Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:13]=[CH:12][C:6](/[CH:7]=[CH:8]/[C:9]([OH:11])=O)=[CH:5][CH:4]=1.[CH2:16]([N:23]1[CH2:28][CH2:27][N:26]([C:29](=[O:51])[C@@H:30]([NH:38][CH2:39][C:40]2[CH:45]=[CH:44][C:43]([CH2:46][CH2:47][CH2:48][CH2:49][CH3:50])=[CH:42][CH:41]=2)[CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:25][CH2:24]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O>ClCCl.CCN(C(C)C)C(C)C>[CH2:31]([C@H:30]([N:38]([CH2:39][C:40]1[CH:41]=[CH:42][C:43]([CH2:46][CH2:47][CH2:48][CH2:49][CH3:50])=[CH:44][CH:45]=1)[C:9](=[O:11])[CH:8]=[CH:7][C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:15])[F:14])=[CH:13][CH:12]=1)[C:29]([N:26]1[CH2:25][CH2:24][N:23]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:28][CH2:27]1)=[O:51])[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: O=C(O)/C=C/c1ccc(C(F)(F)F)cc1
Reactant: CCCCCc1ccc(CN[C@@H](Cc2ccccc2)C(=O)N2CCN(Cc3ccccc3)CC2)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CCCCCc1ccc(CN(C(=O)C=Cc2ccc(C(F)(F)F)cc2)[C@@H](Cc2ccccc2)C(=O)N2CCN(Cc3ccccc3)CC2)cc1
Reaction time: 1 h
Yield: 58.8 %

Procedure:
In an inert atmosphere, trans-4-trifluoromethyl-cinnamic acid (21.4 mg, 0.099 mmol) was dissolved in 2 mL dichloromethane followed by the addition of 1-chloro-N,N-2-trimethylpropenyl amine (16.4 μl, 0.122 mmol). Stirring was continued at rt for 1 h. This solution was then added to a solution of 1-(4-benzyl-piperazin-1-yl)-(S)-2-(4-pentyl-benzylamino)-3-phenyl-propan-1-one (43.5 mg, 0.09 mmol) in dichloromethane (1 mL) and Hünig's base (39 μl). The resulting mixture was stirred for 1 h at rt, followed by the addition of water (3 mL). The layers were separated. The aq. layer was extracted with dichloromethane (2×2 mL) and the combined organic layers were dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by prep. TLC (silicagel, heptane/EtOAc=1/1) to give 36.1 mg (58%) of N—[(S)-1-benzyl-2-(4-benzyl-piperazin-1-yl)-2-oxo-ethyl]-N-(4-pentyl-benzyl)-3-(4-trifluoromethyl-phenyl)-acrylamide. LC-MS: tR=1.02 min; [M+H]+=682.48.
Reaction SMILES: [CH:1]1([CH2:4][C:5]2([CH:15]=O)[CH2:14][CH2:13][C:8]3([O:12][CH2:11][CH2:10][O:9]3)[CH2:7][CH2:6]2)[CH2:3][CH2:2]1.[CH3:17][C:18]([S:21]([NH2:23])=[O:22])([CH3:20])[CH3:19].O>O1CCCC1.[O-]CC.[Ti+4].[O-]CC.[O-]CC.[O-]CC>[CH:1]1([CH2:4][C:5]2([CH:15]=[N:23][S:21]([C:18]([CH3:20])([CH3:19])[CH3:17])=[O:22])[CH2:6][CH2:7][C:8]3([O:9][CH2:10][CH2:11][O:12]3)[CH2:13][CH2:14]2)[CH2:2][CH2:3]1
Reactant: CC(C)(C)S(N)=O
Reactant: O=CC1(CC2CC2)CCC2(CC1)OCCO2
Agent: [Ti+4]
Agent: CC[O-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)S(=O)N=CC1(CC2CC2)CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 5 h

Procedure:
The crude aldehyde was dissolved in tetrahydrofuran (40 mL) and 2-methyl-2-propanesulfinamide (1.81 g, 14.9 mmol, 1.1 eq.) and titanium(IV) ethoxide (4.27 mL, 20.3 mmol, 1.5 eq.) were added. The resulting mixture was stirred for 5 h under reflux and 16 h at room temperature, before being treated with water (10 mL) and filtered through celite. The filter cake was washed with ethyl acetate, the aqueous layer was separated and extracted twice with ethyl acetate. The combined organic layers were dried over magnesium sulphate, filtered, and concentrated in vacuo. The crude product was purified by flash chromatography (SiO2, 0%→100% ethyl acetate in heptane) to yield 1.90 g of the title compound (19). Rt=1.58 min (Method B). Detected mass: 328.3 (M+H+).
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:11][O:10][CH2:9][C@H:8]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C@@H:7]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C@@H:6]([CH3:28])[O:5][C:4]1=[O:29].[OH:30][C:31]1[C:32]([C:39](O)=[O:40])=[N:33][CH:34]=[CH:35][C:36]=1[O:37][CH3:38].CN1CCOCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[CH2:13]([O:12][C@@H:8]1[C@@H:7]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C@@H:6]([CH3:28])[O:5][C:4](=[O:29])[C@H:3]([NH:2][C:39](=[O:40])[C:32]2[C:31]([OH:30])=[C:36]([O:37][CH3:38])[CH:35]=[CH:34][N:33]=2)[CH2:11][O:10][CH2:9]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COc1ccnc(C(=O)O)c1O
Reactant: C[C@H]1OC(=O)[C@H](N)COC[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: COc1ccnc(C(=O)N[C@@H]2COC[C@H](OCc3ccccc3)[C@@H](OCc3ccccc3)[C@@H](C)OC2=O)c1O
Temperature: 25 °C
Reaction time: 4 h
Yield: 60.5 %

Procedure:
To a mixture of (3R,7S,8S,9R)-3-amino-7,8-bis(benzyloxy)-9-methyl-1,5-dioxonan-2-one hydrochloride (85.0 mg, 0.2015 mmol) and 3-hydroxy-4-methoxypicolinic acid (54.0 mg, 0.321 mmol) in DCM (1.20 mL) was added 4-methylmorpholine (0.141 mL, 1.29 mmol) followed by HATU (135.0 mg, 0.343 mmol) and the mixture was stirred at room temperature for 4 h. The reaction mixture was directly purified by flash chromatography (SiO2, hexanes/EtOAc gradient) to yield the title compound as a colorless oil (65.4 mg, 61%): IR (neat) 3368, 2933, 1748, 1648, 1527, 1242, 1066 cm−1; 1H NMR (400 MHz, CDCl3) δ 11.98 (s, 1H), 8.86 (d, J=8.0 Hz, 1H), 8.01 (d, J=5.2 Hz, 1H), 7.41-7.27 (m, 10H), 6.86 (d, J=5.2 Hz, 1H), 5.36 (qd, J=6.7, 3.1 Hz, 1H), 5.06 (ddd, J=8.0, 6.1, 1.9 Hz, 1H), 4.71 (d, J=11.4 Hz, 1H), 4.68 (d, J=11.8 Hz, 1H), 4.60 (d, J=11.3 Hz, 1H), 4.58 (d, J=11.8 Hz, 1H), 4.16 (dd, J=12.2, 3.6 Hz, 1H), 4.12 (dd, J=9.4, 2.2 Hz, 2H), 3.98 (dd, J=11.7, 6.1 Hz, 1H), 3.94 (s, 3H), 3.71 (dd, J=11.9, 1.7 Hz, 1H), 3.57-3.50 (m, 1H), 1.38 (d, J=6.8 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 169.86, 169.07, 155.41, 148.82, 140.81, 138.27, 138.10, 130.51, 128.58, 128.54, 128.14, 128.05, 128.00, 127.85, 109.64, 78.70, 75.15, 74.37, 72.35, 71.55, 56.21, 53.37, 15.28; HRMS-ESI (m/z) [M]+ calcd for C29H32N2O8, 536.2159; found, 536.2162.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]([CH3:15])[CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][C:3]=1[N+:16]([O-:18])=[O:17].[NH2:19][CH2:20][CH2:21][CH2:22][C:23]1[N:24]=[CH:25][NH:26][CH:27]=1>O1CCOCC1>[NH:26]1[CH:27]=[C:23]([CH2:22][CH2:21][CH2:20][NH:19][C:2]2[CH:7]=[CH:6][C:5]([C:8]3[CH:9]([CH3:15])[CH2:10][C:11](=[O:14])[NH:12][N:13]=3)=[CH:4][C:3]=2[N+:16]([O-:18])=[O:17])[N:24]=[CH:25]1
Reactant: CC1CC(=O)NN=C1c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: NCCCc1c[nH]cn1
Solvent: C1COCCO1
Product: CC1CC(=O)NN=C1c1ccc(NCCCc2c[nH]cn2)c([N+](=O)[O-])c1

Procedure:
2.67 g (10 mmol) of 6-(4-chloro-3-nitro-phenyl)-5-methyl-4,5-dihydro-3(2H)-pyridazinone are boiled under reflux with 2.5 g (20 mmol) of 4-(3-aminopropyl)-1H-imidazole in 50 ml of dioxane for 5 hours.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:20])[C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=3)=[CH:8][O:9]2)=[CH:4][CH:3]=1.[C:21](OC(=O)C)(=[O:23])[CH3:22]>N1C=CC=CC=1>[C:21]([O:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:20])[C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=3)=[CH:8][O:9]2)=[CH:4][CH:3]=1)(=[O:23])[CH3:22]
Reactant: COc1cccc(-c2coc3cc(O)ccc3c2=O)c1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: COc1cccc(-c2coc3cc(OC(C)=O)ccc3c2=O)c1

Procedure:
7-Acetoxy-3′-methoxyisoflavone was prepared from 7-hydroxy-3′-methoxyisoflavone (1.7 g, 6.3 mmol), acetic anhydride (6 ml) and pyridine (1.0 ml) as described for 4′,7-diacetoxydaidzein. Yield: (1.6 g, 81%) m.p. 118° C. 1H NMR (CDCl3): δ 2.36 (s, 3H, OCOCH3), 3.85 (s, 3H, OMe), 6.95 (dd, 1H, J 2.0 Hz 8.3 Hz, H6), 6.70-7.40 (m, 5H, ArH), 8.01 (s, 1H, H2), 8.32 (d, 1H, J 8.7 Hz, H5).
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][S:5](=[O:8])(=[O:7])[N:4]([C:9]2[CH:19]=[CH:18][C:12]([C:13]([O:15]CC)=[O:14])=[CH:11][CH:10]=2)[CH2:3]1.[OH-].[Na+]>O1CCCC1>[CH3:1][CH:2]1[CH2:6][S:5](=[O:8])(=[O:7])[N:4]([C:9]2[CH:19]=[CH:18][C:12]([C:13]([OH:15])=[O:14])=[CH:11][CH:10]=2)[CH2:3]1
Reactant: CCOC(=O)c1ccc(N2CC(C)CS2(=O)=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC1CN(c2ccc(C(=O)O)cc2)S(=O)(=O)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of ethyl 4-iodobenzoate (571 mg), 4-methylisothiazolidine 1,1-dioxide (280 mg) described in Preparation Example 9, potassium carbonate (572 mg) and copper(I) iodide (197 mg) were added toluene (6 mL) and N,N′-dimethylethylenediamine (230 μL), and the mixture was stirred with heating under reflux for 9 hr. The reaction mixture was cooled, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated. The obtained residue was purified by column chromatography (hexane:ethyl acetate) to give ethyl 4-(4-methyl-1,1-dioxo-1λ6-isothiazolidin-2-yl)benzoate. The obtained ethyl 4-(4-methyl-1,1-dioxo-1λ6-isothiazolidin-2-yl)benzoate was dissolved in tetrahydrofuran (5 mL), 1N aqueous sodium hydroxide solution was added, and the mixture was stirred at room temperature for 1 hr. The solvent was evaporated from the reaction mixture, 1N hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated. To the obtained residue was added diethyl ether, and the precipitate was collected by filtration to give the title compound (210 mg).
Reaction SMILES: [N+]([O-])(O)=[O:2].[CH:5]1([N:8]2[C:17]3[C:12](=[CH:13][C:14]([F:24])=[C:15](N4CCNCC4)[N:16]=3)[C:11](=[O:25])[C:10]([C:26]([OH:28])=[O:27])=[CH:9]2)[CH2:7][CH2:6]1>S(=O)(=O)(O)O>[CH:5]1([N:8]2[C:17]3[C:12](=[CH:13][C:14]([F:24])=[C:15]([OH:2])[N:16]=3)[C:11](=[O:25])[C:10]([C:26]([OH:28])=[O:27])=[CH:9]2)[CH2:7][CH2:6]1
Reactant: O=C(O)c1cn(C2CC2)c2nc(N3CCNCC3)c(F)cc2c1=O
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=C(O)c1cn(C2CC2)c2nc(O)c(F)cc2c1=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 2 ml of 70% nitric acid in 10 ml of 98% sulfuric acid was added in portions 1.0 g (3.0 mmole) of 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-1,8-naphthyridine-3-carboxylic acid, keeping the temperature between 25°-30° C. The resulting solution was stirred at room temperature for 18 hours and poured onto 40 g of ice. The mixture was stirred at room temperature for 24 hours, concentrated in vacuo, the pH adjusted to 12 with aqueous sodium hydroxide, and filtered through a fiber glass pad. The filtrate was acidified to pH 3.5 with 6.0 M hydrochloric acid, the resulting precipitate removed by filtration, washed with water then ether and dried in vacuo to give 0.23 g of the title compound, mp 325°-327° C.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][C:19]3[CH:27]=[CH:26][C:25]([CH3:28])=[C:24]4[C:20]=3[CH2:21][CH2:22][CH2:23]4)[CH:13]=[N:12]2)[C:8](O)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:29][C:30]1([CH3:42])[O:34][C@H:33]([CH2:35][N:36]2[CH:40]=[CH:39][C:38]([NH2:41])=[N:37]2)[CH2:32][O:31]1>>[CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][C:19]3[CH:27]=[CH:26][C:25]([CH3:28])=[C:24]4[C:20]=3[CH2:21][CH2:22][CH2:23]4)[CH:13]=[N:12]2)[C:8]([NH:41][C:38]2[CH:39]=[CH:40][N:36]([CH2:35][C@@H:33]3[CH2:32][O:31][C:30]([CH3:42])([CH3:29])[O:34]3)[N:37]=2)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Cc1ccc(Oc2cnn(C(CC3CCCC3)C(=O)O)c(=O)c2)c2c1CCC2
Reactant: CC1(C)OC[C@@H](Cn2ccc(N)n2)O1
Product: Cc1ccc(Oc2cnn(C(CC3CCCC3)C(=O)Nc3ccn(C[C@@H]4COC(C)(C)O4)n3)c(=O)c2)c2c1CCC2

Procedure:
Using the method described in Example 49, 3-cyclopentyl-2-[4-(7-methyl-indan-4-yloxy)-6-oxo-6H-pyridazin-1-yl]-propionic acid (Intermediate 71) and 1-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-pyrazol-3-ylamine (Intermediate 4) afforded 3-cyclopentyl-N-[1-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-pyrazol-3-yl]-2-[4-(7-methyl-indan-4-yloxy)-6-oxo-6H-pyridazin-1-yl]-propionamide as an off-white solid as a mixture of diastereomers (1.09 g, 74%).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH:4]([CH3:8])[C:3]1=[O:9].[CH3:10][Mg]Br>CCOCC>[CH3:10][C:3]1([OH:9])[CH:4]([CH3:8])[CH2:5][CH2:6][CH2:7][CH:2]1[CH3:1]
Reactant: CC1CCCC(C)C1=O
Reactant: C[Mg]Br
Solvent: CCOCC
Product: CC1CCCC(C)C1(C)O
Temperature: -78 °C
Reaction time: 3 h

Procedure:
A solution of 2,6-dimethylcyclohexanone (35 g, 0.277 mole) in ether (200 ml) was cooled to -78° C. and treated with a 2-fold excess of a solution of methyl magnesium bromide in ether (2.8M, 198 ml). After stirring at -78° C. for 3 hours the reaction mixture was warmed to 0° C. and quenched carefully with water and brine. The organic layer was separated, dried (MgSO4) and the ether evaporated under reduced pressure to give 1,2,6-trimethylcyclohexanol (32.2 g).
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.C[O:12][C:13]([C:15]1[C:16]2[CH:17]=[CH:18][N:19]([S:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)(=[O:28])=[O:27])[C:20]=2[C:21]([O:24][CH3:25])=[CH:22][CH:23]=1)=O>C(Cl)Cl.[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+]>[C:29]1([S:26]([N:19]2[C:20]3[C:16](=[C:15]([CH2:13][OH:12])[CH:23]=[CH:22][C:21]=3[O:24][CH3:25])[CH:17]=[CH:18]2)(=[O:28])=[O:27])[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: COC(=O)c1ccc(OC)c2c1ccn2S(=O)(=O)c1ccccc1
Agent: CC(C)C[Al+]CC(C)C
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: [H-]
Solvent: ClCCl
Product: COc1ccc(CO)c2ccn(S(=O)(=O)c3ccccc3)c12
Reaction time: 1 h

Procedure:
Diisobutylaluminum hydride (1.5 M toluene, 1.4 mL, 2.1 mmol) is added dropwise to a −78° C. solution of 1-benzenesulfonyl-7-methoxy-1H-indole-4-carboxylic acid methyl ester (0.34 g, 0.98 mmol, Santangelo, et. al., Synth. Commun. 1993, 23, 2717–2725) in CH2Cl2 (7 mL). After stirring for 1 h, the solution is diluted with 10% aq. Rochelle's salt (100 mL) and extracted twice with EtOAc (100 mL). The organics are washed with aq. Rochelle's salt and brine. The organics are dried (MgSO4) and concentrated under reduced pressure to provide (1-benzenesulfonyl-7-methoxy-1H-indol-4-yl)-methanol as a crispy foam which is used as is without further purification.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:12][CH2:13][CH3:14])[CH2:5][O:6][CH2:7][CH2:8][CH2:9][CH2:10][OH:11])[CH3:2].[Cl:15][C:16]1[CH:21]=[C:20]([O:22][CH2:23][CH:24]=[C:25]([Cl:27])[Cl:26])[CH:19]=[C:18]([Cl:28])[C:17]=1O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[Cl:15][C:16]1[CH:21]=[C:20]([O:22][CH2:23][CH:24]=[C:25]([Cl:27])[Cl:26])[CH:19]=[C:18]([Cl:28])[C:17]=1[O:11][CH2:10][CH2:9][CH2:8][CH2:7][O:6][CH2:5][CH:4]([O:3][CH2:1][CH3:2])[O:12][CH2:13][CH3:14]
Reactant: Oc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Reactant: CCOC(COCCCCO)OCC
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(COCCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl)OCC
Yield: 92.1 %

Procedure:
To a mixture of 2.30 g of 4-(2,2-diethoxyethoxy)butanol, 2.94 g of 2,6-dichloro-4-(3,3-dichloro-2-propenyloxy)phenol, 2.94 g of triphenylphosphine and 30 ml of tetrahydrofuran was slowly added dropwise 2.48 g of diisopropyl azodicarboxylate with stirring under ice cooling. After stirring at room temperature for 24 hours, the reaction mixture was concentrated. The residue was subjected to silica gel chromatography, which afforded 4.48 g of 3,5-dichloro-1-(3,3-dichloro-2-propenyloxy)-4-(4-(2,2-diethoxyethoxy)butyloxy)benzene (yield, 73%), nD24.5 1.5165.
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10](C(O)=O)[CH:11]=2)[CH:6]=[CH:5][N:4]=1.ClC1C2C(=CC([C:27]([O:29][CH2:30][CH3:31])=[O:28])=CC=2)C=CN=1>>[CH3:1][NH:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:10][CH:11]=2)[CH:6]=[CH:5][N:4]=1
Reactant: CNc1nccc2ccc(C(=O)O)cc12
Reactant: CCOC(=O)c1ccc2c(Cl)nccc2c1
Product: CCOC(=O)c1ccc2c(NC)nccc2c1

Procedure:
The title compound was prepared by a method analogous to that described in Step 1 of Intermediate 31, using ethyl 1-chloroisoquinoline-6-carboxylate. +ESI (M+H) 231.1; 1H NMR (400 MHz, CDCl3, δ): 8.39 (s, 1H), 8.06-8.14 (m, 2H), 8.00 (d, J=5.9 Hz, 1H), 7.02 (d, J=6.0 Hz, 1H), 4.44 (q, J=7.3 Hz, 2H), 3.25 (d, J=4.7 Hz, 3H), 1.43 (t, J=7.1 Hz, 3H).
Reaction SMILES: [OH-:1].[Na+].S(=O)(=O)(O)O.[C:8]([OH:11])(=O)[CH3:9]>>[OH:1][CH2:9][C:9]([C@@H:8]([C@H:8]([C@H:9]([CH2:8][OH:11])[OH:1])[OH:11])[OH:11])=[O:1]
Reactant: [OH-]
Reactant: CC(=O)O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: O=C(CO)[C@H](O)[C@@H](O)[C@@H](O)CO
Temperature: 40 °C
Yield: 85 %

Procedure:
Methanesulfonyl chloride (1.5 g) was added to a solution of 9 (1.2 g) in pyridine (2 ml). After being kept at room temperature for 2 days, ice was added and the mixture was extracted with chloroform. The organic layer was washed with water and evaporated to give methyl 4,6-O-isopropylidene-1,3-di-O-methanesulfonyl-α-L-sorbofuranoside as a syrup. The syrup was stirred in 60% acetic acid at 55° C. for 2.5 hours. The solution was brought up to pH about 10 with 10N sodium hydroxide and heated at 40° C. for 3 hours. The reaction mixture was neutralized with 10N sulfuric acid and concentrated. The residue was triturated with ethanol. After the salt was filtered off, the ethanol solution was concentrated and the residue was dissolved in a mixture of ethanol and 10N sulfuric acid (1:4). The solution was heated to 80° C. for 30 min. Ethanol was evaporated off and the mixture was heated for 5 minutes. The reaction mixture was neutralized with 10N sodium hydroxide and the salt was removed by repeated precipitation with ethanol. After filtration, the filtrate was concentrated to give L-fructose in more than 85% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[C:17]([O:19][CH2:20][CH:21]=[C:22]([Cl:24])[Cl:23])[CH:16]=[C:15]([Cl:25])[C:3]=1[O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][CH2:11][C:12](=O)[CH3:13].Cl.[C:27]([O:31][NH2:32])([CH3:30])([CH3:29])[CH3:28].Cl>N1C=CC=CC=1>[C:27]([O:31][N:32]=[C:12]([CH2:11][O:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][O:4][C:3]1[C:2]([Cl:1])=[CH:18][C:17]([O:19][CH2:20][CH:21]=[C:22]([Cl:24])[Cl:23])=[CH:16][C:15]=1[Cl:25])[CH3:13])([CH3:30])([CH3:29])[CH3:28]
Reactant: CC(=O)COCCCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Reactant: CC(C)(C)ON
Agent: Cl
Solvent: c1ccncc1
Product: CC(COCCCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl)=NOC(C)(C)C
Temperature: 25 °C
Reaction time: 24 h
Yield: 89.8 %

Procedure:
To a mixture of 0.43 g of 5-(2,6-dichloro-4-(3,3-dichloro-2-propenyloxy)phenoxy)pentyloxyacetone and 10 ml of pyridine was added 0.15 g of O-tert-butylhydroxylamine hydrochloride. After stirring at room temperature for 24 hours, the reaction mixture was poured into diluted hydrochloric acid, and extracted twice with diethyl ether. The diethyl ether layers were combined, washed with water, dried over anhydrous magnesium sulfate, and concentrated, which afforded 0.45 g (yield, 90%) of 5-(2,6-dichloro-4-(3,3-dichloro-2-propenyloxy)phenoxy)pentyloxyacetone O-tert-butyloxime, nD25.5 1.5170.
Reaction SMILES: [H-].[Na+].[C:3](OC)(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:13]([C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:18][CH:17]=1)(=[O:15])[CH3:14]>CN(C=O)C>[OH:15]/[C:13](/[C:16]1[CH:17]=[CH:18][C:19]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:20][CH:21]=1)=[CH:14]\[C:3](=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(=O)c1ccc(NC(=O)OC(C)(C)C)cc1
Reactant: COC(=O)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1ccc(/C(O)=C/C(=O)c2ccccc2)cc1
Temperature: 25 °C
Yield: 83.5 %

Procedure:
NaH (60% dispersion, 0.388 g, 16.2 mmol) was added to a solution of methyl benzoate (0.629 g, 4.62 mmol) and 1,1-dimethylethyl (4-acetylphenyl)carbamate (N-BOC-4-aminoacetophenone 1.09 g, 4.62 mmol) in anhydrous DMF (20 mL) at 0° C. The reaction was allowed to warm to room temperature overnight then quenched with saturated aqueous NH4Cl and neutralized with 1M HCl. The reaction was diluted with ethyl acetate (80 mL) and the organic layer washed successively with saturated aqueous NaHCO3 and brine. The organic phase was separated and dried over Na2SO4, filtered, and concentrated in vacuo to provide the condensation product as a yellow oil (1.31 g, 83% yield). The product was used in the subsequent step without further purification.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.CC#N.C(=O)=O.C([Li])CCC.[O:20]1CC[CH2:22][CH2:21]1.CN(C)C(=O)C>C1(C)C=CC=CC=1>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([C:21](=[O:20])[CH3:22])=[N:3][CH:4]=1
Reactant: Brc1ccc(Br)nc1
Reactant: C1CCOC1
Agent: O=C=O
Agent: [Li]CCCC
Solvent: CC#N
Solvent: CC(=O)N(C)C
Solvent: Cc1ccccc1
Product: CC(=O)c1ccc(Br)cn1
Temperature: -40 °C
Reaction time: 0.67 h

Procedure:
In a 3-neck 1000 ml round bottom flask, 2,5-dibromopyridine (10.0 g, 42.2 mmol) was dissolved in toluene (400 ml) and cooled to −40° C. (CH3CN/dry ice). 1.6 M of n-butyllithium in tetrahydrofuran (26.38 mL, 42.21 mmol) was slowly added to the cooled solution to form a deep reddish solution, which was stirred at −40° C. for 40 minutes. N,N-Dimethylacetamide (7.14 mL, 76.8 mmol) was added with no discernable change. The mixture was allowed to slowly warm to room temperature. Then, the mixture was quenched by adding 25 ml sat'd ammonium chloride. Added 100 ml H2O and extracted with EtOAc (250 ml). The organic phase was washed with water (200 ml). The combined aqueous phases were extracted with EtOAc (100 ml). The combined organic extracts were washed with brine, dried (Na2SO4), filtered and evaporated in vacuo to generate 6.31 g of a tan solid. 1H-NMR (CDCl3): δ 8.74 (d, J=1.9 Hz, 1H), 7.96 (m, 2H), 2.70 (s, 3H). HPLC: RT=3.237 min., 60 area % @ 210 nm; RT=3.238 min., 87 area % @254 nm. LCMS: MS (ESI—) for C8H7BrO m/z 201.0 (M+H)+.
Reaction SMILES: CC1N=C(N2CCN(C3C=CC=CC=3)C2=O)SC=1C(OCC)=O.[Cl:24][C:25]1[CH:48]=[CH:47][C:28]([CH2:29][N:30]2[CH2:34][CH2:33][N:32]([C:35]3[S:36][C:37]([C:41]([O:43]CC)=[O:42])=[C:38]([CH3:40])[N:39]=3)[C:31]2=[O:46])=[CH:27][CH:26]=1>>[Cl:24][C:25]1[CH:26]=[CH:27][C:28]([CH2:29][N:30]2[CH2:34][CH2:33][N:32]([C:35]3[S:36][C:37]([C:41]([OH:43])=[O:42])=[C:38]([CH3:40])[N:39]=3)[C:31]2=[O:46])=[CH:47][CH:48]=1
Reactant: CCOC(=O)c1sc(N2CCN(Cc3ccc(Cl)cc3)C2=O)nc1C
Agent: CCOC(=O)c1sc(N2CCN(c3ccccc3)C2=O)nc1C
Product: Cc1nc(N2CCN(Cc3ccc(Cl)cc3)C2=O)sc1C(=O)O
Yield: 96 %

Procedure:
Following the procedure as described in Example 6, making variations as required to replace ethyl 4-methyl-2-(2-oxo-3-phenylimidazolidin-1-yl)thiazole-5-carboxylate with ethyl 2-(3-(4-chlorobenzyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylate, the title compound was obtained in 96% yield: 1H NMR (300 DMSO-d6) δ 7.45 (d, J=7.2 Hz, 2H), 7.29 (d, J=7.2 Hz, 2H), 4.39 (s, 2H), 4.06-3.91 (m, 2H), 3.51-3.39 (m, 2H), 2.53 (s, 3H): MS (ES+) m/z 352.2 (M+1), 354.2 (M+1).
Reaction SMILES: C(N[C@H]1[C@H]([C@@H]([C@@H](CO)O)O)OC(O)(C(=O)O)C[C@@H]1O)(=O)C.[C:22]([NH:25][C@@H:26]1[C@@H:32]([OH:33])[C@H:31]([OH:34])[C@@H:30]([CH2:35][OH:36])[O:29][CH:27]1[OH:28])(=[O:24])[CH3:23]>>[C:22]([NH:25][C@H:26]1[C@@H:32]([OH:33])[C@H:31]([OH:34])[C@@H:30]([CH2:35][OH:36])[O:29][CH:27]1[OH:28])(=[O:24])[CH3:23]
Reactant: CC(=O)N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O
Agent: CC(=O)N[C@H]1[C@H]([C@H](O)[C@H](O)CO)OC(O)(C(=O)O)C[C@@H]1O
Product: CC(=O)N[C@@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O

Procedure:
In accomplishing these and other objects, there is provided a process for preparing N-acetylneuraminic acid, comprising the steps of (a) isomerizing N-acetylglucosamine in a reactor, in the presence of N-acylglucosamine-2-epimerase (E.C. 5.1.3.8), to give N-acetylmannosamine, and (b) reacting the N-acetylmannosamine with pyruvic acid in the presence of N-acetylneuraminic acid pyruvate lyase (E.C. 4.1.3.3) in the same reactor to give N-acetylneuraminic acid, wherein both the epimerase and the lyase are present in a reactor simultaneously, and steps (a) and (b) occur simultaneously.