Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:47])[O:7][C:6]2[CH:8]=[CH:9][C:10]([C@H:12]3[O:16][C:15](=[O:17])[N:14]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][O:27][CH2:28][C:29]4[CH:30]=[C:31]([NH:35][C:36](=[O:46])[C:37]5[CH:42]=[CH:41][CH:40]=[C:39]([N+:43]([O-])=O)[CH:38]=5)[CH:32]=[CH:33][CH:34]=4)[CH2:13]3)=[CH:11][C:5]=2[CH2:4][O:3]1>CCOC(C)=O.CCO.[Pt]=O>[NH2:43][C:39]1[CH:38]=[C:37]([CH:42]=[CH:41][CH:40]=1)[C:36]([NH:35][C:31]1[CH:32]=[CH:33][CH:34]=[C:29]([CH2:28][O:27][CH2:26][CH2:25][O:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][N:14]2[CH2:13][C@@H:12]([C:10]3[CH:9]=[CH:8][C:6]4[O:7][C:2]([CH3:47])([CH3:1])[O:3][CH2:4][C:5]=4[CH:11]=3)[O:16][C:15]2=[O:17])[CH:30]=1)=[O:46]
Reactant: CC1(C)OCc2cc([C@@H]3CN(CCCCCCOCCOCc4cccc(NC(=O)c5cccc([N+](=O)[O-])c5)c4)C(=O)O3)ccc2O1
Agent: O=[Pt]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC1(C)OCc2cc([C@@H]3CN(CCCCCCOCCOCc4cccc(NC(=O)c5cccc(N)c5)c4)C(=O)O3)ccc2O1
Yield: 97.2 %

Procedure:
A solution of N-[3-({2-({6-[(5R)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazolidin-3-yl]hexyl}oxy)ethoxy}methyl)phenyl]-3-nitrobenzamide (2.11 g) in EtOAc (30 ml) and EtOH (30 ml) was hydrogenated over platinum oxide (100 mg). After 1.25 h the mixture was filtered through celite and the filtrate evaporated in vacuo to give the title compound (1.955 g). LCMS RT=3.49 min, ES+ve 618 (MH)+.
Reaction SMILES: Cl.[OH:2][CH:3]1[O:11][C@@H:10]([CH2:12][OH:13])[C@H:8]([OH:9])[C@@H:6]([OH:7])[C@@H:4]1[NH2:5].C([O-])(O)=O.[Na+].F[C:20]1[C:28]2[C:24](=[N:25][O:26][N:27]=2)[C:23]([N+:29]([O-:31])=[O:30])=[CH:22][CH:21]=1>O.CO>[CH:21]1[CH:22]=[C:23]([N+:29]([O-:31])=[O:30])[C:24]2[C:28](=[N:27][O:26][N:25]=2)[C:20]=1[NH:5][C@@H:4]([C@H:6]([OH:7])[C@@H:8]([OH:9])[C@@H:10]([OH:11])[CH2:12][OH:13])[CH:3]=[O:2]
Reactant: N[C@@H]1C(O)O[C@@H](CO)[C@H](O)[C@H]1O
Reactant: O=[N+]([O-])c1ccc(F)c2nonc12
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: O=C[C@@H](Nc1ccc([N+](=O)[O-])c2nonc12)[C@H](O)[C@@H](O)[C@@H](O)CO
Temperature: 37 °C
Reaction time: 2 h

Procedure:
In a brown flask, L-glucosamine hydrochloride (40.0 mg) and NaHCO3 (26.0 mg) were placed and dissolved in water (800 μl). A solution in which 4-fluoro-7-nitro-2,1,3-benzoxadiazole (NBD-F) (92.0 mg) was dissolved in methanol (4.0 ml) was added thereto, and under an argon atmosphere, the resulting mixture was stirred for 2 hours at a bath temperature of 37° C. Thereafter, the mixture was stirred at room temperature for an additional 40 minutes. Methanol was removed by concentration under reduced pressure, and the resulting precipitates (unnecessary substances derived from NBD-F) were removed by filtration. The precipitates were washed with water, and the filtrate and the washing solution were combined, followed by purification by HPLC. A target fraction was collected and lyophilized, whereby a target product was obtained (yield: 48.7 mg, yield ratio: 76%).
Reaction SMILES: [F:1][C:2]1[CH:30]=[CH:29][CH:28]=[CH:27][C:3]=1[O:4][C:5]1[N:10]=[C:9]2[O:11][C:12]([C:14]3[CH:24]=[C:23]([CH3:25])[C:17]([O:18][CH2:19][C:20]([OH:22])=[O:21])=[C:16]([CH3:26])[CH:15]=3)=[N:13][C:8]2=[CH:7][CH:6]=1.F[C:32]1C=CC=CC=1OC1N=C2OC(C3C=C(C)C(O)=C(C)C=3)=NC2=CC=1.BrC(C)C(OC(C)(C)C)=O>>[F:1][C:2]1[CH:30]=[CH:29][CH:28]=[CH:27][C:3]=1[O:4][C:5]1[N:10]=[C:9]2[O:11][C:12]([C:14]3[CH:15]=[C:16]([CH3:26])[C:17]([O:18][CH:19]([CH3:32])[C:20]([OH:22])=[O:21])=[C:23]([CH3:25])[CH:24]=3)=[N:13][C:8]2=[CH:7][CH:6]=1
Reactant: Cc1cc(-c2nc3ccc(Oc4ccccc4F)nc3o2)cc(C)c1O
Reactant: Cc1cc(-c2nc3ccc(Oc4ccccc4F)nc3o2)cc(C)c1OCC(=O)O
Agent: CC(Br)C(=O)OC(C)(C)C
Product: Cc1cc(-c2nc3ccc(Oc4ccccc4F)nc3o2)cc(C)c1OC(C)C(=O)O

Procedure:
2-{4-[5-(2-Fluorophenoxy)oxazolo[5,4-b]pyridin-2-yl]-2,6-dimethylphenoxy}propionic acid was prepared analogously to Example 1 (steps (e) and (f)) by reaction of 4-[5-(2-fluorophenoxy)oxazolo[5,4-b]pyridin-2-yl]-2,6-dimethylphenol with tert-butyl 2-bromopropionate and subsequent ester cleavage.
Reaction SMILES: [C:1]([C:4]1[C:20]([O:21][CH2:22][C@@H:23]([N:28]2[C:36](=[O:37])[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[C:29]2=[O:38])[CH2:24][CH:25]([CH3:27])[CH3:26])=[CH:19][C:7]2[N:8]([CH3:18])[C:9](=[O:17])[C:10]3[C:15]([C:6]=2[CH:5]=1)=[CH:14][CH:13]=[N:12][C:11]=3[CH3:16])(=[O:3])[CH3:2].[CH3:39][Mg]Br>C1COCC1>[OH:3][C:1]([C:4]1[C:20]([O:21][CH2:22][C@@H:23]([N:28]2[C:29](=[O:38])[C:30]3[C:35](=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:36]2=[O:37])[CH2:24][CH:25]([CH3:27])[CH3:26])=[CH:19][C:7]2[N:8]([CH3:18])[C:9](=[O:17])[C:10]3[C:15]([C:6]=2[CH:5]=1)=[CH:14][CH:13]=[N:12][C:11]=3[CH3:16])([CH3:39])[CH3:2]
Reactant: CC(=O)c1cc2c3ccnc(C)c3c(=O)n(C)c2cc1OC[C@H](CC(C)C)N1C(=O)c2ccccc2C1=O
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: Cc1nccc2c1c(=O)n(C)c1cc(OC[C@H](CC(C)C)N3C(=O)c4ccccc4C3=O)c(C(C)(C)O)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 35.3 %

Procedure:
To a solution of (S)-2-(1-((9-acetyl-4,6-dimethyl-5-oxo-5,6-dihydrobenzo[c][2,7]naphthyridin-8-yl)oxy)-4-methylpentan-2-yl)isoindoline-1,3-dione (220 mg, 0.430 mmol) in THF (6 mL) was added methyl magnesium bromide (1.4 M in diethyl ether) (0.922 mL, 1.290 mmol) at −10° C. and stirred for overnight at RT. The reaction mixture was carefully quenched with water and diluted with EtOAc. The organic layer was separated, dried over sodium sulphate and concentrated under reduced pressure. The residue was purified via silica gel chromatography to afford (S)-2-(1-((9-(2-hydroxypropan-2-yl)-4,6-dimethyl-5-oxo-5,6-dihydrobenzo[c][2,7]naphthyridin-8-yl)oxy)-4-methylpentan-2-yl)isoindoline-1,3-dione (0.2 g, 0.152 mmol, 35% yield) as a brown gummy solid. LC/MS (ESI) m/e 528.2 [(M+H)+, calcd for C31H34N3O5 528.2; LC/MS retention time (method D): tR=0.89 min.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:8]=[C:9]([C:12]#[N:13])[O:10][CH:11]=1.[CH2:14]([Sn:18](Cl)([CH2:23][CH2:24][CH2:25][CH3:26])[CH2:19][CH2:20][CH2:21][CH3:22])[CH2:15][CH2:16][CH3:17]>CCOCC>[CH2:23]([Sn:18]([CH2:14][CH2:15][CH2:16][CH3:17])([CH2:19][CH2:20][CH2:21][CH3:22])[C:7]1[CH:8]=[C:9]([C:12]#[N:13])[O:10][CH:11]=1)[CH2:24][CH2:25][CH3:26]
Reactant: N#Cc1cc(Br)co1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [Li]CCCC
Solvent: CCOCC
Product: CCCC[Sn](CCCC)(CCCC)c1coc(C#N)c1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 53 %

Procedure:
n-Butyllithium (1.6M, 3.7 mL, 5.93 mmol) was added to a solution of 4-bromofuran-2-carbonitrile (850 mg, 4.94 mmol) in anhydrous ether (15 mL) stirred at −78° C. under nitrogen. After 10 min, tri-n-butylstannyl chloride (1.61 g, 4.94 mmol) was added, then the reaction mixture was allowed to warm to room temperature, and stirred for another 1 h. The mixture was quenched, and washed with 1N sodium hydroxide, dried through MgSO4, and then the solvent was evaporated to give a brown oily residue. Purification by flash chromatography using a gradient of ammoniated methanol in chloroform gave the sub-title compound as a yellow oil (1.0 g).
Reaction SMILES: [OH:1][CH2:2][C:3]12[CH2:10][O:9][C:6]([CH3:11])([O:7][CH2:8]1)[O:5][CH2:4]2.CC(C)=[O:14].OS(O)(=O)=O.O=[Cr](=O)=O>CC(C)=O>[C:2]([C:3]12[CH2:4][O:5][C:6]([CH3:11])([O:7][CH2:8]1)[O:9][CH2:10]2)([OH:14])=[O:1]
Reactant: CC12OCC(CO)(CO1)CO2
Reactant: CC(C)=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Product: CC12OCC(C(=O)O)(CO1)CO2

Procedure:
To a solution of 4-(hydroxymethyl)-1-methyl-2,6,7-trioxabicyclo[2.2.2]octane (10.0 g, 0.062 mol) in 200 mL of acetone is added Jones reagent (chromium trioxide and sulfuric acid) until an orange color persisted. The excess oxidant is removed by the addition of 2-propanol until a green color is obtained and the solvents are evaporated under reduced pressure. The residue is partitioned between dichloromethane (100 mL) and water (50 mL) and the layers are separated. The organic layer is washed with water, dried over anhydrous sodium sulfate and evaporated under reduced pressure to give 4-carboxy-1-methyl-2,6,7-trioxabicyclo[2.2.2]octane.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5](OC)=[C:4]([N+:13]([O-:15])=[O:14])[CH:3]=1.[OH:16][CH:17]([CH2:20][OH:21])[CH2:18][NH2:19]>>[Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([NH:19][CH2:18][CH:17]([OH:16])[CH2:20][OH:21])=[C:4]([N+:13]([O-:15])=[O:14])[CH:3]=1
Reactant: COc1c([N+](=O)[O-])cc(Cl)cc1[N+](=O)[O-]
Reactant: NCC(O)CO
Product: O=[N+]([O-])c1cc(Cl)cc([N+](=O)[O-])c1NCC(O)CO

Procedure:
0.25 g of 4-chloro-2,6-dinitro-anisole (Kohn and Kramer, Monatsh, Chemie 49, 154) was dissolved in 2 ml of 2,3-dihydroxy-propylamine at 5° to 10° C. and stirred at this temperature for half an hour, whereupon the orange solution was pour on ice and the precipitated yellow crystals were filtered with suction. 0.2 g (64 Percent of the theoretical yield) of the dye was obtained, it had a melting of 82° C.
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[CH2:12]([O:19][C:20]1[CH:29]=[CH:28][C:27]2[N:26]=[CH:25][C:24]3[N:30]=[C:31]([CH2:37][O:38][CH3:39])[N:32]([CH2:33][CH:34]([CH3:36])[CH3:35])[C:23]=3[C:22]=2[CH:21]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[CH2:12]([O:19][C:20]1[CH:29]=[CH:28][C:27]2[N+:26]([O-:6])=[CH:25][C:24]3[N:30]=[C:31]([CH2:37][O:38][CH3:39])[N:32]([CH2:33][CH:34]([CH3:36])[CH3:35])[C:23]=3[C:22]=2[CH:21]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COCc1nc2cnc3ccc(OCc4ccccc4)cc3c2n1CC(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: COCc1nc2c[n+]([O-])c3ccc(OCc4ccccc4)cc3c2n1CC(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.2 %

Procedure:
3-Chloroperoxybenzoic acid (60% pure, 3.5 g, 12.3 mmol) was added portionwise to a solution of 8-benzyloxy-1-(2-methylpropyl)-2-methoxymethyl-1H-imidazo[4,5-c]quinoline (4.2 g, 11.19 mmol) in 200 mL of dichloromethane. The reaction was stirred at ambient temperature for 2 hours, and then 100 mL of 2% aqueous sodium carbonate was added. The aqueous layer was extracted with two 100 mL portions of dichloromethane and the organic fractions were combined, dried, and concentrated to give 4.3 g of crude 8-benzyloxy-1-(2-methylpropyl)-2-methoxymethyl-5-oxido-1H-imidazo[4,5-c]quinoline as a light brown solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][CH:3]=1.[Li]CCCC.CN(CCN(C)C)C.[C:22]([O:26][C:27]([N:29]1[CH2:34][CH2:33][CH:32]([CH:35]=[O:36])[CH2:31][CH2:30]1)=[O:28])([CH3:25])([CH3:24])[CH3:23]>C1COCC1>[C:22]([O:26][C:27]([N:29]1[CH2:34][CH2:33][CH:32]([CH:35]([C:2]2[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][CH:3]=2)[OH:36])[CH2:31][CH2:30]1)=[O:28])([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Reactant: Clc1ccc(Br)cc1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(C(O)c2ccc(Cl)cc2)CC1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 29.4 %

Procedure:
To a solution of 4-bromochlorobenzene (1.35 g, 7.03 mmol) in THF (30 mL) cooled to −78° C. was added n-BuLi (2.5M in THF, 3.00 mL, 7.5 mmol) and the mixture was stirred at −78° C. for 30 minutes. TMEDA (1.06 mL, 7.02 mmol) and 4-formyl-piperidine-1-carboxylic acid tert-butyl ester (1.00 g, 4.69 mmol) in THF (10 mL) were added and the mixture stirred at −78° C. for 3 hours. The reaction was quenched with saturated aqueous NH4Cl (30 mL) and after work-up and purification afforded 4-[(4-chloro-phenyl)-hydroxy-methyl]-piperidine-1-carboxylic acid tert-butyl ester as a white solid (450 mg, 30%).
Reaction SMILES: [CH:1]([O:4][NH:5][C:6](=[O:15])[O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([CH3:3])[CH3:2].[C:16]([O-])([O-])=O.[K+].[K+].CI>CC(C)=O>[CH:1]([O:4][N:5]([CH3:16])[C:6](=[O:15])[O:7][CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)([CH3:3])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CC(C)ONC(=O)OCc1ccccc1
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: CC(C)ON(C)C(=O)OCc1ccccc1
Temperature: 70 °C
Yield: 93.3 %

Procedure:
An ACE® pressure tube was charged with benzyl isopropoxycarbamate (4.98 g, 23.80 mmol), anhydrous K2CO3 (4.94 g, 35.70 mmol), methyl iodide (6.7 mL, 107.10), and anhydrous acetone (30 mL). The reaction mixture was heated at 70° C. for 24 h. The reaction mixture was filtered, and the acetone was evaporated. The resulting slurry was dissolved in EtOAc, washed with water (3×50 mL), dried (Na2SO4), and filtered. The solvent was removed to yield benzyl isopropoxy(methyl)carbamate (4.96 g, 93%). 400 MHz 1H-NMR (DMSO-d6, ppm) 7.41-7.30 (5H, m), 5.12 (2H, s), 4.08 (1H, septet, J=6.2 Hz), 3.08 (3H, s), 1.12 (6H, d, J=6.2 Hz).
Reaction SMILES: [F:1][C:2]1[C:9]([F:10])=[C:8]([O:11]C)[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].Cl.N1C=CC=CC=1>O>[F:1][C:2]1[C:9]([F:10])=[C:8]([OH:11])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: COc1ccc(C=O)c(F)c1F
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: O=Cc1ccc(O)c(F)c1F
Temperature: 170 °C
Yield: 67.6 %

Procedure:
Combine 2,3-difluoro-4-methoxy-benzaldehyde (2.76 g, 16.0 mmol) and pyridine hydrochloride (18.5 g, 160 mmol) in a round bottom flask equipped with nitrogen inlet. Heat the mixture at 170° C. two hours, cool to near ambient temperature and dilute with water. Extract aqueous with EtOAc (2×), wash extract with 0.1 N aq. HCl (2×), water (2×) and brine, dry (MgSO4) and concentrate. Purify on silica gel (20% EtOAc/Hexane) to give 2,3-difluoro-4-hydroxy-benzaldehyde (1.71 g) as a yellow solid. 1HNMR (CDCl3): 10.18 (s, 1H), 7.59 (t, 1H), 6.90 (t, 1H), 6.14 (s, 1H).
Reaction SMILES: [CH:1]1([CH2:5][NH:6][C:7]#[N:8])[CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:16][C:17](=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19].O>COCCOC>[C:18]([C:17]1[O:22][C:7](=[NH:8])[N:6]([CH2:5][CH:1]2[CH2:4][CH2:3][CH2:2]2)[CH:16]=1)([CH3:21])([CH3:20])[CH3:19]
Reactant: N#CNCC1CCC1
Reactant: CC(C)(C)C(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Solvent: O
Product: CC(C)(C)c1cn(CC2CCC2)c(=N)o1
Temperature: 80 °C
Yield: 80 %

Procedure:
A mixture of N-(cyclobutylmethyl)cyanamide (0.40 g, 3.6 mmol), cesium carbonate (2.4 g, 7.3 mmol) and 1-bromo-3,3-dimethylbutan-2-one (0.50 mL, 3.6 mmol, Aldrich) in 1,2-dimethoxyethane (20 mL) was heated to 80° C. overnight. The mixture was poured into water, and extracted with ethyl acetate (2×20 mL). The combined organic extracts were dried over Na2SO4, filtered, concentrated under reduced pressure to provide the title compound (0.6 g). LCMS (APCI+) m/z 209 (M+H)+.
Reaction SMILES: FC(F)(F)C(OC(=O)C(F)(F)F)=O.[C:14]([OH:17])(=[O:16])[CH3:15].[CH:18]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH:27]([CH3:29])[CH3:28])[C:22]=1O)([CH3:20])[CH3:19]>O>[C:14]([O:17][C:22]1[C:21]([CH:18]([CH3:19])[CH3:20])=[CH:26][CH:25]=[CH:24][C:23]=1[CH:27]([CH3:29])[CH3:28])(=[O:16])[CH3:15]
Reactant: CC(C)c1cccc(C(C)C)c1O
Reactant: CC(=O)O
Solvent: O
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: CC(=O)Oc1c(C(C)C)cccc1C(C)C
Temperature: 0 °C
Reaction time: 2 h
Yield: 86 %

Procedure:
3.45 g (16.4 mmol) of trifluoroacetic anhydride is added to 0.83 ml (14.6 mmol) of acetic acid at 0° C. while leaving the mixture to return to ambient temperature over 2 hours. The mixture is then cooled down to 0° C. and 1.95 g (11.0 mmol) of 2,6-diisopropylphenol is added dropwise. The reaction medium is maintained under stirring for 12 hours before being poured into ice-cooled water. After extraction with dichloromethane, the organic phase is washed with sodium chloride in a saturated aqueous solution before being dried over magnesium sulphate, filtered and concentrated under vacuum. A colourless oil is obtained with a yield of 86%. This product is sufficiently pure to be used directly in the following stage.
Reaction SMILES: [C:1]1([C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4])[OH:2].[CH3:9]O>>[C:3]1([O:4][CH3:9])[C:1](=[CH:8][CH:7]=[CH:6][CH:5]=1)[OH:2]
Reactant: CO
Reactant: Oc1ccccc1O
Product: COc1ccccc1O

Procedure:
An apparatus as shown in FIGS. 1, 2, 3 and 4 was used to generate a mixed vapor of catechol and methyl alcohol and to produce guaiacol from the mixed gas.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:13]=[C:14]([NH:19]/[C:20](/[NH:32]C(=O)OCC2C=CC=CC=2)=[N:21]/C(=O)OCC2C=CC=CC=2)[C:15]([CH3:18])=[N:16][CH:17]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[OH-].[OH-].[Pd+2]>[NH2:32][C:20]([NH:19][C:14]1[CH:13]=[C:12]([CH2:11][CH2:10][CH2:9][NH:8][C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:2])[CH3:4])[CH:17]=[N:16][C:15]=1[CH3:18])=[NH:21]
Reactant: Cc1ncc(CCCNC(=O)OC(C)(C)C)cc1N/C(=N/C(=O)OCc1ccccc1)NC(=O)OCc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: Cc1ncc(CCCNC(=O)OC(C)(C)C)cc1NC(=N)N
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.3 %

Procedure:
To a solution of dibenzyl {(Z)-[(5-{3-[(tert-butoxycarbonyl)amino]propyl}-2-methylpyridin-3-yl)amino]methylylidene}biscarbamate (3.34 g, 5.80 mmol) in MeOH (100 mL) was added palladium hydroxide on carbon (0.41 g). The reaction vessel was flushed with hydrogen gas and then allowed to stir at rt under an atmosphere of hydrogen gas overnight. The reaction mixture was filtered over a pad of Celite® and the filtrate was concentrated to give tert-butyl [3-(5-{[amino(imino)methyl]amino}-6-methylpyridin-3-yl)propyl]carbamate (1.77 g, 5.76 mmol, 99%) as a white solid. LCMS (FA): Rt=0.76 min, m/z=308.0 (M+H).
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])[CH2:2][C:3]([O:5][CH3:6])=[O:4].[H-].[Na+].[N+:12]([C:15]1[CH:39]=[CH:38][C:18]([CH2:19][O:20][C:21]([N:23]2[CH2:27][C@H:26]([O:28][Si:29]([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30])[CH2:25][C@H:24]2[CH2:36]I)=[O:22])=[CH:17][CH:16]=1)([O-:14])=[O:13].Cl>CN(C)C=O.O>[N+:12]([C:15]1[CH:16]=[CH:17][C:18]([CH2:19][O:20][C:21]([N:23]2[CH2:27][C@H:26]([O:28][Si:29]([C:32]([CH3:33])([CH3:35])[CH3:34])([CH3:30])[CH3:31])[CH2:25][C@H:24]2[CH2:36][CH:2]([C:1]([O:8][CH3:9])=[O:7])[C:3]([O:5][CH3:6])=[O:4])=[O:22])=[CH:38][CH:39]=1)([O-:14])=[O:13]
Reactant: COC(=O)CC(=O)OC
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1C[C@@H](CI)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C(C[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1)C(=O)OC
Temperature: 25 °C
Reaction time: 15 h

Procedure:
Dimethyl malonate (660 mg) and 180 mg of 50% sodium hydride in 12.5 ml of dry dimethylformamide were stirred at room temperature in a nitrogen stream for 15 minutes, and 1.34 g of (2S,4R)-1-(p-nitrobenzyloxycarbonyl)-2-iodomethyl-4-t-butyldimethylsilyloxypyrrolidine was added thereto. The resulting mixture was stirred at room temperature for 15 hours, neutralized with 3.75 ml of 1N hydrochloric acid, diluted with water, extracted with ethyl acetate, washed with water, dried over anhydrous sodium sulfate and distilled to remove the solvent. The residue was purified by silica gel chromatogrphy to obtain (2R,4R)-1-(p-nitrobenzyloxycarbonyl)-2-(2,2-dimethoxycarbonylethyl)-4-t-butyldimethylsilyloxypyrrolidine.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[C@@H:7]1[CH2:11][C@@H:10]([OH:12])[CH2:9][N:8]1[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])([CH3:4])([CH3:3])[CH3:2].[CH3:21][S:22](Cl)(=[O:24])=[O:23]>N1C=CC=CC=1.C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:20])[C@@H:7]1[CH2:11][C@@H:10]([O:12][S:22]([CH3:21])(=[O:24])=[O:23])[CH2:9][N:8]1[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)[C@@H]1C[C@@H](OS(C)(=O)=O)CN1C(=O)OC(C)(C)C
Reaction time: 2 h

Procedure:
To a solution of (4R)-1-(tert-butyloxycarbonyl)-4-hydroxy-L-proline tert-butyl ester (573 mg, 1.99 mmol) in pyridine (3.5 mL) cooled to 0° C. was added methanesulfonyl chloride (0.31 mL, 3.99 mmol). The reaction mixture was stirred for 2 hours at ice temperature, diluted with ethyl acetate (30 mL), washed with 1M sodium hydrogencarbonate solution, 1M citric acid, water, dried (Na2SO4), and evaporated. The crude product was purified by flash silica gel chromatography eluting with 1% methanol/dichloromethane; yield 686 mg (94%). 400 MHz 1H NMR (CDCl3): δ1.42-1.44 (2s, 18H); 2.20 (m, 1H); 2.60 (m, 1H); 3.02 (s, 3H); 3.68-3.86 (m, 2H); 4.29 (m, 1H); 5.22 (m, 1H).
Reaction SMILES: [Cl:1]/[C:2](/[C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1)=[CH:3]\[C@H:4]1[C@H:6]([C:7](O)=[O:8])[C:5]1([CH3:11])[CH3:10].S(Cl)([Cl:21])=O>C(Cl)(Cl)(Cl)Cl>[Cl:1][C:2]([C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1)=[CH:3][CH:4]1[CH:6]([C:7]([Cl:21])=[O:8])[C:5]1([CH3:11])[CH3:10]
Reactant: O=S(Cl)Cl
Reactant: CC1(C)[C@@H](/C=C(\Cl)c2ccc(Cl)cc2)[C@@H]1C(=O)O
Solvent: ClC(Cl)(Cl)Cl
Product: CC1(C)C(C=C(Cl)c2ccc(Cl)cc2)C1C(=O)Cl

Procedure:
4.2 g (0.0147 mole) of (+)-trans-Z-3-(2-chloro-2-(4-chloro-phenyl)-vinyl)-2,2-dimethyl-1-cyclopropane-carboxylic acid were dissolved in 50 ml of carbon tetrachloride, and 8.8 g of thionyl chloride were slowly added dropwise at 40° C., whilst stirring. The mixture was then heated under reflux for 4 hours. At the end of the reaction time, excess thionyl chloride and carbon tetrachloride were distilled off under a waterpump vacuum. Last residues of solvent were removed by brief incipient distillation at a bath temperature of 60° C./2 mm Hg. 4.0 g (89.7% of theory) of (+)-trans-Z-(3-(2-chloro-2-(4-chloro-phenyl)-vinyl)-2,2-dimethyl-cyclopropane-carboxylic acid chloride were obtained as a crystalline solid with a melting point of 65°-70° C. ##STR12##
Reaction SMILES: Cl[C:2]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH3:20])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([Cl:11])[CH:9]=2)[NH:4][C:3]1=[O:12].FC(F)(F)C(O)=O.[NH2:28][C@@H:29]([CH2:35][CH2:36][C:37]([NH2:39])=[O:38])[C:30]([N:32]([CH3:34])[CH3:33])=[O:31]>>[Cl:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[NH:4][C:3](=[O:12])[C:2]2([NH:28][C@@H:29]([CH2:35][CH2:36][C:37]([NH2:39])=[O:38])[C:30]([N:32]([CH3:34])[CH3:33])=[O:31])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH3:20]
Reactant: COc1ccccc1C1(Cl)C(=O)Nc2ccc(Cl)cc21
Reactant: CN(C)C(=O)[C@@H](N)CCC(N)=O
Solvent: O=C(O)C(F)(F)F
Product: COc1ccccc1C1(N[C@@H](CCC(N)=O)C(=O)N(C)C)C(=O)Nc2ccc(Cl)cc21

Procedure:
With 1.03 g of 3,5-dichloro-3-(2-methoxyphenyl)-1,3-dihydro-2H-indol-2-one and the compound obtained in Step 68-2 (3.66 mmol, crude form) as starting materials, respectively 168 mg (Isomer A, colorless amorphous) and 204 mg (Isomer B, colorless amorphous) of two species of diastereoisomers of the title compound were obtained by a similar method to Step 4-2.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:13][CH2:12][CH2:11][C@@H:10](C=C)[N:9]2[C:16](=[O:20])[CH2:17][CH:18]=[CH2:19])=[CH:4][CH:3]=1>C(Cl)Cl.CC1C=C(C)C(N2[CH-]N(C3C(C)=CC(C)=CC=3C)CC2)=C(C)C=1.C1CCC([PH+](C2CCCCC2)C2CCCCC2)CC1.C1C=CC(C=[Ru](Cl)Cl)=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]2[CH2:13][CH2:12][CH2:11][C@@H:10]3[N:9]2[C:16](=[O:20])[CH2:17][CH:18]=[CH:19]3)=[CH:6][CH:7]=1
Reactant: C=CCC(=O)N1[C@H](C=C)CCC[C@@H]1c1ccc(F)cc1
Agent: Cl[Ru](Cl)=Cc1ccccc1
Agent: C1CCC([PH+](C2CCCCC2)C2CCCCC2)CC1
Agent: Cc1cc(C)c(N2[CH-]N(c3c(C)cc(C)cc3C)CC2)c(C)c1
Solvent: ClCCl
Product: O=C1CC=C[C@@H]2CCC[C@H](c3ccc(F)cc3)N12
Temperature: 25 °C
Yield: 82.4 %

Procedure:
A solution of 1-[(2R*,6S*)-2-(4-fluorophenyl)-6-vinylpiperidin-1-yl]-3-buten-1-one (744 mg) and tricyclohexylphosphine[1,3-bis(2,4,6-trimethylphenyl)-4,5-dihydroimidazol-2-ylidene][benzylidene]ruthenium (IV) dichloride (116 mg) in methylene chloride (250 mL) was heated under reflux for two hours. The reaction solution was left to cool to room temperature and then concentrated. The residue was purified by silica gel column chromatography (elution solvent: heptane:ethyl acetate=4:1->ethyl acetate) to obtain 550 mg of the title compound. The property values of the compound are as follows.