are added pyridine (0.5 ml) and bis(salicylidene)ethylenediiminocobalt(II) (32 mg). The mixture is stirred in oxygen streams at atmospheric temperature and pressure. The reaction product is isolated as in Example 7 and recrystallized from hexane. The above procedure yields 6-(9-hydroxynonyl)-2,3-dimethoxy-5-methyl-1,4-benzoquinone (1.2 g) as orange-yellow needles melting at 45° C.
Reaction SMILES: [CH:1]([NH:4][CH:5]([CH3:7])[CH3:6])([CH3:3])[CH3:2].C1(S(O[CH2:18][CH:19]([CH3:21])[CH3:20])(=O)=O)C=CC=CC=1.[OH-].[K+]>>[CH:1]([N:4]([CH2:18][CH:19]([CH3:21])[CH3:20])[CH:5]([CH3:7])[CH3:6])([CH3:3])[CH3:2]
Reactant: CC(C)NC(C)C
Reactant: CC(C)COS(=O)(=O)c1ccccc1
Agent: [K+]
Agent: [OH-]
Product: CC(C)CN(C(C)C)C(C)C
Reaction time: 72 h
Yield: 68 %

Procedure:
A mixture of diisopropylamine (20.24 g, 0.2 mol) and isobutyl phenylsulfonate (29.83 g, 0.1 mol) was refluxed with stirring for 72 hours. Aqueous 5M potassium hydroxide (30 ml, 0.15 mol) was added. The organic phase was separated and the aqueous phase was extracted with n-pentane (50 ml). The organic solutions were combined, dried over anhydrous magnesium sulfate and the produce was isolated by distillation to yield 10.70 g, 68% of the title product, bp 75-77° C./45 mm Hg. 1H NMR CDCl3 δ ppm, 0.83 (d, J=6.5 Hz, 6H, CH3), 0.95 (d, J=6.5 Hz, 12H, CH3), 1.59 (nonet, J=6.5 Hz, 1H, CH), 2.10 (d, J=6.5 Hz, 2H, CH2), 2.95 (sep, J=6.5 Hz, 2H, CH).
Reaction SMILES: [NH2:1][C:2]1[C:11](Br)=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH:13]([N:16]([CH:28]([CH3:30])[CH3:29])[C:17]([C:19]1[CH:24]=[CH:23][N:22]=[CH:21][C:20]=1B(O)O)=[O:18])([CH3:15])[CH3:14].C(=O)([O-])[O-].[Cs+].[Cs+].O>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[NH2:1][C:2]1[C:11]([C:24]2[CH:23]=[N:22][CH:21]=[CH:20][C:19]=2[C:17](=[O:18])[N:16]([CH:28]([CH3:30])[CH3:29])[CH:13]([CH3:14])[CH3:15])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: CC(C)N(C(=O)c1ccncc1B(O)O)C(C)C
Reactant: COC(=O)c1cccc(Br)c1N
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1cccc(-c2cnccc2C(=O)N(C(C)C)C(C)C)c1N
Yield: 31 %

Procedure:
Methyl 2-amino-3-bromobenzoate (1.0 eq, 652 mg, 2.61 mmol) and 4-(diisopropylcarbamoyl)pyridin-3-ylboronic acid (prepared according to the procedure described in PCT patent application WO2005/105814), 1.0 eq, 600 mg, 2.61 mmol) were combined with cesium carbonate (2.0 eq, 1.699 g, 5.21 mmol) in dioxane containing 5% of water (6 ml). The mixture was degassed by bubbling nitrogen for 10 minutes. PdCl2(dppf) (0.05 eq, 95 mg) was added and the reaction stirred at reflux for 2 hours. Dioxane was evaporated, water was added and the material extracted with CH2Cl2 (3×). The combined extracts were dried over Na2SO4 and the solvents removed in vacuo. The material was purified by flash chromatography on silica gel (eluant 0.5% MeOH in CH2Cl2) to afford methyl 2-amino-3-(4-(diisopropylcarbamoyl)pyridin-3-yl)benzoate as a greenish foam (244 mg, 31% yield). LCMS (ES): >95% pure, m/z 356 [M+1]+.
Reaction SMILES: [C:1]1([C:7]2[NH:11][CH:10]=[C:9]([C:12](OCC)=[O:13])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].C([Al+]CC(C)C)C(C)C.O>O1CCCC1.C1(C)C=CC=CC=1>[C:1]1([C:7]2[NH:11][CH:10]=[C:9]([CH2:12][OH:13])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)c1c[nH]c(-c2ccccc2)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Solvent: Cc1ccccc1
Product: OCc1c[nH]c(-c2ccccc2)c1
Temperature: -78 °C
Reaction time: 1 h
Yield: 86.9 %

Procedure:
A solution (100 mL) of ethyl 5-phenyl-1H-pyrrole-3-carboxylate (2.16 g) in tetrahydrofuran was cooled to −78° C., and a 1.5 mol/L solution (24 mL) of diisobutylaluminum hydride in toluene was added dropwise over 10 min. The mixture was further stirred at −78° C. for 1 hr, water (2 mL) was added dropwise over 2 min, and the mixture was further stirred at room temperature for 1 hr. The reaction mixture was filtered using celite and anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound as a pale-red powder (yield 1.51 g, 87%).
Reaction SMILES: Br.Br.[N:3]1([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.[C:16](OC(=O)C)(=[O:18])[CH3:17].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[C:16]([N:6]1[CH2:5][CH2:4][N:3]([C:9]2[CH:10]=[CH:11][C:12]([OH:15])=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)(=[O:18])[CH3:17]
Reactant: Oc1ccc(N2CCNCC2)cc1
Reactant: CC(=O)OC(C)=O
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CC(=O)N1CCN(c2ccc(O)cc2)CC1

Procedure:
A mixture of 33.8 parts of 4-(1-piperazinyl)-phenol dihydrobromide, 11.2 parts of acetic acid anhydride, 42 parts of potassium carbonate and 300 parts of 1,4-dioxane is stirred and refluxed for 3 days. The reaction mixture is filtered and the filtrate is evaporated. The solid residue is stirred in water and sodium hydrogen carbonate is added. The whole is stirred for 30 minutes. The precipitated product is filtered off and dissolved in a diluted hydrochloric acid solution. The solution is extracted with trichloromethane. The acid aqueous phase is separated and neutralized with ammonium hydroxide. The product is filtered off and crystallized from ethanol, yielding 5.7 parts of 1-acetyl-4-(4-hydroxyphenyl)piperazine; mp. 181.3° C.
Reaction SMILES: P([O-])([O-])[O-].[C:5]1([C:11]#[CH:12])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.CCC[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].C(=O)=O>>[CH2:12]=[CH:11][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[C:18]1([C:17]#[CH:16])[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CCCCCCCCCCC
Agent: O=C=O
Agent: [O-]P([O-])[O-]
Solvent: C#Cc1ccccc1
Product: C=Cc1ccccc1
Temperature: -60 °C
Reaction time: 20 h

Procedure:
To a 300 mL stainless steel autoclave equipped with two sapphire windows containing Rh(acac)(CO)2 (10.4 mg, 4×10-2 mmol) and phosphite ligand MCP-1 (8×10-2 mmol) was added phenylacetylene (204 mg, 2.0 mmol) and n-undecane (156 mg, 1.0 mmol) (the internal standard for GC analysis). The air was replaced by CO through pressurization (2-3 atm) and release for 2-3 times, and CO (7 atm) was introduced followed by H2 (14 atm). The reaction vessel was cooled to -60° C. and CO2 (78 atm) was introduced. The mixture was allowed to stir at 60° C. and 100 atm for 20 h. The autoclave was cooled to 0° C. and all the gasses were carefully released. The conversion of the reaction was estimated by 1H NMR analysis and the products ratio and yields were determined by GLC analysis using an authentic sample of each aldehyde. Products were also identified by 1H NMR analyses. Under these conditions, a considerable amount of styrene formed through hydrogenation of phenylacetylene remained unreacted (20%) at 80% conversion. A mixture of saturated and unsaturated aldehydes was formed in 60% yield, which consisted of 3-phenylpropanal (46%). 2-phenylpropanal (48%), 3-phenylpropenal (0.4%), and 2-phenylpropenal (5.6%).
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]([O:9]CC)=[O:8])=[C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[O:4][N:3]=1>C(O)C>[CH3:1][C:2]1[C:6]([C:7]([OH:9])=[O:8])=[C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[O:4][N:3]=1
Reactant: CCOC(=O)c1c(C)noc1-c1ccccc1
Solvent: CCO
Product: Cc1noc(-c2ccccc2)c1C(=O)O
Temperature: 25 °C
Yield: 16.9 %

Procedure:
The ethyl 3-methyl-5-phenyl-4-isoxazole carboxylate (1.45 g) obtained in the above reaction was dissolved in ethanol (45 ml) and distilled water (15 ml), potassium hydroxide (1.3 g) was added thereto at room temperature, and the mixture was stirred under heat reflux for 1 hour. After the completion of the reaction, the mixture was concentrated to remove ethanol, distilled water was added thereto, and the mixture was acidified (pH=4) using 1%-aqueous hydrochloric acid. Extraction by liquid separation using dichloromethane and washing with a saturated saline solution were then performed. The product was dried over sodium sulfate followed by concentration and the residue was purified by silica gel column chromatography using a chloroform-methanol elution system. Thus, 3-methyl-5-phenyl-4-isoxazole carboxylic acid (215 mg, yield 16.9%), a starting compound for the Curtius reaction described in Example 1, was obtained.
Reaction SMILES: [CH:1]1([S:4][C:5]2[CH:20]=[CH:19][CH:18]=[CH:17][C:6]=2/[CH:7]=[N:8]/[CH2:9][CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:3][CH2:2]1.CCN(CC)CC>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[CH:1]1([S:4][C:5]2[CH:20]=[CH:19][CH:18]=[CH:17][C:6]=2[CH:7]2[CH:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:10][CH2:9][NH:8]2)[CH2:2][CH2:3]1
Reactant: CCOC(=O)CCC/N=C/c1ccccc1SC1CC1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C1CCNC1c1ccccc1SC1CC1
Reaction time: 3 h

Procedure:
To 160C (15 mmol) in CH2Cl2 (100 mL) at −15° C. was added Et3N (2.1 mL, 15 mmol) followed by TiCl4 (1.0 M in CH2Cl2, 30 mL, 30 mmol). The mixture was stirred from −15° C. to rt over 3.0 h before it was quenched with sat. K2CO3 (100 mL) at 0° C. and stirred at rt for 1.0 h. The mixture was filtered through a pad of wet celite, extracted with CH2Cl2 (3×40 mL). The organic layer was washed with water, dried over Na2SO4. A small portion of the dried organic layer was concentrated to give crude ethyl 2-(2-(cyclopropylthio)phenyl)pyrrolidine-3-carboxylate: 1H NMR indicated a mixture of cis and trans isomer in ca. 1:1 ratio. LC-MS 292 (M+H). To the above ethyl 2-(2-(cyclopropylthio)phenyl)pyrrolidine-3-carboxylate in CH2Cl2 was added Et3N (2.1 mL, 15 mmol) and di-tert-butyl dicarbonate (1.0 M in THF, 15 mL, 15 mmol). The mixture was stirred at rt over night before it was quenched with 0.5 N HCl (50 mL). The organic layer was washed with brine, dried (Na2SO4), filtered and concentrated. The resulting residue was purified via silica gel chromatography (0-30% ethyl acetate/hexanes) to provide 160D (3.3 g, 56%) as an oil. 1H NMR (400 MHz, CDCl3) δ ppm: a mixture of cis and trans isomer in 1:1 ratio: 0.66-0.75 (m, 2H) 0.87 (t, J=7.03 Hz, 3H) 1.05-1.08 (m, 2H) 1.14-1.16 (s, 9H) 2.02-2.18 (m, 3H) 3.43-4.19 (m, 5H) 7.06-7.13 (m, 2H) 7.16-7.25 (m, 1H) 7.51-7.60 (m, 1H); LC-MS 292 (M+H).
Reaction SMILES: O=[C:2]1[C:11]2[N:10]=[CH:9][CH:8]=[CH:7][C:6]=2[CH2:5][CH2:4][CH2:3]1.Cl.[NH2:13][OH:14].C([O-])(=O)C.[Na+]>C(O)C.O.O>[N:13](=[C:2]1[C:11]2[N:10]=[CH:9][CH:8]=[CH:7][C:6]=2[CH2:5][CH2:4][CH2:3]1)[OH:14]
Reactant: NO
Reactant: O=C1CCCc2cccnc21
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: ON=C1CCCc2cccnc21
Yield: 79.7 %

Procedure:
A solution of 2.22 g of 8-oxo-5,6,7,8-tetrahydroquinoline, 2.1 g of hydroxylamine hydrochloride, and 4.1 g of sodium acetate in 15 mL of 3:1 ethanol-water was heated at 70° C. for 1 h. The reaction mixture was then diluted with water and extracted with dichloromethane. Evaporation of the extracts gave 1.95 g of product which was pure enough by NMR to be used in the next step.
Reaction SMILES: [CH2:1]([O:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]2[O:13][C:12](B(O)O)=[CH:11][C:10]=2[CH:17]=1)[CH3:2].[C:18]([O:22][C:23](=[O:36])[N:24]([C:26]1[CH:31]=[CH:30][C:29](Br)=[C:28]([N+:33]([O-:35])=[O:34])[N:27]=1)[CH3:25])([CH3:21])([CH3:20])[CH3:19].CCN(CC)CC>C(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>[C:18]([O:22][C:23](=[O:36])[N:24]([C:26]1[CH:31]=[CH:30][C:29]([C:12]2[O:13][C:9]3[CH:8]=[CH:7][C:6]([O:5][CH2:4][O:3][CH2:1][CH3:2])=[CH:17][C:10]=3[CH:11]=2)=[C:28]([N+:33]([O-:35])=[O:34])[N:27]=1)[CH3:25])([CH3:21])([CH3:19])[CH3:20]
Reactant: CCOCOc1ccc2oc(B(O)O)cc2c1
Reactant: CN(C(=O)OC(C)(C)C)c1ccc(Br)c([N+](=O)[O-])n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOCOc1ccc2oc(-c3ccc(N(C)C(=O)OC(C)(C)C)nc3[N+](=O)[O-])cc2c1
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 58 %

Procedure:
To a degassed solution of 5-ethoxymethoxy-benzofuran boronic acid (4) (0.69 g, 2.63 mmol) in ethanol (17.5 mL), (5-bromo-6-nitro-pyridin-2-yl)-methyl-carbamic acid tert-butyl ester 12 (0.50 g, 1.51 mmol), Pd(PPh3)2Cl2 (0.14 g, 0.20 mmol) and Et3N (0.48 mL, 3.46 mmol) were added. The reaction mixture was stirred at 90° C. for 30 minutes. The reaction mixture was cooled to 0° C. and clear filtered. Volatiles were removed under reduced pressure. The residue was diluted with water and the mixture was extracted with ethyl acetate. The organic extract was washed with brine and concentrated under reduced pressure. The crude product was purified by flash column chromatography. Evaporation of solvent gave title compound 13 (58% yield).
Reaction SMILES: C1C=C(Cl)C=[C:3]([C:8]([O:10][OH:11])=O)C=1.[CH3:12][C:13]1[S:17][CH:16]=[C:15](/[CH:18]=[C:19](/[C@H:21]2[O:39][C:37](=[O:38])[CH2:36][C@H:35]([OH:40])[C:34]([CH3:42])([CH3:41])[C:32](=[O:33])[C@H:31]([CH3:43])[C@@H:30]([OH:44])[C@@H:29]([CH3:45])[CH2:28][CH2:27][CH2:26][C@H:24]3[O:25][C@H:23]3[CH2:22]2)\[CH3:20])[N:14]=1>>[CH3:12][C:8]1([CH3:3])[O:10][O:11]1.[CH3:12][C:13]1[S:17][CH:16]=[C:15](/[CH:18]=[C:19](/[C@H:21]2[O:39][C:37](=[O:38])[CH2:36][C@H:35]([OH:40])[C:34]([CH3:42])([CH3:41])[C:32](=[O:33])[C@H:31]([CH3:43])[C@@H:30]([OH:44])[C@@H:29]([CH3:45])[CH2:28][CH2:27][CH2:26][C@H:24]3[O:25][C@H:23]3[CH2:22]2)\[CH3:20])[N:14]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: C/C(=C\c1csc(C)n1)[C@@H]1C[C@@H]2O[C@@H]2CCC[C@H](C)[C@H](O)[C@@H](C)C(=O)C(C)(C)[C@@H](O)CC(=O)O1
Product: CC1(C)OO1

Procedure:
The cis-olefin 49 was converted to epothilone A (1) by the action of mCPBA (0.8-1.2 equivalents) in a reaction that, in addition to 1 (35% yield), produced the isomeric epoxides 51 (13% yield), 52 (or 53) (9% yield, stereochemistry unassigned) and 53 (or 52) (7% yield, stereochemistry unassigned), as well as bis(epoxides) 54 (or 55) and 55 (or 54) (10% total yield, stereochemistry unassigned). Reaction of olefin 49 with excess mCPBA (1.3-2.0 equivalents) gave a different product distribution: 1 (15%), 51 (10%), 52 (or 53) (10%), 53 (or 52) (8%), 54 (or 55) (8%), 55 (or 54) (7%), 56 (5%), and 57 (5%). The action of dimethyldioxirane (Murray et al. J. Org. Chem. 1985, 50, 2847-2853) (Methylene chloride, 0° C.) on 49 gave mainly 1 (50%) and 51 (15%), together with small amounts of 53 (or 54) and 54 (or 53) (10% total yield).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([O:12][CH3:13])=[C:6]([CH:11]=1)[C:7](=[NH:10])OC.[C@@H:14]1(N)[CH2:19][CH2:18][CH2:17][CH2:16][C@H:15]1[NH2:20]>CCO>[Br:1][C:2]1[CH:11]=[C:6]([C:7]2[NH:20][C@@H:15]3[CH2:16][CH2:17][CH2:18][CH2:19][C@H:14]3[N:10]=2)[C:5]([O:12][CH3:13])=[N:4][CH:3]=1
Reactant: COC(=N)c1cc(Br)cnc1OC
Reactant: N[C@@H]1CCCC[C@H]1N
Solvent: CCO
Product: COc1ncc(Br)cc1C1=N[C@@H]2CCCC[C@H]2N1
Temperature: 80 °C
Reaction time: 12 h
Yield: 69.7 %

Procedure:
To a solution of methyl 5-bromo-2-methoxynicotinimidate (6.1 g, 18.5 mmol) in EtOH (100 mL) was added trans-Cyclohexane-1,2-diamine (2.1 g, 18.5 mmol) at room temperature, the mixture was stirred at 80° C. for 12 hours. The solvent was removed and the resulting residue was washed with dichloromethane (50 mL*2), then dry to provide trans-2-(5-bromo-2-methoxypyridin-3-yl)-3a,4,5,6,7,7a-hexahydro-1H-benzo[d]imidazole (4 g, yield 70.2%). 1HNMR (400 MHz, CDCl3) δ 8.56 (d, J=2.4 Hz, 1H), 8.43 (s, J=2.4 Hz, 1H), 4.14 (s, 3H), 3.51˜3.53 (m, 2H), 2.45˜2.49 (m, 2H), 1.91˜1.93 (m, 2H), 1.61˜1.63 (m, 2H), 1.36˜1.41 (m, 2H), 1.25 (s, 1H). MS (M+H)+: 310/312.