Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1CCCC1.[CH3:6][CH2:7][C:8](=O)[CH2:9][CH3:10].[OH:12][C:13]1[CH:18]=[C:17]([OH:19])[CH:16]=[CH:15][C:14]=1[C:20](=[O:22])[CH3:21]>CO>[CH2:7]([C:8]1([CH2:9][CH3:10])[CH2:21][C:20](=[O:22])[C:14]2[C:13](=[CH:18][C:17]([OH:19])=[CH:16][CH:15]=2)[O:12]1)[CH3:6]
Reactant: CCC(=O)CC
Reactant: CC(=O)c1ccc(O)cc1O
Solvent: CO
Solvent: C1CCNC1
Product: CCC1(CC)CC(=O)c2ccc(O)cc2O1
Reaction time: 24 h
Yield: 39.5 %

Procedure:
Pyrrolidine (9.3 g) and pentan-3-one (11.3 g) were added to a solution of 1-(2,4-dihydroxyphenyl)ethanone (14 g) in methanol (150 mL) and the solution was stirred for 24 hours and then heated under reflux for 10 hours. The reaction mixture was concentrated in vacuo, and to the residue was added water (10 mL). To the mixture was added 1N hydrochloric acid solution to adjust its pH to 5 to 6, and extracted with ethyl acetate (25 mL×3). The combined organic layer was dried over sodium sulfate, filtered and the filtrate was concentrated in vacuo. The resultant crude product was purified by column chromatography on silica gel (Solvent; petroleum ether/ethyl acetate=10/1) to give the titled compound (8 g) as a colorless powder.
Reaction SMILES: [CH3:1][N:2]=[C:3]=[O:4].[CH2:5]1[CH:13]2[N:8]([CH2:9][CH2:10][CH:11]([C:14]3[C:22]4[C:17](=[CH:18][CH:19]=[C:20]([NH2:23])[CH:21]=4)[NH:16][CH:15]=3)[CH2:12]2)[CH2:7][CH2:6]1>CN(C)C=O>[CH3:1][NH:2][C:3]([NH:23][C:20]1[CH:21]=[C:22]2[C:17](=[CH:18][CH:19]=1)[NH:16][CH:15]=[C:14]2[CH:11]1[CH2:12][CH:13]2[N:8]([CH2:7][CH2:6][CH2:5]2)[CH2:9][CH2:10]1)=[O:4]
Reactant: CN=C=O
Reactant: Nc1ccc2[nH]cc(C3CCN4CCCC4C3)c2c1
Solvent: CN(C)C=O
Product: CNC(=O)Nc1ccc2[nH]cc(C3CCN4CCCC4C3)c2c1
Reaction time: 72 h
Yield: 55.8 %

Procedure:
The methylisocyanate (220 mg, 3.9 mmol) was added to a solution of 3-(octahydroindolizin-7-yl)-5-amino-1H-indole (500 mg, 1.95 mmol) in 10 ml of dimethylformamide. The reaction was allowed to stir for 72 hours. TLC indicated the reaction was complete so the reaction was concentrated to give a purple gum. This material was chromatographed on a short FLORISIL™ column using 20% methanol in methylene chloride (ammonium hydroxide) as solvent to give 340 mg of a white foam. The white foam was recrystallized from methanol/ethyl acetate to give 165 mg of product. (27.1%).
Reaction SMILES: [CH2:1]([C:4]1([C:14]2[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][C:15]=2Br)[N:10]2[CH:11]=[N:12][CH:13]=[C:9]2[CH2:8][CH2:7][CH2:6][CH2:5]1)[CH:2]=[CH2:3].C(=O)([O-])[O-].[Na+].[Na+].FC1C=CC(B(O)O)=CC=1>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.COCCOC>[CH2:3]=[C:2]1[C:21]2[C:14](=[CH:15][CH:16]=[C:17]([C:18]#[N:19])[CH:20]=2)[C:4]2([N:10]3[CH:11]=[N:12][CH:13]=[C:9]3[CH2:8][CH2:7][CH2:6][CH2:5]2)[CH2:1]1
Reactant: C=CCC1(c2ccc(C#N)cc2Br)CCCCc2cncn21
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: OB(O)c1ccc(F)cc1
Solvent: COCCOC
Product: C=C1CC2(CCCCc3cncn32)c2ccc(C#N)cc21
Temperature: 130 °C
Reaction time: 0.42 h

Procedure:
To 4-(5-allyl-6,7,8,9-tetrahydro-5H-imidazo[1,5-a]azepin-5-yl)-3-bromobenzonitrile (0.275 g, 0.76 mmol) is added DME (3.0 mL). To this solution is added aqueous 2M sodium carbonate (1.5 ml, 3.0 mmol) followed by 4-fluorophenylboronic acid (0.269 g, 1.92 mmol). This mixture is transferred to a microwave safe vial Tetrakis(triphenylphosphine) palladium(0) (0.04 g, 0.034 mmol) is added, and the vessel sealed. The mixture is stirred briefly (30 seconds) and place in a microwave for 25 minutes at 130° C. The vial is allowed to cool and unsealed. The mixture is extracted with ethyl acetate and washed with saturated aqueous sodium bicarbonate. The separated organic layer is concentrated in vacuo. The resulting material is subjected to two sequential chromatography procedures (1: Silica gel, 1:50 to 1:25 methanol:methylene chloride. 2: Reverse phase HPLC, gradient 10-95% % Acetonitrile:Water, pH2, over 8 minutes) to give the product. MS (ESI) m/z 276 (M+11); 1H NMR (400 MHz, CDCl3) δ ppm 1.47-1.61 (m, 1H), 1.85-1.99 (m, 1H), 2.01-2.16 (m, 3H), 2.25-2.36 (m, 1H), 2.63 (t, 1H), 2.99 (d, J=16.4 Hz, 1H), 3.10 (dd, J=15.5, 5.7 Hz, 1H), 3.23-3.32 (m, 1H), 5.21-5.25 (m, 1H), 5.62-5.67 (m, 1H), 6.50 (s, 1H), 6.78 (s, 1H), 7.54-7.58 (m, 1H), 7.66-7.70 (m, 1H), 7.88 (s, 1H).
Reaction SMILES: [CH2:1]([C:3]1[C:7](I)=[C:6]([CH:9]=[O:10])[NH:5][C:4]=1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH3:2].[O-]P([O-])([O-])=O.[K+].[K+].[K+].[O:26]1[C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=2[CH:28]=[C:27]1B(O)O>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(COC)OC>[O:26]1[C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=2[CH:28]=[C:27]1[C:7]1[C:3]([CH2:1][CH3:2])=[C:4]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[NH:5][C:6]=1[CH:9]=[O:10]
Reactant: CCc1c(C(=O)OC(C)(C)C)[nH]c(C=O)c1I
Reactant: OB(O)c1cc2ccccc2o1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: CCc1c(C(=O)OC(C)(C)C)[nH]c(C=O)c1-c1cc2ccccc2o1
Temperature: 85 °C

Procedure:
Tert-butyl 3-ethyl-5-formyl-4-iodo-1H-pyrrole-2-carboxylate was obtained following the procedures described in Example 1. To a mixture of tert-butyl 3-ethyl-5-formyl-4-iodo-1H-pyrrole-2-carboxylate (0.0597 g, 0.172 mmol), K3PO4 (0.180 g, 0.85 mmol), Pd(PPh3)4(0.0120 g, 0.010 mmol), and 1-benzofuran-2-ylboronic acid (0.0330 g, 0.21 mmol) under N2 was added dimethoxyethane (2.5 mL). The reaction was heated to 85° C. and refluxed for 5 h. After cooling to ambient temperature, the reaction was filtrated through a pad of silica gel and concentration. The resultant residue was purified by normal phase chromatography (5-15% ethyl acetate/hexanes). Proton NMR for the product was consistent with the title compound as a 2:1 mixture of atropdiastereomers. 1H NMR (500 MHz, CDCl3) δ 10.17 (s, 0.7 H); 9.59 (s, 0.3H); 7.64 (app. d, J=7.6 Hz, 1H); 7.52 (app. d, J=8.1 Hz, 1H); 7.34 (app. t, J=7.7 Hz, 1H); 7.28 (app. t, J=7.6 Hz, 1H), 6.92 (s, 0.7H); 6.80 (s, 0.3H); 3.00 (q, J=7.3 Hz, 1.4H); 2.79 (q, J=7.5 Hz, 0.6H); 1.62 (s, 6.3H); 1.59 (s, 2.7H); 1.28 (t, J=7.3 Hz, 2.1H); 1.23 (t, J=7.6 Hz, 0.9H). HRMS (ES) exact mass calculated for C20H21NNaO4 (M+Na+): 362.1362. Found 362.1362.
Reaction SMILES: [CH3:1][C:2]([CH3:32])([CH3:31])[C:3](=[O:30])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([C:17]2[S:21][C:20]3[CH:22]=[C:23]([C:26]([OH:28])=[O:27])[CH:24]=[CH:25][C:19]=3[CH:18]=2)([CH2:15][CH3:16])[CH2:13][CH3:14])=[CH:8][C:7]=1[CH3:29].[BH4-].[Na+]>>[CH2:13]([C:12]([C:17]1[S:21][C:20]2[CH:22]=[C:23]([C:26]([OH:28])=[O:27])[CH:24]=[CH:25][C:19]=2[CH:18]=1)([C:9]1[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH:3]([OH:30])[C:2]([CH3:31])([CH3:32])[CH3:1])=[C:7]([CH3:29])[CH:8]=1)[CH2:15][CH3:16])[CH3:14]
Reactant: CCC(CC)(c1ccc(OCC(=O)C(C)(C)C)c(C)c1)c1cc2ccc(C(=O)O)cc2s1
Agent: [BH4-]
Agent: [Na+]
Product: CCC(CC)(c1ccc(OCC(O)C(C)(C)C)c(C)c1)c1cc2ccc(C(=O)O)cc2s1
Yield: 99.6 %

Procedure:
2-{1-[4-(3,3-Dimethyl-2-oxo-butoxy)-3-methyl-phenyl]-1-ethyl-propyl}-benzo[b]thiophene-6-carboxylic acid (53 mg, 0.117 mmol) is reduced by NaBH4 (9 mg, 0.234 mmol) as in a reaction analogous to Example 2 to afford the title compound (53 mg, 99%).
Reaction SMILES: [N:1]1([C@H:6]2[CH2:10][CH2:9][CH2:8][C@H:7]2[NH2:11])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:12]([C:14]1[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][CH3:24])[C:15]=1[C:16](O)=[O:17])[CH3:13]>>[CH2:12]([C:14]1[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][CH3:24])[C:15]=1[C:16]([NH:11][C@@H:7]1[CH2:8][CH2:9][CH2:10][C@@H:6]1[N:1]1[CH2:2][CH2:3][CH2:4][CH2:5]1)=[O:17])[CH3:13]
Reactant: N[C@@H]1CCC[C@@H]1N1CCCC1
Reactant: CCc1cccc(CC)c1C(=O)O
Product: CCc1cccc(CC)c1C(=O)N[C@@H]1CCC[C@@H]1N1CCCC1

Procedure:
The title compound, white solid, MS: m/e=315.2 [(M+H)+], was prepared in accordance with the general method of example 5 from cis-2-pyrrolidin-1-yl-cyclopentylamine (intermediate Q) and 2,6-diethylbenzoic acid.
Reaction SMILES: [C:1]([CH2:3][C:4]([NH2:6])=[O:5])#[N:2].[Na].CN(C)[CH:10]=[C:11]([C:15]1[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[CH:17][CH:16]=1)[C:12](=O)[CH3:13]>C(O)C>[C:21]([C:18]1[CH:19]=[CH:20][C:15]([C:11]2[CH:10]=[C:3]([C:1]#[N:2])[C:4](=[O:5])[NH:6][C:12]=2[CH3:13])=[CH:16][CH:17]=1)#[N:22]
Reactant: CC(=O)C(=CN(C)C)c1ccc(C#N)cc1
Reactant: N#CCC(N)=O
Agent: [Na]
Solvent: CCO
Product: Cc1[nH]c(=O)c(C#N)cc1-c1ccc(C#N)cc1
Reaction time: 5 h

Procedure:
6.2 g of cyanacetamide are added to a freshly prepared solution of 1.14 g sodium in 200 ml of absolute ethanol. 10.6 g 4-dimethylamino-3-(4-cyanophenyl)-3-buten-2-one are added and the solution is stirred 5 hours at boiling temperature, whereby the sodium salt of the title compound soon begins to crystallize out. The mixture is allowed to cool, the crystalline product is filtered and washed with ethanol and ether (m.p. of the sodium salt>300°) (m.p. of the free form>300°).
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][C:8]([NH2:10])=[CH:9][C:4]=2[NH:3][CH:2]=1.[CH3:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16]Br)=[CH:14][CH:13]=1.C([O-])([O-])=O.[K+].[K+]>>[CH3:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16][N:1]2[C:5]3[CH:6]=[CH:7][C:8]([NH2:10])=[CH:9][C:4]=3[N:3]=[CH:2]2)=[CH:14][CH:13]=1
Reactant: Cc1ccc(CBr)cc1
Reactant: Nc1ccc2nc[nH]c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1ccc(Cn2cnc3cc(N)ccc32)cc1

Procedure:
The compound was synthesized starting from benzimidazol-5-amine (133 mg; 1 mmol; 1 eq.), 4-methylbenzylbromide (407 mg; 2.2 mmol; 2.2 eq.) and K2CO3 (304 mg; 2.2 mmol; 2.2 eq.) according to method 5; Yield: 0.109 g (32.0%); MS m/z: 342.1 [M+H]+; 1H-NMR (500 MHz, DMSO d6): δ 2.23 (s, 6H); 4.57 (s, 4H); 6.66 (br s, 1H); 6.71 (dd, 1H, 4J=2.1 Hz, 3J=8.9 Hz); 7.09 (d, 4H, 3J=7.9 Hz); 7.14 (d, 4H, 3J=7.9 Hz); 7.30 (d, 1H, 3J=8.5 Hz); 7.88 (s, 1H); 11.88 (br s, 1H); HPLC (METHOD [A]): rt 17.36 min (98.1%)
Reaction SMILES: [Na].[CH2:2]([CH:5]([C:11]([O:13]CC)=O)[C:6](OCC)=[O:7])[CH:3]=[CH2:4].C(O)(=O)C.[CH:20]([NH2:22])=[NH:21]>C(O)C>[CH2:2]([C:5]1[C:11]([OH:13])=[N:21][CH:20]=[N:22][C:6]=1[OH:7])[CH:3]=[CH2:4]
Reactant: C=CCC(C(=O)OCC)C(=O)OCC
Reactant: N=CN
Agent: [Na]
Solvent: CC(=O)O
Solvent: CCO
Product: C=CCc1c(O)ncnc1O
Temperature: 0 °C
Reaction time: 24 h
Yield: 43.9 %

Procedure:
Sodium metal (4.5 g) was added slowly into ethanol (100 mL) in a 500 mL round bottom flask under nitrogen atmosphere. The reaction mixture was stirred at room temperature until all the sodium metal dissolved, before being cooled to 0° C. Diethyl 2-allylmalonate (12 g) was added into the reaction mixture, followed by formamidine acetate (6.24 g) under nitrogen atmosphere at 0° C. The reaction was stirred at room temperature for 24 hours under nitrogen atmosphere, before being quenched by acetic acid (20 mL), followed by water (100 mL). The white precipitate was filtered, washed with water (4×50 mL), methanol (2×50 mL) and dried under vacuum to afford 5-allylpyrimidine-4,6-diol (4 g) as white solid. 1H NMR (DMSO-d6): δ 2.96 (d, 2H), 4.85 (dd, 1H), 4.91 (dd, 1H), 5.76 (dd, 1H), 7.89 (s, 1H), 11.64 (bs, 2H).
Reaction SMILES: [CH3:1][C:2]([C:6]1[CH:12]=[CH:11][C:9]([NH2:10])=[C:8]([N+:13]([O-])=O)[CH:7]=1)([CH3:5])[CH2:3][CH3:4].O.[Cl-].[Ca+2].[Cl-]>CCO.[Fe]>[CH3:5][C:2]([C:6]1[CH:7]=[C:8]([NH2:13])[C:9]([NH2:10])=[CH:11][CH:12]=1)([CH3:1])[CH2:3][CH3:4]
Reactant: CCC(C)(C)c1ccc(N)c([N+](=O)[O-])c1
Agent: [Fe]
Agent: [Ca+2]
Agent: [Cl-]
Solvent: CCO
Solvent: O
Product: CCC(C)(C)c1ccc(N)c(N)c1
Yield: 66.9 %

Procedure:
To a stirred solution of 4-(1,1-dimethylpropyl)-2-nitroaniline (Preparation 94, 11 g, 0.052 mol) in EtOH:water (240 mL:60 mL) was added iron powder (14.8 g, 0.254 mol) and calcium chloride (11.7 g, 0.105 mol). The reaction was heated to reflux for 6 hours before cooling and concentrating in vacuo. The residue was extracted with EtOAc, dried over Na2SO4, concentrated in vacuo and purified using silica gel column chromatography eluting with 50% EtOAc in hexane to afford the title compound (6.2 g, 65%).
Reaction SMILES: [O:1]=[C:2]1[C:6]([CH2:7][C@H:8]([NH:16]C(OC(C)(C)C)=O)[C:9]([O:11]C(C)(C)C)=[O:10])=[CH:5][C:4](=[O:24])[N:3]1[CH3:25]>C(C(O)=O)(F)(F)F>[O:1]=[C:2]1[C:6]([CH2:7][C@H:8]([NH2:16])[C:9]([OH:11])=[O:10])=[CH:5][C:4](=[O:24])[N:3]1[CH3:25]
Reactant: CN1C(=O)C=C(C[C@H](NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C1=O
Solvent: O=C(O)C(F)(F)F
Product: CN1C(=O)C=C(C[C@H](N)C(=O)O)C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.5 %

Procedure:
Compound 12 (1 g, 2.8 mmol) was dissolved in CF3CO2H (20 mL) which had been precooled in an ice bath. This mixture was stirred overnight at room temperature. The acid was removed under vacuum and the residue dried under high vacuum overnight. This residue was dissolved in water (1 mL) and subjected to cation-exchange chromatography (AG 50W-X8, column volume=3 mL). The column was eluted with water, and the fractions corresponding to product were evaporated to dryness. The residue was dissolved in a small amount of water and lyophilized to give 0.33 g (59%) of 3 as a white solid: mp 190°-194° C. dec; [α]D +2.5° (c 0.28, H2O); 1H NMR (300 MHz, D2O) δ 2.9 (s, 3 H, CH3), 2.96-3.0 (m, 2 H, CH2), 3.97 (dd, J=6.41 and 7.02 Hz 1 H α-CH ) 6.6 (m, 1 H, C=CH ); 13C NMR (75 MHz, D2O) δ 23.53 (CH3), 26.57 (CH2), 52.96 (α-C), 130.07 (C=C), 143.79 (C=C), 172.59 (C=O), 172.72 (C=O), 173.01 (C=O). FAB-MS m/z 199 (MH)+. Anal. (C8H10N2O4.1/3H2O) C, H, N.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:14]=[CH:13][C:9]([C:10](O)=[O:11])=[C:8]([F:15])[CH:7]=2)[CH2:3][CH2:2]1.B.C1COCC1.O>C1COCC1>[CH:1]1([CH2:4][O:5][C:6]2[CH:14]=[CH:13][C:9]([CH2:10][OH:11])=[C:8]([F:15])[CH:7]=2)[CH2:2][CH2:3]1
Reactant: O=C(O)c1ccc(OCC2CC2)cc1F
Agent: B
Solvent: C1CCOC1
Solvent: O
Product: OCc1ccc(OCC2CC2)cc1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 87.4 %

Procedure:
To a solution of 4-(cyclopropylmethoxy)-2-fluorobenzoic acid (5.00 g, 23.8 mmol) in THF (100 mL) was added dropwise 1 M borane-THF solution (54.7 mL, 54.7 mmol), and the mixture was stirred at room temperature for 3 hr. To the reaction mixture was slowly added dropwise water (100 mL). To this solution was further added water, and the mixture was extracted with ethyl acetate. The extract was washed with 10% aqueous potassium carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The solution was purified by basic silica gel column chromatography (ethyl acetate), and the obtained residue was triturated with hexane to give the title compound (4.08 g, yield 87%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([S:10]([CH3:13])(=[O:12])=[O:11])[CH:3]=1.[NH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.CC(C)([O-])C.[Na+]>O1CCOCC1.CCOCC.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:13][S:10]([C:4]1[CH:3]=[C:2]([N:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[CH:7]=[CH:6][C:5]=1[O:8][CH3:9])(=[O:12])=[O:11]
Reactant: C1CNCCN1
Reactant: COc1ccc(Br)cc1S(C)(=O)=O
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: CCOCC
Product: COc1ccc(N2CCNCC2)cc1S(C)(=O)=O
Temperature: 25 °C

Procedure:
A mixture of 4-bromo-2-methanesulfonyl-1-methoxy-benzene (0.65 g,), piperazine (0.43 g,), sodium tert-butoxide (0.13 g) BINAP (19 mg) and [Pd2(dba)3 (27 mg) in dioxane (5 ml) was heated under argon at 100° C. for 24 h. After cooling to room temperature, the reaction mixture was taken up in Et2O (40-50 ml) and washed with brine (15-20 ml). The organic fraction was dried (MgSO4), filtered and evaporated to dryness. The crude material was purified by flash chromatography on silica gel using CH2Cl2:MeOH (9:1 (v/v)) Yield 0.14 g: MS m/z (rel. intensity, 70 eV)) 270 (M+, 23), 229 (11), 228 (bp), 148 (7), 56 (17).
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[I:6][C:7]1[C:16](=O)[C:15]2[C:10](=[CH:11][C:12]([O:20][CH3:21])=[C:13]([O:18][CH3:19])[CH:14]=2)[NH:9][CH:8]=1>CN(C=O)C>[Cl:3][C:16]1[C:15]2[C:10](=[CH:11][C:12]([O:20][CH3:21])=[C:13]([O:18][CH3:19])[CH:14]=2)[N:9]=[CH:8][C:7]=1[I:6]
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1cc2[nH]cc(I)c(=O)c2cc1OC
Solvent: CN(C)C=O
Product: COc1cc2ncc(I)c(Cl)c2cc1OC
Temperature: 100 °C
Reaction time: 2 h

Procedure:
Phosphorus oxychloride (6.743 g, 4.100 mL, 43.98 mmol) was added to a solution of 3-iodo-6,7-dimethoxyquinolin-4(1H)-one (13.237 g, 39.98 mmol) in DMF (100 mL). The mixture was stirred at 100° C. for 2 h then cooled to RT. The mixture was poured into ice water and the resulting precipitate was filtered and dried to afford 4-chloro-3-iodo-6,7-dimethoxyquinoline as a light brown solid. MS (ESI, pos. ion) m/z: 349.9 (M+H). Mass Calc'd for C11H9ClINO2: 349.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][O:9][C:10](=[O:22])[CH2:11][NH:12][C:13](=[O:21])[C@H:14]([CH2:16][O:17][CH2:18][CH:19]=[CH2:20])[NH2:15].[C:23]([O:27][C:28]([NH:30][C@H:31]([C:37]([NH:39][C@H:40]([C:44]([NH:46][C@H:47]([C:51](O)=[O:52])[CH:48]([CH3:50])[CH3:49])=[O:45])[CH:41]([CH3:43])[CH3:42])=[O:38])[CH2:32][O:33][CH2:34][CH:35]=[CH2:36])=[O:29])([CH3:26])([CH3:25])[CH3:24].C(N(CC)C(C)C)(C)C.C1C=C2N=NN(O)C2=CC=1.O.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[CH3:8][O:9][C:10](=[O:22])[CH2:11][NH:12][C:13](=[O:21])[C@H:14]([CH2:16][O:17][CH2:18][CH:19]=[CH2:20])[NH:15][C:51](=[O:52])[C@H:47]([CH:48]([CH3:50])[CH3:49])[NH:46][C:44](=[O:45])[C@H:40]([CH:41]([CH3:42])[CH3:43])[NH:39][C:37](=[O:38])[C@H:31]([CH2:32][O:33][CH2:34][CH:35]=[CH2:36])[NH:30][C:28]([O:27][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:29]
Reactant: C=CCOC[C@H](N)C(=O)NCC(=O)OC
Reactant: C=CCOC[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@H](C(=O)N[C@H](C(=O)O)C(C)C)C(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: C=CCOC[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@H](C(=O)N[C@H](C(=O)N[C@@H](COCC=C)C(=O)NCC(=O)OC)C(C)C)C(C)C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
O-allyl L-seryl methyl ester trifluoroacetate 20 (7.03 g, 21.3 mmol), N-tert-butoxycarbonyl O-allyl L-seryl L-valyl L-valine 15 (9.45 g, 21.3 mmol) and N,N-diisopropylethyl amine (2.75 g, 21.3 mmol) were dissolved in CH2Cl2 (100 mL) and the solution cooled to 0° C. (icebath). HOBt hydrate (3.26 g, 21.3 mmol) and then EDC hydrochloride (4.49 g, 23.4 mmol) were added in small portions. The reaction mixture was stirred for 1 h 30 min at 0° C. after which the icebath was removed and the mixture stirred for 14 h 30 min. The volume was then increased by addition of CH2Cl2 (200 mL) and the mixture stirred for another 7 hours before the volume was increased to 400 mL. The suspension was washed with 2M aqueous H2SO4 (150+300+450 mL), 7.5% (w/w) aqueous K2CO3 (150+300+450 mL), saturated brine (400 mL) and water (400+600 mL). The suspension was then diluted with CH2Cl2 (1.5 L) and dried with 3 Å molecular sieves resulting in a slightly turbid solution.
Reaction SMILES: [C:1]1([CH3:23])[CH:6]=[CH:5][C:4]([N:7]2[CH2:11][CH:10]([CH2:12][O:13][C:14]3[CH:21]=[CH:20][C:17]([CH:18]=[O:19])=[CH:16][CH:15]=3)[O:9][C:8]2=[O:22])=[CH:3][CH:2]=1.ClC1C=CC(N2CC(COC3C=CC(C=O)=CC=3)OC2=O)=CC=1>>[C:1]1([CH3:23])[CH:2]=[CH:3][C:4]([N:7]2[CH2:11][CH:10]([CH2:12][O:13][C:14]3[CH:21]=[CH:20][C:17]([CH2:18][OH:19])=[CH:16][CH:15]=3)[O:9][C:8]2=[O:22])=[CH:5][CH:6]=1
Reactant: Cc1ccc(N2CC(COc3ccc(C=O)cc3)OC2=O)cc1
Agent: O=Cc1ccc(OCC2CN(c3ccc(Cl)cc3)C(=O)O2)cc1
Product: Cc1ccc(N2CC(COc3ccc(CO)cc3)OC2=O)cc1
Yield: 63 %

Procedure:
The same procedure of Example 20 was repeated except that 4-[3-(4-tolyl)-2-oxooxazolidin-5-yl]methoxybenzaldehyde (compound 20) obtained in Example 2 was used in lieu of 4-[3-(4-chlorophenyl)-2-oxooxazolidin-5-yl]methoxybenzaldehyde to give the title compound (compound 175) in a yield of 63%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@@H:8]([C:13]2[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=2)[CH2:9][C:10](O)=[O:11])[CH:5]=[CH:6][CH:7]=1.[NH2:23][C:24]1[CH:54]=[CH:53][CH:52]=[C:51]([F:55])[C:25]=1[CH2:26][CH2:27][C@H:28]1[O:33][CH2:32][C@@H:31]([CH2:34][O:35][C:36](=[O:43])[NH:37][CH2:38][C:39]([F:42])([F:41])[F:40])[N:30]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:29]1.O=P(Cl)(Cl)Cl>N1C=CC=CC=1>[F:55][C:51]1[CH:52]=[CH:53][CH:54]=[C:24]([NH:23][C:10](=[O:11])[CH2:9][C@@H:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)[C:13]2[CH:14]=[CH:15][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:17][CH:18]=2)[C:25]=1[CH2:26][CH2:27][C@H:28]1[O:33][CH2:32][C@@H:31]([CH2:34][O:35][C:36](=[O:43])[NH:37][CH2:38][C:39]([F:42])([F:40])[F:41])[N:30]([C:44]([O:46][C:47]([CH3:48])([CH3:49])[CH3:50])=[O:45])[CH2:29]1
Reactant: CS(=O)(=O)c1ccc([C@@H](CC(=O)O)c2cccc(F)c2)cc1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](CCc2c(N)cccc2F)OC[C@H]1COC(=O)NCC(F)(F)F
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: CC(C)(C)OC(=O)N1C[C@@H](CCc2c(F)cccc2NC(=O)C[C@H](c2ccc(S(C)(=O)=O)cc2)c2cccc(F)c2)OC[C@H]1COC(=O)NCC(F)(F)F
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
The product from step 1 (34 mg, 0.1 mmol) and the product from step 4 of Example 99 (50 mg, 0.1 mmol) were dissolved in pyridine (1 mL) and the stirred solution was cooled to −10° C. in an ice/acetone bath. To the cold solution was added POCl3 (0.01 mL, 0.12 mmol). The mixture was stirred at −10° C. for 30 min. The reaction was quenched by the addition of saturated aqueous NaHCO3 solution (1 mL) and the mixture was allowed to warm to ambient temperature. The mixture was diluted with water (10 mL) and extracted with dichloromethane (3×10 mL). The combined dichloromethane phases were dried (Na2SO4), filtered, and the filtrate solvents were removed in vacuo. The residue was purified on a 12 g silica gel column using a gradient elution of 0-100% EtOAc:hexanes. Fractions containing product were combined and the solvents were removed in vacuo to give the title compound as a gum. (M+H-Boc)+=684.
Reaction SMILES: [N:1]1[CH:6]=[C:5]([C:7]([OH:9])=O)[N:4]=[CH:3][C:2]=1[C:10]([OH:12])=[O:11].C1C=CC2N(O)N=NC=2C=1.Cl.CN(C)CCCN=C=NCC.CCN(C(C)C)C(C)C.[NH2:44][CH2:45][CH2:46][N:47]1[CH:51]=[CH:50][C:49]([C:52]2[CH:59]=[CH:58][C:55]([C:56]#[N:57])=[C:54]([Cl:60])[CH:53]=2)=[N:48]1>C(Cl)Cl.O>[Cl:60][C:54]1[CH:53]=[C:52]([C:49]2[CH:50]=[CH:51][N:47]([CH2:46][CH2:45][NH:44][C:7]([C:5]3[N:4]=[CH:3][C:2]([C:10]([OH:12])=[O:11])=[N:1][CH:6]=3)=[O:9])[N:48]=2)[CH:59]=[CH:58][C:55]=1[C:56]#[N:57]
Reactant: N#Cc1ccc(-c2ccn(CCN)n2)cc1Cl
Reactant: O=C(O)c1cnc(C(=O)O)cn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: N#Cc1ccc(-c2ccn(CCNC(=O)c3cnc(C(=O)O)cn3)n2)cc1Cl
Yield: 49.9 %

Procedure:
Pyrazine-2,5-dicarboxylic acid (0.53 g; 3.18 mmol), anhydrous HOBt (0.43 g; 3.18 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.61 g; 3.18 mmol) and DIPEA (0.55 ml; 3.18 mmol) were dissolved in 5 ml of dry DCM. 4-(1-(2-Aminoethyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (0.6 g; 2.12 mmol) and DIPEA (0.55 ml; 3.18 mmol) were dissolved in 5 ml of dry DCM and added dropwise to the previous mixture. The reaction mixture was stirred overnight after which pyrazine-2,5-dicarboxylic acid (0.27 g; 1.59 mmol), anhydrous HOBt (0.52 g; 3.81 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.41 g: 2.12 mmol) and DIPEA (0.37 ml; 2.12 mmol) were added to drive the reaction to completion. After 2.5 h the mixture was diluted with 20 ml of DCM. After addition of 10 ml of water, the product precipitated and was filtered yielding 0.42 g of crude product which was used without further purification.