Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:24]=[CH:25][C:26]=1[O:27][CH3:28])[CH2:6][NH:7][C:8](=[O:23])[C:9]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:10]=1[NH:18][C@H:19]([CH3:22])[CH2:20][OH:21].F[B-](F)(F)F.[CH3:34][O+](C)C.C(C1C=C(C)C=C(C(C)(C)C)N=1)(C)(C)C>ClCCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:24]=[CH:25][C:26]=1[O:27][CH3:28])[CH2:6][NH:7][C:8](=[O:23])[C:9]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:10]=1[NH:18][C@H:19]([CH3:22])[CH2:20][O:21][CH3:34]
Reactant: C[O+](C)C
Reactant: COc1ccc(CNC(=O)c2cc([N+](=O)[O-])ccc2N[C@H](C)CO)cc1OC
Agent: Cc1cc(C(C)(C)C)nc(C(C)(C)C)c1
Agent: F[B-](F)(F)F
Solvent: ClCCCl
Product: COC[C@@H](C)Nc1ccc([N+](=O)[O-])cc1C(=O)NCc1ccc(OC)c(OC)c1
Yield: 70 %

Procedure:
To a solution of (R)-N-(3,4-dimethoxybenzyl)-2-(2-hydroxy-1-methylethylamino)-5-nitrobenzamide (200 mg) in 1,2-dichloroethane (10 mL) were added trimethyloxonium tetrafluoroborate (91.2 mg) and 2,6-di-tert-butyl-4-methylpyridine (158 mg), and the mixture was heated for 3 hours under reflux. The mixture was washed with 1N-hydrochloric acid, water, an aqueous saturated sodium bicarbonate solution and brine. Then, the resultant was dried over magnesium sulfate and evaporated in vacuo. The residue was purified by a silica gel column chromatography eluting with a mixture of hexane and ethyl acetate (3:1 to 1:1). The obtained product was triturated with diisopropyl ether to give (R)-N-(3,4-dimethoxybenzyl)-2-(2-methoxy-1-methylethylamino)-5-nitrobenzamide as yellow powders (145 mg).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH2:5][CH:6]([C:15]([O:17]CC1C=CC=CC=1)=[O:16])[CH2:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH3:2].C>C(O)C.[Pd]>[CH2:1]([O:3][C:4](=[O:25])[CH2:5][CH:6]([C:15]([OH:17])=[O:16])[CH2:7][C:8]([O:10][C:11]([CH3:13])([CH3:14])[CH3:12])=[O:9])[CH3:2]
Reactant: CCOC(=O)CC(CC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CC(CC(=O)OC(C)(C)C)C(=O)O
Reaction time: 24 h

Procedure:
A solution of the compound of example 69 (2.29 g, 6.54 mmol) in ethanol (95%, 500 mL) was hydrogenated in the presence of a catalytic amount of palladium (10% on (charcoal). After 24 h of stirring, the reaction was complete. The mixture was filtered over a celite pad and the solvent evaporated. The residue was distributed between ethyl acetate and water. The aqueous phase was extracted twice more with ethyl acetate. The recombined organic layer was washed with brine, dried over sodium sulfate, filtered, and evaporated. The product was sufficiently pure on the basis of its 1H-NMR spectrum to be used in the next step. 1H-NMR(CDCl3, 400 MHz: 1.23(t, J=7.1, 3H); 1.41(s, 9H); 2.53-2.81(m, 4H); 3.25(m, 1H); 4.13(m, 2H).
Reaction SMILES: C([NH:8][C@H:9]([C:17]([NH:19][C:20]1[N:21]([CH3:25])[CH:22]=[CH:23][N:24]=1)=[O:18])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(OC(C)(C)C)=O.[ClH:26]>>[ClH:26].[ClH:26].[CH3:25][N:21]1[CH:22]=[CH:23][N:24]=[C:20]1[NH:19][C:17](=[O:18])[C@H:9]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[NH2:8]
Reactant: Cn1ccnc1NC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Agent: Cl
Product: Cn1ccnc1NC(=O)[C@@H](N)Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66.3 %

Procedure:
2-(N-Boc-phenylalanyl)amino-1-methylimidazole (0.3 g) was dissolved in conc. hydrochloric acid (10 ml), and the solution was stirred at room temperature for 30 minutes. The solvent was evaporated, and the precipitated colorless powder was separated by filtration using diethyl ether to give the title compound (0.23 g, 66.3%).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[CH2:9][C@@H:8]([CH2:10][O:11][C:12](=[O:14])[CH3:13])[O:7][C@H:6]1[N:15]1[C:24]2[N:23]=[CH:22][N:21]=[C:19](O)[C:18]=2[N:17]=[CH:16]1)(=[O:3])[CH3:2].CN(C)C=O.S(Cl)([Cl:32])=O.O>C(Cl)Cl>[Cl:32][C:19]1[N:21]=[CH:22][N:23]=[C:24]2[C:18]=1[N:17]=[CH:16][N:15]2[C@@H:6]1[O:7][C@H:8]([CH2:10][O:11][C:12](=[O:14])[CH3:13])[CH2:9][C@H:5]1[O:4][C:1](=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@@H]1C[C@@H](OC(C)=O)[C@H](n2cnc3c(O)ncnc32)O1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O
Product: CC(=O)OC[C@@H]1C[C@@H](OC(C)=O)[C@H](n2cnc3c(Cl)ncnc32)O1
Temperature: 0 °C
Yield: 89.9 %

Procedure:
32.7 g (97.2 mmols) of 2′,5′-di-O-acetyl-3′-deoxyinosine was suspended in 449 ml of methylene chloride in a 1-liter reactor, to which were added 30.1 ml (389 mmols) of dimethylformamide and 28.0 ml (389 mmols) of thionyl chloride, and reacted for about 7 hours while heating under reflux. The reaction mixture was cooled to 0° C., and then dropwise added to 500 ml of water that had been cooled at 0° C. to stop the reaction. The reaction mixture was separated into layers, and the organic layer was taken out, and washed with water, an aqueous saturated solution of sodium hydrogencarbonate and a saturated saline solution in that order. The solvent was evaporated, and 31.0 g of an oily product was obtained. This crude product was directly subjected to the next reaction.
Reaction SMILES: O[CH:2]([C:12]1[CH:17]=[CH:16][C:15]([S:18][CH3:19])=[CH:14][CH:13]=1)[CH:3]([NH:6][C:7]([O:9]CC)=[O:8])CO.[K].C([O-])(=[O:25])CCC>C1(C)C=CC=CC=1>[CH3:19][S:18][C:15]1[CH:14]=[CH:13][C:12]([CH:2]2[O:9][C:7](=[O:8])[NH:6][CH:3]2[OH:25])=[CH:17][CH:16]=1
Reactant: CCOC(=O)NC(CO)C(O)c1ccc(SC)cc1
Reactant: CCCC(=O)[O-]
Agent: [K]
Solvent: Cc1ccccc1
Product: CSc1ccc(C2OC(=O)NC2O)cc1

Procedure:
Compound (F) (5 g; 17.5 mmols) has been dissolved in warm toluene (25 ml). To this solution, an equimolar amount of potassium ter.butyrate has been added and the reaction mixture has been refluxed for 3 hours. Afterwards, almost all the solvent has been evaporated; water and ice have been added to the residue and the precipitate has been collected by filtration. The thus obtained crude (G) has been recrystallized from ethanol (3.7 g; yield, 88%); m.p. 130°-131° C.
Reaction SMILES: C1C=CC2N(O)N=NC=2C=1.C(N=C=NCCCN(C)C)C.[NH2:22][CH2:23][C:24]1[N:29]=[C:28]2[S:30][C:31]3[CH2:32][N:33]([CH2:37][C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)[CH2:34][CH2:35][C:36]=3[C:27]2=[C:26]([C:44]2[CH:49]=[CH:48][C:47]([O:50][CH3:51])=[C:46]([O:52][CH3:53])[CH:45]=2)[C:25]=1[Cl:54].[N:55]1([CH2:60][C:61](O)=[O:62])[CH:59]=[N:58][CH:57]=[N:56]1>O.CN(C)C=O>[CH2:37]([N:33]1[CH2:34][CH2:35][C:36]2[C:27]3[C:28]([S:30][C:31]=2[CH2:32]1)=[N:29][C:24]([CH2:23][NH:22][C:61](=[O:62])[CH2:60][N:55]1[CH:59]=[N:58][CH:57]=[N:56]1)=[C:25]([Cl:54])[C:26]=3[C:44]1[CH:49]=[CH:48][C:47]([O:50][CH3:51])=[C:46]([O:52][CH3:53])[CH:45]=1)[C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1
Reactant: COc1ccc(-c2c(Cl)c(CN)nc3sc4c(c23)CCN(Cc2ccccc2)C4)cc1OC
Reactant: O=C(O)Cn1cncn1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(-c2c(Cl)c(CNC(=O)Cn3cncn3)nc3sc4c(c23)CCN(Cc2ccccc2)C4)cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 44.8 %

Procedure:
N-hydroxybenotriazole (HOBt) (0.427 g) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (WSC) (0.535 g) were added to an ice-cooled mixture of the compound (1.0 g) obtained in Example 18B, (1,2,4-triazol-1-yl)acetic acid (0.325 g) and N,N-dimethylformamide (DMF) (20 ml), the mixture was stirred at room temperature for 8 hours, poured over water and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4) and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-methanol (20:1, v/v) to yield 7-benzyl-3-chloro-4-(3,4-dimethoxyphenyl)-5,6,7,8-tetrahydro-2-(1,2,4-triazol-1-ylacetylaminomethyl)thieno[2,3-b:5,4-c']dipyridine (0.55 g, 50%), which was then recrystallized from ethyl acetate-hexane to yield a colorless powder having a melting point of 101 to 102° C.
Reaction SMILES: C(NC1C=CC([NH:11][C:12]2[C:20]([S:21](=[O:34])(=[O:33])[NH:22][C:23]3[CH:28]=[CH:27][C:26]([NH:29]C(=O)C)=[CH:25][CH:24]=3)=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][C:13]=2[NH:35][CH2:36][CH:37]=[CH:38][CH3:39])=CC=1)(=O)C.[OH-].[Na+]>>[NH2:11][C:12]1[C:20]([S:21](=[O:34])(=[O:33])[NH:22][C:23]2[CH:28]=[CH:27][C:26]([NH2:29])=[CH:25][CH:24]=2)=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[C:14]([NH:11][C:12]2[CH:20]=[CH:19][CH:15]=[CH:14][CH:13]=2)[C:13]=1[NH:35][CH2:36][CH:37]=[CH:38][CH3:39]
Reactant: CC=CCNc1cc(C(=O)O)cc(S(=O)(=O)Nc2ccc(NC(C)=O)cc2)c1Nc1ccc(NC(C)=O)cc1
Agent: [Na+]
Agent: [OH-]
Product: CC=CCNc1c(N)c(S(=O)(=O)Nc2ccc(N)cc2)cc(C(=O)O)c1Nc1ccccc1
Temperature: 25 °C

Procedure:
The mixture of 1.3 g of 4-(4-acetamidophenylamino)-3-but-2-enylamino-5-(4-acetamidophenylsulfamoyl)-benzoic acid and 13 ml of 2 N aqueous sodium hydroxide is refluxed for 1 hour under nitrogen. After cooling to room temperature it is filtered, the filtrate acidified with glacial acetic acid to a pH of 4-5 and the precipitate formed filtered off and washed with water, to yield the 4-(4-aminophenylamino-3-but-2-enylamino-5-(4-aminophenylsulfamoyl)-benzoic acid melting at about 130°.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][C:13]2[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][CH:14]=2)[CH:6]=[CH:7][C:8]=1[O:9]C.Br>>[OH:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][C:13]2[CH:14]=[CH:15][C:16]([NH2:17])=[CH:18][CH:19]=2)[CH:6]=[CH:7][C:8]=1[OH:9]
Reactant: COc1ccc(CCc2ccc(N)cc2)cc1OC
Agent: Br
Product: Nc1ccc(CCc2ccc(O)c(O)c2)cc1
Temperature: 25 °C

Procedure:
A mixture of 20 g (78 mmol) of 4-[2-[3,4-dimethoxyphenyl)ethyl]aniline which is prepared in Preparation 1 above and 300 ml of of 48% hydrobromic acid is stirred at reflux under nitrogen for seven hours and at room temperature overnight. The resultant precipitate is collected, washed withether, and redissolved in 1N.NaOH. The solution is acidified to pH 6 with glacial HOAc and the resultant precipitate is collected as crude product. Recrystallization from H2O and then from MeOH yields the 4-[2-(3,4-dihydroxyphenyl)ethyl]benzenamine as an acetate salt; yield, 13.4 g (76%), mp 216°-218° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:12])=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6](O)=[O:7].C1C=CC2N(O)N=[N:19]C=2C=1.N>C(Cl)Cl.CN(C=O)C>[CH3:1][O:2][C:3]1[C:4]([CH3:12])=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([NH2:19])=[O:7]
Reactant: On1nnc2ccccc21
Reactant: COc1cccc(C(=O)O)c1C
Agent: N
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1cccc(C(N)=O)c1C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 58.5 %

Procedure:
3-Methoxy-2-methylbenzoic acid (5.0 g, 30 mmol) in CH2Cl2 (90 ml) and DMF (90 ml) was treated with HOBt (4.06 g, 30 mmol) and WSCDI (5.75 g, 30 mmol) and the resulting mixture stirred at RT for 20 min. After cooling to 0° C. ammonia (2H in EtOH, 30 ml, 60 mmol) was added and the mixture stirred for a further 2 h. The mixture was filtered, the solvent was removed from the filtrate. The crude material was taken up in CH2Cl2 and washed with water and brine and dried (Na2SO4), which gave a white solid (2.9 g) on isolation.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:32])[C@H:4]([CH:29]([CH3:31])[CH3:30])[NH:5][C:6](=[O:28])[C@H:7]([CH:25]([CH3:27])[CH3:26])[NH:8][C:9](=[O:24])[C@H:10]([CH2:19][O:20][CH2:21][CH:22]=[CH2:23])[NH:11]C(OC(C)(C)C)=O>C(O)=O>[CH3:1][O:2][C:3](=[O:32])[C@H:4]([CH:29]([CH3:31])[CH3:30])[NH:5][C:6](=[O:28])[C@H:7]([CH:25]([CH3:27])[CH3:26])[NH:8][C:9](=[O:24])[C@H:10]([CH2:19][O:20][CH2:21][CH:22]=[CH2:23])[NH2:11]
Reactant: C=CCOC[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@H](C(=O)N[C@H](C(=O)OC)C(C)C)C(C)C
Solvent: O=CO
Product: C=CCOC[C@H](N)C(=O)N[C@H](C(=O)N[C@H](C(=O)OC)C(C)C)C(C)C
Yield: 81.7 %

Procedure:
N-tert-butoxycarbonyl O-allyl L-seryl L-valyl L-valine methyl ester (8) (6.80 g, 14.9 mmol) was stirred in formic acid (70 mL) at room temperature for 9 hours and the formic acid evaporated. The residue was diluted with 110 mL water and the aqueous solution washed with Et2O (3×30 mL). The pH was adjusted to pH 9 by addition of solid K2CO3 and the resulting solution extracted with EtOAc (3×55 mL). The combined organic extracts were washed with saturated brine (30 mL) and dried with anhydrous MgSO4. The solvent was evaporated affording a white solid (4.35 g, 82%); δH (200 MHz; do-DMSO) 8.26 (1H, d, J 8, NH(Valx)), 8.03 (1H, d, J 9, NH(Valy)), 5.85 (1H, ddt, J 5, 10 and 17, CH═CH2)), 5.24 (1H, ddt, J 1, 3 and 17, CH═CHH), 5.12 (1H, ddt, J 1, 3 and 10, CH═CHH), 4.36 (1H, dd, J 6 and 9, CαH(Valy)), 4.12 (1H, dd, J 6 and 8, CαH(Valx)), 3.93 (2H, dt, J 1 and 5, CH2CH═CH2), 3.61 (3H, s, OCH3), 3.49 (2H, d, J 5, CH2,), 3.43-3.39 (1H, m, CαH(Ser(All))), 2.38 (2H, br s, NH2), 2.12-1.86 (2H, m, CH(CH3)2), 0.91-0.78 (12H, m, CH3)
Reaction SMILES: [Cl-].[CH:2]1([S:5]([NH:8][C:9]([C@@:11]2([NH3+:16])[CH2:13][C@H:12]2[CH:14]=[CH2:15])=[O:10])(=[O:7])=[O:6])[CH2:4][CH2:3]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:41]([C@@H:45]1[NH:69][CH2:68][CH2:67][CH2:66][CH2:65][CH2:64][CH2:63][C:62]2[CH:70]=[C:58]([CH:59]=[CH:60][CH:61]=2)[C:57]2=[CH:71][C:53](=[CH:54][CH:55]=[CH:56]2)[CH2:52][O:51][C@H:50]2[CH2:72][N:47]([C@H:48]([C:73](O)=[O:74])[CH2:49]2)[C:46]1=[O:76])([CH3:44])([CH3:43])[CH3:42].CCN(C(C)C)C(C)C>CN(C=O)C>[C:41]([C@@H:45]1[NH:69][CH2:68][CH2:67][CH2:66][CH2:65][CH2:64][CH2:63][C:62]2[CH:70]=[C:58]([CH:59]=[CH:60][CH:61]=2)[C:57]2=[CH:71][C:53](=[CH:54][CH:55]=[CH:56]2)[CH2:52][O:51][C@H:50]2[CH2:72][N:47]([C@H:48]([C:73]([NH:16][C@:11]3([C:9]([NH:8][S:5]([CH:2]4[CH2:4][CH2:3]4)(=[O:7])=[O:6])=[O:10])[CH2:13][C@H:12]3[CH:14]=[CH2:15])=[O:74])[CH2:49]2)[C:46]1=[O:76])([CH3:44])([CH3:42])[CH3:43]
Reactant: C=C[C@@H]1C[C@]1([NH3+])C(=O)NS(=O)(=O)C1CC1
Reactant: CC(C)(C)[C@@H]1NCCCCCCc2cccc(c2)-c2cccc(c2)CO[C@@H]2C[C@@H](C(=O)O)N(C2)C1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@H]2CN1C(=O)[C@H](C(C)(C)C)NCCCCCCc1cccc(c1)-c1cccc(c1)CO2)C(=O)NS(=O)(=O)C1CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(1R,2S)-1-{[(cyclopropylsulfonyl)amino]carbonyl}-2-vinylcyclopropanaminium chloride 48 (prepared as described in WO 03/099274) (1.2 eq.) and HATU (1.2 eq.) were added to a 0.1M solution of (9R,11S,14S)-14-tert-butyl-13-oxo-8-oxa-12,15-diazatetracyclo[20.3.1.12,6.19,12]octacosa-1(26),2(28),3,5,22,24-hexaene-11-carboxylic acid 105 in DMF containing DIPEA (4.0 eq.). The reaction mixture was stirred at RT overnight. The reaction mixture was concentrated to dryness, dissolved in DMSO and purified by RP-HPLC (stationary phase: column WATERS XTERRA C18, 5 μm, 19×150. Mobile phase: MeCN/H2O buffered with 0.1% TFA from 30% to 90% of MeCN in 14 minutes, run time 18 minutes). Fractions containing the pure compound were combined and freeze dried to afford compound 142 (TFA salt) as an off white solid (30% over 4 steps). 1H NMR (400 MHz, DMSO-d6, 300 K) δ 10.65 (s, 1H), 8.89 (s, 1H), 8.65-8.49 (bs, 1H), 8.25-8.11 (bs, 1H), 7.62-7.56 (m, 2H), 7.51-7.38 (m, 4H), 7.31 (d, J 7.3, 1H), 7.24 (d, J 7.3, 1H), 5.69-5.53 (m, 1H), 5.24 (d, J 17.2, 1H), 5.14 (d, J 11.9, 1H), 4.71 (d, J 12.4, 1H), 4.61 (d, J 12.4, 1H), 4.31 (bt, 1H), 4.37 (bs, 1H), 4.16 (d, J 8.8, 1H), 4.04 (d, J 11.9, 1H), 3.79 (dd, J 11.5, 3.9, 1H), 3.00-2.91 (m, 1H), 2.91-2.81 (m, 1H), 2.80-2.68 (m, 2H), 2.22 (q, J 17.5, 8.8, 1H), 2.02-1.91 (m, 1H), 1.83-1.69 (m, 2H), 1.68-1.56 (m, 2H), 1.41-1.24 (m, 5H), 1.22-1.02 (m, 13H), 0.91 (t, J 7.3, 4H). MS (ES+) m/z 705 (M+H)+.
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:7]([N:35]2[CH2:47][CH2:46][N:38]3[C:39]4[CH2:40][CH2:41][CH2:42][CH2:43][C:44]=4[CH:45]=[C:37]3[C:36]2=[O:48])=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)=[O:26])=[CH:21][N:20]=2)[C:15](=[O:33])[N:14]([CH3:34])[N:13]=1)(=O)C>C(O)(C)C.C1COCC1.O>[OH:4][CH2:5][C:6]1[C:7]([N:35]2[CH2:47][CH2:46][N:38]3[C:39]4[CH2:40][CH2:41][CH2:42][CH2:43][C:44]=4[CH:45]=[C:37]3[C:36]2=[O:48])=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)=[O:26])=[CH:21][N:20]=2)[C:15](=[O:33])[N:14]([CH3:34])[N:13]=1
Reactant: CC(=O)OCc1c(-c2cc(Nc3ccc(C(=O)N4CCOCC4)cn3)c(=O)n(C)n2)ccnc1N1CCn2c(cc3c2CCCC3)C1=O
Solvent: O
Solvent: C1CCOC1
Solvent: CC(C)O
Product: Cn1nc(-c2ccnc(N3CCn4c(cc5c4CCCC5)C3=O)c2CO)cc(Nc2ccc(C(=O)N3CCOCC3)cn2)c1=O
Temperature: 35 °C
Reaction time: 0.5 h
Yield: 61.4 %

Procedure:
A mixture of 227a (131 mg, 0.20 mmol) and lithium hydroxide·1 water (120 mg, 2.0 mmol) in i-propanol/THF/water (4 mL/4 mL/2 mL) was stirred at 35° C. for 0.5 h. The mixture was evaporated in vacuo and the residue was extracted with dichloromethane (3×10 mL). The combined dichloromethane extract was concentrated under reduced pressure and the residue was purified by reverse-phase prep-HPLC to afford 227 as a white solid (75 mg, 62%). MS-ESI: [M+H]+ 611.2. 1H NMR (500 MHz, DMSO-d6) δ 9.75 (s, 1H), 8.64 (s, 1H), 8.54 (d, J=5.0 Hz, 1H), 8.36 (d, J=2.0 Hz, 1H), 7.79-7.77 (m, 1H), 7.59 (d, J=8.5 Hz, 1H), 7.43 (d, J=5.0 Hz, 1H), 6.58 (s, 1H), 4.82 (s, 1H), 4.60-4.57 (m, 1H), 4.38-4.36 (m, 1H), 4.29-4.19 (m, 2H), 4.10-4.05 (m, 1H), 3.93-3.90 (m, 1H), 3.80 (s, 3H), 3.60-3.50 (m, overlap, 8H), 2.66-2.54 (m, 2H), 2.48-2.46 (m, 2H), 1.81-1.66 (m, 4H).
Reaction SMILES: [C:1]([NH:8][C@@H:9]([CH2:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[CH:29][CH:28]=1)[C@@H:10]([OH:25])[CH2:11][C@@H:12]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1)[C:13]([OH:15])=[O:14])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[C:41]([Si:45]([CH3:48])([CH3:47])Cl)([CH3:44])([CH3:43])[CH3:42].N1C=CN=C1>CN(C=O)C.C(OCC)(=O)C>[C:1]([NH:8][C@@H:9]([CH2:26][C:27]1[CH:28]=[CH:29][C:30]([O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[CH:31][CH:32]=1)[C@@H:10]([O:25][Si:45]([C:41]([CH3:44])([CH3:43])[CH3:42])([CH3:48])[CH3:47])[CH2:11][C@@H:12]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1)[C:13]([OH:15])=[O:14])([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: COc1ccc(C[C@H](C[C@H](O)[C@H](Cc2ccc(OCc3ccccc3)cc2)NC(=O)OC(C)(C)C)C(=O)O)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(C[C@H](C[C@H](O[Si](C)(C)C(C)(C)C)[C@H](Cc2ccc(OCc3ccccc3)cc2)NC(=O)OC(C)(C)C)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2.5 g (4.54 mmol) of 5(S)-(Boc-amino)-4(S)-hydroxy-6-(p-benzyloxy-phenyl)-2(R)-[(p-methoxyphenyl)methyl]hexanoic acid in 42 ml of DMF are silylated, under a protective gas, with 3.15 g (20.9 mmol) of tert-butyldimethylchlorosilane and 2.53 g (37.3 mmol) of imidazole at RT for 20 h. The reaction mixture is diluted with ethyl acetate, and this mixture is washed with sat. NaHCO3 solution, water and saline. The aqueous phases are exitacted 2× with ethyl acetate, and the organic phases are dried with Na2SO4 and evaporated. The residue is dissolved in 50 ml of methanol and 13 ml of THF, and this solution is treated with 3.8 g of potassium carbonate and 13 ml of water, and stirred at RT for 1 h. Subsequently, the reaction mixture is partially evaporated and the residue is diluted with ice-cold 10% citric acid solution; this mixture is then extracted 3× with ethyl acetate. The organic phases are washed with 2 portions of water and saline, dried with Na2SO4 and evaporated. Column chromatography (SiO2, hexane/ethyl acetate, 2:1) results in the pure title compound: TLC Rf (C)=0,13; tRet (II)=21.7 min.
Reaction SMILES: BrC[CH2:3][C:4]1[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[C:5]=1[C:6]([O:8][CH3:9])=[O:7].[OH:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:18][CH:17]=1>>[CH3:14][C:10]1[C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([CH:13]=[CH:12][CH:11]=1)[CH2:3][O:15][C:16]1[CH:17]=[CH:18][C:19]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:20][CH:21]=1
Reactant: CCOC(=O)Cc1ccc(O)cc1
Reactant: COC(=O)c1c(C)cccc1CCBr
Product: CCOC(=O)Cc1ccc(OCc2cccc(C)c2C(=O)OC)cc1

Procedure:
Reaction of methyl 2-bromoethyl-6-methylbenzoate with ethyl p-hydroxyphenylacetate as described in Example 1b provides ethyl 4-(3-methyl-2-methoxycarbonylbenzyloxy)phenylacetate as an oil.
Reaction SMILES: [CH2:1]([N:4]1[CH:16]=[C:15]2[C:6]([C:7](=[O:17])[NH:8][C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=32)=[N:5]1)[CH2:2][CH3:3].CN(C)CCN(C)C.C([Li])CCC.[C:31](=[O:33])=[O:32]>CCCCCC.O.C(OCC)C.O1CCCC1>[O:17]=[C:7]1[C:6]2=[N:5][N:4]([CH2:1][CH2:2][CH3:3])[C:16]([C:31]([OH:33])=[O:32])=[C:15]2[C:14]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[NH:8]1
Reactant: CCCn1cc2c(n1)c(=O)[nH]c1ccccc12
Reactant: O=C=O
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: O
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCCn1nc2c(=O)[nH]c3ccccc3c2c1C(=O)O
Temperature: 5 °C
Reaction time: 0.33 h
Yield: 56.3 %

Procedure:
A 12 L reaction vessel was charged with 2-propyl-2,5-dihydro-4H-pyrazolo[3,4-c]quinolin-4-one (103.40 g, 455 mmol), tetrahydrofuran (THF, 6.1 L), and N,N,N′,N′-tetramethylethylenediamine (392 mL, 2.59 mol), and the resulting suspension was cooled in an ice bath. n-Butyllithium (510 mL of a 2.5 M solution in hexane, 1.27 mol) was added over 65 minutes, and the reaction was allowed to stir at 5° C. for 20 minutes. The contents of the 12 L vessel were transferred via cannula over a period of 20 minutes to a 22 L vessel containing dry ice (3 kg) and diethyl ether (2 L). The reaction was stirred overnight, water (3 L) was added, the organic layer was drawn off, and the aqueous layer was washed with chloroform (4×500 mL). The aqueous layer was acidified by treatment with 2 M HCl (1.6 L), and the resulting suspension was stirred overnight. The solid was collected by filtration and dried on suction for 2 days to afford 69.47 g of 4-oxo-2-propyl-4,5-dihydro-2H-pyrazolo[3,4-c]quinoline-1-carboxylic acid as an off-white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:14]=[C:13]([C@H:15]3[CH2:20][CH2:19][CH2:18][CH2:17][N:16]3[C:21](=[O:30])[CH2:22][O:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[O:12][N:11]=2)=[CH:6][CH:5]=1)([O-])=O.[NH4+].[Cl-]>CO.[Zn]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[N:14]=[C:13]([C@H:15]3[CH2:20][CH2:19][CH2:18][CH2:17][N:16]3[C:21](=[O:30])[CH2:22][O:23][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[O:12][N:11]=2)=[CH:8][CH:9]=1
Reactant: O=C(COc1ccccc1)N1CCCC[C@@H]1c1nc(-c2ccc([N+](=O)[O-])cc2)no1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Product: Nc1ccc(-c2noc([C@H]3CCCCN3C(=O)COc3ccccc3)n2)cc1
Reaction time: 0.5 h

Procedure:
(R)-1-{2-[3-(4-Nitro-phenyl)-[1,2,4]oxadiazol-5-yl]-piperidin-1-yl}-2-phenoxy-ethanone were dissolved in 100 ml MeOH. 50 ml sat. NH4Cl and Zn-powder were added. The suspension was briefly heated to reflux and stirred for 30 min. After filtration the MeOH was evaporated and the product isolated via extraction ethylacetate/water.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[NH2:6].[N:7]1([C:12](N2C=CN=C2)=[S:13])[CH:11]=[CH:10][N:9]=[CH:8]1>C(#N)C.O1CCCC1>[S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[NH:6][C:12]([N:7]1[CH:11]=[CH:10][N:9]=[CH:8]1)=[S:13]
Reactant: Nc1nccs1
Reactant: S=C(n1ccnc1)n1ccnc1
Solvent: CC#N
Solvent: C1CCOC1
Product: S=C(Nc1nccs1)n1ccnc1
Temperature: 60 °C
Reaction time: 5 h
Yield: 83.1 %

Procedure:
To thiazol-2-amine (2.12 g, 21.17 mmol) in acetonitrile (30 mL) and tetrahydrofuran (5 mL) was added di(1H-imidazol-1-yl)methanethione (4.90 g, 27.5 mmol). The reaction was stirred at 60° C. for 5 hours. The reaction was cooled to room temperature and the precipitate was filtered and washed with cold acetonitrile (2×15 mL) to afford an orange-brown powder. The product, N-(thiazol-2-yl)-1H-imidazole-1-carbothioamide (3.70 g, 17.60 mmol, 83% yield), was taken directly to the next step without any further characterization.