Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][O:9][C:10]1[CH:54]=[CH:53][C:13]([CH2:14][N:15]([CH2:44][C:45]2[CH:50]=[CH:49][C:48]([O:51][CH3:52])=[CH:47][CH:46]=2)[C:16]2[N:21]=[C:20]([CH3:22])[N:19]=[C:18]([C:23]3[CH:24]=[C:25]([CH2:30][N:31]4[CH2:36][CH2:35][N:34](C(OC(C)(C)C)=O)[CH2:33][CH2:32]4)[CH:26]=[N:27][C:28]=3[F:29])[CH:17]=2)=[CH:12][CH:11]=1.C(N(CC)CC)C.[CH3:62][S:63](Cl)(=[O:65])=[O:64]>ClCCl>[F:29][C:28]1[C:23]([C:18]2[N:19]=[C:20]([CH3:22])[N:21]=[C:16]([N:15]([CH2:44][C:45]3[CH:50]=[CH:49][C:48]([O:51][CH3:52])=[CH:47][CH:46]=3)[CH2:14][C:13]3[CH:53]=[CH:54][C:10]([O:9][CH3:8])=[CH:11][CH:12]=3)[CH:17]=2)=[CH:24][C:25]([CH2:30][N:31]2[CH2:36][CH2:35][N:34]([S:63]([CH3:62])(=[O:65])=[O:64])[CH2:33][CH2:32]2)=[CH:26][N:27]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2cc(-c3cc(CN4CCN(C(=O)OC(C)(C)C)CC4)cnc3F)nc(C)n2)cc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2cc(-c3cc(CN4CCN(S(C)(=O)=O)CC4)cnc3F)nc(C)n2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88 %

Procedure:
2,2,2-Trifluoroacetic acid (0.7 mL, 9.09 mmol) was added dropwise to tert-butyl 4-((5-(6-(bis(4-methoxybenzyl)amino)-2-methylpyrimidin-4-yl)-6-fluoropyridin-3-yl)methyl)piperazine-1-carboxylate (64.3 mg, 0.100 mmol) in dichloromethane (1.0 mL) at 25° C., and the resulting solution was stirred at 25° C. for 30 min. The reaction mixture was then concentrated in vacuo, and the residue was taken up in DCM (3.0 mL) and cooled to 0° C. Triethylamine (0.105 mL, 0.750 mmol) was added to the resulting solution, immediately followed by methanesulfonyl chloride (0.015 mL, 0.200 mmol). The resulting mixture was stirred at 0° C. for 20 min and then was concentrated onto silica gel and chromatographically purified (ISCO, 4 g, 0 to 100% (10% MeOH-EtOAc)/hexanes) to provide 6-(2-fluoro-5-((4-(methylsulfonyl)piperazin-1-yl)methyl)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-2-methylpyrimidin-4-amine (54.5 mg, 0.088 mmol, 88% yield) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 8.45 (d, J=9.39 Hz, 1H); 8.14 (s, 1H); 7.17 (d, J=6.85 Hz, 4H); 6.86 (d, J=8.80 Hz, 5H); 4.74 (br. s., 4H); 3.79 (s, 6H); 3.60 (s, 2H); 3.25 (br. s., 4H); 2.78 (s, 3H); 2.62 (s, 3H); 2.58 (br. s., 4H). 19F NMR (377 MHz, CDCl3) δ −70.62 (d, J=8.01 Hz, 1F). m/z (ESI, +ve ion) 621.1 (M+H)+.
Reaction SMILES: [C:1]1(=O)[CH:6]=[CH:5][C:4](=[O:7])[CH:3]=[CH:2]1.C(O)(=O)C.[CH3:13][O:14][CH2:15][C:16]([NH2:22])=[CH:17][C:18]([O:20][CH3:21])=[O:19].S(S([O-])=O)([O-])=O.[Na+].[Na+].[OH-].[Na+]>C(OCC)(=O)C>[OH:7][C:4]1[CH:3]=[C:2]2[C:1](=[CH:6][CH:5]=1)[NH:22][C:16]([CH2:15][O:14][CH3:13])=[C:17]2[C:18]([O:20][CH3:21])=[O:19]
Reactant: O=C1C=CC(=O)C=C1
Reactant: COCC(N)=CC(=O)OC
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COCc1[nH]c2ccc(O)cc2c1C(=O)OC
Yield: 44.6 %

Procedure:
32.4 g (300 mmol) of 1,4-benzoquinone was dissolved in 200 ml of ethyl acetate, 200 ml (350 mmol) of acetic acid was added thereto, followed by dropwise addition of 14.5 g (100 mmol) of methyl 4-methoxy-3-amino-2-butenoate. With stirring, the reaction mixture was heated for 15 hours while keeping the inner temperature at 50° C. To this was then added dropwise 200 ml of an aqueous solution containing 52.2 g (300 mmol) of sodium hydrosulfite. The mixture was further stirred at room temperature for 2 hours while controlling the reaction mixture within a pH range of from 4.5 to 7.5 with 5 N sodium hydroxide. Thereafter, crystals thus precipitated were collected by filtration and washed with ethyl acetate to obtain 7.33 g of crude crystals. The filtrate and the washings were combined and then allowed to separate into organic and water layers. The water layer was extracted with 50 ml of ethyl acetate, and the resulting ethyl acetate layer was combined with the organic layer. The thus combined organic layer was washed with saturated sodium chloride aqueous solution and then dried over anhydrous magnesium sulfate. After anhydrous magnesium sulfate was filtered off and the solvent was distilled off under reduced pressure, the resulting residue was purified by an alumina column chromatography (eluent: ethyl acetate). Main fractions thus obtained were concentrated, and the concentrated residue was slurried with 150 ml of ethyl acetate. The thus obtained crude product was combined with the crude crystals previously collected by filtration, and the combined product was recrystallized from 260 ml of ethyl acetate to obtain 10.5 g of the title compound with a yield of 44.2%.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH:21]1[C:46](=[O:47])[N:23]2[C:24]([C:30]([O:32][CH:33]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[O:31])=[C:25]([CH:28]=[CH2:29])[CH2:26][S:27][C@H:22]12)[C:9](=[O:20])[CH:10]([C:12]1[N:13]=[C:14]([NH:17]C=O)[S:15][CH:16]=1)[NH2:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl>CO.O1CCCC1>[C:1]([O:5][C:6]([N:8]([CH:21]1[C:46](=[O:47])[N:23]2[C:24]([C:30]([O:32][CH:33]([C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)[C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)=[O:31])=[C:25]([CH:28]=[CH2:29])[CH2:26][S:27][C@H:22]12)[C:9](=[O:20])[CH:10]([C:12]1[N:13]=[C:14]([NH2:17])[S:15][CH:16]=1)[NH2:11])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(N(C(=O)OC(C)(C)C)C(=O)C(N)c3csc(NC=O)n3)[C@H]2SC1
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: C=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(N(C(=O)OC(C)(C)C)C(=O)C(N)c3csc(N)n3)[C@H]2SC1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 7.5 %

Procedure:
A mixture of benzhydryl 7-[N-tert-butoxycarbonyl-2-(2-formamidothiazol-4-yl)glycinamido]-3-vinyl-3-cephem-4-carboxylate (5.6 g) and conc. hydrochloric acid (2.6 ml) in methanol (60 ml) and tetrahydrofuran (15 ml) was stirred at ambient temperature for 2.5 hours. The precipitated substance in the reaction mixture was collected by filtration, and washed with a mixture of methanol and water (1:2 by volume) and then water, followed by drying to give benzhydryl 7-[N-tert-butoxycarbonyl-2-(2-aminothiazol-4-yl)glycinamido]-3-vinyl-3-cephem-4-carboxylate (0.4 g).
Reaction SMILES: [NH:1]=[C:2]1[C:7]([CH3:8])=[N:6][CH:5]=[C:4]([CH3:9])[N:3]1[NH2:10].CC1C=C(C)C=C(C)C=1S([O-])(=O)=O.C(N(CC)CC)C.Cl[C:32](=[O:40])[CH:33]([CH3:39])[CH2:34][C:35]([O:37][CH3:38])=[O:36]>C(#N)C>[NH2:10][N:3]1[C:4]([CH3:9])=[CH:5][N:6]=[C:7]([CH3:8])/[C:2]/1=[N:1]/[C:32](=[O:40])[CH:33]([CH3:39])[CH2:34][C:35]([O:37][CH3:38])=[O:36]
Reactant: COC(=O)CC(C)C(=O)Cl
Reactant: Cc1ncc(C)n(N)c1=N
Agent: Cc1cc(C)c(S(=O)(=O)[O-])c(C)c1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC(=O)CC(C)C(=O)/N=c1/c(C)ncc(C)n1N
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 69.8 %

Procedure:
To a solution of 2-imino-3,6-dimethylpyrazin-1(2H)-amine-2,4,6-trimethylbenzenesulfonate (2 g, 5.92 mmol) in acetonitrile (60 mL) was added triethylamine (1.8 g, 17.76 mmol). The mixture was stirred at 50° C. for 30 min. Methyl 4-chloro-3-methyl-4-oxobutanoate (1.35 g, 8.23 mmol) was added. The mixture was stirred for an additional 10 min. Then the solution was evaporated to give 1.1 g of the crude product as a brown solid. ESI MS: m/z 267 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[C:7]2[O:8][C:9]([C:11]3[O:12][C:13]([CH3:16])=[CH:14][N:15]=3)=[CH:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.S(C1C=CC([N+]([O-])=O)=CC=1)(O[CH2:21][C@H:22]1[O:24][CH2:23]1)(=O)=O>>[CH2:21]([O:1][C:2]1[C:7]2[O:8][C:9]([C:11]3[O:12][C:13]([CH3:16])=[CH:14][N:15]=3)=[CH:10][C:6]=2[CH:5]=[CH:4][CH:3]=1)[C@H:22]1[O:24][CH2:23]1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)OC[C@@H]2CO2)cc1
Reactant: Cc1cnc(-c2cc3cccc(O)c3o2)o1
Product: Cc1cnc(-c2cc3cccc(OC[C@@H]4CO4)c3o2)o1
Yield: 79.6 %

Procedure:
By the reactions in the same manner as in Starting Material Synthesis Example 1 using 2-(7-hydroxybenzo(b)furan-2-yl)-5-methyloxazole (2.0 g) obtained in Starting Material Synthesis Example 65 and (S)-glycidyl nosylate (1.8 g), (S)-7-glycidyloxy-2-(5-methyloxazol-2-yl)benzo(b)furan (1.5 g) was obtained. Then, by the reactions in the same manner as in Example 1 using 4-(naphthalen-2-yl)piperidine (0.7 g), the title compound (0.26 g) was obtained, melting point 147-149° C.
Reaction SMILES: F[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([F:8])[CH:7]=1.[NH2:9][C:10]1[CH:14]=[CH:13][N:12]([CH3:15])[N:11]=1.Cl[C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([OH:27])[CH:25]=2)[N:20]=[CH:19][N:18]=1>>[F:8][C:6]1[CH:7]=[C:2]([O:27][C:24]2[CH:25]=[C:26]3[C:21](=[CH:22][CH:23]=2)[N:20]=[CH:19][N:18]=[C:17]3[NH:9][C:10]2[CH:14]=[CH:13][N:12]([CH3:15])[N:11]=2)[CH:3]=[N:4][CH:5]=1
Reactant: Oc1ccc2ncnc(Cl)c2c1
Reactant: Cn1ccc(N)n1
Reactant: Fc1cncc(F)c1
Product: Cn1ccc(Nc2ncnc3ccc(Oc4cncc(F)c4)cc23)n1

Procedure:
The compound of Example 119 was manufactured by the same method as in Example 95, by a similar method thereto or by a combination of such a method with a conventional method using 3,5-difluoropyridine, 3-amino-1-methyl-1H-pyrazole and 4-chloro-6-hydroxy-quinazoline.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[CH3:8][CH2:9][CH2:10][CH2:11][CH2:12]C.C([Li])CCC.[Cl-].[NH4+].CC[O:23][CH2:24][CH3:25]>>[C:24]([C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1)(=[O:23])[CH2:25][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCOCC
Reactant: Brc1cccnc1
Reactant: CCCCCC
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Product: CCCCCCC(=O)c1cccnc1
Reaction time: 0.25 h
Yield: 36 %

Procedure:
A solution of 10.0 g (63.3 mmol) of 3-bromopyridine in 100 ml of ether was cooled to -78° C., to which 40 ml of 1.6M (64 mmol) n-butyllithium hexane solution was added dropwise. The mixture was stirred for 15 minutes after completion of the addition, to which a solution of 7.52 g (67.7 mmol) of heptanitrile in 15 ml of ether was added dropwise and stirred at -78° C. to room temperature further for 1 hour. To the reaction mixture an aqueous solution of ammonium chloride was added, from which the product was extracted with ethyl acetate. The extract was washed with water and dried, and the solvent was evaporated off. The residue was purified with silica gel column chromatography (eluted with isopropyl ether), to give 3.9 g (36%) of 3-heptanoylpyridine (an oil).
Reaction SMILES: O[CH2:2][CH2:3][N:4]([CH3:38])[C:5]([C:7]1[C:12]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:11]([OH:21])[N:10]=[C:9]([CH2:22][C:23]2([C:28]3[C:37]4[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=4)[CH:31]=[CH:30][CH:29]=3)[CH2:27][CH2:26][CH2:25][CH2:24]2)[N:8]=1)=[O:6].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.CO>ClCCl.C(OCC)(=O)C>[CH2:14]([O:13][C:12]1[C:11](=[O:21])[N:10]=[C:9]([CH2:22][C:23]2([C:28]3[C:37]4[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=4)[CH:31]=[CH:30][CH:29]=3)[CH2:27][CH2:26][CH2:25][CH2:24]2)[N:8]2[CH2:2][CH2:3][N:4]([CH3:38])[C:5](=[O:6])[C:7]=12)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CN(CCO)C(=O)c1nc(CC2(c3cccc4ccccc34)CCCC2)nc(O)c1OCc1ccccc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CO
Product: CN1CCn2c(CC3(c4cccc5ccccc45)CCCC3)nc(=O)c(OCc3ccccc3)c2C1=O
Temperature: 0 °C
Yield: 101.3 %

Procedure:
To a solution of 5-benzyloxy-6-hydroxy-2-(1-naphthalen-1-yl-cyclopentylmethyl)-pyrimidine-4-carboxylic acid (2-hydroxyethyl)-methyl-amide (351) (85 mg, 0.17 mmol) in dichloromethane (20 mL) was added triphenyl phosphine (174 mg, 0.67 mmol) and the reaction mixture was cooled to 0° C., followed by the addition of diisopropyl azodicarboxylate (0.2 mL, 0.1 mmol). The reaction mixture was stirred for 15 min at the same temperature (silica TLC, 5% methanol in ethyl acetate; Rf=0.3). The dichloromethane was removed in vacuum and the crude mass was purified by silica gel (normal, 100-200 mesh) column chromatography using a gradient eluent mixture of 50% ethyl acetate in hexane to 100% ethyl acetate to get 9-benzyloxy-2-methyl-6-(1-naphthalen-1-yl-cyclopentylmethyl)-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,8-dione (352) (85 mg, semi pure) as a white sticky solid.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[N:5][C:6](=[O:9])[NH:7][CH:8]=1.C(N(CC)CC)C.Cl[CH2:18][N:19]([CH:26]=[O:27])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(Cl)Cl>[CH:26]([N:19]([CH2:18][N:5]1[CH:4]=[C:3]([Cl:2])[CH:8]=[N:7][C:6]1=[O:9])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:27]
Reactant: O=CN(CCl)c1ccccc1
Reactant: O=c1ncc(Cl)c[nH]1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=CN(Cn1cc(Cl)cnc1=O)c1ccccc1
Temperature: 40 °C
Reaction time: 18 h

Procedure:
5-Chloropyrimidin-2-one hydrochloride (3.0 mmol) and triethylamine (6 mmol) were stirred together in CH2Cl2 (50 ml) for 15 minutes before a solution of N-chloromethylformanilide (see Prepartion 12) (3 mmol) in CH2Cl2 was added. The mixture was stirred at 40° C. for 18 hours before the solvent was distilled off. The residue was washed with water and ether. Yield: 0.79 g (50%), m. p. 200° C. (EtOH). 1H NMR (DMSO-d6, δ): 5.68 (s, CH2), 7.32 (Ph), 8.05-8.65 (CHO, H-4 and H-6). IR (KBr, cm-1): 1660 (CO), 1680 (CO). MS (70 eV, m/e (% rel. int.)): 263 (M+, 1), 143 (7), 134 (41), 116 (6), 107 (6), 106 (100), 105 (57), 104 (10), 79 (10), 78 (7), 77 (41), 52 (11), 51 (20).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]1[CH2:9][O:8][C:7]2[CH:10]=[CH:11][C:12]([C:14]([OH:16])=[O:15])=[CH:13][C:6]=2[O:5]1.[N+:17]([O-])([OH:19])=[O:18].S(=O)(=O)(O)O.O>C(O)(=O)C>[CH3:1][O:2][CH2:3][CH:4]1[CH2:9][O:8][C:7]2[CH:10]=[C:11]([N+:17]([O-:19])=[O:18])[C:12]([C:14]([OH:16])=[O:15])=[CH:13][C:6]=2[O:5]1
Reactant: COCC1COc2ccc(C(=O)O)cc2O1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: COCC1COc2cc([N+](=O)[O-])c(C(=O)O)cc2O1
Reaction time: 0.5 h

Procedure:
The titled compound of Example 3 (0.788 g, 3.51 mmol) was dissolved in 2 ml of acetic acid, and added a mixture of nitric acid (3 ml) and sulfuric acid (3 ml), followed by stirring for 30 min. Then, to the reaction mixture was added 10 ml of water to give a solid, which was then fitered and washed with acetic acid and ether in a sequential order to prepare the titled compound (0.510 g, 54%).
Reaction SMILES: [NH:1]([C:8]1[S:9][CH:10]=[C:11]([CH:13]=[CH:14][CH2:15][OH:16])[N:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.O.Cl>CS(C)=O>[NH:1]([C:8]1[S:9][CH:10]=[C:11](/[CH:13]=[CH:14]/[CH:15]=[O:16])[N:12]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCC=Cc1csc(Nc2ccccc2)n1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: O
Product: O=C/C=C/c1csc(Nc2ccccc2)n1
Reaction time: 0.5 h

Procedure:
2.6 g of the crude alcohol thus obtained were dissolved in 20 ml of dimethyl sulfoxide, and 3.4 g of triethylamine were added to the resulting solution. Next, a solution of 5.3 g of a sulfur trioxide pyridine complex in dimethyl sulfoxide (10 ml) was added dropwise to the reaction mixture at room temperature, and the mixture was stirred at the same temperature for 30 minutes. The reaction mixture was then poured into water, acidified with 3N hydrochloric acid, and extracted with ethyl acetate. After the extract was dried over anhydrous sodium sulfate, the solvent was evaporated off under reduced pressure. The residue was purified by silica gel column chromatography, using as eluent a 10:1 mixture of benzene and ethyl acetate, giving the desired compound as pale yellow crystals.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[CH3:5][C:6]1([CH3:17])[C:10]2[CH:11]=[C:12]([CH:15]=[O:16])[CH:13]=[CH:14][C:9]=2[O:8][CH2:7]1.[Br:18]Br.Cl>ClCCl>[Br:18][C:14]1[C:9]2[O:8][CH2:7][C:6]([CH3:17])([CH3:5])[C:10]=2[CH:11]=[C:12]([CH:15]=[O:16])[CH:13]=1
Reactant: BrBr
Reactant: CC1(C)COc2ccc(C=O)cc21
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC1(C)COc2c(Br)cc(C=O)cc21
Reaction time: 3 h
Yield: 91.4 %

Procedure:
To a solution of AlCl3 (1.22 g, 9.18 mmol) in dry dichloromethane (15 mL) was added dropwise at room temperature 3,3-dimethyl-2,3-dihydro-benzofuran-5-carbaldehyde (647 mg, 3.67 mmol) in dichloromethane (15 mL) followed by bromine (0.23 mL, 4.41 mmol) and the reaction stirred for 3 hours. 1N HCl was added slowly and the layers separated. The aqueous layer was extracted twice with dichloromethane. The combined organic layers were washed successively with water and brine, dried over anhydrous magnesium sulfate, filtered and evaporated. The residue was chromatographed on silica gel (20% ethyl acetate in hexane) to give 856 mg of 7-bromo-3,3-dimethyl-2,3-dihydro-benzofuran-5-carbaldehyde (91%). 1H NMR (300 MHz; CDCl3): 1.40(s, 6H), 4.46 (s, 2H), 7.61 (s, 1H), 7.83 (s, 1H), 9.80 (s, 1H).
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:12][CH2:11][N:10]([C:13]([N:15]2[C@@:19]([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=3)([CH3:20])[C@@:18]([C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=3)([CH3:28])[N:17]=[C:16]2[C:36]2[CH:37]=[N:38][C:39]([C:45]([CH3:48])([CH3:47])[CH3:46])=[CH:40][C:41]=2[O:42][CH2:43][CH3:44])=[O:14])[CH2:9]1)(C)(C)C.S(Cl)(Cl)=O>CO.FC(F)(F)C(O)=O>[NH2:7][CH:8]1[CH2:12][CH2:11][N:10]([C:13]([N:15]2[C@@:19]([C:21]3[CH:22]=[CH:23][C:24]([Cl:27])=[CH:25][CH:26]=3)([CH3:20])[C@@:18]([C:29]3[CH:30]=[CH:31][C:32]([Cl:35])=[CH:33][CH:34]=3)([CH3:28])[N:17]=[C:16]2[C:36]2[CH:37]=[N:38][C:39]([C:45]([CH3:46])([CH3:48])[CH3:47])=[CH:40][C:41]=2[O:42][CH2:43][CH3:44])=[O:14])[CH2:9]1
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CC[C@H](NC(=O)OC(C)(C)C)C1
Solvent: CO
Solvent: O=S(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(N)C1
Temperature: 77.5 °C
Reaction time: 1 h

Procedure:
{(S)-1-[(4S,5R)-2-(6-tert-Butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-pyrrolidin-3-yl}-carbamic acid tert-butyl ester (12.6 mg, example 125) was diluted with methanol (1.5 mL) and trifluoroacetic acid (0.1 mL). The mixture was stirred at 75-80° C. for 1 h. Thionyl chloride (0.3 mL) was added dropwise and the mixture was stirred at 80° C. for 1 h. The mixture was then concentrated and diluted with methanol (2 mL) and neutralized with 15% solution of sodium hydroxide. Purification of the crude product on a preparative HPLC (reversed phase, eluting with acetonitrile and water) gave the title product as a mixture of diastereomers (5.4 mg). HR-MS (ES, m/z) calculated for C33H40Cl2N5O2 [(M+H)+] 608.2554, observed 608.2554.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[C@H:4]([NH:15][C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17])[CH2:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]=[CH:9]2.C([OH:31])(C)(C)C>[Zn]>[CH3:1][O:2][C:3](=[O:26])[C@H:4]([NH:15][C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17])[CH2:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:31])[CH2:9]2
Reactant: CC(C)(C)O
Reactant: COC(=O)[C@@H](Cc1ccc2[nH]ccc2c1)NC(=O)OCc1ccccc1
Agent: [Zn]
Product: COC(=O)[C@@H](Cc1ccc2c(c1)CC(=O)N2)NC(=O)OCc1ccccc1
Temperature: 27.5 °C
Reaction time: 3.5 h
Yield: 41 %

Procedure:
PyHBr3 (1.28 g, 4.02 mmol) was added in small portions over 30 min to a solution of (R)-2-benzyloxycarbonylamino-3-(1H-indol-5-yl)-propionic acid methyl ester (0.47 g, 1.34 mmol) in t-butanol (10 mL) while the reaction temperature was maintained between 25-30° C. The resulting mixture was stirred at room temperature for 3.5 h. The solvent was removed in vacuo, and the residue was extracted with ethyl acetate (2×). The combined organic phases were washed with brine and dried over sodium sulfate. After filtration, solvents were removed and the residue was azeotropically dried with anhydrous ethanol. The residue was dissolved in glacial acetic acid (10 mL) and zinc powder (0.88 g, 13.4 mmol) was added. The mixture was stirred at room temperature overnight. After the acetic acid was removed in vacuo, the residue was purified by flash chromatography on silica gel using ethyl acetate/hexanes [(1:3) first and then (3:2)] as eluent to afford the title compound as a white solid (41% for 2 steps). 1H-NMR (CDCl3, 500 MHz) δ 8.03 (s, 1H), 7.36-7.31 (m, 5H), 6.94 (s, 1H), 6.91 (d, J=8.0 Hz, 1H), 6.73 (d, J=7.5 Hz, 1H), 5.26 (d, J=8.0 Hz, 1H), 5.11 (d, J=12.0 Hz, 1H), 5.05 (d, j=12.5 Hz, 1H), 4.61 (dd, J=13.5, 6.0 hz, 1H), 3.72 (s, 3H), 3.45 (s, 2H), 3.10 (dd, J=14.0, 5.5 Hz, 1H), 3.00 (dd, J=14.0, 6.0 Hz, 1H). 13CNMR (CDCl3, 125 MHz) δ 177.7, 172.2, 155.7, 141.7, 136.3, 129.8, 128.9, 128.6, 128.3, 128.2, 125.8, 125.6, 109.8, 67.1, 55.1, 52.5, 38.0, 36. Mass spec. 369.20 (MH)+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([CH:12]=[O:13])[CH:8]=[CH:7]2.N1C=CN=C1.[C:19]([Si:23](Cl)([CH3:25])[CH3:24])([CH3:22])([CH3:21])[CH3:20]>C(Cl)Cl>[Si:23]([O:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([CH:12]=[O:13])[CH:8]=[CH:7]2)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:25])[CH3:24]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=Cc1ccc2cccc(O)c2n1
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)Oc1cccc2ccc(C=O)nc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 82.5 %

Procedure:
8-Hydroxyquinoline-2-carbaldehyde (5.00 g, 28.9 mmol) and imidazole (4.32 g, 63.5 mmol) were dissolved in DCM (50 mL) under N2. The reaction mixture was cooled to 0° C. after which time tert-butylchlorodimethylsilane (4.94 g, 31.8 mmol) was added. After stirring for 16 hours at ambient temperature, the reaction mixture was partitioned between DCM and H2O. The organic layer was washed with H2O and aqueous saturated NaHCO3, dried over Na2SO4, filtered and concentrated under reduced pressure to afford an orange oil. The residue was purified via flash column chromatography (10:1 Hexane/EtOAc) to provide 6.85 g (83%) of desired product as a yellow/orange oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH2:20])=[C:18]([CH3:24])[CH:17]=1.C1(C)C=CC=CC=1.C(N(CC)CC)C.Cl[C:40](Cl)([O:42][C:43](=[O:49])OC(Cl)(Cl)Cl)Cl.[CH3:51][C:52]1[CH:57]=[CH:56][C:55]([S:58][CH2:59][CH2:60]CO)=[CH:54][CH:53]=1>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH:20][C:43](=[O:49])[O:42][CH2:40][CH2:60][CH2:59][S:58][C:55]2[CH:56]=[CH:57][C:52]([CH3:51])=[CH:53][CH:54]=2)=[C:18]([CH3:24])[CH:17]=1
Reactant: COc1cc2nccc(Oc3cc(C)c(N)cc3C)c2cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Cc1ccc(SCCCO)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3cc(C)c(NC(=O)OCCCSc4ccc(C)cc4)cc3C)c2cc1OC
Temperature: 25 °C
Yield: 58.7 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,5-dimethylaniline (85 mg) was added to toluene/triethylamine=10/1 (8 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (120 mg) in methylene chloride was then added to the solution, and the mixture was heated under reflux for 15 min. Subsequently, 3-[(4-methylphenyl)sulfanyl]-1-propanol (72 mg) was added thereto, and the mixture was further stirred with heating under reflux for 2 hr. After the completion of the reaction, the reaction solution was allowed to cool to room temperature before distilled water was added thereto. The mixture was subjected to separatory extraction with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution and saturated brine. The washed solution was dried over sodium sulfate and was concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (82 mg, yield 56%).