Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([O:13][C:14]2[C:23]3[C:18](=[CH:19][C:20]([O:24][CH3:25])=[CH:21][CH:22]=3)[N:17]=[C:16]([N:26]3[CH:30]=[CH:29][CH:28]=[N:27]3)[CH:15]=2)[CH2:10][C@H:9]1[C:31](O)=[O:32])=[O:7])([CH3:4])([CH3:3])[CH3:2].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.[NH2:67][C@@H:68]([CH2:77][CH2:78][CH3:79])[C@H:69]([OH:76])[C:70]([NH:72][CH:73]1[CH2:75][CH2:74]1)=[O:71]>C(Cl)Cl.CN(C)C=O>[CH:73]1([NH:72][C:70](=[O:71])[C@@H:69]([OH:76])[C@@H:68]([NH:67][C:31]([C@@H:9]2[CH2:10][C@@H:11]([O:13][C:14]3[C:23]4[C:18](=[CH:19][C:20]([O:24][CH3:25])=[CH:21][CH:22]=4)[N:17]=[C:16]([N:26]4[CH:30]=[CH:29][CH:28]=[N:27]4)[CH:15]=3)[CH2:12][N:8]2[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[O:32])[CH2:77][CH2:78][CH3:79])[CH2:74][CH2:75]1
Reactant: COc1ccc2c(O[C@@H]3C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C3)cc(-n3cccn3)nc2c1
Reactant: CCC[C@H](N)[C@H](O)C(=O)NC1CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCC[C@H](NC(=O)[C@@H]1C[C@@H](Oc2cc(-n3cccn3)nc3cc(OC)ccc23)CN1C(=O)OC(C)(C)C)[C@H](O)C(=O)NC1CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.8 %

Procedure:
To a solution of (2S,4R)-1-(tert-butoxycarbonyl)-4-(7-methoxy-2-(1H-pyrazol-1-yl)quinolin-4-yloxy)pyrrolidine-2-carboxylic acid (5.0 g, 11.0 mmol) dissolved in a mixture of methylene chloride (135 mL) and N,N-dimethylformamide (45 mL) was added 2-(1H-7-Azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU, (4.97 g, 42.6 mmol) and diisopropylethylamine (7.2 mL, 41.11 mmol), followed by the hydrochloride salt of (2S,3S)-3-amino-N-cyclopropyl-2-hydroxyhexanamide (2.45 g, 11.0 mmol). The reaction mixture was stirred at room temperature for 2 hours under nitrogen atmosphere. Completion of reaction was monitored by TLC. The reaction mixture was diluted with methylene chloride (200 mL) and washed with 10% hydrochloric acid (100 mL), followed by with 10% sodium bicarbonate solution (100 mL), water (100 mL) and brine (100 mL). The organic layer was dried over sodium sulfate, filtered, and the filtrate concentrated under reduced pressure to provide 5.4 g (67.6%) of (2S,4R)-tert-butyl 2-((2S,3S)-1-(cyclopropylamino)-2-hydroxy-1-oxohexan-3-ylcarbamoyl)-4-(7-methoxy-2-(1H-pyrazol-1-yl)quinolin-4-yloxy)pyrrolidine-1-carboxylate as an off-white solid (HPLC purity: 98.59% by area, HPLC retention time: 14.74 minutes).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]1[NH:14][C:15]([C:18]2[CH:23]=[CH:22][C:21]([Br:24])=[C:20]([CH2:25][OH:26])[CH:19]=2)=[CH:16][N:17]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.C1C=CN=CC=1.O=S(=O)=O>CS(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]1[NH:14][C:15]([C:18]2[CH:23]=[CH:22][C:21]([Br:24])=[C:20]([CH:25]=[O:26])[CH:19]=2)=[CH:16][N:17]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCCC1c1ncc(-c2ccc(Br)c(CO)c2)[nH]1
Agent: O=S(=O)=O
Solvent: CS(C)=O
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCCC1c1ncc(-c2ccc(Br)c(C=O)c2)[nH]1
Reaction time: 0.5 h
Yield: 93.1 %

Procedure:
To the solution of 2-[5-(4-bromo-3-hydroxymethyl-phenyl)-1H-imidazol-2-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester (196 mg, 0.46 mmol) in DMSO (3.5 ml) was added triethylamine (0.40 ml). The mixture was stirred for 30 minutes, and pyridine-sulfur trioxide (500 mg) was added. The mixture was stirred for 2 hours and was quenched with ice-water. The stirring was continued for additional 30 minutes and the mixture was extracted with EtOAc. The organic phase was washed with water and brine, and was dried with sodium sulfate. Concentration gave 2-[5-(4-Bromo-3-formyl-phenyl)-1H-imidazol-2-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester (180 mg).
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:9]3[CH:10]=[CH:11][C:12]([S:14]([CH:17]4[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]4)(=[O:16])=[O:15])=[CH:13][C:8]=3[N:7]=[C:6]2[CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:3][CH2:2]1.C(N(CC)CC)C.[C:35]1([C:41](Cl)([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>ClCCl>[CH:1]1([CH2:4][N:5]2[C:9]3[CH:10]=[CH:11][C:12]([S:14]([CH:17]4[CH2:22][CH2:21][N:20]([C:41]([C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=5)([C:48]5[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=5)[C:42]5[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=5)[CH2:19][CH2:18]4)(=[O:15])=[O:16])=[CH:13][C:8]=3[N:7]=[C:6]2[CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:2][CH2:3]1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)Cc1nc2cc(S(=O)(=O)C3CCNCC3)ccc2n1CC1CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)Cc1nc2cc(S(=O)(=O)C3CCN(C(c4ccccc4)(c4ccccc4)c4ccccc4)CC3)ccc2n1CC1CC1
Reaction time: 14 h
Yield: 93.7 %

Procedure:
To a solution of 1-(cyclopropylmethyl)-2-neopentyl-5-(piperidin-4-ylsulfonyl)-1H-benzo[d]imidazole (STEP D, 1.31 g, 3.36 mmol) and triethylamine (945 microL, 6.73 mmol) in dichloromethane (12 mL) was added triphenylmethyl chloride (1.22 g, 4.37 mmol) at room temperature. After stirring for 14 h, the mixture was diluted with dichloromethane and washed with saturated sodium bicarbonate aqueous solution. The organic layer was dried over sodium sulfate and concentrated in vacuo. The precipitate was washed with a mixture of diethyl ether and hexane (1:1) to give the title compound (1.99 g, 94%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.CCN(CC)CC.[Si:16](Cl)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([O:8][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Oc1cccc(Br)c1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1cccc(Br)c1
Reaction time: 0.5 h
Yield: 96.5 %

Procedure:
To a solution of 3-bromophenol (50 g, 289 mmol) in 340 mL DMF was added Et3N (35 g, 347 mmol) and tert-butyldimethylsilyl chloride (52 g, 347 mmol). The mixture was stirred for 0.5 h, and then diluted with ET2O (2 L). The organic phase was washed with 5% aqueous HCl and brine, and dried over MgSO4. Flash chromatography using hexane:EtOAc (95:5) gave 80.1 g (96%) of product.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:10]2[C:19]3[C:14](=[CH:15][C:16]([F:22])=[C:17](F)[C:18]=3[Cl:20])[C:13](=[O:23])[C:12]([C:24]([OH:26])=[O:25])=[CH:11]2)[C:5]([F:9])=[CH:6][C:7]=1[F:8].C(OC([NH:34][CH2:35][CH2:36][CH:37]1[CH2:40][NH:39][CH2:38]1)=O)(C)(C)C.[F:41][C:42]([F:47])([F:46])[C:43]([OH:45])=[O:44].Cl.O1CCOCC1>C(N(CC)CC)C>[F:41][C:42]([F:47])([F:46])[C:43]([OH:45])=[O:44].[NH2:1][C:2]1[CH:3]=[C:4]([N:10]2[C:19]3[C:14](=[CH:15][C:16]([F:22])=[C:17]([N:39]4[CH2:40][CH:37]([CH2:36][CH2:35][NH2:34])[CH2:38]4)[C:18]=3[Cl:20])[C:13](=[O:23])[C:12]([C:24]([OH:26])=[O:25])=[CH:11]2)[C:5]([F:9])=[CH:6][C:7]=1[F:8]
Reactant: CC(C)(C)OC(=O)NCCC1CNC1
Reactant: Nc1cc(-n2cc(C(=O)O)c(=O)c3cc(F)c(F)c(Cl)c32)c(F)cc1F
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: NCCC1CN(c2c(F)cc3c(=O)c(C(=O)O)cn(-c4cc(N)c(F)cc4F)c3c2Cl)C1

Procedure:
Reaction was carried out as in Example 231 except that 1-(3-amino-4,6-difluorophenyl)-8-chloro-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 3-t-butoxycarbonylaminoethylazetidine, and triethylamine were used. For deprotection, trifluoroacetic acid was used rather than 4N hydrochloric acid/dioxane to give the title compound.
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:10][CH2:9][C@@H:8]([C:11]2[N:15]3[CH:16]=[CH:17][N:18]=[C:19](Cl)[C:14]3=[CH:13][N:12]=2)[CH2:7][CH2:6]1)(=[O:3])[CH3:2].[C:21](=O)([O-])[O-].[K+].[K+].CB1OB(C)OB(C)O1.ClCCl>O1CCOCC1>[C:1]([O:4][C@H:5]1[CH2:10][CH2:9][C@@H:8]([C:11]2[N:15]3[CH:16]=[CH:17][N:18]=[C:19]([CH3:21])[C:14]3=[CH:13][N:12]=2)[CH2:7][CH2:6]1)(=[O:3])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CC(=O)O[C@H]1CC[C@@H](c2ncc3c(Cl)nccn32)CC1
Agent: CB1OB(C)OB(C)O1
Agent: [K+]
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC(=O)O[C@H]1CC[C@@H](c2ncc3c(C)nccn32)CC1
Temperature: 95 °C
Reaction time: 1 h

Procedure:
To (cis)-4-(8-chloroimidazo[1,5-a]pyrazin-3-yl)cyclohexyl acetate (48.0 mmol, 14.09 g) in dry dioxane (275 ml) under a nitrogen atmosphere were added dry potasium carbonate (71.9 mmol, 9.94 g), trimethylboroxine (144 mmol, 20.03 ml, 50 wt % solution in tetrahydrofuran) and 1,1′-bis(diphenylphosphino)ferrocene palladium (II) chloride complex with dichloromethane (4.80 mmol, 3.88 g) and the reaction mixture was stirred at 95° C. for one hour. The reaction mixture was cooled to room temperature, filtered over decalite, the filter rinsed with dioxane and the filtrate concentrated in vacuo. The residue was purified by column chromatography (silica gel; dichloromethane with gradient 0 to 6% of methanol) to give (cis)-4-(8-methylimidazo[1,5-a]pyrazin-3-yl)cyclohexyl acetate (12.8 g).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8]2[S:9][CH:10]=[C:11]([CH2:13][CH2:14][NH2:15])[N:12]=2)[CH:2]=1.[C:16](O)(=O)C.C=O>CO>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8]2[S:9][C:10]3[CH2:16][NH:15][CH2:14][CH2:13][C:11]=3[N:12]=2)[CH:2]=1
Reactant: NCCc1csc(Nc2cccnc2)n1
Reactant: CC(=O)O
Agent: C=O
Solvent: CO
Product: c1cncc(Nc2nc3c(s2)CNCC3)c1
Reaction time: 2 h
Yield: 57.3 %

Procedure:
2-(3-Pyridyl)amino-4-(2-aminoethyl)thiazole (0.50 g, from preceding preparation) and acetic acid (0.19 ml, 3.3 mmol) were dissolved in methanol (23 ml) and treated with formaldehyde (0.19 ml of a 37% aqueous solution, 2.3 mmol). The reaction was allowed to stir at room temperatue for 18 hours, at which point additional formaldehyde (0.02 ml of a 37% aqueous solution, 0.25 mmol) was added. After an additional 2 hours, the reaction mixture was filtered; the filtrate was concentrated in vacuo, dissolved in aqueous base, and extracted with methylene chloride. The organic extracts were dried over sodium sulfate and concentrated to provide the title product (310 mg, 1.3 mmol, 57% 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]([CH2:33][C:34]2[CH:39]=[CH:38][C:37]([C:40]3[C:41]([C:46]#[N:47])=[CH:42][CH:43]=[CH:44][CH:45]=3)=[CH:36][CH:35]=2)[C:19](=[O:32])[C:20]([CH:24]([OH:31])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[C:21]([CH3:23])[N:22]=1)[CH2:14][CH2:15][CH3:16]>O>[CH2:13]([C:17]1[N:18]([CH2:33][C:34]2[CH:35]=[CH:36][C:37]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=3[C:46]3[NH:3][C:4](=[O:7])[O:5][N:47]=3)=[CH:38][CH:39]=2)[C:19](=[O:32])[C:20]([CH:24]([OH:31])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[C:21]([CH3:23])[N:22]=1)[CH2:14][CH2:15][CH3:16]
Reactant: [NH3+]O
Reactant: O=C([O-])O
Reactant: CCCCc1nc(C)c(C(O)c2ccccc2)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CCCCc1nc(C)c(C(O)c2ccccc2)c(=O)n1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 46.8 %

Procedure:
A mixture of hydroxylammonium chloride (0.92 g), sodium hydrogen carbonate (1.3 g) and dimethyl sulfoxide (5 mL) was stirred at 40° C. for 30 min, 4′-{[2-butyl-5-[hydroxy(phenyl)methyl]-4-methyl-6-oxopyrimidin-1(6H)-yl]methyl}biphenyl-2-carbonitrile (0.36 g) was added, and the mixture was stirred at 90° C. for 24 hr. The mixture was allowed to cool to room temperature, water was added to the reaction mixture, and the precipitated solid was collected by filtration. The obtained solid was dissolved in ethyl acetate. The solution was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated and the residue was dissolved in tetrahydrofuran (10 mL). N,N′-carbonyldiimidazole (0.13 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.12 mL) were added, and the mixture was stirred at room temperature for 30 min. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid and then with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.19 g, 46%).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([NH:6][CH2:7][C:8](=[O:12])[NH:9]2)=[CH:4][C:3]=1[CH3:13].[N+:14]([O-])([OH:16])=[O:15].C(O)(C(F)(F)F)=[O:19]>>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([NH:6][C:7](=[O:19])[C:8](=[O:12])[NH:9]2)=[C:4]([N+:14]([O-:16])=[O:15])[C:3]=1[CH3:13]
Reactant: O=[N+]([O-])O
Reactant: Cc1cc2c(cc1Cl)NC(=O)CN2
Reactant: O=C(O)C(F)(F)F
Product: Cc1c(Cl)cc2[nH]c(=O)c(=O)[nH]c2c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred suspension of 7-chloro-3,4-Dihydro-6-methyl-quinoxaline-2(1H)-one (0.100 g, 0.51 mmol) in TFA (3.0 mL) prepared as in Example 8, excess fuming HNO3 (0.30 mL) was added and the resulting red solution was stirred overnight at room temperature. The solvent was removed under vacuum and the residue diluted with water (4.0 mL). The precipitated solid was filtered and dried under vacuum to yield 0.067 g (52%) pure (HPLC) title compound as a light yellow powder; mp-darkens at 340° C.; 1H NMR (DMSO-d6) δ 2.184 (s, 3H), 7.263 (s, 1H), 11.948 (s, 1H), 12.144 (s, 1H); Anal for C9H6CIN3O4 ·H2O calcd C, 40.85; H, 2.28; N, 15.87, found C, 40.63; H, 2.05; N, 15.75.
Reaction SMILES: C(OC([N:8]1[CH:12]2[CH2:13][CH2:14][CH:9]1[CH:10]([C:15]1[CH:16]=[N:17][C:18]([F:31])=[C:19]([C:21]3[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][CH:22]=3)[CH:20]=1)[CH2:11]2)=O)(C)(C)C.C(O)(C(F)(F)F)=O.[NH4+].[OH-]>C(Cl)Cl.O>[CH3:30][S:27]([C:24]1[CH:23]=[CH:22][C:21]([C:19]2[CH:20]=[C:15]([CH:10]3[CH2:11][CH:12]4[NH:8][CH:9]3[CH2:14][CH2:13]4)[CH:16]=[N:17][C:18]=2[F:31])=[CH:26][CH:25]=1)(=[O:28])=[O:29]
Reactant: CC(C)(C)OC(=O)N1C2CCC1C(c1cnc(F)c(-c3ccc(S(C)(=O)=O)cc3)c1)C2
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)c1ccc(-c2cc(C3CC4CCC3N4)cnc2F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.8 %

Procedure:
Compound 17 (312 mg, 0.7 mmol) was dissolved in anhydrous CH2Cl2 (3 mL) and cooled in an ice-water bath. TFA (3 mL) was added in 30 min. After stirring at room temperature for 1 hr, the mixture was poured into a cold solution of NH4OH in water (1:1). The mixture was then extracted with CH2Cl2. The organic phase was washed with brine, then dried over anhydrous Na2SO4 and evaporated to dryness. After flash chromatography on a silica gel column with CH2Cl2-MeOH, the free base was isolated as a clear oil (242 mg, 99%). 1H NMR (CDCl3): δ (ppm) 1.5-1.7 (m, 5H), 1.8-1.9 (m, 1H), 2.87 (dd, 1H, J=5.1, 9.0 Hz), 3.11 (s, 3H), 3.65 (br s, 1H), 3.84 (m, 1H), 7.7-7.8 (m, 2H), 8.0-8.05 (m, 2H), 8.09 (dd, 1H, J=2.4, 3.6 Hz), 8.15 (m, 1H). 13C NMR (CDCl3): δ (ppm) 29.6, 30.5, 31.7, 40.8, 44.6, 44.9, 56.8, 63.2, 121.6 (d, J=112.5 Hz), 128.0, 130.2 (d, J=12.3 Hz), 140.3 (d, J=14.7 Hz), 141.3 (d, J=18.6 Hz), 146.6 (d, J=57.6 Hz), 157.6, 160.8.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([NH:10][C:11](=[O:47])[C@@H:12]([NH:20][C:21](=[O:46])[C@H:22]([NH:38]C(OC(C)(C)C)=O)[C:23]2[CH:28]=[CH:27][C:26]([O:29][CH2:30][C@H:31]3[CH2:35][O:34]C(C)(C)[O:32]3)=[CH:25][CH:24]=2)[CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[S:8][CH:9]=1)=[O:4].FC(F)(F)C(O)=O>ClCCl>[CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([NH:10][C:11](=[O:47])[C@@H:12]([NH:20][C:21](=[O:46])[C@H:22]([NH2:38])[C:23]2[CH:24]=[CH:25][C:26]([O:29][CH2:30][C@H:31]([OH:32])[CH2:35][OH:34])=[CH:27][CH:28]=2)[CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[S:8][CH:9]=1)=[O:4]
Reactant: COC(=O)c1csc(NC(=O)[C@H](Cc2ccccc2)NC(=O)[C@H](NC(=O)OC(C)(C)C)c2ccc(OC[C@H]3COC(C)(C)O3)cc2)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1csc(NC(=O)[C@H](Cc2ccccc2)NC(=O)[C@H](N)c2ccc(OC[C@H](O)CO)cc2)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 90.8 %

Procedure:
To a solution of 2-((S)-2-{(R)-2-tert-butoxycarbonylamino-2-[4-((S)-2,2-dimethyl-[1,3]dioxolan4-ylmethoxy)-phenyl]-acetylamino}-3-phenyl-propionylamino)-thiazole-4-carboxylic acid methyl ester (170 mg, 0.25 mmol) in dichloromethane (2.0 mL) was added trifluoroacetic acid (0.5 mL, 6.5 mmol) at 0° C. The reaction was warmed to room temperature and stirred for 4 hours. The solvent was removed under vacuum and the residue was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution. The aqueous layer was extracted with ethyl acetate and the extracts were combined, washed with brine and dried over sodium sulfate to give 2-((S)-2-{(R)-2-amino-2-[4-((R)-2,3-dihydroxy-propoxy)-phenyl]-acetylamino}-3-phenyl-propionylamino)-thiazole-4-carboxylic acid methyl ester as a foam (120 mg, 90%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11][CH2:10][CH2:9][CH:8]=[C:7]([OH:12])[C:6]=2[CH:13]=1.I([O-])(=O)(=O)=[O:15].[Na+]>CO.O1CCOCC1.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:15])[CH2:10][CH2:9][CH:8]=[C:7]([OH:12])[C:6]=2[CH:13]=1
Reactant: OC1=CCCSc2ccc(Cl)cc21
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: C1COCCO1
Solvent: O
Product: O=S1CCC=C(O)c2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The starting material is prepared as follows: The solution of 6.4 g of 7-chloro-5-hydroxy-2,3-dihydro-1-benzothiepin in 65 ml of dry methanol and 65 ml of dry dioxane is treated dropwise at 0° in 1 hour with the solution of 7.0 g of sodium metaperiodate in 65 ml water. The mixture is stirred at 0° for two hours after the addition period and then allowed to warm to room temperature for overnight. It is filtered and the solid rinsed with 30 ml of methanol. The combined filtrate and wash is concentrated to a smaller volume and treated with 40 ml of water. The mixture is extracted with chloroform, the extract separated, washed with water, dried and evaporated, to yield the 7-chloro-5-hydroxy-2,3-dihydro-1-benzothiepin-1-oxide boiling at 154-157/0.25 mmHg.
Reaction SMILES: C(O[BH-](O[C:11](=[O:13])[CH3:12])OC(=O)C)(=O)C.[Na+].[N+:15]([C:18]1[CH:19]=[C:20]2[C:26](=[CH:27][CH:28]=1)[CH:25]1O[CH:21]2[CH2:22][NH:23][CH2:24]1)([O-:17])=[O:16].C(=O)C.ClC(Cl)C>C(O)(=O)C>[CH2:22]([N:23]1[CH2:12][CH:11]2[O:13][CH:25]([C:26]3[C:20]2=[CH:19][C:18]([N+:15]([O-:17])=[O:16])=[CH:28][CH:27]=3)[CH2:24]1)[CH3:21]
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: O=[N+]([O-])c1ccc2c(c1)C1CNCC2O1
Agent: CC=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: CCN1CC2OC(C1)c1cc([N+](=O)[O-])ccc12
Temperature: 25 °C
Reaction time: 5 h
Yield: 50.6 %

Procedure:
Sodium triacetoxyborohydride (530 mg, 2.5 mmol) was added to a solution of 4-nitro-12-oxa-10-aza-tricyclo[6.3.1.0*2,7*]dodeca-2,4,6-triene (200 mg, 0.97 mmol), acetaldehyde (0.15 mL, 2.5 mmol), acetic acid (0.1 mL) and dichloroethane (5 mL). The reaction was stirred at room temperature for 5 h. The reaction was then quenched with saturated aqueous NaHCO3 (10 mL), extracted with CH2Cl2 (2×10 mL), dried over MgSO4, filtered, and concentrated. The remaining residue was purified with silica gel chromatography (10-100% EtOAc in hexanes) to give 10-Ethyl-4-nitro-12-oxa-10-aza-tricyclo[6.3.1.0*2,7*]dodeca-2,4,6-triene as a yellow oil (115 mg, 51%). MS (m/e) 235 (M+1).
Reaction SMILES: [C:1](OC[Cl:9])(=O)C(C)(C)C.[Cl:10][C:11]1[CH:25]=[CH:24][CH:23]=[CH:22][C:12]=1[CH2:13][NH:14][CH2:15][CH2:16][C:17]1[S:18][CH:19]=[CH:20][CH:21]=1>CS(C)=O>[ClH:9].[Cl:10][C:11]1[CH:25]=[CH:24][CH:23]=[CH:22][C:12]=1[CH2:13][N:14]1[CH2:15][CH2:16][C:17]2[S:18][CH:19]=[CH:20][C:21]=2[CH2:1]1
Reactant: Clc1ccccc1CNCCc1cccs1
Reactant: CC(C)(C)C(=O)OCCl
Solvent: CS(C)=O
Product: Cl
Product: Clc1ccccc1CN1CCc2sccc2C1
Yield: 51 %

Procedure:
66.5 g (0.44 M) chloromethyl pivalate is reacted by heating, for 3 hours, with a solution of 103 g (0.4 M) N-(2-chloro-benzyl)-2-(2-thienyl)ethylamine in 300 ml dimethylsulfoxide, to give the title compound in a yield of 51%.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[CH2:2][C:3]([NH:5][C@H:6]([C:24]([N:26]1[CH2:65][CH2:64][CH2:63][C@H:27]1[C:28]([NH:30][C@H:31]([C:33]([NH:35][C@H:36]([C:53]([O:55][CH2:56][C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1)=[O:54])[CH2:37][CH2:38][CH2:39][CH2:40][NH:41][C:42]([O:44][CH2:45][C:46]1[CH:52]=[CH:51][CH:50]=[CH:49][C:47]=1[Cl:48])=[O:43])=[O:34])[CH3:32])=[O:29])=[O:25])[CH2:7][CH2:8][CH2:9][NH:10][C:11](=[NH:23])[NH:12][S:13]([C:16]1[CH:22]=[CH:21][C:19]([CH3:20])=[CH:18][CH:17]=1)(=[O:15])=[O:14])=[O:4].C(Cl)(Cl)[Cl:74].CO>Cl.C(OCC)(=O)C>[NH:1]([Cl:74])[CH2:2][C:3]([NH:5][C@H:6]([C:24]([N:26]1[CH2:65][CH2:64][CH2:63][C@H:27]1[C:28]([NH:30][C@H:31]([C:33]([NH:35][C@H:36]([C:53]([O:55][CH2:56][C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1)=[O:54])[CH2:37][CH2:38][CH2:39][CH2:40][NH:41][C:42]([O:44][CH2:45][C:46]1[CH:52]=[CH:51][CH:50]=[CH:49][C:47]=1[Cl:48])=[O:43])=[O:34])[CH3:32])=[O:29])=[O:25])[CH2:7][CH2:8][CH2:9][NH:10][C:11](=[NH:23])[NH:12][S:13]([C:16]1[CH:22]=[CH:21][C:19]([CH3:20])=[CH:18][CH:17]=1)(=[O:15])=[O:14])=[O:4]
Reactant: ClC(Cl)Cl
Reactant: Cc1ccc(S(=O)(=O)NC(=N)NCCC[C@H](NC(=O)CNC(=O)OC(C)(C)C)C(=O)N2CCC[C@H]2C(=O)N[C@@H](C)C(=O)N[C@@H](CCCCNC(=O)OCc2ccccc2Cl)C(=O)OCc2ccccc2)cc1
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)NC(=N)NCCC[C@H](NC(=O)CNCl)C(=O)N2CCC[C@H]2C(=O)N[C@@H](C)C(=O)N[C@@H](CCCCNC(=O)OCc2ccccc2Cl)C(=O)OCc2ccccc2)cc1

Procedure:
The solution of 100 mg (0.081 mmol) of Boc-Gly-Arg(Tos)-Pro-Ala-Lys(ClZ)-OBzl (SEQ ID NO: 14) in 3 ml of hydrogen chloride in ethyl acetate (4 mol/L) was stirred at room temperature for 2 h and TLC (chloroform/methanol, 10:1) indicated complete disappearance of Boc-Gly-Arg(Tos)-Pro-Ala-Lys(ClZ)-OBzl (SEQ ID NO: 14). The reaction mixture was evaporated under reduced pressure with ethyl acetate, repeatedly, to remove hydrogen chloride. The residue was triturated with ether to provide the title compound as a colorless powder, which was used for the next reaction directly.
Reaction SMILES: [F:1][CH:2]([F:28])[C:3]1[CH:7]=[C:6]([CH:8]([F:10])[F:9])[N:5]([CH2:11][C:12]([N:14]2[CH2:19][CH2:18][CH:17]([C:20]3[S:21][CH:22]=[C:23]([CH:25]=[N:26][OH:27])[N:24]=3)[CH2:16][CH2:15]2)=[O:13])[N:4]=1.[CH:29]([C:31]1[CH:36]=[CH:35][C:34]([NH:37][C:38](=[O:44])[O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[CH:33][CH:32]=1)=[CH2:30].C(=O)([O-])O.[K+].ClN1C(=O)CCC1=O>C(OCC)(=O)C.O>[F:28][CH:2]([F:1])[C:3]1[CH:7]=[C:6]([CH:8]([F:9])[F:10])[N:5]([CH2:11][C:12]([N:14]2[CH2:15][CH2:16][CH:17]([C:20]3[S:21][CH:22]=[C:23]([C:25]4[CH2:30][CH:29]([C:31]5[CH:32]=[CH:33][C:34]([NH:37][C:38](=[O:44])[O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[CH:35][CH:36]=5)[O:27][N:26]=4)[N:24]=3)[CH2:18][CH2:19]2)=[O:13])[N:4]=1
Reactant: C=Cc1ccc(NC(=O)OC(C)(C)C)cc1
Reactant: O=C(Cn1nc(C(F)F)cc1C(F)F)N1CCC(c2nc(C=NO)cs2)CC1
Agent: O=C([O-])O
Agent: O=C1CCC(=O)N1Cl
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)Nc1ccc(C2CC(c3csc(C4CCN(C(=O)Cn5nc(C(F)F)cc5C(F)F)CC4)n3)=NO2)cc1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
To a solution of 2-(1-{[3,5-bis(difluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazole-4-carbaldehyde oxime (1.50 g) and tert-butyl (4-vinylphenyl)carbamate (0.94 g) in ethyl acetate (140 ml) were added, at room temperature, potassium hydrogencarbonate (1.79 g) and N-chlorosuccinimide (0.50 g), and then one drop of water. After the reaction mixture had been stirred at 60° C. for 3 h, ethyl acetate and water were added, and the mixture was extracted with ethyl acetate. The organic extracts were dried over sodium sulphate and concentrated under reduced pressure. The residue was purified by chromatography. This gave tert-butyl (4-{3-[2-(1-{[3,5-bis(difluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-O-1,3-thiazol-4-yl]-4,5-dihydro-1,2-oxazol-5-yl}phenyl)carbamate (0.90 g).