Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([CH:4]1[CH2:8][CH2:7][C:6]([CH3:12])([C:9]([OH:11])=O)[CH2:5]1)([CH3:3])[CH3:2].[F:13][C:14]([F:28])([F:27])[C:15]1[C:16]([N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[N:17][CH:18]=[CH:19][CH:20]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C)C=O>[CH:1]([CH:4]1[CH2:8][CH2:7][C:6]([C:9]([N:24]2[CH2:25][CH2:26][N:21]([C:16]3[C:15]([C:14]([F:28])([F:13])[F:27])=[CH:20][CH:19]=[CH:18][N:17]=3)[CH2:22][CH2:23]2)=[O:11])([CH3:12])[CH2:5]1)([CH3:2])[CH3:3]
Reactant: CC(C)C1CCC(C)(C(=O)O)C1
Reactant: FC(F)(F)c1cccnc1N1CCNCC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: CC(C)C1CCC(C)(C(=O)N2CCN(c3ncccc3C(F)(F)F)CC2)C1
Temperature: 150 °C
Yield: 42 %

Procedure:
To a stirred solution of 3-isopropyl-1-methylcyclopentanecarboxylic acid (89 mg, 0.52 mmol) and 1-(3-(trifluoromethyl)pyridin-2-yl)piperazine (242 mg, 1.04 mmol) in N,N-dimethylformamide (1 mL) was added benzotriazole-1 yl-oxy-tris-(dimethylamino)-phosphonium hexafluorophosphate (700 mg, 1.56 mmol). The reaction was heated in a microwave at 150° C. for 5 minutes. The reaction mixture was purified with HPLC to yield 1-[(3-isopropyl-1-methylcyclopentyl)carbonyl]-4-[3-(trifluoromethyl)pyridin-2-yl]piperazine in 42% yield (83.3 mg) as off-white solid.
Reaction SMILES: [C:1]([O:4][CH:5]1[C:9]2=[N:10][CH:11]=[C:12]([N+:32]([O-])=O)[C:13]([N:14]3[CH2:19][C@H:18]([C:20]([F:23])([F:22])[F:21])[CH2:17][C@H:16]([NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:15]3)=[C:8]2[CH2:7][CH2:6]1)(=[O:3])[CH3:2].CC(O)=O>CCOC(C)=O.[Fe]>[C:1]([O:4][CH:5]1[C:9]2=[N:10][CH:11]=[C:12]([NH2:32])[C:13]([N:14]3[CH2:19][C@H:18]([C:20]([F:21])([F:23])[F:22])[CH2:17][C@H:16]([NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:15]3)=[C:8]2[CH2:7][CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC1CCc2c1ncc([N+](=O)[O-])c2N1C[C@@H](NC(=O)OC(C)(C)C)C[C@@H](C(F)(F)F)C1
Agent: [Fe]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CC(=O)OC1CCc2c1ncc(N)c2N1C[C@@H](NC(=O)OC(C)(C)C)C[C@@H](C(F)(F)F)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.9 %

Procedure:
To a mixture of 4-[(3S,5R)-3-[(tert-butoxycarbonyl)amino]-5-(trifluoromethyl)piperidin-1-yl]-3-nitro-6,7-dihydro-5H-cyclopenta[b]pyridin-7-yl acetate (92.3 mg, 0.189 mmol) and iron powder (295.6 mg, 5.293 mmol) was added AcOH (2.0 mL). The mixture was stirred at room temperature for 3 h. The reaction mixture was diluted with EtOAc, filtered through a pad of diatomaceous earth (eluted with EtOAc). The filtrate was washed with a saturated aqueous solution of Na2CO3, dried over Na2SO4, and concentrated to give the crude sub-title compound as dark semi-solid (86.6 mg). The crude product was used directly in the next step without further purification. LCMS calc. for C21H30F3N4O4 (M+H)+: m/z=459.2. found 459.2.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[CH:5]1[CH:15]=[C:14]([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=2)[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:7][CH:6]1[NH:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[CH:26]=1)[CH3:2].ClC1C=C([N+]([O-])=O)C=CC=1.N1CCCCC1>C(O)(=O)C>[CH2:1]([O:3][C:4](=[O:32])[C:5]1[CH:15]=[C:14]([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=2)[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:7][C:6]=1[NH:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[CH:26]=1)[CH3:2]
Reactant: CCOC(=O)C1=CC(Nc2cccc(Cl)c2)C(C(=O)OCC)C=C1Nc1cccc(Cl)c1
Agent: O=[N+]([O-])c1cccc(Cl)c1
Solvent: CC(=O)O
Solvent: C1CCNCC1
Product: CCOC(=O)c1cc(Nc2cccc(Cl)c2)c(C(=O)OCC)cc1Nc1cccc(Cl)c1

Procedure:
20 parts of 2,5-bis-(m-chloroanilino)-dihydroterephthalic acid diethyl ester are oxidized by heating for three hours to 125° to 130° C. with 40 parts of m-chloronitrobenzene, with addition of 2 parts of glacial acetic acid and 0.6 part of piperidine. The 2,5-bis-(m-chloroanilino)-terephthalic acid diethyl ester is obtained having a content of chlorine of 14.7% (calculated: 15.0%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][CH:11]=2)=[CH:5][CH:4]=1.[BH4-].[Na+].[Si]([O:27][C:28]1[CH:35]=[CH:34][C:31]([CH2:32]Cl)=[CH:30][CH:29]=1)(C(C)(C)C)(C)C.O>CN(C)C=O>[OH:27][C:28]1[CH:35]=[CH:34][C:31]([CH2:32][N:9]([C:10]2[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][CH:11]=2)[C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)=[CH:30][CH:29]=1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(CCl)cc1
Reactant: COc1ccc(Nc2ccc(C#N)cc2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(N(Cc2ccc(O)cc2)c2ccc(C#N)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
224 mg of 4-[N(4-methoxyphenyl)amino]benzonitrile was dissolved in 1.2 ml of N,N-dimethylformamide, and 48 mg of sodium borohydride was added thereto under cooling with ice, followed by stirring at room temperature for 30 minutes. The previously prepared 4-(t-butyldimethylsilyloxy)benzyl chloride was dissolved in 1.2 ml of N,N- dimethylformamide and added to the reaction mixture under cooling with ice, followed by stirring at room temperature for 2 days. After water was added to the reaction mixture, the product was extracted with ethyl acetate. After the extract was washed with water and dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The resulting residue was dissolved in 1.2 ml of tetrahydrofuran, and 1.2 ml of a 1 M tetrahydrofuran solution of tetrabutylammonium fluoride was added thereto, followed by stirring at room temperature for 15 minutes. After a saturated aqueous solution of sodium hydrogen carbonate was added to the reaction mixture, the product was extracted with ethyl acetate. After the extract was washed with water and dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (using ethyl acetate as the eluent) to obtain 229 mg of 4-[N-(4-hydroxybenzyl)-N-(4-methoxyphenyl)amino]benzonitrile.
Reaction SMILES: [F:1][C:2]([F:14])([C:5]([F:13])([F:12])[C:6]([F:11])([F:10])[CH:7]([F:9])[F:8])[CH2:3][OH:4].CN(C=O)C.C(=O)([O-])[O-].[K+].[K+].[F:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29](F)[N:28]=1>O>[F:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([O:4][CH2:3][C:2]([F:14])([F:1])[C:5]([F:12])([F:13])[C:6]([F:10])([F:11])[CH:7]([F:8])[F:9])[N:28]=1
Reactant: Fc1cccc(F)n1
Reactant: OCC(F)(F)C(F)(F)C(F)(F)C(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Fc1cccc(OCC(F)(F)C(F)(F)C(F)(F)C(F)F)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.1 %

Procedure:
A reaction flask was loaded with 2,2,3,3,4,4,5,5-octafluoropentanol (16.1 g), DMF (42 ml), anhydrous potassium carbonate (9.6 g), followed by stirring at room temperature for one hour. To this mixture, 2,6-difluoropyridine (8.0 g) was dropwise added. The temperature was raised to 60° C., and the mixture was stirred for four hours. The heating was stopped, and water was added to the reaction mixture, followed by extraction with ethyl acetate. The extract was condensed by an evaporator to give 2-fluoro-6-(2,2,3,3,4,4,5,5-octafluoropentyloxy)-pyridine (20 g).
Reaction SMILES: [C:1]1([CH2:11][C:12]([OH:14])=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH3:15][NH:16][C@@H:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20][CH2:19][C@H:18]1[N:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1>>[CH3:15][N:16]([C@@H:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20][CH2:19][C@H:18]1[N:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1)[C:12](=[O:14])[CH2:11][C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)Cc1cccc2ccccc12
Reactant: CN[C@@H]1c2ccccc2CC[C@H]1N1CCCC1
Product: CN(C(=O)Cc1cccc2ccccc12)[C@@H]1c2ccccc2CC[C@H]1N1CCCC1
Yield: 54.9 %

Procedure:
Using the procedure of Step C of Example 1, 2.3 g of 1-naphthylacetic acid and 2 g of the product of Step B of Example 1 were reacted to obtain 5.3 g of crude product which was purified by chromatography on silica (methylene chloride 9-methanol 1). After crystallization from ethyl ether, 1.9 g of product melting at 117° C. were obtained which was crystallized from isopropyl ether to obtain 1.1 g of the expected product melting at 125° C.
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[CH:11](=O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(O)(=O)C.C([BH3-])#N.[Na+].Cl>CO>[CH2:11]([N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=Cc1ccccc1
Reactant: c1ccc2c(c1)CCCN2
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: c1ccc(CN2CCCc3ccccc32)cc1
Reaction time: 3 h

Procedure:
1,2,3,4-tetrahydroquinoline (2.66 g, 0.02 mol), benzaldehyde (3.12 g, 0.03 mol) and glacial acetic acid (0.67 ml, 0.012 mol) were dissolved in methanol (10 ml). Sodium cyanoborohydride (0.675 g, 0.0107 mol) was added portionwise, controlling the resulting vigorous gas evolution by the rate of addition. After 3 hours, the reaction mixture was poured into 50 ml 1N HCl and extracted 3×40 ml ether. The organic layers were combined, dried (MgSO4) and stripped to yield crude title product contaminated with benzyl alcohol. The crude product was dissolved in 50 ml ether, cooled to 0° C. and diffused with HCl gas until precipitation of hydrochloride salt was complete. The ether was decanted from the resulting semi-solid salt. The salt was washed with 20 ml fresh ether, the ether decanted, and the washed salt taken up in 50 ml of fresh ether and 50 ml of H2O. The pH was adjusted to 12 with 1N NaOH, and the ether layer separated, dried (K2CO3) and stripped to 2.47 g of product still containing some residual benzyl alcohol. Repeated conversion to hydrochloride salt and back to free base gave purified title product, 2.02 g.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:14]([O:16]C)=[O:15])=[CH:4][C:5]([Br:13])=[C:6]2[C:11]=1[N:10]([CH3:12])[CH2:9][CH2:8][CH2:7]2.[Li+].[OH-]>C1COCC1.O>[NH2:1][C:2]1[C:3]([C:14]([OH:16])=[O:15])=[CH:4][C:5]([Br:13])=[C:6]2[C:11]=1[N:10]([CH3:12])[CH2:9][CH2:8][CH2:7]2
Reactant: COC(=O)c1cc(Br)c2c(c1N)N(C)CCC2
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CN1CCCc2c(Br)cc(C(=O)O)c(N)c21
Temperature: 65 °C
Reaction time: 20 h

Procedure:
To a solution of methyl 8-amino-5-bromo-1-methyl-1,2,3,4-tetrahydroquinoline-7-carboxylate (1.40 g, 4.68 mmol) in 2:1 THF/H2O (18 mL) at rt was added LiOH (224 mg, 9.36 mmol). The solution was warmed to 65° C. and stirred for 20 h. The resulting solution was cooled to rt and the THF was removed in vacuo. The aqueous residue remaining was acidified with 1 M aqueous HCl and the resulting tan solid that precipitated was collected by filtration and dried in vacuo to afford 8-amino-5-bromo-1-methyl-1,2,3,4-tetrahydroquinoline-7-carboxylic acid in pure form.
Reaction SMILES: [CH2:1]([C@:4]12[CH2:12][CH2:11][C@@H:10]3[C@@H:13]4[C:18]([CH2:19][CH2:20][C@H:9]3[C@@H:8]1[CH2:7][CH2:6][C@@H:5]2[OH:22])=[CH:17][C:16](=[O:21])[CH2:15][CH2:14]4)[CH2:2][CH3:3].[C:23](Cl)(=O)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH2:1]([C@:4]12[CH2:12][CH2:11][C@@H:10]3[C@@H:13]4[C:18]([CH2:19][CH2:20][C@H:9]3[C@@H:8]1[CH2:7][CH2:6][C@@H:5]2[O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[CH:17][C:16](=[O:21])[CH2:15][CH2:14]4)[CH2:2][CH3:3]
Reactant: CCC[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@H]43)[C@@H]1CC[C@@H]2O
Reactant: O=C(Cl)c1ccccc1
Product: CCC[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@H]43)[C@@H]1CC[C@@H]2OCc1ccccc1

Procedure:
Esterify 13β-propyl-17β-hydroxy-gon-4-en-3-one (2.5 g.) with benzoyl chloride (2.0 g.). Purify the product by chromatography on Florex and recrystallize from ethyl acetate to obtain the title compound, m.p. 198°-200°; ultraviolet absorption peak at 240 mμ (ε25,000); infrared absorption peaks at 5.84, 6.00 μ.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[N:12]=[C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[N:10]=[C:9]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26](=[O:37])[NH:27][C:28]4[CH:36]=[CH:35][C:31]([C:32](O)=[O:33])=[CH:30][CH:29]=4)=[CH:21][CH:20]=3)[N:8]=2)[CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH:71]1[CH2:76][CH2:75][NH:74][CH2:73][CH2:72]1>CN1C(=O)CCC1>[O:1]1[CH2:6][CH2:5][N:4]([C:7]2[N:12]=[C:11]([N:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)[N:10]=[C:9]([C:19]3[CH:20]=[CH:21][C:22]([NH:25][C:26]([NH:27][C:28]4[CH:36]=[CH:35][C:31]([C:32]([N:71]5[CH2:76][CH2:75][NH:74][CH2:73][CH2:72]5)=[O:33])=[CH:30][CH:29]=4)=[O:37])=[CH:23][CH:24]=3)[N:8]=2)[CH2:3][CH2:2]1
Reactant: O=C(Nc1ccc(C(=O)O)cc1)Nc1ccc(-c2nc(N3CCOCC3)nc(N3CCOCC3)n2)cc1
Reactant: C1CNCCN1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(C(=O)N2CCNCC2)cc1)Nc1ccc(-c2nc(N3CCOCC3)nc(N3CCOCC3)n2)cc1
Yield: 30.3 %

Procedure:
To the solution of 4-(3-(4-(4,6-dimorpholino-1,3,5-triazin-2-yl)phenyl)ureido)benzoic acid (50 mg; 0.099 mmol), Hunig's base (103 μL, 0.594 mmol), HBTU (188 mg, 0.495 mmol) in 2 mL of NMP was reacted according to example 68 with piperazine (34 mg, 0.396 mmol). Evaporated the solvent and purified by HPLC to give the product (17.2 mg, 30% yield); MS (ESI) m/z=573.6
Reaction SMILES: [OH:1][CH:2]([CH:21]=[CH2:22])[CH:3]([NH:8][C:9]([C:11]1[C:12]([C:17]([F:20])([F:19])[F:18])=[N:13][N:14]([CH3:16])[CH:15]=1)=[O:10])[C:4](=[O:7])[NH:5][CH3:6].[C:23](O)(=[O:25])[CH3:24].CN(C1C=CC=CN=1)C>C(Cl)Cl>[C:23]([O:1][CH:2]([CH:3]([C:4](=[O:7])[NH:5][CH3:6])[NH:8][C:9]([C:11]1[C:12]([C:17]([F:20])([F:19])[F:18])=[N:13][N:14]([CH3:16])[CH:15]=1)=[O:10])[CH:21]=[CH2:22])(=[O:25])[CH3:24]
Reactant: CC(=O)O
Reactant: C=CC(O)C(NC(=O)c1cn(C)nc1C(F)(F)F)C(=O)NC
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Product: C=CC(OC(C)=O)C(NC(=O)c1cn(C)nc1C(F)(F)F)C(=O)NC
Temperature: 25 °C
Reaction time: 16 h

Procedure:
134 mg (0.42 mmol) of N-(2-hydroxy-1-methylcarbamoylbut-3-enyl)-1-methyl-3-trifluoromethyl-1H-pyrazole-4-carboxamide, 28 mg (0.46 mmol) of acetic acid and 20 mg (0.17 mmol) of dimethylaminopyridine were dissolved in CH2Cl2. At 0° C., 88 mg (0.46 mmol) of 1-(3-dimethylaminopropyl)-3-(ethylcarbodiimide) hydrochloride were added. After 16 h of stirring at RT, the reaction solution was washed and the solvent was removed. This gave 0.10 g (66% of theory) of the title compound as a colorless powder (M+(m/z)=362).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH2:9].[C:10](OC(=O)C)(=[O:12])[CH3:11].C(O)C>N1C=CC=CC=1>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:12])[CH3:11]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc(I)cc1F
Solvent: c1ccncc1
Solvent: CCO
Product: CC(=O)Nc1ccc(I)cc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88 %

Procedure:
To a stirred solution of 2-fluoro-4-iodo-phenylamine (61 g, 257 mmol) in anhydrous pyridine (25 mL) was added drop-wise acetic anhydride (32.8 mL, 321 mmol) at such a rate to maintain the internal temperature between 10° C. and 20° C. At the end of the addition, the reaction was stirred for an additional 0.5 h at rt followed by heating on an oil bath (external temperature 50–60° C.). The reaction was monitored by thin layer chromatography. Once complete (ca. 1.5 h), the mixture was cooled and the reaction mixture solidified. The solid was slurried with cold ethanol (50 mL) and filtered. The solid was washed with cold ethanol (mL) and dried to a fine white crystalline material. The filtrate was concentrated and taken up in ethanol (20 mL) and cooled overnight. Further product was obtained. 63 g (226 mmol) was isolated as a fine white, crystalline solid. Yield: 88%; mp 153° C.; 1H NMR (400 MHz, CDCl3) δ 8.15 (t, J=8 Hz, 1H), 7.33 (br s, 1H), 7.49 (m, 2H), 2.24 (s, 3H, Me).
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([O:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[NH:19]2)=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11].C(=O)([O-])[O-].[K+].[K+].Br[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][Cl:37]>CN(C=O)C>[CH2:8]([O:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[N:19]2[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][Cl:37])=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11]
Reactant: ClCCCCCBr
Reactant: CCCCOc1nc(N)c2nc(OC)[nH]c2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: CCCCOc1nc(N)c2nc(OC)n(CCCCCCl)c2n1
Temperature: 50 °C
Reaction time: 18 h

Procedure:
2-(Butyloxy)-8-(methyloxy)-9H-purin-6-amine trifluoroacetate salt (for example, as prepared for Intermediate 6) (2 g, 5.69 mmol) and potassium carbonate (1.967 g, 14.23 mmol) were suspended in DMF (20 mL) and heated to 50° C., under nitrogen for 1 hour. The mixture was cooled to room temperature, 1-bromo-5-chloropentane (commercially available, for example, from Aldrich) (0.75 mL, 5.69 mmol) was added and stirring was continued at room temperature for 18 hours. The reaction mixture was partitioned between DCM (40 mL) and water (40 mL) and the layers were separated using a hydrophobic frit. The aqueous layer was extracted again with DCM (10 mL) and the combined organics were washed with saturated lithium chloride solution, separated (hydrophobic frit) and concentrated in vacuo to give the title compound as a yellow oil (1.946 g).
Reaction SMILES: [CH3:1][C:2]1[N:6]2[N:7]=[C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([NH2:17])[CH:12]=3)[CH:9]=[CH:10][C:5]2=[N:4][N:3]=1.C(N(CC)C(C)C)(C)C.[CH:27]1([C:30](Cl)=[O:31])[CH2:29][CH2:28]1>ClCCl>[CH3:1][C:2]1[N:6]2[N:7]=[C:8]([C:11]3[CH:12]=[C:13]([NH:17][C:30]([CH:27]4[CH2:29][CH2:28]4)=[O:31])[CH:14]=[CH:15][CH:16]=3)[CH:9]=[CH:10][C:5]2=[N:4][N:3]=1
Reactant: Cc1nnc2ccc(-c3cccc(N)c3)nn12
Reactant: O=C(Cl)C1CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1nnc2ccc(-c3cccc(NC(=O)C4CC4)c3)nn12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 7.6 g of 3-methyl-6-(3-aminophenyl)-1,2,4-triazolo[4,3-b]pyridazine in 1.5 liters of dichloromethane was added 6 ml of N,N-diisopropylethylamine and 3.1 ml of cyclopropane carboxylic acid chloride. The solution was stirred at room temperature for 4 hours, washed with 200 ml of saturated sodium bicarbonate solution, dried and the solvent removed in vacuo. The residue was crystallized from dichloromethane-hexane to give 2.24 g of tan crystals, mp 255°-258° C. A sample recrystallized from dichloromethane-hexane gave white crystals, mp 259°-262° C.
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@H:10]([N:11]=[C:12]=[S:13])[C@@H:9]([O:14][C:15](=[O:17])[CH3:16])[C@H:8]([O:18][C:19](=[O:21])[CH3:20])[C@@H:7]([CH2:22][O:23][C:24](=[O:26])[CH3:25])[O:6]1)(=[O:3])[CH3:2].Cl.[CH2:28]([NH2:31])[CH2:29][CH3:30].C(N(CC)CC)C.C([O-])(O)=O.[Na+]>CC#N>[C:1]([O:4][C@H:5]1[C@H:10]([NH:11][C:12]([NH:31][CH2:28][CH2:29][CH3:30])=[S:13])[C@@H:9]([O:14][C:15](=[O:17])[CH3:16])[C@H:8]([O:18][C:19](=[O:21])[CH3:20])[C@@H:7]([CH2:22][O:23][C:24](=[O:26])[CH3:25])[O:6]1)(=[O:3])[CH3:2]
Reactant: CCCN
Reactant: CC(=O)OC[C@H]1O[C@@H](OC(C)=O)[C@H](N=C=S)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCCNC(=S)N[C@H]1[C@H](OC(C)=O)O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reaction time: 1 h
Yield: 87.2 %

Procedure:
To a stirred solution of (2S,3R,4R,5S,6R)-6-(acetoxymethyl)-3-isothiocyanato-tetrahydro-2H-pyran-2,4,5-triyl triacetate (530 mg, 1.36 mmol) in CH3CN (7 mL) was added neat propylamine hydrochloride (260 mg, 2.72 mmol) followed by triethylamine (378 μL, 2.72 mmol) and the resulting mixture was stirred for 1 h. Saturated aqueous NaHCO3 (20 mL) was added, then the resulting mixture was extracted with CH2Cl2 (3×10 mL) and the combined organic extracts were dried (MgSO4) and concentrated. The resulting crude material was purified by flash chromatography on silica gel (hexane/EtOAc 1:1) to give (2S,3R,4R,5S,6R)-6-(acetoxymethyl)-3-(3-propylthioureido)-tetrahydro-2H-pyran-2,4,5-triyl triacetate as a white foam (532 mg, 87% yield). 1H NMR (500 MHz, CDCl3) δ 0.97 (t, 3H, J=7.5 Hz), 1.59-1.64 (m, 2H), 1.53-1.59 (m, 2H), 2.06 (s, 3H), 2.08 (s, 3H), 2.12 (s, 3H), 2.15 (s, 3H), 3.35 (br s, 2H), 3.81-3.85 (m, 1H), 4.13-4.17 (m, 2H), 4.20-4.25 (m, 1H), 4.29 (dd, 1H, J=4.5, 12.5 Hz), 5.17-5.23 (m, 2H), 5.73 (d, 1H, J=8.5 Hz), 6.07 (br s, 1H).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:9])=[N:4][C:5](Cl)=[CH:6][CH:7]=1.[CH3:10][C@@H:11]1[CH2:16][NH:15][CH2:14][CH2:13][NH:12]1.CCN(CC)CC>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:15]2[CH2:14][CH2:13][NH:12][C@H:11]([CH3:10])[CH2:16]2)=[N:4][C:3]=1[CH3:9]
Reactant: Cc1nc(Cl)ccc1Br
Reactant: C[C@@H]1CNCCN1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1nc(N2CCN[C@H](C)C2)ccc1Br
Temperature: 165 °C
Yield: 35.6 %

Procedure:
In a 10 mL microwave vial equipped with a magnetic stir bar were mixed 3-bromo-6-chloro-2-methylpyridine (515 mg, 2.496 mmol), (R)-2-methylpiperazine (250 mg, 2.496 mmol), and Et3N (1.044 mL, 7.49 mmol) in DMF (4 mL). The resulting yellow suspension was heated in a microwave reactor to 165° C. for 4 hours. The reaction mixture was subsequently partitioned between 0.25N HCl (40 mL) and EtOAc (40 mL). The phases were separated and the aqueous layer was back-extracted with EtOAc (40 mL). The organic layers were combined, washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified using flash chromatography (12 g column) eluting with a gradient of 0-100% EtOAc in heptanes and then 0-20% MeOH in DCM. The pure fractions were combined and concentrated to give the title compound as a clear syrup (240 mg, 35.6%).
Reaction SMILES: [CH3:1][CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[C:3]([Cl:5])=[O:4].[CH3:16]C(CCCCCCCCCC)C(O)=O>>[CH3:1][C:2]([CH3:16])([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[C:3]([Cl:5])=[O:4]
Reactant: CCCCCCCCCCC(C)C(=O)Cl
Reactant: CCCCCCCCCCC(C)C(=O)O
Product: CCCCCCCCCCC(C)(C)C(=O)Cl

Procedure:
In a similar manner to that described in Example 25 except for the use of 2-methyldodecanoyl chloride [synthesized by chlorinating 2-methyldodecanoic acid which was synthesized by the process described in Organic Synthesis, 4,616, by the method as described in B. D. Roth. et al., Journal of Medicinal Chemistry, 35, 1609-1617 (1992)] instead of 2,2-dimethyldodecanoyl chloride, 82.5 mg of the desired compound was obtained as a white powder.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12](I)=[C:13]([OH:15])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:17]([O:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]#[CH:28])=[CH:23][CH:22]=1)[CH2:18][CH3:19].CN(C)C(N(C)C)=N>CN(C=O)C.C(OCC)(=O)C.[Cu]I>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[CH:28]=[C:27]([C:24]3[CH:25]=[CH:26][C:21]([O:20][CH2:17][CH2:18][CH3:19])=[CH:22][CH:23]=3)[O:15][C:13]=2[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C#Cc1ccc(OCCC)cc1
Reactant: Oc1cc(OCc2ccccc2)ccc1I
Agent: [Cu]I
Agent: CN(C)C(=N)N(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCOc1ccc(-c2cc3ccc(OCc4ccccc4)cc3o2)cc1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 46.4 %

Procedure:
To a solution of 5-(benzyloxy)-2-iodophenol (2.65 g), 4-propoxyphenylacetylene (1.97 g) and 1,1,3,3-tetramethylguanidine (3.08 mL) in DMF (15 mL) were added bistriphenylphosphinedichloropalladium(II) (288 mg) and copper(I) iodide (156 mg) under a nitrogen atmosphere, and the mixture was stirred at 60° C. for 30 min. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (1.35 g).