Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2](=[N:8][OH:9])[C:3]([O:5][CH2:6][CH3:7])=[O:4].CO[C:12]([C:14]1[CH:19]=[CH:18][C:17]([C:20]([C:25]2[CH:30]=[CH:29][C:28]([O:31][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=3)=[CH:27][N:26]=2)([CH3:24])[CH:21]([CH3:23])[CH3:22])=[CH:16][CH:15]=1)=[CH2:13].C(N(CC)CC)C.C(O)(C(F)(F)F)=O>C1COCC1>[CH3:24][C:20]([C:17]1[CH:16]=[CH:15][C:14]([C:12]2[O:9][N:8]=[C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH:13]=2)=[CH:19][CH:18]=1)([C:25]1[CH:30]=[CH:29][C:28]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=2)=[CH:27][N:26]=1)[CH:21]([CH3:23])[CH3:22]
Reactant: CCOC(=O)C(Cl)=NO
Reactant: C=C(OC)c1ccc(C(C)(c2ccc(OCc3ccccn3)cn2)C(C)C)cc1
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cc(-c2ccc(C(C)(c3ccc(OCc4ccccn4)cn3)C(C)C)cc2)on1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
Ethyl 2-chloro-2-(hydroxyimino)acetate (3.15 g, 20.7 mmol) was added to a stirred solution of 1b (crude product from Step B; 6.91 mmol) and triethylamine (9.60 mL, 69.1 mmol) in THF (100 mL) at rt. After approximately 1 h, the reaction mixture was acidified to pH ˜1 by the addition of TFA, and the resulting mixture was heated to 50° C. After 1 h, the reaction mixture was concentrated in vacuo, the residue redissolved in TFA (30 mL) and the resulting solution was heated to 50° C. for an additional 1 h. After evaporation of the volatiles in vacuo, the crude residue was dissolved in EtOAc and carefully neutralized by the addition of saturated aqueous sodium bicarbonate. The organic layer was separated, dried (sodium sulfate), concentrated in vacuo, and the resulting crude residue was purified by flash chromatography on silica gel (gradient elution; 0%-100% EtOAc/hexanes as eluent) to afford the title compound 1c. m/z (ES) 472 (MH)+. 1HNMR (500 MHz, CDCl3): δ 8.61 (d, 1H, J=3.5 Hz), 8.40 (d, 1H, J=2.2 Hz), 7.77 (m, 1H), 7.70 (d, 2H, J=8.5 Hz), 7.55 (d, 1H, J=7.7 Hz), 7.49 (d, 2H, J=8.4 Hz), 7.20 (m, 3H), 6.87 (s, 1H), 5.24 (s, 2H), 4.48 (q, 211, J=7.1 Hz), 3.11 (m, 1H, J=6.6 Hz), 1.70 (s, 3H), 1.46 (t, 311, J=7.1 Hz), 0.87 (d, 3H, J=6.7 Hz), 0.80 (d, 3H, J=6.9 Hz).
Reaction SMILES: [CH3:1][S:2][S:3][CH:4]([CH3:8])[C:5](O)=[O:6].ClC(OCC(C)C)=O.CN1CCOCC1.[NH2:24][C:25]1[CH:26]=[C:27]2[C:32](=[CH:33][CH:34]=1)[N:31]=[CH:30][N:29]=[C:28]2[NH:35][C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([Br:42])[CH:37]=1>O1CCCC1.C(Cl)Cl.CO>[Br:42][C:38]1[CH:37]=[C:36]([NH:35][C:28]2[C:27]3[C:32](=[CH:33][CH:34]=[C:25]([NH:24][C:5](=[O:6])[CH:4]([S:3][S:2][CH3:1])[CH3:8])[CH:26]=3)[N:31]=[CH:30][N:29]=2)[CH:41]=[CH:40][CH:39]=1
Reactant: CSSC(C)C(=O)O
Reactant: Nc1ccc2ncnc(Nc3cccc(Br)c3)c2c1
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CSSC(C)C(=O)Nc1ccc2ncnc(Nc3cccc(Br)c3)c2c1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 49.1 %

Procedure:
A solution of 2 grams of disulfide acid from Example 72 in 50 mL of tetrahydrofuran was cooled in an ice bath. A 1.7 mL portion of isobutyl chloroformate followed by a 1.4 mL portion of N-methyl morpholine were added. After stirring for 5 minutes at 0° C., 1.0 grams of 6-amino 4-(3-bromoanilino)quinazoline was added. The mixture was stirred for 3 hours at 0° C. and then allowed to warm to room temperature. The reaction was quenched with water and the tetrahydrofuran was evaporated under vacuum. Addition of methylene chloride followed by washing the methylene chloride layer with water and evaporation of the solvent gave a crude product. Silica gel chromatography with methanol in methylene chloride gave 0.7 grams white solid of product.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=2)[C:13]([CH2:24][C:25](O)=[O:26])=[CH:12][N:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH2:31][CH2:30][NH:29]1>>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=2)[C:13]([CH2:24][C:25]([N:29]2[CH2:30][CH2:31][C:32]3[C:37](=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH2:28]2)=[O:26])=[CH:12][N:11]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: COc1cc2c(CC(=O)O)cnc(CNC(=O)OC(C)(C)C)c2cc1OC
Reactant: c1ccc2c(c1)CCNC2
Product: COc1cc2c(CC(=O)N3CCc4ccccc4C3)cnc(CNC(=O)OC(C)(C)C)c2cc1OC

Procedure:
As described in Example 1, 94 mg of [1-(tert-butoxycarbonylamino-methyl)-6,7-dimethoxy-isoquinolin-4-yl]-acetic acid was coupled with 1,2,3,4-tetrahydro-isoquinoline to give 94 mg of {4-[2-(3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]-6,7-dimethoxy-isoquinolin-1-ylmethyl}-carbamic acid tert-butyl ester. MS: APCI (M+H) calc'd for C28H33N3O5+H 492.6; found 492.0.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[N:12]=[CH:11][NH:10][C:9]=2[CH:13]=1)=[O:4].[OH-].[Na+].[Cl:16][CH2:17][CH2:18][CH2:19][CH2:20]Br>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[Cl:16][CH2:17][CH2:18][CH2:19][CH2:20][N:10]1[C:9]2[CH:13]=[C:5]([C:3]([O:2][CH3:1])=[O:4])[CH:6]=[CH:7][C:8]=2[N:12]=[CH:11]1
Reactant: COC(=O)c1ccc2nc[nH]c2c1
Reactant: ClCCCCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Product: COC(=O)c1ccc2ncn(CCCCCl)c2c1
Temperature: 60 °C
Yield: 63.4 %

Procedure:
6-methoxycarbonyl-1H-benzimidazole (17.6 g, 0.10 mol) was dissolved into 200 ml of 20% wt. sodium hydroxide, 4-chlorobromobutane (34.3 g, 0.20 mol) and tetrabutyl ammonium bromide (1.0 g) were added, and mixed for 5 min. The mixture was heated to 60° C., stirred to react for 2 hours. Post treatment was performed based on common method one for synthesis. Oily products were separated and purified by chromatography with neutral Al2O3 to produce 16.9 g of 1-(4-chlorobutyl)-6-methoxycarbonyl-1H-benzimidazole, with a yield of 63.4%.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[N:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[NH:15][CH:14]=[C:13]([C:19]([O:21]CC)=[O:20])[C:12]2=[O:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].[Cl-].[NH4+]>C(O)C>[CH2:1]([NH:8][C:9]1[N:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[NH:15][CH:14]=[C:13]([C:19]([OH:21])=[O:20])[C:12]2=[O:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1c[nH]c2ccc(NCc3ccccc3)nc2c1=O
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CCO
Product: O=C(O)c1c[nH]c2ccc(NCc3ccccc3)nc2c1=O
Yield: 63.9 %

Procedure:
A mixture of ethyl 6-benzylamino-4-oxo-1,4-dihydro-1,5-naphthyridine-3-carboxylate (60 mg), 1N NaOH (2 mL), and ethanol (0.5 mL) was heated at reflux for 2 h. The reaction mixture was cooled in an ice bath and saturated aqueous ammonium chloride was added. The resulting precipitate was collected, rinsed with water and ether, then dried to afford 35 mg of 6-benzylamino-4-oxo-1,4-dihydro-1,5-naphthyridine-3-carboxylic acid as a brown solid.
Reaction SMILES: C(N1CCC(O)C1)C1C=CC=CC=1.N1C=CC=CC=1.C(Cl)(=O)C1C=CC=CC=1.C([O-])(O)=O.[Na+].C([N:41]1[CH2:45][CH2:44][CH:43]([O:46][C:47](=[O:54])[C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[CH2:42]1)C1C=CC=CC=1.ClC(OC(Cl)C)=O>ClCCl.CO>[C:47]([O:46][C@H:43]1[CH2:44][CH2:45][NH:41][CH2:42]1)(=[O:54])[C:48]1[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=1
Reactant: O=C(OC1CCN(Cc2ccccc2)C1)c1ccccc1
Agent: CC(Cl)OC(=O)Cl
Agent: O=C([O-])O
Agent: OC1CCN(Cc2ccccc2)C1
Solvent: ClCCl
Solvent: O=C(Cl)c1ccccc1
Solvent: CO
Product: O=C(O[C@H]1CCNC1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of N-benzyl-3-hydroxypyrrolidine (0.50 g, 2.84 mmol) in dichloromethane (5 mL) and pyridine (0.46 mL, 5.68 mmol) is added benzoyl chloride (0.4 mL, 3.41 mmol) at 0° C., and the mixture is stirred for 1 hour while warming to room temperature. After addition of saturated aqueous NaHCO3, the mixture is extracted with EtOAc. The combined organic layer is dried over MgSO4, filtered, and concentrated. The resulting N-benzyl-3-benzoyloxypyrrolidine is used for next step without further purification. To a crude mixture of N-benzyl-3-benzoyloxypyrrolidine (114 mg, 0.41 mmol) in dichloromethane (1 mL) is added α-chloroethyl chloroformate (57 μL, 0.49 mmol) at 0° C., and the mixture is stirred for 1 hour while warming to room temperature. After removing dichloromethane, resulting mixture is diluted with MeOH. The reaction mixture is heated to 80° C. for 0.5 hour. After cooling to room temperature, solvent is evaporated under reduced pressure to obtain (S)-(−)-3-benzoyloxypyrrolidine which is used for next reaction without further purification.
Reaction SMILES: [C:1]([C:3]1[CH:15]=[C:14]2[C:6]([C:7]3[C:8](=[O:30])[C:9]4[CH:21]=[CH:20][C:19](OS(C(F)(F)F)(=O)=O)=[CH:18][C:10]=4[C:11]([CH3:17])([CH3:16])[C:12]=3[NH:13]2)=[CH:5][CH:4]=1)#[N:2].[OH:31][CH2:32][CH2:33][N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1>>[OH:31][CH2:32][CH2:33][N:34]1[CH2:39][CH2:38][N:37]([C:19]2[CH:20]=[CH:21][C:9]3[C:8](=[O:30])[C:7]4[C:6]5[C:14](=[CH:15][C:3]([C:1]#[N:2])=[CH:4][CH:5]=5)[NH:13][C:12]=4[C:11]([CH3:17])([CH3:16])[C:10]=3[CH:18]=2)[CH2:36][CH2:35]1
Reactant: OCCN1CCNCC1
Reactant: CC1(C)c2cc(OS(=O)(=O)C(F)(F)F)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21
Product: CC1(C)c2cc(N3CCN(CCO)CC3)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21

Procedure:
According to the same method as the method for synthesizing Compound B2-1, the title compound was prepared from Compound B1 and N-(2-hydroxyethyl)piperazine.
Reaction SMILES: C([O:4][C:5]1[C:6]([C:30]([CH3:33])([CH3:32])[CH3:31])=[CH:7][C:8]2[O:12][C:11]([CH3:24])([CH2:13][O:14][C:15]3[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=3)[CH2:10][C:9]=2[C:25]=1[C:26]([CH3:29])([CH3:28])[CH3:27])(=O)C.[H-].C([Al+]CC(C)C)C(C)C.[Cl-].[NH4+].Cl>C1(C)C=CC=CC=1>[C:26]([C:25]1[C:9]2[CH2:10][C:11]([CH3:24])([CH2:13][O:14][C:15]3[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=3)[O:12][C:8]=2[CH:7]=[C:6]([C:30]([CH3:33])([CH3:32])[CH3:31])[C:5]=1[OH:4])([CH3:29])([CH3:28])[CH3:27]
Reactant: CC(=O)Oc1c(C(C)(C)C)cc2c(c1C(C)(C)C)CC(C)(COc1ccc([N+](=O)[O-])cc1)O2
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: CC1(COc2ccc([N+](=O)[O-])cc2)Cc2c(cc(C(C)(C)C)c(O)c2C(C)(C)C)O1
Temperature: 25 °C
Reaction time: 2 h
Yield: 36.4 %

Procedure:
Under a nitrogen atmosphere, 1.0 g of 5-acetoxy-4,6-di-t-butyl-2-methyl-2-(4-nitrophenoxymethyl)-2,3-dihydrobenzofuran was dissolved in 30 ml of toluene. To the solution was added 5.5 ml of diisobutyl aluminum hydride (1.0 M in toluene) and the mixture was stirred at room temperature for 2 hours. After reaction, the reaction solution was combined with a saturated aqueous ammonium chloride solution and 10% hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and then concentrated. The concentrate was purified by silica gel column chromatography eluting with n-hexane containing 5% ethyl acetate to give 0.33 g of 4,6-di-t-butyl-5-hydroxy-2-methyl-2-(4-nitrophenoxymethyl)-2,3-dihydrobenzofuran as a pale yellow oil (yield 36%).
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=1)#[N:2].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:45][CH2:46][CH2:47][N:48]1[C:52](=[O:53])/[C:51](=[CH:54]/[C:55]2[CH:60]=[CH:59][C:58]([O:61][CH2:62][CH3:63])=[CH:57][CH:56]=2)/[S:50][C:49]1=[O:64]>CN(C=O)C.C(OCC)(=O)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:7]([NH:45][CH2:46][CH2:47][N:48]2[C:52](=[O:53])/[C:51](=[CH:54]/[C:55]3[CH:60]=[CH:59][C:58]([O:61][CH2:62][CH3:63])=[CH:57][CH:56]=3)/[S:50][C:49]2=[O:64])=[O:9])=[CH:10][CH:11]=1)#[N:2]
Reactant: CCOc1ccc(/C=C2\SC(=O)N(CCN)C2=O)cc1
Reactant: N#Cc1ccc(C(=O)O)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1ccc(/C=C2\SC(=O)N(CCNC(=O)c3ccc(C#N)cc3)C2=O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.1 %

Procedure:
To a solution of 4-cyanobenzoic acid (46 mg, 0.31 mmol) in 3 mL of DMF was added DIPEA (131 μL, 0.75 mmol) followed by HBTU (114 mg, 0.30 mmol). After being stirred at room temperature for 1 h, compound 76 (101 mg, 0.25 mmol) was added and then the reaction mixture was stirred at room temperature overnight. The reaction solution was diluted with 50 mL of ethyl acetate and washed with water (30 mL×5), collected the organic layer, dried over Na2SO4, filtered, concentrated and purified by silica column chromatography (15% ethyl acetate in hexanes) to afford 97 mg (92.1%) of the title compound 25d as a light-yellow solid.
Reaction SMILES: [CH:1](NC(C)C)(C)C.[Li]CCCC.[F:13][C:14]([F:27])([F:26])[O:15][C:16]1[CH:17]=[C:18]([CH2:22][C:23]([OH:25])=[O:24])[CH:19]=[CH:20][CH:21]=1.CI>O1CCCC1.CCCCCC.O>[F:13][C:14]([F:26])([F:27])[O:15][C:16]1[CH:17]=[C:18]([CH:22]([CH3:1])[C:23]([OH:25])=[O:24])[CH:19]=[CH:20][CH:21]=1
Reactant: O=C(O)Cc1cccc(OC(F)(F)F)c1
Reactant: CC(C)NC(C)C
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: O
Solvent: CI
Product: CC(C(=O)O)c1cccc(OC(F)(F)F)c1
Temperature: -70 °C
Reaction time: 0.25 h

Procedure:
A solution of diisopropylamine (3.1 ml) in tetrahydrofuran (30 ml) was cooled to 0° C. before dropwise addition of 1.6M nBuLi in hexane (13.5 ml) and then stirred for 15 minutes and cooled to −70° C. 3-(trifluoromethoxy)-phenylacetic acid (2 g) was dissolved in tetrahydrofuran (20 ml) and added dropwise to the reaction mixture which was then allowed to warm to 0° C., stirred for 30 minutes and then cooled back to −70° C. Methyl iodide (0.9 ml) was then added slowly and the solution stirred for further 1.5 hours at −70° C. Water was added the solution washed with diethyl ether, the aqueous phase was acidified by addition of 25% aqueous HCl and then extracted twice with diethyl ether, dried over Mg2SO4, filtered and concentrated. The residue was purified by flash column chromatography (SiO2; hexane/EtOAc 3:1) to afford 2-(3-trifluoromethoxy-phenyl)-propionic acid (1.5 g) as a light yellow oil. MS (ISP): 232.9 ([M−H]+)).
Reaction SMILES: C1(C)C=CC=CC=1.[F:8][C:9]1[CH:10]=[C:11]([CH:27]=[CH:28][CH:29]=1)[C:12]([C@@H:14]1[CH2:19][CH2:18][CH2:17][N:16]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:15]1)=[O:13].CO>C1COCC1.CCOC(C)=O>[F:8][C:9]1[CH:10]=[C:11]([C@H:12]([OH:13])[CH:14]2[CH2:19][CH2:18][CH2:17][N:16]([C:20]([O:22][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:21])[CH2:15]2)[CH:27]=[CH:28][CH:29]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](C(=O)c2cccc(F)c2)C1
Solvent: CO
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCCC([C@@H](O)c2cccc(F)c2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 38.2 %

Procedure:
To a solution of 1 M R-CBS-oxazaborolidine in toluene (33 mL, 33 mmol, 0.15 eq) and 10 M BH3 in THF (22 mL, 0.22 mol, 1.0 eq) at −15° C. under nitrogen was added dropwise a solution of (R)-tert-butyl 3-(3-fluorobenzoyl)piperidine-1-carboxylate (67.5 g, 0.22 mol) in anhydrous THF (300 mL). After addition, the reaction mixture was stirred for 1 hr at rt. Methanol (200 mL) was added dropwise carefully at 0° C. The solvent was removed under reduced pressure to provide the crude product. The crude product was dissolved in EtOAc until the alcohol was just dissolved (about 5 mL/1 g), the solvent was removed on the rotary evaporator until a few crystals appeared. To the above solution was added petroleum ether (about 300 mL) under stirring, which was allowed to stir at rt for 2 hr and then filtered, the crystals were washed with petroleum ether and re-crystallized to afford the pure R)-tert-butyl 3-((R)-(3-fluorophenyl)(hydroxy)methyl)piperidine-1-carboxylate (26 g, 39%).
Reaction SMILES: [NH:1]([C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24])[C@H:2]([C:20]([OH:22])=O)[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:19])[NH:8][S:9]([C:12]1[CH:18]=[CH:17][C:15]([CH3:16])=[CH:14][CH:13]=1)(=[O:11])=[O:10].CN1CCOCC1.ClC(OCC(C)C)=O.Cl.[NH2:49][C@H:50]([C:55]([NH:57][C@H:58]([C:63]([NH:65][C@H:66]([C:72]([NH:74][CH2:75][C:76]([NH:78][C@H:79]([C:84]([NH:86][C@H:87]([C:91]([NH2:93])=[O:92])[CH:88]([CH3:90])[CH3:89])=[O:85])[CH2:80][CH:81]([CH3:83])[CH3:82])=[O:77])=[O:73])[CH2:67][CH2:68][C:69](=[O:71])[NH2:70])=[O:64])[CH2:59][CH:60]([CH3:62])[CH3:61])=[O:56])[CH2:51][CH:52]([CH3:54])[CH3:53].C(O)C(F)(F)F>CN(C)C=O.[Pd].O.C(O)(=O)C>[NH:1]([C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24])[C@H:2]([C:20]([NH:49][C@H:50]([C:55]([NH:57][C@H:58]([C:63]([NH:65][C@H:66]([C:72]([NH:74][CH2:75][C:76]([NH:78][C@H:79]([C:84]([NH:86][C@H:87]([C:91]([NH2:93])=[O:92])[CH:88]([CH3:90])[CH3:89])=[O:85])[CH2:80][CH:81]([CH3:82])[CH3:83])=[O:77])=[O:73])[CH2:67][CH2:68][C:69](=[O:71])[NH2:70])=[O:64])[CH2:59][CH:60]([CH3:62])[CH3:61])=[O:56])[CH2:51][CH:52]([CH3:54])[CH3:53])=[O:22])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:19])[NH:8][S:9]([C:12]1[CH:18]=[CH:17][C:15]([CH3:16])=[CH:14][CH:13]=1)(=[O:10])=[O:11]
Reactant: Cc1ccc(S(=O)(=O)NC(=N)NCCC[C@H](NC(=O)OCc2ccccc2)C(=O)O)cc1
Reactant: CC(C)C[C@H](NC(=O)CNC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CC(C)C)C(=O)N[C@H](C(N)=O)C(C)C
Agent: [Pd]
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: CC(=O)O
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)NC(=N)NCCC[C@H](NC(=O)OCc2ccccc2)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@H](C(N)=O)C(C)C)cc1
Temperature: -5 °C
Reaction time: 0.25 h

Procedure:
In 300 ml of dimethylformamide is dissolved 37.8 g (81.7 millimoles) of Z-Arg(Tos)-OH, and 8.25 g of N-methylmorpholine is added to the solution. Then, the mixture is cooled to -5° C. and 10.8 g of isobutyl chloroformate is dropped to the mixture over a period of 5 minutes. The mixture is stirred for 15 minutes and mixed with a liquid mixture formed by adding 5.9 g of N-methylmorpholine to a solution of 39.5 g (58.4 millimoles) of HCl .H-Leu-Leu-Gln-Gly-Leu-Val-NH2 [prepared by reducing the Z-compound having a melting point of 261° to 265° C. and an optical rotation [α]D25 of 43.9° (C=2, acetic acid) with equivalent amounts of HCl and trifluoroethanol in the presence of 10% Pd-C] in 400 ml of dimethylformamide. The mixture is stirred at -5° C. for 2.5 hours and added to 3 l of water. The formed precipitate is recovered by filtration, washed with methanol and dissolved in acetic acid, and the solution is added to water. The formed precipitate is recovered by filtration, washed with water and dried to obtain 52.5 g of intended Z-Arg(Tos)-Leu-Leu-Gln-Gly-Leu-Val-NH2 (the yield being 83%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].CCN(CC)CC.[C:19]1([CH3:29])[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1>C(Cl)Cl>[CH3:29][C:19]1[CH:24]=[CH:23][C:22]([S:25]([O:1][CH2:2][CH2:3][NH:4][C:5]([O:6][C:7]([CH3:8])([CH3:10])[CH3:9])=[O:11])(=[O:27])=[O:26])=[CH:21][CH:20]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)NCCO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCCNC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79 %

Procedure:
To a mixture of tert-butyl 2-hydroxyethylcarbamate (6.4 g, 40 mmol) and Et3N (7.2 mL, 52 mmol) in DCM (50 mL) was added para-toluene sulfonylchloride, TsCl (8.4 g, 44 mmol). The mixture was stirred at room temperature (rt) overnight (ON). The reaction mixture was concentrated and the residue was partitioned between EA and water. The organic layer was separated, dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel chromatography (PE/EA=5/1) to give 2-(tert-butoxycarbonylamino)ethyl 4-methylbenzenesulfonate (10.0 g, 79%) as white solid.
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][NH2:11])=[CH:6][CH:5]=1.[Br:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17]Br)=[CH:15][CH:14]=1>>[ClH:1].[Br:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][N:10]([C:7]2[CH:8]=[CH:9][C:4]([O:3][CH3:2])=[CH:5][CH:6]=2)[NH2:11])=[CH:15][CH:14]=1
Reactant: COc1ccc(NN)cc1
Reactant: BrCc1ccc(Br)cc1
Agent: Cl
Product: COc1ccc(N(N)Cc2ccc(Br)cc2)cc1

Procedure:
4-Methoxyphenylhydrazine hydrochloride is reacted with 4-bromobenzyl bromide in the presence of a base to provide N-(4-bromo-benzyl)-N-(4-methoxy-phenyl)-hydrazine hydrochloride. N-(4-bromo-benzyl)-N-(4-methoxy-phenyl)-hydrazine hydrochloride is reacted with 5-tert-butylsulfanyl-2,2-dimethyl-4-oxo-pentanoic acid alkyl esters of structure 2-4 (where R1 is C1-C6 alkyl) to provide 3-[1-(4-bromo-benzyl)-3-tert-butylsulfanyl-5-methoxy-1H-indol-2-yl]-2,2-dimethyl-propionic acid alkyl esters of structure 3-1. In one aspect, R1 is selected from methyl, ethyl, propyl, isopropyl, and butyl. In another aspect, R1 is methyl or ethyl. In another aspect, R1 is ethyl.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:15][CH:14]=3)=[N:10][C:9]=2[C:23]([NH:25][C:26]2[S:27][CH:28]=[CH:29][N:30]=2)=[O:24])=[CH:4][CH:3]=1.CO.[CH:33](=O)[CH2:34][CH2:35][CH2:36][CH:37]=O.C([BH3-])#N.[Na+]>O1CCCC1.O>[C:19]([C:16]1[CH:15]=[CH:14][C:13]([C:11]2[NH:12][C:8]([C:5]3[CH:4]=[CH:3][C:2]([N:1]4[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]4)=[CH:7][CH:6]=3)=[C:9]([C:23]([NH:25][C:26]3[S:27][CH:28]=[CH:29][N:30]=3)=[O:24])[N:10]=2)=[CH:18][CH:17]=1)([CH3:22])([CH3:20])[CH3:21]
Reactant: O=CCCCC=O
Reactant: CC(C)(C)c1ccc(-c2nc(C(=O)Nc3nccs3)c(-c3ccc(N)cc3)[nH]2)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(-c2nc(C(=O)Nc3nccs3)c(-c3ccc(N4CCCCC4)cc3)[nH]2)cc1
Temperature: 25 °C
Reaction time: 408 h
Yield: 10.3 %

Procedure:
5-(4-Aminophenyl)-2-(4-tert-butylphenyl)-N-(2-thiazolyl)-imidazole-4-carboxamide (1.0 g) obtained in Example 77 was dissolved in tetrahydrofuran (55 ml), methanol (55 ml) and KH2PO4-Na2HPO4 buffer (pH 6.5, 70 ml), and 25% glutaraldehyde aqueous solution (1.22 g) and sodium cyanoborohydride (1.32 g) were added under ice-cooling. The mixture was stirred at room temperature for 17 days. Water (100 ml) was added and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous hydrogencarbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was subjected to silica gel column chromatography to give the objective 2-(4-tert-butylphenyl)-5-(4-piperidinophenyl)-N-(2-thiazolyl)-imidazole-4-carboxamide (0.12 g), melting point 250-252° C. (decomposition).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([C:7]([CH3:9])=[CH2:8])[S:5][CH:6]=1.[F:10][C:11]([F:50])([F:49])[C:12]1[CH:13]=[C:14]([C@H:22]2[O:26][C:25](=[O:27])[N:24]([CH2:28][C:29]3[CH:34]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:32]=[CH:31][C:30]=3B3OC(C)(C)C(C)(C)O3)[C@H:23]2[CH3:48])[CH:15]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:17]=1.C([O-])([O-])=O.[K+].[K+]>C1COCC1>[F:50][C:11]([F:10])([F:49])[C:12]1[CH:13]=[C:14]([C@H:22]2[O:26][C:25](=[O:27])[N:24]([CH2:28][C:29]3[CH:34]=[C:33]([C:35]([F:36])([F:37])[F:38])[CH:32]=[CH:31][C:30]=3[C:2]3[N:3]=[C:4]([C:7]([CH3:9])=[CH2:8])[S:5][CH:6]=3)[C@H:23]2[CH3:48])[CH:15]=[C:16]([C:18]([F:19])([F:21])[F:20])[CH:17]=1
Reactant: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1cc(C(F)(F)F)ccc1B1OC(C)(C)C(C)(C)O1
Reactant: C=C(C)c1nc(Br)cs1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=C(C)c1nc(-c2ccc(C(F)(F)F)cc2CN2C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2C)cs1
Temperature: 100 °C

Procedure:
In a tube were placed 4-bromo-2-isopropenyl-1,3-thiazole (20 mg, 0.097 mmol), (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-3-[2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)benzyl]-1,3-oxazolidin-2-one (29.4 mg, 0.0492 mmol), THF (340 μL), 1M aqueous K2CO3 (340 μL), and 1,1-bis(di-t-butylphosphino)ferrocene palladium chloride (3.2 mg, 4.9×10−3 mmol). The mixture was degassed with N2. The tube was sealed and heated at 100° C. for 1.5 hours. The reaction was then cooled to room temperature, diluted with EtOAc (50 mL), and washed with water and brine (15 mL each). The organic layer was dried over Na2SO4, filtered, and concentrated. Purification of the residue by flash chromatography on silica gel (5 to 25% EtOAc/hexanes) and then by PTLC (90% CH2Cl2/hexanes) afforded (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-(2-isopropenyl-1,3-thiazol-4-yl)-5-(trifluoromethyl)benzyl]-4-methyl-1,3-oxazolidin-2-one. Rf=0.16 (15% EtOAc/hexanes). LCMS=595.1 (M+1)+. 1H NMR (CD2Cl2, 500 MHz) δ 7.90 (s, 1H), 7.64-7.76 (m, 5H), 7.38 (s, 1H), 5.89 (s, 1H), 5.60 (d, J=8.1 Hz, 1H), 5.37 (d, J=1.2 Hz, 1H), 4.99 (d, J=16.0 Hz, 1H), 4.66 (d, J=16.0 Hz, 1H), 3.94 (m, 1H), 2.25 (s, 3H), 0.59 (d, J=6.4 Hz, 3H).