Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]([C:19]([F:22])([F:21])[F:20])[O:8][C:9]2[C:15]([CH:16]=[CH2:17])=[CH:14][C:13]([Cl:18])=[CH:12][C:10]=2[CH:11]=1)=[O:5])=C.[OH-].[Na+]>C1COCC1.C(O)C.O>[Cl:18][C:13]1[CH:14]=[C:15]([CH:16]=[CH2:17])[C:9]2[O:8][CH:7]([C:19]([F:21])([F:20])[F:22])[C:6]([C:4]([OH:5])=[O:3])=[CH:11][C:10]=2[CH:12]=1
Reactant: C=COC(=O)C1=Cc2cc(Cl)cc(C=C)c2OC1C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: C=Cc1cc(Cl)cc2c1OC(C(F)(F)F)C(C(=O)O)=C2
Temperature: 25 °C
Reaction time: 18 h
Yield: 90 %

Procedure:
The ester (Step 1) (0.350 g, 1.05 mmol) was dissolved in a solution of THF:ethanol:water (7:2:1; 10 mL), was treated with sodium hydroxide (0.46 mL, 1.05 mmol of a 2.5 N solution), and stirred at room temperature for 18 hours. The solvent was removed in vacuo and the residue was dissolved in water (10 mL). Diethyl ether (10 mL) was added and the mixture acidified with concentrated HCl. The layers were separated, and the aqueous phase was extracted with diethyl ether (2×10 mL). The organic phases were combined, dried over MgSO4, filtered, and evaporated to yield a yellow solid, which was recrystallized in diethyl ether-hexane to afford the title compound as a yellow solid (0.288 g, 90%): mp 183.2–185.8° C. 1H NMR (CDCl3/300 MHz) 7.77 (s, 1H), 7.49 (d, 1H, J=2.2 Hz), 7.16 (d, 1H, J=2.4 Hz), 6.93 (dd, 1H, J=11.3, 17.7 Hz), 5.82 (d, 1H, J=17.7 Hz), 5.74 (q, 1H, J=6.9 Hz), 5.43 (d, 1H, J=11.1 Hz). FABLRMS m/z 303 (M−H). ESHRMS m/z 303.0014 (M−H, Calc'd. 303.003582). Anal. Calc'd. for C13H8ClF3O3+1.58% H2O: C, 50.44; H, 2.78. Found: C, 50.42; H, 2.65.
Reaction SMILES: [NH:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=O)[C:2]1=[O:3].Cl.[NH2:13][OH:14].C([O-])(=O)C.[Na+]>C(O)C.O>[OH:14][N:13]=[C:4]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[NH:1][C:2]1=[O:3]
Reactant: NO
Reactant: O=C1Nc2ccccc2C1=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=C1Nc2ccccc2C1=NO
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 63.9 %

Procedure:
To a suspension of 73.6 g of isatin in 1.2 l of ethanol was added a solution of 64.1 g of hydroxylamine hydrochloride and 64.1 g of sodium acetate in 500 ml of water. The mixture was stirred at room temperature for 30 minutes and concentrated. The residue was washed with water and recrystallized from ethanol to give 51.8 g (64%) of 3-(hydroxyimino)indolin-2-one as yellow crystals.
Reaction SMILES: [NH2:1][C:2]([CH3:20])([CH3:19])[C:3]([NH:5][C:6]1[S:7][CH:8]=[CH:9][C:10]=1[C:11](=O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:4].C(O)(=O)C>C(O)C>[CH3:19][C:2]1([CH3:20])[C:3](=[O:4])[NH:5][C:6]2[S:7][CH:8]=[CH:9][C:10]=2[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:1]1
Reactant: CC(C)(N)C(=O)Nc1sccc1C(=O)c1ccccc1
Solvent: CCO
Solvent: CC(=O)O
Product: CC1(C)N=C(c2ccccc2)c2ccsc2NC1=O
Yield: 48 %

Procedure:
55 mg of the compound of Example 2 was boiled in ethanol containing acetic acid at reflux. The cyclised title compound was obtained in 48% yield.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][NH:6]2.[O:11]1[CH:16]=[CH:15][CH2:14][CH2:13][CH2:12]1>>[Cl:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH:12]1[CH2:13][CH2:14][CH2:15][CH2:16][O:11]1
Reactant: C1=COCCC1
Reactant: Clc1ncnc2[nH]cnc12
Product: Clc1ncnc2c1ncn2C1CCCCO1

Procedure:
In one embodiment, PG2 is 2-tetrahydropyranyl. In some embodiments, X is selected from fluoro, chloro, bromo, and iodo. In one embodiment, X is chloro. In certain embodiments, the step comprises combining 6-chloro-9H-purine with 3,4-dihydro-2H-pyran to afford 6-chloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purine.
Reaction SMILES: [H-].C([O:4][C:5]([C:7]1[N:8]=[C:9]2[N:17]=[C:16]3[N:11]([CH2:12][CH2:13][CH2:14][CH2:15]3)[N:10]2[CH:18]=1)=O)C.C(O)C.[Cl-].[NH4+]>C1(C)C=CC=CC=1.C1COCC1.C(OCC)(=O)C>[N:8]1[C:7]([CH:5]=[O:4])=[CH:18][N:10]2[N:11]3[C:16]([CH2:15][CH2:14][CH2:13][CH2:12]3)=[N:17][C:9]=12
Reactant: CCOC(=O)c1cn2c(n1)nc1n2CCCC1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: CCO
Product: O=Cc1cn2c(n1)nc1n2CCCC1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 58.4 %

Procedure:
1.01 M Diisobutylalminium hydride in toluene (1.06 mL) was added dropwise to the solution of 4,5,6,7-tetrahydro-1,3a,3b,8-tetraaza-cyclopenta[a]indene-2-carboxylic acid ethyl ester (100 mg) in dry THF (5 mL) at −78° C. under a nitrogen atmosphere. The reaction mixture was stirred for 30 minutes at −78° C. and treated with ethanol (ca. 1 mL). The mixture was warmed to 0° C. and stirred for 1 h at 0° C. The reaction solution was diluted with ethyl acetate (20 mL), treated with 0.5 mL saturated ammonium chloride solution, and sonicated for ca. 5 minutes (until a precipitate was deposited enough). The mixture was dried (Na2SO4) and filtered through a pad of Celite. The filtrate was concentrated under reduced pressure. The residue was crystallized from dichloromethane and diethyl ether to give the title compound (47.4 mg, 58%). 1H-NMR (400 MHz, CDCl3) δ 2.16–2.27 (m, 4H), 3.14 (t, 2H, J=6.1 Hz), 4.39 (t, 2H, J=5.7 Hz), 7.53 (s, 1H), 10.01 (s, 1H).
Reaction SMILES: [C:1]([CH2:3][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5]1)#[N:2].FC(F)(F)C(O)=O.N1C2C(=CC=CC=2)C=C1.B>B.C1COCC1>[C:1]([CH2:3][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5]1)#[N:2]
Reactant: N#CCn1ccc2ccccc21
Agent: B
Agent: c1ccc2[nH]ccc2c1
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: N#CCN1CCc2ccccc21
Reaction time: 1.5 h

Procedure:
In an operation carried out in a manner similar to that described in Example XIV, 105 milligrams of 1-cyanomethyl indole was dissolved in 1.5 milliliters of 1 M BH3.THF under nitrogen. Then, while cooling and stirring in an ice bath, 1.0 milliliter of trifluoroacetic acid was added dropwise to the indole-borane reagent mixture and after completion of the addition, stirring was continued for 1.5 hours while maintaining nitrogen atmosphere to obtain a 1-cyanomethyl-2,3-dihydroindole product in the reaction mixture. The product was recovered by adding first water, then methylene chloride, stirring the mixture (about 15 minutes), making alkaline (pH>9), separating the methylene chloride solution, drying the latter and evaporating the solvent from the dried solution in vacuo.
Reaction SMILES: Cl.O1CCOCC1.[OH:8][C@@H:9]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH2:27][CH:28]2[CH2:32][CH2:31][CH2:30][O:29]2)[CH:21]=1)[CH2:10][CH2:11][NH:12]C(=O)OC(C)(C)C>C(Cl)Cl>[NH2:12][CH2:11][CH2:10][C@H:9]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH2:27][CH:28]2[CH2:32][CH2:31][CH2:30][O:29]2)[CH:21]=1)[OH:8]
Reactant: CC(C)(C)OC(=O)NCC[C@@H](O)c1cccc(OCC2CCCO2)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: NCC[C@@H](O)c1cccc(OCC2CCCO2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
HCl/dioxane (4M, 2.5 mL) was added at 0° C. to a solution of tert-butyl ((3R)-3-hydroxy-3-(3-((tetrahydrofuran-2-yl)methoxy)phenyl)propyl)carbamate (0.25 g, 0.71 mmol) in DCM (10 mL) and the reaction mixture was stirred at room temperature for 2 h. After completion of the reaction the solvent was removed under reduced pressure. Purification by column chromatography (MeOH:DCM with 1% aq. NH4OH, 1-10% gradient) gave Example 14 as a mixture of diastereomers as an off white semi-solid. Yield (0.22 g, 95%); 1H NMR (400 MHz, DMSO-d6): δ 7.20 (t, J=8.0 Hz, 1H), 6.87 (d, J=8.0 Hz, 2H), 6.78-6.76 (m, 1H), 4.64-4.61 (m, 1H), 4.15-4.11 (dd, 1H), 3.93-3.87 (m, 2H), 3.78-3.75 (m, 1H), 3.70-3.64 (m, 1H), 2.69-2.66 (m, 2H), 2.01-1.95 (m, 1H), 1.88-1.79 (m, 2H), 1.70-1.65 (dd, J=6.8 Hz, 3H); MS: m/z 252.14 [M+H]+.
Reaction SMILES: C([Mg]Br)#C.[O:5]1[CH2:9][CH2:8][CH2:7]C1.[F:10][C:11]([F:20])([F:19])[C:12]1[S:13][CH:14]=[C:15](C=O)[N:16]=1.[Cl-].[NH4+]>C(Cl)Cl>[C:8]([CH:9]([C:15]1[N:16]=[C:12]([C:11]([F:20])([F:19])[F:10])[S:13][CH:14]=1)[OH:5])#[CH:7]
Reactant: C1CCOC1
Reactant: O=Cc1csc(C(F)(F)F)n1
Agent: C#C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Product: C#CC(O)c1csc(C(F)(F)F)n1
Reaction time: 0.5 h

Procedure:
11 ml of a molar solution of ethynyl magnesium bromide were added to a solution of tetrahydrofuran (THF) with 2 g of 2-(trifluoromethyl) 4-thiazolecarboxaldehyde and the reaction mixture was stirred for 30 minutes at about 20°-25° C. It was poured into a solution of ammonium chloride and extraction was carried out with methylene chloride. The extracts were dried, filtered and evaporated to dryness to obtain 2.1 g of the desired product.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[C:5]([N+:11]([O-])=O)[CH:4]=1.[N:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20](=O)[CH3:21].[OH-].[K+]>CCO.ClCCl.[Fe].O>[Cl:2][C:3]1[CH:4]=[C:5]2[C:6]([CH:7]=[CH:21][C:20]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][N:14]=3)=[N:11]2)=[CH:9][CH:10]=1
Reactant: CC(=O)c1ccccn1
Reactant: O=Cc1ccc(Cl)cc1[N+](=O)[O-]
Agent: [Fe]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: ClCCl
Solvent: CCO
Product: Clc1ccc2ccc(-c3ccccn3)nc2c1
Temperature: 95 °C
Reaction time: 0.17 h

Procedure:
Iron powder (167 g, 2990 mmol), water (60 mL), and concentrated hydrochloric acid (3 mL, ˜36 mmol) were added consecutively to a solution of 4-chloro-2-nitrobenzaldehyde (55.7 g, 300 mmol) in EtOH (600 mL). After stirred (mechanically) at 95° C. for 10 min, another aliquot of concentrated hydrochloric acid (2 mL, ˜24 mmol) was added. Stirring was continued at 95° C. for another 80 min. 1-Pyridin-2-ylethanone (33 mL, 294.1 mmol) and solid KOH (50.5 g, 900 mmol) were then added in portions with caution. The resulting mixture was stirred at 95° C. for 4 h. After cooled to rt, the reaction was diluted with dichloromethane (500 mL) and filtered through a Celite pad. The filtrate was concentrated to approximately 100 mL. The desired precipitated product was collected by filtration; 1H-NMR (CDCl3, 400 MHz) δ 7.37-7.40 (m, 1H), 7.51 (dd, J=2.0, 8.8 Hz, 1H), 7.79 (d, J=8.4 Hz, 1H), 7.89 (dt, J=1.6, 8.0 Hz, 1H), 8.19 (s, 1H), 8.26 (d, J=8.8 Hz, 1H), 8.57 (d, J=8.8 Hz, 1H), 8.64 (d, J=8.4 Hz, 1H), 8.74-8.75 (m, 1H); MS (ES+): m/z 241 (MH+, 35Cl), 243 (MH+, 37Cl); HPLC: tR=3.95 min (OpenLynx, polar—5 min).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][CH:16]=[CH:15][C:4]=1[CH2:5][NH:6][C:7]1[C:12]([CH2:13][OH:14])=[CH:11][CH:10]=[CH:9][N:8]=1>C(Cl)(Cl)Cl.[O-2].[O-2].[Mn+4]>[CH3:1][O:2][C:3]1[CH:18]=[CH:17][CH:16]=[CH:15][C:4]=1[CH2:5][NH:6][C:7]1[N:8]=[CH:9][CH:10]=[CH:11][C:12]=1[CH:13]=[O:14]
Reactant: COc1ccccc1CNc1ncccc1CO
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: COc1ccccc1CNc1ncccc1C=O
Temperature: 60 °C
Reaction time: 8 h
Yield: 92.8 %

Procedure:
8.03 g (32.9 mmol) of (2-(2-methoxybenzylamino)-3-pyridinyl)methanol was dissolved in chloroform (100 mL), and 8.60 g (98.7 mmol) of manganese dioxide was added thereto. The resulting mixture was stirred overnight at 60° C. The reaction mixture was filtered, and the filtrate was concentrated. Thus, 7.40 g (yield: 93%) of the title compound was obtained as an orange-colored solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([CH2:13][CH2:14][CH:15]=O)[O:10][N:9]=2)=[CH:4][CH:3]=1.[CH3:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:12]=[C:11]([CH2:13][CH2:14][CH2:15][N:28]3[CH2:27][CH2:26][N:25]([C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=4[O:18][CH3:17])[CH2:30][CH2:29]3)[O:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: COc1ccccc1N1CCNCC1
Reactant: O=CCCc1cc(-c2ccc(Cl)cc2)no1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccccc1N1CCN(CCCc2cc(-c3ccc(Cl)cc3)no2)CC1
Yield: 101.4 %

Procedure:
About 2 min after dissolving 3-[3-(4-chlorophenyl)isoxazol-5-yl]propanal (10 mg, 0.04 mmol) and 1-(2-methoxyphenyl)piperazine (16.2 mg, 0.08 mmol) in 2 mL of dry methylene chloride, were added NaBH(OAc)3 (26.7 mg, 0.13 mmol) and molecular sieves (5 beads). The reaction mixture was reacted for 16.5 hr and followed the same processes as in Example 1 to obtain 16.7 mg (96.5%) of the target compound.
Reaction SMILES: [C:1]([O:8][CH2:9][CH:10]([O:17][C:18](=[O:24])[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[C:11](=[N+]=[N-])[C:12](=[O:14])[CH3:13])(=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].CC(C)=[O:27].CC1(C)OO1>CC(C)=O>[C:1]([O:8][CH2:9][CH:10]([O:17][C:18](=[O:24])[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[C:11](=[O:27])[C:12](=[O:14])[CH3:13])(=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCC(=O)OCC(OC(=O)CCCCC)C(=[N+]=[N-])C(C)=O
Reactant: CC(C)=O
Agent: CC1(C)OO1
Product: CCCCCC(=O)OCC(OC(=O)CCCCC)C(=O)C(C)=O
Reaction time: 1 h

Procedure:
To a solution of methyl diazo dihexanoate 10 (38 mg, 0.112 mmol) in acetone (1 mL) was added dimethyldioxirane acetone solution (2.5 mL, ca. 0.07-0.09 M). The resulting mixture was stirred for 1 h and solvent and excess reagents were removed under reduced pressure to obtain 22 as bright yellow oil (yield=36.8 mg, quantitative).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=O)[NH:8][C:7]([NH:14][C:15]1[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=1)=[CH:6]2.O=P(Cl)(Cl)[Cl:23]>>[Cl:23][C:9]1[C:10]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[CH:12][CH:11]=2)[CH:6]=[C:7]([NH:14][C:15]2[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=2)[N:8]=1
Reactant: COc1ccc2c(=O)[nH]c(Nc3cc(C)[nH]n3)cc2c1
Reactant: O=P(Cl)(Cl)Cl
Product: COc1ccc2c(Cl)nc(Nc3cc(C)[nH]n3)cc2c1
Temperature: 150 °C
Reaction time: 2 h
Yield: 68 %

Procedure:
6-Methoxy-3-(5-methyl-1H-pyrazol-3-ylamino)-2H-isoquinolin-1-one (4.7 g, 0.017 mol) and POCl3 (60 ml) were sealed in 3 different bottles (20 ml). The mixture was heated at 150° C. for 15 minutes under microwave irradiation. The mixture was concentrated, and the residue was treated with 15 ml MeOH, stirred for 2 hours at room temperature. The solid was collected and dried to give product (3.4 g, 68% yield). LC-MS: 289 (MH+)
Reaction SMILES: B.CSC.[Br:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=1)[CH:9]=[CH2:10].[OH-:14].[Na+].OO>C1COCC1.O>[Br:5][C:6]1[CH:7]=[C:8]([CH2:9][CH2:10][OH:14])[CH:11]=[CH:12][CH:13]=1
Reactant: [OH-]
Reactant: C=Cc1cccc(Br)c1
Agent: B
Agent: OO
Agent: [Na+]
Solvent: CSC
Solvent: O
Solvent: C1CCOC1
Product: OCCc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Borane-dimethylsulphide complex (2.0M in THF, 49 ml) was added dropwise to a stirred solution of 3-bromostyrene (10 g, 55 mmol) in THF (130 ml) at 0° C. and the solution was stirred for 3 h at room temperature. 10% Aqueous sodium hydroxide was added cautiously, followed by hydrogen peroxide (30% wt. solution in water, 6 ml) dropwise. After a further 16 h, the mixture was diluted with water, extracted twice with ethyl acetate, the combined extracts washed with saturated sodium bisulphite solution and saturated sodium chloride solution, dried over sodium sulphate and evaporated to give a colourless oil. Purification by flash chromatography, eluting with 30% diethyl ether/hexane gave a colourless oil, [M+Si(CH3)3 derivative]+ 272.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.[C:6]([C:9]1[CH:10]=[CH:11][C:12](Br)=[N:13][CH:14]=1)(=[O:8])[CH3:7].C(=O)([O-])[O-].[K+].[K+].[Cl-].[NH4+]>CN(C)C=O.O>[C:6]([C:9]1[CH:10]=[CH:11][C:12]([N:1]2[CH:5]=[N:4][CH:3]=[N:2]2)=[N:13][CH:14]=1)(=[O:8])[CH3:7]
Reactant: CC(=O)c1ccc(Br)nc1
Reactant: c1nc[nH]n1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)c1ccc(-n2cncn2)nc1
Temperature: 100 °C
Yield: 85 %

Procedure:
622 mg (corresponding to 9.00 mmol) of 1H-1,2,4-triazole was dissolved in 10 mL of dimethylformamide. Then, 600 mg (corresponding to 3.00 mmol) of 5-acetyl-2-bromopyridine and 1.24 g (corresponding to 9.00 mmol) of potassium carbonate were added thereto. The resulting solution was heated at 100° C. for 3 hours. After the completion of the reaction, the reaction solution was cooled down to room temperature, supplemented with a saturated ammonium chloride aqueous solution and water, and extracted 3 times with dichloromethane. The combined dichloromethane layer was washed with water and a saturated saline solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (elution solvent: dichloromethane/ethyl acetate=4/1), to obtain 480 mg (corresponding to 2.55 mmol) of 5-acetyl-2-(1H-1,2,4-triazole-1-yl)pyridine (FIG. 4, step 1).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH:8]=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[N:10]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[N+:11]=[N-:12].[O-]CC.[Na+]>O>[N:10]([CH:13]([CH:8]([C:7]1[C:2]([Cl:1])=[N:3][CH:4]=[CH:5][CH:6]=1)[OH:9])[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[N+:11]=[N-:12]
Reactant: CCOC(=O)CN=[N+]=[N-]
Reactant: O=Cc1cccnc1Cl
Agent: CC[O-]
Agent: [Na+]
Solvent: O
Product: CCOC(=O)C(N=[N+]=[N-])C(O)c1cccnc1Cl
Temperature: 0 °C
Reaction time: 2 h
Yield: 74 %

Procedure:
A mixture of 2.0 g of 2-chloro-3-formylpyridine (prepared as described in Preparation 75), 7.5 g of ethyl azidoacetate and 87 ml of a 65 mM ethanolic solution of sodium ethoxide was stirred at 0° C. for 2 hours. At the end of this time, the reaction mixture was poured into water, after which it was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of ammonium chloride and a saturated aqueous solution of sodium chloride, in that order, and dried over anhydrous sodium sulfate, after which the solvent was removed by distillation under reduced pressure. The residue was purified by column chromatography through silica gel, using a 3:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 2.83 g of the title compound having Rf=0.61 (on silica gel thin layer chromatography using a 2:1 by volume mixture of hexane and ethyl acetate as the developing solvent).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].C([O:10][C:11]1[C:20]([CH3:21])=[CH:19][C:18]([CH2:22][CH2:23][CH2:24][O:25][P:26]([O:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:27])=[CH:17][C:12]=1[C:13]([O:15][CH3:16])=[O:14])(=O)C>CO>[CH2:37]([O:36][P:26]([O:25][CH2:24][CH2:23][CH2:22][C:18]1[CH:19]=[C:20]([CH3:21])[C:11]([OH:10])=[C:12]([CH:17]=1)[C:13]([O:15][CH3:16])=[O:14])([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27])[C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1
Reactant: COC(=O)c1cc(CCCOP(=O)(OCc2ccccc2)OCc2ccccc2)cc(C)c1OC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: COC(=O)c1cc(CCCOP(=O)(OCc2ccccc2)OCc2ccccc2)cc(C)c1O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
K2CO3 (108 mg, 0.784 mmol) was added to a stirred solution of methyl 2-(acetyloxy)-5-(3-{[bis(benzyloxy)phosphoryl]oxy}propyl)-3-methylbenzoate (206.3 mg, 0.392 mmol) in MeOH (26.1 mL) at 25° C. The reaction was stirred at 25° C. for 1 h. The reaction mixture was concentrated in vacuo and the resulting residue was partitioned between water (20 mL) and EtOAc (20 mL). The aqueous layer was separated and extracted with EtOAc (2×20 mL). The combined organic extracts were dried (MgSO4) and concentrated in vacuo to afford methyl 5-(3-{[bis(benzyloxy)phosphoryl]oxy}propyl)-2-hydroxy-3-methylbenzoate, as a colorless oil. LCMS calc.=485.2; found=485.0 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[C:19]([OH:20])=[CH:18][C:5]2[S:6][C:7]([C:10]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)=[O:11])=[C:8]([CH3:9])[C:4]=2[CH:3]=1.[N+:21]([O-])([OH:23])=[O:22]>C(OCC)(=O)C>[OH:1][C:2]1[C:19]([OH:20])=[C:18]([N+:21]([O-:23])=[O:22])[C:5]2[S:6][C:7]([C:10]([N:12]3[CH2:13][CH2:14][O:15][CH2:16][CH2:17]3)=[O:11])=[C:8]([CH3:9])[C:4]=2[CH:3]=1
Reactant: O=[N+]([O-])O
Reactant: Cc1c(C(=O)N2CCOCC2)sc2cc(O)c(O)cc12
Solvent: CCOC(C)=O
Product: Cc1c(C(=O)N2CCOCC2)sc2c([N+](=O)[O-])c(O)c(O)cc12

Procedure:
(5,6-Dihydroxy-3-methylbenzo[b]thiophen-2-yl)morpholin-4-yl-methanone (0.10 g) was dissolved to ethyl acetate (60 ml). Nitric acid (2 eq, 2 M solution in dichloromethane) was added in small portions at 55° C. 15 minutes after last addition the mixture was cooled, washed with water, dried with Na2SO4 and concentrated to small volume. The precipitated product was filtered.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([CH:10]3[CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][CH2:11]3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1.C(=O)(O)[O-].[Na+]>ClCCl.FC(F)(F)C(O)=O>[NH:13]1[CH2:12][CH2:11][CH:10]([C:6]2[CH:5]=[C:4]3[C:9](=[CH:8][CH:7]=2)[NH:1][N:2]=[CH:3]3)[CH2:15][CH2:14]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc3[nH]ncc3c2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: c1cc2[nH]ncc2cc1C1CCNCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.8 %

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of tert-butyl 4-(1H-indazol-5-yl)piperidine-1-carboxylate (compound 62.4, 200 mg, 0.60 mmol) in dichloromethane (3 mL) and trifluoroacetic acid (1 mL). The resulting solution was stirred for 1 h at room temperature, then the pH of the solution was carefully adjusted to 8-9 with aqueous sodium bicarbonate (aq. sat.). The mixture was extracted with dichloromethane (3×30 mL) and the combined organic layers were dried (Na2SO4), filtered, and concentrated under reduced pressure to yield the title compounds as a yellow oil (100 mg, 75%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([SH:8])[CH:5]=[CH:6][CH:7]=1.[CH3:9][CH:10]([CH:13]=[CH2:14])[CH2:11]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>ClCCl>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([S:8][CH2:9][CH:10]([CH3:11])[CH:13]=[CH2:14])[CH:3]=1
Reactant: C=CC(C)CO
Reactant: Cc1cccc(S)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: C=CC(C)CSc1cccc(C)c1
Yield: 22 %

Procedure:
A mixture of 3-methylbenzenethiol (1.80 ml, 23.82 mmol), 2-methyl-3-buten-1-ol (2.73 ml, 26.47 mmol) and triphenylphosphine (6.94 g, 26.47 mmol) in dichloromethane (10 ml) was treated with diethyl azodicarboxylate (4.59 ml, 29.12 mmol) at room temperature. The mixture was concentrated in vacuo and dissolved in diethyl ether to remove triphenylphosphine oxide. The organic phase was purified by flash column chromatography on silica, eluting with hexane, to afford the title compound as a clear oil (1.01 g, 20%).
Reaction SMILES: Br[CH2:2][C:3]1[C:11]2[N:10]=[CH:9]N(C(OC(C)(C)C)=O)[C:7]=2[CH:6]=[CH:5][CH:4]=1.[CH2:19]([N:22]([CH:26]([C:32](OCC)=O)[C:27](OCC)=O)[CH2:23]CC)CC>C1COCC1.CCOCC>[CH3:19][N:22]([CH3:23])[CH:26]1[CH2:32][C:7]2[C:11]3=[C:3]([CH:2]=[CH:9][N:10]3[CH2:27]1)[CH:4]=[CH:5][CH:6]=2
Reactant: CC(C)(C)OC(=O)n1cnc2c(CBr)cccc21
Reactant: CCCN(CCC)C(C(=O)OCC)C(=O)OCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: CN(C)C1Cc2cccc3ccn(c23)C1

Procedure:
This compound was prepared by following the procedure of Example 18, but substituting methyl 7-(bromomethyl)-1H-indole-1-carboxylate for t-butyl 4-(bromomethyl)-1H-benzimidazole-1-carboxylate and diethyl (dimethylamino)malonte for diethyl (dipropylamino)malonate. The bulk of the product was converted to the maleate salt, mp 114°-115° C. from THF/ether.