Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:11]=2[N:12]=1.[NH:21]1[CH:25]=[N:24][CH:23]=[N:22]1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[N:21]1([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][C:7]=2[C:8]2[O:9][C:10]3[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:11]=3[N:12]=2)[CH:25]=[N:24][CH:23]=[N:22]1
Reactant: Fc1cnccc1-c1nc2cc(C(F)(F)F)ccc2o1
Reactant: c1nc[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: FC(F)(F)c1ccc2oc(-c3ccncc3-n3cncn3)nc2c1
Temperature: 50 °C
Yield: 79.1 %

Procedure:
A mixture of 0.28 g of 2-(3-fluoropyridin-4-yl)-5-(trifluoromethyl)benzoxazole, 0.10 g of 1H-1,2,4-triazole, 0.55 g of potassium carbonate and 2 ml of DMF was stirred while heating at 50° C. for 1.5 hours. Then, the reaction mixture was cooled to room temperature. Water was added to the reaction mixture, followed by extraction with ethyl acetate twice. The combined organic layers were washed with a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.26 g of 2-[3-(1,2,4-triazole-1-yl)pyridin-4-yl]-5-(trifluoromethyl)benzoxazole (hereinafter, referred to as “active compound 63”).
Reaction SMILES: [O:1]([C:8]1[CH:16]=[CH:15][C:11]([C:12](Cl)=[O:13])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:17]([NH2:25])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][NH2:24].[C:26](=[O:29])([O-])[O-].[K+].[K+]>C(Cl)CCl>[O:1]([C:8]1[CH:16]=[CH:15][C:11]([C:12]([NH:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][NH:25][C:26](=[O:29])[C:11]2[CH:15]=[CH:16][C:8]([O:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:9][CH:10]=2)=[O:13])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccc(Oc2ccccc2)cc1
Reactant: NCCCCCCCN
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCCl
Product: O=C(NCCCCCCCNC(=O)c1ccc(Oc2ccccc2)cc1)c1ccc(Oc2ccccc2)cc1

Procedure:
m.p. 164°-165° C., 9.9 g., was prepared as in Example 23 using 12.0 g. of 4-phenoxybenzoyl chloride (from 16.0 g. of 4-phenoxybenzoic acid as in Example 6) in 20 ml. of ethylene dichloride, 3.8 g. of 1,7-heptanediamine, 40 ml. of ethylene dichloride, 6.9 g. of potassium carbonate, 63 ml. of water and recrystallization from ethylene dichloride.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:19]#[N:20])=[N:4][C:5]([C:9]2[CH:14]=[CH:13][C:12](=[O:15])[N:11]([CH:16]([CH3:18])[CH3:17])[N:10]=2)=[CH:6][N+:7]=1[O-].P(Cl)(Cl)([Cl:23])=O.O.[CH3:27][N:28]([CH:30]=O)[CH3:29]>>[Cl:23][C:6]1[N:7]=[C:2]([N:1]=[CH:27][N:28]([CH3:30])[CH3:29])[C:3]([C:19]#[N:20])=[N:4][C:5]=1[C:9]1[CH:14]=[CH:13][C:12](=[O:15])[N:11]([CH:16]([CH3:18])[CH3:17])[N:10]=1
Reactant: CN(C)C=O
Reactant: CC(C)n1nc(-c2c[n+]([O-])c(N)c(C#N)n2)ccc1=O
Reactant: O=P(Cl)(Cl)Cl
Solvent: O
Product: CC(C)n1nc(-c2nc(C#N)c(N=CN(C)C)nc2Cl)ccc1=O
Reaction time: 3 h

Procedure:
A solution of 3-amino-6-(1-isopropyl-6-oxo-1,6-dihydro-3-pyridazinyl)-2-pyrazinecarbonitrile 4-oxide (1.54 g) in DMF (30 ml) was stirred at 0° C. Phosphorous oxychloride (1.58 ml) was dropped to the solution and the reaction mixture was stirred under same condition for 3 hours. Water was added to the reaction mixture. The reaction mixture was stirred at 20° C. for 20 hours to give a yellow precipitate. The precipitate was collected by filtration to obtain yellow powder. The residue was purified by silica gel column chromatography eluted with a mixture of n-hexane and EtOAc. The fractions were concentrated in vacuo to obtain N′-[6-chloro-3-cyano-5-(1-isopropyl-6-oxo-1,6-dihydro-3-pyridazinyl)-2-pyrazinyl]-N,N-dimethylimidoformamide (1.0 g) as white powder.
Reaction SMILES: [N+]([C:4]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[C:5]=1[C:6]#[N:7])([O-])=O.[CH3:15][O:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21][OH:22])=[CH:19][CH:18]=1>>[N+:12]([C:8]1[CH:9]=[CH:10][CH:11]=[C:4]([O:22][CH2:21][C:20]2[CH:23]=[CH:24][C:17]([O:16][CH3:15])=[CH:18][CH:19]=2)[C:5]=1[C:6]#[N:7])([O-:14])=[O:13]
Reactant: N#Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Reactant: COc1ccc(CO)cc1
Product: COc1ccc(COc2cccc([N+](=O)[O-])c2C#N)cc1
Yield: 81 %

Procedure:
Prepared as in Example 112c from 2,6-dinitrobenzonitrile and 4-methoxybenzyl alcohol to provide 2-nitro-6-(4-methoxybenzyloxy)benzonitrile (2.40 g, 81%). 1H NMR (400 MHz, CDCl3) δ 3.82 (s, 3H), 5.26 (s, 2H), 6.93 (m, 2H), 7.35 (dd, J=8.6, 0.7 Hz, 1H), 7.38 (m, 2H), 7.65 (t, J=8.6 Hz, 1H), 7.83 (dd, J=8.2, 0.8 Hz, 1H).
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[Li][CH2:11][CH2:12][CH2:13][CH3:14].Br[CH2:16][CH2:17][CH2:18]Br>CCCCCC.C1COCC1>[CH:1]1([CH2:14][CH2:13][CH2:12][CH:11]2[C:8]3[C:18](=[CH:3][CH:2]=[CH:1][CH:9]=3)[CH:17]=[CH:16]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: C1=Cc2ccccc2C1
Reactant: [Li]CCCC
Reactant: BrCCCBr
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C1=CC(CCCC2C=Cc3ccccc32)c2ccccc21
Temperature: -78 °C
Yield: 72 %

Procedure:
12.8 mL of indene (91% by GC, 0.1 mol) and 130 mL of THF were placed in a 250 mL flask equipped with stirring bar and dropping funnel. After cooling to −78° C., 62.6 mL of 1.6 M BuLi solution in hexane were added dropwise. At the end of the addition the reaction mixture was allowed to warm to room temperature. The so obtained dark solution was transferred into a 250 mL dropping funnel connected to a 0.5 L flask, and then added dropwise over 1 h to a solution of 10.1 g (5 mL, 0.05 mol) of 1,3-dibromopropane in 100 mL THF under vigorous stirring, while keeping the temperature of the reaction mixture in the range −70 to −75° C. throughout the addition. The cooling bath was removed and the mixture stirred overnight. 10 mL MeOH were then added and the solvents removed under reduced pressure. The obtained solid was suspended in 100 mL of a 4:1 hexane-CH2Cl2 mixture and passed through silica gel using the same mixture as eluent. The solvents were removed under reduced pressure and the resulting slightly yellow crystalline product was washed twice with small portions of cold ethanol and dried in vacuum. Yield 72%, purity 95.2% (G.C.).
Reaction SMILES: [Na].[CH2:2]([O:4][C:5]([CH:7]1[CH:16]([NH2:17])[CH2:15][CH2:14][C:9]2([O:13][CH2:12][CH2:11][O:10]2)[CH2:8]1)=[O:6])[CH3:3]>C(O)C>[NH2:17][C@@H:16]1[CH2:15][CH2:14][C:9]2([O:13][CH2:12][CH2:11][O:10]2)[CH2:8][C@H:7]1[C:5]([O:4][CH2:2][CH3:3])=[O:6]
Reactant: CCOC(=O)C1CC2(CCC1N)OCCO2
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)[C@@H]1CC2(CC[C@H]1N)OCCO2
Temperature: 25 °C
Yield: 85.8 %

Procedure:
Sodium metal (27.7 g, 1.2 mole) was reacted with ethanol (1 l), then ethyl-8-amino-1,4-dioxaspiro[4.5]-decane-7-carboxylate (137.7 g, 0.6 mole) in ethanol (400 ml) was added. The mixture was refluxed for 11/2 hours, then cooled to room temperature, poured into ice, and made basic. The product was extracted with methylene chloride, dried with sodium sulfate and evaporated to give 118.0 g (85.7%) of the title product.
Reaction SMILES: [CH3:1][C:2]1(O)[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][CH2:4][C:3]1([CH3:11])[CH3:10].C1(C)C=CC(S(O)(=O)=O)=CC=1.O.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC=CC=1>[CH3:1][C:2]1[C:3]([CH3:11])([CH3:10])[CH2:4][CH2:5][C:6]([CH3:9])([CH3:8])[CH:7]=1
Reactant: CC1(C)CCC(C)(C)C(C)(O)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O
Product: CC1=CC(C)(C)CCC1(C)C

Procedure:
22.6 of 1,2,2,5,5-pentamethylcyclohexanol are dissolved in 280 ml of benzene and, after the addition of 100 mg of p-toluenesulphonic acid, the mixture is boiled on a water separator for 7 hours. After cooling the solution, some solid sodium carbonate is added thereto, the mixture is filtered and the filtrate is evaporated at normal pressure. The residue is distilled in a water-jet vacuum. There are obtained 15.8 g of 1,3,3,6,6-pentamethylcyclohexen as a colorless liquid, b.p. 56°-57° C./17 mm.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([O:17][C:18](=[O:27])[NH:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][OH:26])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.Cl[C:35]([O:37][C:38]1[CH:43]=[CH:42][C:41]([N+:44]([O-:46])=[O:45])=[CH:40][CH:39]=1)=[O:36]>C(Cl)Cl>[CH2:1]([O:8][C:9]([N:11]1[CH2:12][CH2:13][CH:14]([O:17][C:18](=[O:27])[NH:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][O:26][C:35]([O:37][C:38]2[CH:39]=[CH:40][C:41]([N+:44]([O-:46])=[O:45])=[CH:42][CH:43]=2)=[O:36])[CH2:15][CH2:16]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: O=C(NCCCCCCO)OC1CCN(C(=O)OCc2ccccc2)CC1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(NCCCCCCOC(=O)Oc1ccc([N+](=O)[O-])cc1)OC1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 39.5 %

Procedure:
A solution of the alcohol (50 g, 0.13 moles) produced in Example 22 and pyridine (10.7 ml, 0.13 moles) in 500 ml of methylene chloride was added dropwise under nitrogen to a solution of 4-nitrophenyl chloroformate (26.64 g, 0.13 mol) in 500 ml of methylene chloride at room temperature. After the addition, the reaction was stirred overnight at room temperature. A solid had formed which was removed by filtration. The filtrate was extracted two times with 1N HCl, multiple times with saturated Na2CO3, dried (MgSO4) and the solvent removed under reduced pressure. Recrystallization of the crude reaction product from hexane gave 27.9 g (39%) of the title compound as a light yellow crystalline solid, mp 78-80° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[N:8]([S:9]([C:12]2[CH:18]=[CH:17][C:15]([CH3:16])=[CH:14][CH:13]=2)(=[O:11])=[O:10])[C:7]2[CH:19]=[CH:20][C:21]([N+]([O-])=O)=[CH:22][C:6]=2[N:5]=1.COCC1NC2C=CC([N+]([O-])=O)=CC=2[N:30]=1.CC1C=CC(S(Cl)(=O)=O)=CC=1.CC(C)([O-])C.[Na+]>O1CCCC1.C(OCC)(=O)C.O>[CH3:1][O:2][CH2:3][C:4]1[N:8]([S:9]([C:12]2[CH:13]=[CH:14][C:15]([CH3:16])=[CH:17][CH:18]=2)(=[O:11])=[O:10])[C:7]2[CH:19]=[C:20]([NH2:30])[CH:21]=[CH:22][C:6]=2[N:5]=1
Reactant: COCc1nc2cc([N+](=O)[O-])ccc2n1S(=O)(=O)c1ccc(C)cc1
Reactant: COCc1nc2cc([N+](=O)[O-])ccc2[nH]1
Agent: CC(C)(C)[O-]
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COCc1nc2ccc(N)cc2n1S(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 42 %

Procedure:
2-(Methoxymethyl)-5-nitro-1-tosyl-1H-benzo[d]imidazole. 2-(Methoxymethyl)-5-nitro-1H-benzo[d]imidazole (1.23 g, 5.94 mmol) and 4-methylbenzene-1-sulfonyl chloride (1.358 g, 7.12 mmol) were dissolved in tetrahydrofuran (50 mL) and sodium tert-butoxide (1.141 g, 11.87 mmol) was added. The mixture was stirred at room temperature for 16 h. The reaction mixture was poured into a separatory funnel containing water and 50% ethyl acetate. The organic layer was concentrated on a rotary evaporator nearly to dryness and purified on silica column eluting with 0-50% ethyl acetate in hexane. The fractions containing product were concentrated on a rotary evaporator to give the desired product as white solid (0.9 g, 42% yield). MS (ESI) m/z 362.3 [M+1]+.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].I[CH2:8][CH2:9][CH3:10].[C:11]([C:14]1[C:15]([CH2:19][C:20]([O:22][CH3:23])=[O:21])=[CH:16][S:17][CH:18]=1)([OH:13])=[O:12]>CN(C=O)C.O>[CH2:8]([O:13][C:11]([C:14]1[C:15]([CH2:19][C:20]([O:22][CH3:23])=[O:21])=[CH:16][S:17][CH:18]=1)=[O:12])[CH2:9][CH3:10]
Reactant: COC(=O)Cc1cscc1C(=O)O
Reactant: CCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCOC(=O)c1cscc1CC(=O)OC
Reaction time: 3 h

Procedure:
Potassium carbonate (670 mg) and, after 15 minutes, 1-iodopropane (0.26 ml) were added successively to a stirred solution of methyl (4-carboxy-3-thienyl)acetate (490 mg) in DMF (10 ml). After 3 h, the resulting mixture was diluted with water and extracted with ether. The extracts were washed with water, dried, and concentrated to give methyl [4-(prop-1-yloxycarbonyl)-3-thienyl]acetate (600 mg, quantitative yield) as a yellow liquid, pure by GC, IR (film): 1735, 1710 cm-1, 1H nmr: delta 1.00 (3H, t), 1.75 (2H, q), 3.69 (3H, s), 3.92 (2H, s), 4.20 (2H, t), 7.13 (1H, d J 3.5 Hz), 8.12 (1H, d J 3.5 Hz) ppm.
Reaction SMILES: C1(C)C=CC=CC=1.[CH3:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]=C=O)=[CH:11][C:10]=1[N:18]=C=O.B(F)(F)F.CCOCC>O>[C:9]1([CH3:8])[C:10]([NH2:18])=[CH:11][C:12]([NH2:15])=[CH:13][CH:14]=1
Reactant: Cc1ccc(N=C=O)cc1N=C=O
Agent: FB(F)F
Solvent: O
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: Cc1ccc(N)cc1N
Yield: 97 %

Procedure:
20 parts toluene, 1.74 parts (0.01 mole) 2,4-toluenediisocyanate, 2.8 parts (0.02 mole) boron trifluoride etherate and 0.40 part (0.02 mole) distilled water were combined and reacted as described in Example 1. The neutralization and isolation procedures described in Example 2 were conducted. 1.17 parts (97% yield) 2,4-toluenediamine were recovered having a melting point of 96° C.-98° C.
Reaction SMILES: [CH2:1](P(=O)(OCC)OCC)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:16]1([S:22]([C:25]([CH3:37])([CH3:36])[CH2:26][CH2:27][CH2:28][N:29]2[CH2:34][CH2:33][CH2:32][C:31](=O)[CH2:30]2)(=[O:24])=[O:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[H-].[Na+]>CN1CCN(C)C1=O>[C:16]1([S:22]([C:25]([CH3:37])([CH3:36])[CH2:26][CH2:27][CH2:28][N:29]2[CH2:30][CH2:31][CH2:32]/[C:33](=[CH:1]/[C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)/[CH2:34]2)(=[O:24])=[O:23])[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CC(C)(CCCN1CCCC(=O)C1)S(=O)(=O)c1ccccc1
Reactant: CCOP(=O)(Cc1ccccc1)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCN(C)C1=O
Product: CC(C)(CCCN1CCC/C(=C/c2ccccc2)C1)S(=O)(=O)c1ccccc1
Reaction time: 0.5 h

Procedure:
A solution of diethyl benzylphosphonate (0.53 ml, 2.54 mmol) and 1-(4-benzenesulfonyl-4-methylpentyl)-3-piperidinone (0.7 g, 2.17 mmol) in 1,3-dimethylimidazolidin-2-one (5 ml) was added dropwise to a stirred slurry of sodium hydride (60% dispersion in mineral oil, 117 mg, 2.93 mmol) in 1,3-dimethylimidazolidin-2-one (3 ml). The reaction was stirred for 30 minutes then quenched by the addition of water. The mixture was extracted with dichloromethane. The combined organic layers were dried (MgSO4) and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel, eluting with 20–75% ethyl acetate/chloroform, followed by preparative HPLC.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([NH2:7])=[N:4][CH:3]=1.C1N=CN([C:13]([N:15]2[CH:19]=N[CH:17]=[CH:16]2)=[O:14])C=1.N1CCC[CH2:21]1>CN(C)C1C=CN=CC=1.O1CCCC1>[CH3:1][C:2]1[S:6][C:5]([NH:7][C:13]([N:15]2[CH2:16][CH2:17][CH2:21][CH2:19]2)=[O:14])=[N:4][CH:3]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: C1CCNC1
Reactant: Cc1cnc(N)s1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: Cc1cnc(NC(=O)N2CCCC2)s1
Reaction time: 48 h

Procedure:
A solution of 5-methylthiazol-2-amine (4.8 g, 42 mmol), N,N-carbonyldiimidazole (9.8 g, 61 mmol), and 4-dimethylaminopyridine (0.1 g, 1.0 mmol) in tetrahydrofuran (90 mL) was heated at 65° C. for 6 hours. Pyrrolidine (5.1 mL, 61 mmol) was then added and heating was continued at 65° C. for 48 hours. The mixture was concentrated, and the residue was diluted with methanol and then triturated with diethyl ether. The solids were collected by filtration, washed with diethyl ether, and recrystallized from ethyl acetate to give the title compound.
Reaction SMILES: F[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=[O:7])=[CH:4][CH:3]=1.[NH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.[OH-].[Li+].[OH-].[Na+]>CN(C=O)C.C1COCC1.O>[N:12]1([C:2]2[CH:11]=[CH:10][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=2)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: COC(=O)c1ccc(F)cc1
Reactant: C1CCNCC1
Agent: [Li+]
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccc(N2CCCCC2)cc1
Temperature: 50 °C
Reaction time: 16 h

Procedure:
A mixture of methyl 4-fluorobenzoate (Lancaster 14154; 500 mg; 3.24 mmol; 1 eq.) and piperidine (Fluka 80640; 828.62 mg; 9.73 mmol; 3 eq.) in DMF (2 mL) was stirred at 50° C. for 16 hours. The reaction mixture was then passed through a short pad of silica and the obtained solution evaporated in vacuo to give a colourless oil. The oil was taken up in THF (15 mL) and lithium hydroxide (388.41 mg; 16.22 mmol; 5 eq.) was added followed by water (15 mL). The reaction mixture was stirred at room temperature for 6 hours then at 60° C. for 16 hours. NaOH (155.5 mg, 6.48 mmol, 2 eq) was then added and the reaction mixture was refluxed for 24 hours. After cooling, the solution was diluted with water and washed with Et2O. The aqueous layer was then acidified to pH 5-6 with acetic acid and the formed precipitate was collected by filtration, washed with water and dried under high vacuum to afford the title compound as a white solid.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([N:7]([C:14]2[CH:19]=[CH:18][C:17](Br)=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:3][CH:2]=1.[NH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>[C:4]1([N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:14]2[CH:19]=[CH:18][C:17]([NH:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:16][CH:15]=2)[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=1
Reactant: Brc1ccc(N(c2ccccc2)c2ccccc2)cc1
Reactant: Nc1ccccc1
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: c1ccc(Nc2ccc(N(c3ccccc3)c3ccccc3)cc2)cc1
Temperature: 25 °C
Yield: 85.1 %

Procedure:
4-bromo triphenylamine 7.6 g (23.45 mmol), aniline 21.85 g (0.235 mol), sodium tert-butoxide 6.76 g (70 mmol). Pd2(dba)3[(tris(dibenzilidene acetone)dipalladium(0))] 0.86 g (0.938 mmol) and tri(tert-butyl)phosphine 0.23 g (1.173 mmol) in 500 ml round bottom flask were dissolved with toluene 200 ml, and refluxed for 12 hours. After the reaction was terminated, the reaction solution was cooled to room temperature, and 200 ml of distilled water was added thereto to extract an organic layer. The organic layer was dried over MgSO4, concentrated, and purified by silica gel column chromatography. The eluate was concentrated and dried to give N,N,N′-triphenyl-p-phenylenediamine (6.71 g, 85%).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.C[N:8]([CH3:11])C=O.[F:12]/[CH:13]=[C:14](\[CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1)/CO.O>C1(C)C=CC=CC=1>[NH2:8][CH2:11]/[C:14](=[CH:13]/[F:12])/[CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1
Reactant: CN(C)C=O
Reactant: OC/C(=C/F)CCc1ccc(F)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: Cc1ccccc1
Product: NC/C(=C/F)CCc1ccc(F)cc1
Temperature: -5 °C
Reaction time: 0.5 h

Procedure:
Combine oxalyl chloride (25.2 g, 0.198 mol) and toluene (200 mL). Cool to -5° C. Add N,N-dimethylformamide (15.0 g, 0.21 mol) as a solution in toluene (20 mL). Warm to 25° C. After 30 minutes, add a solution of (E)-2-(fluoromethylene)-4-(p-fluorophenyl)butan-1-ol (24.7 g, 30% by weight in toluene, 0.124 mol). After 18 hours, add water (500 mL) and stir for 30 minutes. Separate the organic layer, dry over Na2SO4, filter, and evaporate in vacuo to give the title compound.
Reaction SMILES: [C:1]1([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:6]=[CH:5][C:4]([C:7]2[N:8]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)[C:9](=[O:23])[C:10]3[N:11]=[C:12]([CH3:22])[N:13]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[C:14]=3[N:15]=2)=[CH:3][CH:2]=1.C1C(=O)N([Br:44])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[C:1]1([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:2]=[CH:3][C:4]([C:7]2[N:8]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)[C:9](=[O:23])[C:10]3[N:11]=[C:12]([CH2:22][Br:44])[N:13]([C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=4)[C:14]=3[N:15]=2)=[CH:5][CH:6]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1nc2c(=O)n(-c3ccc(Cl)cc3)c(-c3ccc(-c4ccccc4)cc3)nc2n1-c1ccccc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: O=c1c2nc(CBr)n(-c3ccccc3)c2nc(-c2ccc(-c3ccccc3)cc2)n1-c1ccc(Cl)cc1
Temperature: 80 °C
Yield: 77.9 %

Procedure:
A solution of 2-biphenyl-4-yl-1-(4-chloro-phenyl)-8-methyl-9-phenyl-1,9-dihydro-purin-6-one (51 mg, 0.104 mmol) in CCl4 (2 mL) was treated sequentially with NBS (24 mg, 0.135 mmol) followed by AIBN (22 mg, 0.135 mmol). The reaction was heated at 80° C. for 3 h, allowed to cool to room temperature, and concentrated in vacuo. The crude oil was purified by flash column chromatography (silica, 0 30% Hex/EtOAc) to provide 2-biphenyl-4-yl-8-bromomethyl-1-(4-chloro-phenyl)-9-phenyl-1,9-dihydro-purin-6-one (46 mg, 78%) as a white solid. HPLC-MS calculated for C30H20BrClN4O (M+H+): 567.1. Found: 567.1.
Reaction SMILES: [OH:1][CH:2]([C:15]1[CH:20]=[CH:19][C:18]([C:21](=[N:23][OH:24])[NH2:22])=[CH:17][CH:16]=1)[CH2:3][N:4]1[CH2:7][CH:6]([C:8]([O:10]C(C)(C)C)=[O:9])[CH2:5]1.CCN(C(C)C)C(C)C.[C:34]1([C:40]2[C:44]([C:45]([F:48])([F:47])[F:46])=[C:43]([C:49](F)=O)[O:42][N:41]=2)[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C(#N)C.C(OCC)(=O)C>[OH:1][CH:2]([C:15]1[CH:16]=[CH:17][C:18]([C:21]2[N:22]=[C:49]([C:43]3[O:42][N:41]=[C:40]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[C:44]=3[C:45]([F:48])([F:46])[F:47])[O:24][N:23]=2)=[CH:19][CH:20]=1)[CH2:3][N:4]1[CH2:5][CH:6]([C:8]([OH:10])=[O:9])[CH2:7]1
Reactant: CC(C)(C)OC(=O)C1CN(CC(O)c2ccc(C(N)=NO)cc2)C1
Reactant: O=C(F)c1onc(-c2ccccc2)c1C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Solvent: CCOC(C)=O
Product: O=C(O)C1CN(CC(O)c2ccc(-c3noc(-c4onc(-c5ccccc5)c4C(F)(F)F)n3)cc2)C1
Reaction time: 1 h

Procedure:
To a mixture of tert-butyl 1-(2-hydroxy-2-(4-(N′-hydroxycarbamimidoyl)phenyl)ethyl)azetidine-3-carboxylate (111 mg, 0.33 mmol) and DIEA (0.115 mL, 0.660 mmol) in acetonitrile (10 mL) was added 3-phenyl-4-(trifluoromethyl)isoxazole-5-carbonyl fluoride, Int-I-G (86 mg, 0.33 mmol). After 1 hour, TBAF (0.330 mL, 0.330 mmol) was added and the reaction was stirred overnight. The reaction mixture was diluted with ethyl acetate and washed with H2O. The organic layer was dried with MgSO4, filtered, and concentrated. Crude residue was treated with TFA/DCM to remove t-butyl ester. The resulting material was concentrated in vacuo and purified by HPLC to yield 36 mg of 1-(2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)ethyl)azetidine-3-carboxylic acid as the tetrabutylammonium salt. 1H NMR (400 MHz, MeOH-d3) δ ppm 8.22 (2H, d, J=8.35 Hz), 7.68 (4H, d, J=8.35 Hz), 7.53-7.65 (3H, m), 5.04 (1H, dd, J=10.11, 3.08 Hz), 4.45 (4H, t, J=9.89 Hz), 3.73 (1H, br. s.), 3.36-3.62 (2H, m). MS (m+1)=501. HPLC Peak RT=3.23 minutes (Analytical Method A). Purity=98%.
Reaction SMILES: [C:1](O)([C:3]([F:6])([F:5])[F:4])=O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCN(CC)CC.[CH3:34][O:35][C:36]([C:38]1[CH:39]=[C:40]([C:45]2[CH:50]=[CH:49][C:48]([CH3:51])=[CH:47][CH:46]=2)[CH:41]=[C:42]([NH2:44])[CH:43]=1)=[O:37].C(Cl)(Cl)(Cl)[Cl:53]>>[CH3:34][O:35][C:36]([C:38]1[CH:39]=[C:40]([C:45]2[CH:50]=[CH:49][C:48]([CH3:51])=[CH:47][CH:46]=2)[CH:41]=[C:42](/[N:44]=[C:1](\[Cl:53])/[C:3]([F:6])([F:5])[F:4])[CH:43]=1)=[O:37]
Reactant: O=C(O)C(F)(F)F
Reactant: COC(=O)c1cc(N)cc(-c2ccc(C)cc2)c1
Reactant: ClC(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(/N=C(\Cl)C(F)(F)F)cc(-c2ccc(C)cc2)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 60 %

Procedure:
A mixture of CF3COOH (5.19 mmol, 398 mL), PPh3 (15.56 mmol, 4.08 g) and NEt3 (6.22 mmol, 868 μL) in 10 mL of CCl4 was stirred at 0° C. for 10 minutes. 5-Amino-4′-methyl-biphenyl-3-carboxylic acid methyl ester (1.5 g, 6.22 mmol) was then added to the reaction mixture and the mixture was heated to reflux for 2 hours. Solvent was removed under reduced pressure and the residue was purified by flash column chromatography, eluting with n-hexane:ethyl acetate (10:1), giving the 5-[1-chloro-2,2,2-trifluoro-eth-(Z)-ylideneamino]-4′-methyl-biphenyl-3-carboxylic acid methyl ester as light yellow oil (1.3 g, 60% yield).