Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]([CH3:62])[C@H:9]([C:13]([NH:15][C@H:16]([C:20]([N:22]([C@@H:24]([C@@H:58]([CH3:61])[CH2:59][CH3:60])[C@H:25]([O:56][CH3:57])[CH2:26][C:27]([N:29]1[CH2:33][CH2:32][CH2:31][C@H:30]1[C@H:34]([O:54][CH3:55])[C@@H:35]([CH3:53])[C:36]([NH:38][C@@H:39]([CH2:43][C:44]1[C:52]2[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=2)[NH:46][CH:45]=1)[C:40]([NH2:42])=[O:41])=[O:37])=[O:28])[CH3:23])=[O:21])[CH:17]([CH3:19])[CH3:18])=[O:14])[CH:10]([CH3:12])[CH3:11].C(=O)([O-])O.[Na+].[O:68]=[C:69]1[CH:73]=[CH:72][C:71](=[O:74])N1C(OC)=O>O1CCOCC1>[O:68]=[C:69]1[CH:73]=[CH:72][C:71](=[O:74])[N:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]([CH3:62])[C@H:9]([C:13]([NH:15][C@H:16]([C:20]([N:22]([C@@H:24]([C@@H:58]([CH3:61])[CH2:59][CH3:60])[C@H:25]([O:56][CH3:57])[CH2:26][C:27]([N:29]1[CH2:33][CH2:32][CH2:31][C@H:30]1[C@H:34]([O:54][CH3:55])[C@@H:35]([CH3:53])[C:36]([NH:38][C@@H:39]([CH2:43][C:44]1[C:52]2[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=2)[NH:46][CH:45]=1)[C:40]([NH2:42])=[O:41])=[O:37])=[O:28])[CH3:23])=[O:21])[CH:17]([CH3:18])[CH3:19])=[O:14])[CH:10]([CH3:12])[CH3:11]
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(N)=O)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)CCCCCCN)C(C)C
Reactant: COC(=O)N1C(=O)C=CC1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(N)=O)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)CCCCCCN1C(=O)C=CC1=O)C(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
14 mg (16 μmol) of N-(6-aminohexyl)-N-methyl-L-valyl-N-[(3R,4S,5S)-1-{(2S)-2-[(1R,2R)-3-{[(2S)-1-amino-3-(1H-indol-3-yl)-1-oxopropan-2-yl]amino}-1-methoxy-2-methyl-3-oxopropyl]pyrrolidin-1-yl}-3-methoxy-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinamide (Intermediate 88) were taken up in 750 μl of dioxane and admixed with 1.5 ml of saturated sodium hydrogencarbonate solution and then with 3.2 mg (21 μmol) of methyl 2,5-dioxo-2,5-dihydro-1H-pyrrole-1-carboxylate. The reaction mixture was stirred at RT for 1 h and then concentrated under reduced pressure. The remaining residue was purified by means of preparative HPLC. After lyophilization, 5.5 mg (36% of theory) of the title compound were obtained.
Reaction SMILES: P(Br)(Br)[Br:2].C1CCC(C2(CN3N=CN=C3)CCN(C([C@H](NC([C@@H:31]3[NH:40][CH2:39][C:38]4[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=4)[CH2:32]3)=O)CC3C=CC(Cl)=CC=3)=O)CC2)CC1.[CH2:47](Br)[CH:48]=[CH2:49].CCN(C(C)C)C(C)C>C(Cl)Cl.CN(C=O)C>[BrH:2].[CH2:49]([N:40]1[CH2:31][CH2:32][CH:33]2[C:38](=[CH:37][CH:36]=[CH:35][CH2:34]2)[CH2:39]1)[CH:48]=[CH2:47]
Reactant: C=CCBr
Reactant: O=C(N[C@H](Cc1ccc(Cl)cc1)C(=O)N1CCC(Cn2cncn2)(C2CCCCC2)CC1)[C@H]1Cc2ccccc2CN1
Reactant: BrP(Br)Br
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Br
Product: C=CCN1CCC2CC=CC=C2C1
Temperature: 25 °C
Reaction time: 24 h
Yield: 27.6 %

Procedure:
resin 2 (0.65 mmol g−1 (est.), 1.49 g) in dry DCM (25 cm3) were treated with PBr3 (2.28 mmol, 216 mm3) at 20° C. for 12 h. The resin was filtered off, washed with DCM (200 cm3), dried at air and transferred to a flask with DMF (20 cm3) and THIQ (5.7 mmol, 725 mm3) was added. The resin was stirred at r.t. for 24 h, washed with DMF, MeOH, DCM, and MeOH. It was dried under high vacuum. 1.45 g (0.5 mmol g−1 (est.)) of it was resuspended in DMF (10 cm3) and allyl bromide (150 mm3, 1.7 mmol) was added. After 5 d at 20° C. the solid was filtered off, washed with DMF (100 cm3) and DCM (100 cm3). The resin was then treated with DIPEA (1.00 mmol, 175 mm3) in DCM (25 cm3). After 2 days the solid material was filtered off and washed with DCM and MeOH. Yield of resin 3 1.28 g (max. est. yield: 1.25 g). The solvent was removed from the filtrate and gave analytical pure 4 (0.47 mmol, 120 mg, 59%) as a white solid.
Reaction SMILES: [CH:1]1[C:14]2[C:5](=[N:6][C:7]3[C:12]([C:13]=2[NH:15][C:16]2[CH:21]=[CH:20][C:19]([N:22]4[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]4)=[CH:18][CH:17]=2)=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:3][CH:2]=1.[C:28](Cl)(=[O:30])[CH3:29].N1C=CC=CC=1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH:1]1[C:14]2[C:5](=[N:6][C:7]3[C:12]([C:13]=2[NH:15][C:16]2[CH:17]=[CH:18][C:19]([N:22]4[CH2:27][CH2:26][N:25]([C:28](=[O:30])[CH3:29])[CH2:24][CH2:23]4)=[CH:20][CH:21]=2)=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:3][CH:2]=1
Reactant: CC(=O)Cl
Reactant: c1ccc2c(Nc3ccc(N4CCNCC4)cc3)c3ccccc3nc2c1
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CC(=O)N1CCN(c2ccc(Nc3c4ccccc4nc4ccccc34)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 1 %

Procedure:
35 mg (0.10 mmol) of 9-[4-(piperazin-1-yl)phenyl]aminoacridine (Example 16) was dissolved in 2 ml of chloroform, 7.1 μl (0.10 mmol) of acetyl chloride and catalytical amounts of pyridine and triethylamine were added. After 2 h of stirring at room temperature, the solvents were removed under vacuum, and the residue was purified by silica gel chromatography (eluent chloroform: methanol 6:1). The fractions with the title compound were combined, evaporated, taken up to water and extracted with chloroform. After drying over sodium sulfate, the organic layer was evaporated to obtain the title compound (6%, overall yield 1%).
Reaction SMILES: [NH2:1][C@H:2]([C:4]([NH:6][C@H:7]([C:12]([NH:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])=[O:13])[C@H:8]([CH2:10][CH3:11])[CH3:9])=[O:5])[CH3:3].[CH3:20][C@@H:21]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])[C@H:22]([NH:33][C:34]([O:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:35])[C:23](ON1C(=O)CCC1=O)=[O:24]>CN(C)C=O>[NH:33]([C:34]([O:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:35])[C@H:22]([C:23]([NH:1][C@H:2]([C:4]([NH:6][C@H:7]([C:12]([NH:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])=[O:13])[C@H:8]([CH2:10][CH3:11])[CH3:9])=[O:5])[CH3:3])=[O:24])[C@@H:21]([CH3:20])[O:44][C:45]([CH3:47])([CH3:48])[CH3:46]
Reactant: C[C@@H](OC(C)(C)C)[C@H](NC(=O)OCc1ccccc1)C(=O)ON1C(=O)CCC1=O
Reactant: CC[C@H](C)[C@H](NC(=O)[C@H](C)N)C(=O)NCC(=O)OC
Solvent: CN(C)C=O
Product: CC[C@H](C)[C@H](NC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)OCc1ccccc1)[C@@H](C)OC(C)(C)C)C(=O)NCC(=O)OC

Procedure:
1.36 g of H-Ala-Ile-Gly-OMe (compare Example 1) and 2.5 g of Z-Thr(tBu)-OSU in 3 ml of dimethylformamide are stirred for 20 hours at room temperature. The tetrapeptide derivative is precipitated by ether, filtered off and washed with ether. After recrystallisation from ethanol the melting point is 229°-230°C. [α]D20 = -43° (c = 1 in methanol). Rf = 0.55 in the system chloroform-methanol (95:5) on silica gel.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH:8]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)[CH:9]3[CH2:15][CH2:14][CH2:13][CH:10]32)=C(OS(C(F)(F)F)(=O)=O)[CH:4]=1.C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CO.[C:63]([O:66][CH2:67]C)(=[O:65])[CH3:64]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:67][O:66][C:63]([C:64]1[C:6]2[CH2:7][CH:8]([C:16]3[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=3)[CH:9]3[CH2:15][CH2:14][CH2:13][CH:10]3[C:11]=2[CH:12]=[C:3]([O:2][CH3:1])[CH:4]=1)=[O:65]
Reactant: COc1ccc(C2Cc3c(OS(=O)(=O)C(F)(F)F)cc(OC)cc3C3CCCC23)cc1
Reactant: CCOC(C)=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(CCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: CO
Product: COC(=O)c1cc(OC)cc2c1CC(c1ccc(OC)cc1)C1CCCC21
Yield: 88 %

Procedure:
Combine trifluoro-methanesulfonic acid 8-methoxy-4-(4-methoxy-phenyl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalen-6-yl ester (0.1 g, 0.22 mmol), palladium acetate (0.0393 g, 0.18 mmol), 1,3-bis(diphenylphosphino)-propane (0.0723 g, 0.18 mmol), with dDMSO (6 ml) and methanol (2 m), and heat at 80-85° C. for 12 hours under an atmosphere of carbon monoxide. Remove solvent in vacuo, take in ethyl acetate and wash 5× with water. Dry over anhydrous sodium sulfate and chromatograph the residue on silica gel with 10% ethyl acetate in hexanes to yield the titled compound (0.07 g, 88%). 1H NMR (CDCl3): 7.21 (d, J=7.9, Hz, 2H), 7.19 (s, 1H), 6.9(s, 1H), 6.86 (d, J=7.9 Hz, 2H), 3.86 (s, 3H), 3.82 (s, 3H), 3.8 (s, 3H), 3.45 (m, 1H), 3.22 (m, 1H), 3.1 (m, 2H), 2.58 (m, 1H), 2.2 (m, 1H), 1.6-1.3 (m, 5H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][C:5]([C:8]2[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=2)[C:11]([OH:13])=[O:12])=[N:6][CH:7]=1.S(Cl)(Cl)=O.[CH3:21]O>>[OH:1][C:2]1[CH:7]=[N:6][C:5]([C:8]2[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=2)[C:11]([O:13][CH3:21])=[O:12])=[N:4][CH:3]=1
Reactant: CO
Reactant: O=C(O)c1cccc(-c2ncc(O)cn2)c1
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cccc(-c2ncc(O)cn2)c1
Temperature: 80 °C

Procedure:
78.8 g of 3-(5-hydroxypyrimidin-2-yl)benzoic acid are suspended in 1.4 l of absolute methanol, and 32.7 ml of thionyl chloride (449.8 mmol) are subsequently carefully added dropwise at RT. The reaction batch is warmed at 80° C. for 2 h. A further 20 ml of thionyl chloride (275.7 mmol) are added, and the mixture is warmed at 80° C. for a further 2 h. In order to complete the reaction, a further 10 ml of thionyl chloride (137.8 mmol) are added, and the mixture is warmed at 80° C. for a further 2 h. For work-up, 1000 ml of methanol are removed in a rotary evaporator, and the resultant residue is filtered off. The mother liquor is reduced to about 200 ml in the rotary evaporator, and the crystals formed are filtered off. The two crystal batches are combined, dried to constant weight at 50° C. in a vacuum drying cabinet.
Reaction SMILES: C1(S([N:10]2[C:14]3[CH:15]=[N:16][C:17]([C:28]#[N:29])=[C:18]([CH2:19][CH:20]4[CH2:25][CH2:24][N:23]([CH2:26][CH3:27])[CH2:22][CH2:21]4)[C:13]=3[C:12]3[CH:30]=[CH:31][CH:32]=[N:33][C:11]2=3)(=O)=O)C=CC=CC=1.C(N(CC)CC)C>CO>[CH2:26]([N:23]1[CH2:24][CH2:25][CH:20]([CH2:19][C:18]2[C:13]3[C:12]4[CH:30]=[CH:31][CH:32]=[N:33][C:11]=4[NH:10][C:14]=3[CH:15]=[N:16][C:17]=2[C:28]#[N:29])[CH2:21][CH2:22]1)[CH3:27]
Reactant: CCN1CCC(Cc2c(C#N)ncc3c2c2cccnc2n3S(=O)(=O)c2ccccc2)CC1
Solvent: CO
Solvent: CCN(CC)CC
Product: CCN1CCC(Cc2c(C#N)ncc3[nH]c4ncccc4c23)CC1
Yield: 50.9 %

Procedure:
A solution of 9-benzenesulfonyl-5-(1-ethyl-piperidin-4-ylmethyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile (200 mg, 0.4 mmol) and triethylamine (4 mL) in methanol (40 mL) was stirred at ambient temperature for 6 days. The mixture was concentrated in vacuo and the residue purified by flash chromatography (silica, 2 g column, Si-SPE, 0-20% MeOH in DCM). The resultant material was triturated with acetonitrile and methanol to afford the title compound as a white solid (65 mg, 51%). 1H NMR (DMSO-D6, 400 MHz): 12.85 (s, 1H), 8.90 (s, 1H), 8.70 (dd, J=4.8, 1.5 Hz, 1H), 8.65 (dd, J=8.0, 1.6 Hz, 1H), 7.46 (dd, J=8.0, 4.8 Hz, 1H), 2.86-2.77 (m, 2H), 2.24 (q, J=7.2 Hz, 2H), 1.84-1.58 (m, 5H), 1.54-1.40 (m, 2H), 0.95 (t, J=7.1 Hz, 3H). LCMS (Method H): RT=4.56 min, M+H+=320.
Reaction SMILES: [H-].[Na+].[CH2:3]([C:5]1[N:14]=[C:13]([CH2:15][CH3:16])[CH:12]=[C:11]2[C:6]=1[CH:7]=[CH:8][C:9](=[O:17])[NH:10]2)[CH3:4].[N+:18]([C:21]1[CH:28]=[CH:27][C:24]([CH2:25]Br)=[CH:23][CH:22]=1)([O-:20])=[O:19].O>CN(C=O)C>[CH2:3]([C:5]1[N:14]=[C:13]([CH2:15][CH3:16])[CH:12]=[C:11]2[C:6]=1[CH:7]=[CH:8][C:9](=[O:17])[N:10]2[CH2:25][C:24]1[CH:27]=[CH:28][C:21]([N+:18]([O-:20])=[O:19])=[CH:22][CH:23]=1)[CH3:4]
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: CCc1cc2[nH]c(=O)ccc2c(CC)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCc1cc2c(ccc(=O)n2Cc2ccc([N+](=O)[O-])cc2)c(CC)n1
Reaction time: 0.25 h
Yield: 83.9 %

Procedure:
Sodium hydride (50% dispersion in oil; 0.2 g) was added to a stirred solution of 5,7-diethyl-1,6-naphthyridin-2(1H)-one (1.0 g) in DMF (10 ml) under argon. The mixture was stirred for 15 minutes, then 4-nitrobenzyl bromide (1.1 g) was added and the mixture was stirred for 16 hours. The reaction mixture was poured into water (50 ml) and extracted with ethyl acetate (2×30 ml). The combined extracts were washed with saturated sodium chloride solution (10 ml), dried (MgSO4) and the solvent was removed by evaporation. The residue was purified by flash chromatography eluting with ethyl acetate/dichloromethane (1:4 v/v) to give 5,7-diethyl-1-(4-nitrobenzyl)-1,6-naphthyridin-2(1H)-one (B) as yellow solid (1.4 g), m.p. 105°-106° C.; NMR (CDCl3): 1.22(t, 3H), 1.36(t, 3H), 2.77(q, 2H), 3.11(q, 2H), 5.77(s, 2H), 6.69(s, 1H), 6.77(d, 1H), 7.38(d, 2H), 8.03(d, 1H), 8.19(d, 2H); mass spectrum (+ve CI): 338 (M+H)+ ; microanalysis, found: C, 67.0; H, 5.7; N, 12.4; C19H19N3O3 requires C, 67.6; H, 5.7; N, 12.5%.
Reaction SMILES: [C:1]1([CH3:8])[C:6]([OH:7])=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:9](=O)([O-])[O-].[K+].[K+].CN(C=O)C.IC>O>[CH3:9][O:7][C:6]1[CH:5]=[CH:4][CH:3]=[CH:2][C:1]=1[CH3:8]
Reactant: Cc1ccccc1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CI
Product: COc1ccccc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 84 %

Procedure:
o-cresol (5 g, 0.046 mol) and anhydrous potassium carbonate (19.17 g, 0.14 mol) were dissolved into DMF (75 mL) and then iodomethane (6.65 g, 0.046 mmol) was dropped under an ice bath. The system was stirred overnight at room temperature. At the end of reaction, the reaction system was added with water and then extracted with ethyl acetate, and the organic phase was washed with saturated brine, then dried and evaporated in vacuum to obtain the product 4.72 g (83.5%) by column chromatography.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C:19]3[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[C:21]([N+:28]([O-:30])=[O:29])[CH:20]=3)=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.C[N+:32](C)=C(N(C)C)ON1C2C=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F.Cl.[C:56]([O:60][C:61](=[O:73])[C@H:62]([CH2:64][CH2:65][C:66]([O:68][C:69]([CH3:72])([CH3:71])[CH3:70])=[O:67])[NH2:63])([CH3:59])([CH3:58])[CH3:57].COC(C)(C)C>ClCCl.C(N(CC)CC)C>[CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C:19]3[CH:27]=[CH:26][C:22]([C:23]([NH:63][C@@:62]([C:61]([O:60][C:56]([CH3:58])([CH3:59])[CH3:57])=[O:73])([CH2:64][CH2:65][C:66]([O:68][C:69]([CH3:72])([CH3:71])[CH3:70])=[O:67])[NH2:32])=[O:24])=[C:21]([N+:28]([O-:30])=[O:29])[CH:20]=3)=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: CC(C)(C)OC(=O)CC[C@H](N)C(=O)OC(C)(C)C
Reactant: O=C(Nc1ccc(C(=O)O)c([N+](=O)[O-])c1)OCC1c2ccccc2-c2ccccc21
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: COC(C)(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CC[C@@](N)(NC(=O)c1ccc(NC(=O)OCC2c3ccccc3-c3ccccc32)cc1[N+](=O)[O-])C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 20 h
Yield: 99.3 %

Procedure:
To a suspension of 17.2 g 4-(((9H-fluorene-9-yl)methoxy)carbonylamino)-2-nitrobenzoic acid in 222 ml dichloromethane were added 17.7 g of N,N,N′,N′-tetramethyl-O-(1H-benzotriazol-1-yl)-uronium-hexafluoro-phosphate. After stirring for 15 min. at room temperature a solution of 13.8 g of L-glutamic acid-di-tert.butylester hydrochloride in 172 ml dichloromethane and 12.9 ml triethylamine were added dropwise within 30 min. The mixture was stirred under nitrogen at room temperature for 20 hours. After addition of 860 ml of methyl-tert.-butylether the mixture was washed five times with aqueous sodium H carbonate (5%), 5 times with aqueous citric acid (5%) and two times with brine. The organic layer was dried over magnesium sulphate and evaporated to dryness under vacuum to give 27.9 g of crude di-tert-butyl 2-(4-(((9H-fluorene-9-yl)methoxy)carbonylamino)-2-nitrobenzamido)-L-glutamate as a yellow foam. The crude product was purified by flash chromatography using silica gel 60 and ethylacetate/n-heptane/45:55 as eluent. After evaporation of product fractions 23.8 g of di-tert-butyl-N-(4-(((9H-fluorene-9-yl)methoxy)carbonylamino)-2-nitrobenzamido)-L-glutamate were obtained as a yellow foam (HPLC, purity: 99.9% area).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[CH:6][CH:5]=1.[Cl:12][C:13]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:14]=1[CH:15]=O.[CH2:22]=[C:23]([CH3:25])[CH3:24].FC(F)(F)S([O-])(=O)=O.[Yb+3].FC(F)(F)S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O>CC#N.O>[CH3:1][O:2][C:3]([C:4]1[CH:5]=[C:6]2[C:7](=[CH:8][CH:9]=1)[NH:10][CH:15]([C:14]1[CH:17]=[C:18]([Cl:21])[CH:19]=[CH:20][C:13]=1[Cl:12])[CH2:22][C:23]2([CH3:25])[CH3:24])=[O:11]
Reactant: COC(=O)c1ccc(N)cc1
Reactant: C=C(C)C
Reactant: O=Cc1cc(Cl)ccc1Cl
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: CC#N
Solvent: O
Product: COC(=O)c1ccc2c(c1)C(C)(C)CC(c1cc(Cl)ccc1Cl)N2
Temperature: 80 °C
Reaction time: 18 h

Procedure:
To a stirred solution of 4-aminobenzoic acid methyl ester (1.5 g, 10 mmol) and 2,5-dichloro-benzaldehyde (1.8 g, 10 mmol) in MeCN (5 mL) were added isobutene (2.1 mL, 30 mmol) and ytterbium(III) trifluoromethanesulfonate (Yb(OTf)3) (1.3 g, 2 mmol). The resulting mixture was stirred at 80° C. for 18 hours in sealed tube. The mixture was diluted with water (50 mL), extracted with diethyl ether (50 mL×3). The extracts were washed with water (100 mL) and brine (100 mL) and then dried over anhydrous Na2SO4. The solvent was removed in vacuo and the residue was purified by ISCO combi-flash chromatography (gradient elution, 0-10% ethyl acetate in petroleum ether) to 2-(2,5-dichloro-phenyl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid methyl ester (1.8 g, 50%) as a light yellow solid (reference: Kiselyov, A. S. et al., Tetrahedron 54 (1998) 5089): MS (ESI+) [(M+H)+] 364.2.
Reaction SMILES: [CH:1]([OH:3])=O.C(OC(=O)C)(=O)C.[CH3:11][O:12][C:13]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][C:14]=1[NH2:15]>C1COCC1>[CH3:11][O:12][C:13]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][C:14]=1[NH:15][CH:1]=[O:3]
Reactant: COc1ccc([N+](=O)[O-])cc1N
Reactant: O=CO
Solvent: C1CCOC1
Solvent: CC(=O)OC(C)=O
Product: COc1ccc([N+](=O)[O-])cc1NC=O
Temperature: 55 °C
Reaction time: 2 h
Yield: 102 %

Procedure:
A mixture of formic acid (0.45 ml, 0.012 mole) and acetic anhydride (1.06 ml, 0.011 mole) was stirred at 55° C. under Ar for 2 h, and cooled to room temperature. Dry THF (10 ml) was added. To this solution was added 2-methoxy-5-nitroaniline (0.69 g, 0.004 mole). After stirring for 1 h, the suspension was evaporated in vacuo to leave the title compound as a brown solid (0.80 g, 99%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8](Cl)=[O:9])=[CH:6][C:5]([N:11]=[C:12]2[N:20]3[N:15]([CH2:16][CH2:17][CH2:18][CH2:19]3)[C:14](=[O:21])[S:13]2)=[C:4]([F:22])[CH:3]=1.[OH:23][CH2:24][CH2:25][C:26]1[S:30][CH:29]=[N:28][C:27]=1[CH3:31].C(N(CC)CC)C>C(OC)(=O)C>[Cl:1][C:2]1[C:7]([C:8]([O:23][CH2:24][CH2:25][C:26]2[S:30][CH:29]=[N:28][C:27]=2[CH3:31])=[O:9])=[CH:6][C:5]([N:11]=[C:12]2[N:20]3[N:15]([CH2:16][CH2:17][CH2:18][CH2:19]3)[C:14](=[O:21])[S:13]2)=[C:4]([F:22])[CH:3]=1
Reactant: O=C(Cl)c1cc(N=c2sc(=O)n3n2CCCC3)c(F)cc1Cl
Reactant: Cc1ncsc1CCO
Solvent: COC(C)=O
Solvent: CCN(CC)CC
Product: Cc1ncsc1CCOC(=O)c1cc(N=c2sc(=O)n3n2CCCC3)c(F)cc1Cl
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of 3.6 g of 9-[4-chloro-2-fluoro-5-(chlorocarbonyl)-phenylimino]-8-thia-1,6-diazabicyclo[4.3.0]nonan7-one in 10 ml of methyl acetate is added dropwise, with stirring, at room temperature to a solution of 1.2 ml of 5-(2-hydroxyethyl)-4-methylthiazole and 1.5 ml of triethylamine in 50 ml of methyl acetate. After stirring at room temperature for 12 hours, the precipitated triethylamine hydrochloride is filtered off and the filtrate is concentrated by evaporation, yielding 3.8 g of the title compound in the form of an oil with nD22 1.6030.
Reaction SMILES: [N+]([O-])([O-])=O.[C:5]([C:8]1[C:13]([C:14]([OH:16])=[O:15])=[CH:12][C:11]([CH2:17][CH3:18])=[CH:10][NH+:9]=1)([OH:7])=[O:6].C(Cl)Cl.[CH2:22](C(C)=O)[CH:23](C)C>>[CH2:17]([C:11]1[CH:12]=[C:13]([C:14]([OH:16])=[O:15])[C:8]([C:5]([OH:7])=[O:6])=[N:9][CH:10]=1)[CH3:18].[CH2:17]([C:11]1[CH:10]=[N:9][C:8]2[C:13]([CH:12]=1)=[CH:14][CH:23]=[CH:22][C:5]=2[OH:7])[CH3:18]
Reactant: CC(=O)CC(C)C
Reactant: CCc1c[nH+]c(C(=O)O)c(C(=O)O)c1
Agent: O=[N+]([O-])[O-]
Solvent: ClCCl
Product: CCc1cnc(C(=O)O)c(C(=O)O)c1
Product: CCc1cnc2c(O)cccc2c1
Temperature: 25 °C

Procedure:
The nitrate salt obtained in Example 1 is dispersed in a mixture of lo0 mL of methylene chloride and 100 mL of methyl isobutyl ketone, heated at reflux temperature for 1 hour, cooled to room temperature and filtered. The filter cake is washed with a 1:1 mixture of methylene chloride:methyl isobutyl ketone and dried in vacuo to give 5-ethyl-2,3-pyridinedicarboxylic acid, 34.6 g, (89% isolated yield from 3-ethyl-8-hydroxyquinoline), 94.5% pure by HPLC.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[N:9](C(=O)C)[CH2:10][CH2:11][N:12]=2)=[C:6](Cl)[N:5]([NH2:17])[CH:4]([CH3:18])[N:3]=1.[CH3:19][OH:20]>>[Cl:1][C:2]1[C:7]([C:8]2[NH:9][CH2:10][CH2:11][N:12]=2)=[C:6]([O:20][CH3:19])[N:5]([NH2:17])[CH:4]([CH3:18])[N:3]=1
Reactant: CC(=O)N1CCN=C1C1=C(Cl)N(N)C(C)N=C1Cl
Reactant: CO
Product: COC1=C(C2=NCCN2)C(Cl)=NC(C)N1N
Yield: 80 %

Procedure:
10.0 g 4,6-dichloro-2-methyl-5-(1-acetyl-2-imidazolin-2-yl)-aminopyrimidine are boiled in 400 ml methanol for 48 hours under reflux. The solution is concentrated, and the residue mixed with warm tetrahydrofuran. The crystals are recrystallized from isopropanol/ether. 6.4 g (80%) of 4-chloro-6-methoxy-2-methyl-5-(2-imidazolin-2-yl)-aminopyrimidine is obtained as the hydrochloride, melting point 189° C. Melting point of the base 217°-219° C. (decomposition). 1H-NMR spectrum is DMSO-d6, delta values in ppm: 2.53 (s, CH3), 3.65 (s, N-CH2 --CH2 -N), 3.98 (s, OCH3), 8.66 (twice NH, deuterizable).
Reaction SMILES: [CH3:1][C@H:2]1[C@H:7]2[C@H:8]3[C@H:18]([CH2:19][CH2:20][C@:5]2([CH3:6])[C@@H:4]([OH:21])[CH2:3]1)[C@:16]1([CH3:17])[CH:11](CCC[CH2:15]1)[CH2:10][CH2:9]3.[C:22]([O-:25])(=O)[CH3:23].[NH4+:26]>C(O)CO>[CH3:1][C@H:2]1[C@H:7]2[C@H:8]3[C@H:18]([CH2:19][CH2:20][C@:5]2([CH3:6])[C@@H:4]([OH:21])[CH2:3]1)[C@:16]1([CH3:17])[C:11]([NH:26][C:22](=[O:25])[CH2:23][CH2:15]1)=[CH:10][CH2:9]3
Reactant: [NH4+]
Reactant: C[C@@H]1C[C@H](O)[C@@]2(C)CC[C@H]3[C@@H](CCC4CCCC[C@@]43C)[C@H]12
Reactant: CC(=O)[O-]
Solvent: OCCO
Product: C[C@@H]1C[C@H](O)[C@@]2(C)CC[C@H]3[C@@H](CC=C4NC(=O)CC[C@@]43C)[C@H]12
Temperature: 0 °C
Reaction time: 2 h

Procedure:
The secoacid (10) (1.24 g, 3.7 mmol) was mixed with ammonium acetate (1.7 g, 22.2 mmol) and ethylene glycol (23 mL) in a 50 mL round bottomed flask fitted with a stirrer bar and a rubber septum. The flask was heated under nitrogen to 1800 slowly over 40 minutes at kept there for 2 h. The mixture was cooled to 70° and the solution poured into 200 mL of ice water. The product precipitated out, was filtered and washed with water. The precipitate was dried under reduced pressure. Recovered product: (0.72 g, 2.2 mmol, 61%) δH (CDCl3) 0.90 (s, 3H), 0.99 (d, J=7 Hz,), 1.11 (s, 3H), 3.60 (t, J=7 Hz, 1H), 4.81 (m, 1H), 7.37(bs, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[C:5]([N+:11]([O-:13])=[O:12])[C:4]=1[O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].S(N)(=O)(=O)[OH:21].C(O)(C)C.Cl([O-])=O.[Na+]>C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]([OH:21])=[O:8])=[C:5]([N+:11]([O-:13])=[O:12])[C:4]=1[O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: NS(=O)(=O)O
Reactant: CCCCCOc1c(OC)ccc(C=O)c1[N+](=O)[O-]
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: CCCCCOc1c(OC)ccc(C(=O)O)c1[N+](=O)[O-]
Reaction time: 0.33 h
Yield: 79.6 %

Procedure:
4-Methoxy-2-nitro-3-pentyloxybenzaldehyde (70 g, 261.9 mmol), amidosulfuric acid (76.3 g, 785.7 mmol) and isopropanol (210 ml) were mixed, an aqueous sodium chlorite (38.5 g, 340.5 mmol) solution (350 ml) was added dropwise to this solution while cooling in a water bath. After stirring for 20 minutes, ethyl acetate (300 ml) was added to separate the organic layer. The aqueous layer was extracted with ethyl acetate (200 ml). The organic layers were combined, washed with saturated brine (150 ml), and dried over anhydrous magnesium sulfate. The drying agent was filtered off and the filtrate was concentrated under reduced pressure. The precipitated crystals were collected by filtration to give 4-methoxy-2-nitro-3-pentyloxybenzoic acid (59.02 g, 80%) as pale-yellow crystals.