Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][N:11]([CH2:13][C:14]1[C:15]([C:25]2[CH:26]=[C:27]3[C:31](=[CH:32][CH:33]=2)[N:30](C(OC(C)(C)C)=O)[N:29]=[CH:28]3)=[N:16][N:17](C2CCCCO2)[CH:18]=1)[CH3:12])=O)(C)(C)C.O.CC#N>O1CCCC1.Cl>[NH2:8][CH2:9][CH2:10][N:11]([CH2:13][C:14]1[C:15]([C:25]2[CH:26]=[C:27]3[C:31](=[CH:32][CH:33]=2)[NH:30][N:29]=[CH:28]3)=[N:16][NH:17][CH:18]=1)[CH3:12]
Reactant: CN(CCNC(=O)OC(C)(C)C)Cc1cn(C2CCCCO2)nc1-c1ccc2c(cnn2C(=O)OC(C)(C)C)c1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CC#N
Product: CN(CCN)Cc1c[nH]nc1-c1ccc2[nH]ncc2c1
Reaction time: 0.02 h
Yield: 28.8 %

Procedure:
A solution of (R/S) tert-butyl 5-(4-(((2-(tert-butoxycarbonylamino)ethyl)(methyl)amino)methyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-indazole-1-carboxylate (50 mg, 0.09 mmol, 1.00 equiv) in tetrahydrofuran (10 mL) and 12N hydrochloric acid (2 mL) was stirred overnight at 25° C. The resulting mixture was concentrated under vacuum to remove most of the THF. The pH value of the solution was adjusted to 9 with 10% sodium carbonate solution. The resulting mixture was concentrated under vacuum. The residue was dissolved in 5 mL of methanol and then purified by Pre-HPLC with the following conditions (1#-Pre-HPLC-005 (Waters)): Column, XBridge Shield RP18 OBD Column, 5 μm, 19×150 mm; mobile phase, water with 10 mmol NH4HCO3 and CH3CN (18% CH3CN up to 58% in 10 min, up to 95% in 1 min, down to 18% in 2 min); Detector, UV 254/220 nm to give 7 mg (29%) of (2-aminoethyl)([[3-(1H-indazol-5-yl)-1H-pyrazol-4-yl]methyl])methylamine as a white solid. 1H-NMR (300 MHz, CD3OD): δ 8.14 (s, 1H), 8.10 (s, 1H), 7.72-7.64 (m, 3H), 3.63 (s, 2H), 3.10-3.09 (m, 2H), 2.86-2.77 (m, 2H), 2.24 (s, 3H) ppm. LCMS (method A1, ESI): RT=0.78 min, m/z=271.0 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([NH:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]2[N:23]=[C:22]([O:24][CH3:25])[N:21]=[C:20]([C:26](O)=[O:27])[CH:19]=2)[CH2:14][CH2:13]1)=[O:10].Cl.[O:30]([NH2:32])[CH3:31]>>[Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([NH:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]2[N:23]=[C:22]([O:24][CH3:25])[N:21]=[C:20]([C:26]([NH:32][O:30][CH3:31])=[O:27])[CH:19]=2)[CH2:14][CH2:13]1)=[O:10]
Reactant: CON
Reactant: COc1nc(C(=O)O)cc(N2CCC(NC(=O)c3[nH]c(C)c(Cl)c3Cl)CC2)n1
Agent: Cl
Product: CONC(=O)c1cc(N2CCC(NC(=O)c3[nH]c(C)c(Cl)c3Cl)CC2)nc(OC)n1

Procedure:
The title compound was synthesised by an analogous method to Example 8 starting from 6-(4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}piperidin-1-yl)-2-methoxypyrimidine-4-carboxylic acid (Example 311) and methoxylamine hydrochloride.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[S:6][C:5]2[CH:7]=[C:8]3[C:12](=[CH:13][C:4]=2[S:3]1)[S:11][C:10]([CH3:15])([CH3:14])[S:9]3.[CH3:17][S:18]SC>>[CH3:17][S:18][C:13]1[C:4]2[S:3][C:2]([CH3:16])([CH3:1])[S:6][C:5]=2[CH:7]=[C:8]2[S:9][C:10]([CH3:15])([CH3:14])[S:11][C:12]=12
Reactant: CC1(C)Sc2cc3c(cc2S1)SC(C)(C)S3
Reactant: CSSC
Product: CSc1c2c(cc3c1SC(C)(C)S3)SC(C)(C)S2

Procedure:
2,2,6,6-Tetramethylbenzo[1,2-d;5,4-d']bis-(1,3)dithiole is lithiated with n-BuLl in diethyl either and then reacted with dimethyl disulfide to give 4-methylthio-2,2,6,6-Tetramethylbenzo[1,2-d;5,4-d']bis-(1,3)dithiole. This compound can then be reacted with n-butyl glyoxalate (0.5 eq.) in a solvent consisting of a mixture of concentrated sulfuric acid and glacial acetic acid (1:10) (analogously to: G. Werber, Ann. Chim. 49, 1898 (1959)). After work-up, including neutralization and extraction the product is purified by preparative HPLC. The n-butyl bis[8-(methylthio-2,2,6,6-tetramethylbenzo[1,2-d;5,4-d']bis-(1,3)dithiole]acetate formed can be hydrolyzed with a 10% solution of sodium hydroxide and transferred into other esters, amides, thioesters and anhydrides etc. by standard procedures. If n-butyl bis[8-(methylthio-2,2,6,6-tetramethylbenzo-[1,2-d;5,4-d']bis-(1,3)dithiole] acetate is treated with n-BuLi (3 eq.) in tetrahydrofurane at ambient temperature and exposed to oxygen, the initially formed enolate anion is oxidized to the stable title radical (analogously to P. O'Neill and A. F. Hegarty, J. Org. Chem. 52, 2113 (1987)).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[CH:10]=[C:9]([C:11]([NH:13][CH:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)=[O:12])[NH:8][C:7]=12.C(N(CC)CC)C>CN(C)C=O.[Pd](Cl)Cl>[CH:14]1([NH:13][C:11]([C:9]2[NH:8][C:7]3=[CH:2][N:3]=[CH:4][CH:5]=[C:6]3[CH:10]=2)=[O:12])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]1
Reactant: O=C(NC1CCCCC1)c1cc2ccnc(Cl)c2[nH]1
Agent: Cl[Pd]Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(NC1CCCCC1)c1cc2ccncc2[nH]1
Temperature: 60 °C
Yield: 50 %

Procedure:
7-Chloro-N-cyclohexyl-1H-pyrrolo[2,3-c]pyridine-2-carboxamide (230 mg, 0.828 mmol), triethylamine (0.25 mL) and palladium(II)chloride (3 mg, 2 mol %) were combined in N,N-dimethylformamide (5 mL) under an atmosphere of hydrogen. The reaction mixture was heated at 60° C. for 3 h. The reaction mixture was cooled to room temperature and the catalyst was removed by filtration through a pad of diatomaceous earth and washed with ethyl acetate. Evaporation of the solvents provided crude product (169 mg, 84%) as an off-white solid. Purification by chromatography (SiO2; 0-10% methanol in methylene chloride, 1400 mL) afforded N-cyclohexyl-1H-pyrrolo[2,3-c]pyridine-2-carboxamide (101 mg, 0.414 mmol, 50%) as fine, white needles: mp 298-301° C., 1H NMR (300 MHz, CD3OD) δ 1.20-1.55 (6H, m), 1.65-2.10 (4H, m), 3.90 (1H, m), 7.21 (1H, s), 7.15 (1H, s), 7.65 (1H, d, J=5.7 Hz), 8.09 (1H, d, J=5.7 Hz), 8.77 (1H, s); ESI MS m/z 244 [C14H17N3O+H]+; HPLC (Method A) >99% (AUC), tR=13.2 min.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)=[CH:4][C:3]=1[CH:15]1[C:17]2([C:21](=[O:22])[C:20]([CH3:24])([CH3:23])[O:19][C:18]2([CH3:26])[CH3:25])[O:16]1.S(=O)(=O)(O)O>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([Cl:14])=[CH:12][CH:13]=2)=[CH:4][C:3]=1[CH:15]1[C:21](=[O:22])[C:20]([CH3:23])([CH3:24])[O:19][C:18]([CH3:26])([CH3:25])[C:17]1=[O:16]
Reactant: CC1(C)OC(C)(C)C2(OC2c2cc(-c3ccc(Cl)cc3)ccc2Br)C1=O
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: CC1(C)OC(C)(C)C(=O)C(c2cc(-c3ccc(Cl)cc3)ccc2Br)C1=O
Temperature: 7.5 °C
Reaction time: 0.33 h
Yield: 85.1 %

Procedure:
To an ice-cold solution of 2-(4-bromo-4′-chlorobiphenyl-3-yl)-4,4,6,6-tetramethyl-1,5-dioxaspiro[2.4]heptan-7-one (3.00 g, 6.90 mmol) in dichloromethane (3.5 ml) is added concentrated sulphuric acid (6.5 ml) at such a rate as maintain an internal temperature below 5° C. After the addition is completed the reaction mixture is stirred for a further 20 minutes, after which distilled water (25 ml) is added dropwise at 0° C. The reaction mixture is maintained at 5-10° C. for 5 minutes, then concentrated in vacuo to remove organic solvents. The aqueous phase is filtered and the resulting solid triturated with hexane to afford 4-(4-bromo-4′-chlorobiphenyl-3-yl)-2,2,6,6-tetramethylpyran-3,5-dione (2.56 g, 85%).
Reaction SMILES: [ClH:1].[CH3:2][N:3]1[CH2:8][CH2:7][C:6]2([C:21]3[CH:20]=[CH:19][CH:18]=[C:17]([OH:22])[C:16]=3[O:15][C:14]3[C:9]2=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH2:5][CH2:4]1.[C:23](OC(=O)C)(=[O:25])[CH3:24]>N1C=CC=CC=1>[ClH:1].[CH3:2][N:3]1[CH2:4][CH2:5][C:6]2([C:21]3[CH:20]=[CH:19][CH:18]=[C:17]([O:22][C:23](=[O:25])[CH3:24])[C:16]=3[O:15][C:14]3[C:9]2=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH2:7][CH2:8]1
Reactant: CN1CCC2(CC1)c1ccccc1Oc1c(O)cccc12
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: c1ccncc1
Product: CC(=O)Oc1cccc2c1Oc1ccccc1C21CCN(C)CC1

Procedure:
1'-Methyl-4-hydroxyxanthene-9-spiro-4'-piperidine hydrochloride (0.3 g.) in dry pyridine (10 ml.) is treated with excess acetic anhydride for 12 hours at room temperature. Pyridine and acetic anhydride are removed in vacuo and the residue dissolved in chloroform and treated with ethereal hydrochloric acid. The solvent is removed and the residue recrystallised from isopropanol-light petroleum to give 1'-methyl-4-acetoxyxanthene-9-spiro-4'-piperidine hydrochloride, m.p. 216°-220° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:13]([CH2:17][CH3:18])([CH3:16])[CH2:14][CH3:15])[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)Cl.[CH2:22](O)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(Cl)CCl>CN(C)C1C=CN=CC=1.CCOCC>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:13]([CH2:17][CH3:18])([CH3:16])[CH2:14][CH3:15])[C:10]([O:12][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: OCc1ccccc1
Reactant: CCC(C)(CC)[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CN(C)c1ccncc1
Solvent: CCOCC
Solvent: ClCCl
Solvent: ClCCCl
Product: CCC(C)(CC)[C@@H](NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A 2-dram vial containing a small stir bar was charged with (R)-2-(tert-butoxycarbonylamino)-3-ethyl-3-methylpentanoic acid (10b) (10 mg, 0.04 mmol), CH2Cl2 (1 mL), 4-dimethylaminopyridine (2 mg, 0.02 mmol, 0.5 equiv), benzyl alcohol (20 μL, 0.2 mmol, 5 equiv), and EDC (20 mg, 0.1 mmol, 2.5 equiv). The solution was stirred at room temperature for 3 h, and then diluted with 10 mL Et2O. The mixture was washed with water (2×10 mL), saturated aqueous NaHCO3 (10 mL), and brine (10 mL). The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (7:1 hexanes/Et2O) and analyzed by chiral HPLC analysis: (AD-H, 1 mL/min, 5% IPA/hexanes, 210 nm): tR(major)=10.42 min, tR(minor)=12.87 min.
Reaction SMILES: [SH:1][CH2:2][CH2:3][CH2:4][N:5]1[CH:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:8][NH:7][C:6]1=[O:16].[CH3:17][O:18][C:19]([S:21]Cl)=[O:20]>CO>[CH3:17][O:18][C:19]([S:21][S:1][CH2:2][CH2:3][CH2:4][N:5]1[CH:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:8][NH:7][C:6]1=[O:16])=[O:20]
Reactant: O=C1NCC(c2ccccc2)N1CCCS
Reactant: COC(=O)SCl
Solvent: CO
Product: COC(=O)SSCCCN1C(=O)NCC1c1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 6.7 g of 1-(3-mercaptopropyl-5-phenyl-2-imidazolidinone in 70 ml of methanol, cooled to 0°, there is added dropwise 3.9 g of methoxy carbonylsulfenyl chloride over a fifteen minute period. The solution is allowed to stir at 0° for 1 hour and at room temperature for four hours. The reaction is concentrated in vacuo and the residual oil eluted on a silica gel column with ethyl acetate. The product is purified further by recrystallization from isopropyl ether, m.p. 98°-100° C.
Reaction SMILES: C(O)CCCCCCCO.FC(F)(F)C1C=CC(CBr)=CC=1.[F:23][C:24]([F:43])([F:42])[C:25]1[CH:41]=[CH:40][C:28]([CH2:29][O:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][OH:39])=[CH:27][CH:26]=1.FC(F)(F)C1C=CC(COCCCCCCCC(O)=O)=CC=1.Cl.Cl.[CH2:68]([O:75][C:76](=[O:84])[CH2:77][C@@H:78]([NH2:83])[CH2:79][N:80]([CH3:82])[CH3:81])[C:69]1[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=1>>[CH2:68]([O:75][C:76](=[O:84])[CH2:77][C@@H:78]([NH:83][C:38](=[O:39])[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][O:30][CH2:29][C:28]1[CH:40]=[CH:41][C:25]([C:24]([F:42])([F:43])[F:23])=[CH:26][CH:27]=1)[CH2:79][N:80]([CH3:81])[CH3:82])[C:69]1[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=1
Reactant: CN(C)C[C@H](N)CC(=O)OCc1ccccc1
Reactant: OCCCCCCCCOCc1ccc(C(F)(F)F)cc1
Agent: Cl
Agent: FC(F)(F)c1ccc(CBr)cc1
Agent: O=C(O)CCCCCCCOCc1ccc(C(F)(F)F)cc1
Product: CN(C)C[C@@H](CC(=O)OCc1ccccc1)NC(=O)CCCCCCCOCc1ccc(C(F)(F)F)cc1

Procedure:
The title compound, m/e=445.6 ([M−H]−), was produced in analogy with intermediate 1, steps 1 to 4. Thus, 1,8-octanediol was alkylated in step 1 with 4-trifluoromethyl-benzyl bromide, leading to 8-(4-trifluoromethyl-benzyloxy)-octan-1-ol, which was oxidized in step 2 to 8-(4-trifluoromethyl-benzyloxy)-octanoic acid. This was coupled in step 3 with (R)-3-amino-4-dimethylamino-butyric acid benzyl ester dihydrochloride to produce (R)-3-[8-(4-trifluoromethyl-benzyloxy)-octanoylamino]-4-dimethylamino-butyric acid benzyl ester, which was hydrogenated in step 4.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[N:11]([CH3:12])[CH:10]([CH3:13])[CH2:9][N:5]2[C:6](=[O:8])[N:7]=1.[F:14][C:15]1[CH:16]=[C:17]([CH2:33][OH:34])[CH:18]=[CH:19][C:20]=1[O:21][C:22]1[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[C:24]([F:32])[CH:23]=1>>[F:14][C:15]1[CH:16]=[C:17]([CH:18]=[CH:19][C:20]=1[O:21][C:22]1[CH:27]=[C:26]([C:28]([F:29])([F:30])[F:31])[CH:25]=[C:24]([F:32])[CH:23]=1)[CH2:33][O:34][C:2]1[CH:3]=[C:4]2[N:11]([CH3:12])[CH:10]([CH3:13])[CH2:9][N:5]2[C:6](=[O:8])[N:7]=1
Reactant: CC1Cn2c(cc(Cl)nc2=O)N1C
Reactant: OCc1ccc(Oc2cc(F)cc(C(F)(F)F)c2)c(F)c1
Product: CC1Cn2c(cc(OCc3ccc(Oc4cc(F)cc(C(F)(F)F)c4)c(F)c3)nc2=O)N1C

Procedure:
The title compound was prepared by a procedure similar to that described for E9 starting from 7-chloro-1,2-dimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one and (3-fluo-ro-4-(3-fluoro-5-(trifluoromethyl)phenoxy)phenyl)methanol.
Reaction SMILES: [Br:1][CH2:2][C:3](Br)=[O:4].[CH2:6]([NH:8][CH2:9][CH3:10])[CH3:7].C(N(C(C)C)C(C)C)C.O>C1COCC1.C(OCC)(=O)C>[Br:1][CH2:2][C:3]([N:8]([CH2:9][CH3:10])[CH2:6][CH3:7])=[O:4]
Reactant: CCNCC
Reactant: O=C(Br)CBr
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCN(CC)C(=O)CBr
Reaction time: 1.5 h
Yield: 27 %

Procedure:
A solution of 2-bromoacetyl bromide (20.2 g, 100 mmol) in THF (300 mL) was cooled to 0° C. and treated with diethylamine (7.31 g, 100 mmol). After dropwise addition of ethyldiisopropylamine (15.5 g, 120 mmol) the reaction mixture was allowed to reach RT and was stirred for 90 min. Water (250 mL) and ethyl acetate (300 mL) were added, the layers were separated and the aqueous layer was extracted twice with ethyl acetate (100 mL). The solvents were removed in vacuo and the residue was purified by distillation (bp 120-121° C./24 mbar) to give 5.24 g (27%) of the title compound as pale yellow oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][OH:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[Br:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25]Br)=[C:21]([C:27]([F:30])([F:29])[F:28])[CH:20]=1.[Cl-].[NH4+]>CN(C=O)C.CCOC(C)=O>[Br:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][O:15][CH2:14][CH:11]2[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][CH2:10]2)=[C:21]([C:27]([F:28])([F:29])[F:30])[CH:20]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Reactant: FC(F)(F)c1cc(Br)ccc1CBr
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(COCc2ccc(Br)cc2C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 76.4 %

Procedure:
1-(tert-Butoxycarbonyl)-4-piperidinemethanol (400 mg) was added to a mixture of 60% sodium hydride (90 mg) and DMF (11 mL) under ice-cooling in a nitrogen atmosphere, and the mixture was stirred for 10 minutes. A solution of 4-bromo-1-(bromomethyl)-2-(trifluoromethyl)benzene (550 mg) in DMF (2 mL) was added to the mixture under ice-cooling. After the reaction mixture was stirred for 30 minutes under ice-cooling, the temperature of the reaction mixture was raised to room temperature, and stirring was performed for 30 minutes. After a saturated aqueous ammonium chloride solution was added to the reaction mixture, extraction thereof was performed using an EtOAc-Hex mixed solvent (1:1), and the extract was washed with water and saturated brine. The organic layer was dried over MgSO4 and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Hex:EtOAc=99:1 to 90:10), whereby tert-butyl 4-({[4-bromo-2-(trifluoromethyl)benzyl]oxy}methyl)piperidine-1-carboxylate (598 mg) was obtained as a pale yellow oil.
Reaction SMILES: COC(=O)N[C@@H](C(C)C)C(N1[C@H](C2NC(C3C=CC(C4C=CC5C(=CC=C(C6NC([C@@H]7CCCN7[C:48](=[O:61])[C@H:49]([NH:56][C:57]([O:59][CH3:60])=[O:58])[C:50]7[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=7)=NC=6)C=5)C=4)=CC=3)=CN=2)CC2(OCCO2)C1)=O.Cl.Cl.Cl.[O:69]=[C:70]([N:83]1[C@H:88]([C:89]2[NH:90][C:91]([C:94]3[CH:103]=[CH:102][C:101]4[C:96](=[CH:97][CH:98]=[C:99]([C:104]5[CH:105]=[C:106]6[C:119](=[CH:120][CH:121]=5)[C:110]5[NH:111][C:112]([C@@H:114]7[CH2:118][CH2:117][CH2:116][NH:115]7)=[N:113][C:109]=5[CH:108]=[CH:107]6)[CH:100]=4)[CH:95]=3)=[CH:92][N:93]=2)[C@@H:87]2[CH2:122][C@H:84]1[CH2:85][CH2:86]2)[C@@H:71]([NH:78][C:79](=[O:82])[O:80][CH3:81])[CH:72]1[CH2:77][CH2:76][O:75][CH2:74][CH2:73]1>>[CH3:60][O:59][C:57](=[O:58])[NH:56][C@H:49]([C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)[C:48]([N:115]1[CH2:116][CH2:117][CH2:118][C@H:114]1[C:112]1[NH:111][C:110]2[C:119]3[C:106]([CH:107]=[CH:108][C:109]=2[N:113]=1)=[CH:105][C:104]([C:99]1[CH:98]=[CH:97][C:96]2[C:101](=[CH:102][CH:103]=[C:94]([C:91]4[NH:90][C:89]([C@@H:88]5[C@@H:87]6[CH2:122][C@@H:84]([CH2:85][CH2:86]6)[N:83]5[C:70](=[O:69])[C@@H:71]([NH:78][C:79]([O:80][CH3:81])=[O:82])[CH:72]5[CH2:73][CH2:74][O:75][CH2:76][CH2:77]5)=[N:93][CH:92]=4)[CH:95]=2)[CH:100]=1)=[CH:121][CH:120]=3)=[O:61]
Reactant: COC(=O)N[C@H](C(=O)N1[C@@H]2CC[C@@H](C2)[C@H]1c1ncc(-c2ccc3cc(-c4ccc5c(ccc6nc([C@@H]7CCCN7)[nH]c65)c4)ccc3c2)[nH]1)C1CCOCC1
Reactant: COC(=O)N[C@H](C(=O)N1CC2(C[C@H]1c1ncc(-c3ccc(-c4ccc5cc(-c6cnc([C@@H]7CCCN7C(=O)[C@H](NC(=O)OC)c7ccccc7)[nH]6)ccc5c4)cc3)[nH]1)OCCO2)C(C)C
Agent: Cl
Product: COC(=O)N[C@H](C(=O)N1[C@@H]2CC[C@@H](C2)[C@H]1c1ncc(-c2ccc3cc(-c4ccc5c(ccc6nc([C@@H]7CCCN7C(=O)[C@H](NC(=O)OC)c7ccccc7)[nH]c65)c4)ccc3c2)[nH]1)C1CCOCC1

Procedure:
The title compound was prepared according to the method employed to prepare (S)-1-((S)-8-(5-(4-(6-(2-((S)-1-((R)-2-(methoxycarbonylamino)-2-phenylacetyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)-1,4-dioxa-7-azaspiro[4.4]nonan-7-yl)-3-methyl-1-oxobutan-2-ylcarbamic acid methyl ester, except that methyl (S)-2-oxo-2-((1R,3S,4S)-3-(5-(6-(2-((S)-pyrrolidin-2-yl)-1H-naphtho[1,2-d]imidazol-7-yl)naphthalen-2-yl)-1H-imidazol-2-yl)-2-azabicyclo[2.2.1]heptan-2-yl)-1-(tetrahydro-2H-pyran-4-yl)ethylcarbamate 3HCl salt was used instead of methyl (S)-3-methyl-1-oxo-1-((S)-8-(5-(4-(6-(2-((S)-pyrrolidin-2-yl)-1H-imidazol-5-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)-1,4-dioxa-7-azaspiro[4.4]nonan-7-yl)butan-2-ylcarbamate 3HCl salt. MS (ESI) m/z 915.83 [M+H]+. (59 mg, 88%).
Reaction SMILES: [C:1]([O:4][C:5](=[O:7])[CH3:6])(=O)[CH3:2].[CH2:8]1[O:12][C@@H:11]2[C@@H](O)C[O:15][C@@H:10]2[C@@H:9]1[OH:17].C([O-])(=O)C.[Na+]>C(O)(=O)C>[CH3:6][C:5]([O:4][C@@H:1]1[C@H:11]2[O:12][CH2:8][C@@H:9]([OH:17])[C@H:10]2[O:15][CH2:2]1)=[O:7]
Reactant: O[C@@H]1CO[C@H]2[C@@H]1OC[C@@H]2O
Reactant: CC(=O)OC(C)=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(=O)O[C@H]1CO[C@H]2[C@@H]1OC[C@H]2O

Procedure:
At approx. 100° C., 102 g (1 mol) of acetic acid anhydride are added to 146 g (1 mol) of isosorbide and 1 g of sodium acetate. This mixture is heated for half an hour under reflux and the acetic acid formed is then removed under a water-pump vacuum up to a sump temperature of approx. 140° C. An analysis of the residue shows that isosorbide, isosorbide-2-acetate, isosorbide-5-acetate and isosorbide-2,5-diacetate are present in approximately equal proportions. By the following transacylation and distillation, according to example 1, 182 g of raw isosorbide-2-acetate are obtained. After recrystallizing from 200 ml of acetone 92 g of pure isosorbide-2-acetate with a M.P. of 80° C. are obtained. The residue (90 g) remaining after concentrating the filtrate is again subjected to transacylation after adding 0.5 g of sodium acetate whereby again an almost quantitative yield of raw isosorbide-2-acetate is achieved. From this, 43 g of pure isosorbide-2-acetate and 46 g residue are obtained as described above. By another distillation in the presence of sodium acetate it is possible to prepare from the 46 g residue, 44 g of raw isosorbide-2-acetate from which, by recrystallisation, 26 g of pure isosorbide-2-acetate can be isolated. In this way a total amount of 161 g of pure isosorbide-2-acetate is obtained corresponding to 83% of the theory and 18 g residue which may be used for further transacylations. By repeating the above mentioned procedure resp. by adding the remaining residue to the next acylation batch an almost quantitative yield of pure isosorbide-2-acetate can be obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[CH2:4][C:5](O)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:15])[CH2:6][CH2:7][CH3:8].C1(C)C=CC(S(O)(=O)=O)=CC=1.OS(O)(=O)=O.O>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:17])[CH2:4][CH:5]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:15])[CH2:6][CH2:7][CH3:8]
Reactant: CCCC(O)(CC(=O)OC)c1ccccc1C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: Cc1ccccc1
Product: CCCC(CC(=O)OC)c1ccccc1C

Procedure:
A solution of 58.9 g of 3-hydroxy-3-(o-tolyl)-hexanoic acid methyl ester, 1.1 g p-toluene sulphonic acid and 2.5 ml concentrated H2SO4 in 400 ml toluene is boiled in a water separator under reflux. The resultant reaction solution is concentrated, taken up in CHCl3, washed with NaHCO3 solution, H2O and then NaCl solution and then concentrated. The crude product in CHCl3 is filtered through silica gel and the filtrate concentrated. The product containing 3-(o-tolyl)-hex-2-and/or 3-enoic acid methyl ester is taken up in 400 ml methanol and hydrogenated in the presence of 2.1 g 10% (by weight) Palladium on charcoal at 20° and at 1.1 atmospheres to yield 3-o-tolyl-hexanoic acid methyl ester, which is further worked up as such.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([C:13]([OH:15])=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:16][C@H:17]1[CH2:21][CH2:20][CH2:19][NH:18]1.CN1CCOCC1.ON1C2C=CC=CC=2N=N1.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl.CO>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([C:13]([N:18]2[CH2:19][CH2:20][CH2:21][C@@H:17]2[CH3:16])=[O:15])[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@H]1CCCN1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](C(=O)O)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CO
Solvent: CN1CCOCC1
Product: C[C@H]1CCCN1C(=O)[C@H]1CCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
(3S)-Pyrrolidine-1,3-dicarboxylic acid 1-tert-butyl ester (purchased from Astatech, Inc, 0.5 g, 2.3 mmol) was dissolved in DCM (20 mL) and the solution was cooled to an ice-water bath. To this solution was added a solution of (S)-2-methyl-pyrrolidine (purchased from Advanced Asymmetric, Inc., 235 mg, 2.76 mmol, 1.2 equiv.) in 1 mL of DCM, followed by N-methylmorpholine (700 mg, 6.9 mmol, 3 equiv.) and 1-hydroxylbenzotriazole (HOBT) (404 mg, 3 mmol, 1.3 equiv.) sequentially, and finally EDC.HCl (576 mg, 3 mmol, 1.3 equiv.). The resultant clear light brown solution was stirred at r.t. overnight. TLC (10% MeOH in DCM) and LC/MS detected the product peak at a retention time of 3.238 min with MS 227 (M-t-Bu). The reaction was quenched with aqueous saturated sodium bicarbonate solution (10 mL) and 10 mL of DCM. The two layers were separated, and the aqueous layer was extracted with DCM (15 mL×2). The combined DCM extracts were washed successively with sodium bicarbonate (10 mL) and brine (10 mL), dried (anhydrous potassium carbonate), filtered, and concentrated in vacuum to obtain the title compound, 0.65 g (100% yield), as a thick oil.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([F:12])=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH3:13][CH:14]([S:17]([NH2:20])(=[O:19])=[O:18])[CH2:15][CH3:16]>>[CH:14]([S:17]([NH:20][C:4](=[O:6])[C:3]1[CH:7]=[C:8]([F:12])[C:9]([F:11])=[CH:10][C:2]=1[F:1])(=[O:19])=[O:18])([CH2:15][CH3:16])[CH3:13]
Reactant: O=C(O)c1cc(F)c(F)cc1F
Reactant: CCC(C)S(N)(=O)=O
Product: CCC(C)S(=O)(=O)NC(=O)c1cc(F)c(F)cc1F
Yield: 46 %

Procedure:
Prepared according to Preparation 42 using 2,4,5-trifluorobenzoic acid (0.25 g, 1.4 mmol) and butane-2-sulfonamide (0.0.29 g, 2.1 mmol) to yield the title compound (0.19 g, 45%) as a white solid.