Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N+:15]([O-:17])=[O:16])=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:7]=1.[NH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>CN1C(=O)CCC1>[N+:15]([C:5]1[CH:4]=[CH:3][C:2]([N:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)=[CH:7][C:6]=1[NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([O-:17])=[O:16]
Reactant: C1CCNCC1
Reactant: O=[N+]([O-])c1ccc(Br)cc1Nc1ccccc1
Solvent: CN1CCCC1=O
Product: O=[N+]([O-])c1ccc(N2CCCCC2)cc1Nc1ccccc1
Yield: 98.9 %

Procedure:
A solution of 4-bromo-2-fluoro-1-nitrobenzene (10.0 g, 45 mmol), diisopropanylethylamine (15.8 ml, 90 mmol) and aniline (5.0 ml, 54 mmol) in 100 ml 1-methylpyrrolidin-2-one (NMP) was heated at 100° C. for 16 hours. The solution was cooled to room temperature and added 1,000 ml water. The result red precipitate was filtered and washed with water (100 ml), dried under high vacuum to obtain 5-bromo-2-nitro-N-phenylbenzenamine (10.3 g, 77%). A solution of 5-bromo-2-nitro-N-phenylbenzenamine (0.50 g, 1.7 mmol) and piperidine (0.67 ml, 6.8 mmol) in 10 ml NMP was heated at 100° C. for 16 hours. The reaction was quenched with 100 ml water. The mixture was extracted with ethyl acetate (3×20 ml) and dried over anhydrous sodium sulfate. 2-Nitro-N-phenyl-5-(piperidin-1-yl)benzenamine (0.50 g, 100%) was obtained by flash column chromatograph (30% acetyl acetate in hexanes). 1H NMR (500 MHz, CDCl3) δ (ppm) 1.66 (m, 6H), 3.33 (t, J=5.8 Hz, 4H), 6.34 (dd, J=2.6, 9.7 Hz, 1H), 6.42 (d, J=2.6 Hz, 1H), 7.23-7.46 (m, 5H), 8.14 (d, J=9.7 Hz, 1H), 9.93 (s, 1H). 13C NMR (125 MHz, CDCl3): δ (ppm) 24.8, 25.4, 48.7, 95.6, 106.4, 124.8, 125.6, 129.4, 130.1, 139.7, 146.0, 156.0.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH:6]2[CH2:10][CH2:9][N:8]([C:11]([N:13]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[N:16]([C:23]4[CH:32]=[CH:31][C:26]([C:27]([O:29]C)=[O:28])=[CH:25][CH:24]=4)[CH2:15][CH2:14]3)=[O:12])[CH2:7]2)[CH:3]=[N:2]1.O.[OH-].[Li+]>O1CCCC1.CO.O>[NH:1]1[CH:5]=[C:4]([CH:6]2[CH2:10][CH2:9][N:8]([C:11]([N:13]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[N:16]([C:23]4[CH:24]=[CH:25][C:26]([C:27]([OH:29])=[O:28])=[CH:31][CH:32]=4)[CH2:15][CH2:14]3)=[O:12])[CH2:7]2)[CH:3]=[N:2]1
Reactant: COC(=O)c1ccc(N2CCN(C(=O)N3CCC(c4cn[nH]c4)C3)c3ccccc32)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccc(N2CCN(C(=O)N3CCC(c4cn[nH]c4)C3)c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 95.2 %

Procedure:
4.2 g of methyl 4-[4-{[3-(1H-pyrazol-4-yl)pyrrolidin-1-yl]carbonyl}-3,4-dihydroquinoxalin-1(2H)-yl]benzoate and 50 ml of a tetrahydrofuran/methanol/water 2/1/1 mixture are introduced into a 250 ml round-bottomed flask equipped with a magnetic stirrer and placed in an ice bath. 1.63 g of lithium hydroxide monohydrate are added and the reaction mixture is stirred at ambient temperature for 18 h. After evaporating the organic solvents, citric acid is added up to pH 5. The precipitate is filtered off and dried under vacuum. 3.87 g of 4-[4-{[3-(1H-pyrazol-4-yl)pyrrolidin-1-yl]carbonyl}-3,4-dihydroquinoxalin-1(2H)-yl]benzoic acid are obtained.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=[O:13])=[O:12])[C:6]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:5]2[S:25](Cl)(=[O:27])=[O:26].[C:29]([NH:36][CH2:37][CH2:38][NH2:39])([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30].C(N(CC)CC)C>ClCCl.CCOC(C)=O>[C:32]([O:31][C:29]([NH:36][CH2:37][CH2:38][NH:39][S:25]([C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([I:1])[CH:3]=2)[N:7]([S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:13])=[O:12])[C:6]=1[C:20]([O:22][CH2:23][CH3:24])=[O:21])(=[O:27])=[O:26])=[O:30])([CH3:35])([CH3:34])[CH3:33]
Reactant: CCOC(=O)c1c(S(=O)(=O)Cl)c2cc(I)ccc2n1S(=O)(=O)c1ccccc1
Reactant: CC(C)(C)OC(=O)NCCN
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1c(S(=O)(=O)NCCNC(=O)OC(C)(C)C)c2cc(I)ccc2n1S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The product from Example 4 Step C (235 mg) was combined with Boc-ethylenediamine (74 μL) and triethylamine (178 μL) in 3 mL of dichloromethane and stirred at room temperature for 1 hour. The reaction was diluted with EtOAc and washed with saturated NaHCO3 and brine, dried over Na2SO4 and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel using EtOAc/hexane as mobile phase to give the titled compound. ESI+ MS: 678 [M+H]+.
Reaction SMILES: [C:1]1([NH:7][C:8]2([C:24]([O:26][CH3:27])=[O:25])[CH2:13][CH2:12][N:11]([C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:15])[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:28](Cl)(=[O:32])[O:29][CH2:30][CH3:31]>>[CH2:30]([O:29][C:28]([N:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:8]1([C:24]([O:26][CH3:27])=[O:25])[CH2:9][CH2:10][N:11]([C:14]([O:16][CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[O:15])[CH2:12][CH2:13]1)=[O:32])[CH3:31]
Reactant: COC(=O)C1(Nc2ccccc2)CCN(C(=O)OCc2ccccc2)CC1
Reactant: CCOC(=O)Cl
Product: CCOC(=O)N(c1ccccc1)C1(C(=O)OC)CCN(C(=O)OCc2ccccc2)CC1
Temperature: 110 °C

Procedure:
A mixture of 14.8 parts of O4 -methyl O1 -(phenylmethyl) 4-(phenylamino)-1,4-piperidinedicarboxylate and 203 parts of ethyl carbonochloridate is stirred and refluxed for 24 hours in an oil-bath at 110° C. The reaction mixture is evaporated and the residue is dissolved in trichloromethane. The solution is washed twice with water, dried, filtered and evaporated, yielding 16.2 parts of O4 -methyl O1 -(phenylmethyl) 4-[(ethoxycarbonyl)phenylamino]-1,4-piperidinedicarboxylate as a residue.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:3]=1[O:4][C:5]1[C:10]([C:11]([OH:13])=O)=[CH:9][N:8]=[CH:7][N:6]=1.[I-].ClC1C=CC=C[N+]=1C.C(N(CC)CC)C.[NH:35]1[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[CH2:38][CH2:37][CH2:36]1.C(=O)(O)[O-].[Na+]>ClCCl>[Cl:1][C:2]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:3]=1[O:4][C:5]1[C:10]([C:11]([N:35]2[C:44]3[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=3)[CH2:38][CH2:37][CH2:36]2)=[O:13])=[CH:9][N:8]=[CH:7][N:6]=1
Reactant: O=C(O)c1cncnc1Oc1cc(Cl)ccc1Cl
Reactant: c1ccc2c(c1)CCCN2
Agent: C[n+]1ccccc1Cl
Agent: O=C([O-])O
Agent: [I-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(c1cncnc1Oc1cc(Cl)ccc1Cl)N1CCCc2ccccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 2 %

Procedure:
To a solution of 200 mg (0.7 mmol) 4-(2,5-dichloro-phenoxy)-pyrimidine-5-carboxylic acid in 2 mL dichloromethane were added 197 mg (0.77 mmol) 2-chloro-1-methylpyridinium iodide (commercially available, CAS RN 14338-32-0), 0.2 mL (1.4 mmol) triethylamine and 103 mg (0.77 mmol) 1,2,3,4-tetrahydroquinoline (commercially available, CAS RN 635-46-1). The solution was stirred 2 hours at room temperature. The reaction mixture was poured on saturated aqueous sodium bicarbonate solution and extracted three times with dichloromethane. The combined organic layers were dried over magnesium sulfate and concentrated under vacuum. The residue was purified by preparative HPLC (Phenomenex Gemini column) using a gradient of acetonitrile:water (containing 0.05% formic acid) (10:90 to 98:2) to give 5.6 mg (2%) of the desired compound. MS (ESI): m/z=400.2 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][CH:15]1[C:24]2[C:19](=[CH:20][C:21]([C:25]3[CH:26]=[N:27][NH:28][CH:29]=3)=[CH:22][CH:23]=2)[CH2:18][CH2:17][NH:16]1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:16]3[CH2:17][CH2:18][C:19]4[C:24](=[CH:23][CH:22]=[C:21]([C:25]5[CH:29]=[N:28][NH:27][CH:26]=5)[CH:20]=4)[CH:15]3[CH3:14])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Reactant: CC1NCCc2cc(-c3cn[nH]c3)ccc21
Product: CC1c2ccc(-c3cn[nH]c3)cc2CCN1C(=O)c1cc2ncc(Br)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1-Methyl-6-(1H-pyrazol-4-yl)-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([C:13]([N:15]2[CH2:20][CH2:19][CH2:18][C@@H:17]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)[CH2:16]2)=O)[C@H:10]([NH2:29])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O1CCCC1.C(O)(=O)C>CO>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([CH2:13][N:15]2[CH2:20][CH2:19][CH2:18][C@@H:17]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)[CH2:16]2)[C@H:10]([NH2:29])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1C[C@@H](N)[C@H](C(=O)N2CCC[C@@H](Cc3ccc(F)cc3)C2)C1
Solvent: CO
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C[C@H](CN2CCC[C@@H](Cc3ccc(F)cc3)C2)[C@H](N)C1
Reaction time: 20 h
Yield: 41.4 %

Procedure:
(3S,4R)-3-Amino-4-[(S)-3-(4-fluorobenzyl)-piperidine-1-carbonyl]-pyrrolidine-1-carboxylic acid tert-butyl ester (75 mg, 185 μmol) was treated with borane-tetrahydrofuran complex in tetrahydrofuran (1.0 M; 7.4 mL, 7.4 mmol) and stirred for 20 h . The mixture was treated slowly with 20% acetic acid in methanol (10 mL), and the resulting mixture was stirred at room temperature for 1 h . The solvents were removed, and the residue was dissolved in water, made basic (pH 11) with 50% sodium hydroxide, and extracted with methylene chloride. The combined organic phases were dried (Na2SO4) and concentrated. The residue was purified by flash column chromatography (5% methanol/dichloromethane) to provide the product (30 mg, 40%). 1H NMR (300 mHz, CD3OD) δ7.20 (m, 2H), 6.98 (m, 2H), 3.18-2.42 (15H), 1.80-1.50 (4H), 1.41 (s, 9H); mass spec. (ES+) m/z 392.4.
Reaction SMILES: [Br:1][C:2]1[CH:13]=[C:12]([OH:14])[C:5]2[N:6]([CH:9]3[CH2:11][CH2:10]3)[CH:7]=[N:8][C:4]=2[CH:3]=1.O[C@H:16]([C@H:18]1[CH2:22][N:21]([C@@H:23]([C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)[CH3:24])[C:20](=[O:33])[CH2:19]1)[CH3:17].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[Br:1][C:2]1[CH:13]=[C:12]([O:14][C@@H:16]([C@H:18]2[CH2:22][N:21]([C@@H:23]([C:25]3[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=3)[CH3:24])[C:20](=[O:33])[CH2:19]2)[CH3:17])[C:5]2[N:6]([CH:9]3[CH2:11][CH2:10]3)[CH:7]=[N:8][C:4]=2[CH:3]=1
Reactant: COc1ccc([C@@H](C)N2C[C@H]([C@H](C)O)CC2=O)cc1
Reactant: Oc1cc(Br)cc2ncn(C3CC3)c12
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccc([C@@H](C)N2C[C@H]([C@@H](C)Oc3cc(Br)cc4ncn(C5CC5)c34)CC2=O)cc1
Reaction time: 1 h

Procedure:
5-bromo-1-cyclopropyl-1H-benzo[d]imidazol-7-ol 2.73 (1.4 g, 5.53 mmol), (R)-4-((S)-1-hydroxyethyl)-1-((R)-1-(4-methoxyphenyl)ethyl)pyrrolidin- 2-one 1.05 (2.04 g, 7.75 mmol), and triphenylphosphine (2.04 g, 7.78 mmol) were taken up in THF (30 mL). Diethyl azodicarboxylate (1.2 ml, 7.65 mmol) was added dropwise over 1 min, and the resulting stirred solution was heated to 40 C. After 1 h, add additional portions of intermediate 1.05 (0.27 g, 1.02 mmol), triphenylphosphine (0.27 g, 1.02 mmol), and diethyl azodicarboxylate (0.15 ml, 0.96 mmol) were added. The mixture was stirred an additional 1.5 h and was then concentrated directly onto silica gel. Purification by silica gel chromatography (20-100% acetone:hexanes) provided (R)-4-((R)-1-((5-bromo-1-cyclopropyl-1H-benzo[d]imidazol-7-yl)oxy)ethyl)-1-((R)-1-(4-methoxyphenyl)ethyl)pyrrolidin-2-one (2.74). LCMS-ESI+ (m/z): [M+H]+ calcd for C25H29BrN3O3: 498.14; found: 498.37.
Reaction SMILES: Cl.[CH3:2][C:3]1[C:7]([CH2:8][N:9]2[CH:13]=[C:12]([NH2:14])[CH:11]=[N:10]2)=[C:6]([CH3:15])[O:5][N:4]=1.[CH3:16][O:17][C:18]1[C:19]([C:28](O)=[O:29])=[CH:20][C:21]2[O:26][CH2:25][CH2:24][O:23][C:22]=2[CH:27]=1>>[CH3:2][C:3]1[C:7]([CH2:8][N:9]2[CH:13]=[C:12]([NH:14][C:28]([C:19]3[C:18]([O:17][CH3:16])=[CH:27][C:22]4[O:23][CH2:24][CH2:25][O:26][C:21]=4[CH:20]=3)=[O:29])[CH:11]=[N:10]2)=[C:6]([CH3:15])[O:5][N:4]=1
Reactant: Cc1noc(C)c1Cn1cc(N)cn1
Reactant: COc1cc2c(cc1C(=O)O)OCCO2
Agent: Cl
Product: COc1cc2c(cc1C(=O)Nc1cnn(Cc3c(C)noc3C)c1)OCCO2
Yield: 50 %

Procedure:
Prepared as in Example 4-73 from 1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-amine hydrochloride (example 4-1a) and 7-methoxy-2,3-dihydrobenzo[b][1,4]dioxine-6-carboxylic acid (example 4-95a). Yield 50%. MS M+H calculated 385.1. Found 385.1. 1H NMR (400 MHz, DMSO): 2.136 (s, 3H), 2.410 (s, 3H), 3.851 (s, 3H), 4.214 (bs, 2H), 4.296 (bs, 2H), 5.120 (s, 2H), 6.688 (s, 1H), 7.290 (s, 1H), 7.6006 (s, 1H), 8.069 (s, 1H), 9.856 (s, 1H).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:10]=[C:11]([F:13])[CH:12]=1)C=O)([CH3:4])([CH3:3])[CH3:2].C1(C)C(S(O)(=O)=O)=CC=CC=1.C(N(CC)CC)C.[CH:32](OC)([O:35][CH3:36])[O:33][CH3:34]>CO>[C:1]([C:5]1[CH:12]=[C:11]([F:13])[CH:10]=[C:7]([CH:32]([O:35][CH3:36])[O:33][CH3:34])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(OC)OC
Reactant: CC(C)(C)c1cc(F)cc(C=O)c1
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: CCN(CC)CC
Solvent: CO
Product: COC(OC)c1cc(F)cc(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.5 %

Procedure:
3-tert-Butyl-5-fluoro-benzaldehyde (252 g, 1.4 moles) was dissolved in methanol (4 vol, 1000 ml) and trimethyl orthoformate (1 vol, 252 ml). Toluenesulfonic acid (3.4% w/w, 6 g) was added in one portion and the resulting solution stirred at rt for 1 hour. Triethylamine (0.12 vol, 30 mL) was added and the reaction concentrated to an oil, and then re-suspended in ethyl acetate (3 L) and NaHCO3 (aq. sat., 1 L) and water (1 L) with vigorous mixing. The organic phase was washed with additional water (1 L), polish filtered and then concentrated to provide an orange oil (311.2 g, 98.5%), used directly in the next reaction.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[N:20]=[N:19][C:18]([NH2:21])=[CH:17][CH:16]=1.[CH3:22][O:23][C:24](=[O:29])[CH2:25][C:26](Cl)=[O:27]>>[CH3:22][O:23][C:24](=[O:29])[CH2:25][C:26]([NH:21][C:18]1[N:19]=[N:20][C:15]([O:14][CH2:13][C:3]2[C:4]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)=[N:5][O:6][C:2]=2[CH3:1])=[CH:16][CH:17]=1)=[O:27]
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(N)nn1
Reactant: COC(=O)CC(=O)Cl
Product: COC(=O)CC(=O)Nc1ccc(OCc2c(-c3ccccc3)noc2C)nn1
Yield: 32 %

Procedure:
As described for example 18, 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridazin-3-ylamine (200 mg, 0.7 mmol) was converted, using chlorocarbonyl-acetic acid methyl ester instead of methoxyacetyl chloride, to the title compound (88 mg, 32%) which was obtained as a white solid. MS: m/e=383.3 [M+H]+.
Reaction SMILES: [OH:1][CH:2]1[O:10][C@H:9]([CH2:11][OH:12])[C@@H:7]([OH:8])[C@H:5]([OH:6])[C@H:3]1[NH2:4].C(=O)C1C=[CH:18][C:17]([O:20]C)=CC=1>>[C:2]([O:1][CH:2]1[O:10][C@H:9]([CH2:11][O:12][C:17](=[O:20])[CH3:18])[C@@H:7]([O:8][C:9](=[O:10])[CH3:11])[C@H:5]([O:6][C:5](=[O:6])[CH3:7])[C@H:3]1[NH2:4])(=[O:1])[CH3:3]
Reactant: COc1ccc(C=O)cc1
Reactant: N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O
Product: CC(=O)OC[C@H]1OC(OC(C)=O)[C@H](N)[C@@H](OC(C)=O)[C@@H]1OC(C)=O

Procedure:
Other N-acyl derivatives of glucosamines of formula I (i.e. where both R1 and R2 are not a hydrogen atom) can be obtained by deacetylation of the respective derivatives of 1,3,4,6-tetra-O-D-glucosamine by means of alcoholic hydrochloric acid. See Examples 4, 7, and 8. The 1,3,4,6-tetra-O-acetyl-D-glucosamine (R1 =R2 =acetyl in formula II) reagent is synthesized from D-glucosamine by reaction of the latter with a protecting agent for the amino group (e.g. p-anisaldehyde) to form a Schiff's base. See Example 1(a) . The Schiff's base is then acetylated with acetic anhydride (Example 1(b)), then hydrolized with hydrochloric acid (Example 1(c)) and treated with sodium acetate (for example) to obtain 1,3,4,6-tetra-O-acetyl-D-glucosamine. Examples 1(d) and 2(a). The resultant 1,3,4,6-tetra-O-acetyl-D-glucosamine is condensed with the acylated amino acid or oligopeptide in the presence of DCC as described above.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[ClH:7].[N:8]12[CH2:15][CH2:14][CH:11]([CH2:12][CH2:13]1)[C@@H:10]([NH:16][C:17]([C:19]1[S:20][C:21]3[C:27](Br)=[CH:26][CH:25]=[CH:24][C:22]=3[CH:23]=1)=[O:18])[CH2:9]2.[CH3:29][O:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1B(O)O>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[ClH:7].[N:8]12[CH2:15][CH2:14][CH:11]([CH2:12][CH2:13]1)[C@@H:10]([NH:16][C:17]([C:19]1[S:20][C:21]3[C:27]([C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=4[O:30][CH3:29])=[CH:26][CH:25]=[CH:24][C:22]=3[CH:23]=1)=[O:18])[CH2:9]2
Reactant: COc1ccccc1B(O)O
Reactant: O=C(N[C@H]1CN2CCC1CC2)c1cc2cccc(Br)c2s1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: Cl
Solvent: CN(C)C=O
Product: COc1ccccc1-c1cccc2cc(C(=O)N[C@H]3CN4CCC3CC4)sc12
Temperature: 80 °C

Procedure:
0.22 ml of 2 M aqueous sodium carbonate solution and 6.1 mg (0.007 mmol) of PdCl2(dppf) are added to a mixture of 60 mg (0.15 mmol) of N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-7-bromo-1-benzothiophene-2-carboxamide hydrochloride (Example 8A) and 22.7 mg (0.15 mmol) of 2-methoxyphenylboronic acid in 1 ml of DMF. The reaction mixture is heated at 80° C. for 14 h, then filtered through kieselguhr and evaporated to dryness. Purification of the crude product by preparative HPLC, subsequent addition of 1N hydrochloric acid and drying under high vacuum result in 12.8 mg (18% of theory) of the title compound.
Reaction SMILES: O[CH2:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].[C:13](O)(=[O:31])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]/[CH:21]=[CH:22]\[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30].C(=O)([O-])[O-].[Na+].[Na+].[PH2]([O-])=O.[Na+]>>[CH3:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]/[CH:22]=[CH:21]\[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][C:13]([O:12][CH2:11][CH:9]([OH:10])[C@H:7]1[O:8][CH2:2][C@H:3]([OH:4])[C@H:5]1[OH:6])=[O:31]
Reactant: OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)CO
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)O
Agent: O=C([O-])[O-]
Agent: O=[PH2][O-]
Agent: [Na+]
Product: CCCCCCCC/C=C\CCCCCCCC(=O)OCC(O)[C@H]1OC[C@H](O)[C@H]1O
Temperature: 190 °C
Reaction time: 0.5 h

Procedure:
After 497 g of a 70% by weight sorbitol aqueous solution (aldehyde value of sorbitol: 5.0 ppm), 863 g of oleic acid, 3.0 g of sodium carbonate, and 1.7 g of sodium hypophosphite were charged into a 2000 mL four-neck flask fitted with a stirring apparatus, a thermometer, and a nitrogen gas inlet, replacement with nitrogen was performed at room temperature for 30 minutes. Thereafter, the temperature was raised stepwise to 110° C., 140° C., 190° C., and 230° C. After the temperature reached 230° C. as a reaction temperature, the reaction was carried out under a nitrogen stream at normal pressure. At the time point when the spot of oleic acid as a raw material disappeared on thin-layer chromatography, it was judged that the reaction was completed. The reaction time was 5 hours and, after the completion of the reaction was confirmed, the product was filtrated at 80° C. to obtain sorbitan monooleate.
Reaction SMILES: N#N.[CH3:3][O:4][C:5]1[C:10]([O:11][CH3:12])=[C:9]([O:13][CH3:14])[CH:8]=[CH:7][C:6]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+].[CH3:24][O:25][C:26](=[O:34])[C:27]1[CH:32]=[CH:31][CH:30]=[C:29](Br)[CH:28]=1>C1(C)C=CC=CC=1.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.CCO>[CH3:24][O:25][C:26]([C:27]1[CH:28]=[C:29]([C:6]2[CH:7]=[CH:8][C:9]([O:13][CH3:14])=[C:10]([O:11][CH3:12])[C:5]=2[O:4][CH3:3])[CH:30]=[CH:31][CH:32]=1)=[O:34]
Reactant: COC(=O)c1cccc(Br)c1
Reactant: COc1ccc(B(O)O)c(OC)c1OC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: COC(=O)c1cccc(-c2ccc(OC)c(OC)c2OC)c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 59 %

Procedure:
(The following reaction is done in an N2 atmosphere.) To a solution of 2,3,4-Trimethoxyphenylboronic acid (32) (1.40 g, 6.60 mmol) in toluene (15.0 mL) is added EtOH (2.0 mL), Pd(PPh3)4 (208 mg, 0.18 mmol) and Na2CO3.10 H2O (4.81 g, 16.80 mmol) in water (5.2 mL). The resulting mixture is carefully degassed (5 times alternating vacuum and flushing with N2). A solution of Methyl-3-bromobenzoate (9) (1.29 g, 6.00 mmol) in toluene (9.0 mL) is added by syringe, the resulting mixture is again carefully degassed and stirred overnight at 100° C. Partition the mixture between brine/EtOAc (1+1), separate layers, extract the aqu. layer with EtOAc (3×), wash the combined organic layer with brine, dry with Na2SO4 and remove solvent. Purify crude product by preparative radial chromatography (silica gel, EtOAc/CyH 1+5) to obtain 2′,3′,4′-Trimethoxy-biphenyl-3-carboxylic acid methyl ester (33) as a yellowish oil (1.07 g, 58%). 1H NMR (400 MHz, CDCl3): 3.66 (s, 3H); 3.89 (s, 3H); 3.92 (s, 6H); 6.74 (d, 1H, J=8.6 Hz); 7.03 (d, 1H, J=8.6 Hz); 7.44 (t, 1H, J=7.8 Hz); 7.70 (d, 1H, J=7.6 Hz); 7.97 (d, 1H, J=7.8 Hz); 8.15 (br.s 1H).
Reaction SMILES: [Br:1][C:2]1[C:10]2[N:9]=[C:8]([CH3:11])[NH:7][C:6]=2[CH:5]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[CH:3]=1.Br[CH2:19][C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Br:1][C:2]1[C:10]2[N:9]=[C:8]([CH3:11])[N:7]([CH2:19][C:20]3[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH:23]=[CH:22][CH:21]=3)[C:6]=2[CH:5]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[CH:3]=1
Reactant: Cc1nc2c(Br)cc(N3CCOCC3)cc2[nH]1
Reactant: BrCc1cccc2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nc2c(Br)cc(N3CCOCC3)cc2n1Cc1cccc2ccccc12
Temperature: 80 °C
Reaction time: 4 h
Yield: 72 %

Procedure:
To a mixture of 4-(4-bromo-2-methyl-1H-benzo[d]imidazol-6-yl)morpholine (0.5 g, 1.688 mmol), prepared as described in example 1, in N,N-Dimethylformamide (DMF) (10 mL) was added 1-(bromomethyl)naphthalene (0.448 g, 2.026 mmol) and potassium carbonate (0.700 g, 5.06 mmol). The resulting reaction mixture was stirred at 80° C. for 4 h. It was cooled to room temperature and poured into water (100 mL). The aqueous mixture was extracted with DCM (100 mL×2). The combined organic phases were washed with Brine (100 mL) and concentrated. The crude material was purified on silica column (20˜90% EtOAc in Hexane) to give the product as solid (0.53 g, 72%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.57 (s, 3H) 2.97-3.13 (m, 4H) 3.61-3.89 (m, 4H) 5.76 (s, 2H) 6.53 (dd, J=7.07, 1.01 Hz, 1H) 6.56 (d, J=2.02 Hz, 1H) 7.17 (d, J=2.02 Hz, 1H) 7.32 (m, 1H) 7.58-7.73 (m, 2H) 7.83 (m, 1H) 7.98 (m, 1H) 8.08 (d, J=8.06 Hz, 1H); MS (ES+) m/e 436.1 [M+H]+.
Reaction SMILES: Br[C:2]1C=CC(C=C)=C(C)[CH:3]=1.[Br:11][C:12]1[CH:13]=[C:14]([CH2:21][CH3:22])[C:15](I)=[C:16]([CH2:18][CH3:19])[CH:17]=1.C[Si](C)(C)C=C>>[Br:11][C:12]1[CH:13]=[C:14]([CH2:21][CH3:22])[C:15]([CH:2]=[CH2:3])=[C:16]([CH2:18][CH3:19])[CH:17]=1
Reactant: C=Cc1ccc(Br)cc1C
Reactant: CCc1cc(Br)cc(CC)c1I
Agent: C=C[Si](C)(C)C
Product: C=Cc1c(CC)cc(Br)cc1CC
Yield: 90 %

Procedure:
Using a procedure analogous to that used to prepare 30A, 37A (1.9 g, 5.6 mmol) was reacted with trimethyl(vinyl)silane to yield 37B (1.2 g, 90%) as a red oil. 1H NMR (400 MHz, CDCl3) δ ppm 1.14 (t, J=7.47 Hz, 6 H) 2.60 (q, J=7.62 Hz, 4 H) 5.21 (dd, J=17.80, 1.98 Hz, 1 H) 5.51 (dd, J=11.42, 1.76 Hz, 1 H) 6.64(dd, J=18.02, 11.42 Hz, 1 H) 7.18 (s, 2 H).