Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4](/[CH:10]=[C:11](\[C:14]2[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=2)/[C:12]#[N:13])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].C([NH:33][C@H:34]([C:39]([NH2:41])=[O:40])[CH2:35][CH2:36][CH2:37][NH2:38])(OC(C)(C)C)=O.[ClH:42].O1CCOCC1.C(OCC)C>ClCCl>[NH2:1][C:2]1[CH:3]=[C:4](/[CH:10]=[C:11](\[C:14]2[CH:15]=[C:16]([O:24][CH3:25])[C:17]([O:22][CH3:23])=[C:18]([O:20][CH3:21])[CH:19]=2)/[C:12]#[N:13])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[ClH:42].[NH2:33][C@H:34]([C:39]([NH2:41])=[O:40])[CH2:35][CH2:36][CH2:37][NH2:38]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCN)C(N)=O
Agent: COc1ccc(/C=C(/C#N)c2cc(OC)c(OC)c(OC)c2)cc1N
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Solvent: C1COCCO1
Product: NCCC[C@H](N)C(N)=O

Procedure:
(E)-3-(3Amino-4-methoxyphenyl)-2-(3,4,5-trimethoxyphenyl)-prop-2-enenitrile-Boc-L-ornithineamide (730 mg, 1.11 mmols) was dissolved in 5 ml of dichloromethane, and 5 ml of a solution of 4-M hydrochloric acid and dioxane were added thereto. The mixture was reacted at room temperature for 1 hour. One-hundred milliliters of diethyl ether were added thereto, and the resulting mixture was filtered. The thus-obtained powder was recrystallized from a mixture of methanol and ethyl acetate at a ratio by volume of 1:1 to produce 286 mg (0.542 mmols) of the final compound in a yield of 48%.
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])/[CH:2]=[CH:3]/[C:4]([OH:6])=[O:5].C(=O)([O-])O.[Cs+].[C:15]([O:23][CH2:24][CH2:25]Cl)(=[O:22])/[CH:16]=[CH:17]/[C:18]([O:20][CH3:21])=[O:19]>CN1C(=O)CCC1>[C:4]([O:6][CH2:25][CH2:24][O:23][C:15](=[O:22])/[CH:16]=[CH:17]/[C:18]([O:20][CH3:21])=[O:19])(=[O:5])/[CH:3]=[CH:2]/[C:1]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)/C=C/C(=O)O
Reactant: COC(=O)/C=C/C(=O)OCCCl
Agent: O=C([O-])O
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: COC(=O)/C=C/C(=O)OCCOC(=O)/C=C/C(=O)OC
Yield: 17 %

Procedure:
Following general procedure A, methyl hydrogen fumarate (0.22 g, 1.7 mmol) in NMP (4 mL) was reacted with CsHCO3 (0.38 g, 1.9 mmol) and chloroethyl methyl (2E)but-2-ene-1,4-dioate (0.27 g, 1.4 mmol) to afford 0.068 g (17% yield) of the title compound (45) after purification by silica gel flash chromatography (Biotage) using a mixture of ethyl acetate (EtOAc) and hexanes (1:3). 1H NMR (CDCl3, 400 MHz): δ 7.03 (q, J=5.2 Hz, 1H), 6.90 (d, J=16.0 Hz, 1H), 6.82 (d, J=16.0 Hz, 1H), 3.82 (s, 3H), 1.60 (d, J=5.2 Hz, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4]([NH:6][NH2:7])=[O:5])[CH3:2].C(N(CC)CC)C.[CH3:15][C:16]1[CH:21]=[C:20]([CH3:22])[CH:19]=[C:18]([CH3:23])[C:17]=1[CH2:24][C:25](Cl)=[O:26]>O1CCCC1>[CH2:1]([O:3][C:4]([NH:6][NH:7][C:25](=[O:26])[CH2:24][C:17]1[C:16]([CH3:15])=[CH:21][C:20]([CH3:22])=[CH:19][C:18]=1[CH3:23])=[O:5])[CH3:2]
Reactant: CCOC(=O)NN
Reactant: Cc1cc(C)c(CC(=O)Cl)c(C)c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)NNC(=O)Cc1c(C)cc(C)cc1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of hydrazinecarboxylic acid ethyl ester (ethyl carbazate, 32.8 g, 314.9 mmol) and triethylamine (44.1 ml, 32.0 g, 316.4 mmol) in tetrahydrofuran (1000 ml) at 0° C. was added (2,4,6-trimethyl-phenyl)-acetyl chloride (62.0 g, 315.2 mmol) dropwise. The thick suspension was stirred at room temperature for one hour and the solvent evaporated. The residue was suspended in a mixture of t-butyl methyl ether (500 ml) and water (500 ml), stirred, filtered and the solid washed with small portions of water and t-butyl methyl ether. The solid was dried in vacuo over phosphorus pentoxide at 40° C. Yield: 78.4 g of N′-[2-(2,4,6-trimethyl-phenyl)-acetyl]-hydrazinecarboxylic acid ethyl ester as a white solid, mp 184-186° C.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[F:19][C:20]1[CH:25]=[CH:24][C:23]([CH:26]2[O:30]C(=O)[O:28][C:27]2=O)=[CH:22][CH:21]=1>C1COCC1>[CH2:12]([O:11][C:9]1[CH:8]=[CH:7][C:3]([C:4]([NH2:6])=[O:5])=[C:2]([NH:1][C:27](=[O:28])[CH:26]([C:23]2[CH:24]=[CH:25][C:20]([F:19])=[CH:21][CH:22]=2)[OH:30])[CH:10]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: NC(=O)c1ccc(OCc2ccccc2)cc1N
Reactant: O=C1OC(=O)C(c2ccc(F)cc2)O1
Solvent: C1CCOC1
Product: NC(=O)c1ccc(OCc2ccccc2)cc1NC(=O)C(O)c1ccc(F)cc1
Temperature: 63 °C
Yield: 63 %

Procedure:
To a solution of 2-amino-4-(benzyloxy)benzamide (4.0 g, 16.5 mmol) in THF (60 mL) was added a solution of 5-(4-fluorophenyl)-1,3-dioxolane-2,4-dione (3.65 g, 18.6 mmol) from Example 16 in THF (20 mL) portionwise at rt. After heating to 63° C. for 18 h, the solution was cooled and concentrated. After addition of H2O, the solution was extracted twice with DCM. The combined organic phases were washed with brine and dried over sodium sulfate. Chromatography on silica gel eluting with 10 to 80% EtOAc/DCM afforded 4-(benzyloxy)-2-(2-(4-fluorophenyl)-2-hydroxyacetamido)benzamide as a foamy solid (4.1 g, 64%). 1H NMR (300 MHz, DMSO-d6) δ ppm 5.06 (m, 1H), 5.12 (s, 2 H) 6.68-6.74 (m, 1H) 7.14-7.20 (m, 2 H) 7.32-7.51 (m, 6 H) 7.77 (d, J=8.85 Hz, 1 H) 8.05 (br. s., 1 H) 8.30 (d, J=2.64 Hz, 1 H) 12.73 (s, 1 H). LC-MS (ESI) m/z 392 (M−2).
Reaction SMILES: O=C1[CH:8]2[CH:3]1[CH2:4][CH2:5][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:7]2.C[OH:17].[Cl-].[NH4+].[N-:20]=[N+:21]=[N-:22].[Na+]>O>[N:20]([CH:3]1[CH2:4][CH2:5][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:7][CH:8]1[OH:17])=[N+:21]=[N-:22]
Reactant: CC(C)(C)OC(=O)N1CCC2C(=O)C2C1
Reactant: [N-]=[N+]=[N-]
Reactant: CO
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(N=[N+]=[N-])C(O)C1

Procedure:
To the solution of tert-butyl 7-oxo-3-azabicyclo[4.1.0]heptane-3-carboxylate (180.6 g, 0.60 mol) obtained in Step 2 in a mixed solvent of 700 ml of methanol and 100 ml of water, were added ammonium chloride (NH4Cl; 64.0 g, 1.2 mol) and sodium azide (NaN3; 98.0 g, 1.5 mol). The reaction mixture was refluxed for 8 hours and evaporated under reduced pressure to remove methanol. The resulting residue was extracted with ethyl acetate and then dried on magnesium sulfate. The resulting residue was purified with column chromatography to give the titled compound (62.0 g).
Reaction SMILES: C(O[C:6](=[O:15])[NH:7][CH2:8][CH2:9][NH:10][S:11]([CH3:14])(=[O:13])=[O:12])(C)(C)C.FC(F)(F)C(O)=O.COC([C:27]1[C:28]([OH:51])=[C:29]2[C:34](=[CH:35][N:36]=1)[N:33]([CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:32](=[O:44])[C:31]([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)=[CH:30]2)=O>C(Cl)Cl>[CH3:14][S:11]([NH:10][CH2:9][CH2:8][NH:7][C:6]([C:27]1[C:28]([OH:51])=[C:29]2[C:34](=[CH:35][N:36]=1)[N:33]([CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:32](=[O:44])[C:31]([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)=[CH:30]2)=[O:15])(=[O:12])=[O:13]
Reactant: COC(=O)c1ncc2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Reactant: CC(C)(C)OC(=O)NCCNS(C)(=O)=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)NCCNC(=O)c1ncc2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 33.1 %

Procedure:
(2-Methanesulfonylamino-ethyl)-carbamic acid tert-butyl ester (94 mg, 0.38 mmol) was dissolved in CH2Cl2 (2 mL). Trifluoroacetic acid (1 mL) was added, and the mixture was stirred at r.t. for 2 h. Solvent and excess TFA were removed by evaporation, and the residue was taken up in EtOH (3 mL). NaOMe was added with vigorous stirring until pH was about 8. The resulting mixture was transferred to a microwave vial containing 1-benzyl-5-hydroxy-2-oxo-3-phenyl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (38 mg, 0.098 mmol), and the mixture was heated at 140° C. for 6 h in a microwave reactor. The solvent was evaporated, and the residue was partitioned between EtOAc and 0.1 M HCl. The organic layer was dried over MgSO4 and concentrated. The crude product was purified by silica gel chromatography (0-5% MeOH/CH2Cl2) to give 16 mg of the title compound. MS: (+) m/z 493.32 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[C:22]([OH:24])=O)[C:5]([NH:7][CH2:8][C:9]1[NH:13][C:12]2[CH:14]=[CH:15][C:16]([Cl:18])=[CH:17][C:11]=2[N:10]=1)=[O:6].[CH3:25][O:26][CH2:27][C@H:28]1[CH2:32][CH2:31][CH2:30][NH:29]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[C:22]([N:29]1[CH2:30][CH2:31][CH2:32][C@@H:28]1[CH2:27][O:26][CH3:25])=[O:24])[C:5]([NH:7][CH2:8][C:9]1[NH:13][C:12]2[CH:14]=[CH:15][C:16]([Cl:18])=[CH:17][C:11]=2[N:10]=1)=[O:6]
Reactant: O=C(NCc1nc2cc(Cl)ccc2[nH]1)c1ccc(C(=O)O)c(Cl)c1
Reactant: COC[C@H]1CCCN1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: COC[C@H]1CCCN1C(=O)c1ccc(C(=O)NCc2nc3cc(Cl)ccc3[nH]2)cc1Cl

Procedure:
Prepared analogously to Example 1d from 3-chloro-N-(5-chloro-1H-benzimidazol-2-ylmethyl)-4-carboxybenzamide, (R)-2-methoxymethylpyrrolidine, TBTU, and triethylamine in DMSO at ambient temperature. HPLC-MS results: retention time: 3.56 minutes; C22H22Cl2N4O3 (461.35); mass spectrum: (M+H)+=461.2.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[Br:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][CH2:16][Cl:17]>C1(C)C(C)=CC=CC=1>[Cl-:17].[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N+:3]=1[CH2:16][O:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[Br:8]
Reactant: Nc1ccccn1
Reactant: ClCOc1ccccc1Br
Solvent: Cc1ccccc1C
Product: Nc1cccc[n+]1COc1ccccc1Br
Product: [Cl-]
Temperature: 25 °C
Reaction time: 40 h
Yield: 101.2 %

Procedure:
To a solution of 7.1 g of 2-aminopyridine in 35 ml of xylene is added, dropwise, a solution of 11.1 g of o-bromo-α-chloroanisole in 45 ml of xylene. The mixture is warmed at 50° for 5 minutes and allowed to stir for 40 hours at room temperature. The solid is filtered and dried to give about 16.0 g of the product. This is recrystallized from 2-propanol to give about 14.0 g of the title product, mp 171°-173°.
Reaction SMILES: C([O:4][CH:5]1[C:14]2[N:13]=[CH:12][C:11]([CH3:15])=[C:10]([O:16][CH2:17][CH:18]=[CH2:19])[C:9]=2[CH2:8][CH2:7][CH2:6]1)(=O)C.[OH-].[Na+]>CO.O>[CH2:17]([O:16][C:10]1[C:9]2[CH2:8][CH2:7][CH2:6][CH:5]([OH:4])[C:14]=2[N:13]=[CH:12][C:11]=1[CH3:15])[CH:18]=[CH2:19]
Reactant: C=CCOc1c(C)cnc2c1CCCC2OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: C=CCOc1c(C)cnc2c1CCCC2O

Procedure:
5.0 Grams of 8-acetoxy-4-allyloxy-3-methyl-5,6,7,8-tetrahydroquinoline was dissolved in 20 ml of methanol. Then a solution prepared by dissolving 2.3 g of sodium hydroxide in 20 ml of water was added thereto, and the mixture was refluxed for 1 hour. After the reaction was completed, methanol was removed by evaporation, and to the residue thus obtained was added water, and was extracted with chloroform. The chloroform layer was washed with an aqueous solution saturated with sodium chloride, then dried with anhydrous magnesium sulfate. Chloroform was removed by evaporation to obtain 3.5 g of 4-allyloxy-8-hydroxy-3-methyl-5,6,7,8-tetrahydroquinoline in the form of brown oily substance.
Reaction SMILES: [CH3:1][O:2][N:3]=[CH:4][C:5]1[CH:10]=[C:9]([NH2:11])[C:8]([Cl:12])=[CH:7][C:6]=1[Cl:13].[C:14]1(=O)[O:19][C:17](=[O:18])[C:16]2[CH2:20][CH2:21][CH2:22][CH2:23][C:15]1=2.O>C(O)(=O)C>[CH3:1][O:2][N:3]=[CH:4][C:5]1[CH:10]=[C:9]([N:11]2[C:17](=[O:18])[C:16]3[CH2:20][CH2:21][CH2:22][CH2:23][C:15]=3[C:14]2=[O:19])[C:8]([Cl:12])=[CH:7][C:6]=1[Cl:13]
Reactant: O=C1OC(=O)C2=C1CCCC2
Reactant: CON=Cc1cc(N)c(Cl)cc1Cl
Solvent: CC(=O)O
Solvent: O
Product: CON=Cc1cc(N2C(=O)C3=C(CCCC3)C2=O)c(Cl)cc1Cl
Reaction time: 15 h

Procedure:
18 g (82 mmol) of 5-amino-2,4-dichlorobenzaldehyde (O-methyl)oxime were added to a solution of 12.5 g (82 mmol) of 3,4,5,6-tetrahydrophthalic anhydride in 300 ml of acetic acid, whereupon the mixture was stirred for 15 hours at reflux temperature. The reaction mixture was subsequently poured into 1 l water. The product was then extracted with 300 ml of methyl tert-butyl ether. The extract was washed with saturated aqueous sodium hydrogen carbonate solution, dried over magnesium sulfate and finally concentrated. The residue was purified by means of silica gel chromatography (eluent: hexane/ethyl acetate=4:1). Yield: 20.9 g; m.p.: 122-124° C.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][CH3:15])=[C:8]2[C:3]=1[C:4](=[O:26])[C:5]([C:16]1[CH:25]=[CH:24][C:19]([C:20]([O:22]C)=[O:21])=[CH:18][CH:17]=1)=[CH:6][NH:7]2.C(O)C.C1COCC1.[OH-].[Li+]>O>[F:1][C:2]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][CH3:15])=[C:8]2[C:3]=1[C:4](=[O:26])[C:5]([C:16]1[CH:17]=[CH:18][C:19]([C:20]([OH:22])=[O:21])=[CH:24][CH:25]=1)=[CH:6][NH:7]2
Reactant: CCCOc1ccc(F)c2c(=O)c(-c3ccc(C(=O)OC)cc3)c[nH]c12
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: CCCOc1ccc(F)c2c(=O)c(-c3ccc(C(=O)O)cc3)c[nH]c12
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.5 %

Procedure:
Methyl 4-(5-fluoro-4-oxo-8-propoxy-1,4-dihydroquinolin -3-yl)benzoate (330 mg, 0.93 mmol) was suspended in a mixed solvent of ethanol (3 ml) and THF (3 ml). A 1.24N lithium hydroxide aqueous solution (2 ml) was added, and the mixture was stirred at room temperature for 3 hours. Water was added to the reaction mixture, and then the resulting mixture was extracted with dichloromethane. The organic layer was washed with water, dried over magnesium sulfate, and concentrated to dryness under reduced pressure to thereby obtain 300 mg of powdery white 4-(5-fluoro-4-oxo-8-propoxy-1,4-dihydroquinolin-3-yl)benzoic acid (yield: 95%).
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:13]([CH2:23][O:24]C(=O)C)[C@@H:12]([CH2:28][O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[O:11][C@@H:10]1[O:37][C@@H:38]1[C@@H:45]([CH2:46][O:47][CH2:48][C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[O:44][C@H:41]([O:42][CH3:43])[C@H:40]([O:55][CH2:56][C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)[C@H:39]1[O:63][CH2:64][C:65]1[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO>C1(C)C=CC=CC=1.C[O-].[Na+]>[CH2:1]([O:8][C@@H:9]1[C@@H:14]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C@H:13]([CH2:23][OH:24])[C@@H:12]([CH2:28][O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[O:11][C@@H:10]1[O:37][C@@H:38]1[C@@H:45]([CH2:46][O:47][CH2:48][C:49]2[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=2)[O:44][C@H:41]([O:42][CH3:43])[C@H:40]([O:55][CH2:56][C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)[C@H:39]1[O:63][CH2:64][C:65]1[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CO[C@H]1O[C@H](COCc2ccccc2)[C@@H](O[C@H]2O[C@H](COCc3ccccc3)[C@@H](COC(C)=O)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Product: CO[C@H]1O[C@H](COCc2ccccc2)[C@@H](O[C@H]2O[C@H](COCc3ccccc3)[C@@H](CO)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Methyl 4-O-(2,3,6-tri-O-benzyl-4-deoxy-4-acetyloxymethyl-α-D-glucopyranosyl)-2,3,6-tri-O-benzyl-α-D-glucopyranoside (3.19 g, 3.35 mmol) is dissolved in hot toluene (20 ml) and methanol (80 ml) is added, followed by a few drops of 1 M methanolic sodium methoxide. The mixture is stirred at room temperature during 2 h. The reaction mixture is made neutral with Amberlite IR 120 (H+) resin, filtered and concentrated under reduced pressure so as to afford methyl 4-O-(2,3,6-tri-O-benzyl-4-deoxy-4-hydroxymethyl-α-D-glucopyranosyl)-2,3,6-tri-O-benzyl-α-D-glucopyranoside as an amorphous solid.
Reaction SMILES: [H-].[Na+].[I-].[Cl:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH:7]=[CH:8][N:9]1[C:17]([CH2:18][N+](C)(C)C)=[C:16]([CH3:23])[N:15]=[C:10]12.[CH2:24]([OH:27])[C:25]#[CH:26]>>[Cl:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH:7]=[CH:8][N:9]1[C:17]([CH2:18][O:27][CH2:24][C:25]#[CH:26])=[C:16]([CH3:23])[N:15]=[C:10]12
Reactant: C#CCO
Reactant: Cc1nc2c3cccc(Cl)c3ccn2c1C[N+](C)(C)C
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Product: C#CCOCc1c(C)nc2c3cccc(Cl)c3ccn12
Temperature: 100 °C
Reaction time: 2 h

Procedure:
To a solution of 60% sodium hydride (0.235 g) in propargyl alcohol (9.36 ml) was added 7-chloro-2-methyl-3-trimethylammoniomethylimidazo[2,1-a]isoquinoline iodide (2.08 g) and the mixture was heated at 100° C. with stirring for 2 hours. After being cooled, the mixture was evaporated in vacuo and the residue was dissolved in chloroform. The solution was washed with water, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel (20 g) with a mixture of chloroform and methanol (100:1) as an eluent to give 7-chloro-2-methyl-3-propargyloxymethylimidazo[2,1-a]isoquinoline. This compound was treated with a solution of hydrogen chloride in ethanol to give 7-chloro-2-methyl-3-propargyloxymethylimidazo[2,1-a]isoquinoline hydrochloride (1 g).
Reaction SMILES: [CH3:1]C1C=CC(OCC2C=CC=CC=2)=CC=1.C1(C=NC2C=CC=CC=2)C=CC=CC=1.[C:30]1([N:36]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C1(C)C=CC=CC=1>[CH3:1][C:47]1[CH:46]=[CH:45][C:44]([N:36]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH2:37][C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)=[CH:49][CH:48]=1
Reactant: Cc1ccc(OCc2ccccc2)cc1
Reactant: c1ccc(CN(c2ccccc2)c2ccccc2)cc1
Agent: C(=Nc1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: Cc1ccc(N(Cc2ccccc2)c2ccccc2)cc1
Yield: 51 %

Procedure:
Methyl-4-(phenylmethoxy)benzene (1.98 g, 0.01 mol) and N-(phenylmethylene)benzenamine (1.81 g, 0.01 mol) were reacted in Na/DMF (1 g: 50 mL) at 75° C. for 30 min. Aqueous work-up, extraction with petroleum ether, 3×100 mL, and chromatography with petroleum ether/ethyl acetate 95:5 afforded a total of 1 g. of solid which by HPLC chromatography contained N,N-diphenyl-benzenemethanamine and the title compund in the ratio 6:94 (51% yield by HPLC). The purer fractions from chromatograpy on silica were combined and the solvent removed. The residual oil was dissolved in methanol and some petroleum ether. On cooling this crystallized the title compound. Two recrystallizations from methanol gave the title compund (98.1% pure; 36% yield), mp 85°-6° C. 1H NMR (200 MHz, CDCl3) δ (assignment): 2.29 (s, 3H, methyl), 4.97 (s, 2H, --NCH2Ph), 6.80-6.97 (m, 3H, aromatic) 7.06-7.27 (d, 4H, J=1.37 Hz, --NC6H4CH3), 7.14-7.36 (m, 7H, aromatic). MS [m/e (70 eV, % of base peak)] PhCH2N(Ph)(C6H4)CH3 273 (M+., 96.5), 196 (M+. -Ph., 31.7), 182 (M+. -PhCH3., 100), 167 (M+. -PhCH2. -CH3. 81.2), 91 (C7H7+, 98.3). FTIR (CDCl3): 3089, 3064, 3030, 2924, 2864, 1596, 1572, 1512, 1497, 1453 cm-1.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:5]=1[OH:11].Br[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH2:19][C:20]([O:22][CH3:23])=[O:21].C(OCC)(=O)C>CN(C=O)C>[Cl:3][C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:5]=1[O:11][CH:19]([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:13]=1)[C:20]([O:22][CH3:23])=[O:21]
Reactant: COC(=O)Cc1ccccc1Br
Reactant: Cc1ccc(O)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)C(Oc1ccc(C)cc1Cl)c1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 83.1 %

Procedure:
To a suspension of 0.282 g (7.04 mmol) of a 60% oil dispersion of sodium hydride in DMF was added 1.00 g (7.04 mmol) of 2-chloro-4-methylphenol and the mixture was stirred under an N2 atmosphere at room temperature. After 10 minutes, a solution of 1.94 g (8.45 mmol) of methyl 2-bromophenylacetate dissolved in 10 mL of DMF was added and the reaction was stirred an additional 1.5 hours. The reaction was then diluted into ethyl acetate, washed with water, dried (MgSO4), filtered and evaporated. The residue was purified on a silica gel flash chromatography column eluted with 4% ethyl acetate/hexane to afford 1.70 g (83%) of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]2[C:8](=[O:15])[N:9]([CH2:11][CH:12]([CH3:14])[CH3:13])[N:10]=[C:4]2[C:3]=1I.[Cl:17][C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][N:5]2[C:8](=[O:15])[N:9]([CH2:11][CH:12]([CH3:14])[CH3:13])[N:10]=[C:4]2[C:3]=1[C:21]1[CH:22]=[CH:23][C:18]([Cl:17])=[CH:19][CH:20]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: CC(C)Cn1nc2c(I)c(Br)ccn2c1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)Cn1nc2c(-c3ccc(Cl)cc3)c(Br)ccn2c1=O
Temperature: 100 °C
Reaction time: 15 h
Yield: 40 %

Procedure:
To a stirring, degassed mixture of 7-bromo-8-iodo-2-isobutyl-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (100 mg, 0.25 mmol), 4-chlorophenylboronic acid (40 mg, 0.28 mmol), and tetrakis(triphenylphosphine)palladium (15 mg, 0.013 mmol) in dioxane (2.0 mL) at 20° C. was added K2CO3 (40 mg, 0.28 mmol) in water (0.6 mL). The resulting reaction mixture was stirred at 100° C. for 15 h under argon. Analysis by HPLC/MS indicated that starting material had been consumed. The reaction mixture was brought to room temperature and was concentrated under reduced pressure. The crude product was purified by reverse phase preparative HPLC (acetonitrile-water-TFA) to isolate the title compound (38 mg, 0.10 mmol) as a yellow solid. MS: [M+H]+=380. 1H NMR (CD3OD): δ 7.73 (d, J=1.8 Hz, 1H), 7.50 (q, 4H), 6.93 (d, J=1.9, 1H), 3.71 (d, J=1.8, 2H), 2.12 (m, 1H), 0.90 (d, J=1.7, 6H).
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[NH:14][N:13]=[C:12]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.I[CH2:26][CH2:27][CH2:28][CH3:29].C(OC(N1CCC2C(=C(C3C=CC(Cl)=CC=3)N(CCCC)N=2)CC1)=O)(C)(C)C>>[CH2:26]([N:14]1[C:15]2[CH2:16][CH2:17][NH:8][CH2:9][CH2:10][C:11]=2[C:12]([C:18]2[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=2)=[N:13]1)[CH2:27][CH2:28][CH3:29]
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]nc(-c3ccc(Cl)cc3)c2CC1
Reactant: CCCCI
Agent: CCCCn1nc2c(c1-c1ccc(Cl)cc1)CCN(C(=O)OC(C)(C)C)CC2
Product: CCCCn1nc(-c2ccc(Cl)cc2)c2c1CCNCC2

Procedure:
The title compound (0.033 g) was prepared from 3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 59, Step C; 0.1 g) using 1-iodobutane (0.038 mL) in place of benzyl chloride. The reaction sequence also yielded 2-butyl-3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester in the alkylation step. MS (ESI): exact mass calculated for C17H22ClN3, 303.15; found, m/z 304.2 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.39-7.34 (m, 4H), 4.07 (t, J=7.2 Hz, 2H), 3.37-3.35 (m, 2H), 3.27-3.25 (m, 2H), 3.14-3.12 (m, 2H), 2.95-2.92 (m, 2H), 1.69-1.66 (m, 2H), 1.22-1.20 (m, 2H), 0.86 (t, J=7.4 Hz, 3H).
Reaction SMILES: C[O:2][C:3](=[O:26])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([NH:12][C:13]([C:15]2[O:16][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:18][CH:19]=2)=[O:14])[N:7]=1.CCO.[OH-].[Na+]>C1COCC1>[C:20]1([C:17]2[O:16][C:15]([C:13]([NH:12][C:8]3[N:7]=[C:6]([CH:5]=[CH:4][C:3]([OH:26])=[O:2])[CH:11]=[CH:10][CH:9]=3)=[O:14])=[CH:19][CH:18]=2)[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: COC(=O)C=Cc1cccc(NC(=O)c2ccc(-c3ccccc3)o2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(O)C=Cc1cccc(NC(=O)c2ccc(-c3ccccc3)o2)n1
Reaction time: 2 h

Procedure:
The ester (39) (35 mg, 0.10 mmol) was hydrolysed using Method C, except that EtOH (2 mL), THF (1 mL) and 1 M NaOH (2 mL) were used, and the reaction was stirred for 2 hours. After work-up, the crude product was purified by preparative HPLC to give the title compound. Yield: 9.8 mg, 29%; LC-MS tr 2.00 min; HPLC Purity: 97%; MS (ES+) m/z 335 (M+H); 1H NMR (400 MHz; MeOH): δ 6.95 (d, 1H), 7.05 (d, 1H), 7.35-7.55 (m, 5H), 7.65 (d, 1H), 7.85-8.00 (m, 3H), 8.30 (d, 1H)