Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][C:12]([C:18]#[N:19])([CH3:17])[CH2:13][CH2:14][CH2:15][CH3:16])(=O)=O)=CC=1.[C:21]1([CH:28]=[CH:27][C:25]([OH:26])=[CH:24][CH:23]=1)[OH:22].[O-]CCCC.[Na+].[OH-].[Na+].[Cl-].[Na+]>C(O)CCC>[C:18]([C:12]([CH3:17])([CH2:13][CH2:14][CH2:15][CH3:16])[CH2:11][O:22][C:21]1[CH:28]=[CH:27][C:25]([OH:26])=[CH:24][CH:23]=1)#[N:19]
Reactant: Oc1ccc(O)cc1
Reactant: CCCCC(C)(C#N)COS(=O)(=O)c1ccc(C)cc1
Agent: CCCC[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CCCCO
Product: CCCCC(C)(C#N)COc1ccc(O)cc1
Temperature: 120 °C
Reaction time: 20 h
Yield: 21.4 %

Procedure:
While 480 mg (1.6 mM) of (+) 2-cyano-2-methylhexyl p-toluenesulfonate, 357 mg (3.2 mM) of hydroquinone and 1.5 ml of n-butanol were stirred in a nitrogen atmosphere, sodium butoxide obtained by dissolving 83.3 mM (2.1 mM) of sodium hydroxide in 2.2 ml of n-butanol was added dropwise, followed by stirring for 20 hours under heating at 120° C. After the reaction, 5 ml of saturated sodium chloride aqueous solution was added, followed by extraction with ether. The ether layer was washed with distilled water and dried on sodium sulfate, followed by distilling-off of the solvent to obtain 296 mg of a crude product, which was then purified by thine layer chromatography (developer solvent: methylene chloride) to obtain 81.3 mg of (-)-p-(2-cyano-2-methylhexyloxy)phenol (Yield: 19.1%). [α]D -1.8 degree (c 0.836, benzene).
Reaction SMILES: [NH2:1][CH:2]1[C:17](=[O:18])[N:4]2[C:5]([C:14]([OH:16])=[O:15])=[C:6]([CH2:9][O:10][C:11](=[O:13])[CH3:12])[CH2:7][S:8][C@H:3]12.C/C(/O[Si](C)(C)C)=N\[Si](C)(C)C.S1C2C=CC=CC=2N=C1S[C:41](=[O:50])[C:42]([C:44]1[N:45]=[C:46]([NH2:49])[S:47][CH:48]=1)=[O:43]>ClCCl>[NH2:49][C:46]1[S:47][CH:48]=[C:44]([C:42](=[O:43])[C:41]([NH:1][CH:2]2[C:17](=[O:18])[N:4]3[C:5]([C:14]([OH:16])=[O:15])=[C:6]([CH2:9][O:10][C:11](=[O:13])[CH3:12])[CH2:7][S:8][C@H:3]23)=[O:50])[N:45]=1
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Reactant: Nc1nc(C(=O)C(=O)Sc2nc3ccccc3s2)cs1
Agent: C/C(=N\[Si](C)(C)C)O[Si](C)(C)C
Solvent: ClCCl
Product: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=O)c3csc(N)n3)[C@H]2SC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
5.44 g of 7-amino-3-acetoxymethylceph-3-em-4-carboxylic acid are suspended under a nitrogen atmosphere in 50 ml of dry di-chloromethane, and mixed with 5.4 ml of N,O-bis(trimethylsilyl)acetamide. The preparation is stirred at room temperature until a clear solution is present, and then cooled to -15°. 8.4 g of 2-(2-amino-4-thiazolyl)-2-oxothioacetic-acid-S-benzothiazol-2-ylester are added, and stirred for two hours at -15° and then for two hours at 0°. The solvent is carefully drawn off in a rotary evaporator, and the oily residue is rubbed with 50 ml of ethanol, whereby the title compound precipitates. 6.3 g are obtained in the form of a yellow powder.
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[CH:16][CH:15]=[CH:14][C:5]=1[C:6]([NH:8][C:9]1[NH:13][N:12]=[N:11][N:10]=1)=[O:7])([O-])=O.[OH-].[Na+].[H][H]>[Pd].C(O)C>[NH2:1][C:4]1[CH:17]=[CH:16][CH:15]=[CH:14][C:5]=1[C:6]([NH:8][C:9]1[NH:13][N:12]=[N:11][N:10]=1)=[O:7]
Reactant: O=C(Nc1nnn[nH]1)c1ccccc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Nc1ccccc1C(=O)Nc1nnn[nH]1

Procedure:
A solution was prepared from 19 g of 2-nitro-N-(1H-tetrazol-5-yl)benzamide in 100 ml of aqueous 1 N sodium hydroxide and 100 ml of ethanol. A 0.5-gram quantity of 5% Pd/C catalyst was added and the mixture was hydrogenated in a Parr apparatus at 1520 mm Hg pressure until uptake of hydrogen stopped. The catalyst was removed by filtration and the filtrate was treated with aqueous 1 N hydrochloric acid. The white solid which formed was separated by filtration and dried to give 2-amino-N-(1H-tetrazol-5-yl)benzamide melting at about 253°-254° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[C:8]([F:12])=[CH:7][C:3]=1[C:4](Cl)=[O:5].[CH2:13]([OH:15])[CH3:14]>>[Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[C:8]([F:12])=[CH:7][C:3]=1[C:4]([O:15][CH2:13][CH3:14])=[O:5]
Reactant: O=C(Cl)c1cc(F)c(Cl)cc1Cl
Reactant: CCO
Product: CCOC(=O)c1cc(F)c(Cl)cc1Cl
Temperature: 0 °C
Yield: 97 %

Procedure:
84 g of 2,4-dichloro-5-fluoro-benzoyl chloride are added dropwise to 250 ml of anhydrous ethanol at 50° to 60° C., the temperature being maintained by occasional cooling with ice-water. The mixture is then refluxed for about a further hour, the excess alcohol is distilled off and the residue is fractionated in vacuo. 84.9 g (~97%) of ethyl 2,4-dichloro-5-fluoro-benzoate are obtained at 132°-135° C./8 mbar.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][CH:7]2[CH2:11][CH2:10][NH:9][CH2:8]2)[CH2:4][CH2:3]1.FC(F)(F)C(O)=O>>[CH2:5]([O:6][CH:7]1[CH2:11][CH2:10][NH:9][CH2:8]1)[CH:2]([CH3:4])[CH3:3]
Reactant: C1CC(OCC2CC2)CN1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)COC1CCNC1

Procedure:
The compound as its trifluoroacetic acid salt was obtained from (S)-3-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester following a reaction sequence according to the synthesis of comp. no. 22a. Trifluoroacetic acid was used instead of hydrogen chloride in the final deprotection. LC/MS (method 5): Rt=0.78 min; m/z=144.2 (M+H+).
Reaction SMILES: [CH2:1]([O:7][C:8](=[O:26])[C:9]1[C:14]([O:15][CH3:16])=[CH:13][C:12]([O:17][CH3:18])=[CH:11][C:10]=1[O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH:24]=[CH2:25])[CH2:2][CH2:3][CH2:4]C=C>ClCCl>[CH3:16][O:15][C:14]1[C:9]2[C:8](=[O:26])[O:7][CH2:1][CH2:2][CH2:3][CH2:4][CH:25]=[CH:24][CH2:23][CH2:22][CH2:21][CH2:20][O:19][C:10]=2[CH:11]=[C:12]([O:17][CH3:18])[CH:13]=1
Reactant: C=CCCCCOC(=O)c1c(OC)cc(OC)cc1OCCCCC=C
Solvent: ClCCl
Product: COc1cc(OC)c2c(c1)OCCCCC=CCCCCOC2=O
Yield: 93.8 %

Procedure:
To a solution of bis(tricyclohexylphosphine)benzylidine ruthenium IV dichloride (39 mg, 0.045 mmol) in dichloromethane (150 ml) at reflux was transferred a solution of 2-hex-5-enyloxy-4,6-dimethoxy-benzoic acid hex-5-enyl ester (430 mg, 1.18 mmol) in dichloromethane (100 ml). After 5 hours at reflux, the solvent was removed and chromatography gave the 1,3-dimethoxy-6,7,8,9,12,13,14,15-octahydro-5,16-dioxa-benzocyclopentadecen-17-one (370 mg).
Reaction SMILES: [C:1]([O:5][C:6](=[O:9])[CH2:7]Br)([CH3:4])([CH3:3])[CH3:2].C([O:13][CH2:14][CH3:15])(=O)C>C1COCC1>[C:1]([O:5][C:6](=[O:9])[CH2:7][O:5][C@H:1]1[CH2:3][CH2:15][C@H:14]([OH:13])[CH2:2]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(C)=O
Reactant: CC(C)(C)OC(=O)CBr
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CO[C@H]1CC[C@H](O)C1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Dissolve 2.5 g (24.5 mmol) of cis/trans-cyclopentanediol in 5 ml of THF and, at 0° C., add 16.3 ml (16.3 mmol) of phosphazene base P4-t-Bu (approx. 1M solution in hexane). After 10 min, add the resulting solution dropwise to an ice-cooled solution of 4.77 g (24.5 mmol) of bromoacetic acid tert-butyl ester. After the end of the addition, warm to RT and stir the mixture overnight. Remove fractions of the THF under reduced pressure, dilute with ethyl acetate and wash successively with 1N hydrochloric acid, pH 7 buffer solution and satd. sodium chloride solution, dry over sodium sulphate and concentrate under reduced pressure. From the residue, isolate the product by chromatography on silica gel (eluent: cyclohexane/ethyl acetate 10:1→2:1). 631.4 mg (10.7% of theory) of the target compound are obtained as a cis/trans mixture.
Reaction SMILES: [CH2:1]([C:3]([OH:10])([CH2:8][CH3:9])[CH2:4][CH2:5][CH2:6][OH:7])[CH3:2].[CH:11]12[CH:20]3[CH2:21][CH:17]([CH:18]=[CH:19]3)[CH:16]1[CH:15]1[CH2:22][CH:12]2[CH:13]([C:23](OC)=[O:24])[CH2:14]1>>[CH:11]12[CH:20]3[CH2:21][CH:17]([CH:18]=[CH:19]3)[CH:16]1[CH:15]1[CH2:22][CH:12]2[CH:13]([C:23]([O:7][CH2:6][CH2:5][CH2:4][C:3]([CH2:8][CH3:9])([OH:10])[CH2:1][CH3:2])=[O:24])[CH2:14]1
Reactant: CCC(O)(CC)CCCO
Reactant: COC(=O)C1CC2CC1C1C3C=CC(C3)C21
Product: CCC(O)(CC)CCCOC(=O)C1CC2CC1C1C3C=CC(C3)C21
Yield: 89 %

Procedure:
By following the procedure of Synthesis Example 2 except that 4-ethyl-1,4-hexanediol was used instead of 4-methyl-1,4-pentanediol and methyl 8-tetracyclo-[4.4.0.12,5.17,10]dodecene-3-carboxylate used instead of methyl 5-norbornene-2-carboxylate, there was obtained 4-ethyl-4-hydroxyhexyl 8-tetracyclo[4.4.0.12,5.17,10]dodecene-3-carboxylate. Yield 89%.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[Br:11][C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][CH:13]=1.S(=O)(=O)(O)O.C(O)(=O)C>[Cl-].[Zn+2].[Cl-].O>[NH2:16][C:15]1[CH:17]=[CH:18][C:12]([Br:11])=[CH:13][C:14]=1[C:6]([C:5]1[CH:9]=[CH:10][C:2]([F:1])=[CH:3][CH:4]=1)=[O:7]
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: Nc1ccc(Br)cc1
Agent: O=S(=O)(O)O
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CC(=O)O
Solvent: O
Product: Nc1ccc(Br)cc1C(=O)c1ccc(F)cc1
Temperature: 130 °C
Reaction time: 1 h
Yield: 46.4 %

Procedure:
To neat 4-fluorobenzoyl chloride (50.00 g, 315 mmol) in a flask at 130° C. was added 4-bromoaniline (17.00 g, 100 mmol) in several portions. After it was stirred at 130° C. for 1 hour and the temperature was raised to 190° C., to the reaction mixture was added zinc chloride (11.00 g, 80.7 mmol) in several portions, then it was heated at 220° C. for 22 hours. Once cooled to 180° C., to the mixture was carefully added concentrated sulfuric acid (50 mL), acetic acid (70 mL), water (70 mL), and another portion of sulfuric acid (50 mL). The mixture was heated at 120° C. overnight. It was poured into water (500 mL) and a white solid was precipitated. It was collected by filtration and was dissolved in ethyl acetate and washed with 5% sodium carbonate until pH of the aqueous phase reached 8. The filtrate was basified with sodium carbonate and extracted with ethyl acetate. The combined ethyl acetate layers were dried over magnesium sulfate, filtered, and concentrated. The residue was then purified by chromatography (SiO2, 15–20% ethyl acetate/hexane) to provide the title compound (13.64 g, 46% yield). 1H NMR (CDCl3) δ 7.67 (m, 2H), 7.51 (d, 1H), 7.37 (dd, 1H), 7.14–7.20 (m, 2H), 6.65 (d, 1H), 6.02 (br s, 2H); ES-MS (m/z) 296 [M+3]+, 294 [M+1]+.
Reaction SMILES: [Mg].[Li+].[Cl-].CC(C[AlH]CC(C)C)C.Br[C:14]1[CH:15]=[C:16]([O:22][CH3:23])[C:17]([F:21])=[C:18]([F:20])[CH:19]=1.[Br:24][C:25]1[CH:26]=[C:27]([C:31]([C:39]2[CH:44]=[CH:43][CH:42]=[C:41]([F:45])[C:40]=2[C:46]#[N:47])=[N:32]S(C(C)(C)C)=O)[CH:28]=[CH:29][CH:30]=1.Cl>C1COCC1.CO>[Br:24][C:25]1[CH:26]=[C:27]([C:31]2([C:14]3[CH:15]=[C:16]([O:22][CH3:23])[C:17]([F:21])=[C:18]([F:20])[CH:19]=3)[C:39]3[C:40](=[C:41]([F:45])[CH:42]=[CH:43][CH:44]=3)[C:46]([NH2:47])=[N:32]2)[CH:28]=[CH:29][CH:30]=1
Reactant: COc1cc(Br)cc(F)c1F
Reactant: CC(C)(C)S(=O)N=C(c1cccc(Br)c1)c1cccc(F)c1C#N
Agent: CC(C)C[AlH]CC(C)C
Agent: Cl
Agent: [Cl-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1cc(C2(c3cccc(Br)c3)N=C(N)c3c(F)cccc32)cc(F)c1F
Reaction time: 0.08 h
Yield: 14 %

Procedure:
Magnesium turnings (0.692 g, 28.47 mmol) were stirred under Ar(g) for 10 min and LiCl 0.5M in THF (28.5 mL, 14.24 mmol) was added followed by DIBAL-H 1M in THF (0.228 mL, 0.23 mmol). The mixture was stirred for 5 min and then 5-bromo-1,2-difluoro-3-methoxybenzene (2.54 g, 11.39 mmol) in 5 mL THF was added in one portion and stirred for 1 h. The mixture was added to N-((3-bromophenyl)(2-cyano-3-fluorophenyl)methylene)-2-methylpropane-2-sulfinamide (4.64 g, 11.39 mmol) in THF (20 mL) and stirred 1 h. MeOH (3 mL) was added and the mixture was treated with HCl in 2.0 MeOH (22.78 mL, 22.78 mmol) for 1 h. NaHCO3(sat) was added and the mixture was extracted with EtOAc. The organic phase was washed with brine, dried over MgSO4 and concentrated. The residue was purified by preparative HPLC to give 714 mg (14%) of the title product as a solid. MS (ES+) m/z 447, 449 [M+H]+.
Reaction SMILES: [F:1][C:2]1[C:7]2[N:8]=[CH:9][O:10][C:6]=2[CH:5]=[C:4]([C:11]([NH:13][O:14][CH2:15][CH2:16][O:17]C=C)=[O:12])[C:3]=1[NH:20][C:21]1[CH:26]=[CH:25][C:24]([I:27])=[CH:23][C:22]=1[F:28].Cl.C([O-])(O)=O.[Na+]>C(Cl)Cl>[F:1][C:2]1[C:7]2[N:8]=[CH:9][O:10][C:6]=2[CH:5]=[C:4]([C:11]([NH:13][O:14][CH2:15][CH2:16][OH:17])=[O:12])[C:3]=1[NH:20][C:21]1[CH:26]=[CH:25][C:24]([I:27])=[CH:23][C:22]=1[F:28]
Reactant: C=COCCONC(=O)c1cc2ocnc2c(F)c1Nc1ccc(I)cc1F
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=C(NOCCO)c1cc2ocnc2c(F)c1Nc1ccc(I)cc1F
Reaction time: 1 h
Yield: 52.2 %

Procedure:
To a solution of compound 4-fluoro-5-((2-fluoro-4-iodophenyl)amino)-N-(2-(vinyloxy)ethoxy)benzo[d]oxazole-6-carboxamide (598 mg, 1.17 mmol) in CH2Cl2 (5 mL) was added 1.0 N HCl (aq., 6.7 mL, 6.72 mmol) dropwise. After stirring for 1 h, the reaction mixture was treated with saturated NaHCO3 (aq.). The organic layer was washed with water (30 mL×2) and brine (30 mL), dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by column chromatography on silica gel (CH2Cl2/MeOH, 15:1, v/v) and gave the desired product (white solid, 290 mg, 52% yield). 1H NMR (400 MHz, DMSO-d6): δ 11.75 (s, 1H), 8.96 (s, 1H), 8.01 (s, 1H), 7.88 (s, 1H), 7.53 (d, J=9.4 Hz, 1H), 7.28 (d, J=8.7 Hz, 1H), 6.39 (m, 1H), 4.70 (s, 1H), 3.83 (m, 2H), 3.56 (m, 2H). MS (ES+): m/z 476.34 [MH+].
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[C:10]([CH3:21])=[N:11][C:12]([O:16][CH2:17][C:18]([OH:20])=O)=[N:13][C:14]=1[CH3:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:22]([N:29]1[CH2:34][CH2:33][CH:32]([NH:35][CH3:36])[CH2:31][CH2:30]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(N(CC)CC)C>C(#N)C>[CH2:22]([N:29]1[CH2:34][CH2:33][CH:32]([N:35]([CH3:36])[C:18](=[O:20])[CH2:17][O:16][C:12]2[N:13]=[C:14]([CH3:15])[C:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[C:10]([CH3:21])[N:11]=2)[CH2:31][CH2:30]1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: Cc1nc(OCC(=O)O)nc(C)c1NC(=O)OC(C)(C)C
Reactant: CNC1CCN(Cc2ccccc2)CC1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1nc(OCC(=O)N(C)C2CCN(Cc3ccccc3)CC2)nc(C)c1NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 150.7 %

Procedure:
Compound 9 (74.74 g), 1-benzyl-N-methylpiperidine-4-amine (66.78 g: 1.3 eq.) and triethylamine (127.20 g: 5 eq.) were suspended in acetonitrile (800 mL). While the suspension was cooled on ice, a 50% propanephosphonic acid anhydride ethyl acetate solution (191.99 g) was added portionwise. The equipment used to add 50% propanephosphonic acid anhydride ethyl acetate solution was thoroughly washed with acetonitrile (192 mL) and stirred at room temperature (20 to 30° C.) overnight. Subsequently, the mixture was concentrated under reduced pressure. To the resulting residue, chloroform (250 mL) and a saturated aqueous sodium bicarbonate solution (140 mL) were sequentially added and the mixture was transferred to a separation funnel. The reaction container was thoroughly washed with chloroform (175 mL) and separation was performed. Once the organic layer was separated, chloroform (175 mL) was added to the aqueous layer and separation was performed again. The collected organic layer was dried over magnesium sulfate and was suction-filtered. The filtrate was evaporated under reduced pressure to give 183.27 g of the crude desired product of Compound 30 as a yellow amorphous.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[CH3:11].[H][H]>C(O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[CH3:11]
Reactant: Cc1cc([N+](=O)[O-])ccc1F
Reactant: [H][H]
Solvent: CCO
Product: Cc1cc(N)ccc1F

Procedure:
To a solution of 20 g (129 mmol) of 2-fluoro-5-nitrotoluene in 400 mL of ethanol was added 2 g of 10% Pd--C. The mixture was shaken under 45 P.S.I. H2 until hydrogen uptake ceased. The catalyst was filtered away and washed with ethanol, then the combined filtrate and washings were concentrated to 15.2 g (94%) of a colorless oil.
Reaction SMILES: Cl.[N:2]12CCC([CH2:6][CH2:7]1)[C:4](=O)[CH2:3]2.[CH3:11][O:12][C:13]([O:16][CH3:17])([CH3:15])[CH3:14].CS(O)(=O)=O>P([O-])([O-])([O-])=O>[CH3:11][O:12][C:13]1([O:16][CH3:17])[CH:15]2[CH2:6][CH2:7][N:2]([CH2:3][CH2:4]2)[CH2:14]1
Reactant: O=C1CN2CCC1CC2
Reactant: COC(C)(C)OC
Agent: CS(=O)(=O)O
Agent: Cl
Agent: O=P([O-])([O-])[O-]
Product: COC1(OC)CN2CCC1CC2

Procedure:
A mixture of 3-quinuclidinone hydrochloride (5.00 g, 30.9 mmol), 2,2 dimethoxypropane (50 ml), and methanesulfonic acid (0.1 ml) was refluxed for 8 h. The reaction mixture was poured in pH 7.4 phosphate buffer (20 ml) and washed 4 times with ethyl acetate. The aqueous phase was made basic by the addition of 4 M NaOH. Extraction with 3 portions of ethyl acetate gave, after drying and evaporation the title compound as a colorless oil. Yield 4.00 g (75%).
Reaction SMILES: [N+:1]([O:4][C@H:5]([CH2:27][O:28][N+:29]([O-:31])=[O:30])[CH2:6][CH2:7][CH2:8][C:9]([O:11][C@@H:12]1[CH2:16][O:15][C@@H:14]2[C@H:17]([O:20]C3CCCCO3)[CH2:18][O:19][C@H:13]12)=[O:10])([O-:3])=[O:2].C(O)C>>[N+:1]([O:4][C@H:5]([CH2:27][O:28][N+:29]([O-:31])=[O:30])[CH2:6][CH2:7][CH2:8][C:9]([O:11][C@@H:12]1[CH2:16][O:15][C@@H:14]2[C@H:17]([OH:20])[CH2:18][O:19][C@H:13]12)=[O:10])([O-:3])=[O:2]
Reactant: O=C(CCC[C@@H](CO[N+](=O)[O-])O[N+](=O)[O-])O[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2OC1CCCCO1
Solvent: CCO
Product: O=C(CCC[C@@H](CO[N+](=O)[O-])O[N+](=O)[O-])O[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2O
Temperature: 45 °C
Reaction time: 4 h

Procedure:
To a solution of (5S)-((3R,3aR,6R,6aR)-6-(tetrahydro-2H-pyran-2-yloxy)hexahydrofuro[3,2-b]furan-3-yl) 5,6-bis(nitrooxy)hexanoate (2.27 g, 5.04 mmol) in ethanol (40 mL) pyridinium p-toluensulfonate (127 mg, 0.504 mmol) was added The reaction mixture was stirred at 45° C. for 4 hrs. The reaction mixture was filtered, concentrated under reduced pressure. The crude residue was purified by flash chromatography (Biotage SP1, EtOAc/n-hexane from 10 to 60%), affording the title product as pale yellow oil.
Reaction SMILES: [C:1]([C:4]1[C:9]([O:10][CH2:11][CH2:12][NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[C:8](Br)[C:7]([CH3:22])=[C:6]([Cl:23])[CH:5]=1)(=[O:3])[CH3:2].[CH3:24][C:25]1(C)C(C)(C)OB(C=C)O1.ClCCl.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.Cl[Pd]Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].O>[C:1]([C:4]1[C:9]([O:10][CH2:11][CH2:12][NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[C:8]([CH:24]=[CH2:25])[C:7]([CH3:22])=[C:6]([Cl:23])[CH:5]=1)(=[O:3])[CH3:2]
Reactant: C=CB1OC(C)(C)C(C)(C)O1
Reactant: CC(=O)c1cc(Cl)c(C)c(Br)c1OCCNC(=O)OC(C)(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: ClCCl
Solvent: C1COCCO1
Product: C=Cc1c(C)c(Cl)cc(C(C)=O)c1OCCNC(=O)OC(C)(C)C
Temperature: 50 °C
Yield: 72.4 %

Procedure:
A mixture of tert-butyl [2-(6-acetyl-2-bromo-4-chloro-3-methylphenoxy)ethyl]carbamate (6.5 g, 16 mmol), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (3.3 mL, 19 mmol), [1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium(II), complex with dichloromethane (1:1) (600 mg, 0.8 mmol) and potassium carbonate (6.6 g, 48 mmol) in 1,4-dioxane (100 mL), and water (50 mL) was heated at 80° C. for 3 hours and 50° C. overnight. The reaction mixture was cooled to room temperature and extracted with ethyl acetate (3×10 mL). The organic layers were combined and washed with brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified on a silica gel with ethyl acetate in hexanes (0-25%) to afford the desired compound (4.1 g, 72%). LCMS calculated for C18H24ClNO4Na (M+Na)+: m/z=376.1; found: 376.0.
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH2:3][CH2:2]1.[CH3:8][N:9]([CH3:13])[CH2:10][CH2:11][NH2:12].O1CCOCC1>C(C(C)=O)C>[CH3:8][N:9]([CH3:13])[CH2:10][CH2:11][NH:12][C:1](=[O:7])[CH2:2][CH2:3][C:4]([OH:6])=[O:5]
Reactant: CN(C)CCN
Reactant: O=C1CCC(=O)O1
Solvent: CCC(C)=O
Solvent: C1COCCO1
Product: CN(C)CCNC(=O)CCC(=O)O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
1.4 g of succinic anhydride and then 1.5 cm3 of 2-dimethylaminoethylamine are added to 15 cm3 of dioxane. After stirring for 18 hours at room temperature, the solvent is evaporated under reduced pressure (2.7 kPa) at 20° C., to give a residue which is taken up hot in 40 cm3 of methyl ethyl ketone. After cooling, the solubilized fraction is removed. The residual gum is crystallized hot from 15 cm3 of acetone. After filtration, the solid is rinsed with a minimum of acetone and then with diethyl ether, and dried under reduced pressure (2.7 kPa) at 20° C. to give 2.03 g of N-(2-dimethylaminoethyl)succinamic acid in the form of a white solid melting at 155° C.
Reaction SMILES: O.[OH-].[Li+].[C:4]1(/[C:10](=[N:17]/[O:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]3[N:29]=[C:30]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[S:31][CH:32]=3)=[CH:22][CH:21]=2)/[CH2:11][CH2:12][C:13]([O:15]C)=[O:14])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.O.Cl>O1CCCC1>[C:4]1(/[C:10](=[N:17]/[O:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]3[N:29]=[C:30]([C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=4)[S:31][CH:32]=3)=[CH:22][CH:21]=2)/[CH2:11][CH2:12][C:13]([OH:15])=[O:14])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: COC(=O)CC/C(=N\OCc1ccc(OCc2csc(-c3ccccc3)n2)cc1)c1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)CC/C(=N\OCc1ccc(OCc2csc(-c3ccccc3)n2)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.6 %

Procedure:
Lithium hydroxide monohydrate (54.8 mg) was added to a solution of methyl E-4-phenyl-4-[4-(2-phenyl-4-thiazolylmethoxy)benzyloxyimino]butyrate (424 mg) in tetrahydrofuran (10 ml)-water (4 ml)-metbanol (4 ml) and stirred at room temperature for 2 hours. 1N hydrochloric acid (1.4 ml) was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated solution of sodium chloride, dried (MgSO4) and concentrated. The remaining crystals were recrystallized from ethyl acetate-hexane to obtain E-4-phenyl-4-[4-(2-phenyl-4-thiazolylmethoxy)benzyloxyimino]butyric acid (369 mg, yield 90%) as colorless crystals. m.p. 104-105° C.
Reaction SMILES: [OH:1][C@H:2]([CH2:17][N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)[CH2:3][N:4]1[CH2:9][CH2:8][C:7]2[NH:10][C:11]([CH:14]=O)=[C:12]([CH3:13])[C:6]=2[C:5]1=[O:16].[F:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[NH:30][C:29](=[O:34])[CH2:28]2.N1CCCCC1>C(O)C>[F:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[NH:30][C:29](=[O:34])/[C:28]/2=[CH:14]\[C:11]1[NH:10][C:7]2[CH2:8][CH2:9][N:4]([CH2:3][C@H:2]([OH:1])[CH2:17][N:18]3[CH2:19][CH2:20][O:21][CH2:22][CH2:23]3)[C:5](=[O:16])[C:6]=2[C:12]=1[CH3:13]
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(C[C@H](O)CN1CCOCC1)CC2
Reactant: O=C1Cc2cc(F)ccc2N1
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1c(/C=C2\C(=O)Nc3ccc(F)cc32)[nH]c2c1C(=O)N(C[C@H](O)CN1CCOCC1)CC2
Temperature: 25 °C
Yield: 100.6 %

Procedure:
(R)-5-(2-Hydroxy-3-morpholin-4-yl-propyl)-3-methyl-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde 1f (200 g, 0.623 mmol), 5-fluoro-1,3-dihydro-indol-2-one (84.67 mg, 0.56 mmol) and piperidine (30.8 μL, 0.31 mmol) were dissolved in 1.09 mL of ethanol under stirring at room temperature. The reaction system was stirred at 80° C. in an oil bath in dark for 2 hours.The reaction was completed until TLC showed the disappearance of starting materials, and the oil bath was removed. The reaction system was allowed to cool down to room temperature to precipitate solids. The resulting solids were filtered to give the title compound (R,Z)-2-(5-fluoro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-5-(2-hydroxy-3-morpholin-4-yl-propyl)-3-methyl-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one 1 (256 mg, 90%) as a yellow solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([B:8]2[O:12][C:11]([CH3:14])([CH3:13])[C:10]([CH3:16])([CH3:15])[O:9]2)=[CH:4][N:3]=1.CN.C[CH2:20][N:21](C(C)C)C(C)C>O1CCOCC1>[CH3:20][NH:21][C:2]1[CH:7]=[CH:6][C:5]([B:8]2[O:12][C:11]([CH3:14])([CH3:13])[C:10]([CH3:16])([CH3:15])[O:9]2)=[CH:4][N:3]=1
Reactant: CC1(C)OB(c2ccc(Cl)nc2)OC1(C)C
Reactant: CCN(C(C)C)C(C)C
Agent: CN
Solvent: C1COCCO1
Product: CNc1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (200 mg, 0.84 mmol), methanamine (277 mg, 8.4 mmol), and DIPEA (0.35 mL, 2.01 mmol) in dioxane (5 mL) was stirred at room temperature for 16 hours. It was then concentrated under reduced pressure, and the residue was treated in EtOAc. The insoluble solid was removed by filtration, and the organic solution was concentrated under reduced pressure to give the title compound.