Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]=[C:9]([C:13]2([CH3:18])OCC[O:14]2)[CH2:8]1)=[O:6])[CH:2]=[CH2:3].O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>CC(C)=O>[CH2:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]=[C:9]([C:13](=[O:14])[CH3:18])[CH2:8]1)=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)N1CCC=C(C2(C)OCCO2)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: C=CCOC(=O)N1CCC=C(C(C)=O)C1
Reaction time: 1 h
Yield: 77.2 %

Procedure:
To a solution of 2-(1-allyloxycarbonyl-1,2,5,6-tetrahydropyridin-3-yl)-2-methyl-1,3-dioxolane (6.95 g) in acetone (140 ml) was added p-toluenesulfonic acid dihydrate (523 mg) at room temperature and the mixture was stirred at the same temperature for 1 hour. Then, saturated aqueous sodium hydrogen carbonate solution was added for neutralization of the acid and the reaction mixture was concentrated under reduced pressure. The concentrate was diluted with ethyl acetate and water, followed by stirring, and the aqueous layer was separated and extracted with 2 portions of ethyl acetate. The organic layers were combined, washed successively with saturated aqueous sodium hydrogen carbonate solution, water and aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was then distilled off under reduced pressure and the residue was purified by column chromatography to give 1-allyloxycarbonyl-3-acetyl-1,2,5,6-tetrahydropyridine (4.43 g).
Reaction SMILES: [CH:1]1([N:7]([CH3:29])[C:8](=[O:28])[N:9]([CH2:13][CH2:14][CH2:15][O:16][C:17]2[CH:18]=[C:19]3[C:24](=[CH:25][CH:26]=2)[NH:23][C:22](=[O:27])[CH:21]=[CH:20]3)[CH2:10][CH:11]=[CH2:12])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H][H]>C(O)C.[C].[Pd]>[CH:1]1([N:7]([CH3:29])[C:8](=[O:28])[N:9]([CH2:13][CH2:14][CH2:15][O:16][C:17]2[CH:18]=[C:19]3[C:24](=[CH:25][CH:26]=2)[NH:23][C:22](=[O:27])[CH:21]=[CH:20]3)[CH2:10][CH2:11][CH3:12])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C=CCN(CCCOc1ccc2[nH]c(=O)ccc2c1)C(=O)N(C)C1CCCCC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCCN(CCCOc1ccc2[nH]c(=O)ccc2c1)C(=O)N(C)C1CCCCC1
Yield: 69.6 %

Procedure:
6-[3-(3-Cyclohexyl-3-methyl-1-allylureido)propoxy]carbostyril (3.0 g) is dissolved in ethanol (90 ml), and thereto is added 10% palladium-carbon (0.3 g), and the mixture is subjected to catalytic hydrogenation under 1 atm of hydrogen gas at room temperature. After the reaction is complete, the catalyst is removed by filtration, and the filtrate is concentrated under reduced pressure. The residue is purified by silica gel column chromatography (solvent; methylene chloride:methanol=20:1), and recrystallized from ethanol-diethyl ether to give 6-[3-(3-cyclohexyl-3-methyl-1-propylureido)propoxy]carbostyril (2.1 g) as colorless flakes.
Reaction SMILES: [CH3:1][O-:2].[Na+].[Br:4][C:5]1[CH:10]=[C:9](F)[CH:8]=[CH:7][C:6]=1[C:12]([C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH3:21])=[CH:16][CH:15]=1)=[O:13].O>CN(C=O)C>[Br:4][C:5]1[CH:10]=[C:9]([O:2][CH3:1])[CH:8]=[CH:7][C:6]=1[C:12]([C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH3:21])=[CH:16][CH:15]=1)=[O:13]
Reactant: CCc1ccc(C(=O)c2ccc(F)cc2Br)cc1
Reactant: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCc1ccc(C(=O)c2ccc(OC)cc2Br)cc1
Reaction time: 3 h

Procedure:
Sodium methoxide (10.5 g) is added portionwise to (2-bromo-4-fluoro-phenyl)-(4-ethyl-phenyl)-methanone (43.0 g) dissolved in DMF (200 mL). The solution is stirred overnight, before another portion of sodium methoxide (5.5 g) is added. After another 3 h of stirring, water is added and the resulting mixture is extracted with ethyl acetate. The organic phase is dried (sodium sulphate), the solvent is removed and the residue is chromatographed on silica gel (cyclohexane/ethyl acetate 20:1->9:1).
Reaction SMILES: [CH2:1]([N:8]1[C:12]([CH:13]2[CH2:15][CH2:14]2)=[C:11]([C:16]2[CH:17]=[C:18]3[C:22](=[CH:23][CH:24]=2)[NH:21][N:20]=[C:19]3[NH2:25])[N:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)C.[CH:30](=O)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CN(C)C=O>[CH2:30]([NH:25][C:19]1[C:18]2[C:22](=[CH:23][CH:24]=[C:16]([C:11]3[N:10]=[N:9][N:8]([CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[C:12]=3[CH:13]3[CH2:15][CH2:14]3)[CH:17]=2)[NH:21][N:20]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: O=Cc1ccccc1
Reactant: Nc1n[nH]c2ccc(-c3nnn(Cc4ccccc4)c3C3CC3)cc12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: c1ccc(CNc2n[nH]c3ccc(-c4nnn(Cc5ccccc5)c4C4CC4)cc23)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of Example 89B (18.3 mg, 0.05 mmol) in dimethylformamide (2 mL) was added acetic acid (15 mg, 0.25 mmol) and benzaldehyde (6.4 mg, 0.06 mmol). The reaction mixture was stirred at room temperature overnight. Sodium triacetoxyborohydride (NaBH(OAc)3, 32 mg, 0.15 mmol) was added to the mixture. The reaction was stirred at room temperature for 3 hours, concentrated and purified by reverse phase-HPLC (CH3CN/H2O/NH4OAc) to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 13.09 (s, 1H), 9.24 (s, 1H), 8.02-8.10 (m, 3H), 7.84-7.90 (m, 1H), 7.49-7.67 (m, 4H), 7.25-7.45 (m, 5H), 5.70 (s, 2H), 3.30 (s, 2H), 1.88-1.95 (m, 1H), 1.01-1.09 (m, 2H), 0.43 (d, J=4.04 Hz, 2H). MS (ESI+) m/z 421 (M+H)+.
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:10]=[C:11]3[C:17]4[CH:18]=[CH:19][C:20]([C:22](N(OC)C)=[O:23])=[CH:21][C:16]=4[O:15][CH2:14][CH2:13][N:12]3[CH:28]=2)=[N:7][C:6]([CH3:29])=[N:5]1)([CH3:3])[CH3:2].O1CCC[CH2:31]1.C[Mg]Br>CCOCC>[CH:1]([N:4]1[C:8]([C:9]2[N:10]=[C:11]3[C:17]4[CH:18]=[CH:19][C:20]([C:22](=[O:23])[CH3:31])=[CH:21][C:16]=4[O:15][CH2:14][CH2:13][N:12]3[CH:28]=2)=[N:7][C:6]([CH3:29])=[N:5]1)([CH3:3])[CH3:2]
Reactant: CON(C)C(=O)c1ccc2c(c1)OCCn1cc(-c3nc(C)nn3C(C)C)nc1-2
Reactant: C1CCOC1
Agent: C[Mg]Br
Solvent: CCOCC
Product: CC(=O)c1ccc2c(c1)OCCn1cc(-c3nc(C)nn3C(C)C)nc1-2
Temperature: 0 °C

Procedure:
2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-N-methoxy-N-methyl-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-9-carboxamide (2.0 g, 0.0050 mol) was dissolved in Tetrahydrofuran (20 mL, 0.3 mol). The reaction was cooled at 0° C. 3.0 M of Methylmagnesium bromide in Ether was added dropwise. The reaction was allowed to warm to room temperature over a 1 hour period. LCMS shows complete conversion to desired product. The reaction was cooled back to 0° C. and quenched with saturated aqueous ammonium chloride. The reaction mixture was diluted with H2O and the crude product was extracted with Ethyl Acetate The organic extracts were combined, dried over Na2SO4, filtered and concentrated to dryness. The crude was purified on silica gel (0→10% MeOH/DCM) to yield 1-(2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)ethanone as an orange solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[O:6][CH:5]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:8]=2[Cl:14])[C:4](=[O:15])[O:3]1.C=O.[OH-].C[N+](C)(C)C.[C:25](O)(=[O:27])C>N1C=CC=CC=1.CO>[CH3:1][C:2]1([CH3:16])[O:6][C:5]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:8]=2[Cl:14])([CH2:25][OH:27])[C:4](=[O:15])[O:3]1
Reactant: CC1(C)OC(=O)C(c2ccc(Cl)cc2Cl)O1
Reactant: CC(=O)O
Agent: C=O
Agent: C[N+](C)(C)C
Agent: [OH-]
Solvent: CO
Solvent: c1ccncc1
Product: CC1(C)OC(=O)C(CO)(c2ccc(Cl)cc2Cl)O1
Temperature: -5 °C
Reaction time: 12 h

Procedure:
104.4 g (0.4 mole) of 2,2-dimethyl-4-(2,4-dichlorophenyl)-1,3-dioxolan-5-one are dissolved in 700 ml of pyridine and to the solution are added 48 g of paraformaldehyde. Then 40 ml of a 40% solution of tetramethylammonium hydroxide in methanol are slowly added dropwise. The mixture is stirred for 12 hours, cooled to -5° C., and a solution of 100 ml of glacial acetic acid and 400 ml of pyridine is added dropwise until the pH value is 6.5 to 7. The reaction solution is poured into ice-water and extracted with methylene chloride. The extract is dried over sodium sulfate and the product is crystallised by addition of diethyl ether. The crystalline precipitate is washed with a small amount of diethyl ether and petroleum ether. It has a melting point of 182°-185° C.
Reaction SMILES: [Br-:1].[Li+].CC1C=CC(S(O[C@@H:14]2[CH2:18][O:17][C@@H:16]3[C@H:19]([CH3:22])[CH2:20][O:21][C@H:15]23)(=O)=O)=CC=1>CN(C)C=O.O>[Br:1][C@H:14]1[CH2:18][O:17][C@@H:16]2[C@H:19]([CH3:22])[CH2:20][O:21][C@H:15]12
Reactant: [Br-]
Reactant: Cc1ccc(S(=O)(=O)O[C@@H]2CO[C@H]3[C@@H]2OC[C@H]3C)cc1
Agent: [Li+]
Solvent: O
Solvent: CN(C)C=O
Product: C[C@@H]1CO[C@H]2[C@@H]1OC[C@@H]2Br
Temperature: 110 °C
Reaction time: 1.5 h
Yield: 61.9 %

Procedure:
A stirred mixture of lithium bromide (596 mg, 6.85 mmol) and tosylate (91a) (0.68 g, 2.28 mmol) in dimethylformamide (5 mL) was heated at 110° C. for 1 hour, then at 125° C. for 1.5 hours, then at 130° C. for 2 hours under an atmosphere of argon then diluted with water (20 mL). The product was extracted into diethyl ether (4×10 mL) then the combined organic layers washed with water (3×10 mL), brine (10 mL), dried (MgSO4), filtered and reduced in vacuo to leave an orange oil. Flash chromatography over silica, eluting with ethyl acetate:heptane mixtures 0:100 to 35:65 gave bromide (92) as a colourless oil (292 mg, 62%). TLC (Rf=0.80, EtOAc:heptane 1:2), [α]D20.5+75.2° (c=1.13, CHCl3); δH (500 MHz, CDCl3) 1.10 (3H, d, J=6.80 Hz, CH3CH), 2.24-2.33 (1H, m, CH3CH), 3.30 (1H, dd, J=11.23 and 8.20 Hz, 1×CH2CHCH3), 4.13 (2H, m, CH2CHBr), 4.20 (1H, t, J=7.99 Hz, 1×CH2CHCH3), 4.28-4.30 (1H, m, CHBr), 4.68 and 4.74 (2H total, t, J=3.87 Hz and dd, J=3.55 and 0.92 Hz respectively, BrCHCHCHO); δC (125 MHz, CDCl3) 9.842 (CH3CH), 39.904 (CH3CH), 51.616 (CHBr), 74.993 and 76.118 (CH2CHBr and CH2CHCH3), 84.708 and 89.891 (BrCHCHCHO).
Reaction SMILES: C([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:19]([N:21]([C:28]1[CH:33]=[CH:32][C:31]([CH:34]([CH3:36])[CH3:35])=[CH:30][CH:29]=1)[CH2:22][C:23]1[CH:24]=[N:25][NH:26][CH:27]=1)=[O:20])C1C=CC=CC=1.Cl.Cl[CH2:39][CH2:40][N:41]([CH3:43])[CH3:42].[H-].[Na+]>CN(C)C=O>[CH3:42][N:41]([CH3:43])[CH2:40][CH2:39][N:25]1[CH:24]=[C:23]([CH2:22][N:21]([C:28]2[CH:33]=[CH:32][C:31]([CH:34]([CH3:36])[CH3:35])=[CH:30][CH:29]=2)[C:19]([CH:14]2[C:15]3[C:10](=[C:9]([OH:8])[CH:18]=[CH:17][CH:16]=3)[CH2:11][CH2:12][CH2:13]2)=[O:20])[CH:27]=[N:26]1
Reactant: CN(C)CCCl
Reactant: CC(C)c1ccc(N(Cc2cn[nH]c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)c1ccc(N(Cc2cnn(CCN(C)C)c2)C(=O)C2CCCc3c(O)cccc32)cc1
Reaction time: 24 h
Yield: 53.6 %

Procedure:
To a solution of 5-benzyloxy-N-(4-isopropylphenyl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.35 g) in dimethylformamide were added 2-chloro-N,N-dimethylethylamine hydrochloride (0.12 g) and sodium hydride (0.035 g), and the mixture was stirred for one day. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was evaporated, and the obtained residue was reacted and treated in the same manner as in Example 17 to give N-({1-[2-(dimethylamino)ethyl]pyrazol-4-yl}methyl)-5-hydroxy-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.18 g). melting point: 92° C.
Reaction SMILES: [Na].[SH:2][CH2:3][CH2:4][OH:5].[Br-].[Br-].[Br-].[Br-].O[CH2:11][C:12]([CH2:17]O)([CH2:15]O)[CH2:13]O>C(O)C>[OH:5][CH2:4][CH2:3][S:2][CH2:17][C:12]([CH2:11][S:2][CH2:3][CH2:4][OH:5])([CH2:13][S:2][CH2:3][CH2:4][OH:5])[CH2:15][S:2][CH2:3][CH2:4][OH:5]
Reactant: OCC(CO)(CO)CO
Reactant: OCCS
Agent: [Br-]
Agent: [Na]
Solvent: CCO
Product: OCCSCC(CSCCO)(CSCCO)CSCCO

Procedure:
To 400 parts of ethanol were successively added 9.2 parts of metallic sodium, 31.2 parts of 2-mercaptoethanol amd 38.8 parts of pentaerythritol tetrabromide, and the resulting mixture was heated under reflux. Thereafter, the deposited sodium bromide was removed, and the ethanol was removed by distillation to obtain tetrakis(2-hydroxyethylthiomethyl)methane. This compound was added to 80 parts of chloroform, and 60 parts of thionyl chloride was dropped into the resulting mixture. Subsequently, the mixture was heated under reflux, and then the solvent chloroform and unreacted thionyl chloride were removed by distillation under reduced pressure. The residual oily substance was poured into ice water and extracted with ether, and the ether extract was dehydrated over anhydrous sodium sulfate and then freed from the ether by distillation to obtain tetrakis(2-chloroethylthiomethyl)methane. To this compound were successively added 0.4 part of phosphoric acid and 80 parts of 30% aqueous hydrogen peroxide, and the resulting mixture was heated under reflux and then cooled to deposit tetrakis(2-chloroethylsulfonylmethyl)methane. The deposited compound was recovered by filtration and dissolved in 200 parts of acetone, and the resulting solution was incorporated with 40 parts of triethylamine and then stirred at room temperature to deposit triethylamine hydrochloride. This hydrochloride was removed, and the acetone was removed by distillation to deposit solids. The deposited solids were recrystallized from acetone-ethanol to obtain tetrakis(vinylsulfonylmethyl)methane.
Reaction SMILES: [C:1]([O:8][CH2:9][CH3:10])(=[O:7])[C:2](OCC)=[O:3].Cl[CH2:12][Si:13]([CH3:16])([CH3:15])[CH3:14].[Mg].[Cl-].[NH4+]>O1CCCC1>[OH:3][C:2]([CH2:12][Si:13]([CH3:16])([CH3:15])[CH3:14])([CH2:12][Si:13]([CH3:16])([CH3:15])[CH3:14])[C:1]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCOC(=O)C(=O)OCC
Reactant: C[Si](C)(C)CCl
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCOC(=O)C(O)(C[Si](C)(C)C)C[Si](C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.7 %

Procedure:
Under a nitrogen atmosphere and with ice cooling, a solution of 293 g diethyl oxalate in 500 ml tetrahydrofuran was slowly added dropwise to a Grignard reagent solution which had been prepared from 540 g of chloromethyltrimethylsilane, 107 g of magnesium and 2,000 ml of tetrahydrofuran. The solution was stirred for 3 hours at room temperature, after which an aqueous solution of ammonium chloride was added for hydrolysis. Usual work-up procedure including extraction, washing, drying and concentration yielded 525 g (crude yield 95%) of ethyl 2-hydroxy-3-trimethylsilyl-2-trimethylsilylmethylpropionate.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[C:26]([NH:28][C:29]([NH:31][C:32]2[CH:37]=[N:36][C:35]([C:38]#[N:39])=[CH:34][N:33]=2)=[O:30])[CH:25]=[CH:24][C:3]=1[O:4][CH2:5][CH2:6][N:7]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=1[F:23])C(=O)OC(C)(C)C.FC(F)(F)C(O)=O>O1CCCC1>[Cl:1][C:2]1[CH:27]=[C:26]([NH:28][C:29]([NH:31][C:32]2[CH:37]=[N:36][C:35]([C:38]#[N:39])=[CH:34][N:33]=2)=[O:30])[CH:25]=[CH:24][C:3]=1[O:4][CH2:5][CH2:6][NH:7][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=1[F:23]
Reactant: CC(C)(C)OC(=O)N(CCOc1ccc(NC(=O)Nc2cnc(C#N)cn2)cc1Cl)Cc1ccc(F)cc1F
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cnc(NC(=O)Nc2ccc(OCCNCc3ccc(F)cc3F)c(Cl)c2)cn1
Temperature: 40 °C
Yield: 10.1 %

Procedure:
To a solution of tert-butyl 2-(2-chloro-4-(3-(5-cyanopyrazin-2-yl)ureido)phenoxy)ethyl-(2,4-difluorobenzyl)carbamate (0.53 g, 0.95 mmol) in tetrahydrofuran (5 mL) at 0° C. was added trifluoroacetic acid (1.19 g, 9.5 mmol), and the resulting mixture was heated at 40° C. for 12 hours. The solvent was removed under reduced pressure to leave a residue that was purified by preparative HPLC (Preparative HPLC Method 1) to give the title compound (44 mg, 10%).
Reaction SMILES: [H-].[Na+].[O:3]([CH2:10][CH2:11][OH:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Cl:13][C:14]1[CH:19]=[C:18]([C:20]([Cl:23])([Cl:22])[Cl:21])[CH:17]=[C:16](Cl)[N:15]=1>O>[Cl:13][C:14]1[CH:19]=[C:18]([C:20]([Cl:21])([Cl:22])[Cl:23])[CH:17]=[C:16]([O:12][CH2:11][CH2:10][O:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[N:15]=1
Reactant: OCCOc1ccccc1
Reactant: Clc1cc(C(Cl)(Cl)Cl)cc(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: Clc1cc(C(Cl)(Cl)Cl)cc(OCCOc2ccccc2)n1

Procedure:
A solution was prepared by dissolving 5.28 grams (0.11 mole) of sodium hydride (as a 50 percent oil mixture) in 15.20 grams (0.11 mole) of 2-phenoxyethanol. To this solution was added, over a 30 minute period, 26.54 grams (0.1 mole) of 2,6-dichloro-4-(trichloromethyl)pyridine. The mixture was heated and refluxed for 4 hours. The reaction mixture was diluted with 700 ml of water and extracted with methylene chloride. The extract was washed with water, dried with sodium sulfate and filtered. The methylene chloride and other volatile impurities were removed by distillation under reduced pressure. The 2-chloro-6-(2-phenoxyethoxy)-4-(trichloromethyl)pyridine product which was recovered distilled at 95° C. under0.05 mm of pressure. The product was recovered in a yield of 27 grams (73.5 percent of theoretical). The product solidified upon standing at 60°-62° C. Upon analysis, the product was found to have carbon, hydrogen, nitrogen, and chlorine contents of 46.22, 3.15, 3.94 and 37.92 percent, respectively, as compared with the theoretical contents of 45.81, 3.02, 3.82 and 38.64 percent, respectively, calculated for the above named compound.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[CH:15]=[CH:16][C:17](B(O)O)=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])[CH3:3].[C:22]([O:33][CH3:34])(=[O:32])[C:23]1[CH:31]=[CH:30][C:28]([OH:29])=[C:25]([O:26][CH3:27])[CH:24]=1.C(N(CC)CC)C>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:27][O:26][C:25]1[CH:24]=[C:23]([C:22]([O:33][CH3:34])=[O:32])[CH:31]=[CH:30][C:28]=1[O:29][C:17]1[CH:16]=[CH:15][C:12]2[CH2:13][CH2:14][N:8]([C:6]([O:5][C:2]([CH3:4])([CH3:3])[CH3:1])=[O:7])[CH2:9][CH2:10][C:11]=2[CH:18]=1
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(B(O)O)cc2CC1
Reactant: COC(=O)c1ccc(O)c(OC)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(Oc2ccc3c(c2)CCN(C(=O)OC(C)(C)C)CC3)c(OC)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 32.6 %

Procedure:
(3-{[(1,1-Dimethylethyl)oxy]carbonyl}-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)boronic acid (E264, Step 2) (500 mg, 1.72 mmol) was dissolved in dry dichloromethane (15 ml) and treated sequentially with methyl vanillate (313 mg, 1.72 mmol), molecular sieves (4A, 1.0 g), copper acetate (467 mg, 2.58 mmol) and triethylamine (1.20 ml, 8.60 mmol) and the resulting mixture was stirred at room temperature for 18 hours. The mixture was diluted with dichloromethane, filtered through celite and evaporated in vacuo. The residue was dissolved in ethyl acetate and washed with saturated sodium bicarbonate solution. The organic portion was dried under magnesium sulfate and evaporated in vacuo. The resulting residue was purified by column chromatography eluting with a mixture of (0.1:9.9) to afford the title compound (240 mg). MS (ES+) m/e 328 [(M+H)—CO2tBu]+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[N:5]2[C:9](=[O:23])[N:10]([CH2:12][C:13]3[CH:14]=[N:15][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:17][CH:18]=3)[N:11]=[C:4]2[CH:3]=1.[Cl:24][C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1.C([O-])([O-])=O.[Na+].[Na+].O>C1(C)C=CC=CC=1.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>[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([C:2]2[N:7]=[C:6]([CH3:8])[N:5]3[C:9](=[O:23])[N:10]([CH2:12][C:13]4[CH:14]=[N:15][C:16]([C:19]([F:20])([F:21])[F:22])=[CH:17][CH:18]=4)[N:11]=[C:4]3[CH:3]=2)=[CH:27][CH:26]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: Cc1nc(Cl)cc2nn(Cc3ccc(C(F)(F)F)nc3)c(=O)n12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1nc(-c2ccc(Cl)cc2)cc2nn(Cc3ccc(C(F)(F)F)nc3)c(=O)n12
Temperature: 100 °C
Reaction time: 8 h
Yield: 80.1 %

Procedure:
To a stirred solution of 7-chloro-5-methyl-2-((6-(trifluoromethyl)pyridin-3-yl)methyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one (2.0 g, 5.8 mmol), 4-chlorophenylboronic acid (1.2 g, 7.58 mmol), and tetrakis(triphenylphosphine)palladium (0.67 g, 0.58 mmol) in toluene (25 mL) at room temperature under argon was added aqueous Na2CO3 solution (2 M, 5.8 mL, 11.6 mmol). The resulting reaction mixture was stirred at 100° C. under argon overnight, after which time analysis by HPLC/MS indicated that the reaction was complete. After cooling the reaction mixture to room temperature, water (50 mL) was added. The resulting mixture was extracted with EtOAc (50 mL). The organic layer was washed with saturated aqueous NaCl, then dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by triturating with MeOH (15 mL) to obtain 1.95 g of the title compound as an off-white solid. HPLC/MS: retention time=3.85 min, [M+H]30 =420.
Reaction SMILES: C([NH:8][C:9]1[C:17]2[O:16][C:15]([CH3:19])([CH3:18])[C:14](=[O:20])[C:13]=2[C:12]([CH3:21])=[C:11]([CH3:22])[C:10]=1[CH3:23])C1C=CC=CC=1>C(OCC)(=O)C.CCCCCC>[NH2:8][C:9]1[C:17]2[O:16][C:15]([CH3:18])([CH3:19])[C:14](=[O:20])[C:13]=2[C:12]([CH3:21])=[C:11]([CH3:22])[C:10]=1[CH3:23]
Reactant: Cc1c(C)c(NCc2ccccc2)c2c(c1C)C(=O)C(C)(C)O2
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Cc1c(C)c(N)c2c(c1C)C(=O)C(C)(C)O2

Procedure:
Using 7-(benzylamino)-2,2,4,5,6-pentamethyl-1-benzofuran-3 (2H)-one obtained in Reference Example 53, the title compound was synthesized in the same manner as in Reference Example 30. Yield: quantitative. Melting point: 141-142° C. (ethyl acetate-hexane).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:26])[C@H:5]([CH2:22][CH2:23][S:24][CH3:25])[NH:6][C:7](=[O:21])[C:8]1[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][C:9]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.Cl.[CH3:28][N:29]1[CH:33]=[C:32]([CH2:34][C:35](O)=[O:36])[N:31]=[CH:30]1.C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>C(Cl)Cl>[CH3:2][O:3][C:4](=[O:26])[C@H:5]([CH2:22][CH2:23][S:24][CH3:25])[NH:6][C:7](=[O:21])[C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:35](=[O:36])[CH2:34][C:32]2[N:31]=[CH:30][N:29]([CH3:28])[CH:33]=2)=[CH:10][C:9]=1[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: COC(=O)[C@H](CCSC)NC(=O)c1ccc(N)cc1-c1ccccc1
Reactant: Cn1cnc(CC(=O)O)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@H](CCSC)NC(=O)c1ccc(NC(=O)Cc2cn(C)cn2)cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 77.9 %

Procedure:
4-Amino-2-phenylbenzoyl methionine methyl ester hydrochloride (compound 8, 111.8 mg, 0.2833 mmol) and N-methylimidazole-4-yl-acetic acid hydrochloride (50 mg, 0.2832 mmol) were suspended in 10 mL of methylene chloride. To this solution was added diisopropylethylamine (197 μL, 4.0 eq) and O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (107.4 mg, 0.2833 mmol). After stirring at ambient temperature for 2 days, the reaction was worked up by washing with dilute HCl (PH=3.0) and concentrated sodium bicarbonate. After evaporating solvents, the residue was purified by flash column chromatography (CH2Cl2-Methanol, 10:1) to give [4-(1-Methylimidazole-4-ylacetamido)-2-phenylbenzoyl]methionine methyl ester (106 mg, 78%); m.p. 69-70° C.; 1H NMR (CDCl3) δ 9.89 (s, 1H, amide), 7.67 (d, J=8.4 Hz, 1H), 7.60 (d, J=8.4 Hz, 1H), 7.55 (s, 1H), 7.46 (s, 1H, imidazole), 7.34-7.42 (m, 5H), 6.81 (s, 1H, imidazole), 5.90 (d, J=7.7 Hz, 1H, amide), 4.63 (ddd, J=5.1, 7.3 and 7.7 Hz, 1H, Met α H), 3.72 (s, 3H, OCH3), 3.64 (s, 5H, N-methyl and imidazole acetyl), 2.10 (t, J=7.6 Hz, 2H), 1.98 (s, 3H), 1.83-1.94 (m, 1H), 1.66-1.75 (m, 1H); 13C NMR (CDCl3) δ 171.7, 169.0, 168.9, 140.3, 140.1, 139.8, 137.3, 135.3, 129.6, 129.3, 128.5, 128.3, 127.5, 120.6, 118.5, 118.0, 52.1, 51.6, 36.3, 33.3, 30.8, 29.4, 15.0; LRMS (EI) for C25H28O4N4S 480 (M+, 20), 406 (100), 318 (50); HRMS (EI) calcd 480.1813, obsd 480.1829.