Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O1CCCC1.[S:6]1[CH2:11][CH2:10][CH2:9][S:8][CH2:7]1.C([Li])CCC.[C:17]([C:25]1[CH:33]=[CH:32][CH:31]=[C:30]2[C:26]=1[CH2:27][CH2:28][C:29]2=[O:34])(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CCCCCC>[C:17]([C:25]1[CH:33]=[CH:32][CH:31]=[C:30]2[C:26]=1[CH2:27][CH2:28][C:29]2([CH:7]1[S:8][CH2:9][CH2:10][CH2:11][S:6]1)[OH:34])(=[O:24])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=C1CCc2c1cccc2C(=O)c1ccccc1
Reactant: C1CSCSC1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=C(c1ccccc1)c1cccc2c1CCC2(O)C1SCCCS1
Temperature: -20 °C
Reaction time: 0.5 h

Procedure:
In 100 ml. of dry tetrahydrofuran is dissolved 3.6 g. of 1,3-dithian and while the solution is chilled to -30°C in nitrogen gas streams and stirred, 10 ml. of a 20 % solution of n-butyl lithium in hexane is added dropwise over a period of about 15 minutes. After the dropwise addition has been completed, the solution is stirred at that temperature for 2 hours and, then, at -5°C for 30 minutes. The solution is chilled again to -20°C and, under stirring, a solution of 7.1 g. of 4-benzoylindan-1-one in 75 ml. of dry tetrahydrofuran is added dropwise. After the dropwise addition has been completed, the mixture is stirred at that temperature for 1 hour, after which it is allowed to stand at 0°C overnight. Then, the solvent is distilled off undr reduced pressure. To the residue is added 15 ml. of dilute hydrochloric acid, followed by extraction with ether. The extract is washed with water and aqueous sodium chloride and, then, dried. The solvent is distilled off under reduced pressure and the residue is purified by column chromatography on silica gel (500 g. silica gel, eluted with a 20:1 mixture of benzene and ethyl acetate). The described procedure gives 2-(4-benzoyl-1-hydroxy-1-indanyl)-1,3-dithian as an oily product. The infrared absorption spectrum (neat) of this product is in good agreement with the assumed structure, absorbing at 1660 cm-1 (ketone) and 3450 cm-1 (hydroxyl).
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][O:4][CH2:3]1.[Br:7][CH2:8][C:9](Br)=[O:10].N1C=CC=CC=1.C(C1OC1)Cl>C1C=CC=CC=1>[Br:7][CH2:8][C:9]([O:1][CH:2]1[CH2:6][CH2:5][O:4][CH2:3]1)=[O:10]
Reactant: OC1CCOC1
Reactant: O=C(Br)CBr
Solvent: c1ccccc1
Solvent: ClCC1CO1
Solvent: c1ccncc1
Product: O=C(CBr)OC1CCOC1
Reaction time: 1 h

Procedure:
In a four-neck, 2-liter flask, 42.5 g (0.48 mole) 3-hydroxy tetrahydrofuran was dissolved in 600 ml benzene. The resultant solution was cooled to below 20°C in an ice-water bath. 135.3 g (58.4 ml, 0.67 mole) bromoacetyl bromide was then added to the solution. 75.9 g (77.6 ml, 0.96 mole) pyridine was added dropwise to the solution over a 30-minute period. When the addition was complete, stirring was continued for 1 hour at the above temperature. The reaction mixture was then removed from the cooling bath and allowed to come to room temperature. The solution was first washed with 350 ml of water, then with 100 ml 1N HCl, and finally with 100 ml saturated NaHCO3 solution. The remaining benzene solution was dried with MgSO4 and filtered. The benzene solvent was removed by evaporation in vacuo, leaving the product oil. The yield was 70.1 g, or 69.9% of the theoretical yield of 100.3 g. The refractive index of the product was nD30 = 1.5022. The structure of the product was confirmed by spectral evidence. Epichlorohydrin (1% by weight) was added as a stabilizer.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:9][C:10]([C:12]2[C:17]([NH:18][C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)=[CH:16][CH:15]=[C:14]([CH3:25])[N:13]=2)=[O:11])=[N:6][C:7]=1[CH3:8].Br[C:27]1C=NC=CC=1C>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:9][C:10]([C:12]2[C:17]([NH:18][C:19]3[CH:20]=[N:21][CH:22]=[CH:23][C:24]=3[CH3:27])=[CH:16][CH:15]=[C:14]([CH3:25])[N:13]=2)=[O:11])=[N:6][C:7]=1[CH3:8]
Reactant: Cc1ccc(Nc2cccnc2)c(C(=O)Nc2ccc(F)c(C)n2)n1
Reactant: Cc1ccncc1Br
Product: Cc1ccc(Nc2cnccc2C)c(C(=O)Nc2ccc(F)c(C)n2)n1

Procedure:
The title compound, was prepared from 3-Amino-6-methyl-pyridine-2-carboxylic acid (5-fluoro-6-methyl-pyridin-2-yl)-amide (example 11) and 3-Bromo-4-methylpyridine in accordance with the general method of example 20 to yield the final compound as a light yellow crystalline solid, MS (ISP): m/e=352.0 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[N:7]2[N:8]=[C:9]([CH2:11][P+](C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[N:10]=[C:6]2[C:5]([CH3:31])=[CH:4][CH:3]=1.[C:32]1([C:38]2[N:39]=[C:40]([CH:43]=O)[NH:41][CH:42]=2)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[CH3:1][C:2]1[N:7]2[N:8]=[C:9]([CH:11]=[CH:43][C:40]3[NH:41][CH:42]=[C:38]([C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=4)[N:39]=3)[N:10]=[C:6]2[C:5]([CH3:31])=[CH:4][CH:3]=1
Reactant: O=Cc1nc(-c2ccccc2)c[nH]1
Reactant: Cc1ccc(C)n2nc(C[P+](c3ccccc3)(c3ccccc3)c3ccccc3)nc12
Product: Cc1ccc(C)n2nc(C=Cc3nc(-c4ccccc4)c[nH]3)nc12

Procedure:
One example of a synthetic route for the synthesis of the PET-preursor compound of formula IIa is shown in scheme 4: The (5,8-Dimethyl-[1,2,4]triazolo[1,5-a]pyridin-2-ylmethyl)-triphenylphosphonium salt 1 is coupled under basic conditions with commercially available 4-phenyl-1H-imidazole-2-carbaldehyde 2 (Anichem Inc. catalog number FH10994) to form the 5,8-Dimethyl-2-[2-(4-phenyl-1H-imidazol-2-yl)-vinyl]-[1,2,4]triazolo[1,5-a]pyridine, compound 3.
Reaction SMILES: [CH:1]([CH:3]([CH:9]=O)[C:4]([O:6][CH2:7][CH3:8])=[O:5])=O.[NH:11]([C:13]1[N:14]=[C:15]([NH2:31])[C:16]2[N:17]=[CH:18][N:19]([C:29]=2[N:30]=1)[C@@H:20]1[O:28][C@H:25]([CH2:26][OH:27])[C@@H:23]([OH:24])[C@H:21]1[OH:22])[NH2:12]>CC(O)C>[OH:22][C@@H:21]1[C@H:23]([OH:24])[C@@H:25]([CH2:26][OH:27])[O:28][C@H:20]1[N:19]1[CH:18]=[N:17][C:16]2[C:29]1=[N:30][C:13]([N:11]1[CH:1]=[C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH:9]=[N:12]1)=[N:14][C:15]=2[NH2:31]
Reactant: NNc1nc(N)c2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2n1
Reactant: CCOC(=O)C(C=O)C=O
Solvent: CC(C)O
Product: CCOC(=O)c1cnn(-c2nc(N)c3ncn([C@@H]4O[C@H](CO)[C@@H](O)[C@H]4O)c3n2)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Ethyl 2-formyl-3-oxopropionate (23.93 g, 0.17 mol) was placed in a flask equipped with mechanical stirrer, gas inlet, gas outlet and reflux condenser. 2-Propanol was added to the flask followed by 2-hydrazinoadenosine (44.45 g, 0.15 mol). The mixture was heated to reflux under stirring for 2-4 hours, following the progress of the reaction by TLC analysis. When the reaction was judged complete, the heat source was removed and the mixture cooled to room temperature. The suspension was cooled under stirring in an ice-bath for 1.5 to 2 hours. The solids were isolated by vacuum filtration, and washed with ice-cold 2-propanol. The product, ethyl 1-{9-[(4S,2R,3R,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-6-aminopurin-2-yl}pyrazole-4-carboxylate, was dried under reduced pressure to a constant weight.
Reaction SMILES: [CH:1]([O:4][N:5]1C(=O)C2C(=CC=CC=2)C1=O)([CH3:3])[CH3:2].NN.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1.C(N(CC)C(C)C)(C)C>O1CCCC1.ClCCl>[CH:1]([O:4][NH:5][S:26]([C:23]1[CH:24]=[CH:25][C:20]([O:19][CH3:18])=[CH:21][CH:22]=1)(=[O:28])=[O:27])([CH3:3])[CH3:2]
Reactant: CC(C)ON1C(=O)c2ccccc2C1=O
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Agent: NN
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(S(=O)(=O)NOC(C)C)cc1
Reaction time: 1.5 h
Yield: 68.9 %

Procedure:
A vigorously stirred solution of 2-isopropoxy-1H-isoindole-1,3(2H)-dione [2.50 g, 12.2 mmol, Synth. Comm., 22(10), 1427-1432 (1992)] in 35 mL of tetrahydrofuran under an Argon atmosphere at ambient temperature was treated with anhydrous hydrazine (0.421 mL, 13.41 mmol). After 1.5 hours, 4-methoxybenzenesulphonyl chloride (3.024 g, 14.63 mmol), dichloromethane (20 mL) and N,N-diisopropylethylamine (6.38 mL, 36.6 mmol) was added with continued stirring. After an additional 2 hours at ambient temperature, the reaction mixture was evaporated in vacuo to a residue and partitioned between ethyl acetate and 1N hydrochloric acid. The layers were separated and the aqueous layer was extracted again with ethyl acetate. The combined organic layers were washed with 5% w/v potassium carbonate and brine, dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to a residue. The crude material was purified on flash grade silica gel eluting with 30% ethyl acetate in hexane. Fractions containing the product were combined, evaporated in vacuo, and dried under high vacuum to provide N-(isopropoxy)-4-methoxy-1-benzenesulfonamide (2.061 g, 69%) as a white solid. H1-NMR (chloroform-D3): 1.22 (d, 6H), 3.92 (s, 3H), 4.27 (m, 1H), 6.70 (s, 1H), 7.05 (d, 2H), 7.90 (d, 2H). MS(ESI): 268 (M+Na).
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[CH3:7][CH:8]([O:10][C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1)[CH3:9].Br[C:21]1[C:22]([NH2:27])=[N:23][CH:24]=[CH:25][CH:26]=1>COCCOC.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>[CH3:7][CH:8]([O:10][C:11]1[CH:16]=[CH:15][C:14]([C:21]2[C:22]([NH2:27])=[N:23][CH:24]=[CH:25][CH:26]=2)=[CH:13][CH:12]=1)[CH3:9]
Reactant: Nc1ncccc1Br
Reactant: CC(C)Oc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CC(C)Oc1ccc(-c2cccnc2N)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 90.6 %

Procedure:
A mixture of sodium carbonate (906 mg), tetrakis(triphenylphosphine)palladium(0) (247 mg), 4-(1-methylethoxy)phenylboronic acid (1000 mg) and 3-bromopyridin-2-amine (0.739 g) in 1,2-dimethoxyethane (50 mL) and water (10 mL) was stirred under a nitrogen atmosphere at 80° C. overnight. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (883 mg) as a pale-yellow solid.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[O:9][C:10]3[CH:20]=[C:19]4[C:14]([CH:15]=[CH:16][CH:17]=[CH:18]4)=[CH:13][C:11]=3[N:12]=2)[CH2:4][CH2:3]1.[CH2:21]([I:24])[CH:22]=[CH2:23]>CN(C=O)C>[I-:24].[CH2:21]([N+:2]1([CH3:1])[CH2:7][CH2:6][N:5]([C:8]2[O:9][C:10]3[CH:20]=[C:19]4[C:14]([CH:15]=[CH:16][CH:17]=[CH:18]4)=[CH:13][C:11]=3[N:12]=2)[CH2:4][CH2:3]1)[CH:22]=[CH2:23]
Reactant: C=CCI
Reactant: CN1CCN(c2nc3cc4ccccc4cc3o2)CC1
Solvent: CN(C)C=O
Product: C=CC[N+]1(C)CCN(c2nc3cc4ccccc4cc3o2)CC1
Product: [I-]
Reaction time: 1 h
Yield: 95.5 %

Procedure:
Under cooling with ice, 18 mg of 2-(4-methyl-1-piperazinyl)naphtho[2,3-d]oxazole dissolved in 5 ml of DMF was mixed with 14 mg of allyl iodide, and the reaction was carried out for 1 hour at the same temperature and then for 1.5 hours at room temperature. The reaction mixture was concentrated under a reduced pressure, and 10 ml of ethyl acetate was added to the resulting residue. Thereafter, the precipitate thus formed was collected by filtration, dissolved in 5 ml of water and then lyophilized to obtain 28 mg of the title compound.
Reaction SMILES: [C:1]([CH:4]([C:12](=O)[CH3:13])[CH:5]([C:9](=O)[CH3:10])[C:6](=O)[CH3:7])(=O)[CH3:2].[CH2:15]([O:17][C:18]1[CH:23]=[CH:22][C:21]([NH2:24])=[C:20]([S:25][CH3:26])[CH:19]=1)[CH3:16].[NH2:27][NH2:28]>>[CH2:15]([O:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]2[C:1]([CH3:2])=[C:4]3[C:5]([C:9]([CH3:10])=[N:27][N:28]=[C:12]3[CH3:13])=[C:6]2[CH3:7])=[C:20]([S:25][CH3:26])[CH:19]=1)[CH3:16]
Reactant: CCOc1ccc(N)c(SC)c1
Reactant: NN
Reactant: CC(=O)C(C(C)=O)C(C(C)=O)C(C)=O
Product: CCOc1ccc(-n2c(C)c3c(C)nnc(C)c3c2C)c(SC)c1

Procedure:
Utilizing the general procedure outlined in Example 48, 1,1,2,2-tetraacetylethane (200 mg, 1.0 mol), 4-ethoxy-2-methylsulfanyl-phenyl amine (140 mg, 0.8 mmol) and hydrazine (50 μL) reacted to give 6-(4-Ethoxy-2-methylsulfanyl-phenyl)-1,4,5,7-tetramethyl-6H-pyrrolo[3,4-d]pyridazine as yellow solid: 1H NMR (CDCl3, 500 MHz) δ 7.05 (d, 1H), 6.88 (s, 1H), 6.82 (d, 1H), 4.16 (q, 2H), 2.81 (s, 6H), 2.42 (s, 6H), 1.53 (t, 3H); MS (ESI) 342 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([C:19]2[CH:29]=[CH:28][C:22]([C:23]([O:25]CC)=[O:24])=[CH:21][CH:20]=2)[CH2:6][O:5][C:4]2[CH:7]=[C:8]3[C:13](=[CH:14][C:3]1=2)[C:12]([CH3:16])([CH3:15])[CH2:11][CH2:10][C:9]3([CH3:18])[CH3:17].[OH-].[Na+].[OH-].[Li+].C1COCC1>O.CO>[CH3:1][C:2]1([C:19]2[CH:20]=[CH:21][C:22]([C:23]([OH:25])=[O:24])=[CH:28][CH:29]=2)[CH2:6][O:5][C:4]2[CH:7]=[C:8]3[C:13](=[CH:14][C:3]1=2)[C:12]([CH3:15])([CH3:16])[CH2:11][CH2:10][C:9]3([CH3:17])[CH3:18]
Reactant: CCOC(=O)c1ccc(C2(C)COc3cc4c(cc32)C(C)(C)CCC4(C)C)cc1
Agent: [Li+]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CC1(C)CCC(C)(C)c2cc3c(cc21)OCC3(C)c1ccc(C(=O)O)cc1

Procedure:
A mixture of ethyl (+)-4-(3,5,5,8,8-pentamethyl-2,3,5,6,7,8-hexahydronaphtho[2,3-b]furan3-yl)benzoate (200 mg, 0.5 mmol), sodium hydroxide (100 mg, 2.4 mmol) and lithium hydroxide (100 mg, 2.4 mmol), in 5 ml of a solution of THF, methanol and water (5/1/1) was heated under reflux for 24 h. The reaction medium was concentrated in a rotary evaporator under vacuum at 40° C. After adding 5 ml of water and 5 ml of ethyl ether and acidifying with a concentrated hydrochloric acid solution to pH 1, the organic phase was washed twice with 5 ml of water, dried over magnesium sulfate and concentrated in a rotary evaporator under vacuum at 40° C. The solids obtained were washed with heptane.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH2:4][CH:5]([C:8]1[NH:9][CH:10]=[CH:11][N:12]=1)[CH2:6][NH2:7].[C:14](OC(=O)C)(=[O:16])[CH3:15].C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3](=[O:13])[CH2:4][CH:5]([C:8]1[NH:9][CH:10]=[CH:11][N:12]=1)[CH2:6][NH:7][C:14](=[O:16])[CH3:15]
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)CC(CN)c1ncc[nH]1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: COC(=O)CC(CNC(C)=O)c1ncc[nH]1

Procedure:
0.01 mol of the compound obtained in stage B of Example 16 is dissolved in 50 cm3 of chloroform. 0.01 mol of acetic anhydride and 0.015 mol of sodium carbonate are added. The whole is heated under reflux for five hours while stirring. The reaction mixture is then cooled, evaporated to dryness and extracted with chloroform twice. The chloroform phases are combined and dried over calcium chloride and the solvent is evaporated in vacuo on a water bath. The residue is purified by chromatography.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([OH:8])[C:3]=1[NH:9][C:10](=[O:13])[O:11][CH3:12].CC#N.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[I:29]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[F:1][C:2]1[C:7]([I:29])=[CH:6][CH:5]=[C:4]([OH:8])[C:3]=1[NH:9][C:10](=[O:13])[O:11][CH3:12]
Reactant: O=C1CCC(=O)N1I
Reactant: COC(=O)Nc1c(O)cccc1F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC#N
Solvent: ClC(Cl)Cl
Solvent: O
Product: COC(=O)Nc1c(O)ccc(I)c1F
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 22.9 %

Procedure:
To a mixture of methyl (2-fluoro-6-hydroxyphenyl)carbamate (1.06 g) and MeCN (90 mL) was added p-toluenesulfonic acid monohydrate (1.09 g), followed by stirring at room temperature for 5 minutes. To the reaction mixture was added N-iodosuccinimide (1.29 g), followed by stirring at room temperature overnight. The reaction mixture was diluted with chloroform, and washed with a 10% aqueous sodium thiosulfate solution and brine in this order. The organic layer was dried over Na2SO4 and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: Hex/EtOAc=85/15-75/25) to obtain methyl (2-fluoro-6-hydroxy-3-iodophenyl)carbamate (408 mg).
Reaction SMILES: [Br:1][C:2]1[C:3]([NH:16][C@H:17]2[CH2:22][CH2:21][C@H:20]([O:23][CH3:24])[CH2:19][CH2:18]2)=[N:4][C:5]([N:9]2C(C)=CC=C2C)=[N:6][C:7]=1[CH3:8].Cl.NO.C(O)C>O>[Br:1][C:2]1[C:3]([NH:16][C@H:17]2[CH2:22][CH2:21][C@H:20]([O:23][CH3:24])[CH2:19][CH2:18]2)=[N:4][C:5]([NH2:9])=[N:6][C:7]=1[CH3:8]
Reactant: CO[C@H]1CC[C@H](Nc2nc(-n3c(C)ccc3C)nc(C)c2Br)CC1
Agent: Cl
Agent: NO
Solvent: CCO
Solvent: O
Product: CO[C@H]1CC[C@H](Nc2nc(N)nc(C)c2Br)CC1
Temperature: 25 °C

Procedure:
A solution of 5-bromo-2-(2,5-dimethyl-1H-pyrrol-1-yl)-N-(trans-4-methoxycyclohexyl)-6-methylpyrimidin-4-amine (1.07 g, 2.72 mmol) and hydroxylamine hydrochloride (945 mg, 13.6 mmol) in 10:1 ethanol:water (27.5 mL) was heated to reflux for 7 hours, then room temperature overnight. Another 0.5 eq of hydroxylamine hydrochloride was added and the solution was refluxed for another 4 hours, then cooled to room temperature and concentrated. The crude product was purified by flash chromatography eluting with chloroform/methanol (0.5-3%) to afford 5-bromo-N4-(trans-4-methoxycyclohexyl)-6-methylpyrimidine-2,4-diamine (767 mg, 89%).
Reaction SMILES: Br[C:2]1[C:3]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[N:4][N:5]2[C:10](Cl)=[CH:9][CH:8]=[CH:7][C:6]=12.[F:19][C:20]1[CH:25]=[C:24](B(O)O)[CH:23]=[CH:22][N:21]=1>>[F:18][C:15]1[CH:16]=[CH:17][C:12]([C:3]2[C:2]([C:24]3[CH:23]=[CH:22][N:21]=[C:20]([F:19])[CH:25]=3)=[C:6]3[CH:7]=[CH:8][CH:9]=[C:10]([C:24]4[CH:23]=[CH:22][N:21]=[C:20]([F:19])[CH:25]=4)[N:5]3[N:4]=2)=[CH:13][CH:14]=1
Reactant: Fc1ccc(-c2nn3c(Cl)cccc3c2Br)cc1
Reactant: OB(O)c1ccnc(F)c1
Product: Fc1ccc(-c2nn3c(-c4ccnc(F)c4)cccc3c2-c2ccnc(F)c2)cc1
Yield: 34.4 %

Procedure:
In a similar manner to that in Example 28, from 3-bromo-7-chloro-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridine (305 mg, 0.94 mmol) and 2-fluoropyridin-4-ylboronic acid (182 mg, 1.30 mmol) after heating to 100° C. for 1.5 hours was formed 2-(4-fluorophenyl)-3,7-bis(2-fluoropyridin-4-yl)pyrazolo[1,5-α]pyridine (90 mg, 24%). 1H NMR (CDCl3): δ 8.47 (d, 1H), 8.29 (d 1H), 7.89 (br d, 1H), 7.78 (d, 1H), 7.72 (s, 1H), 7.58 (dd, 2H), 7.44 (dd, 1H), 7.20 (br d, 1H), 7.15 (d, 1H), 7.13 (t, 2H), 7.05 (s, 1H); MS m/z 403 (M+1).
Reaction SMILES: [N:1]([O-:3])=O.[Na+].N[C:6]1[CH:7]=[C:8]([CH3:13])[C:9]([CH3:12])=N[CH:11]=1.[F:14][P-](F)(F)(F)(F)F.[H+]>Cl.O>[CH3:12][C:9]1[C:8]([CH3:13])=[CH:7][C:6]([F:14])=[CH:11][N+:1]=1[O-:3]
Reactant: Cc1cc(N)cnc1C
Reactant: F[P-](F)(F)(F)(F)F
Reactant: O=N[O-]
Agent: Cl
Agent: [H+]
Agent: [Na+]
Solvent: O
Product: Cc1cc(F)c[n+]([O-])c1C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Sodium nitrite (5.6 g) was added portionwise to a stirred solution of 5-amino-3-methyl-2-picoline (5 g) in conc. hydrochloric acid (25 ml) and water (30 ml) at -5° to 0° over 15 minutes. After a further 15 minutes at this temperature, 65% hexafluorophosphoric acid (25 ml) was added dropwise causing precipitation of the hexafluorophosphate salt which was filtered off, washed with water, ethanol, and ether and dried under vacuum (12.33 g). The salt was added portionwise, with rapid stirring, to petroleum ether (100 ml, b.p. 120°-160°) at 60° over 20 minutes. After a further 5 minutes the mixture was cooled to room temperature, the petroleum ether layer decanted, and extracted with 2N hydrochloric acid. The acidic and oily residues were combined, extracted with ether, basified (NaOH) and extracted again with dichloromethane. After drying (K2CO3), m-chloroperbenzoic acid (8.45 g) was added to the dichloromethane solution and the mixture allowed to stand for 16 hours. Ammonia gas was passed through the solution and the precipitated benzoate salts filtered off. The filtrate was evaporated to dryness to give 2,3-dimethyl-5-fluoropyridine-N-oxide (2.66 g) m.p. indeterminate.
Reaction SMILES: N[C:2]1[C:9]([Cl:10])=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].C[Si]([N-:15][Si](C)(C)C)(C)C.[Na+].Cl[C:22]1[C:31]2[C:26](=[CH:27][N:28]=[CH:29][CH:30]=2)[C:25]2[CH:32]=[CH:33][CH:34]=[C:35]([C:36]3[NH:40][CH:39]=[N:38][N:37]=3)[C:24]=2[N:23]=1>CN1C(=O)CCC1.Cl>[N:38]1[N:37]=[C:36]([C:35]2[C:24]3[N:23]=[C:22]([NH:15][C:8]4[CH:7]=[CH:6][C:3]([C:4]#[N:5])=[CH:2][C:9]=4[Cl:10])[C:31]4[C:26]([C:25]=3[CH:32]=[CH:33][CH:34]=2)=[CH:27][N:28]=[CH:29][CH:30]=4)[NH:40][CH:39]=1
Reactant: N#Cc1cccc(Cl)c1N
Reactant: Clc1nc2c(-c3nnc[nH]3)cccc2c2cnccc12
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: N#Cc1ccc(Nc2nc3c(-c4nnc[nH]4)cccc3c3cnccc23)c(Cl)c1
Temperature: 80 °C
Reaction time: 0.08 h

Procedure:
4 amino-3-chlorobenzonitrile was charged in a vial. NaHMDS (1 M solution in THF, 0.2 ml) was added and the solution stirred at 80° C. for 5 min. A suspension of 5-chloro-7-(4H-1,2,4-triazol-3-yl)benzo[c][2,6]naphthyridine (30 mg) in NMP (0.5 ml) was added and the solution stirred at 80° C. for 30 min. The mixture was cooled down, a few drops of HCl and NMP (1 ml) were added and mixture was purified by preparative HPLC to provide 4-(7-(4H-1,2,4-triazol-3-yl)benzo[c][2,6]naphthyridin-5-ylamino)-3-chlorobenzonitrile (25 mg).
Reaction SMILES: [OH:1][C:2]1[C:7]([CH2:8][CH2:9][CH3:10])=[C:6]([OH:11])[CH:5]=[CH:4][C:3]=1[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[OH:20])=[O:13].[H-].[Na+].Br[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]#[N:30].C(OCC)C.O>CN(C)C=O>[OH:1][C:2]1[C:7]([CH2:8][CH2:9][CH3:10])=[C:6]([CH:5]=[CH:4][C:3]=1[C:12](=[O:13])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[OH:20])[O:11][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]#[N:30]
Reactant: N#CCCCCCBr
Reactant: CCCc1c(O)ccc(C(=O)c2ccccc2O)c1O
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Solvent: CN(C)C=O
Product: CCCc1c(OCCCCCC#N)ccc(C(=O)c2ccccc2O)c1O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 12.5 g of (2,4-dihydroxy-3-propylphenyl)(2-hydroxyphenyl)methanone in 460 ml of dimethylformamide were added 1.83 g of 60% sodium hydride in oil. The mixture was stirred for one hour under a nitrogen atmosphere. A solution of 4.9 ml of 6-bromohexanenitrile in a small volume of dimethylformamide was added. The reaction was stirred at 60° C. overnight, cooled to 25° C., and poured into a diethyl ether/water mixture. The layers were separated, and the organic layer was washed three times with water, dried over magnesium sulfate, filtered, and evaporated. Purification by high pressure liquid chromatography over silica gel eluting with a 15-35% ethyl acetate/hexane gradient, and evaporation of the desired fractions provided 6.1 g of the desired title product. Crystallization from ethyl acetate/hexane provided material with a melting point of 62°-63° C.