Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:9]([N:11]1[CH2:15][C@H:14]([CH3:16])[C@@H:13]([C:17]2([NH:20]C(OC(C)(C)C)=O)[CH2:19][CH2:18]2)[CH2:12]1)=O)C1C=CC=CC=1.C(N(CC)CC)C.[NH2:35][C:36]1[C:45]([F:46])=[C:44](F)[C:43](C)=[C:42]2[C:37]=1[C:38](=[O:56])[C:39]([C:53]([OH:55])=[O:54])=[CH:40][N:41]2[C@@H:49]1[CH2:51][C@@H:50]1[F:52].CS(C)=O>C(O)C.[C].[Pd]>[NH2:35][C:36]1[C:45]([F:46])=[C:9]([N:11]2[CH2:15][C@H:14]([CH3:16])[C@@H:13]([C:17]3([NH2:20])[CH2:18][CH2:19]3)[CH2:12]2)[C:43]([CH3:44])=[C:42]2[C:37]=1[C:38](=[O:56])[C:39]([C:53]([OH:55])=[O:54])=[CH:40][N:41]2[C@@H:49]1[CH2:51][C@@H:50]1[F:52]
Reactant: Cc1c(F)c(F)c(N)c2c(=O)c(C(=O)O)cn([C@@H]3C[C@@H]3F)c12
Reactant: C[C@H]1CN(C(=O)OCc2ccccc2)C[C@@H]1C1(NC(=O)OC(C)(C)C)CC1
Agent: [Pd]
Solvent: CCO
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: Cc1c(N2C[C@H](C)[C@@H](C3(N)CC3)C2)c(F)c(N)c2c(=O)c(C(=O)O)cn([C@@H]3C[C@@H]3F)c12
Temperature: 150 °C
Reaction time: 18 h
Yield: 4.4 %

Procedure:
(3R,4R)-1-Benzyloxycarbonyl-3-(1-tert-butoxycarbonylaminocyclopropyl)-4-methylpyrrolidine (793 mg, 2.12 mmol) was dissolved in ethanol (50 ml), and the solution was mixed with 5% palladium-carbon (790 mg) to carry out hydrogenation under a pressure of 5 atmospheres. After completing the reaction, the 5% palladium carbon was removed by filtration and ethanol was evaporated. The thus obtained residue was dissolved in dimethyl sulfoxide (8 ml), and the solution was mixed with triethylamine (2 ml) and 5-amino-6,7-difluoro-1-[(1R,2S)-2-fluorocyclopropyl)-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid (330 mg, 1.06 mmol) and stirred at 150° C. for 18 hours. After completing the reaction, dimethyl sulfoxide was evaporated, and the thus obtained residue was mixed with chloroform (100 ml) and washed with 10% citric acid (100 ml) and saturated brine (100 ml) in that order. The organic layer was dried over anhydrous sodium sulfate and then the solvent was evaporated. To the thus obtained residue, which was cooled in an ice bath, was added dropwise concentrated hydrochloric acid (10 ml), followed by 1 hour of stirring at room temperature. After completing the reaction, the reaction solution was washed with dichloromethane (20 ml). The aqueous layer was adjusted to pH 12 with a sodium hydroxide aqueous solution and then to pH 7.4 with hydrochloric acid, subsequently carrying out extraction with chloroform (100 ml×4). The organic layers were combined and dried over anhydrous sodium sulfate and then the solvent was evaporated. The thus obtained residue was subjected to silica gel thin layer chromatography and developed with the bottom layer of a mixture solvent of chloroform:methanol=3:1, and then the resulting silica gel was scratched off and extracted with the same solvent system. The solvent was evaporated and the thus obtained residue was dissolved in a 1 N hydrochloric acid aqueous solution (6 ml) and stirred at room temperature for 10 minutes. After evaporating the solvent, the resulting crude product was recrystallized from isopropyl alcohol to obtain 20.1 mg (4%) of the title compound.
Reaction SMILES: [O:1]=[C:2]1[O:8][C@H:7]([C@H:9]([CH2:11][OH:12])[OH:10])[C:5]([OH:6])=[C:3]1[OH:4].CCCO.CCCO.CCCO.CCCO.[Zr:29]>CO>[O:1]=[C:2]1[O:8][C@H:7]([C@H:9]([CH2:11][OH:12])[OH:10])[C:5]([O-:6])=[C:3]1[OH:4].[Zr+4:29].[O:1]=[C:2]1[O:8][C@H:7]([C@H:9]([CH2:11][OH:12])[OH:10])[C:5]([O-:6])=[C:3]1[OH:4].[O:1]=[C:2]1[O:8][C@H:7]([C@H:9]([CH2:11][OH:12])[OH:10])[C:5]([O-:6])=[C:3]1[OH:4].[O:1]=[C:2]1[O:8][C@H:7]([C@H:9]([CH2:11][OH:12])[OH:10])[C:5]([O-:6])=[C:3]1[OH:4]
Reactant: [Zr]
Reactant: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Solvent: CO
Solvent: CCCO
Product: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Product: [Zr+4]
Reaction time: 0.5 h

Procedure:
Ascorbic acid (2 g, 0.014 moles) was dissolved in 50 ml of methanol. Zirconium n-propoxide (70% in n-propanol, 2.56 ml, 0.00569 moles) was slowly added to the ascorbic acid:methanol solution. After addition was complete, the mixture was stirred for 30 minutes with some precipitate observed. The methanol was distilled off to yield zirconium ascorbate as a white powder. The powder was dried in a 45° C. oven for 24 hours.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][NH:8][C:9]([C@H:11]([C@@H:21]([CH2:30][CH:31]([CH3:33])[CH3:32])[C:22]([NH:24][NH:25][CH2:26][CH:27]([CH3:29])[CH3:28])=[O:23])[CH2:12]/[CH:13]=[CH:14]/[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:10].[C:34]([NH:37][CH2:38][C:39](O)=[O:40])(=[O:36])[CH3:35].Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O>[C:34]([NH:37][CH2:38][C:39]([N:25]([CH2:26][CH:27]([CH3:28])[CH3:29])[NH:24][C:22](=[O:23])[C@@H:21]([C@@H:11]([C:9](=[O:10])[NH:8][O:7][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][O:1]1)[CH2:12]/[CH:13]=[CH:14]/[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:30][CH:31]([CH3:33])[CH3:32])=[O:40])(=[O:36])[CH3:35]
Reactant: CC(C)CNNC(=O)[C@H](CC(C)C)[C@H](C/C=C/c1ccccc1)C(=O)NOC1CCCCO1
Reactant: CC(=O)NCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Product: CC(=O)NCC(=O)N(CC(C)C)NC(=O)[C@H](CC(C)C)[C@H](C/C=C/c1ccccc1)C(=O)NOC1CCCCO1
Temperature: 25 °C
Reaction time: 16 h
Yield: 78.1 %

Procedure:
A solution of 0.459 g of (E)-2(R)-[1(S)-[(tetrahydro-2(RS)-pyranyloxy)carbamoyl]-4-phenyl-3-butenyl]-2′-isobutyl-4-methylvalerohydrazide in 4 ml of dimethylformamide was cooled to 0° C. and treated with 0.351 g of N-acetyl-glycine and 690 mg of 1-ethyl-3-(3-dimethylaminopropyl)carbodimide hydrochloride. The mixture was stirred at room temperature for 16 hours and evaporated. The residue in ethyl acetate was washed with 5% sodium hydrogen carbonate solution and water, dried over anhydrous magnesium sulphate and evaporated. The resulting solid was triturated with diethyl ether and filtered off to give 0.436 g of (E)-2′-(2-acetamidoacetyl)-2(R)-[1(S)-[(tetrahydro-2(RS)-pyranyloxy)carbamoyl]-4-phenyl-3-butenyl]-2′-isobutyl-4-methylvalerohydrazide in the form of a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:10][CH2:9][CH:8]([C:11]([O:13]CC)=[O:12])[S:7]1)=[O:5])[CH3:2].[OH-].[K+].C(OCC)C.Cl>C(O)C.O>[C:11]([CH:8]1[CH2:9][CH2:10][CH:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[S:7]1)([OH:13])=[O:12]
Reactant: CCOC(=O)C1CCC(C(=O)OCC)S1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: CCOCC
Product: CCOC(=O)C1CCC(C(=O)O)S1
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.8 %

Procedure:
To a solution of 2,5-diethoxycarbonyltetrahydrothiophene (2.4 g) in ethanol (10 ml), potassium hydroxide (0.64 g) dissolved in ethanol (10 ml) was added dropwise and the mixture was stirred for 1 hour at room temperature. To the reaction mixture, diethyl ether and water were added. Aqueous layer was acidified with 2N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated in vacuo to give 1.6 g (78%) of 2-carboxy-5-ethoxycarbonyltetrahydrothiophene.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][N:3]=1.[CH3:11][NH2:12]>O1CCOCC1.C1(C)C=CC=CC=1>[CH3:11][NH:12][C:6](=[O:7])[C:5]1[CH:9]=[CH:10][C:2]([Cl:1])=[N:3][CH:4]=1
Reactant: O=C(Cl)c1ccc(Cl)nc1
Reactant: CN
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Product: CNC(=O)c1ccc(Cl)nc1
Reaction time: 3 h

Procedure:
26.2 of crude 6-chloro-nicotinic acid chloride are introduced in portions into a solution of 25 ml of anhydrous methylamine in a mixture of 150 ml of dioxane and 50 ml of toluene whilst cooling at 0° C. to -5° C., and the mixture is then stirred for 3 hours longer, without further cooling. The reaction mixture is evaporated in vacuo, the residue is stirred with 100 ml of water and the undissolved material is filtered off and dried, giving crude 6-chloro-nicotinic acid N-methylamide of melting point 150°-154° C.
Reaction SMILES: [S:1]1[C:5]2[CH2:6][NH:7][CH2:8][C:4]=2[CH:3]=[C:2]1[C:9]([O:11][CH3:12])=[O:10].[C:13](O)(=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15].F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.CN1CCOCC1>C(Cl)Cl>[C:13]([N:7]1[CH2:8][C:4]2[CH:3]=[C:2]([C:9]([O:11][CH3:12])=[O:10])[S:1][C:5]=2[CH2:6]1)(=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)C(=O)O
Reactant: COC(=O)c1cc2c(s1)CNC2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: COC(=O)c1cc2c(s1)CN(C(=O)C(C)(C)C)C2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of methyl 5,6-dihydro-4H-thieno[2,3-c]pyrrole-2-carboxylate (0.023 g, 0.127 mmol) and pivalic acid (0.014 g, 0.14 mmol) in methylene chloride (0.92 mL) was added N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (0.055 g, 0.146 mmol) and N-methylmorpholine (0.035 mL, 0.32 mmol) respectively. The reaction mixture was stirred at room temperature overnight. The reaction was diluted with additional DCM (2 mL) and washed with saturated aqueous NaHCO3 (2 mL). The aqueous layer was extracted with additional DCM (3 mL), and the combined organic layers were concentrated to afford an oily residue. LCMS (FA) ES+ 268.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:17])=[C:6]([C@:8]2([CH3:16])[C@@H:13]([F:14])[CH2:12][O:11][C:10]([NH2:15])=[N:9]2)[CH:7]=1.[CH3:18][O:19][C:20]1[CH:21]=[CH:22][C:23]([C:26](O)=[O:27])=[N:24][CH:25]=1>>[NH2:15][C:10]1[O:11][CH2:12][C@H:13]([F:14])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:26]([C:23]3[CH:22]=[CH:21][C:20]([O:19][CH3:18])=[CH:25][N:24]=3)=[O:27])[CH:3]=[CH:4][C:5]=2[F:17])([CH3:16])[N:9]=1
Reactant: C[C@]1(c2cc(N)ccc2F)N=C(N)OC[C@@H]1F
Reactant: COc1ccc(C(=O)O)nc1
Product: COc1ccc(C(=O)Nc2ccc(F)c([C@@]3(C)N=C(N)OC[C@@H]3F)c2)nc1

Procedure:
The condensation of (4R,5R)-4-(5-amino-2-fluoro-phenyl)-5-fluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate A8.2) and 5-methoxy-pyridine-2-carboxylic acid (CAS 29082-92-6) following procedure I yielded the title compound as a white solid. MS (ISP): m/z=377.3 [M+H]+.
Reaction SMILES: [CH2:1]([C:11]1[NH:15][N:14]=[N:13][N:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].C(N(CC)CC)C.Br[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32]>C(#N)C>[CH2:1]([C:11]1[N:12]=[N:13][N:14]([CH:30]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:24]=2)[C:31]([O:33][CH2:34][CH3:35])=[O:32])[N:15]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCOC(=O)Cc1ccccc1Br
Reactant: CCCCCCCCCCc1nnn[nH]1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCCCCCCCCCc1nnn(C(C(=O)OCC)c2ccccc2)n1
Yield: 33.9 %

Procedure:
The 5-decyl-1H-tetrazole, (4.0 g, 0.019 mol), triethylamine (2.9 mL, 0.021 mol) and ethyl 2-bromophenylacetate (5.09 g, 0.021 mol) were dissolved in 200 mL acetonitrile and heated to reflux for 2 hours. Cooled and concentrated in vacuo to give a yellow oil. Chromatography to separate the regioisomers gave ethyl (±)-5-decyl-α-phenyl-2H-tetrazole-2-acetate as a clear oil (2.40 g, 34%).
Reaction SMILES: S(Cl)(Cl)=O.[NH2:5][C@H:6]([C:8]([OH:10])=[O:9])[CH3:7].[CH2:11](O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH2:11]([O:9][C:8](=[O:10])[C@H:6]([CH3:7])[NH2:5])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: OCc1ccccc1
Reactant: C[C@H](N)C(=O)O
Solvent: O=S(Cl)Cl
Product: C[C@H](N)C(=O)OCc1ccccc1
Temperature: -10 °C
Yield: 67 %

Procedure:
Thionylchloride (9.8 ml, 135 mmol, 1.2 eqv) was added dropwise during 15 min. to benzyl alcohol (210 ml) stirred under nitrogen and cooled to −10° C. Alanine (10.0 g, 112 mmol, 1.0 eqv) was added in portions during 10 min. The reaction mixture was heated overnight at 60-70° C. The reaction mixture was evaporated in vacuo and the residue was dissolved in water (150 ml). The pH was adjusted to 1-2 by addition of 4N HCl (aq.) and the aqueous phase was extracted with dichloromethane (2×200 ml). The organic phase was washed with hydrochloric acid (pH 1, 1×50 ml). The aqueous phases were collected, alkalinized (to pH 9-10) by addition of 2N NaOH (aq.) and subsequently extracted with dichloromethane (2×200 ml and 1×100 ml—alkaline extract). The alkaline extract was dried (Na2SO4), filtered and evaporated under reduced pressure affording 13.39 g (67%) of the title compound as a colorless oil. The product was characterized as its hydrochloride: The product (0.50 g, 2.8 mmol) was dissolved in ether (5 ml) and HCl in ether (2 ml) was added. The precipitate was collected by filtration and washed with ether (2×5 ml) yielding 0.57 g (95%) of white crystalline alanine benzyl ester hydrochloride. 1H-NMR (D2O/TMS): δ 1.48 (unresolved d, 3H, Me); 4.15 (unresolved q, 1H, CH); 5.20 (s, 2H, CH2); 7.38 (br s, 5H, Ph). 13C-NMR (D2O/TMS): δ 14.7 (Me); 48.4 (CH); 68.1 (CH2); 128.1, 128.5, 134.3 (Ph); 170.1 (C═O). MS(FAB+) m/z (%): 180 (100, M-HCl+H). Anal. Calcd. for C10H14,ClNO2: C, 55.69; H, 6.54; N, 6.49. Found: C, 55.60; H, 6.56; N, 6.40.
Reaction SMILES: C([O:4][C:5]1[CH:22]=[CH:21][C:8]([CH:9]=[C:10]2[C:15](=[O:16])[NH:14][C:13]3[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=3[S:11]2)=[CH:7][C:6]=1[C:23]([CH3:26])([CH3:25])[CH3:24])(=O)C.O1CCCC1.[OH-].[Li+].Cl>O.CO>[C:23]([C:6]1[CH:7]=[C:8]([CH:21]=[CH:22][C:5]=1[OH:4])[CH:9]=[C:10]1[C:15](=[O:16])[NH:14][C:13]2[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=2[S:11]1)([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(=O)Oc1ccc(C=C2Sc3ccccc3NC2=O)cc1C(C)(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CC(C)(C)c1cc(C=C2Sc3ccccc3NC2=O)ccc1O
Reaction time: 0.17 h
Yield: 91 %

Procedure:
To a solution of 2-(4-acetoxy-3-tert.-butylbenzylidene)-3,4-dihydro-3-oxo-2H-1,4-benzothiazine (Reference compound No. 1-2, 0.31 g) in the mixture of tetrahydrofuran (12 ml) and methanol (3 ml), lithium hydroxide (0.18 g) dissolved in water (8 ml) was added dropwise under ice cooling. After the addition, the mixture was stirred for additional 10 minutes. The reaction mixture was poured into 1N hydrochloric acid and the whole was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated in vacuo to give 0.25 g (91%) of 2-(3-tert.-butyl-4-hydroxybenzylidene)-3,4-dihydro-3-oxo-2H-1,4-benzothiazine as crystals.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:2].Cl.[C:11]([O:14][CH2:15][CH3:16])(=[O:13])[CH3:12]>O1CCCC1>[OH:3][C:1]([CH:12]1[CH2:16][CH2:15][O:14][C:11]1=[O:13])([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCOC(C)=O
Reactant: CC(=O)c1ccccc1
Agent: Cl
Solvent: C1CCOC1
Product: CC(O)(c1ccccc1)C1CCOC1=O
Reaction time: 4 h
Yield: 62.5 %

Procedure:
Under argon atmosphere, 39.7 mL (4.43 mmol, 1.5 equivalents) of the solution of 2-bromozinc-γ-butyrolactone in tetrahydrofuran obtained in Example 61 was added dropwise to a solution of 1.25 mL (10.7 mmol) of acetophenone in 10 mL of THF at 6˜8° C. The mixture was stirred at 4˜6° C. for 4 hours. 15 mL of 1N hydrochloric acid was added dropwise at 20° C. or lower, followed by dilution with 50 mL of ethyl acetate. Then, the layers were separated. The organic layer was washed successively with 10 mL of 1N hydrochloric acid, 10 mL of water, 20 ml, 15 mL and 10 mL of an aqueous saturated sodium bicarbonate solution, and 10 mL (×2) of an aqueous saturated sodium chloride solution. After washing, the organic layer was dried with anhydrous magnesium sulfate. After concentration under reduced pressure, purification with silica gel column (developing solvent; ethyl acetate/n-hexane=1/3, 1/2, 1/1) afforded 1.88 g of the desired product (NMR yield 62.5%; internal standard dioxane). 0.92 g of the desired product was obtained as crystals (yield 42%).
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([SH:16])=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18].C(=O)([O-])[O-].[K+].[K+].Cl[C:26]1[S:27][C:28]2[C:34]([C:35]([CH3:38])([CH3:37])[CH3:36])=[CH:33][CH:32]=[C:31]([C:39]([CH3:42])([CH3:41])[CH3:40])[C:29]=2[N:30]=1.CN(C)C=O>C(OCC)(=O)C>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([S:16][C:26]4[S:27][C:28]5[C:34]([C:35]([CH3:37])([CH3:36])[CH3:38])=[CH:33][CH:32]=[C:31]([C:39]([CH3:42])([CH3:41])[CH3:40])[C:29]=5[N:30]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18]
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(S)cc3CC[C@@H]12
Reactant: CC(C)(C)c1ccc(C(C)(C)C)c2sc(Cl)nc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN1C(=O)CC[C@]2(C)c3ccc(Sc4nc5c(C(C)(C)C)ccc(C(C)(C)C)c5s4)cc3CC[C@@H]12
Yield: 17.1 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-8-mercapto-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one (100 mg, 0.38 mmol), potassium carbonate (158 mg, 1.14 mmol), 2-chloro-4,7-di(t-butyl)benzothiazole (130 mg, 0.46 mmol) and 1.5 mL of anhydrous dimethylformamide, fitted with a reflux condenser, and the stirred mixture was heated at 60°, under nitrogen, for 18 h. The mixture was cooled, diluted with ethyl acetate (75 mL) and washed with brine (4×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (80% ethyl acetate/hexanes eluent) to give 33 mg (17%) of the title compound as an amorphous foam. FDMS: m/e=506.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[O:9][C@H:10]2[C@@H:12]([C@:13]([C:18]3[CH:23]=[C:22]([NH:24][C@H:25]([C:30]4[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][N:31]=4)[C:26]([F:29])([F:28])[F:27])[CH:21]=[CH:20][C:19]=3[F:37])([CH:15]([F:17])[F:16])[N:14]=1)[CH2:11]2)(C)(C)C.C(OC(=O)[NH:45][C:46]1[O:47][C@H:48]2[C@@H:50]([C@:51]([C:56]3[CH:61]=[C:60]([NH:62][C@@H:63]([C:68]4[CH:73]=[CH:72][C:71]([Cl:74])=[CH:70][N:69]=4)[C:64]([F:67])([F:66])[F:65])[CH:59]=[CH:58][C:57]=3[F:75])([CH:53]([F:55])[F:54])[N:52]=1)[CH2:49]2)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:36][C:33]1[CH:34]=[CH:35][C:30]([C@@H:25]([NH:24][C:22]2[CH:21]=[CH:20][C:19]([F:37])=[C:18]([C@:13]3([CH:15]([F:16])[F:17])[C@@H:12]4[C@@H:10]([CH2:11]4)[O:9][C:8]([NH2:7])=[N:14]3)[CH:23]=2)[C:26]([F:27])([F:28])[F:29])=[N:31][CH:32]=1.[Cl:74][C:71]1[CH:72]=[CH:73][C:68]([C@H:63]([NH:62][C:60]2[CH:59]=[CH:58][C:57]([F:75])=[C:56]([C@:51]3([CH:53]([F:54])[F:55])[C@@H:50]4[C@@H:48]([CH2:49]4)[O:47][C:46]([NH2:45])=[N:52]3)[CH:61]=2)[C:64]([F:65])([F:66])[F:67])=[N:69][CH:70]=1
Reactant: CC(C)(C)OC(=O)NC1=N[C@@](c2cc(N[C@H](c3ccc(Cl)cn3)C(F)(F)F)ccc2F)(C(F)F)[C@H]2C[C@H]2O1
Reactant: CC(C)(C)OC(=O)NC1=N[C@@](c2cc(N[C@@H](c3ccc(Cl)cn3)C(F)(F)F)ccc2F)(C(F)F)[C@H]2C[C@H]2O1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC1=N[C@@](c2cc(N[C@@H](c3ccc(Cl)cn3)C(F)(F)F)ccc2F)(C(F)F)[C@H]2C[C@H]2O1
Product: NC1=N[C@@](c2cc(N[C@H](c3ccc(Cl)cn3)C(F)(F)F)ccc2F)(C(F)F)[C@H]2C[C@H]2O1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97 %

Procedure:
To a solution of tert-butyl((1R,5S,6R)-5-(5-(((R)-1-(5-chloropyridin-2-yl)-2,2,2-trifluoroethyl)amino)-2-fluorophenyl)-5-(difluoromethyl)-2-oxa-4-azabicyclo[4.1.0]hept-3-en-3-yl)carbamate and tert-butyl((1R,5S,6R)-5-(5-(((S)-1-(5-chloropyridin-2-yl)-2,2,2-trifluoroethyl)amino)-2-fluorophenyl)-5-(difluoromethyl)-2-oxa-4-azabicyclo[4.1.0]hept-3-en-3-yl)carbamate (1:1 mixture of diastereomers, 0.070 g, 0.12 mmol) in DCM (2 mL) at room temperature was added trifluoroacetic acid (2.00 mL, 0.124 mmol). The reaction mixture was stirred at room temperature for 30 min and concentrated. The concentrate was partitioned between saturated NaHCO3 and EtOAc. The aqueous phase was discarded. The organic phase was washed with brine and dried over MgSO4. The filtrate was concentrated under reduced pressure and the residue was purified by flash column chromatography on silica gel (12 g, 20% to 60% EtOAc in heptane) to give (1R,5S,6R)-5-(5-(((R)-1-(5-chloropyridin-2-yl)-2,2,2-trifluoroethyl)amino)-2-fluorophenyl)-5-(difluoromethyl)-2-oxa-4-azabicyclo[4.1.0]hept-3-en-3-amine and (1R,5S,6R)-5-(5-(((S)-1-(5-chloropyridin-2-yl)-2,2,2-trifluoroethyl)amino)-2-fluorophenyl)-5-(difluoromethyl)-2-oxa-4-azabicyclo[4.1.0]hept-3-en-3-amine (1:1 mixture of diastereomers, 0.056 g, 0.120 mmol, 97% yield) as a white solid. MS m/z=465.0 [M+H]+. Calculated for C19H15ClF6N4O 464.1. 1H NMR (400 MHz, CDCl3) δ 0.86-0.95 (m, 1H), 1.32-1.41 (m, 1H), 1.73-1.85 (m, 1H), 3.83-3.90 (m, 1H), 4.50 (br s, 2H), 4.87-4.97 (m, 1H), 5.33 (dd, J=11.93, 7.63 Hz, 1H), 6.02-6.34 (m, 1H), 6.60-6.66 (m, 1H), 6.87-6.96 (m, 2H) 7.27-7.35 (m, 1H), 7.65-7.70 (m, 1H), 8.57-8.59 (m, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7][OH:8])([O-:3])=[O:2].[H-].[Na+].Br[CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17]>CN(C=O)C>[N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7][O:8][CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cccc(CO)c1
Reactant: CC(C)(C)OC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)COCc1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 88 %

Procedure:
3-Nitrobenzyl alcohol (5 g, 32.6 mM) was dissolved in DMF (200 ml) and cooled to 5°. Sodium hydride (60% in oil, 1.57 g, 39.2 mM) was added to the stirred solution in portions over 30 minutes, and the mixture cooled to -20°. t-Butyl bromoacetate (5.27 ml, 32.6 mM) was run in dropwise, and the mixture allowed to warm to ambient temperature overnight. Solvent was evaporated, the residue treated with water, and organics extracted into ethyl acetate. The combined organic layers were washed with water and brine, and dried over MgSO4. Crude product was purified by chromatography on silica, eluting with a gradient from hexane/dichloromethane (95:5) to dichloromethane, to give t-butyl 3-nitrobenzyloxyacetate (7.71 g, 88%).
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6](=[O:35])[C@H:7]([CH2:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=1)[NH:8][C:9](=[O:25])[CH2:10][C:11]([NH:14][C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16])([CH3:13])[CH3:12]>O.O1CCOCC1>[CH2:18]([O:17][C:15]([NH:14][C:11]([CH3:13])([CH3:12])[CH2:10][C:9]([NH:8][C@H:7]([C:6]([OH:35])=[O:5])[CH2:26][C:27]1[CH:28]=[CH:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=1)=[O:25])=[O:16])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: COC(=O)[C@H](Cc1ccc(OC)cc1)NC(=O)CC(C)(C)NC(=O)OCc1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(C[C@H](NC(=O)CC(C)(C)NC(=O)OCc2ccccc2)C(=O)O)cc1
Reaction time: 1 h

Procedure:
0.184 g (4.39 mmol) of lithium hydroxide hydrate dissolved in 8 ml of water is added dropwise to a solution of 1.7 g (3.84 mmol) of N-[3-[1-(benzyloxy)formamido]-3-methylbutyryl]-3-(p-methoxyphenyl)-L-alanine methyl ester in 16 ml of dioxan. The solution is stirred at 0° for 1 hour, then treated with 20 ml of water and extracted twice with ether. The aqueous phase is acidified with 6N hydrochloric acid and extracted twice with ether. The combined ether extracts are washed with saturated sodium chloride solution, dried over sodium sulphate and then evaporated under reduced pressure. N-[3-[1-(Benzyloxy)formamido]-3-methylbutyryl]-3-(p-methoxyphenyl)-L-alanine is obtained as a colourless oil, MS: 429 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][CH:8]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[Br-:19].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.O>C1COCC1>[C:1]([O:5][C:6](=[O:18])[NH:7][CH:8]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([Br:19])[CH:15]=2)[NH:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: [Br-]
Reactant: CC(C)(C)OC(=O)NC1CNc2ccccc2C1
Agent: c1cc[nH+]cc1
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)NC1CNc2ccc(Br)cc2C1
Yield: 1863.5 %

Procedure:
To a solution of XXIII (2.7 g, 10.9 mmol) in THF was added dropwise a solution of pyridinium tribromide (3.83, 0.41 mmol) in 50 mL of THF at rt. The reaction mixture was stirred for 15 min before 60 mL of water was added into the flask. The aqueous phase was extracted with EtOAc. The combined organic phase was washed with saturated NaCl, dried over Na2SO4 and concentrated. The residue was purified by flash silica gel chromatography to give (6-bromo-1,2,3,4-tetrahydro-quinoline-3-yl)-carbamic acid tert-butyl ester XXIV (2.5 g, 70%) as white solid.