Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9]Br)=[CH:5][CH:4]=1.[CH:11]1[C:16]([C:17]2[CH:18]=[CH:19][C:20]([F:24])=[CH:21][C:22]=2[F:23])=[CH:15][C:14]([C:25]([OH:27])=[O:26])=[C:13]([OH:28])[CH:12]=1.O>CCCC[N+](CCCC)(CCCC)CCCC.[F-]>[F:23][C:22]1[CH:21]=[C:20]([F:24])[CH:19]=[CH:18][C:17]=1[C:16]1[CH:11]=[CH:12][C:13]([OH:28])=[C:14]([C:25]([O:27][CH2:9][C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[O:26])[CH:15]=1
Reactant: COc1ccc(CBr)cc1
Reactant: O=C(O)c1cc(-c2ccc(F)cc2F)ccc1O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Product: COc1ccc(COC(=O)c2cc(-c3ccc(F)cc3F)ccc2O)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 83.3 %

Procedure:
PMBBr (1.20 mL, 8.325 mmol) was added to a solution of diflunisal (1.50 g, 5.995 mmol) in TBAF (7 mL, 1 M solution in THF) and the mixture was stirred at r.t. overnight (16 h). The reaction mixture was poured into H2O (100 mL) and extracted with EtOAc (70 mL). It was dried over Na2SO4 (anhydrous), filtered and concentrated. The crude residue was flash chromatographed on SiO2 (5→10% EtOAc/hexanes) to furnish 1.85 g of 4-methoxybenzyl 2′,4′-difluoro-4-hydroxybiphenyl-3-carboxylate (white solid, yield: 83%).
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:9](=[C:16]1[N:24]2[CH:20]3[CH2:21][CH2:22][CH:23]2[CH2:25][CH:18]([CH2:19]3)[C:17]1=[O:26])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[Cl-].[NH4+]>CCOCC.C1(C)C=CC=CC=1>[C:1]1([CH:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:16]2[N:24]3[CH:20]4[CH2:21][CH2:22][CH:23]3[CH2:25][CH:18]([CH2:19]4)[C:17]2=[O:26])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1C(=Cc2ccccc2)N2C3CCC2CC1C3
Reactant: Br[Mg]c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: O=C1C2CC3CCC(C2)N3C1C(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 53 %

Procedure:
To a 100 ml three-necked round-bottomed flask equipped with a rubber septum and nitrogen inlet were added 5 ml dry toluene and 4.43 ml (13.3 mmol) of a 3.0M solution of phenyl magnesium bromide in ether. The solution was cooled to 0° C., and a solution of 2.07 g (8.87 mmol) 8-benzylidene-9-azatricyclo[4.3.1.04,9 ]decan-7-one in 20 ml toluene was added over 5 min. The reaction was allowed to stir at 0° C. for 1 hour and then poured into saturated aqueous ammonium chloride. The mixture was extracted into ethyl acetate, and the organic layer washed with saturated aqueous ammonium chloride and brine, dried over sodium sulfate, and evaporated. The residue was chromatographed on silica gel using hexane/ethyl acetate as eluent and the product fractions combined to afford 1.47 g (53%) of a white solid, mp 137°-138° C.
Reaction SMILES: [CH2:1]([C:3]1[N:8]=[CH:7][N:6]=[C:5](O)[C:4]=1[F:10])[CH3:2].P(Cl)(Cl)([Cl:13])=O>C(N(CC)CC)C.ClCCl>[Cl:13][C:5]1[C:4]([F:10])=[C:3]([CH2:1][CH3:2])[N:8]=[CH:7][N:6]=1
Reactant: CCc1ncnc(O)c1F
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCc1ncnc(Cl)c1F
Temperature: 25 °C
Yield: 90 %

Procedure:
To a mixture of the compound of part (iv) (40 kg), dichloromethane (120 L) and triethylamine (28.4 g) was slowly added phosphor us oxychloride (47.2 kg) over 3 hours maintaining the reaction temperature below 40° C. during the addition. The mixture was heated under reflux for 5 hours, cooled to 25° C. and cautiously quenched into 3N aqueous hydrochloric acid solution (176 L), maintaining the temperature below 20° C. during this operation. The layers were separated, the aqueous phase extracted with dichloromethane (50 L) and the combined organic layers washed with water (50 L). The organic layer was concentrated under reduced pressure to provide the product as an oil (40.69 kg).
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][CH:8]([CH3:23])[C:9]([NH:11][C:12]1[N:13]=[C:14](Br)[C:15]2[C:20]([CH:21]=1)=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:10])([CH3:4])([CH3:3])[CH3:2].[C:25]([Si:27]([CH3:30])([CH3:29])[CH3:28])#[CH:26].CCN(C(C)C)C(C)C>CN1C(=O)CCC1.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]([O:5][C:6](=[O:24])[NH:7][CH:8]([CH3:23])[C:9](=[O:10])[NH:11][C:12]1[N:13]=[C:14]([C:26]#[C:25][Si:27]([CH3:30])([CH3:29])[CH3:28])[C:15]2[C:20]([CH:21]=1)=[CH:19][CH:18]=[CH:17][CH:16]=2)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(NC(=O)OC(C)(C)C)C(=O)Nc1cc2ccccc2c(Br)n1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CC(NC(=O)OC(C)(C)C)C(=O)Nc1cc2ccccc2c(C#C[Si](C)(C)C)n1

Procedure:
A mixture of tert-butyl-N-[1-[(1-bromoisoquinolin-3-yl)amino]-1-oxopropan-2-yl]-carbamate B4a (500 mg, 1.27 mmol), ethynyl(trimethyl)silane (137 mg, 1.4 mmol), copper(I) iodide (23 mg, 0.12 mmol), Dichlorobis(triphenylphosphine)palladium(II) (90 mg, 0.13 mmol) and DIPEA (700 μl, 4.12 mmol) is stirred under argon atmosphere in NMP (4 ml) for 1 h at 80° C. The mixture is concentrated in vacuo and the product purified by RP HPLC. Yield: 319 mg (61%). HPLC-MS: M+H=412; tR=2.11 min (*Method—4).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([CH2:18][C:19]([O:21]CC)=O)[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH3:24]>>[C:1]1([C:7]2[N:8]=[C:9]([CH2:18][C:19]([NH2:24])=[O:21])[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)Cc1nc(-c2ccccc2)c(-c2ccccc2)o1
Reactant: N
Product: NC(=O)Cc1nc(-c2ccccc2)c(-c2ccccc2)o1
Temperature: 130 °C
Yield: 34 %

Procedure:
A mixture of ethyl 4,5-diphenyl-2-oxazoleacetate (10.24 g, 33 mmol) and ammonia (35 mL) was heated in a bomb at about 130° C. for about 24 hours. After evaporation of the NH3, the residue was chromatographed on a column of silica gel using EtOAc/hexanes (4:1) as eluent to give the title compound (3.21 g, 34%), mp 129°-133° C. IR (KBr) 3340, 3200, 1665 cm-1 ; 1H NMR (CDCl3) δ3.83 (2H, s, CH2CONH2), 7.27 to 7.40 (6H, m, aromatic H), 6.50 to 6.68 (4H, m, aromatic H); MS m/z 279 (MH+).
Reaction SMILES: [Br:1][C:2]1[C:18]([Cl:19])=[CH:17][C:16]2[C:4](=[C:5]3[C:14]([N:15]=2)=[CH:13][C:12]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[NH:6]3)[CH:3]=1.[CH3:20]I>>[ClH:19].[Br:1][C:2]1[C:18]([Cl:19])=[CH:17][C:16]2[C:4](=[C:5]3[C:14]([N:15]=2)=[CH:13][C:12]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[NH+:6]3[CH3:20])[CH:3]=1
Reactant: Clc1cc2nc3cc4ccccc4[nH]c-3c2cc1Br
Reactant: CI
Product: C[NH+]1C2=c3cc(Br)c(Cl)cc3=NC2=Cc2ccccc21
Product: Cl
Temperature: 150 °C

Procedure:
In a large teflon lined steel bomb fitted with a stir bar was placed 7-bromo-8-chloroquindoline from Example 75 (0.350 g, 1.06 mmol) and methyl iodide (1.97 mL, 31.7 mmol). The bomb was flushed with nitrogen, sealed, and heated to 150° C. for 24 h. The bomb was cooled, opened and the contents were transferred to a flask using chloroform to wash the inside of the bomb. The chloroform suspension was concentrated to a dry orange residue. The orange residue was suspended in chloroform, adsorbed onto Na2CO3 and chromatographed over basic alumina using 100% chloroform until starting material could not be detected by TLC. The column was eluted with 2% methanol in chloroform and the violet fractions were collected. After concentrating to a small volume (~50 mL) the violet solution was acidified with ethereal 1 M HCl to a bright yellow endpoint. The mixture was cooled below room temperature, filtered and dried under high vacuum at 45° C. for several days to yield 0.311 (77%) of the title compound as a bright orange solid, mp >246° C.; 1H NMR (DMSO-d6) δ 13.33 (s, 1H), 9.38 (s, 1H), 9.21 (s, 1H), 8.82 (d, J=8.8, 1H), 8.60 (d, J=8.0, 1H), 8.17-8.35 (m, 2H), 7.98 (t, J=7.6, 1 H), 5.02 (s, 3H); 13C NMR (DMSO-d6) δ 144.42, 137.91, 136.67, 135.73, 133.85, 133.09, 130.27, 130.00, 127.53, 126.76, 126.08, 118.02, 114.48, 114.36, 113.63, 40.46; MS (LSIMS, m/z) 347 (M+2+).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:13]([CH3:14])=[C:12]([C:15]([OH:17])=[O:16])[N:11]=[N:10]2)=[CH:4][CH:3]=1.[Cl:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.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:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:13]([CH3:14])=[C:12]([C:15]([OH:17])=[O:16])[N:11]=[N:10]2)=[CH:4][CH:3]=1
Reactant: OB(O)c1ccccc1Cl
Reactant: Cc1c(C(=O)O)nnn1Cc1ccc(Br)cc1
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: COCCOC
Product: Cc1c(C(=O)O)nnn1Cc1ccc(-c2ccccc2Cl)cc1
Temperature: 85 °C
Yield: 53.3 %

Procedure:
To a solution of 1-[(4-bromophenyl)methyl]-5-methyl-1H-1,2,3-triazole-4-carboxylic acid (0.2 g, 0.67 mmol) in DME (10 mL) were added (2-chlorophenyl)boronic acid, (0.137 g, 0.88 mmol), Pd tetrakis (20 mg, 10% mol/mol) and a 2M solution of sodium carbonate (1.34 mL, 4 eq). The reaction was heated at 85° C. for 48 hours. After evaporation of DME, water was added and the reaction was extracted with ethyl acetate (2×40 mL). The aqueous phase was adjusted to PH=7 by addition of a 1N HCl solution and extracted with ethyl acetate. The combined organic phases were dried over sodium sulphate and evaporated in vacuo to give the title compound as a solid (117 mg, 40%). HRMS calculated for C17H14ClN3O2(M+H)+328.0853. found: 328.0865, Rt: 2.04 min.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH:4]([C:8]1[CH:13]=[C:12]([F:14])[C:11]([F:15])=[C:10]([F:16])[CH:9]=1)[C:5](Cl)=[O:6].[C:17]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])(=[O:20])[NH:18][NH2:19].C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>C1COCC1>[Cl:1][CH2:2][CH2:3][CH:4]([C:8]1[CH:13]=[C:12]([F:14])[C:11]([F:15])=[C:10]([F:16])[CH:9]=1)[C:5]([NH:19][NH:18][C:17]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[O:6]
Reactant: O=C(Cl)C(CCCl)c1cc(F)c(F)c(F)c1
Reactant: CC(C)(C)OC(=O)NN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NNC(=O)C(CCCl)c1cc(F)c(F)c(F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
oxalyl chloride (0.63 mL) and DMF (1 drop) were added to a solution of 4-chloro-2-(3,4,5-trifluorophenyl)butyric acid (1.17 g) in methylene chloride (30 mL) at 0° C., and the reaction solution was stirred at room temperature for one hour. The reaction solution was concentrated under reduced pressure to obtain 4-chloro-2-(3,4,5-trifluorophenyl)butyryl chloride. A solution of 4-chloro-2-(3,4,5-trifluorophenyl)butyryl chloride in THF (5 mL) was added to a solution of tert-butyl carbazate (600 mg) and triethylamine (3.1 mL) in THF (20 mL) at 0° C., and the reaction solution was stirred at room temperature for one hour. The reaction solution was added to a saturated sodium bicarbonate solution, followed by extraction with ethyl acetate. The resulting extract was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate system) to obtain 1.35 g of the title compound. The property value of the compound is as follows.
Reaction SMILES: CC[Mg+].[Br-].[Br:5][C:6]1[N:7]=[C:8]([CH2:20][O:21][CH2:22][CH2:23][O:24][Si:25]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26])[N:9]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:10]=1Br.CN([CH:35]=[O:36])C>C(OCC)C.C1COCC1>[Br:5][C:6]1[N:7]=[C:8]([CH2:20][O:21][CH2:22][CH2:23][O:24][Si:25]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26])[N:9]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:10]=1[CH:35]=[O:36]
Reactant: CC(C)(C)[Si](C)(C)OCCOCc1nc(Br)c(Br)n1COCC[Si](C)(C)C
Reactant: CN(C)C=O
Agent: CC[Mg+]
Agent: [Br-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(C)[Si](C)(C)OCCOCc1nc(Br)c(C=O)n1COCC[Si](C)(C)C
Reaction time: 3 h
Yield: 69 %

Procedure:
3N EtMgBr (0.086 mL of a 3N solution in diethyl ether, 0.26 mmol) was added to a solution of 4,5-dibromo-2-{[(2-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}ethyl)oxy]methyl}-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole (0.12 g, 0.21 mmol) in THF (2 mL). The reaction mixture was stirred for 3 h, DMF was added (0.5 mL, 4.9 mmol), and stirring was continued overnight. The solution was quenched by addition of sat'd NH4Cl and extracted with EtOAc and CH2Cl2. The organic phase was dried (Na2SO4), filtered, and purified by silica gel chromatography (0-30% EtOAc/hex) to afford the title compound (0.073 g, 69%) as a clear oil. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 9.77 (s, 1H), 5.84 (s, 2H), 5.27-5.47 (m, 1H), 4.60-4.77 (m, 1H), 3.74 (ddd, J=9.16, 4.85, 4.67 Hz, 2H), 3.47-3.62 (m, 4H), 0.83-0.95 (m, 11H), 0.04 (s, 6H), −0.06-0.01 (m, 9H).
Reaction SMILES: [C:1]([C:3]1[C:4]([CH3:27])=[C:5]([C@@H:10]2S[CH2:14][C@@H:13]3[CH2:16][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:18][CH2:19][N:12]3[CH2:11]2)[CH:6]=[CH:7][C:8]=1[F:9])#[N:2].O[O:29][S:30]([O-:32])=O.[K+].[OH2:34]>C(#N)C.ClCCl>[C:1]([C:3]1[C:4]([CH3:27])=[C:5]([C@@H:10]2[S:30](=[O:32])(=[O:29])[CH2:14][C@@H:13]3[CH2:16][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:18][CH2:19][N+:12]3([O-:34])[CH2:11]2)[CH:6]=[CH:7][C:8]=1[F:9])#[N:2]
Reactant: O
Reactant: Cc1c([C@H]2CN3CCN(C(=O)OC(C)(C)C)C[C@H]3CS2)ccc(F)c1C#N
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: CC#N
Solvent: ClCCl
Product: Cc1c([C@H]2C[N+]3([O-])CCN(C(=O)OC(C)(C)C)C[C@H]3CS2(=O)=O)ccc(F)c1C#N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(3S,9aS)-tert-butyl 3-(3-cyano-4-fluoro-2-methylphenyl)hexahydropyrazino[2,1-c][1,4]thiazine-8(1H)-carboxylate (20 mg, 0.051 mmol) was dissolved in acetonitrile (0.5 mL) and water (0.2 ml) and cooled to 0° C. OXONE (86.1 mg, 0.140 mmol) was added. The ice bath was removed and the reaction mixture was stirred at room temperature overnight. LC-MS showed the completion of the reaction. The reaction mixture was diluted with dichloromethane and water. The organic layer was separated and the aqueous layer was extracted with DCM again. The organic layers were combined and washed with brine, dried (Na2SO4) and concentrated: LC-MS: M+1=440, M+41=481.
Reaction SMILES: [CH2:1]([NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH:2]=[CH2:3].N1C=CC=CC=1.Cl[C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19].Cl>ClCCl>[CH2:1]([N:4]([C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH:2]=[CH2:3]
Reactant: C=CCNc1ccccc1
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: C=CCN(C(=O)OCc1ccccc1)c1ccccc1
Reaction time: 3 h

Procedure:
Under nitrogen, to a solution of allylphenylamine (3 ml) in dichloromethane (30 ml) were added pyridine (2.1 ml) and benzyl chloroformate (3.5 ml) at 5° C., and the mixture was stirred at the same temperature for 3 hours. The resulting mixture was poured into aqueous 1N hydrogen chloride and extracted with ethyl acetate. The organic layer was successively washed with saturated aqueous sodium hydrogencarbonate and brine, dried over anhydrous magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=20:1 to 10:1) to give N-allyl-N-phenylbenzyloxycarbonylamine (5.5 g).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[C@@H:12]1[O:16][C:15](=[O:17])[NH:14][C@H:13]1[CH3:18].[H-].[Na+].[F:21][C:22]([F:36])([F:35])[C:23]1[CH:24]=[C:25]([CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1)[CH2:26]Br>>[F:21][C:22]([F:35])([F:36])[C:23]1[CH:24]=[C:25]([CH:28]=[C:29]([C:31]([F:34])([F:32])[F:33])[CH:30]=1)[CH2:26][N:14]1[C@@H:13]([CH3:18])[C@H:12]([C:3]2[CH:4]=[C:5]([C:8]([F:9])([F:10])[F:11])[CH:6]=[CH:7][C:2]=2[I:1])[O:16][C:15]1=[O:17]
Reactant: FC(F)(F)c1cc(CBr)cc(C(F)(F)F)c1
Reactant: C[C@@H]1NC(=O)O[C@H]1c1cc(C(F)(F)F)ccc1I
Agent: [H-]
Agent: [Na+]
Product: C[C@H]1[C@H](c2cc(C(F)(F)F)ccc2I)OC(=O)N1Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
Following the procedure described in EXAMPLE 96, 0.108 g of (4S,5S)-5-[2-iodo-5-(trifluoromethyl)phenyl]4-methyl-1,3-oxazolidin-2-one, 23 mg of sodium hydride, and 107 mg of 3,5-bis(trifluoromethyl)benzyl bromide provided the title compound. Mass spectrum (ESI) 598.1 (M+1). 1H NMR (500 MHz, CDCl3): δ 8.00 (d, J=8.5 Hz, 1H), 7.77 (s, 1H), 7.58 (br s, 3H), 7.34 (dd, J=1.5 Hz, 8 Hz, 1H), 5.36 (d, J=4 Hz, 1H), 4.89 (d, J=16 Hz, 1H), 4.31 (d, J=16 Hz, 1H), 4.48 (dq, J=6 Hz, 4 Hz, 1H), 1.55 (d, J=6.5 Hz, 3H).
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[C:11]([CH:13]([O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])[C:14]([F:17])([F:16])[F:15])[CH:10]=[CH:9][N:8]=1.CON(C)[C:29](=[O:31])[CH3:30].[Cl-].[NH4+]>C1(C)C=CC=CC=1.O.C1COCC1>[Si:19]([O:18][CH:13]([C:11]1[CH:10]=[CH:9][N:8]=[C:7]([C:29](=[O:31])[CH3:30])[CH:12]=1)[C:14]([F:17])([F:16])[F:15])([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]
Reactant: CC(C)(C)[Si](C)(C)OC(c1ccnc(Br)c1)C(F)(F)F
Reactant: CON(C)C(C)=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(=O)c1cc(C(O[Si](C)(C)C(C)(C)C)C(F)(F)F)ccn1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 71.6 %

Procedure:
To toluene (9 mL) were added dropwise at −78° C. n-butyllithium (2.66 mol/L solution in n-hexane, 1.12 mL, 2.97 mmol) and a solution of 2-bromo-4-(1-(tert-butyldimethylsilyloxy)-2,2,2-trifluoroethyl)pyridine (1.00 g, 2.70 mmol) obtained in Step 2 in toluene (3.0 mL), and the mixture was stirred at the same temperature for 30 minutes. THF (3.0 mL) was added to the resulting solution and the mixture was stirred at −78° C. for 30 minutes. N-methoxy-N-methylacetamide (1.38 mL, 13.5 mmol) was added and the mixture was stirred for 2 hours allowing the temperature to rise slowly to room temperature. A saturated aqueous ammonium chloride solution and water were added to the reaction mixture. Extraction with ethyl acetate and drying over anhydrous magnesium sulfate were performed. After filtration, the solvent in the filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=4/1) to give 1-(4-(1-(tert-butyldimethylsilyloxy)-2,2,2-trifluoroethyl)pyridin-2-yl)ethanone (645 mg, 72% yield).
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH2:13]([C:17]1[N:18]=[C:19]([CH3:47])[N:20]([CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[C:42]([F:46])[CH:41]=2)[C:21](=[O:38])[C:22]=1[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[C:31]([C:36]#[N:37])=[CH:32][CH:33]=[CH:34][CH:35]=2)=[CH:26][CH:25]=1)[CH2:14][CH2:15][CH3:16]>C(OCC)(=O)C>[CH2:13]([C:17]1[N:18]=[C:19]([CH3:47])[N:20]([CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[C:42]([F:46])[CH:41]=2)[C:21](=[O:38])[C:22]=1[CH2:23][C:24]1[CH:25]=[CH:26][C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:36]2[NH:3][C:4](=[O:7])[O:5][N:37]=2)=[CH:28][CH:29]=1)[CH2:14][CH2:15][CH3:16]
Reactant: O=C([O-])O
Reactant: [NH3+]O
Reactant: CCCCc1nc(C)n(Cc2cccc(F)c2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCCc1nc(C)n(Cc2cccc(F)c2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 66 %

Procedure:
A mixture of hydroxylammonium chloride (1.83 g), sodium hydrogen carbonate (2.96 g) and dimethyl sulfoxide (15 mL) was stirred at 40° C. for 30 min, 4′-{[4-butyl-1-(3-fluorobenzyl)-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (0.86 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was dissolved in tetrahydrofuran (20 mL), N,N′-carbonyldiimidazole (0.34 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.29 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogen sulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.64 g, 69%).
Reaction SMILES: [NH:1]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[C@@H:2]([C:30](ON1C(=O)CCC1=O)=[O:31])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:29])[N:8]([C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20])[C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10].[NH2:47][CH2:48][C:49]([OH:51])=[O:50].C([O-])(O)=O.[Na+]>O1CCOCC1.O>[NH:1]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[C@@H:2]([C:30]([NH:47][CH2:48][C:49]([OH:51])=[O:50])=[O:31])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:29])[N:8]([C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])[C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20]
Reactant: NCC(=O)O
Reactant: CC(C)(C)OC(=O)N[C@H](CCCNC(=N)N(C(=O)OCc1ccccc1)C(=O)OCc1ccccc1)C(=O)ON1C(=O)CCC1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N[C@H](CCCNC(=N)N(C(=O)OCc1ccccc1)C(=O)OCc1ccccc1)C(=O)NCC(=O)O
Reaction time: 24 h

Procedure:
To a solution of Boc—(D)—Arg(Cbz2)—OSu (1 g, 1.6 mmol) in dioxane (10 mL) was added a solution of Gly (300 mg, 4 mmol) and NaHCO3 (400 mg, 4.76 mmol) in water (10 mL). The solution was stirred for 24 h. Solvents were evaporated and residue was dissolved in a mixture of EtOAc (20 mL) and 1 N HCl (6 mL). The separated organic layer was washed with sat. NaCl (10 mL), dried over MgSO4, filtered and evaporated to give a solid residue which was used directly without further purification. ES—MS (M+H)+=600
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[C:9]([CH3:14])[N:8]([CH:15]1[CH2:20][CH2:19][C:18](=[O:21])[NH:17][C:16]1=[O:22])[C:7]2=[O:23].C(N(CC)CC)C.[Cl:31][C:32]1[CH:33]=[C:34]([N:39]=[C:40]=[O:41])[CH:35]=[CH:36][C:37]=1[CH3:38]>C1COCC1>[Cl:31][C:32]1[CH:33]=[C:34]([NH:39][C:40]([NH:2][CH2:3][C:4]2[CH:5]=[C:6]3[C:11](=[CH:12][CH:13]=2)[N:10]=[C:9]([CH3:14])[N:8]([CH:15]2[CH2:20][CH2:19][C:18](=[O:21])[NH:17][C:16]2=[O:22])[C:7]3=[O:23])=[O:41])[CH:35]=[CH:36][C:37]=1[CH3:38]
Reactant: Cc1nc2ccc(CN)cc2c(=O)n1C1CCC(=O)NC1=O
Reactant: Cc1ccc(N=C=O)cc1Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1ccc(NC(=O)NCc2ccc3nc(C)n(C4CCC(=O)NC4=O)c(=O)c3c2)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.7 %

Procedure:
To a stirred suspension of 3-(6-aminomethyl-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione hydrogen chloride (0.46 g, 1.4 mmol) and triethylamine (0.27 mL, 1.9 mmol) in THF (10 mL) at 5˜10° C., was added 3-chloro-4-methyl-phenyl isocyanate (0.24 mL, 1.8 mmol), and the mixture was stirred at room temperature overnight. The mixture was quenched with methanol (˜1 mL), and the solvent was evaporated. The residue was purified by flash column chromatography (Silica gel, methanol/methylene chloride 4%/96%) to give 1-(3-chloro-4-methyl-phenyl)-3-[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-6-ylmethyl]-urea as an off-white solid (450 mg, 70% yield); HPLC, Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 10/90 CH3CN/0.1% H3PO4, grad. to 95/5 in 5 min, kept 5 min, 6.38 min (98.4%); mp, 186-188° C.; 1HNMR (DMSO-d6) δ 2.15-2.23 (m, 4H, CHH and CH3Ar), 2.56-2.86 (m, 6H, CHCH2, CH3), 4.40 (d, J=6 Hz, 2H, CH2NH), 5.26 (dd, J=6, 11 Hz, 1H, CH), 6.81 (t, J=5 Hz, 1H, CH2NH), 7.11-7.95 (m, 6H, Ar), 8.75 (s, 1H, NH), 11.02 (s, 1H, NH); 13C NMR (DMSO-d6) δ 18.71, 20.93, 23.39, 30.61, 42.34, 56.53, 116.45, 117.66, 120.01, 123.67, 126.54, 127.39, 130.99, 132.96, 133.95, 139.05, 139.58, 145.76, 154.51, 155.08, 160.47, 169.47, 172.60. LCMS MH=468, 470; Anal Calcd For C23H22N5O4Cl+0.6H2O: C, 57.71; H, 4.88; N, 14.63; Cl, 7.41. Found: C, 57.63; H, 4.96; N, 14.50; Cl, 7.64.