Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1>>[C:3]1([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][S:22]([C:19]1[CH:18]=[CH:17][C:16]([O:15][CH3:14])=[CH:21][CH:20]=1)(=[O:24])=[O:23]
Reactant: Nc1ccccc1-c1ccccc1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Product: COc1ccc(S(=O)(=O)Nc2ccccc2-c2ccccc2)cc1

Procedure:
The title compound was prepared from 2-aminobiphenyl (Aldrich) and 4-methoxy-benzenesulfonyl chloride according to the method described in Example 1b.
Reaction SMILES: C(OCC)C.C(O)(=O)C(O)=O.[CH2:12]([O:15][CH:16]([O:20][CH2:21][CH:22]=[CH2:23])[C:17]([O-:19])=[O:18])[CH:13]=[CH2:14].[Na+]>O>[CH2:21]([O:20][CH:16]([O:15][CH2:12][CH:13]=[CH2:14])[C:17]([OH:19])=[O:18])[CH:22]=[CH2:23]
Reactant: C=CCOC(OCC=C)C(=O)[O-]
Agent: O=C(O)C(=O)O
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: C=CCOC(OCC=C)C(=O)O
Reaction time: 0.17 h
Yield: 93.4 %

Procedure:
100 g of diethyl oxide then a solution of 17.6 g (0.14 mole) of oxalic acid crystallised with two molecules of water in 62 g of water are introduced at ambient temperature and under agitation into an aqueous solution containing 29.1 g (0.15hole) of sodium diallyloxyacetate in 71 g of water. The biphasic medium obtained is agitated vigorously for 10 minutes then it is decanted. The ethereal phase is then dried over anhydrous sodium sulphate, filtered and finally concentrated to dryness under vacuum. In this way 24 g (0.14 mole) of pure diallyloxyacetic acid is obtained. This acid is in the form of an oil, it has a pka of 2.9 and it is soluble in water and in standard organic solvents such as diethyl oxide, dichloromethane; however, in aqueous solution, it hydrolyses.
Reaction SMILES: [C:1]([C:4]1[CH:8]=[C:7]([C:9]([NH:11][C@H:12]([CH3:29])[CH2:13][N:14]2[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[C:23]([F:25])[C:22]([C:26]#[N:27])=[C:21]([F:28])[CH:20]=3)=[N:15]2)=[O:10])[NH:6][N:5]=1)(=[O:3])[CH3:2].[BH4-].[Na+]>>[C:26]([C:22]1[C:23]([F:25])=[CH:24][C:19]([C:16]2[CH:17]=[CH:18][N:14]([CH2:13][C@H:12]([NH:11][C:9]([C:7]3[NH:6][N:5]=[C:4]([CH:1]([OH:3])[CH3:2])[CH:8]=3)=[O:10])[CH3:29])[N:15]=2)=[CH:20][C:21]=1[F:28])#[N:27]
Reactant: CC(=O)c1cc(C(=O)N[C@H](C)Cn2ccc(-c3cc(F)c(C#N)c(F)c3)n2)[nH]n1
Agent: [BH4-]
Agent: [Na+]
Product: CC(O)c1cc(C(=O)N[C@H](C)Cn2ccc(-c3cc(F)c(C#N)c(F)c3)n2)[nH]n1

Procedure:
The title compound was prepared from (R)-3-acetyl-N-(1-(3-(4-cyano-3,5-difluorophenyl)-1H-pyrazol-1-yl)propan-2-yl)-1H-pyrazole-5-carboxamide (90 mg, 0.226 mmol) and sodium tetrahydroborate (17 mg, 0.452 mmol) using the method of Example 84. Yield 41 mg. 1H NMR (400 MHz; CDCl3): δ 1.57 (d, 3H), 1.59 (d, 3H), 4.26 (m, 1H), 4.45 (m, 1H), 4.58 (m, 1H), 5.06 (q, 1H), 6.61 (m, 2H), 7.50 (d, 1H), 7.58 (m, 2H), 7.73 (bs, 1H), 10.44 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[C:11]2[O:10][C:9]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)=[CH:8][C:7](=[O:18])[C:6]=2[CH:5]=[CH:4][C:3]=1[O:19]CC1C=CC=CC=1.C1CCCCC=1>C(OCC)(=O)C.[Pd]>[OH:19][C:3]1[CH:4]=[CH:5][C:6]2[C:7](=[O:18])[CH:8]=[C:9]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[O:10][C:11]=2[C:2]=1[CH3:1]
Reactant: Cc1c(OCc2ccccc2)ccc2c(=O)cc(N3CCOCC3)oc12
Agent: [Pd]
Solvent: C1=CCCCC1
Solvent: CCOC(C)=O
Product: Cc1c(O)ccc2c(=O)cc(N3CCOCC3)oc12
Yield: 73.9 %

Procedure:
Part A: 8-Methyl-2-(4-morpholinyl)-7-(phenylmethoxy)-4H-1-benzopyran-4-one (8.59 g, 24.4 mmol.) is suspended in 250 ml of ethyl acetate. 9.9 ml of cyclohexene is added followed by 0.85 g of 10% Palladium on carbon. The mixture is heated at reflux for 18 hours. The reaction is allowed to cool and filtered, the solid is taken up in methanol, decanted and filtered. The methanol is evaporated to give 4.71 g (74%) of the phenol (mp>250° C.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]2[C:7](=[O:10])[CH2:8][O:9][C:5]=2[C:4]=1/[CH:13]=[CH:14]/[CH2:15][CH:16]1[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]1.[NH:29]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:31]([CH:38]=O)=[N:30]1.N1CCCCC1>CO>[NH:29]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:31](/[CH:38]=[C:8]2\[O:9][C:5]3[C:4](/[CH:13]=[CH:14]/[CH2:15][CH:16]4[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]4)=[C:3]([O:2][CH3:1])[CH:12]=[CH:11][C:6]=3[C:7]\2=[O:10])=[N:30]1
Reactant: COc1ccc2c(c1/C=C/CC1CCN(C(=O)OC(C)(C)C)CC1)OCC2=O
Reactant: O=Cc1n[nH]c2ccccc12
Solvent: CO
Solvent: C1CCNCC1
Product: COc1ccc2c(c1/C=C/CC1CCN(C(=O)OC(C)(C)C)CC1)O/C(=C\c1n[nH]c3ccccc13)C2=O
Temperature: 60 °C
Reaction time: 2 h
Yield: 74 %

Procedure:
A solution of tert-butyl (E)-4-[3-(6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl)allyl]piperidine-1-carboxylate (0.0313 g, 0.0807 mmol) in methanol (3 mL) was added with 1H-indazole-3-carboxaldehyde (0.0118 g, 0.0807 mmol) and piperidine (0.0800 mL, 0.810 mmol), and the mixture was stirred at 60° C. for 2 hours. The reaction mixture was concentrated, and the resulting residue was purified by silica gel column chromatography (chloroform/methanol) to obtain tert-butyl 4-((E)-3-{(Z)-2-[(1H-indazol-3-yl)methylene]-6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl}allyl)piperidine-1-carboxylate (0.0308 g, 74%).
Reaction SMILES: [C:1]1([N:7]2[C:19]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:13]3[C:8]2=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:20]N1C(=O)CCC1=O.C1(C)C=CC=CC=1>C(OCC)(=O)C>[Br:20][C:16]1[CH:17]=[CH:18][C:19]2[N:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:8]3[C:13]([C:14]=2[CH:15]=1)=[CH:12][CH:11]=[CH:10][CH:9]=3
Reactant: O=C1CCC(=O)N1Br
Reactant: c1ccc(-n2c3ccccc3c3ccccc32)cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Brc1ccc2c(c1)c1ccccc1n2-c1ccccc1

Procedure:
In a 1 L conical flask, 24 g (100 mmol) of 9-phenyl-9H-carbazole, 18 g (100 mmol) of N-bromosuccinimide, 450 mL of toluene, and 200 mL of ethyl acetate were stirred at room temperature for 45 hours. This suspension was washed with water, and magnesium sulfate was added thereto, so that moisture was removed. This suspension was filtered, and the obtained filtrate was concentrated and dried. The amount and yield of a solid, which was the substance to be produced, were 32 g and 99%, respectively.
Reaction SMILES: [CH2:1]([C:3]1[NH:4][C:5]2[C:6]([N:12]=1)=[N:7][CH:8]=[CH:9][C:10]=2[CH3:11])[CH3:2].ClC1C=CC=C(C(OO)=[O:21])C=1>C(Cl)(Cl)Cl>[CH2:1]([C:3]1[NH:4][C:5]2[C:6]([N:12]=1)=[N+:7]([O-:21])[CH:8]=[CH:9][C:10]=2[CH3:11])[CH3:2]
Reactant: CCc1nc2nccc(C)c2[nH]1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: CCc1nc2c([nH]1)c(C)cc[n+]2[O-]
Yield: 96.6 %

Procedure:
A solution of 2-ethyl-7-methylimidazo[4,5-b]pyridine (28 g, 174 mmol) and m-chloroperbenzoic acid (80-90%, 44.6 g) in CHCl3 (300 mL) was heated at reflux for 0.5 hours. The mixture was concentrated and purified (SiO2, 100% CH2Cl2 gradient to 30% CH2Cl2 /MeOH) to give 29.8 g of 2-ethyl-7-methylimidazo[4,5-b]pyridine-4-oxide as a solid. 1H NMR (300 MHz, CD3OD) δ8.13 (d, 1H, J=6 Hz), 7.13 (d, 1H, J=6 Hz), 3.01 (q, 2H, J=7.5 Hz), 2.60 (s, 3H), 1.46 (t, 3H, J=7.5 Hz). A mixture of the N-oxide (29.75 g, 0.168 mol), CHCl3 (25 mL) and POCl3 (160 mL) was heated to 80° C. for 1 hours. After pouring over ice, the mixture was neutralized by careful addition of NH4OH and extracted with EtOAc. Concentration gave 23.8 g of 5-chloro-2-ethyl-7-methylimidazo[4,5-b]pyridine as a solid. 1H NMR (250 MHz, CDCl3) δ7.07 (s, 1H) 3.10 (q, 2H, J=7.5 Hz), 2.67 (s, 3H), 1.48 (t, 3H, J=7.5 Hz).
Reaction SMILES: [S:1](Cl)(Cl)=O.[C:5]([OH:15])(=[O:14])[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.N1C=CC=CC=1>>[S:1]1[C:13]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[CH:7]=[C:6]1[C:5]([OH:15])=[O:14]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)CCc1ccccc1
Solvent: c1ccncc1
Product: O=C(O)c1cc2ccccc2s1
Temperature: 150 °C
Reaction time: 3 h

Procedure:
Thionyl chloride (5 eq.) was added dropwise to a round-bottom flask containing a mixture of hydrocinnamic acid (1 eq.) and pyridine (0.1 eq.) heated to 150° C. TLC after 3 h showed complete consumption of starting material. The reaction mixture was cooled to it and water (10 vol), 35% HCl (1 vol.), and THF (15 vol) were added and the mixture heated at 60° C. for 30 minutes. After 30 minutes, the THF was removed in vacuo and the obtained precipitate was filtered, dissolved in a 3:1 water:ethanol mixture (20 vol) and heated at 90° C. for 1 hr. After 1 h, the solution was cooled to it and allowed to stir overnight. The separated solid was filtered and recrystallized from toluene to get the corresponding benzothiophene-2-carboxylic acid. The results for various substituted chlorobenzothiophene carboxylic acids are given in Table 1.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([NH:12][NH:13][C:14](=O)[C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH2:26][C@H:25]([CH3:27])[O:24][C@H:23]([CH3:28])[CH2:22]3)=[CH:17][CH:16]=2)=O)=[CH:6][CH:5]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:32].O.[OH-].[Na+]>C(COC)OC>[CH3:1][O:2][C:3](=[O:30])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[S:32][C:14]([C:15]3[CH:20]=[CH:19][C:18]([N:21]4[CH2:26][C@H:25]([CH3:27])[O:24][C@H:23]([CH3:28])[CH2:22]4)=[CH:17][CH:16]=3)=[N:13][N:12]=2)=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(C(=O)NNC(=O)c2ccc(N3C[C@@H](C)O[C@@H](C)C3)cc2)cc1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: COCCOC
Product: COC(=O)c1ccc(-c2nnc(-c3ccc(N4C[C@@H](C)O[C@@H](C)C4)cc3)s2)cc1
Temperature: 25 °C
Yield: 128.9 %

Procedure:
To a solution of 4-[N′-[4-(cis-2,6-dimethylmorpholin-4-yl)benzoyl]hydrazinocarbonyl]benzoic acid methyl ester (100 mg) in dimethoxyethane (3 ml) was added phosphorus pentasulfide (82 mg). The mixture was refluxed for 5 hours. After cooling to ambient temperature, the reaction mixture was poured into cold water and the mixture was adjusted to pH 11 with 1N-sodium hydroxide aqueous solution. The resulting precipitates were filtered, washed with water and dried to give 4-[5-[4-(cis-2,6-dimethylmorpholin-4-yl)phenyl][1,3,4]thiadiazol-2-yl]benzoic acid methyl ester (97.4 mg).
Reaction SMILES: [ClH:1].[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([NH:19][C:20]([C:22]2[N:26]3[CH:27]=[CH:28][CH:29]=[C:30]([O:31][CH2:32][C:33]4[C:38]([F:39])=[CH:37][CH:36]=[CH:35][C:34]=4[F:40])[C:25]3=[N:24][C:23]=2[CH3:41])=[O:21])[CH2:10][NH:11]C(=O)OC(C)(C)C)=[CH:5][CH:4]=1>C(OCC)C>[ClH:2].[ClH:1].[NH2:11][CH2:10][CH:9]([NH:19][C:20]([C:22]1[N:26]2[CH:27]=[CH:28][CH:29]=[C:30]([O:31][CH2:32][C:33]3[C:38]([F:39])=[CH:37][CH:36]=[CH:35][C:34]=3[F:40])[C:25]2=[N:24][C:23]=1[CH3:41])=[O:21])[C:6]1[CH:5]=[CH:4][C:3]([Cl:2])=[CH:8][CH:7]=1
Reactant: Cc1nc2c(OCc3c(F)cccc3F)cccn2c1C(=O)NC(CNC(=O)OC(C)(C)C)c1ccc(Cl)cc1
Agent: Cl
Solvent: CCOCC
Product: Cc1nc2c(OCc3c(F)cccc3F)cccn2c1C(=O)NC(CN)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 5.5 h

Procedure:
3.5 ml (7.0 mmol) of a 2 M solution of hydrochloric acid in diethyl ether were added to 396 mg of rac-tert-butyl {2-(4-chlorophenyl)-2-[({8-[(2,6-difluorobenzyl)oxy]-2-methylimidazo[1,2-a]-pyridin-3-yl}carbonyl)amino]ethyl}carbamate (Example 78A, 0.69 mmol), and the mixture was stirred at RT for 5.5 h. The resulting precipitate was filtered off, washed with diethyl ether and dried under high vacuum. This gave 341 mg of the title compound (90% of theory).
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Cl:11][C:12]1[CH:13]=[C:14](Cl)[C:15]2[N:16]([CH:18]=[C:19]([CH3:21])[N:20]=2)[CH:17]=1.Cl>CN(C)C=O>[ClH:11].[CH2:3]([O:10][C:14]1[C:15]2[N:16]([CH:18]=[C:19]([CH3:21])[N:20]=2)[CH:17]=[C:12]([Cl:11])[CH:13]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: OCc1ccccc1
Reactant: Cc1cn2cc(Cl)cc(Cl)c2n1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cn2cc(Cl)cc(OCc3ccccc3)c2n1
Temperature: -40 °C
Reaction time: 2 h

Procedure:
1.8 g commercial 80% sodium hydride in paraffin is added in small portions at room temperature to 5.4 ml benzyl alcohol dissolved in 300 ml dry dimethylformamide. The benzylate solution is stirred for a further 2 hours. Thereafter it is cooled to -40° C., mixed with 10.0 g 6,8-dichloro-2-methyl-imidazo[1,2-a]pyridine and stirred for a further 4 hours. The temperature is allowed to rise gradually to 12° C. and the mixture is stirred at this temperature for 48 hours. Thereafter the solution is poured onto 1.5 kg icewater, the solution brought to pH=7 with 1 N-HCl and extracted 3×with 100 ml ethyl acetate each time. The combined extracts are dried with sodium sulfate and evaporated to dryness on the rotary evaporator. After dissolution in 100 ml 2-propanol, the title compound is precipitated by addition of saturated HCl-ether solution. After the precipitate has been filtered off under suction, it is recrystallized twice from isopropanol, 4.5 g of the title compound of m.p. 180°-182° C. being obtained.
Reaction SMILES: [CH3:1][NH:2][S:3]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[CH2:9]2)(=[O:5])=[O:4].C[N:17]1[CH2:22][CH2:21][C:20]2=[C:23]([CH:26]=O)[NH:24][CH:25]=[C:19]2[C:18]1=[O:28].N1CCCCC1>C(O)C>[CH3:1][NH:2][S:3]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[C:9]2=[CH:26][C:23]1[NH:24][CH:25]=[C:19]2[C:20]=1[CH2:21][CH2:22][NH:17][C:18]2=[O:28])(=[O:5])=[O:4]
Reactant: CN1CCc2c(c[nH]c2C=O)C1=O
Reactant: CNS(=O)(=O)c1ccc2c(c1)CC(=O)N2
Solvent: C1CCNCC1
Solvent: CCO
Product: CNS(=O)(=O)c1ccc2c(c1)C(=Cc1[nH]cc3c1CCNC3=O)C(=O)N2
Temperature: 80 °C

Procedure:
A mixture of 2-oxo-2,3-dihydro-1H-indole-5-sulfonic acid methylamide (45.2 mg, 0.2 mmol), 5-methyl-4-oxo-4,5,6,7-tetrahydro-2H-pyrrolo[3,4-c]pyridine-1-carbaldehyde (35.6 mg, 0.2 mmol) and piperidine (0.1 mL) in ethanol (1 mL) was heated at 80° C. for 4 hours. The precipitate was collected by vacuum filtration, washed with ethanol and dried to give the title compound.
Reaction SMILES: [C:1]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH:8]=[CH:9][C:10](Cl)=[O:11].O1CCC[CH2:20]1.C[Mg]Br>C1(C)C=CC=CC=1>[C:1]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH:8]=[CH:9][C:10](=[O:11])[CH3:20]
Reactant: O=C(Cl)C=CCc1ccccc1-c1ccccc1
Reactant: C1CCOC1
Agent: C[Mg]Br
Solvent: Cc1ccccc1
Product: CC(=O)C=CCc1ccccc1-c1ccccc1
Temperature: -30 °C
Reaction time: 0.5 h

Procedure:
10.0 g. (0.039 mole) of crude acid chloride from Example 5, Step (c), is dissolved in 200 ml. of dry tetrahydrofuran and the solution placed in a 500 ml. round bottom flask fitted with a septum inlet and magnetic stirrer, and held under a nitrogen atmosphere. The solution is cooled to -30° C. in a dry ice/isopropanol bath and 19.5 ml (0.039 mole) of a commercial 2M methyl magnesium bromide solution in dry toluene is added, dropwise, over 30 minutes. After the addition is complete, the mixture is allowed to warm to room temperature and then stirred for 1 hour. The reaction is quenched by the addition of 20 ml. of saturated ammonium chloride solution and the organic layer is separated. The aqueous layer is extracted twice with 20 ml. portions of ether and the combined organic extracts are then dried over anhydrous magnesium sulphate and evaporated to yield the heading compound, m.p. 130° to 133° C., after recrystallization from petroleum ether.
Reaction SMILES: [N:1]([CH2:4][C:5]1[O:6][CH:7]=[C:8]([OH:12])[C:9](=[O:11])[CH:10]=1)=[N+:2]=[N-:3].[OH-].[Na+].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CO>[N:1]([CH2:4][C:5]1[O:6][CH:7]=[C:8]([O:12][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:9](=[O:11])[CH:10]=1)=[N+:2]=[N-:3]
Reactant: BrCc1ccccc1
Reactant: [N-]=[N+]=NCc1cc(=O)c(O)co1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: [N-]=[N+]=NCc1cc(=O)c(OCc2ccccc2)co1
Temperature: 25 °C
Reaction time: 1 h
Yield: 55.7 %

Procedure:
To a stirred solution of 2-azidomethyl-5-hydroxy-pyran-4-one (3) (70.0 g, 419.1 mmol) in methanol (500 mL) was added NaOH (20 g, 502.9 mmol, 2M) and benzyl bromide (60.14 mL, 502.9 mmol) and the reaction mixture was stirred at room temperature for 1 h. After completion of the reaction, solvent was evaporated to remove volatile compounds under reduce pressure, then it was diluted with water and extracted with ethyl acetate. Then the combined organic layer was washed with water and brine, dried over Na2SO4, concentrated under reduced pressure and purified using normal column chromatography (using 20% ethyl acetate in hexane) to get 2-azidomethyl-5-benzyloxy-pyran-4-one (4) (60.0 g, 55.0%) as a light brown solid.
Reaction SMILES: C([O:8][CH2:9][CH2:10][C@@H:11]1[CH2:14][C@H:13]([N:15]2[CH:23]=[N:22][C:21]3[C:16]2=[N:17][CH:18]=[N:19][C:20]=3[NH2:24])[CH2:12]1)C1C=CC=CC=1.B(Cl)(Cl)Cl.N.CO>C(Cl)Cl>[OH:8][CH2:9][CH2:10][C@@H:11]1[CH2:14][C@H:13]([N:15]2[CH:23]=[N:22][C:21]3[C:16]2=[N:17][CH:18]=[N:19][C:20]=3[NH2:24])[CH2:12]1
Reactant: Nc1ncnc2c1ncn2[C@H]1C[C@@H](CCOCc2ccccc2)C1
Agent: ClB(Cl)Cl
Agent: N
Solvent: ClCCl
Solvent: CO
Product: Nc1ncnc2c1ncn2[C@H]1C[C@@H](CCO)C1
Temperature: -78 °C
Yield: 57.9 %

Procedure:
In a 10 mL flask with 9-[cis-3-(benzyloxyethyl)cyclobutyl]adenine (0.24 g, 0.74 mmol) inside, dry CH2Cl2 5 mL was added. After cooling to −78° C., BCl3 (1.0 M in CH2Cl2, 2.2 mL, 2.22 mmol) was added drop by drop. This was allowed to warm up to 0° C. and after 6 hr, the reaction was quenched by adding 7 N NH3 in MeOH (2.6 mL, 18.3 mmol) and the solvent was removed by rotovap. The crude material was applied directly to silica gel flash chromatography to give the desired product 0.1 g (58%). 1H NMR (CD3OD, 300 MHz): δ 1.75-1.84 (m, 2H), 2.27-2.44 (m, 3H), 2.71-2.80 (m, 2H), 3.56-3.62 (m, 2H), 4.82-4.95 (m, 1H), 8.22 (s, 1H), 8.30 (s, 1H). MS (FAB): expected for C11H15N5O (M+H)+ 234.27. Found 234.13489. IR (neat) νmax 3327, 3184, 2929, 1648, 1600, 1574, 1477, 1416, 1333, 1305, 1248, 1045, 798, 720, 648.
Reaction SMILES: [Cl:1][C:2]1[N:7]2[N:8]=[C:9]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[C:10]([C:11](=O)[C:12]#[CH:13])=[C:6]2[CH:5]=[CH:4][CH:3]=1.Cl.[C:23]([NH2:31])(=[NH:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[O-]CC.[Na+]>C(O)C.O>[Cl:1][C:2]1[N:7]2[N:8]=[C:9]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[C:10]([C:11]3[CH:12]=[CH:13][N:31]=[C:23]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[N:30]=3)=[C:6]2[CH:5]=[CH:4][CH:3]=1
Reactant: N=C(N)c1ccccc1
Reactant: C#CC(=O)c1c(-c2ccc(F)cc2)nn2c(Cl)cccc12
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Fc1ccc(-c2nn3c(Cl)cccc3c2-c2ccnc(-c3ccccc3)n2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 70.7 %

Procedure:
To a suspension of 1-[7-chloro-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridin-3-yl]-2-propyn-1-one (36 mg, 0.12 mmol) and benzamidine hydrochloride (25 mg, 0.16 mmol) in ethanol (500 μL) was added sodium ethoxide (52 μL, 3 M in ethanol, 0.16 mmol). The reaction mixture was stirred at room temperature 16 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and brine, then dried over magnesium sulfate. Filtration and concentration, followed by flash chromatography (3:1 hexanes-ethyl acetate) provided 7-chloro-2-(4-fluorophenyl)-3-(2-phenylpyrimidin-4-yl)pyrazolo[1,5-α]pyridine (34 mg, 71%). Rf 0.36 (3:1 hexanes-ethyl acetate); 1H NMR (CDCl3) δ 8.60–8.56 (m, 2H), 8.52–8.48 (m, 2H), 7.67 (m, 2H), 7.56–7.52 (m, 3H), 7.39 (m, 1H), 7.22–7.11 (m, 3H), 6.93 (d, 1H); 19F NMR (CDCl3) δ −112.30; MS m/z 401 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:20][CH3:21])=[C:4]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][CH:12]=3)[NH:8][C:5]2=[N:6][CH:7]=1>CO>[Cl:1][C:2]1[C:3]([O:20][CH3:21])=[C:4]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: COc1c(Cl)cnc2[nH]c(-c3ccc([N+](=O)[O-])cc3)nc12
Solvent: CO
Product: COc1c(Cl)cnc2[nH]c(-c3ccc(N)cc3)nc12

Procedure:
6-Chloro-7-methoxy-2-(4-nitrophenyl)-3H-imidazo[4,5-b]pyridine (0.56 g, 1.8 mmol) was dissolved in methanol (30 ml). (NH4)2S (20% in water, 5 ml, 15 mmol) was added and the mixture was heated to reflux for 5 h. The methanol was removed under reduced pressure and the resulting precipitate was filtered off and washed with ice-cold water giving 0.486 g (96%) of the subtitle compound.
Reaction SMILES: O.[C:2]1([OH:10])[CH:9]=[C:7]([CH3:8])[CH:6]=[C:4]([OH:5])[CH:3]=1.[F:11][C:12]([F:25])([F:24])[O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[S:20](Cl)(=[O:22])=[O:21]>C([O-])(O)=O.[Na+].C(OCC)C.O>[CH3:8][C:7]1[CH:9]=[C:2]([O:10][S:20]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[O:13][C:12]([F:11])([F:24])[F:25])(=[O:22])=[O:21])[CH:3]=[C:4]([OH:5])[CH:6]=1
Reactant: Cc1cc(O)cc(O)c1
Reactant: O=S(=O)(Cl)c1ccccc1OC(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: Cc1cc(O)cc(OS(=O)(=O)c2ccccc2OC(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.4 %

Procedure:
Orcinol monohydrate (1.42 g, 10.0 mmol) and 2-trifluoromethoxybenzenesulfonyl chloride (2.35 g, 9.0 mmol) were mixed in saturated aqueous NaHCO3 (30 mL) and diethyl ether (30 mL). The biphasic mixture was stirred vigorously at ambient temperature overnight. The reaction mixture was diluted with water (50 mL) and extracted into ethyl acetate (3×50 mL). The organic phase was washed with brine (2×50 mL) and dried over Na2SO4. After removing the solvent in vacuo, the residue was purified by flash column chromatography (dichloromethane to 5% ethyl acetate in dichloromethane) to give the title compound as a yellow oil (1.80 g, 57%). 1H-NMR (300 MHz, CDCl3) δ 7.96 (d, J=7.9 Hz, 1H), 7.72 (t, J=7.8 Hz, 1H), 7.50 (d, J=8.1 Hz, 1H), 7.40 (t, J=7.8 Hz, 1H), 6.55 (s, 1H), 6.52 (s, 1H), 6.41 (s, 1H), 5.04 (s, 1H); 2.23 (s, 3H).
Reaction SMILES: Cl[C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[CH:5]=[C:4]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=2)[N:3]=1.[F:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[CH:24][CH:23]=1.C(N(C(C)C)CC)(C)C>CC(O)C>[CH3:20][O:19][C:13]1[CH:12]=[C:11]([C:4]2[N:3]=[C:2]([N:31]3[CH2:30][CH2:29][N:28]([C:25]4[CH:24]=[CH:23][C:22]([F:21])=[CH:27][CH:26]=4)[CH2:33][CH2:32]3)[N:7]3[CH:8]=[CH:9][N:10]=[C:6]3[CH:5]=2)[CH:16]=[CH:15][C:14]=1[O:17][CH3:18]
Reactant: Fc1ccc(N2CCNCC2)cc1
Reactant: COc1ccc(-c2cc3nccn3c(Cl)n2)cc1OC
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(-c2cc3nccn3c(N3CCN(c4ccc(F)cc4)CC3)n2)cc1OC
Temperature: 25 °C
Yield: 64.6 %

Procedure:
The mixture of 5-chloro-7-(3,4-dimethoxyphenyl) imidazo[1,2-c]pyrimidine (57.94 mg, 0.2 mmol), 1-(4-fluorophenyl)piperazine.2HCl (55.69 mg, 0.22 mmol), and diisopropylethylamine (85.31 mg, 0.66 mmol) in 3 ml of 2-propanol was stirred at 90° C. for 3 h, and cooled to room temperature. To the obtained mixture, 3 ml of ice water was added, the produced white solid was collected by filtration, and dried to give the pure product (56 mg, 64.6%) of 7-(3,4-Dimethoxyphenyl)-5-[4-(4-fluorophenyl)piperazin-1-yl]-imidazo[-1,2-c]pyrimidine.
Reaction SMILES: O[CH:2]([C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][CH:28]=1)[NH:25][C:24](=[O:29])[CH2:23][CH2:22]2)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[O:17][CH3:18])[CH2:7][CH2:6]1.Cl.[OH-].[Na+]>O1CCOCC1>[CH3:18][O:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[N:8]1[CH2:9][CH2:10][N:5]([CH2:4][CH:3]=[CH:2][C:19]2[CH:20]=[C:21]3[C:26](=[CH:27][CH:28]=2)[NH:25][C:24](=[O:29])[CH2:23][CH2:22]3)[CH2:6][CH2:7]1
Reactant: COc1ccccc1N1CCN(CCC(O)c2ccc3c(c2)CCC(=O)N3)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: COc1ccccc1N1CCN(CC=Cc2ccc3c(c2)CCC(=O)N3)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2.8 Grams of 6-{1-hydroxy-3-[4-(2-methoxyphenyl)-1-piperazinyl]propyl}-3,4-dihydrocarbostyril was dissolved in 100 ml of dioxane and 5 ml of concentrated hydrochloric acid was added thereto, then the mixture was refluxed for 15 minutes. The reaction mixture was concentrated under a reduced pressure to dryness to obtain a residue. To the residue were added 10N-NaOH and further and stirred at a room temperature for 30 minutes to precipitates crystals. The crystals were colected by filtration, washed with ether then recrystallized from ethanol-chloroform-acetone to obtain 6-{3-[4-(2-methoxyphenyl)-1-piperazinyl]-1-propenyl}-3,4-dihydrocarbostyril in colorless needle-like crystals. Yield: 2.3 g.