Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:3]([C:7]([O:9]CC)=O)=[N:4][O:5][CH:6]=1.[N:12]1([CH2:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21]([O:25][CH2:26]/[CH:27]=[CH:28]\[CH2:29][NH2:30])[CH:20]=2)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1>C1(C)C=CC=CC=1>[OH:1][C:2]1[C:3]([C:7]([NH:30][CH2:29]/[CH:28]=[CH:27]\[CH2:26][O:25][C:21]2[CH:20]=[C:19]([CH2:18][N:12]3[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]3)[CH:24]=[CH:23][N:22]=2)=[O:9])=[N:4][O:5][CH:6]=1
Reactant: CCOC(=O)c1nocc1O
Reactant: NC/C=C\COc1cc(CN2CCCCC2)ccn1
Solvent: Cc1ccccc1
Product: O=C(NC/C=C\COc1cc(CN2CCCCC2)ccn1)c1nocc1O
Yield: 30.8 %

Procedure:
375 mg of ethyl 4-hydroxy-3-isoxazolecarboxylate (prepared as described in Preparation 4) were added to a solution of 520 mg of 4-(4-piperidinomethyl-2-pyridyloxy) -cis-2-butenylamine in 10 ml of toluene, and the resulting mixture was heated under reflux for 6 hours. At the end of this time, the solvent was removed by distillation under reduced pressure, and the residue was dissolved in ethyl acetate. The resulting solution was washed with a saturated aqueous solution of sodium hydrogencarbonate and then with a saturated aqueous solution of sodium chloride, after which it was dried over anhydrous magnesium sulfate. The solvent was then removed by distillation under reduced pressure, and the residue was purified by column chromatography through silica gel, using a 1:19 by volume mixture of methanol and ethyl acetate as the eluent, to give 228 mg (yield 31%) of the title compound as an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].Cl[C:10]1[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=[O:13].N1C2C(=CC=CC=2)C=CC=1.Cl>O.N1C=CC=CC=1>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][C:10]1[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=[O:13]
Reactant: Nc1ccccc1S
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Solvent: c1ccc2ncccc2c1
Product: Nc1ccccc1Sc1cc([N+](=O)[O-])ccc1C(=O)O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Heat a mixture of 466 g (3.72 moles) of 2-aminothiophenol, 250 g (1.24 moles) of 2-chloro-4-nitrobenzoic acid, 1.25 liters of quinoline, 192 g (1.34 moles) of cuprous oxide and 125 ml of pyridine in an oil bath at 160°-170° C. with mechanical stirring for 90 minutes. Cool the mixture to room temperature and add 1.87 liters of concentrated hydrochloric acid followed by 625 ml of water. Separate the precipitate and wash well with water. Extract the washed precipitate into boiling methanol and filter. Treat the hot filtrate with charcoal, filter and strip to dryness. Dissolve the residue in aqueous sodium hydroxide, filter and treat with charcoal. Acidify the filtrate and separate the precipitate. (Yield: 38 g).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.Cl[C:11]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[S:13](=[O:21])(=[O:20])[N:12]=1.[Al+3].[Cl-].[Cl-].[Cl-]>ClCCCl>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[S:13](=[O:20])(=[O:21])[N:12]=2)=[CH:2]1
Reactant: O=S1(=O)N=C(Cl)c2ccccc21
Reactant: c1ccc2[nH]ccc2c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: O=S1(=O)N=C(c2c[nH]c3ccccc23)c2ccccc21
Temperature: 65 °C
Yield: 106.3 %

Procedure:
Indole (117 mg, 1 mmol) and 3-chloro-benzo[d]isothiazole 1,1-dioxide (201 mg, 1 mmol) were treated 5 mL of 1,2-dichloroethane followed by AlCl3 (160 mg, 1.2 mmol). The reaction mixture was heated to 65° C. overnight, then cooled and quenched with water (1 mL). The resulting solid was filtered, washed with water, and dried to give 0.3 grams of the sub-title compound. MS: ESI (negative): 281 (M−H).
Reaction SMILES: [CH2:1]([C:5]1[O:13][C:12]2[C:7](=[N:8][C:9]([CH3:15])=[CH:10][C:11]=2Cl)[CH:6]=1)[CH2:2][CH2:3][CH3:4].[NH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.C([O-])([O-])=O.[K+].[K+]>O>[CH2:1]([C:5]1[O:13][C:12]2[C:7](=[N:8][C:9]([CH3:15])=[CH:10][C:11]=2[N:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: C1CCNCC1
Reactant: CCCCc1cc2nc(C)cc(Cl)c2o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CCCCc1cc2nc(C)cc(N3CCCCC3)c2o1
Temperature: 100 °C
Reaction time: 16 h
Yield: 78.5 %

Procedure:
To a mixture of 2-butyl-7-chloro-5-methylfurano[3,2-b]pyridine (Example 229 (c)) (329 mg, 1.45 mmol) and piperidine (3 mL, 30.4 mmol) was added a mixture of K2CO3 (0.85 g, 5.8 mmol) in H2O (1 ML). Mixture stirred at 100° C. under N2 for 16 h. After cooling, the reaction mixture was concentrated. The residue was diluted with H2O (70 mL) and Et2O (50 mL). The mixture was transferred to a separatory funnel and the organic solution was collected. The aqueous solution was washed with Et2O (2×40 mL). The organic solutions were combined, washed with H2O (50 mL), saturated NaCl (70 mL), dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel with 50:50 EtOAc:hexanes as elutant to give 310 mg (77%) of 2-butyl-5-methyl-7-piperidylfurano[3,2-b]pyridine as a cream colored solid. This material (310 mg, 1.12 mmol) was dissolved in EtOAc (10 mL) and heated to boiling. To the hot solution was added 1M etheral HCl (1.20 mL, 1.20 mmol). The solution was left to cool to 25° C. The resulting solid was collected by filtration, washed with EtOAc (2×5 mL), Et2O (3×5 mL) and dried under vacuum at 25° C. to give 311 mg (69%) of the title compound as a white colored powder. Mp: 172-173° C. 1H NMR (CDCl3; 400 MHz): δ 0.95 (t, 3, J=7.4), 1.42 (hextet, 2, J=7.3), 1.69 (quintet, 2, J=7.7), 1.79 (br s, 6), 2.71 (s, 3), 2.79 (t, 2, J=7.5), 3.85 (br, 4), 6.29 (s, 1), 7.01 (s, 1), 15.56 (s, 1). MS m/z: 2793 (M+1 for free base). Anal. Calcd for C17H24N2O.HCl.0.5H2O: C, 64.24; H, 8.25; N, 8.82; Cl, 11.15. Found C, 64.42; H, 8.23; N, 8.75; Cl, 11.26.
Reaction SMILES: [Na+].[N+:2]([C:5]1[CH:11]=[CH:10][C:8]([O-:9])=[CH:7][CH:6]=1)([O-:4])=[O:3].Cl.Cl[CH2:14][CH2:15][N:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1.C(=O)([O-])[O-].[K+].[K+]>O.C(OCC)(=O)C>[N+:2]([C:5]1[CH:11]=[CH:10][C:8]([O:9][CH2:14][CH2:15][N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)=[CH:7][CH:6]=1)([O-:4])=[O:3]
Reactant: O=[N+]([O-])c1ccc([O-])cc1
Reactant: ClCCN1CCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc(OCCN2CCCC2)cc1
Temperature: 130 °C
Yield: 120.7 %

Procedure:
Two identical reactions were set up side-by-side as follows. To a mixture of p-nitrophenoxide sodium salt (20.0 g, 124 mmol) and N-(2-chloroethyl)pyrrolidine hydrochloride (21.0 g, 123.5 mmol) was added 300 mL of xylenes followed by potassium carbonate (23.5 g, 170 mmol). The heterogenous mixture was heated under nitrogen at 130° C. overnight. The reaction was diluted with water and 200 mL of ethyl acetate. The layers were separated and the organic layer was washed with saturated aqueous sodium chloride. The aqueous layers were back-extracted with one portion of methylene chloride and the combined organic layers were dried over sodium sulfate, filtered, and concentrated. Silica gel flash chromatography of the combined residues from both reactions (10% methanol/ethyl acetate to 20% methanol/ethyl acetate to 50% methanol/ethyl acetate) afforded 35.22 g (60%) of the title compound of Step A. MS 237.4 (M+1)+
Reaction SMILES: [CH3:1][NH:2][C:3]1[N:8]=[CH:7][NH:6][C:5](=[O:9])[CH:4]=1.[CH3:10][O:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16]Cl)=[CH:14][CH:13]=1.[I-].[K+].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH3:10][O:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16][N:6]2[C:5](=[O:9])[CH:4]=[C:3]([NH:2][CH3:1])[N:8]=[CH:7]2)=[CH:14][CH:13]=1
Reactant: COc1ccc(CCl)cc1
Reactant: CNc1cc(=O)[nH]cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CN(C)C=O
Product: CNc1cc(=O)n(Cc2ccc(OC)cc2)cn1
Reaction time: 8 h
Yield: 52 %

Procedure:
6-(Methylamino)pyrimidin-4(3H)-one (100 g, 800 mmol, 1 eq), p-methoxybenzyl chloride (124.8 g, 800 mmol, 1 eq), potassium iodide (13.3 g, 80 mmol, 0.1 eq) and cesium carbonate (260 g, 800 mmol, 1 eq) were stirred at RT in anhydrous DMF (1 L) for 8 hours. The DMF was removed in vacuo and the residue stirred overnight in 20% methanol/DCM. The solid was removed by filtration and washed with 20% methanol/DCM. The solvent was removed in vacuo and the resulting residue taken up in DCM then washed with water. The organic layer was dried over magnesium sulfate and evaporated to give 102 g of the title compound (59%). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.63 (d, J=4.29 Hz, 3H) 3.72 (s, 3H) 4.87 (s, 2H) 6.88 (d, J=8.84 Hz, 2H) 7.25 (d, J=8.59 Hz, 2H) 8.22 (s, 1H). [M+H] calc'd for C13H15N3O2, 246; found, 246.
Reaction SMILES: Cl.C(OCC)(=O)C.C([O:12][C:13]1[C:14]([CH2:19][N:20]2[CH2:25][CH2:24][CH:23]([C:26](=[O:36])[CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[S:34][CH3:35])[CH2:22][CH2:21]2)=[N:15][CH:16]=[CH:17][N:18]=1)(C)(C)C.[OH-].[Na+]>ClCCl>[CH3:35][S:34][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=1[CH2:27][C:26]([CH:23]1[CH2:22][CH2:21][N:20]([CH2:19][C:14]2[C:13](=[O:12])[NH:18][CH:17]=[CH:16][N:15]=2)[CH2:25][CH2:24]1)=[O:36]
Reactant: CSc1ccccc1CC(=O)C1CCN(Cc2nccnc2OC(C)(C)C)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CSc1ccccc1CC(=O)C1CCN(Cc2ncc[nH]c2=O)CC1
Reaction time: 0.5 h
Yield: 84.5 %

Procedure:
After adding 3 ml of 4N hydrogen chloride/ethyl acetate to 200 mg of 1-[1-(3-tert-butoxy-2-pyrazinylmethyl)piperidin-4-yl]-2-[2-(methylthio)phenyl]ethanone while cooling on ice, the mixture was stirred for 30 minutes. A 2N sodium hydroxide solution was added to the reaction solution for neutralization, and extraction was performed with dichloromethane. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. Diethyl ether was added to the residue and the mixture was filtered to obtain the title compound (146 mg, 84% yield).
Reaction SMILES: [C:1]([O:6]CC)(=[O:5])[C:2]([CH3:4])=O.OO.Cl[C:12]1C=C[N:15]=[CH:14][CH:13]=1.OS(O)(=O)=O>O.C1(C)C=CC=CC=1.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Fe+2]>[N:15]1[CH:14]=[CH:13][CH:12]=[CH:4][C:2]=1[C:1]([OH:6])=[O:5]
Reactant: Clc1ccncc1
Reactant: CCOC(=O)C(C)=O
Agent: [Fe+2]
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: O=C(O)c1ccccn1
Temperature: 25 °C
Yield: 90 %

Procedure:
Ethyl pyruvate (0.9-3 eq.) was stirred and cooled (−20-+0ℑ C.) and hydrogen peroxide (30-35%, 0.9-3 eq) was added dropwise. This solution and a solution of Iron sulfate heptahydrate (0.9-3 eq.) in water (1-5 vol.) were then slowly and simultaneously added dropwise into a stirred solution of 4-Chloropyridine (1 eq) in water (1-5 vol.) and conc. H2SO4 (1-4 eq.) and Toluene (0-20 vol.), keeping the temperature below 25ℑ C. The mixture was then stirred at room temperature until the reaction is judged complete. The mixture was poured into ice cold NaOH (10%) solution. Toluene (2-5 vol.) was added (If not already present), the layers were separated. The toluene layer was washed with 0.5N HCl solution and evaporated to yield the crude 2-Pyridinecarboxylic acid, 4-chloro-3,5-dimethyl-, ethyl ester in over 90% yield based on the consumed starting material and over 50% isolated yield.
Reaction SMILES: [C:1]1([N:7]([CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:8]([C:10]2[CH:29]=[CH:28][C:13]3[N:14]([CH3:27])[C:15]([CH2:17][S:18][C:19]4[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][CH:20]=4)=[N:16][C:12]=3[CH:11]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:37].C(=O)([O-])[O-].[NH4+:42].[NH4+].C(OCC)(=O)C.C(O)C.N>C(O)C>[ClH:37].[C:1]1([N:7]([CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:8]([C:10]2[CH:29]=[CH:28][C:13]3[N:14]([CH3:27])[C:15]([CH2:17][S:18][C:19]4[CH:24]=[CH:23][C:22]([C:25](=[NH:42])[NH2:26])=[CH:21][CH:20]=4)=[N:16][C:12]=3[CH:11]=2)=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CSc1ccc(C#N)cc1)n2C)c1ccccc1
Reactant: [NH4+]
Agent: Cl
Agent: N
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CSc1ccc(C(=N)N)cc1)n2C)c1ccccc1
Yield: 90 %

Procedure:
Prepared analogously to Example 27 from 1-methyl-2-[(4-cyanophenyl)thiomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide, and ethanolic hydrochloric acid, ethanol and ammonium carbonate. Yield: 90% of theory, C28H29N5O3S (515.64) Rf value:0.24 (silica gel; ethyl acetate/ethanol/ammonia=50:45:5) ##EQU11##
Reaction SMILES: O=[CH:2][C@H:3]([C@@H:5]([C@@H:7]([C@H:9]([CH3:11])[OH:10])[OH:8])[OH:6])[OH:4].[CH2:12]([NH2:30])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]>C(O)C>[CH2:12]([NH:30][CH:11]1[O:4][C@@H:3]([CH3:2])[C@@H:5]([OH:6])[C@@H:7]([OH:8])[C@@H:9]1[OH:10])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: C[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)C=O
Reactant: CCCCCCCCCCCCCCCCCCN
Solvent: CCO
Product: CCCCCCCCCCCCCCCCCCNC1O[C@@H](C)[C@@H](O)[C@@H](O)[C@@H]1O

Procedure:
3.26 g of L-fucose and 5.38 g of stearylamine were heated at 70° C. in 20 ml of ethanol, with stirring, until a clear solution had formed. The solution was allowed to cool and, when crystallization had ended, the solid was filtered off with suction and washed with ethanol and ether.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[F:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:12][CH3:13].[C:14]1([CH2:20][C:21](Cl)=[O:22])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(Cl)(Cl)Cl>[F:5][C:6]1[CH:11]=[C:10]([C:21](=[O:22])[CH2:20][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:9]=[CH:8][C:7]=1[O:12][CH3:13]
Reactant: O=C(Cl)Cc1ccccc1
Reactant: COc1ccccc1F
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Product: COc1ccc(C(=O)Cc2ccccc2)cc1F
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A suspension of aluminum chloride (9.4 g, 70.5 mmol) in a solution of 2-fluoroanisole (6.6 mL, 58.8 mmol) and anhydrous chloroform (200 mL) was cooled to 0° C. under a blanket of dry nitrogen. A solution of phenylacetyl chloride (8.6 mL, 64.7 mmol) in anhydrous chloroform (50 mL) was added to the vigorously stirred suspension over 20 minutes keeping the reaction temperature <5° C. The yellowish solution was stirred at 0° C. for 1 hour, poured into ice (200 mL) and stirred without temperature control for 16 hours. The layers were separated, and the aqueous layer was extracted with dichloromethane (2×100 mL). The combined organic solution was dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure. The resulting solid was recrystallized from boiling hexane to yield, upon filtration and drying, 1-(3-fluoro-4 methoxyphenyl)-2-phenyl-ethan-1-one (12.9 g, 90%) as white crystals: 1H NMR (CDCl3 /300 MHz) δ 7.82-7.72 (m, 2H), 7.35-7.24 (m, 5H), 6.98 (dd, J=8.46, 8.26 Hz, 1H), 4.22 (s, 2H), 3.94 (s, 3H). 19F NMR (CDCl3 /282.2 MHz) -134.875 (m).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:11][CH2:10][C:9]2[C:4](=[C:5]([N:12]3[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]3)[CH:6]=[CH:7][CH:8]=2)[CH2:3]1.C(N(CC)CC)C.[Cl:26][C:27]1[CH:35]=[CH:34][C:30]([C:31](Cl)=[O:32])=[CH:29][CH:28]=1>C(Cl)Cl>[CH3:18][N:15]1[CH2:16][CH2:17][N:12]([C:5]2[CH:6]=[CH:7][CH:8]=[C:9]3[C:4]=2[CH2:3][C@H:2]([NH:1][C:31](=[O:32])[C:30]2[CH:34]=[CH:35][C:27]([Cl:26])=[CH:28][CH:29]=2)[CH2:11][CH2:10]3)[CH2:13][CH2:14]1
Reactant: CN1CCN(c2cccc3c2C[C@H](N)CC3)CC1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN1CCN(c2cccc3c2C[C@H](NC(=O)c2ccc(Cl)cc2)CC3)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To an ice-cooled solution of (R)-2-amino-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalene (110 mg, 0.45 mmol) and triethylamine (93 μL, 0.67 mmol) in methylene chloride (25 mL) was added dropwise 4-chlorobenzoyl chloride (83 mg, 0.47 mmol) in methylene chloride (5 mL). After the addition, the reaction was allowed to stir at ambient temperature for 15 min and was then washed with diluted aqueous sodium hydrogen carbonate. The phases were separated and the organic phase was dried (Na2SO4), filtered and evaporated in vacuo to give a crude product which was purified on a silica gel column using chloroform/ethanol saturated with NH3 (100:3) as the eluent. Yield: 97 mg (56%) of the title compound as white crystals: mp 204-205° C.; [α]21D −46° (c 1.0, chloroform); EIMS (70 eV) m/z (relative intensity) 383 (19, M+).
Reaction SMILES: [O:1]([CH2:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:17]([CH3:20])([O-:19])=[O:18].C([O-])(=O)C.[NH4+]>C(O)(=O)C>[N+:17](/[CH:20]=[CH:13]/[C:12]1[CH:15]=[CH:16][C:9]([CH2:8][O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:10][CH:11]=1)([O-:19])=[O:18]
Reactant: C[N+](=O)[O-]
Reactant: O=Cc1ccc(COc2ccccc2)cc1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Product: O=[N+]([O-])/C=C/c1ccc(COc2ccccc2)cc1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
A mixture of 4-phenoxymethyl-benzaldehyde described in Manufacturing Example 86-1-2 (3.8 g, 17.8 mmol), nitromethane (4.79 mL, 89 mmol), ammonium acetate (2.74 g, 35.6 mmol) and acetic acid (38 mL) was stirred for 3 hours at 100° C. This mixture was cooled to room temperature, concentrated under a reduced pressure, and diluted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure to obtain the title compound (4.1 g).
Reaction SMILES: [Li+].[OH-].[C:3]([O:7][C:8]([N:10]([C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=1)[S:11]([CH2:14][C:15]([O:17]C)=[O:16])(=[O:13])=[O:12])=[O:9])([CH3:6])([CH3:5])[CH3:4].CCOC(C)=O>O.C1COCC1>[C:3]([O:7][C:8]([N:10]([C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=1)[S:11]([CH2:14][C:15]([OH:17])=[O:16])(=[O:13])=[O:12])=[O:9])([CH3:6])([CH3:5])[CH3:4]
Reactant: COC(=O)CS(=O)(=O)N(C(=O)OC(C)(C)C)c1ccc(OC)c(OC)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(N(C(=O)OC(C)(C)C)S(=O)(=O)CC(=O)O)cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.5 %

Procedure:
A solution of LiOH (28.1 mg, 0.669 mmol) in water (0.66 ml) was added to a solution of methyl 2-(N-(tert-butoxycarbonyl)-N-(3,4-dimethoxyphenyl)sulfamoyl)-acetate (237 mg, 0.609 mmol) in THF (3 ml), and the mixture was stirred at RT for 2 hours. EtOAc was added, and the solution was washed with HCl 1N (6 ml); the organic phase was washed with brine, dried over Na2SO4, filtered and evaporated, to give 2-(N-(tert-butoxycarbonyl)-N-(3,4-dimethoxyphenyl)sulfamoyl)acetic acid (200 mg, 0.533 mmol, 88% yield, MS/ESI+ 397.9 [MNa]+) that was used in the next step without further purification.
Reaction SMILES: [CH2:1]1[O:8][C@@H:7]2[O:9][C@H:2]1[C@@H:3]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C@@H:4]1[O:6][C@@H:5]12.[Br-].C([OH:21])C>>[CH2:11]([O:10][C@@H:3]1[C@H:2]2[CH2:1][O:8][C@H:7]([O:9]2)[C@H:5]([OH:21])[C@H:4]1[OH:6])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CCO
Reactant: c1ccc(CO[C@H]2[C@@H]3O[C@@H]3[C@@H]3OC[C@H]2O3)cc1
Agent: [Br-]
Product: O[C@@H]1[C@@H](O)[C@@H]2OC[C@@H](O2)[C@H]1OCc1ccccc1

Procedure:
Briefly, Jespersen first described synthesis of IFG in a six step synthesis starting from 1,6:2,3-dianhydro-4-O-benzyl-β-D-mannopyranose. This method employed introducing a hydroxymethyl group at C-7 by epoxide opening with vinylmagensium bromide, followed by ozonolysis in ethanol to give 1,6-anhydro-4-O-benzyl-β-D-glucopyranose. Hydrolysis of the anhydro bond with sulfuric acid and oxidative carbon chain cleavage provided a pentodialdose, which was cyclized by reductive amination with ammonia to produce the 4-O-benzyl derivative of IFG. The protecting group was removed by hydrogenation under acid conditions (hydrogen and palladium-on-carbon) to produce the HCl salt of IFG.
Reaction SMILES: [C-:1]1([C:6]#[C:7][C:8]2[CH:13]=[CH:12][C:11](Br)=[CH:10][CH:9]=2)[CH:5]=[CH:4][CH:3]=[CH:2]1.[CH-:15]1[CH:19]=[CH:18][CH:17]=[CH:16]1.[Fe+2:20].[C-]1([C:26]#[C:27][C:28]2[CH:33]=[CH:32][C:31](Br)=[CH:30][CH:29]=2)C=CC=C1.[CH-]1C=CC=C1.[Fe+2].C1(C#C)C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>O1CCCC1.N1C=CC=CC=1.C(NC(C)C)(C)C.[Pd].CC([O-])=O.CC([O-])=O.[Pd+2].[Cu]I>[C-:1]1([C:6]#[C:7][C:8]2[CH:13]=[CH:12][C:11]([C:26]#[C:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:10][CH:9]=2)[CH:5]=[CH:4][CH:3]=[CH:2]1.[CH-:15]1[CH:19]=[CH:18][CH:17]=[CH:16]1.[Fe+2:20]
Reactant: Brc1ccc(C#C[c-]2cccc2)cc1
Agent: [Cu]I
Agent: [Fe+2]
Agent: [Pd+2]
Solvent: CC(C)NC(C)C
Solvent: C#Cc1ccccc1
Solvent: c1ccncc1
Product: C(#Cc1ccc(C#C[c-]2cccc2)cc1)c1ccccc1

Procedure:
1-(Ferrocenylethynyl)-4-(phenylethynyl)benzene 308 was prepared following the general procedure found in General Procedure for the Palladium-Catalyzed Cross-Coupling Reaction for the palladium-catalyzed coupling reaction using 500 mg (1.37 mmol) of 1-(ferrocenylethynyl)-4-bromobenzene 304, 210 mg (2.05 mmol) of phenylacetylene 306, 15.4 mg (0.0686 mmol) Pd(OAc)2, 53.9 mg (0.206 mmol) of PPh3, and 2.6 mg (0.0137 mmol) of CuI in 25 mL tetrahydrofuran, 5 mL pyridine and 5 mL diisopropylamine at 60° C. The residue was purified using a 5:1 hexane/CH2Cl2 solvent mixture to afford 385 mg (73%) of an orange-red solid, m.p. 198° C. Spectral data for 1-(ferrocenylethynyl)-4-(phenylethynyl)benzene 308: IR (cm−1, KBr): 3084 (C—H), 3056 (C—H), 2203 (C≡C), 1594 (C═C, benzene), 1517 (C═C, benzene), 1411 (C═C, ferrocene). H NMR (d in CDCl3): 7.51 (m, 2H), 7.45 (m, 4H), 7.33 (m, 3H), 4.50 (t, J=1.9 Hz, 2H), 4.24 (t, J=1.9 Hz, 2H), 4.23 (s, 5H). Analysis for 1-(ferrocenylethynyl)-4-(phenylethynyl)benzene 308 (C26H18Fe) Calcd: C, 80.84%; H, 4.70%. Found: C, 80.06%; H, 4.72%.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]/OC.CN(C)C=O.[Br:22][C:23]1[N:28]=[C:27]([CH2:29][NH2:30])[CH:26]=[CH:25][C:24]=1[O:31][CH2:32][CH2:33][CH3:34]>C(#N)C>[Br:22][C:23]1[N:28]=[C:27]([CH2:29][NH:30]/[CH:14]=[C:5]2\[C:6](=[O:13])[NH:7][C:8](=[O:12])[C:9]3[C:4]\2=[CH:3][C:2]([I:1])=[CH:11][CH:10]=3)[CH:26]=[CH:25][C:24]=1[O:31][CH2:32][CH2:33][CH3:34]
Reactant: CO/C=C1/C(=O)NC(=O)c2ccc(I)cc21
Reactant: CCCOc1ccc(CN)nc1Br
Solvent: CC#N
Solvent: CN(C)C=O
Product: CCCOc1ccc(CN/C=C2\C(=O)NC(=O)c3ccc(I)cc32)nc1Br
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of (E)-6-iodo-4-(methoxymethylene)isoquinoline-1,3(2H,4H)-dione (329 mg, 1.0 mmole), dimethylformamide (8 mL), and (6-bromo-5-propoxypyridin-2-yl)methanamine (245 mg, 1.0 mmole) is stirred at room temperature for one hour. The reaction mixture is diluted with acetonitrile, filtered, washed with fresh acetonitrile and dried to give a yellow solid, 434 mg, (80%), mp 251-3° C. dec; MS (ES−): m/z 540.2 (M−H).
Reaction SMILES: C[C:2]1[CH:7]=[CH:6][CH:5]=[C:4](C)[C:3]=1[NH:9][C:10](=[O:13])[CH2:11][Cl:12].[C:14]([O:17]C1C=CC(N)=CC=1)(=[O:16])[CH3:15]>>[C:14]([O:17][C:6]1[CH:7]=[CH:2][C:3]([NH:9][C:10](=[O:13])[CH2:11][Cl:12])=[CH:4][CH:5]=1)(=[O:16])[CH3:15]
Reactant: Cc1cccc(C)c1NC(=O)CCl
Reactant: CC(=O)Oc1ccc(N)cc1
Product: CC(=O)Oc1ccc(NC(=O)CCl)cc1

Procedure:
Compound 56 was prepared in the manner of compound 3 substituting compound 55 for compound 1 in part A of Example 1.