Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[C:2](=[NH:9])(OC)[CH2:3][CH2:4][CH2:5][CH3:6].[NH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[C:24]#[N:25])=[CH:14][CH:13]=1.C[O-].[Na+].[Cl-].[Na+]>CO>[C:24]([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:15]1[CH:14]=[CH:13][C:12]([CH2:11][NH:10][C:2](=[NH:9])[CH2:3][CH2:4][CH2:5][CH3:6])=[CH:17][CH:16]=1)#[N:25]
Reactant: CCCCC(=N)OC
Reactant: N#Cc1ccccc1-c1ccc(CN)cc1
Agent: C[O-]
Agent: Cl
Agent: [Cl-]
Solvent: CO
Product: CCCCC(=N)NCc1ccc(-c2ccccc2C#N)cc1

Procedure:
The title compound is prepared by stirring one equivalent of methyl valerimidate hydrochloride, one equivalent of 4-aminomethyl-2'-cyanobiphenyl, and one equivalent of sodium methoxide in methanol. The reaction mixture may then be stripped of solvent and the amidine and residual sodium chloride is used directly in the next reaction.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15](=[O:16])[C:14]([CH3:18])([CH3:17])[N:13]([CH2:19][C:20]3[CH:25]=[CH:24][N+:23]([O-:26])=[C:22]([NH:27][C:28](=O)C)[CH:21]=3)[C:12]2=[O:31])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])O.[Na+].C(Cl)(Cl)=[S:38]>C(O)C>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([N:11]2[C:15](=[O:16])[C:14]([CH3:18])([CH3:17])[N:13]([CH2:19][C:20]3[CH:25]=[CH:24][N:23]4[O:26][C:28](=[S:38])[N:27]=[C:22]4[CH:21]=3)[C:12]2=[O:31])=[CH:9][CH:10]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: S=C(Cl)Cl
Reactant: CC(=O)Nc1cc(CN2C(=O)N(c3ccc(C(C)(C)C)cc3)C(=O)C2(C)C)cc[n+]1[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)c1ccc(N2C(=O)N(Cc3ccn4oc(=S)nc4c3)C(C)(C)C2=O)cc1
Reaction time: 0.5 h
Yield: 91.7 %

Procedure:
To a solution of 240 mg of N-(4-{[3-(4-tert-butylphenyl)-5,5-dimethyl-2,4-dioxoimidazolidin-1-yl]methyl}-1-oxidopyridin-2-yl)acetamide obtained in stage a) below in 6 mL of ethanol are added 109 mg of sodium hydrogen carbonate and 75 mg of thiocarbonyl dichloride. After stirring for 2 hours 30 minutes, the solid in suspension is filtered off, washed with ethanol and dried. 220 mg of 3-(4-tert-butylphenyl)-5,5-dimethyl-1-[(2-thioxo-2H-[1,2,4]oxadiazolo[2,3-a]pyridin-7-yl)methyl]imidazol-idine-2,4-dione are obtained in the form of a beige-coloured powder, the characteristics of which are as follows:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH:11]2[CH2:14][CH2:13][CH2:12]2)=[C:6]([N+:15]([O-])=O)[CH:5]=1>C(O)C.[Pd]>[CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH:11]2[CH2:14][CH2:13][CH2:12]2)=[C:6]([NH2:15])[CH:5]=1
Reactant: COC(=O)c1ccc(NC2CCC2)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCO
Product: COC(=O)c1ccc(NC2CCC2)c(N)c1
Yield: 128.5 %

Procedure:
To a solution of 4-cyclobutylamino-3-nitro-benzoic acid methyl ester (18.959, 56.3 mmol) in ethyl alcohol (300 ml) in a Parr shaker was added 10% Pd/C (0.67 g). The reaction was subjected to an atmosphere of hydrogen (50 psi) until the consumption of hydrogen ceased (2 hours). The reaction mixture was filtered through a pad of Celite® and concentrated to give 15.94 g of 3-Amino-4-cyclobutylamino-benzoic acid methyl ester as a solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=2)[C@@H:9]([NH:18][C:19]2[C:24]([CH2:25][C:26]3[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[C:28]([C:36]([F:39])([F:38])[F:37])[CH:27]=3)=[CH:23][C:22]([C:40]3[NH:44][N:43]=[N:42][N:41]=3)=[CH:21][N:20]=2)[CH2:8][C@H:7]1[CH2:45][CH3:46])=[O:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:54][CH2:55][OH:56].O>CN(C)C=O.C(OCC)(=O)C>[CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=2)[C@@H:9]([NH:18][C:19]2[C:24]([CH2:25][C:26]3[CH:27]=[C:28]([C:36]([F:39])([F:38])[F:37])[CH:29]=[C:30]([C:32]([F:35])([F:33])[F:34])[CH:31]=3)=[CH:23][C:22]([C:40]3[N:41]=[N:42][N:43]([CH2:54][CH2:55][OH:56])[N:44]=3)=[CH:21][N:20]=2)[CH2:8][C@H:7]1[CH2:45][CH3:46])=[O:5])[CH3:2]
Reactant: OCCBr
Reactant: CCOC(=O)N1c2ccc(OC)nc2[C@@H](Nc2ncc(-c3nnn[nH]3)cc2Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C[C@H]1CC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)N1c2ccc(OC)nc2[C@@H](Nc2ncc(-c3nnn(CCO)n3)cc2Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C[C@H]1CC
Temperature: 50 °C
Reaction time: 2 h

Procedure:
(2R*,4S*)-4-{[3,5-Bis(trifluoromethyl)benzyl]-[5-(tetrazol-5-yl)pyridin-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (120 mg), potassium carbonate (51 mg) and excess of 2-bromoethanol are dissolved in N,N-dimethylformamide (3 ml), and the mixture is stirred at 50° C. for 2 hours. Water and ethyl acetate are added to the reaction solution and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by column chromatography (silica gel; hexane: ethyl acetate=2:1→1:1) to give (2R*,4S*)-4-([3,5-bis(trifluoromethyl)benzyl]-{5-[2-(2-hydroxyethyl)-2H-tetrazole-5-yl]pyridin-2-yl})amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (119 mg). MS (m/z): 695 [M+H]+
Reaction SMILES: [Br:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][C:7]2[C:12]([CH3:13])=[CH:11][C:10]([N+:14]([O-])=O)=[C:9]([CH3:17])[CH:8]=2)=[CH:4][CH:3]=1.O.O.[Sn](Cl)Cl.[OH-].[Na+]>O1CCOCC1.Cl>[Br:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][C:7]2[C:12]([CH3:13])=[CH:11][C:10]([NH2:14])=[C:9]([CH3:17])[CH:8]=2)=[CH:4][CH:3]=1
Reactant: Cc1cc([N+](=O)[O-])c(C)cc1Oc1ccc(Br)cc1
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1cc(Oc2ccc(Br)cc2)c(C)cc1N
Temperature: 25 °C
Yield: 51.9 %

Procedure:
A solution of 18.90 g (46.9 mmol) of 4-(4-bromophenoxy)-2,5-dimethylnitrobenzene in 150 ml of dioxane and 150 ml of hydrochloric acid is admixed with 31.77 g (140.8 mmol) of tin(II) chloride dihydrate at room temperature and the mixture is then refluxed for 3.5 h. It is cooled to room temperature, neutralized with 10% strength aqueous sodium hydroxide solution and extracted repeatedly with ethyl acetate, and the extracts are dried over Na2SO4 and filtered, and the solvent is removed under reduced pressure. This is followed by purification by column chromatography (8.10 g, purity 88.0%, yield 51.9%, log P (pH 2.3)=2.88).
Reaction SMILES: [CH3:1][N:2]1[CH2:9][CH2:8][CH2:7][C@H:3]1[C:4]([OH:6])=[O:5].S(Cl)(Cl)=O.[CH3:14]O>>[CH3:14][O:5][C:4](=[O:6])[C@@H:3]1[CH2:7][CH2:8][CH2:9][N:2]1[CH3:1]
Reactant: CO
Reactant: CN1CCC[C@H]1C(=O)O
Solvent: O=S(Cl)Cl
Product: COC(=O)[C@@H]1CCCN1C
Temperature: 25 °C

Procedure:
To a solution of N-methyl (L)-proline, from step 3a, in methanol at 0° C. is added thionyl chloride (1.1 eq) dropwise, and the reaction mixture is slowly allowed to warm to room temperature. Upon completion of the reaction the solvent is removed in vacuo, and the crude product is dissolved in 10% aq. HCl and washed with ether. The aqueous layer is adjusted to pH--12 with K2CO3 (solid) and extracted with CH2Cl2. The combined CH2Cl2 layers are dried (MgSO4) and concentrated to afford the crude product as a clear oil.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:27][C:28]1[CH:29]=[N:30][C:31]([N:38]2[CH2:41][CH:40](OS(C)(=O)=O)[CH2:39]2)=[C:32]([CH:37]=1)[C:33]([O:35]C)=[O:34].[OH-].[Na+]>CN(C)C=O>[C:17]([O:16][C:14]([N:11]1[CH2:12][CH2:13][N:8]([C:4]2[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=2)[O:1][CH:40]2[CH2:41][N:38]([C:31]3[N:30]=[CH:29][C:28]([Cl:27])=[CH:37][C:32]=3[C:33]([OH:35])=[O:34])[CH2:39]2)[CH2:9][CH2:10]1)=[O:15])([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc(O)c2)CC1
Reactant: COC(=O)c1cc(Cl)cnc1N1CC(OS(C)(=O)=O)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(c2cccc(OC3CN(c4ncc(Cl)cc4C(=O)O)C3)c2)CC1
Temperature: 120 °C
Reaction time: 21 h

Procedure:
To a solution of tert-butyl 4-(3-hydroxyphenyl)piperazine-1-carboxylate (D18) (143.18 mg, 0.514 mmole) in dimethylformamide (2 ml), potassium carbonate (71 mg, 0.514 mmol) and the reaction mixture was heated 2 h at 80° C. methyl 5-chloro-2-(3-((methylsulfonyl)oxy)azetidin-1-yl)nicotinate (D63) (150 mg, 0.467 mmol) in dimethylformamide (2 ml) was added dropwise and the resulting mixture stirred 21 h at 120° C. After cooling at room temperature, 1M NaOH (0.935 ml) was added and the mixture stirred 1 h at 120° C. After cooling the reaction mixture was extracted with diethylether (2×10 ml) and the aqueous was evaporated in vacuo. The residue was purified by SPE-Si cartridge (5 g) eluting with a mixture dichloromethane/methanol from 100/0 to 80/20. Collected fractions, after solvent evaporation afforde the title compound (D110) (155 mg)
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.[NH2:18][C:19]([CH3:25])([CH3:24])[C:20]([NH:22][CH3:23])=[O:21]>>[CH3:24][C:19]([NH:18][C:15]([C:7]1[CH:6]=[CH:5][C:4]([CH:1]2[CH2:2][CH2:3]2)=[C:9]([O:10][CH2:11][CH:12]2[CH2:13][CH2:14]2)[N:8]=1)=[O:17])([C:20](=[O:21])[NH:22][CH3:23])[CH3:25]
Reactant: O=C(O)c1ccc(C2CC2)c(OCC2CC2)n1
Reactant: CNC(=O)C(C)(C)N
Product: CNC(=O)C(C)(C)NC(=O)c1ccc(C2CC2)c(OCC2CC2)n1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (Example 42 a) and 2-amino-N,2-dimethyl-propanamide (CAN 106914-07-2) as starting materials, MS (LC/MS): 332.2 [M+H]+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH2:9][C:10](=[O:16])[NH:11]3)=[CH:3][CH:2]=1.[CH2:17]([N:19]([CH2:34][CH3:35])[CH2:20][CH2:21][NH:22][C:23]([C:25]1[C:29]([CH3:30])=[C:28]([CH:31]=O)[NH:27][C:26]=1[CH3:33])=[O:24])[CH3:18]>>[CH2:34]([N:19]([CH2:17][CH3:18])[CH2:20][CH2:21][NH:22][C:23]([C:25]1[C:29]([CH3:30])=[C:28]([CH:31]=[C:9]2[C:8]3[C:12](=[CH:13][CH:14]=[CH:15][C:7]=3[C:4]3[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=3)[NH:11][C:10]2=[O:16])[NH:27][C:26]=1[CH3:33])=[O:24])[CH3:35]
Reactant: O=C1Cc2c(cccc2-c2ccncc2)N1
Reactant: CCN(CC)CCNC(=O)c1c(C)[nH]c(C=O)c1C
Product: CCN(CC)CCNC(=O)c1c(C)[nH]c(C=C2C(=O)Nc3cccc(-c4ccncc4)c32)c1C

Procedure:
4-Pyridin-4-yl-1,3-dihydroindol-2-one was condensed with 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylaminoethyl)-amide to give the title compound.
Reaction SMILES: [H-].[Na+].Cl[C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([N+:14]([O-:16])=[O:15])=[CH:6][N:5]=1.[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][CH:27]([OH:30])[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18].Cl>C1COCC1.O>[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][CH:27]([O:30][C:4]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7]([N+:14]([O-:16])=[O:15])=[CH:6][N:5]=2)[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:18])[CH3:19]
Reactant: O=[N+]([O-])c1cnc(Cl)c2ccccc12
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(Oc2ncc([N+](=O)[O-])c3ccccc23)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 72.5 %

Procedure:
Add NaH (60% in mineral oil, unwashed; 6.23 g, 156 mmol) in portions to a solution of 1-chloro-4-nitroisoquinoline (26.0 g, 125 mmol) and 1-tert-butoxycarbonyl-4-hydroxypiperidine (27.6 g, 137 mmol) in THF (350 mL) stirred at room temperature under nitrogen flow. Stir the dark reddish mixture at 40° C. for 1.5 hours then 55° C. for 1.5 hours. Add additional NaH (1.3 g), and stir the resulting mixture at 55° C. for 2 hours then cool to room temperature overnight. Add hexanes (75 mL), then add water (600 mL) slowly. Adjust the reaction mixture to pH 7 with aqueous HCl (1 N), then separate layers. Discard the aqueous layer and add hexanes (200 mL) to the organic layer. Partially concentrate the mixture under reduced pressure to a volume of 50-100 mL. Add diethyl ether (150 mL) and hexanes (250 mL), then filter the resultant slurry. Wash the cake with diethyl ether/hexanes (1:1) and air-dry to provide 4-(4-nitro-isoquinolin-1-yloxy)-piperidine-1-carboxylic acid tert-butyl ester (33.84 g, 73% yield) as a tan solid. (ES+): m/z 374 (M++H).
Reaction SMILES: [OH: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.[N+:14]([O-])([OH:16])=[O:15]>C(O)(=O)C>[OH:1][C:2]1[C:7]([N+:14]([O-:16])=[O:15])=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: Oc1ccccc1-c1ccccc1
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Product: O=[N+]([O-])c1cccc(-c2ccccc2)c1O

Procedure:
In step (1) of Reaction Scheme 1, a 2-hydroxybiphenyl of Formula II is nitrated using nitric acid in the presence of acetic acid to provide a 2-hydroxy-3-nitrobiphenyl of Formula III. A preferred method of carrying out this reaction is as follows. The biphenyl of Formula II is dissolved in glacial acetic acid at a temperature of 15° to 20° C. Concentrated nitric acid is then added thereto and the resulting mixture is stirred for a short period of time (usually less than about one hour). Thereafter the mixture is diluted with an equal volume of water. The 2-hydroxy-3-nitrobiphenyl of Formula III is separated from the mixture, usually as an oil, and is triturated with hot hexane and purified by chromotography. As an alternative to conducting step (1), known 2-hydroxy-3-nitrobiphenyls may be employed directly in step (2) below.
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.[CH3:45][C:46]1([CH3:61])[CH2:48][CH:47]1[CH:49](O)[C@@H:50]([NH:52][C:53](=[O:59])[O:54][C:55]([CH3:58])([CH3:57])[CH3:56])[CH3:51]>C1COCC1>[CH3:61][C:46]1([CH3:45])[CH2:48][CH:47]1[CH:49]([N:5]1[C:1](=[O:11])[C:2]2[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4]1=[O:6])[C@@H:50]([NH:52][C:53](=[O:59])[O:54][C:55]([CH3:58])([CH3:57])[CH3:56])[CH3:51]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(O)C1CC1(C)C
Reactant: O=C1NC(=O)c2ccccc21
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C[C@H](NC(=O)OC(C)(C)C)C(C1CC1(C)C)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 7.3 %

Procedure:
Phthalimide (0.147 g), triphenylphosphine (0.34 g), and diisopropyl azodicarboxylate (0.684 ml) were added to a THF (5 ml) solution containing tert-butyl ((2S)-1-(2,2-dimethylcyclopropyl)-1-hydroxypropan-2-yl)carbamate (0.20 g), followed by stirring at room temperature for 1.5 hours. The solvent was distilled away under reduced pressure and the obtained residue was purified by silica gel chromatography (n-hexane:ethyl acetate=1:0 to 1:0.2). A yellow liquid of tert-butyl ((2S)-1-(2,2-dimethylcyclopropyl)-1-(1,3-dioxoisoindolin-2-yl)propan-2-yl)carbamate (22.4 mg) was thus obtained.
Reaction SMILES: [N+:1]([CH:4]=[CH:5][C:6]1[CH:7]=[C:8]([O:12][C:13](=[O:15])[CH3:14])[CH:9]=[CH:10][CH:11]=1)([O-:3])=[O:2].C(O)(C)C.[BH4-].[Na+].C(OC(=O)C)(=O)C>C(Cl)(Cl)Cl.N1C=CC=CC=1>[N+:1]([CH2:4][CH2:5][C:6]1[CH:7]=[C:8]([O:12][C:13](=[O:15])[CH3:14])[CH:9]=[CH:10][CH:11]=1)([O-:3])=[O:2]
Reactant: CC(=O)Oc1cccc(C=C[N+](=O)[O-])c1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)Oc1cccc(CC[N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
Dissolve acetic acid 3-(2-nitrovinyl)-phenyl ester (25.56 g, 123.38 mmol) in chloroform (1575 mL). Add silica gel (247 g, 2 g/mmol) and isopropanol (370 mL) with mechanical stirring. Add portionwise sodium borohydride (18.67 g, 493.5 mmol) over 10 minutes. Stir at room temperature for 1 hour. Quench with 1 N hydrochloric acid (130 mL) over 20 minutes and stir at room temperature for 15 minutes. Filter solid and wash with dichloromethane (800 mL). Wash filtrate with saturated aqueous sodium chloride (300 mL), dry (magnesium sulfate), filter and concentrate to give the crude phenol intermediate contaminated with reduced starting material which is used directly in the next step. Dissolve the crude intermediate (23.14 g, ˜110 mmol) in pyridine (75 mL), cool in an ice bath and add acetic anhydride (4.1 mL, 44 mmol). Stir for 1 hour. Concentrate at −20° C., dissolve in ethyl acetate (150 mL), wash with cool 1 N hydrochloric acid (4×200 mL), saturated aqueous sodium chloride and dry (magnesium sulfate) and concentrate. Extract the aqueous washes with ethyl acetate, dry (magnesium sulfate) and concentrate. Combine both lots to give the desired compound as an orange oil (25.55 g, 99% total yield).
Reaction SMILES: [OH:1][C:2]([CH3:20])([CH3:19])[CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:15]2[C:14](=[O:16])[NH:13][C:12](=[O:17])[N:11]([CH3:18])[C:10]=2[N:9]=[CH:8]1.IC.[CH3:23]N1C(=O)C2N(CCCCC(=O)C)C=NC=2N(C)C1=O.C[Mg]Cl.[Br-].CN1C(=O)C2N(CCCC=C(C)C)C=NC=2N(C)C1=O>CCOCC>[OH:1][C:2]([CH3:20])([CH3:19])[CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:15]2[C:14](=[O:16])[N:13]([CH3:23])[C:12](=[O:17])[N:11]([CH3:18])[C:10]=2[N:9]=[CH:8]1
Reactant: Cn1c(=O)[nH]c(=O)c2c1ncn2CCCCC(C)(C)O
Reactant: CC(=O)CCCCn1cnc2c1c(=O)n(C)c(=O)n2C
Agent: CC(C)=CCCCn1cnc2c1c(=O)n(C)c(=O)n2C
Agent: C[Mg]Cl
Agent: [Br-]
Solvent: CI
Solvent: CCOCC
Product: Cn1c(=O)c2c(ncn2CCCCC(C)(C)O)n(C)c1=O

Procedure:
Alternatively, it was possible to prepare the compound, inter alia, from 7-(5-hydroxy-5-methylhexyl)-3-methylxanthine (Example 1b) and iodomethane analogously to Example 3, from 1,3-dimethyl-7-(5-oxohexyl)-xanthine and methylmagnesium chloride or bromide in anhydrous ether analogously to Example 9, and from 1,3-dimethyl-7-(5-methyl-4-hexenyl)-xanthine by acid-catalyzed hydration analogously to Example 14.
Reaction SMILES: BrC1C=C([C:9]2[O:10][C:11]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[CH:16][CH:15]=3)=[N:12][N:13]=2)C=C(Br)C=1.B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.C([O-])(=O)C.[K+]>CS(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:21]([O:20][C:17]1[CH:16]=[CH:15][C:14]([C:11]2[O:10][CH:9]=[N:13][N:12]=2)=[CH:19][CH:18]=1)[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: CCCCCCCCOc1ccc(-c2nnc(-c3cc(Br)cc(Br)c3)o2)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CS(C)=O
Product: CCCCCCCCOc1ccc(-c2nnco2)cc1

Procedure:
Following this general procedure 2-(3,5-Dibromophenyl)-5-[4-(octyloxy)phenyl]-1,3,4-oxadiazole, bis(pinacolato)diboron, potassium acetate, and [1,1′-bis(diphenylphosphino)-ferrocene]dichloropalladium (II) (complexed 1:1 with dichlormethane—Aldrich, 0.089 g, 0.1 mmoles) are reacted in DMSO under nitrogen at 80° C. for 18 hrs. After cooling, the reaction mixture is poured onto ice water, the aqueous layer extracted three times with methylene chloride, the combined organic fractions washed with brine, dried over magnesium sulfate, filtered through a thin silica bed, rotoevaporated to yield the desired 2-(3,5-bis(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)) phenyl)-5-[4-(octyloxy)phenyl]-1,3,4-oxadiazole. These general methods can be used to prepare a wide range of arylene oxadiazole, triazole and thiadiazole diboronic ester intermediates useful in preparing compounds of Formula 1.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[C:7]2[N:15]=[N:14][N:13]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-])=O)[CH:18]=3)[C:8]=2[N:9]=[C:10]([NH2:12])[N:11]=1.Cl[Sn]Cl.[OH-].[Na+]>CCO.Cl.O>[NH2:23][C:19]1[CH:18]=[C:17]([CH:22]=[CH:21][CH:20]=1)[CH2:16][N:13]1[C:8]2[N:9]=[C:10]([NH2:12])[N:11]=[C:6]([C:2]3[O:1][CH:5]=[CH:4][CH:3]=3)[C:7]=2[N:15]=[N:14]1
Reactant: Nc1nc(-c2ccco2)c2nnn(Cc3cccc([N+](=O)[O-])c3)c2n1
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Nc1cccc(Cn2nnc3c(-c4ccco4)nc(N)nc32)c1
Reaction time: 2 h
Yield: 91.8 %

Procedure:
A solution of 7-(2-furyl)-3-(3-nitrobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine (152 mg, 0.45 mmol) in EtOH (2 mL) at 50° C. was treated with a solution of SnCl2 (305 mg, 1.35 mmol) in conc. HCl (0.7 mL), stirred for 2 h, cooled, diluted with water, basified to pH 10 (5-M, NaOH) and filtered to give the title compound (127 mg, 92%) as a white solid.
Reaction SMILES: [CH2:1]([O:3][CH2:4][O:5][C:6]1[CH:13]=[C:12]([O:14][CH2:15][O:16][CH2:17][CH3:18])[CH:11]=[CH:10][C:7]=1C=O)[CH3:2].C1C=C(Cl)C=C(C(OO)=[O:27])C=1>C(Cl)Cl>[CH2:1]([O:3][CH2:4][O:5][C:6]1[CH:13]=[C:12]([O:14][CH2:15][O:16][CH2:17][CH3:18])[CH:11]=[CH:10][C:7]=1[OH:27])[CH3:2]
Reactant: CCOCOc1ccc(C=O)c(OCOCC)c1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CCOCOc1ccc(O)c(OCOCC)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 282.4 %

Procedure:
A solution of 2a (3.78 g, 12.0 mmol) in anhydrous CH2Cl2 (4.0 mL) was slowly added to mCPBA (70%) (3.26 g, 13.2 mmol) in anhydrous CH2Cl2 (16.3 mL) at 0° C. The resulting solution was warmed to room temperature, then refluxed for 12 hours. After cooling to room temperature, the resulting solution was washed with saturated aqueous NaHCO3 solution (3×20 mL) and 10% aqueous Na2S2O3 (30 mL). Combined organic fractions were dried (Na2SO4), filtered, and concentrated. The residue was re-dissolved in MeOH (5 mL) and stirred with excess 10% aqueous NaOH for 3 hours at room temperature. The pH was adjusted to 2 with 6 M HCl and the solution was extracted with CH2Cl2 (3×10 mL). Combined organic fractions were dried (Na2SO4), filtered, and concentrated to give 3a as an orange oil (8.21 g, 94%): 1H NMR (CDCl3, 500 MHz) 6.89-6.85 (m, 2H), 6.67 (dd, J=8.8, 2.7 Hz, 1H), 5.81 (d, J=6.6 Hz, 1H), 5.23 (s, 2H), 5.15 (s, 2H), 3.80-3.73 (m, 4H), 1.29-1.24 (m, 6H); 13C NMR (CDCl3, 125 MHz) δ 151.0, 145.0, 141.5, 115.2, 110.6, 106.0, 94.9, 94.2, 64.8, 64.1, 15.1, 15.1; IR (film) νmax 3362, 2887, 1460, 1286, 1162, 735 cm−1; HRMS (ESI+) m/z: [M+Na]+ calcd for C12H18O5, 265.1052. found, 265.1045.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH3:9].[C:10]1(B(O)O)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[F-].[Cs+]>O1CCOCC1>[C:10]1([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[O:8][CH3:9])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: COc1ccccc1Cl
Reactant: OB(O)c1ccccc1
Agent: [Cs+]
Agent: [F-]
Solvent: C1COCCO1
Product: COc1ccccc1-c1ccccc1
Temperature: 25 °C
Yield: 90.1 %

Procedure:
A 100 mL of reactor equipped with magnetic stir bar was charged with 150 mg (0.161 mmol) of {[(t-Bu)2P(OH)]2PdCl}2 (from Experiment 7), 1.43 g (10.0 mmol) of 2-chloroanisole, 1.83 g (15.0 mmol) of PhB(OH)2 and 4.56 g (30.0 mmol) of CsF in 30.0 mL of dioxane. The resulting mixture was refluxed for 12 h until the starting material was completely consumed as judged by TLC. The reaction was cooled to room temperature, transferred to a separatory funnel, and diluted with 300 mL of diethyl ether. The layers were separated, and organic layer was washed with H2O (2×100 mL), brine (100 mL), and dried over mgSO4, filtered, and the ether and dioxane removed from the filtrate by rotary evaporation. The resulting residue was chromatographed on silicon gel using 2% EtOAc/hexane as eluant. The eluate was concentrated by rotary evaporation followed by high vacuum to give 1.66 g (90% yield) of 2-phenylanisole.