Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([C@@H:4]1[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C@H:5]1[OH:14])(O)=O.[N:15](C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OCC)(=O)C>O1CCCC1>[OH:14][C@H:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH2:12][CH2:13][C@H:4]1[NH2:15]
Reactant: O=C(O)[C@@H]1CCc2ccccc2[C@H]1O
Reactant: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: N[C@@H]1CCc2ccccc2[C@@H]1O

Procedure:
One gram of the hydroxamic acid of (1S,2R)-2-carboxy-1-hydroxytetralin is reacted with equimolar amounts of diethyl azodicarboxylate and triphenylphosphine in tetrahydrofuran at room temperature using the procedure of Bittner, Grinberg and Kartoon (Tet. Lett. 23, 1965-8 (1974)). The product is isolated by acidification and extraction of the reaction mixture with ethyl acetate, followed by basification of the resulting aqueous solution with NaOH, extraction with methyl t-butyl ether, drying of the extracts over MgSO4, filtration, and the removal of solvent by rotary evaporation. The product (1S,2R)-1-hydroxy-2-aminotetralin is isolated as a light yellow oil.
Reaction SMILES: [CH2:1]([NH:5][C:6]1[CH:7]=[C:8]([CH:12]=[C:13]([S:22](=[O:25])(=[O:24])[NH2:23])[C:14]=1[O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:9](N)=O)[CH2:2][CH2:3][CH3:4].[CH2:26]([NH:30]C1C=C(C=C(S(=O)(=O)N)C=1OC1C=CC=CC=1)C(NC)=O)CCC>>[CH2:1]([NH:5][C:6]1[CH:7]=[C:8]([CH:12]=[C:13]([S:22](=[O:25])(=[O:24])[NH2:23])[C:14]=1[O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:9][CH2:26][NH2:30])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNc1cc(C(=O)NC)cc(S(N)(=O)=O)c1Oc1ccccc1
Reactant: CCCCNc1cc(C(N)=O)cc(S(N)(=O)=O)c1Oc1ccccc1
Product: CCCCNc1cc(CCN)cc(S(N)(=O)=O)c1Oc1ccccc1

Procedure:
By replacing in Example 289 3-n-butylamino-4-phenoxy-5-sulfamylbenzamide with an equimolar amount of 3-n-butylamino-4-phenoxy-5-sulfamyl-N-methylbenzamide and following the procedure described, (3-n-butylamino-4-phenoxy-5-sulfamylbenzyl)methylamine is obtained with a melting point of 157°-159° C. The material (IR, analysis) is identical with the material prepared as in Example 115.
Reaction SMILES: CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[CH3:22][CH:23]([O:25][C:26]1[N:31]=[CH:30][C:29]([C:32]([OH:34])=O)=[CH:28][C:27]=1[C:35]([F:38])([F:37])[F:36])[CH3:24].O[NH:40]/[C:41](=[N:58]\[H])/[C:42]1[CH:50]=[C:49]2[C:45]([C:46]([CH2:51][CH2:52][C:53]([O:55][CH2:56][CH3:57])=[O:54])=[CH:47][NH:48]2)=[CH:44][CH:43]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[CH3:24][CH:23]([O:25][C:26]1[N:31]=[CH:30][C:29]([C:32]2[O:34][N:58]=[C:41]([C:42]3[CH:50]=[C:49]4[C:45]([C:46]([CH2:51][CH2:52][C:53]([O:55][CH2:56][CH3:57])=[O:54])=[CH:47][NH:48]4)=[CH:44][CH:43]=3)[N:40]=2)=[CH:28][C:27]=1[C:35]([F:38])([F:37])[F:36])[CH3:22]
Reactant: [H]/N=C(\NO)c1ccc2c(CCC(=O)OCC)c[nH]c2c1
Reactant: CC(C)Oc1ncc(C(=O)O)cc1C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: CCOC(=O)CCc1c[nH]c2cc(-c3noc(-c4cnc(OC(C)C)c(C(F)(F)F)c4)n3)ccc12
Reaction time: 0.5 h
Yield: 63.3 %

Procedure:
EDCI (385 mg) and HOBT (332 mg) were added to a solution of 6-[(1-methylethyl)oxy]-5-(trifluoromethyl)-3-pyridinecarboxylic acid (250 mg) in THF (5 mL) at RT. The resulting solution was stirred for 30 mins. Ethyl 3-{6-[(Z)-(hydroxyamino)(imino)methyl]-1H-indol-3-yl}propanoate (D107) (413 mg) in THF (5 mL) was added and the reaction mixture was stirred at RT for 2 hours. TBAF (1.1 g) was then added. The reaction vessel was sealed and heated in Biotage Initiator using initial normal to 120° C. for 90 mins. After cooling, the reaction was quenched with water, and extracted with EA for 3 times. The combined organic solution was washed with brine, dried over anhydrous sodium sulfate. The dried solution was concentrated. The residue was purified by column chromatography (20% EtOAc in hexane) to afford ethyl 3-(6-{5-[6-[(1-methylethyl)oxy]-5-(trifluoromethyl)-3-pyridinyl]-1,2,4-oxadiazol-3-yl}-1H-indol-3-yl)propanoate (D109) (310 mg) as a pale yellow solid. δH (CDCl3, 400 MHz): 1.25 (3H, t), 1.45 (6H, d), 2.74 (2H, t), 3.15 (2H, t), 4.16 (2H, q), 5.60 (1H, m), 7.17 (1H, t), 7.73 (1H, d), 7.94 (1H, dd), 8.21 (2H, dd), 8.64 (1H, t), 9.14 (1H, d). δF (CDCl3, 376 MHz): −64.3. MS (ES): C24H23F3N4O4 requires 488; found 489.2 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[Cl:19][C:20]1[C:21](=[O:32])[C:22]2[C:27]([C:28](=[O:31])[C:29]=1Cl)=[CH:26][CH:25]=[CH:24][CH:23]=2>CCO>[Cl:19][C:20]1[C:21](=[O:32])[C:22]2[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:28](=[O:31])[C:29]=1[NH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=C1C(Cl)=C(Cl)C(=O)c2ccccc21
Reactant: Cc1ccccc1NS(=O)(=O)c1ccc(N)cc1
Solvent: CCO
Product: Cc1ccccc1NS(=O)(=O)c1ccc(NC2=C(Cl)C(=O)c3ccccc3C2=O)cc1
Temperature: 115 °C
Yield: 0 %

Procedure:
A well-stirred suspension of 4-Amino-N-o-tolyl-benzenesulfonamide 12a (47 mg, 179 mmol) and 2,3-dichloro-1,4-naphthquinone (41 mg, 179 mmol) in 10.0 mL of 95% EtOH/5% water solution mixture was refluxed at 115° C. for three days. The orange precipitate obtained was filtered and washed with hot ethanol (5×5 mL), dried under reduced pressure to afford the title compound (23 mg, 28%). Mp=265-266° C.; 1H NMR (400 MHz, DMSO-d6) δ 9.55 (br s, 1H), 9.45 (br s, 1H), 8.04 (d, J=7.2 Hz, 2H), 7.89-7.80 (m, 2H), 7.49 (d, J=8.4 Hz, 2H), 7.17-7.07 (m, 5H), 6.98-6.96 (m, 1H), 1.97 (s, 3H); ESI-LRMS m/z 453.0 (M+35Cl+H)+, 455.0 (M+37Cl+H)+; ESI-HRMS m/z calculated for C23H8ClN2O4S (M+H)+ 453.0670, found 453.0665.
Reaction SMILES: [O:1]=[C:2]([C:14]1[CH:23]=[C:22]([C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=2)[C:21]2[C:20]([CH3:32])([CH3:31])[CH2:19][CH2:18][C:17]([CH3:34])([CH3:33])[C:16]=2[CH:15]=1)/[CH:3]=[CH:4]/[C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1.O.O.O.O.O.O.O.[Cl-].[Ce+3].[Cl-].[Cl-].[BH4-].[Na+]>>[OH:1][CH:2]([C:14]1[CH:23]=[C:22]([C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=2)[C:21]2[C:20]([CH3:32])([CH3:31])[CH2:19][CH2:18][C:17]([CH3:34])([CH3:33])[C:16]=2[CH:15]=1)/[CH:3]=[CH:4]/[C:5]1[CH:6]=[CH:7][C:8]([C:9]([OH:11])=[O:10])=[CH:12][CH:13]=1
Reactant: Cc1ccc(-c2cc(C(=O)/C=C/c3ccc(C(=O)O)cc3)cc3c2C(C)(C)CCC3(C)C)cc1
Agent: [BH4-]
Agent: [Ce+3]
Agent: [Cl-]
Solvent: O
Product: Cc1ccc(-c2cc(C(O)/C=C/c3ccc(C(=O)O)cc3)cc3c2C(C)(C)CCC3(C)C)cc1
Yield: 50 %

Procedure:
In a manner similar to that of Example 4a, by reacting 400 mg (0.88 mmol) of 4-[(E)-3-oxo-3-(5,5,8,8-tetramethyl-4-p-tolyl-5,6,7,8-tetrahydro-2-naphthyl)propenyl]benzoic acid (Example 23) with 428 mg of cerium chloride heptahydrate and 40 mg of sodium borohydride. The desired product is obtained in the form of a white solid (m=200 mg; yield=50%; m.p.=179° C.).
Reaction SMILES: [OH:1][CH2:2][C:3]([S:6]([CH2:9][CH:10]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])(=[O:8])=[O:7])([CH3:5])[CH3:4].[CH3:28][O:29][CH2:30][C:31](Cl)=[O:32].S(=O)(=O)(O)O>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[CH3:28][O:29][CH2:30][C:31]([O:1][CH2:2][C:3]([S:6]([CH2:9][CH:10]([CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C:11]([O:13][CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:12])(=[O:8])=[O:7])([CH3:5])[CH3:4])=[O:32]
Reactant: COCC(=O)Cl
Reactant: CC(C)(CO)S(=O)(=O)CC(Cc1ccccc1)C(=O)OCc1ccccc1
Agent: CN(C)c1ccncc1
Agent: O=S(=O)(O)O
Solvent: c1ccncc1
Product: COCC(=O)OCC(C)(C)S(=O)(=O)CC(Cc1ccccc1)C(=O)OCc1ccccc1
Reaction time: 15 h
Yield: 36 %

Procedure:
A mixture of 422 mg (1.08 mmol) of benzyl rac-α-[[(2-hydroxyl-1,1-dimethylethyl)sulfonyl]methyl]hydrocinnamate, 2 ml (2.2 mmol) of methoxyacetyl chloride and 100 mg (0.8 mmol) of 4-dimethylaminopyridine in 2 ml of pyridine was stirred at 900 for 15 hours. Subsequently, the mixture was poured on to ice and 150 ml of 3N sulphuric acid and extracted three times with 300 ml of ether each time. The organic extracts were then washed with in each case 150 ml of ice-cold 3N sulphuric acid, water, 1M sodium hydrogen carbonate solution and saturated sodium chloride solution, then dried over magnesium sulphate and evaporated under reduced pressure. For purification, the crude product (540 mg of brown oil) was chromatographed on 50 g of silica gel with a 4:1 mixture of toluene and ethyl acetate. There were obtained 180 mg of benzyl rac-α-[[[2-(methoxyacetoxy)-1,1-dimethylethyl]sulfonyl]methyl]hydrocinnamate as a colourless oil, MS: 463 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH:12]([CH3:14])[CH3:13])[C:5]([OH:7])=O.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[F:36][C:37]1[C:45](/[C:46](/[NH:49]O)=[N:47]/[H])=[C:44]2[C:40]([C:41]([CH2:51][CH2:52][C:53]([O:55][CH2:56][CH3:57])=[O:54])=[CH:42][NH:43]2)=[CH:39][CH:38]=1>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2[O:7][N:47]=[C:46]([C:45]3[C:37]([F:36])=[CH:38][CH:39]=[C:40]4[C:44]=3[NH:43][CH:42]=[C:41]4[CH2:51][CH2:52][C:53]([O:55][CH2:56][CH3:57])=[O:54])[N:49]=2)[CH:8]=[CH:9][C:10]=1[O:11][CH:12]([CH3:14])[CH3:13]
Reactant: [H]/N=C(\NO)c1c(F)ccc2c(CCC(=O)OCC)c[nH]c12
Reactant: CC(C)Oc1ccc(C(=O)O)cc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: CCOC(=O)CCc1c[nH]c2c(-c3noc(-c4ccc(OC(C)C)c(Cl)c4)n3)c(F)ccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 47.4 %

Procedure:
To the solution of 3-chloro-4-[(1-methylethyl)oxy]benzoic acid (D32) (676 mg) in tetrahydrofuran (50 mL) were added EDCI (824 mg) and HOBT (658 mg). The resulting solution was stirred at room temperature for 1 hour. Then ethyl 3-{6-fluoro-7-[(Z)-(hydroxyamino)(imino)methyl]-1H-indol-3-yl}propanoate (D145) (840 mg) was added and the solution was stirred at room temperature for another 2 hours. THF was removed in vacuo and the residue was dissolved in ethyl acetate (50 mL), washed with water (2×10 mL) and dried over sodium sulphate. The organic phase was concentrated. The residue was dissolved in THF (3 mL), TBAF (3 g) was added and the reaction solution was stirred under microwave (120° C., 2.5 hours). The reaction solution was poured into ethyl acetate (100 mL), washed with water (3×20 mL), dried over sodium sulphate. The organic phase was concentrate and the residue was purified by column chromatography to afford ethyl 3-[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-6-fluoro-1H-indol-3-yl]propanoate (D146) (640 mg) as an off white solid. MS (ES): C24H23ClFN3O4 requires 471; found 472.2 (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[S:19][CH:20]=[CH:21][N:22]=2)[CH2:14][CH2:13]1)=[O:10].Cl[S:24]([OH:27])(=[O:26])=[O:25].O>C(Cl)Cl>[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[CH2:13][CH2:14][N:15]([C:18]2[S:19][C:20]([S:24]([OH:27])(=[O:26])=[O:25])=[CH:21][N:22]=2)[CH2:16][CH2:17]1)=[O:10]
Reactant: O=S(=O)(O)Cl
Reactant: Cc1[nH]c(C(=O)NC2CCN(c3nccs3)CC2)c(Cl)c1Cl
Solvent: O
Solvent: ClCCl
Product: Cc1[nH]c(C(=O)NC2CCN(c3ncc(S(=O)(=O)O)s3)CC2)c(Cl)c1Cl
Temperature: 60 °C
Yield: 46.3 %

Procedure:
3,4-Dichloro-5-methyl-N-[1-(1,3-thiazol-2-yl)piperidin-4-yl]-1H-pyrrole-2-carboxamide (Example 329; 692 mg, 1.93 mmol) was dissolved in anhydrous DCM. Chlorosulfonic acid (513 μl, 7.7 mmol) was added slowly and the mixture was heated at 60° C. for 2 h. The mixture was cooled to 0° C. and water was added, whereupon a brown solid separated. This was filtered and washed well with water, dried in vacuo to give the title compound (393 mg).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:21]3[C:12](=[CH:13][C:14]4[O:19][CH2:18][CH2:17][O:16][C:15]=4[CH:20]=3)[O:11][CH2:10]2)[C:2]1=[O:22].CC1C2C=C3C4(C5C(=CC=CC=5)NC4=O)COC3=CC=2ON=1.Br[CH2:46][C:47]1[CH:48]=[CH:49][C:50]([NH:53][C:54](=[O:60])[O:55][C:56]([CH3:59])([CH3:58])[CH3:57])=[N:51][CH:52]=1.BrCC1OC(C(F)(F)F)=CC=1>>[O:22]=[C:2]1[C:3]2([C:21]3[C:12](=[CH:13][C:14]4[O:19][CH2:18][CH2:17][O:16][C:15]=4[CH:20]=3)[O:11][CH2:10]2)[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[N:1]1[CH2:46][C:47]1[CH:48]=[CH:49][C:50]([NH:53][C:54](=[O:60])[O:55][C:56]([CH3:58])([CH3:57])[CH3:59])=[N:51][CH:52]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(CBr)cn1
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCCO3
Agent: Cc1noc2cc3c(cc12)C1(CO3)C(=O)Nc2ccccc21
Agent: FC(F)(F)c1ccc(CBr)o1
Product: CC(C)(C)OC(=O)Nc1ccc(CN2C(=O)C3(COc4cc5c(cc43)OCCO5)c3ccccc32)cn1

Procedure:
Following the procedure as described in EXAMPLE 9 and making non-critical variations using 2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one to replace 3-methylspiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1H)-one, and tert-butyl [5-(bromomethyl)pyridin-2-yl]carbamate to replace 2-(bromomethyl)-5-(trifluoromethyl)furan, tert-butyl {5-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)methyl]pyridin-2-yl}carbamate was obtained (74%) as a colorless solid: mp 238-239° C.; 1H NMR (300 MHz, DMSO-d6) δ9.81 (s, 1H), 8.30-8.27 (m, 1H), 7.79-7.73 (m, 1H), 7.73-7.66 (m, 1H), 7.31-7.24 (m, 1H), 7.20-7.14 (m, 1H), 7.12-6.99 (m, 2H), 6.52 (s, 1H), 6.06 (s, 1H), 4.89 (ABq, J=22.9, 15.5 Hz, 2H), 4.74 (ABq, J=44.4, 9.3 Hz, 2H), 4.23-4.05 (m, 4H), 1.45 (s, 9H); 13C NMR (75 MHz, DMSO-d6) δ 176.7, 154.6, 152.6, 151.8, 146.9, 144.1, 141.8, 137.8, 137.2, 131.6, 128.7, 126.2, 123.6, 123.1, 121.1, 112.2, 110.8, 109.3, 98.8, 79.5, 79.3, 64.1, 63.5, 57.2, 27.9; MS (ES+) m/z 502.1 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@@H:6]([CH:53]([CH3:55])[CH3:54])[C:7]([N:9]1[CH2:13][CH2:12][CH2:11][C@H:10]1[C:14]1[NH:15][C:16]([C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:26]=[C:27]4[C:50](=[CH:51][CH:52]=3)[C:31]3[NH:32][C:33]([C@@H:35]5[CH2:39][C@H:38]([CH2:40][O:41][CH3:42])[CH2:37][N:36]5[C:43](OC(C)(C)C)=[O:44])=[N:34][C:30]=3[CH:29]=[CH:28]4)=[CH:21][CH:20]=2)=[CH:17][N:18]=1)=[O:8])=[O:4].Cl.[CH3:57][O:58][C:59]([NH:61][C@H:62]([C:66]1[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=1)C(O)=O)=[O:60].CCOC(C(C#N)=NOC(N1CCOCC1)=[N+](C)C)=O.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl.CO.CCOC(C)=O.CN(C=O)C>[CH3:1][O:2][C:3]([NH:5][C@@H:6]([CH:53]([CH3:55])[CH3:54])[C:7]([N:9]1[CH2:13][CH2:12][CH2:11][C@H:10]1[C:14]1[NH:15][C:16]([C:19]2[CH:20]=[CH:21][C:22]([C:25]3[CH:26]=[C:27]4[C:50](=[CH:51][CH:52]=3)[C:31]3[NH:32][C:33]([C@@H:35]5[CH2:39][C@H:38]([CH2:40][O:41][CH3:42])[CH2:37][N:36]5[C:43](=[O:44])[C@H:62]([NH:61][C:59](=[O:60])[O:58][CH3:57])[C:66]5[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=5)=[N:34][C:30]=3[CH:29]=[CH:28]4)=[CH:23][CH:24]=2)=[CH:17][N:18]=1)=[O:8])=[O:4]
Reactant: COC[C@H]1C[C@@H](c2nc3ccc4cc(-c5ccc(-c6cnc([C@@H]7CCCN7C(=O)[C@@H](NC(=O)OC)C(C)C)[nH]6)cc5)ccc4c3[nH]2)N(C(=O)OC(C)(C)C)C1
Reactant: COC(=O)N[C@@H](C(=O)O)c1ccccc1
Agent: CCOC(=O)C(C#N)=NOC(N1CCOCC1)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC[C@H]1C[C@@H](c2nc3ccc4cc(-c5ccc(-c6cnc([C@@H]7CCCN7C(=O)[C@@H](NC(=O)OC)C(C)C)[nH]6)cc5)ccc4c3[nH]2)N(C(=O)[C@H](NC(=O)OC)c2ccccc2)C1
Reaction time: 1.5 h
Yield: 67.4 %

Procedure:
(2S,4S)-tert-butyl 2-(7-(4-(2-((S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)phenyl)-1H-naphtho[1,2-d]imidazol-2-yl)-4-(methoxymethyl)pyrrolidine-1-carboxylate (140 mg, 0.187 mmol) was dissolved in DCM (5 mL) and HCl (4 M in dioxane, 1 mL, 4 mmol) was added. After stirring for 1.5 h, the reaction mixture was concentrated under reduced pressure. The crude residue was treated with (R)-2-(methoxycarbonylamino)-2-phenylacetic acid (43 mg, 0.206 mmol), COMU (80 mg, 0.187 mmol), DMF (3 mL) and DIPEA (0.33 mL, 1.9 mmol). After stirring at RT for 20 min, the solution was diluted with 30 mL 10% MeOH/EtOAc. The organic layer was washed successively with saturated aqueous NaHCO3 and brine. The organics were dried over MgSO4, filtered and concentrated under reduced pressure. The resulting residue was purified by silica column chromatography to afford methyl {(1R)-2-[(2S,4S)-2-[7-(4-{2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-imidazol-5-yl}phenyl)-1H-naphtho[1,2-d]imidazol-2-yl]-4-(methoxymethyl)pyrrolidin-1-yl]-2-oxo-1-phenylethyl}carbamate (106 mg, 68%). MS (ESI) m/z 841 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][OH:6].C(=O)([O-])[O-].[Na+].[Na+].Cl[C:17]([O:19][CH2:20][CH2:21][CH2:22][Cl:23])=[O:18].O>CC(C)=O>[OH:6][CH2:5][C:4]1[CH:3]=[C:2]([NH:1][C:17](=[O:18])[O:19][CH2:20][CH2:21][CH2:22][Cl:23])[CH:9]=[CH:8][CH:7]=1
Reactant: Nc1cccc(CO)c1
Reactant: O=C(Cl)OCCCCl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: O=C(Nc1cccc(CO)c1)OCCCCl
Temperature: 25 °C
Reaction time: 18 h

Procedure:
3.7 g (30 mmol) of 3-aminobenzyl alcohol are dissolved in 50 ml of acetone, and 3.2 g (30 mmol) of sodium carbonate are added. 5.7 g (36 mmol) of 3-chloropropyl chloroformate are metered into this suspension at 25° C. The reaction mixture is stirred at room temperature for a further 18 h. Water is added to the reaction mixture for hydrolysis, and the solid is subsequently filtered off. The solution is concentrated by distillation, during which the product deposits as an oil. The product phase is separated off. The aqueous phase is extracted with ethyl acetate. The organic phases are combined, washed with water and dried over sodium sulfate. The mixture is subsequently evaporated to dryness. The crude product is reacted further directly without further purification;
Reaction SMILES: O.NN.C1(=O)[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][N:17]3C(=O)C4=CC=CC=C4C3=O)[N:11]=2)C(=O)C2=CC=CC=C12>C(O)C>[NH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][NH2:17])[N:11]=1
Reactant: O=C1c2ccccc2C(=O)N1Cc1cccc(CN2C(=O)c3ccccc3C2=O)n1
Agent: NN
Solvent: CCO
Solvent: O
Product: NCc1cccc(CN)n1

Procedure:
Hydrazine hydrate (2.4 ml, 50 mmol) was added to a solution of 2,6-bis-(phthalimidomethyl)-pyridine (1.99 g, 5.0 mmol) in 95% ethanol (50 ml). The mixture was refluxed for 3 hours. After cooling it was concentrated on a rotary evaporator and the residue was purified by chromatography on silica gel (eluent: methylene chloride/ethanol, 100/2) to give 2,6-bis-(aminomethyl)-pyridine in the form of a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[C:10]([O:12][CH3:13])[CH:11]=1)[C:8](=[O:14])[CH2:7][CH2:6]2.[Br:15]N1C(=O)CCC1=O.C(Cl)(Cl)Cl>ClCCl>[Br:15][C:4]1[C:3]([O:2][CH3:1])=[CH:11][C:10]([O:12][CH3:13])=[C:9]2[C:5]=1[CH2:6][CH2:7][C:8]2=[O:14]
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1cc2c(c(OC)c1)C(=O)CC2
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: COc1cc(OC)c2c(c1Br)CCC2=O
Yield: 86.4 %

Procedure:
845 mg of 5,7-dimethoxyindan-1-one was dissolved in 40 ml of dichloromethane. Thereafter, 822 mg of N-bromosuccinimide was added to the reaction solution. After completion of the reaction, chloroform was added to the reaction solution. The organic layer was washed with a saturated sodium chloride solution and then dried over anhydrous magnesium sulfate. After removing the drying agent by filtration, the organic layer was concentrated under a reduced pressure. The residue was suspended in acetone, and the suspension was filtered, so as to obtain 1.03 g of 4-bromo-5,7-dimethoxyindan-1-one. The obtained product was suspended in a mixed solution consisting of 30 ml of methanol, 10 ml of tetrahydrofuran, and 20 ml of chloroform. Thereafter, 952 mg of methoxylamine hydrochloride and 935 mg of sodium acetate were added to the reaction solution, and the obtained mixture was stirred at room temperature. Approximately 4 hours later, 952 mg of methoxylamine hydrochloride and 935 mg of sodium acetate were further added to the reaction solution. After completion of the reaction, the reaction solution was concentrated. A saturated sodium bicarbonate aqueous solution and ethyl acetate were added to the resultant product, so as to separate an organic layer. The organic layer was washed with a saturated sodium bicarbonate aqueous solution and a saturated sodium chloride solution, and then dried over anhydrous magnesium sulfate. After removing the drying agent by filtration, the organic layer was concentrated under a reduced pressure. The residue was suspended in t-butyl methyl ether, and the suspension was filtered, so as to obtain 896 mg of the subject compound.
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[CH2:3][CH2:4][CH:5]=[O:6].[Br:9]Br>C(OCC)C>[Br:9][CH:4]([CH2:3][C:2]([F:8])([F:7])[F:1])[CH:5]=[O:6]
Reactant: O=CCCC(F)(F)F
Reactant: BrBr
Solvent: CCOCC
Product: O=CC(Br)CC(F)(F)F
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 90.9 %

Procedure:
A 200 mL round bottom flask was charged with 4,4,4-trifluorobutanal (5 g, 39.7 mmol) and diluted with diethyl ether (79 mL). The flask was placed in an ice bath and the reaction mixture was cooled to 0° C. Bromine (2.043 mL, 39.7 mmol) was then added drop wise over the course of 15 min. After which the reaction was stirred for 15 min and then let warm to rt. After 3.5 hours, NMR showed complete consumption of the starting material to desired product. The mixture was cooled in an ice bath and slowly quenched with sat'd sodium bicarbonate. The contents of the flask were transferred to a separatory funnel where the layers were separated and the organics were washed with bicarbonate, brine, and dried with magnesium sulfate. A short path distillation apparatus was equipped to the flask and the combination was placed in an oil bath set to 40° C. After 15 min, the flask was removed from the oil bath and the crude residue was distilled at moderate vacuum (˜50 torr) to remove any lower boiling point impurities as well as excess diethyl ether. The atmosphere was restored to normal once bubbling had subsided for 5 min. This process was repeated a few times to remove the majority of diethyl ether. 1H NMR consistent with desired. 2-bromo-4,4,4-trifluorobutanal (7.4 g, 91% yield). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 9.54-9.36 (m, 1H), 4.52-4.46 (m, 1H), 3.21 (dqd, J=16.0, 10.1, 5.8 Hz, 1H), 2.73-2.62 (m, 1H).
Reaction SMILES: Cl.O1CCOCC1.C(OC([NH:15][C:16]1[CH:21]=[CH:20][C:19]([C@H:22]2[C@@H:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:26][CH2:25][CH2:24][N:23]2[C:33](=[O:42])[C:34]2[C:39]([CH3:40])=[CH:38][CH:37]=[CH:36][C:35]=2[F:41])=[CH:18][CH:17]=1)=O)(C)(C)C.C([O-])(O)=O.[Na+]>C(Cl)Cl.C(OCC)(=O)C>[NH2:15][C:16]1[CH:21]=[CH:20][C:19]([C@H:22]2[C@@H:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:26][CH2:25][CH2:24][N:23]2[C:33](=[O:42])[C:34]2[C:39]([CH3:40])=[CH:38][CH:37]=[CH:36][C:35]=2[F:41])=[CH:18][CH:17]=1
Reactant: CCOC(=O)[C@H]1CCCN(C(=O)c2c(C)cccc2F)[C@H]1c1ccc(NC(=O)OC(C)(C)C)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: ClCCl
Product: CCOC(=O)[C@H]1CCCN(C(=O)c2c(C)cccc2F)[C@H]1c1ccc(N)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 99.1 %

Procedure:
Step b) 4 N HCl in 1,4-dioxane (110 mL, 440 mmol) was slowly added to a solution of the above ethyl (2R,3S)-2-[4-(tert-butoxycarbonylamino)phenyl]-1-(2-fluoro-6-methylbenzoyl)piperidine-3-carboxylate (19 g, 39.36 mmol) in dry CH2Cl2 (110 mL) at 0° C. After the addition of HCl, the reaction mixture was allowed to attain rt and stirred for 3 h. The solution was then diluted with ethyl acetate (200 mL), cooled to 0° C., and neutralized with saturated aqueous NaHCO3 to get ethyl (2R,3S)-2-(4-aminophenyl)-1-(2-fluoro-6-methylbenzoyl)piperidine-3-carboxylate (15 g, 100%). MS: (ES) m/z 385 (M+H+).