Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([C@@H:11]1[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][C@H:12]1[C:24]([O:26][CH3:27])=[O:25])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:1]([O:8][C:9]([C@@H:11]1[CH2:16][CH2:15][NH:14][CH2:13][C@H:12]1[C:24]([O:26][CH3:27])=[O:25])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@H]1C(=O)OCc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)[C@@H]1CNCC[C@H]1C(=O)OCc1ccccc1
Reaction time: 5 h
Yield: 126.6 %

Procedure:
A solution of 257B (411 mg, 1.04 mmol) in CH2Cl2 (5 mL) was treated with TFA (0.5 mL) at room temperature. The reaction mixture was stirred for 5.0 hours, then concentrated in vacuo. The residue was dissolved in EtOAc (10 mL) and washed with saturated aqueous NaHCO3. The organics were dried (Na2SO4), filtered and concentrated in vacuo to give 365 mg of 257C as a solid.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][O:15]1)[N:9]=[CH:8]2)#[C:2][CH2:3][CH3:4].I[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[CH:27]([C:29]1[CH:30]=[C:31]2[C:36](=[CH:37][CH:38]=1)[CH:35]=[C:34](B(O)O)[CH:33]=[CH:32]2)=[O:28]>>[C:21]1(/[C:2](/[CH2:3][CH3:4])=[C:1](\[C:34]2[CH:35]=[C:36]3[C:31](=[CH:32][CH:33]=2)[CH:30]=[C:29]([CH:27]=[O:28])[CH:38]=[CH:37]3)/[C:5]2[CH:6]=[C:7]3[C:11](=[CH:12][CH:13]=2)[N:10]([CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][O:15]2)[N:9]=[CH:8]3)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Ic1ccccc1
Reactant: CCC#Cc1ccc2c(cnn2C2CCCCO2)c1
Reactant: O=Cc1ccc2cc(B(O)O)ccc2c1
Product: CC/C(=C(/c1ccc2cc(C=O)ccc2c1)c1ccc2c(cnn2C2CCCCO2)c1)c1ccccc1

Procedure:
The title compound was prepared from Intermediate 3, iodobenzene, and (6-formylnaphthalen-2-yl)boronic acid following General Procedure C. 1H NMR (DMSO-d6, 300 MHz): δ 10.05 (s, 1H), 8.47 (s, 1H), 8.13 (s, 1H), 7.97-7.69 (m, 5H), 7.48 (s, 1H), 7.29 (dd, 1H), 7.22-7.07 (m, 6H), 5.87 (dd, 1H), 3.94-3.83 (m, 1H), 3.80-3.68 (m, 1H), 2.59-2.35 (m, 3H), 2.09-1.95 (m, 2H), 1.85-1.68 (m, 1H), 1.65-1.52 (m, 2H), 0.91 (t, 3H). LCMS: 403 [(M-THP+H)+H]+.
Reaction SMILES: [CH:1]1([C:7]2[C:13]3[C:14]([CH3:18])=[C:15]([CH3:17])[S:16][C:12]=3[N:11]3[C:19]([CH3:22])=[N:20][N:21]=[C:10]3[CH:9]([CH2:23][C:24]([OH:26])=O)[N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:27]([N:29](CC)CC)C.C(Cl)(=O)C(C)(C)C.CN>O.O1CCCC1.CN(C)C=O>[CH3:27][NH:29][C:24](=[O:26])[CH2:23][CH:9]1[N:8]=[C:7]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[C:13]2[C:14]([CH3:18])=[C:15]([CH3:17])[S:16][C:12]=2[N:11]2[C:19]([CH3:22])=[N:20][N:21]=[C:10]12
Reactant: Cc1sc2c(c1C)C(C1CCCCC1)=NC(CC(=O)O)c1nnc(C)n1-2
Reactant: CCN(CC)CC
Agent: CC(C)(C)C(=O)Cl
Agent: CN
Solvent: CN(C)C=O
Solvent: O
Solvent: C1CCOC1
Product: CNC(=O)CC1N=C(C2CCCCC2)c2c(sc(C)c2C)-n2c(C)nnc21
Temperature: -5 °C
Reaction time: 2 h

Procedure:
(±)-4-Cyclohexyl-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-6-acetic acid (0.54 g) and triethylamine (0.22 ml) are added to a mixed solvent of dimethylformamide (20 ml) and tetrahydrofuran (10 ml). The mixture is cooled to -5° C. and pivaloyl chloride (0.18 ml) is dropwise added at said temperature. Ten minutes later, a 40% aqueous solution (2 ml) of methylamine is dropwise added at said temperature and the mixture is stirred at room temperature for 2 hours. Water is added to the reaction mixture, and the mixture is extracted with ethyl acetate, washed with water and dried over anhydrous magnesium sulfate. The solvent is distilled away under reduced pressure and the residue is recrystallized from ethyl acetate to give (±)-N-methyl-4-cyclohexyl-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-6-acetamide, melting point 228°-231° C.
Reaction SMILES: C(Cl)Cl.C[O:5][C:6]1[CH:21]=[CH:20][C:9]([CH2:10][N:11]2[NH:17][C:16](=[O:18])[CH:15]3[CH:13]([CH2:14]3)[C:12]2=[O:19])=[CH:8][CH:7]=1.B(Br)(Br)Br>O>[OH:5][C:6]1[CH:7]=[CH:8][C:9]([CH2:10][N:11]2[NH:17][C:16](=[O:18])[CH:15]3[CH:13]([CH2:14]3)[C:12]2=[O:19])=[CH:20][CH:21]=1
Reactant: COc1ccc(CN2NC(=O)C3CC3C2=O)cc1
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: O=C1NN(Cc2ccc(O)cc2)C(=O)C2CC12
Reaction time: 2 h
Yield: 27.6 %

Procedure:
To 5 ml of methylene chloride was added 462 mg (1.87 mmol) of (±)-3-(4-methoxybenzyl)-3,4-diazabicyclo[4.1.0]heptane-2,5-dione obtained in Reference Example 19. The mixture was cooled on a dry ice/ethanol bath, and 0.1 ml (1.1 mmol) of boron tribromide was added thereto dropwise. The temperature was elevated to room temperature, and the mixture was stirred for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, the solvent was removed by distillation under reduced pressure, and the residue was recrystallized from ethanol/chloroform to obtain 120 mg (29.6%) of the titled compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:26]=[CH:25][C:6]([C:7]([NH:9][C:10]2[C:11]([NH2:24])=[CH:12][C:13]([O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])=[CH:14][CH:15]=2)=[O:8])=[CH:5][CH:4]=1.N1C=CC=CC=1.[CH2:33]([C:36]1[CH:44]=[CH:43][C:39]([C:40](Cl)=[O:41])=[CH:38][CH:37]=1)[CH2:34][CH3:35]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:26]=[CH:25][C:6]([C:7]([NH:9][C:10]2[C:11]([NH:24][C:40](=[O:41])[C:39]3[CH:43]=[CH:44][C:36]([CH2:33][CH2:34][CH3:35])=[CH:37][CH:38]=3)=[CH:12][C:13]([O:16][Si:17]([C:20]([CH3:23])([CH3:21])[CH3:22])([CH3:19])[CH3:18])=[CH:14][CH:15]=2)=[O:8])=[CH:5][CH:4]=1
Reactant: COc1ccc(C(=O)Nc2ccc(O[Si](C)(C)C(C)(C)C)cc2N)cc1
Reactant: CCCc1ccc(C(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCc1ccc(C(=O)Nc2cc(O[Si](C)(C)C(C)(C)C)ccc2NC(=O)c2ccc(OC)cc2)cc1
Reaction time: 4 h

Procedure:
To a solution of N1-(4-methoxybenzoyl)-4-(tert-butyldimethylsilyloxy)-1,2-benzenediamine (300 mg, 0.81 mmol) in methylene chloride (20 mL) was added pyridine (0.13 mL, 1.6 mmol) followed by 4-propylbenzoyl chloride (0.15 mL, 0.89 mmol). The reaction mixture was stirred for 4 h, diluted with methylene chloride, washed with saturated aqueous cupric sulfate solution, dried (magnesium sulfate), filtered, and concentrated in vacuo. The residue was chromatographed (silica gel, methylene chloride to 20% ethyl acetate/80% methylene chloride) to give 400 mg (95%) of the the title compound as a solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Cl:8])[N:3]=1.[F:9][C@H:10]1[C@H:15]([OH:16])[CH2:14][CH2:13][N:12]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:11]1.ClC1N=C(OC2CCN(C(OC(C)(C)C)=O)CC2)C=NC=1>>[Cl:8][C:4]1[N:3]=[C:2]([O:16][C@@H:15]2[CH2:14][CH2:13][N:12]([C:17]([O:19][C:20]([CH3:22])([CH3:21])[CH3:23])=[O:18])[CH2:11][C@H:10]2[F:9])[CH:7]=[N:6][CH:5]=1
Reactant: Clc1cncc(Cl)n1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](O)[C@H](F)C1
Agent: CC(C)(C)OC(=O)N1CCC(Oc2cncc(Cl)n2)CC1
Product: CC(C)(C)OC(=O)N1CC[C@@H](Oc2cncc(Cl)n2)[C@H](F)C1

Procedure:
tert-butyl trans-4-[(6-chloropyrazin-2-yl)oxy]-3-fluoropiperidine-1-carboxylate was prepared from 2,6-dichloropyrazine and tert-butyl trans-3-fluoro-4-hydroxypiperidine-1-carboxylate using the conditions described for the preparation of tert-butyl 4-[(6-chloropyrazin-2-yl)oxy]piperidine-1-carboxylate (Compound 1, Step 3). LRMS (ESI) calculated for C14H19ClFN3O3[M+Na]+, 354.1; found 354.1.
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=1[NH2:8])([O-:5])=[O:4].C1(C)C=CC=CC=1.[CH2:20]([O:27][C:28](Cl)=[O:29])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>O1CCCC1.O>[CH2:20]([O:27][C:28]([NH:8][C:7]1[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=1[N+:3]([O-:5])=[O:4])=[O:29])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Nc1ccccc1[N+](=O)[O-]
Reactant: O=C(Cl)OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: O=C(Nc1ccccc1[N+](=O)[O-])OCc1ccccc1
Reaction time: 0.17 h

Procedure:
1.89 g of sodium hydride (60% content) was suspended in 23.76 g of tetrahydrofuran and cooled with ice. To the obtained suspension, 23.1 g of a tetrahydrofuran solution containing 3.00 g of 2-nitroaniline was dropwise added over 1 hr, stirred for 10 minutes, allowed to stand at room temperature and stirred for 30 minutes. To the obtained mixture, 11.12 g of a 33% toluene solution containing benzyloxycarbonyl chloride was added dropwise over 1 hr at room temperature and stirred for 2 hours. To the reaction mixture, water was added at room temperature and extracted, and separated. The obtained organic layer was washed with water and analyzed by high performance liquid chromatography to find the yield of the desired product was 90%.
Reaction SMILES: [Cl:1][CH:2]=[CH:3][CH2:4][NH:5][CH2:6][CH:7]=[CH:8][Cl:9].[CH:10](O)=[O:11]>>[Cl:1][CH:2]=[CH:3][CH2:4][N:5]([CH2:6][CH:7]=[CH:8][Cl:9])[CH:10]=[O:11]
Reactant: O=CO
Reactant: ClC=CCNCC=CCl
Product: O=CN(CC=CCl)CC=CCl

Procedure:
Bis-(3-chloroallyl)amine (2.5 g, 0.015 mol) and 25 ml formic acid were combined and refluxed for 5 hours. The mixture was stripped under a vacuum from a hot-water bath. The yield was 2.6 g of the above-named product.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]3[O:15][CH2:14][C@H:13]([CH2:16]OS(C4C=CC(Br)=CC=4)(=O)=O)[O:12][C:8]3=2)[N:3]=1.[NH:28]1[CH2:31][CH:30]([CH2:32][CH2:33][N:34]2[C:42]3[C:37](=[CH:38][CH:39]=[C:40]([F:43])[CH:41]=3)[CH:36]=[CH:35]2)[CH2:29]1.C(N(CC)CC)C>CS(C)=O>[F:43][C:40]1[CH:41]=[C:42]2[C:37]([CH:36]=[CH:35][N:34]2[CH2:33][CH2:32][CH:30]2[CH2:31][N:28]([CH2:16][CH:13]3[O:12][C:8]4=[C:9]5[C:4](=[CH:5][CH:6]=[C:7]4[O:15][CH2:14]3)[N:3]=[C:2]([CH3:1])[CH:11]=[CH:10]5)[CH2:29]2)=[CH:38][CH:39]=1
Reactant: Fc1ccc2ccn(CCC3CNC3)c2c1
Reactant: Cc1ccc2c3c(ccc2n1)OC[C@H](COS(=O)(=O)c1ccc(Br)cc1)O3
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: Cc1ccc2c3c(ccc2n1)OCC(CN1CC(CCn2ccc4ccc(F)cc42)C1)O3

Procedure:
A solution of (2R)-4-bromobenzenesulfonic acid 8-methyl-2,3-dihydro-[1,4]dioxino[2,3-f]quinolin-2-ylmethyl ester (0.43 g, 0.79 mmol), 1-(2-azetidin-3-yl-ethyl)-6-fluoro-1H-indole (0.25 g, 0.95 mmol) and triethylamine (0.2 mL, 1.4 mmol) in dimethylsulfoxide (20 mL) was heated at 90° C. under nitrogen overnight. The reaction mixture was quenched with 1N sodium hydroxide and extracted with methylene chloride (3×80 mL). The organic layer was washed with water (3×50 mL), dried over anhydrous sodium sulfate, filtered and the solvent removed under vacuum. The crude oil was column chromatographed on silica gel (10% methanol-ethyl acetate). The product-containing fractions were concentrated in vacuum to give 0.3 g of the (S)-enantiomer of the title compound as a brown oil. The hydrochloride salt was prepared in ethyl acetate and collected as a yellow solid: m.p. 115° C. (dec).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[C:4]([N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[N:3]=1.C1(N=C=NC2CCCCC2)CCCCC1.[C:37]1([CH:43]([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[C:44](O)=[O:45])[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.C(Cl)(Cl)[Cl:54]>CN(C)C1C=CN=CC=1>[ClH:54].[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[C:4]([N:16]2[CH2:21][CH2:20][N:19]([C:44](=[O:45])[CH:43]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)[CH2:18][CH2:17]2)[N:3]=1
Reactant: COc1cc2nc(N3CCNCC3)nc(N)c2cc1OC
Reactant: ClC(Cl)Cl
Reactant: O=C(O)C(c1ccccc1)c1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Product: COc1cc2nc(N3CCN(C(=O)C(c4ccccc4)c4ccccc4)CC3)nc(N)c2cc1OC
Product: Cl
Yield: 60 %

Procedure:
2.9 g of 4-amino-6,7-dimethoxy-2-(1-piperazinyl)-quinazoline (prepared according to: J. Med. Chem. 20, 146-149 (1977)) are added in little portions, in about 10' and at room temperature, to a solution of 4.2 g dicyclohexylcarbodiimide 97% and 0.12 g of 4-dimethylaminopyridine in 60 ml CHCl3. The mixture is stirred for 10' at the same temperature and added with 2.55 g of 2,2-diphenylacetic acid and again stirred for 6 h. The residue obtained after evaporation of the solvent is purified by flash chromatography on SiO2 column elating with CHCl3 /MeOH 100:2. The fractions containing the pure base are pooled, the solvents evaporated, the residue is dissolved in warm EtOH 95% and the solution treated with HCl in EtOH about 4N. The salt which crystallizes by cooling the solution is collected by filtration and recrystallized from EtOH 90% to give 3.2 g (60%) of the wanted compound; m.p.: 282°-283° C.
Reaction SMILES: CO[C:3]1[CH:4]([CH:10]([CH3:13])[CH2:11][CH3:12])[CH2:5][CH2:6][CH2:7][CH2:8][N:9]=1.[Cl-:14].[NH4+:15]>CO>[ClH:14].[CH3:13][CH:10]([CH:4]1[CH2:5][CH2:6][CH2:7][CH2:8][NH:9][C:3]1=[NH:15])[CH2:11][CH3:12]
Reactant: CCC(C)C1CCCCN=C1OC
Reactant: [NH4+]
Reactant: [Cl-]
Solvent: CO
Product: CCC(C)C1CCCCNC1=N
Product: Cl

Procedure:
The product of EXAMPLE 117 in MeOH is reacted with ammonium chloride by the method of EXAMPLE 27 to generate the title material.
Reaction SMILES: [CH2:1]([Mg]Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCOCC.[F:15][C:16]([F:37])([F:36])[CH2:17][N:18]1[C:23](=[O:24])[C:22](Cl)=[C:21]([C:26]2[CH:31]=[CH:30][C:29]([S:32]([CH3:35])(=[O:34])=[O:33])=[CH:28][CH:27]=2)[CH:20]=[N:19]1.N>C1COCC1>[F:37][C:16]([F:15])([F:36])[CH2:17][N:18]1[C:23](=[O:24])[C:22]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[C:21]([C:26]2[CH:27]=[CH:28][C:29]([S:32]([CH3:35])(=[O:34])=[O:33])=[CH:30][CH:31]=2)[CH:20]=[N:19]1
Reactant: CS(=O)(=O)c1ccc(-c2cnn(CC(F)(F)F)c(=O)c2Cl)cc1
Reactant: Cl[Mg]Cc1ccccc1
Agent: N
Solvent: CCOCC
Solvent: C1CCOC1
Product: CS(=O)(=O)c1ccc(-c2cnn(CC(F)(F)F)c(=O)c2Cc2ccccc2)cc1
Temperature: 25 °C

Procedure:
The title compound was prepared by adding 1.0 M benzylmagnesium chloride in ether (0.53 mL, 0.53 mmol) to a THF (20 mL) solution of 2-(2,2,2-trifluoroethyl)-4-chloro-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (150 mg, 0.41 mmol), prepared according to the method of Example 193E, at 0° C., then allowing the mixture to warm to room temperature over 2 hours. After an aqueous work-up, the crude material was purified by column chromatography (silica gel, 65:35 hexanes/ethyl acetate) and crystallized from ethyl acetate/hexanes to provide white, crystalline product (yield: 74 mg, 43%). mp 112–114° C. 1H NMR (300 MHz, CDCl3) δ 3.12 (s, 3H), 3.94 (s, 2H), 4.85 (q, J=12 Hz, 2H), 6.99 (dd, J=7.5 Hz, 3 Hz, 2H), 7.2 (m, 3H), 7.48 (d, J=9 Hz, 2H), 7.72 (s, 1H), 8.06 (d, J=9 Hz, 2H). MS (DCI/NH3) m/z 423 (M+H)+. Anal. calc. for C20H17F3N2O3S: C, 56.86; H, 4.05; N, 6.63. Found: C, 56.60; H, 4.13; N, 6.57.
Reaction SMILES: [N:1]([CH:4]([CH2:10][CH2:11][CH3:12])[C:5]([O:7]CC)=[O:6])=[N+:2]=[N-:3].[OH-].[Na+]>CO.O>[N:1]([CH:4]([CH2:10][CH2:11][CH3:12])[C:5]([OH:7])=[O:6])=[N+:2]=[N-:3]
Reactant: CCCC(N=[N+]=[N-])C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCCC(N=[N+]=[N-])C(=O)O
Reaction time: 1.5 h
Yield: 92.9 %

Procedure:
A solution of ethyl 2-azidopentanoate (3.082 g, 18.0 mmol) in a mixture of methanol (10 ml) and water (5 ml) was treated dropwise with 20 ml of 1M sodium hydroxide (20 mmol, 1.1 equiv). After 1.5 h at room temperature, the methanol was evaporated under reduced pressure and the remaining aqueous phase was washed with ether (2×10 ml) and acidified with dilute HCl (3N) at 0° C. The aqueous phase was extracted with dichloromethane (3×25 ml). The combined organic phases were washed with water and dried over anhydrous sodium sulfate. Evaporation of the solvent gave an oil which was distilled (bulb to bulb) to give 2.393 g (93%) of a clear liquid: 80°-85° C./0.5 toor (air bath temperature; ir (firm) νmax : 2110 (N3), 1720 cm-1 (C=O); 1Hmr (CDCl3) δ: 3.90 (1H, dd, J= 6, J=7, H-2), 2.0-1.0 (4H, m, H-3, H-4) and 1.00 ppm (3H, distorted t, J=6, H-5); Anal. calcd for C5H9N3O2 : C 41.95, H 6.34, N 29.36; found: C 42.06, H 6.49, N 29.26.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:4][C:3]=1[CH3:17].C([Sn](CCCC)(CCCC)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1)CCC.CN(C=O)C.[F-].[K+]>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.O>[CH3:17][C:3]1[CH:4]=[C:5]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)[CH:6]=[CH:7][C:2]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1
Reactant: Cc1cc(-c2nc3ccccc3o2)ccc1Br
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(-c2nc3ccccc3o2)ccc1-c1ccccn1
Temperature: 100 °C

Procedure:
Polyphosphoric acid (100 mL) was added to a beaker containing 2-aminophenol (17.7 g, 162 mmol) and 4-bromo-3-methylbenzoic acid (13.6 g, 64 mmol). The mixture was heated at 200° C. for 1 h, then poured into ice water (1 L) and allowed to stand overnight. The mixture was filtered and dried to afford 2-(4-bromo-3-methyl(phenyl))-benzoxazole as a colorless solid. A solution of 2-(4-bromo-3-methyl(phenyl))-benzoxazole (670 mg, 2.3 mmol), 2-(tributylstannyl)pyridine (850 mg, 2.3 mmol), Pd(Ph3P)4 (270 mg, 0.23 mmol) and DMF (23 mL) was degassed with bubbling argon for 15 min. The reaction mixture was heated at 100° C. for 8 h. The reaction was cooled to rt, and KF (500 mg) and H2O (250 mL) were added. The mixture was extracted with MTBE (3×50 mL), and the combined organic extracts were washed with water (2×20 mL), brine (1×20 mL), dried (MgSO4), and concentrated to afford an oil. Purification of the oil by flash chromatography on silica gel (EtOAc:hexanes 1:2) afforded the desired 2-(3-methyl-4-pyridin-2-ylphenyl)-1,3-benzoxazole as a colorless solid: 1H NMR (CDCl3, 300 MHz) δ 8.91 (d, 1H), 8.52 (t, 1H), 8.19 (s, 1H), 8.15 (d, 1H), 7.97 (br t, 1H), 7.89 (d, 1H), 7.70–7.72 (m, 1H), 7.61 (d, 1H), 7.51–7.54 (m, 1H), 7.30–7.33 (m, 2H), 2.45 (s, 3H), MS (ESI) 287 (M+H)+.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[F:9][C:10]1[C:16]([C:17]([F:20])([F:19])[F:18])=[CH:15][CH:14]=[CH:13][C:11]=1[NH2:12].O>CN(C)C=O>[Br:1][C:15]1[CH:14]=[CH:13][C:11]([NH2:12])=[C:10]([F:9])[C:16]=1[C:17]([F:18])([F:19])[F:20]
Reactant: Nc1cccc(C(F)(F)F)c1F
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ccc(Br)c(C(F)(F)F)c1F
Yield: 76.2 %

Procedure:
A solution of N-bromosuccinimide (24.9 g) in N,N-dimethyl formamide was added to a solution of 2-fluoro-3-trifluoromethylaniline (25 g) in dimethyl formamide. The mixture was stirred for four and a half hours. It was poured into water and the oil was separated. The aqueous layers was extracted with ether and the combined organic layers were washed with water, dried (MgSO4) and filtered. The filtrate was evaporated to dryness and the residue was distilled to give 4-bromo-2-fluoro-3-trifluoromethylaniline (27.44 g) as an orange oil, b.p. 88°-94° C./4 mbar.
Reaction SMILES: [C:1]([C:5]1[C:6]([O:17][CH3:18])=[C:7]([CH:10]=[C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH:12]=1)[CH:8]=[O:9])([CH3:4])([CH3:3])[CH3:2].Cl.[C:20]([O:23][CH2:24][CH3:25])(=[O:22])[CH3:21]>O1CCCC1>[C:1]([C:5]1[C:6]([O:17][CH3:18])=[C:7]([CH:8]([OH:9])[CH2:21][C:20]([O:23][CH2:24][CH3:25])=[O:22])[CH:10]=[C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH:12]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1c(C=O)cc(C(C)(C)C)cc1C(C)(C)C
Reactant: CCOC(C)=O
Agent: Cl
Solvent: C1CCOC1
Product: CCOC(=O)CC(O)c1cc(C(C)(C)C)cc(C(C)(C)C)c1OC
Reaction time: 4 h
Yield: 86 %

Procedure:
Under argon atmosphere, 7.5 mL (4.01 mmol, 2 equivalents) of the solution of ethyl bromozincacetate in terahydrofuran obtained in Example 43 was added dropwise to a solution of 0.5 g (2.01 mmol) of 3,5-di-tert-butyl-2-methoxybenzaldehyde in 5 mL of THF at 5˜7° C. The mixture was stirred at 5˜7° C. for 4 hours. 5 mL of 1N hydrochloric acid was added dropwise at 20° C. or lower, followed by dilution with 15 mL of ethyl acetate. Then, the layers were separated. The organic layer was washed successively with 5 mL (×2) of 1N hydrochloric acid, 5 mL of water, 5 mL (×2) of an aqueous saturated sodium bicarbonate solution, and 5 mL (×2) of an aqueous saturated sodium chloride solution. After washing, the organic layer was dried with anhydrous magnesium sulfate. After concentration under reduced pressure, crystals were loosened with 4 mL of n-hexane to obtain 0.58 g of the desired product (yield 86%).
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[N+:12]([C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1[CH2:17]Br)([O-:14])=[O:13]>>[N+:12]([C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1[CH2:17][CH:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:1]([O:9][CH2:10][CH3:11])=[O:8])([O-:14])=[O:13]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: O=[N+]([O-])c1ccccc1CBr
Product: CCOC(=O)C(Cc1ccccc1[N+](=O)[O-])C(=O)OCC
Yield: 74.8 %

Procedure:
In the same manner as in Example 6 (1), a crude product was obtained using diethyl malonate (10.1 g) and 2-nitrobenzyl bromide (13.6 g). This was purified by silica gel column chromatography to give the title compound (13.9 g) as an oil.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[N:14]=[C:13]([C:15]4[CH:16]=[CH:17][C:18]([O:23][CH:24]([CH3:26])[CH3:25])=[C:19]([CH:22]=4)[C:20]#[N:21])[O:12][N:11]=3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1.Br[CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30]>>[C:20]([C:19]1[CH:22]=[C:15]([C:13]2[O:12][N:11]=[C:10]([C:6]3[CH:5]=[C:4]4[C:9](=[CH:8][CH:7]=3)[N:1]([CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])[N:2]=[CH:3]4)[N:14]=2)[CH:16]=[CH:17][C:18]=1[O:23][CH:24]([CH3:26])[CH3:25])#[N:21]
Reactant: CCOC(=O)CBr
Reactant: CC(C)Oc1ccc(-c2nc(-c3ccc4[nH]ncc4c3)no2)cc1C#N
Product: CCOC(=O)Cn1ncc2cc(-c3noc(-c4ccc(OC(C)C)c(C#N)c4)n3)ccc21

Procedure:
Prepared in a similar fashion to (D44) from 5-[3-(1H-indazol-5-yl)-1,2,4-oxadiazol-5-yl]-2-[(1-methylethyl)oxy]benzonitrile (D43) and ethyl bromoacetate. The crude material was purified by trituration with diethyl ether to give the title compound as a yellow solid. MS (ES) C23H21N5O4 requires 431; found (MH+) 432.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][S:6]([NH:9][CH2:10][CH:11]([O:35][CH3:36])[CH2:12][O:13][C:14](=[O:34])[NH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])(=[O:8])=[O:7].[I-:37].[Na+]>C(C(C)=O)C>[I:37][CH2:2][CH2:3][CH2:4][CH2:5][S:6]([NH:9][CH2:10][CH:11]([O:35][CH3:36])[CH2:12][O:13][C:14](=[O:34])[NH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])(=[O:8])=[O:7]
Reactant: [I-]
Reactant: CCCCCCCCCCCCCCCCCCNC(=O)OCC(CNS(=O)(=O)CCCCCl)OC
Agent: [Na+]
Solvent: CCC(C)=O
Product: CCCCCCCCCCCCCCCCCCNC(=O)OCC(CNS(=O)(=O)CCCCI)OC
Yield: 81 %

Procedure:
To a solution of 1.23 g (2.22 mM) of 3-(4-chlorobutylsulfonylamino)-2-methoxy-1-octadecylcarbamoyloxypropane IIIa5 in 20 ml of methyl ethyl ketone is added 0.67 g (4.44 mM) of sodium iodide and the mixture is heated for 3 hours with stirring. After the solvent is evaporated, the residue is purified by the column chromatography on silica gel with a n-hexane-ethyl acetate (1:1) mixture as an eluent. The product is recrystallized from chloroform-n-hexane to give 1.16 g (1.79 mM) of 3-(4-iodobutylsulfonylamino)-2-methoxy-1-octadecylcarbamoyloxypropane IIa5 in 81% yield.