Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br.[N+:2]([C:5]1[CH:24]=[CH:23][CH:22]=[CH:21][C:6]=1[O:7][CH2:8][C:9]([CH2:11][NH:12][C@@H:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH3:14])=O)([O-])=O.[H][H]>C(O)C.[Pt]>[O:7]1[C:6]2[CH:21]=[CH:22][CH:23]=[CH:24][C:5]=2[NH:2][CH:9]([CH2:11][NH:12][C@@H:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH3:14])[CH2:8]1
Reactant: [H][H]
Reactant: C[C@@H](NCC(=O)COc1ccccc1[N+](=O)[O-])c1ccccc1
Agent: [Pt]
Agent: Br
Solvent: CCO
Product: C[C@@H](NCC1COc2ccccc2N1)c1ccccc1

Procedure:
The product from Example 1E (9.7 g, 24.5 mmol) and 5% Pt/C (2.0 g) in ethanol (1 L) was hydrogenated for 16 hours at ambient temperature under 4 atm of hydrogen, filtered through Celite® and concentrated to provide a mixture of diastereomers. The diastereomers were separated by flash chromatography on silica gel with 100:1:1 diethyl ether:ethanol:triethylamine to provide the title compound as the more mobile band. Rf 0.38 (100:1:1 diethyl ether:ethanol:triethylamine); mp 91-92° C.; [α]23D −3.4° (c 1.105, CHCl3); 1H NMR (300 MHz, CDCl3) δ1.35 (d, 3H), 1.45 (bs, 1H), 2.50-2.62 (m, 2H), 3.33 (bm, 1H), 3.73 (q, 1H), 3.86 (dd, 1H), 4.15 (dd, 1H), 4.21 (bs, 1H), 6.62 (m, 2H), 6.75 (m, 2H), 7.20-7.40 (m, 5H).
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7]([OH:9])[CH:6]=[CH:5][N:4]=1.Cl.[CH3:11][C:12]1[CH:17]=[CH:16][C:15]([CH:18]=[O:19])=[CH:14][N:13]=1>Cl.C(Cl)Cl.CO>[OH:9][C:7]1[C:6]([CH:18]([C:15]2[CH:14]=[N:13][C:12]([CH3:11])=[CH:17][CH:16]=2)[OH:19])=[CH:5][N:4]=[C:3]([S:2][CH3:1])[N:8]=1
Reactant: CSc1nccc(O)n1
Reactant: Cc1ccc(C=O)cn1
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: CSc1ncc(C(O)c2ccc(C)nc2)c(O)n1

Procedure:
A mixture of 10.0 g (0.07 mol) of 2-methylthio-4-hydroxypyrimidine and 12.4 g (0.079 mol) of 2-methyl-5-formylpyridine hydrochloride in 75 ml of concentrated hydrochloric acid was heated at reflux for 1 hour. After working up as in Example 1 an oil is obtained which is taken up in methylene chloride-methanol then recrystallized from ethyl acetate to give 4-hydroxy-5-[(6-methyl-3-pyridinyl)hydroxymethyl]-2-methylthiopyrimidine; 9.3 g (50%), m.p. 140°.
Reaction SMILES: C([O:5][C:6](=[O:32])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][N:18]([C:26](=O)[CH2:27][C:28]([CH3:30])=O)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[N:15]=1)([CH3:9])[CH3:8])(C)(C)C.[CH3:33][NH:34][NH2:35]>>[CH3:33][N:34]1[C:26]([N:18]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:17][CH2:16][C:14]2[N:15]=[C:11]([S:10][C:7]([CH3:8])([CH3:9])[C:6]([OH:5])=[O:32])[S:12][CH:13]=2)=[CH:27][C:28]([CH3:30])=[N:35]1
Reactant: CCCCCCCN(CCc1csc(SC(C)(C)C(=O)OC(C)(C)C)n1)C(=O)CC(C)=O
Reactant: CNN
Product: CCCCCCCN(CCc1csc(SC(C)(C)C(=O)O)n1)c1cc(C)nn1C

Procedure:
A compound obtained using 2-[(4-{2-[acetoacetyl(heptyl)amino]ethyl}-1,3-thiazol-2-yl)thio]-2-methylpropionic acid tert-butyl ester synthesized in Example 446-1 and methylhydrazine, and by an operation similar to that of Example 446 was purified by silica gel chromatography (elution solvent; chloroform:methanol=10:1) to give the title compound.
Reaction SMILES: [N:1]1[C:2]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][N+:15]([O-])=[CH:14][CH:13]=2)=[CH:3][N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.C(OC(=O)C)(=[O:21])C>>[N:1]1[C:2]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][NH:15][C:14](=[O:21])[CH:13]=2)=[CH:3][N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: [O-][n+]1ccc(OCc2cn3ccccc3n2)cc1
Reactant: CC(=O)OC(C)=O
Product: O=c1cc(OCc2cn3ccccc3n2)cc[nH]1
Temperature: 80 °C
Reaction time: 1 h
Yield: 63 %

Procedure:
4-(Imidazo[1,2-a]pyridin-2-ylmethoxy)pyridine 1-oxide (1.50 g, 6.25 mmol) was heated at 140° C. in acetic anhydride (18 mL) for 2 h. The mixture was concentrated and heated at 80° C. for 2 h in 1:1 MeOH/H2O (50 mL). The resulting black solution was concentrated. The material was then partially dissolved in iPrOH (20 mL). Et2O (70 mL) was added, and the mixture was allowed to sit at ambient temperature for 1 h. The resulting solids were collected by filtration and washed with Et2O to yield the title compound (951 mg, 63%) as a dark brown solid: 1H NMR (300 MHz, DMSO-d6) δ 11.08 (br s, 1H), 8.54 (m, 1H), 8.01 (s, 1H), 7.53 (d, J=9.0 Hz, 1H), 7.26-7.23 (m, 2H), 6.90 (m, 1H), 5.89-5.87 (m, 2H), 5.14 (s, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][CH:3]=1.F[P-](F)(F)(F)(F)F.[N:18]1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:18])=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(O)cc1
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: NC(=O)c1ccc(O)cc1
Reaction time: 2 h

Procedure:
A solution of freshly prepared 4-hydroxybenzoic acid (635 mg; 4.6 mmol) and BOP (1.7 g; 5.06 mmol) in DMF (20 mL) was added dropwise and at room temperature to a solution of PEI (1 g, 23.2 mmol) in DMF (50 mL). After 2 hours under stirring, the DMF was removed by evaporation under reduced pressure. The crude product was taken in water, dissolved by addition of aqueous sodium hydroxide solution 1M (pH 11) and subjected to dialysis using a SpectraPor 12-14 kDa membrane against water (1 L, 2 changes over 24 h). Lyophilization provided 4-hydroxybenzamide-PEI (0.7 g) at a modification degree of 28%. 1H NMR (D2O) δppm: 2.6 (bm, 2.9H, —NHCH2CH2NH—), 3.22 (m, 0.55H, Phe-CONHCH2CH2NH—), 3.35 (m, 0.55H, Phe-CONHCH2CH2NH) 6.57 (d, J=7.3 Hz, 0.55 H, CHaro), 6.97 (m, 0.55H, CHaro).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:9][CH:8]=[C:7]([O:17][CH3:18])[C:5]=2[N:6]=1.C(N(CC)CC)C.[CH3:26][O:27][C:28]1[CH:36]=[CH:35][CH:34]=[CH:33][C:29]=1[C:30](Cl)=[O:31]>C1COCC1.CN(C1C=CN=CC=1)C>[CH3:26][O:27][C:28]1[CH:36]=[CH:35][CH:34]=[CH:33][C:29]=1[C:30]([NH:1][C:2]1[S:3][C:4]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:9][CH:8]=[C:7]([O:17][CH3:18])[C:5]=2[N:6]=1)=[O:31]
Reactant: COc1ccccc1C(=O)Cl
Reactant: COc1ccc(-c2ccccc2)c2sc(N)nc12
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccccc1C(=O)Nc1nc2c(OC)ccc(-c3ccccc3)c2s1

Procedure:
To a solution of 2-amino-4-methoxy-7-phenyl-benzothiazole (200 mg, 0.67 mmol) in THF (10 m) was added DMAP (10 mg, 0.08 mmol), triethylamine (163 □l, 1.17 mmol) and 2-methoxybenzoyl chloride (136 □l, 1 mmol) in THF (2 ml). The mixture was then heated to reflux for 2 h, after cooling, it was partitioned between 1:1 AcOEt/THF (70 ml) and 5% NaHCO3 solution( 40 ml). The organic phase was washed with saturated NaCl solution (50 ml), dried with Na2SO4, filtered and the solvent removed under reduced presure. The residue was suspended in ether (10 ml), filtered, washed with ether then dried under vacuum (0.05 mmHg, 60° C.), to afford the title compound was a white solid (260 mg, 85% yield), MS: m/e=390.0 (M+).
Reaction SMILES: [H-].[Na+].[P:3]([O-:10])([O:7][CH2:8][CH3:9])[O:4][CH2:5][CH3:6].Cl[CH:12]([F:14])[F:13]>C1COCC1.CCCCCC>[F:13][CH:12]([P:3](=[O:10])([O:7][CH2:8][CH3:9])[O:4][CH2:5][CH3:6])[F:14]
Reactant: FC(F)Cl
Reactant: CCOP([O-])OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOP(=O)(OCC)C(F)F
Yield: 16.2 %

Procedure:
A sample of 6.82 g (171 mmol) of 60% NaH in mineral oil was washed twice with 30 ml of petroleum ether and was suspended in 130 ml of THF under argon. A solution of 22 ml (171 mmol) of diethyl phosphite was added dropwise over 45 minutes and the exotherm was controlled with a water bath. After stirring for an additional hour, 42 g (490 mmol) of chlorodifluoromethane was bubbled through the solution over 4.5 hours, while the internal temperature was maintained between 25° and 35° C. with a cool water bath. The white suspension was allowed to stir overnight, was diluted with hexane and filtered through Celite. The filtrate was evaporated to provide 27.6 g of a crude, pale yellow liquid. The crude material was fractionally distilled at 10 mm to provide 5.21 g (16%) of impure title compound (b.p. 82°-84° C.), followed by 20.66 g (64%) of title compound (b.p. 84°-86° C.) as a colorless liquid which contains a trace of impurity.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4]Br.[H-].[Na+].[F:12][C:13]([F:22])([F:21])[CH2:14][CH2:15][CH:16]([C:19]#[N:20])[C:17]#[N:18]>CN(C)C=O>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][C:16]([CH2:15][CH2:14][C:13]([F:12])([F:21])[F:22])([C:17]#[N:18])[C:19]#[N:20]
Reactant: N#CC(C#N)CCC(F)(F)F
Reactant: Clc1ccccc1CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CC(C#N)(CCC(F)(F)F)Cc1ccccc1Cl
Yield: 75.1 %

Procedure:
Using 0.21 g of 2-chlorobenzyl bromide, 3 ml of N,N-dimethylformamide, 0.05 g of sodium hydride (60% in oil), and 0.17 g of (3,3,3-trifluoropropyl)malononitrile, and according to the process described in the Production Example 26, there was obtained 0.22 g of 2-(2-chlorobenzyl)-2-(3,3,3-trifluoropropyl)malononitrile (the present compound (81)).
Reaction SMILES: [F:1][CH2:2][C:3](=O)[CH2:4][C:5]([O:7]C(C)(C)C)=O.[NH2:13][C:14]1[N:18]=[C:17]([S:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[NH:16][N:15]=1>C(O)(=O)C>[CH2:20]([S:19][C:17]1[N:18]=[C:14]2[N:13]=[C:3]([CH2:2][F:1])[CH:4]=[C:5]([OH:7])[N:15]2[N:16]=1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: Nc1n[nH]c(SCc2ccccc2)n1
Reactant: CC(C)(C)OC(=O)CC(=O)CF
Solvent: CC(=O)O
Product: Oc1cc(CF)nc2nc(SCc3ccccc3)nn12
Reaction time: 5.5 h

Procedure:
A solution containing 20.0 g (114 mmol) of t-butyl 4-fluoroacetoacetate, 23.4 g (114 mmol) of 3-amino-5-benzylthio-1,2,4-triazole in 250 ml of glacial acetic acid was heated at reflux with stirring for 5.5 hr and then allowed to cool and stand overnight. The crystals that formed were ground to reduce their size and then recovered by filtration and dried in a vacuum oven to obtain 18.3 g (55 percent of theory) of the title product as a white powder melting with decomposition at 214°-218° C.
Reaction SMILES: [Br:1][C:2]1[C:3]2[N:4]([C:12]([C:15]([O:17]CC)=[O:16])=[CH:13][N:14]=2)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.C1COCC1.[OH-].[Na+].Cl>C(O)C>[Br:1][C:2]1[C:3]2[N:4]([C:12]([C:15]([OH:17])=[O:16])=[CH:13][N:14]=2)[CH:5]=[C:6]([C:8]([F:11])([F:9])[F:10])[CH:7]=1
Reactant: CCOC(=O)c1cnc2c(Br)cc(C(F)(F)F)cn12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(O)c1cnc2c(Br)cc(C(F)(F)F)cn12
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 84.6 %

Procedure:
To a mixture of ethyl 8-bromo-6-(trifluoromethyl)imidazo[1,2-a]pyridine-3-carboxylate (490 mg) in a mixed solvent of THF (9 mL) and ethanol (3 mL) was added 8N aqueous sodium hydroxide solution (273 μL), and the mixture was stirred at room temperature for 1.5 hr, and then at 50° C. for 1 hr. The reaction solution was neutralized with 6N hydrochloric acid under ice-cooling, and the obtained solid was collected by filtration, and washed with water and IPE to give the title compound (380 mg).
Reaction SMILES: [Cl:1][C:2]([Cl:45])([Cl:44])[C:3]([O:6][C:7]([N:9]1[C@H:14]2[C:15]([C:32]([O:34][CH2:35][CH3:36])=[O:33])=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([O:24][Si](C(C)(C)C)(C)C)=[CH:20][CH:19]=3)[CH2:17][C@@H:10]1[CH2:11][N:12]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:13]2)=[O:8])([CH3:5])[CH3:4].CC1C=CC(S(O)(=O)=O)=CC=1.C([O-])([O-])=O.[Na+].[Na+]>CO>[Cl:45][C:2]([Cl:1])([Cl:44])[C:3]([O:6][C:7]([N:9]1[C@H:14]2[C:15]([C:32]([O:34][CH2:35][CH3:36])=[O:33])=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=3)[CH2:17][C@@H:10]1[CH2:11][N:12]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:13]2)=[O:8])([CH3:4])[CH3:5]
Reactant: CCOC(=O)C1=C(c2ccc(O[Si](C)(C)C(C)(C)C)cc2)C[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]1N2C(=O)OC(C)(C)C(Cl)(Cl)Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: CCOC(=O)C1=C(c2ccc(O)cc2)C[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]1N2C(=O)OC(C)(C)C(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 33.2 %

Procedure:
Compound B10 (7.58 g, 10.7 mmol) was dissolved in MeOH (110 mL) and p-TsOH (2.03 g, 11.8 mmol) was added. The mixture was stirred at rt for 2 h, and aq. 10% Na2CO3 (200 mL) was added. The solvents were partially removed under reduced pressure, and the resulting suspension was extracted with EtOAc. The org. extracts were filtered and washed with aq. 10% Na2CO3 and brine. The org. layer was dried over Na2SO4, filtered, and the solvents were removed under reduced pressure. Purification of the crude by FC (EtOAc/heptane) yielded the title compound (2.10 g, 33%). LC-MS: tR=1.09 min, ES+: 593.25.
Reaction SMILES: Br[CH2:2][C:3](=O)[C:4]([O:6][CH2:7][CH3:8])=[O:5].[I:10][C:11]1[CH:12]=[CH:13][C:14]([NH2:17])=[N:15][CH:16]=1>CN(C=O)C.O>[CH2:7]([O:6][C:4]([C:3]1[N:17]=[C:14]2[CH:13]=[CH:12][C:11]([I:10])=[CH:16][N:15]2[CH:2]=1)=[O:5])[CH3:8]
Reactant: CCOC(=O)C(=O)CBr
Reactant: Nc1ccc(I)cn1
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cn2cc(I)ccc2n1
Reaction time: 2 h
Yield: 58.2 %

Procedure:
A mixture of sulfuric acid (0.5 mL), acetic acid (12 mL) and water (2 mL) was added to a reaction flask containing 2-aminopyridine (2.0 g, 21.26 mmol) and the solution was stirred for 5 minutes. NaIO4 (1.81 g, 8.5 mmol) followed by 12 (2.16 g, 8.5 mmol) was added into the reaction flask and stirred at 80° C. for 4 hrs. The reaction mixture was cooled to ambient temperature, diluted with cold water, basified with 20% aqueous KOH solution and extracted with DCM. The organic layer was washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure to obtain the crude residue. Purification by column chromatography (using silica gel 60-120 and 8% EtOAc in hexane as eluent) and subsequent recrystallisation from ethanol afforded 53 g (58.6% Yield) of 5-iodo-pyridin-2-ylamine. Ethyl bromopyruvate (4.89 g, 25.11 mmol) was added to solution of 5-iodo-pyridin-2-ylamine (5.0 g, 22.83 mmol) in DMF (25 mL) and stirring was continued at 80° C. for 2 hrs. The reaction mixture was diluted with cold water and extracted with ethyl acetate. The organic layer was washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure to obtain the crude residue. The residue obtained was purified by recrystallisation from methanol to afford 4.2 g (57.8% Yield) of 6-iodo-imidazo[1,2-a]pyridine-2-carboxylic acid ethyl ester. A mixture of imidazole (513 mg, 7.5 mmol), cuprous oxide (71 mg, 0.5 mmol), 6-iodo-imidazo[1,2-a]pyridine-2-carboxylic acid ethyl ester (1.6 g, 5.02 mmol), salox (137 mg, 1.0 mmol) and cesium carbonate (3.27 g, 10.05 mmol) in ACN (2 mL) in a seal tube were subjected to reaction in a microwave reactor (time: 15 min, temp: 85° C., power: zero, pressure: zero). The reaction mixture was filtered through celite and the filtrate collected was concentrated under reduced pressure. The residue was diluted with cold water, extracted with ethyl acetate, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (using neutral alumina and 0.2% MeOH in DCM as eluent) to afford 400 mg (31% Yield) of 6-pyrazol-1-yl-imidazo[1,2-a]pyridine-2-carboxylic acid ethyl ester. A mixture of 6-pyrazol-1-yl-imidazo[1,2-a]pyridine-2-carboxylic acid ethyl ester (250 mg, 0.97 mmol) in 8N aqueous HCl (3 mL) was stirred at 100° C. for 2 hrs. The reaction mixture was concentrated under reduced pressure to afford 130 mg (58.5% Yield) of 6-pyrazol-1-yl-imidazo[1,2-a]pyridine-2-carboxylic acid.
Reaction SMILES: [Br:1]Br.[C:3]([C:6]1[CH:7]=[C:8]([C:11]([O:13][CH3:14])=[O:12])[S:9][CH:10]=1)(=[O:5])[CH3:4].Br>C(Cl)(Cl)Cl>[Br:1][CH2:4][C:3]([C:6]1[CH:7]=[C:8]([C:11]([O:13][CH3:14])=[O:12])[S:9][CH:10]=1)=[O:5]
Reactant: BrBr
Reactant: COC(=O)c1cc(C(C)=O)cs1
Agent: Br
Solvent: ClC(Cl)Cl
Product: COC(=O)c1cc(C(=O)CBr)cs1
Temperature: 40 °C
Yield: 63 %

Procedure:
Following the procedure of Japan Kokai Tokkyo Koho JP 60 11,487 CA 103:22580m (1985), a solution of bromine (4.29 g, 26.87 mmoles) in 40 ml of chloroform was added dropwise to a stirred solution of methyl 4-acetyl-2-thiophenecarboxylate, prepared according to Example 15 (4.95 g, 26.87 mmoles) in 150 ml of chloroform containing four drops of 50% (v/v) 48% hydrobromic acid/glacial acetic acid. After 10 minutes at 40° C. the solution was cooled to room temperature, concentrated in vacuo and the residue triturated with methanol (25 ml). Filtration furnished an off-white solid (4.96 g, 63%), m.p. 112-4° C. EIMS (m/z): 264/262 (M+, 11%), 233/231 (M+ --CH3O, 11%) , 171/169 (M+ --CH2Br, base); 1HNMR (CDCl3) delta, 8.31 (1H, d, J=1.5 Hz), 8.17 (1H, d, J=1.5 Hz), 4.29 (2H, s), 3.90 (3H, s).
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[N:7]([CH2:9][CH2:10][O:11][C:12]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:13]=1[C:14](Br)=[CH:15][N:16]2[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].P(=O)(O)(O)[OH:31]>>[C:1]([O:5][C:6](=[O:29])[N:7]([CH2:9][CH2:10][O:11][C:12]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:13]=1[CH2:14][C:15](=[O:31])[N:16]2[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(CCOc1cccc2c1c(Br)cn2Cc1ccccc1)C(=O)OC(C)(C)C
Reactant: O=P(O)(O)O
Product: CN(CCOc1cccc2c1CC(=O)N2Cc1ccccc1)C(=O)OC(C)(C)C

Procedure:
[2-(1-Benzyl-3-bromo-1H-indol-4-yloxy)-ethyl]-methyl-carbamic acid tert-butyl ester was treated with phosphoric acid using the procedure of step 4 of Example 6 to provide [2-(1-benzyl-2-oxo-2,3-dihydro-1H-indol-4-yloxy)-ethyl]-methyl-carbamic acid tert-butyl ester.
Reaction SMILES: [CH3:1][C:2]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[CH:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8].S(=O)(=O)(O)O.O.[C:25](=O)(O)[O-].[K+]>CO>[CH3:1][C:2]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[CH:3][CH2:4][CH2:5][CH2:6][C:7]([O:9][CH3:25])=[O:8]
Reactant: O=C([O-])O
Reactant: CCCCCCCCCC(C)=CCCCC(=O)O
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: CO
Solvent: O
Product: CCCCCCCCCC(C)=CCCCC(=O)OC
Yield: 85 %

Procedure:
98 g of crude 6-methylpentadec-5-enoic acid acid (from the proceeding Example) were dissolved in 305 ml of methanol, treated with 2 ml of sulphuric acid and heated to reflux temperature 2 hours. Then, the mixture was poured into water, made basic with saturated potassium bicarbonate solution, extracted twice with t-butyl methyl ether, concentrated and distilled in a high vacuum (0.1 Torr, 162-170° C.). 75 g (85%) of methyl 6-methylpentadec-5-enoate were obtained having the following characteristics: Z/E=56/46;
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH3:16])=[CH:6][CH:5]=[CH:4][N:3]=1.Cl[CH2:18][C:19](=O)[CH3:20]>C(O)C>[CH3:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[CH2:9][NH:8][C:7]1[C:2]2[N:3]([CH:18]=[C:19]([CH3:20])[N:1]=2)[CH:4]=[CH:5][CH:6]=1
Reactant: Cc1ccccc1CNc1cccnc1N
Reactant: CC(=O)CCl
Solvent: CCO
Product: Cc1cn2cccc(NCc3ccccc3C)c2n1

Procedure:
A solution of 2-amino-3-(2-methylbenzylamino)pyridine (3.25 g) and chloroacetone (1.26 ml) in ethanol (65 ml) was refluxed for 18 hours and then evaporated in vacuo. To the residue was added aqueous sodium bicarbonate solution and the mixture was extracted with methylene chloride. The extract was washed with brine, dried over magnesium sulfate, and evaporated in vacuo. The oily residue was purified by column chromatography on silica gel (40 g) with a mixture of methylene chloride and ethyl acetate (10:1) as an eluent to give 8-(2-methylbenzylamino)-2-methylimidazo[1,2-a]pyridine (1.80 g).
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@H:6]1[C:24]1[CH:29]=[CH:28][C:27]([CH3:30])=[C:26]([CH2:31][C:32]2[S:33][C:34]([C:37]3[CH:38]=[N:39][C:40]([F:43])=[CH:41][CH:42]=3)=[CH:35][CH:36]=2)[CH:25]=1)(=O)C.[OH-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCOCC1.O1CCCC1>[C@@H:6]1([C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[C:26]([CH2:31][C:32]3[S:33][C:34]([C:37]4[CH:38]=[N:39][C:40]([F:43])=[CH:41][CH:42]=4)=[CH:35][CH:36]=3)[CH:25]=2)[O:7][C@H:8]([CH2:19][OH:20])[C@@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]1[OH:4]
Reactant: CC(=O)OC[C@H]1O[C@@H](c2ccc(C)c(Cc3ccc(-c4ccc(F)nc4)s3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: Cc1ccc([C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)cc1Cc1ccc(-c2ccc(F)nc2)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 120.1 %

Procedure:
The above 1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(5(6-fluoro-3-pyridyl)-2-thienylmethyl)-4-methylbenzene 59 (39 mg) was dissolved in 1,4-dioxane (4 ml)-tetrahydrofuran (4 ml), and added thereto was 2N sodium hydroxide (2 ml). The mixture was stirred at room temperature for one hour. The mixture was made acidic by addition of an aqueous citric acid solution, and the mixture was extracted with ethyl acetate. The extract was washed successively with a saturated aqueous sodium hydrogen carbonate solution and brine, and then dried over sodium sulfate. The solvent was evaporated under reduced pressure to give the desired 1-(β-D-glucopyranosyl)-3-(5-(6-fluoro-3-pyridyl)-2-thienylmethyl)-4-methylbenzene 60 (34 mg) as colorless powder. APCI-Mass m/Z 463 (M+NH4).
Reaction SMILES: [S:1]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[S:15])[NH:13][NH2:14])=[CH:7][CH:6]=1)([OH:4])(=[O:3])=[O:2].[Na].[OH:17][C:18]1[CH:27]=[CH:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19]=1[CH:28]=O>>[OH:17][C:18]1[CH:27]=[CH:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19]=1[CH:28]=[N:14][NH:13][C:12]([NH:11][C:8]1[CH:7]=[CH:6][C:5]([S:1]([OH:4])(=[O:2])=[O:3])=[CH:10][CH:9]=1)=[S:15]
Reactant: NNC(=S)Nc1ccc(S(=O)(=O)O)cc1
Reactant: O=Cc1c(O)ccc2ccccc12
Agent: [Na]
Product: O=S(=O)(O)c1ccc(NC(=S)NN=Cc2c(O)ccc3ccccc23)cc1
Yield: 23 %

Procedure:
The procedure described in example 4 was followed here, using 4-(4-sulfophenyl)-3-thiosemicarbazide, sodium salt in place of 4-(naphth-1-yl)thiosemicarbazide and 2-hydroxy-1-naphthaldehyde in place of 2,4,6-trihydroxybenzaldehyde to give the title compound (23%) as a solid. MS (ES−) m/e 400 [M−H]−.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][OH:8])[CH2:3][CH2:2]1.[CH:9](OC)=[O:10].[OH-].[Na+]>ClCCl>[CH:9]([N:1]1[CH2:6][CH2:5][CH:4]([CH2:7][OH:8])[CH2:3][CH2:2]1)=[O:10]
Reactant: COC=O
Reactant: OCC1CCNCC1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: O=CN1CCC(CO)CC1
Reaction time: 1.5 h

Procedure:
4-Piperidinemethanol (10 g, 87 mmol) was dissolved in methyl formate (7 mL, 113 mmol) 0° C., and maintained at that temperature for 30 min, then allowed to reach 20° C. and stirred 90 min. Solid sodium hydroxide was added (0.87 g, pellets) and the mixture was left overnight. Dichloromethane was added, the NaOH removed by filtration and the solution treated with 1M HCl in ether (10 mL). The mixture was filtered through Celite and the solvent was removed under reduced pressure to afford the crude title compound. 1H NMR (400 MHz, CDCl3): 0.85-1.1 (2H, m); 1.55-1.85 (3H, m); 2.5-2.7 (1H, m); 2.95-3.1 (1H, m); 3.3 (2H, d, J 7 Hz); 3.6-3.7 (1H, m); 4.1-4.3 (1H, m); 8 (1H, s).
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6](Br)[CH:7]=1.C([N:16]1[C:24]2[C:19](=[CH:20][C:21]([F:25])=[CH:22][CH:23]=2)[CH:18]=[C:17]1B(O)O)(OC(C)(C)C)=O>>[F:25][C:21]1[CH:20]=[C:19]2[C:24](=[CH:23][CH:22]=1)[NH:16][C:17]([C:6]1[CH:5]=[N:4][CH:3]=[C:2]([F:1])[CH:7]=1)=[CH:18]2
Reactant: Fc1cncc(Br)c1
Reactant: CC(C)(C)OC(=O)n1c(B(O)O)cc2cc(F)ccc21
Product: Fc1cncc(-c2cc3cc(F)ccc3[nH]2)c1

Procedure:
3-Fluoro-5-bromopyridine and N-Boc-5-fluoro-indole-2-boronic acid are processed according to the procedure described in Example 91 to give 5-fluoro-2-(5-fluoro-pyridin-3-yl)-1H-indole. (ESI) m/z 231.04 (M+H)+.