Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:14]=[C:13]2[C:6]([NH:7][CH:8]=[C:9]2[CH2:10][CH2:11][NH2:12])=[CH:5][CH:4]=1.[O:15]1[CH2:19][CH2:18][CH2:17][CH:16]1[C:20](Cl)=[O:21].C(OCC)(=O)C>C1C=CC=CC=1.CCOCC.C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:14]=[C:13]2[C:6](=[CH:5][CH:4]=1)[NH:7][CH:8]=[C:9]2[CH2:10][CH2:11][NH:12][C:20]([CH:16]1[CH2:17][CH2:18][CH2:19][O:15]1)=[O:21]
Reactant: COc1ccc2[nH]cc(CCN)c2c1
Reactant: O=C(Cl)C1CCCO1
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Solvent: ClCCl
Product: COc1ccc2[nH]cc(CCNC(=O)C3CCCO3)c2c1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
5-Methoxytryptamine (540 mg, 2.84 mmole) was suspended in benzene (5 ml). The mixture was cooled in an ice bath and a solution of tetrahydro-2-furoyl chloride (390 μl, 3.7 mmole) in benzene (5 ml) was slowly added. The reaction, mixture was stirred at room temperature for 15 hours and was diluted with ether (25 ml). It was extracted with water (25 ml), NaHCO3 solution (2×25 ml) and saturated NaCl solution (25 ml) dried (MgSO4) and the solvent was removed in vacuo. Further purification was obtained by column chromatography on silica gel. The solvent was 50% ethyl acetate in CH2Cl2. Fractions of 10 ml were collected and the product was eluted in fractions 19-32. The product was obtained as an oil. The yield was 220 mg (−30%).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH:6]([NH:8][C:9]1[N:14]=[C:13]([C:15](=[N:19][O:20]C(=O)C(Cl)Cl)[C:16]([OH:18])=O)[CH:12]=[CH:11][CH:10]=1)=[O:7].[NH2:26][CH:27]1[C:45](=[O:46])[N:29]2[C:30]([C:42]([OH:44])=[O:43])=[C:31]([CH2:34][S:35][C:36]3[N:40]([CH3:41])[N:39]=[N:38][N:37]=3)[CH2:32][S:33][C@H:28]12>CN(C)C=O.C[Si](CC(N)=O)(C)C.C(Cl)Cl>[CH:6]([NH:8][C:9]1[N:14]=[C:13]([C:15](=[N:19][OH:20])[C:16]([NH:26][CH:27]2[C:45](=[O:46])[N:29]3[C:30]([C:42]([OH:44])=[O:43])=[C:31]([CH2:34][S:35][C:36]4[N:40]([CH3:41])[N:39]=[N:38][N:37]=4)[CH2:32][S:33][C@H:28]23)=[O:18])[CH:12]=[CH:11][CH:10]=1)=[O:7]
Reactant: Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Reactant: O=CNc1cccc(C(=NOC(=O)C(Cl)Cl)C(=O)O)n1
Agent: C[Si](C)(C)CC(N)=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NO)c3cccc(NC=O)n3)[C@H]2SC1
Reaction time: 0.5 h
Yield: 68.8 %

Procedure:
A solution of phosphoryl chloride (2.14 g.) in N,N-dimethylformamide (14 ml.) was stirred at 37° to 40° C. for 30 minutes. To the solution were added methylene chloride (14 ml.) and 2-(6-formamidopyridin-2-yl)-2-dichloroacetoxyiminoacetic acid (syn isomer) (4.48 g.) at -20° to -25° C. and stirred at -10° to -15° C. for 30 minutes [solution A]. On the other hand, 7-amino-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (4.6 g.) was dissolved in a solution of trimethylsilylacetamide (14 g.) in methylene chloride (150 ml.) at 40° C., and cooled to -10° to -15° C. The solution was added to the above solution A at -10° to -15° C. and stirred at the same temperature for 30 minutes. After removing methylene chloride from the resultant solution under reduced pressure, ice water and ethyl acetate were added to the residue, and adjusted to pH 4 with an aqueous solution of sodium bicarbonate. The aqueous layer was separated, washed with ethyl acetate, adjusted to pH 2 with 10% hydrochloric acid, and then extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and concentrated under reduced pressure. The residue was triturated with diethyl ether. The precipitates were collected by filtration; washed with diethyl ether and dired to give 7-[2-(6-formamidopyridin-2-yl)-2-hydroxyiminoacetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (5.0 g.), mp. 110° to 115° C.
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[CH2:14][C@@H:13](C(O)O)[O:12][C:11](=[O:18])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C1(C)C(S(O)(=O)=O)=CC=CC=1.[CH:30]([O:35][CH3:36])([O:33][CH3:34])OC.C([O-])(O)=O.[Na+]>ClCCl>[Si:1]([O:8][C@@H:9]1[CH2:14][C@@H:13]([CH:30]([O:33][CH3:34])[O:35][CH3:36])[O:12][C:11](=[O:18])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CC(=O)O[C@H](C(O)O)C1
Reactant: COC(OC)OC
Agent: Cc1ccccc1S(=O)(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COC(OC)[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 1.0 g of (4R,6S)-4-(tert-butyldimethylsilyloxy)-6-(dihydroxymethyl)-tetrahydropyran-2-one (V′) in 100 mL of dichloromethane, 50 mg of toluenesulfonic acid and 4.5 mL of trimethyl orthoformate are added. After 2 hours of stirring at 25° C., 0.2 g of NaHCO3 is added and dichloromethane is distilled off. The residue is flash chromatographed (MTBE/hexane 1/1) and the solvents are distilled off to get the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:14])[C:9](OCC)=[O:10])=[CH:4][CH:3]=1.[H-].C([Al+]CC(C)C)C(C)C>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([CH3:14])[CH2:9][OH:10])=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(C)c1ccc(Br)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Product: CC(CO)c1ccc(Br)cc1
Reaction time: 1 h
Yield: 91.4 %

Procedure:
To a solution of 73A (3.06 g, 11.9 mmol) in 50 mL CH2Cl2 at −78° C., was added a solution of diisobutylaluminum hydride (35.7 mL, 35.7 mmol, 1M in hexanes). The mixture was removed from the cooling bath, stirred 1 h, then recooled to −50° C. and quenched with EtOAc (2 mL). The reaction mixture was diluted with H2O, then extracted with EtOAc (3×). The combined organic extract washed with brine, dried (Na2SO4), filtered through a 1″ pad of SiO2, then concentrated to afford 2.34 g of 73B as a colorless oil. MS (ESI) m/z 197.1 (M-OH)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[NH:7][C:8]([C:10]1[S:11][C:12]([S:32][CH3:33])=[C:13]([S:15]([C:18]2[CH:19]=[C:20]([C:24]3[C:29]([CH3:30])=[CH:28][CH:27]=[CH:26][C:25]=3[NH2:31])[CH:21]=[CH:22][CH:23]=2)(=[O:17])=[O:16])[CH:14]=1)=[NH:9])([CH3:4])([CH3:3])[CH3:2].[Br:35][CH2:36][C:37](Br)=[O:38].CCN(C(C)C)C(C)C.CCOC(C)=O>C(Cl)(Cl)Cl.C(Cl)Cl>[C:1]([O:5][C:6](=[O:34])[NH:7][C:8]([C:10]1[S:11][C:12]([S:32][CH3:33])=[C:13]([S:15]([C:18]2[CH:19]=[C:20]([C:24]3[C:25]([NH:31][C:37](=[O:38])[CH2:36][Br:35])=[CH:26][CH:27]=[CH:28][C:29]=3[CH3:30])[CH:21]=[CH:22][CH:23]=2)(=[O:17])=[O:16])[CH:14]=1)=[NH:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(Br)CBr
Reactant: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(-c2c(C)cccc2N)c1
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(-c2c(C)cccc2NC(=O)CBr)c1
Yield: 76.2 %

Procedure:
Following the procedure described for Example 234, step a, reaction of {[4-(6′-amino-2′-methyl-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester (137 mg, 0.265 mmol, as prepared in Example 25, step c), bromoacetyl bromide (28 μL, 0.32 mmol), and DIEA (70 μL, 0.40 mmol) in chloroform (3 mL) afforded 129 mg (76%) of the title compound as a yellow foamy solid after chromatography (PTLC, 10% EtOAc in DCM, 2×1500μ SiO2 plate). 1H-NMR (CDCl3; 400 MHz): δ 8.05–8.10 (m, 1H), 7.85–7.95 (m, 2H), 7.65–7.73 (m, 2H), 7.46–7.51 (m, 1H), 7.35 (t, 1H, J=7.9 Hz), 7.16 (d, 1H, J=7.7 Hz), 3.64 and 3.74 (AB quartet, 2H, J=14.0 Hz), 2.60 (s, 3H), 2.03 (s, 3H), 1.52 (s, 9H). ESI-MS (m/z): Calcd. for C26H28BrN3O5S3: 637.0 (M+H); found: 637.8, 639.8, 538.0, 540.0 (M−Boc).
Reaction SMILES: I[C:2]1[N:3]=[CH:4][N:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=12.C([Mg]Cl)(C)C.[CH2:16]([Sn:20]([CH2:26][CH2:27][CH2:28][CH3:29])([CH2:22][CH2:23][CH2:24][CH3:25])Cl)[CH2:17][CH2:18][CH3:19]>C1COCC1>[CH2:26]([Sn:20]([CH2:16][CH2:17][CH2:18][CH3:19])([CH2:22][CH2:23][CH2:24][CH3:25])[C:2]1[N:3]=[CH:4][N:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=12)[CH2:27][CH2:28][CH3:29]
Reactant: Ic1ncn2ccccc12
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1ncn2ccccc12
Temperature: -10 °C
Reaction time: 0.33 h

Procedure:
To a solution of 1-iodo-imidazo[1,5-a]pyridine (150 mg, 0.62 mmol) in THF (3 mL) at −10° C. (ice/acetone) was added isopropylmagnesium chloride (2.0 M in THF, 37 mL, 0.74 mmol). The reaction mixture was stirred at −10° C. for 20 min then tributylchlorostannane (0.20 mL, 0.74 mmol) was added. The reaction was stirred at −10° C. for 30 min then warmed to room temperature and stirred for 1 h. The reaction was quenched with water and extracted with EtOAc (2×). The combined organics were dried over MgSO4 and concentrated to afford 1-tributylstannanyl-imidazo[1,5-a]pyridine as a yellow oil which was used without further purification.
Reaction SMILES: [Si]([O:8][C@@H:9]1[C@@:45]2([CH3:46])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:44]2[CH2:43][CH2:42][C@@:41]2([CH3:47])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C:21]([O:24]/[CH:25]=[CH:26]\[CH2:27][C:28]([CH2:39][CH3:40])([O:31][Si](CC)(CC)CC)[CH2:29][CH3:30])([CH3:23])[CH3:22])[CH2:12][C@@H:11]([O:48][Si](C(C)(C)C)(C)C)[CH2:10]1)(C(C)(C)C)(C)C.O1CCCC1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>>[CH2:29]([C:28]([OH:31])([CH2:39][CH3:40])[CH2:27]/[CH:26]=[CH:25]\[O:24][C:21]([CH3:23])([C:20]1[C@:41]2([CH3:47])[C@H:17]([C:16]3[C@H:44]([CH2:43][CH2:42]2)[C@:45]2([CH3:46])[C:13]([CH2:12][C@@H:11]([OH:48])[CH2:10][C@@H:9]2[OH:8])=[CH:14][CH:15]=3)[CH2:18][CH:19]=1)[CH3:22])[CH3:30]
Reactant: CCC(CC)(C/C=C\OC(C)(C)C1=CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C)O[Si](CC)(CC)CC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCC(O)(CC)C/C=C\OC(C)(C)C1=CC[C@H]2C3=CC=C4C[C@@H](O)C[C@H](O)[C@]4(C)[C@H]3CC[C@]12C
Yield: 90.6 %

Procedure:
1α,3β-Bis(tert-butyldimethylsilyloxy)-20-{4-ethyl-4-triethylsilyloxy-(2Z)-hexenyloxy}-20-methylpregna-5,7,16-triene (99 mg, 0.122 mmol) and a 1M tetra-n-butylammonium fluoride tetrahydrofuran solution (5 ml) were subjected to reaction using a procedure similar to that of Example 5(2) (3 hours), worked up and purified by column chromatography (ethyl acetate) to give the titled compound (52 mg, 91%) as a colorless glassy substance.
Reaction SMILES: [CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[O:6][C:5]=2[CH:4]=[CH:3][C:2]=1[CH:16]([CH3:20])[C:17](O)=[O:18].S(Cl)(Cl)=O.O.[NH3:26].Cl>C1C=CC=CC=1.N1C=CC=CC=1.C(Cl)(Cl)Cl>[CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[O:6][C:5]=2[CH:4]=[CH:3][C:2]=1[CH:16]([CH3:20])[C:17]([NH2:26])=[O:18]
Reactant: N
Reactant: CC(C(=O)O)c1ccc2c(c1)CCc1ccccc1O2
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: CC(C(N)=O)c1ccc2c(c1)CCc1ccccc1O2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 132 mg of 2-(10,11-dihydro dibenzo[b,f]oxepin-2-yl)-propionic acid in 2 ml of benzene were added 0.6 ml of thionyl chloride and three drops of pyridine and the mixture was stirred at room temperature for 1 hour, then refluxed with stirring for 1 hour. The solvent was distilled off to obtain the residue, which was dissolved in 2 ml of chloroform and the resulting solution was added to 2 ml of 28% ammonia water. The mixture was stirred at room temperature for 3 hours. The reaction mixture was acidified with hydrochloric acid and extracted with ethyl acetate. The extract was washed with 1N-sodium hydroxide solution, then saturated sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was distilled off to obtain yellowish brown oil, which was chromatographed over silica gel, eluted with chloroform/methanol (200/1). The eluate was crystallized from benzene-n-hexane to give 115 mg of 2-(10,11-dihydro dibenzo[b,f]oxepin-2-yl)-propionamide as pale yellow crystals having a melting point of 122.5°-123° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1F)([O-:3])=[O:2].[CH2:14]([CH2:16][NH2:17])[OH:15].C([O-])([O-])=O.[K+].[K+]>C(#N)C>[N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[NH:17][CH2:16][CH2:14][OH:15])([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(F)c([N+](=O)[O-])c1
Reactant: NCCO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(NCCO)c([N+](=O)[O-])c1
Temperature: 65 °C

Procedure:
A mixture of 3.0 g of 2,4-dinitrofluorobenzene (16.12 mmol, 1 eq) and 1.17 ml ethanolamine (19.34 mmol, 1.2 eq) in acetonitrile (30 ml) with 3.56 g of K2CO3 (25.79 mmol, 1.6 eq) was heated at 65° C. overnight. The reaction mixture became red. The solvent was removed under reduced pressure. The residue was diluted in 1N Na2CO3 and extracted with ethyl acetate (5×50 ml). The combined organic layer was washed with saturated NaCl (3×20 ml), dried over MgSO4 and concentrated under reduced pressure. To this orange solution was added ethanol (20 ml) and the mixture was heated at 80° C. until dissolution was complete. Distilled water (20 ml) was added and the solution was cooled to room temperature over a period of 1 hour. The yellow solid which crystallized was collected by filtration, washed with 30/70:ethanol/water and then distilled water (2×30 ml). The solid was dried by lyophilization.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([NH2:6])=[O:5].O.[OH-].[Na+].O=[C:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH:12]=O>CO.C(O)(=O)C>[C:14]1([C:11]2[N:2]=[CH:3][C:4](=[O:5])[NH:6][CH:12]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=CC(=O)c1ccccc1
Reactant: NCC(N)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Solvent: O
Product: O=c1cnc(-c2ccccc2)c[nH]1
Temperature: -20 °C
Reaction time: 1 h
Yield: 75.6 %

Procedure:
To a mixture of glycine amide hydrochloride (0.73 g), methanol (6.0 mL) and water (1.5 mL) were added a 12.5M aqueous sodium hydroxide solution (0.80 mL) and a solution of sodium hydroxide (0.26 g) in methanol (3.0 mL) at −30° C. Then, a solution of oxo(phenyl)acetaldehyde (1.0 g) in methanol (5.0 mL) was added, and the mixture was stirred at −20° C. for 2 hr and at room temperature for 1 hr. The reaction mixture was neutralized with acetic acid, and the resulting solid was collected by filtration and washed with water to give the title compound (0.86 g).
Reaction SMILES: [C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].Cl[C:7]1[S:8][C:9]([C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])=[C:10]([C:12]([F:15])([F:14])[F:13])[N:11]=1>C(#N)C>[CH3:2][C:1]([NH:5][C:7]1[S:8][C:9]([C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])=[C:10]([C:12]([F:14])([F:13])[F:15])[N:11]=1)([CH3:4])[CH3:3]
Reactant: O=C(OCc1ccccc1)c1sc(Cl)nc1C(F)(F)F
Reactant: CC(C)(C)N
Solvent: CC#N
Product: CC(C)(C)Nc1nc(C(F)(F)F)c(C(=O)OCc2ccccc2)s1
Yield: 42.6 %

Procedure:
By the procedure of Example 39, a stirred mixture of 15 ml of acetonitrile, 2.72 g (38 mmol) of tert-butylamine, and 6 g (19 mmol) of benzyl 2-chloro-4-trifluoromethyl-5-thiazolecarboxylate (prepared as described in U.S. Pat. No. 4,199,506), was heated at reflux for 66 hours. The product was separated and then recrystallized from hexane to yield 2.90 g of an off-white powder product (m.p.=79°-81° C.) identified in Table I.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[CH2:11][CH2:10][C:9]2[C:4](=[C:5]([CH3:19])[C:6]([CH3:18])=[C:7]([OH:17])[C:8]=2[CH2:12][CH:13]=[C:14]([CH3:16])[CH3:15])[O:3]1.[N+]([O-])([O-])=[O:22].[NH4+].[Ce+4].[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.ClCCl.O>C(#N)C.O>[OH:3][C:2]([CH3:20])([CH3:1])[CH2:11][CH2:10][C:9]1[C:4](=[O:22])[C:5]([CH3:19])=[C:6]([CH3:18])[C:7](=[O:17])[C:8]=1[CH2:12][CH:13]=[C:14]([CH3:16])[CH3:15]
Reactant: CC(C)=CCc1c(O)c(C)c(C)c2c1CCC(C)(C)O2
Reactant: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: O
Solvent: CC#N
Solvent: ClCCl
Product: CC(C)=CCC1=C(CCC(C)(C)O)C(=O)C(C)=C(C)C1=O
Reaction time: 0.08 h
Yield: 48.5 %

Procedure:
To a stirring solution of 113 mg 2,2,7,8-tetramethyl-5-(3-methyl-but-2-enyl)-chroman-6-ol (prepared in the method of Walkinshaw, et al., US 2005/0065099 A1, Mar. 24, 2005) in 3.75 mL acetonitrile-water (5:1) at 5° C. was added a yellow solution of cerium(IV) ammonium nitrate (475 mg) in acetonitrile-water (1:4, 2.75 mL) over a period of 5 minutes. The reaction mixture was allowed to stir for an additional 5 minutes, after which it was poured into a separatory funnel containing dichloromethane (30 mL) and water (30 mL). The aqueous layer was removed and the remaining organics were washed once with 1.0 M sodium chloride solution (30 mL). The organics were subsequently dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. Silica gel chromatography (15% ethyl acetate-85% hexanes) provided 58 mg of 2-(3-hydroxy-3-methyl-butyl)-5,6-dimethyl-3-(3-methyl-but-2-enyl)-[1,4]benzoquinone. 1H NMR (CDCl3, 400 MHz) 4.92 (t, 1H), 3.18 (d, 2H), 2.54 (t, 2H), 1.99 (s, 6H), 1.74 (s, 3H), 1.66 (s, 3H), 1.52 (m, 2H), 1.26 (s, 6H).
Reaction SMILES: [NH2:1][C:2]1[N:7]([C:8]2[CH:22]=[CH:21][C:11]([O:12][CH2:13][CH2:14][CH2:15]OS(C)(=O)=O)=[CH:10][CH:9]=2)[C:6](=[O:23])[CH:5]=[CH:4][C:3]=1[C:24](=[O:32])[C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=1.[CH:33]1([O:38][C:39](=[O:46])[C@H:40]([CH2:42][CH:43]([CH3:45])[CH3:44])[NH2:41])[CH2:37][CH2:36][CH2:35][CH2:34]1>>[NH2:1][C:2]1[N:7]([C:8]2[CH:9]=[CH:10][C:11]([O:12][CH2:13][CH2:14][CH2:15][NH:41][C@@H:40]([CH2:42][CH:43]([CH3:44])[CH3:45])[C:39]([O:38][CH:33]3[CH2:34][CH2:35][CH2:36][CH2:37]3)=[O:46])=[CH:21][CH:22]=2)[C:6](=[O:23])[CH:5]=[CH:4][C:3]=1[C:24](=[O:32])[C:25]1[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=1
Reactant: CC(C)C[C@H](N)C(=O)OC1CCCC1
Reactant: CS(=O)(=O)OCCCOc1ccc(-n2c(N)c(C(=O)c3ccc(F)cc3)ccc2=O)cc1
Product: CC(C)C[C@H](NCCCOc1ccc(-n2c(N)c(C(=O)c3ccc(F)cc3)ccc2=O)cc1)C(=O)OC1CCCC1

Procedure:
From Intermediate 4B and L-leucine cyclopentyl ester (Intermediate 8), LCMS purity 97%, m/z 564 [M+H]+, 1H NMR (400 MHz, d6-DMSO), δ: 0.90 (6H, m), 1.60-1.75 (10H, m), 1.90 (2H, m), 2.15 (2H, m), 3.10-3.30 (2H, m), 4.10 (1H, m), 4.15 (2H, m), 5.30 (1H, m), 5.70 (1H, d). 7.15 (2H, d), 7.30 (2H, d), 7.35 (2H, t), 7.50 (1H, d), 7.55 (1H, m) 9.05-30 (2H, m).
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:15][CH2:16][CH2:17][CH2:18][N:19]([CH3:21])[CH3:20])=[C:4]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:5]([CH3:9])=[N:6][C:7]=1[NH2:8].O.[CH:23]([CH:25]=O)=O>C1(C)C=CC=CC=1>[CH3:20][N:19]([CH3:21])[CH2:18][CH2:17][CH2:16][NH:15][C:3]1[C:2]2[C:7](=[N:8][CH:23]=[CH:25][N:1]=2)[N:6]=[C:5]([CH3:9])[C:4]=1[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)c1c(C)nc(N)c(N)c1NCCCN(C)C
Reactant: O=CC=O
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)c1c(C)nc2nccnc2c1NCCCN(C)C

Procedure:
3 g. of crude 5,6-diamino-4-[[3-(dimethylamino)propyl]-amino]-2-methylpyridine-3-carboxylic acid, ethyl ester and 1 g. of glyoxal-monohydrate are refluxed in 20 ml. of toluene for 4 hours. After evaporation of the solvent and addition of a small amount of charcoal, the residue is extracted with 50 ml. of boiling gasoline. On cooling 8-[[3-(dimethylamino)propyl]amino]-6-methylpyrido[2,3-b]pyrazine-7-carboxylic acid, ethyl ester precipitates, m.p. 42°-44° (gasoline).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[H-].[Na+].[CH2:14](Br)[CH:15]=[CH2:16]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:14]=[CH:15][CH3:16])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: C=CCBr
Reactant: O=[N+]([O-])c1cc(O)ccc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC=COc1ccc(Cl)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1 mmol of 2-chloro-5-hydroxy nitrobenzene in 5 mL of DMF was added 1.2 mmol of NaH at 0° C. After 30 min, allyl bromide was added and the mixture was stirred at rt for 16 h. Solvent was removed and the residue was washed with water and extracted with EtOAc to give 2-chloro-5-propenyloxy nitrobenzene.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][C:8]([CH2:12][O:13][C:14]2[C:22]3[C:21]4[CH:23]=[C:24]([C:27]#[N:28])[N:25]=[CH:26][C:20]=4[N:19](COCC[Si](C)(C)C)[C:18]=3[N:17]=[CH:16][CH:15]=2)([CH3:11])[CH2:7][CH2:6]1.Br.[OH-].[Na+].Cl>O1CCOCC1>[CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][C:8]([CH2:12][O:13][C:14]2[C:22]3[C:21]4[CH:23]=[C:24]([C:27]#[N:28])[N:25]=[CH:26][C:20]=4[NH:19][C:18]=3[N:17]=[CH:16][CH:15]=2)([CH3:11])[CH2:7][CH2:6]1
Reactant: COCCN1CCC(C)(COc2ccnc3c2c2cc(C#N)ncc2n3COCC[Si](C)(C)C)CC1
Agent: Br
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Product: COCCN1CCC(C)(COc2ccnc3[nH]c4cnc(C#N)cc4c23)CC1
Temperature: 75 °C
Yield: 26.4 %

Procedure:
4-((1-(2-methoxyethyl)-4-methylpiperidin-4-yl)methoxy)-9-(2-trimethylsilanyl-ethoxymethyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile (36 mg, 0.07 mmol) was dissolved in 1,4-dioxane (0.3 mL) and then treated with 48% HBr(aq) (0.3 mL) and heated at 75° C. for 15 minutes. The cooled reaction mixture was then basified to pH ˜12 by dropwise addition of 6N sodium hydroxide and then immediately acidified to pH ˜8-9 by dropwise addition of concentrated hydrochloric acid, producing a cloudy precipitate. The solid was collected by centrifugation, dissolved in dimethylsulfoxide (1 mL), and purified by preparative HPLC [5-85% methanol in water (0.1% ammonium hydroxide) over 30 min, 35 mL/min] to afford the title compound as a white solid (7 mg, 25%). 1H NMR (500 MHz, d6-DMSO) δ 8.99 (s, 1H), 8.55 (d, J=5.7, 1H), 8.35 (s, 1H), 8.31 (s, 1H), 7.08 (d, J=5.8, 1H), 4.13 (s, 2H), 3.44 (t, J=6.4, 2H), 3.24 (s, 3H), 2.66-2.58 (m, 2H), 2.52 (t, J=6.4, 2H), 2.39 (m, 2H), 1.74 (m, 2H), 1.53 (m, 2H), 1.18 (s, 3H). LCMS (Method G): RT=3.92 min, M+H+=380.0.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][C:8](=O)[CH2:9][O:10]2)=[CH:5][CH:4]=1.[CH2:14]([NH2:17])[CH2:15][CH3:16].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>ClCCl.O>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH:8]([NH:17][CH2:14][CH2:15][CH3:16])[CH2:9][O:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2c(c1)OCC(=O)C2
Reactant: CCCN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Solvent: ClCCl
Product: CCCNC1COc2cc(OC)ccc2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92 %

Procedure:
7-Methoxy-chroman-3-one (1.47 g, 8.25 mmol) and propylamine (748 μl, 9.07 mmol) were dissolved in dichloromethane (20 ml). Acetic acid (710 μl, 12.37 mmol) and sodium trisacetoxyborohydride (3.5 g, 16.51 mmol) were sequentially added to the reaction mixture and the mixture was stirred for 1 hour at room temperature. To the reaction mixture was added dichloromethane and water. The aqueous phase was made alkaline with a 1 molar solution of NaOH. The aqueous phase was separated and extracted (3 times) with dichloromethane. The combined organic phases were dried over magnesium sulfate, filtered, and evaporated to dryness to yield the crude product (1.68 g, 92% yield).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([NH2:8])[N:5]=[C:4]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][CH:11]=2)[CH:3]=1.CCO.O>[Fe].CC(O)=O>[NH2:16][C:13]1[CH:12]=[CH:11][C:10]([NH:9][C:4]2[CH:3]=[C:2]([CH3:1])[N:7]=[C:6]([NH2:8])[N:5]=2)=[CH:15][CH:14]=1
Reactant: Cc1cc(Nc2ccc([N+](=O)[O-])cc2)nc(N)n1
Agent: [Fe]
Solvent: O
Solvent: CC(=O)O
Solvent: CCO
Product: Cc1cc(Nc2ccc(N)cc2)nc(N)n1

Procedure:
To a refluxing suspension of amine E2 (5.46 g, 0.02 mol) in 2:1 EtOH:H2O (100 mL) were sequentially added Fe dust (4.97 g, 0.09 mol) and AcOH (2 mL, 2% v/v), and the resulting dark brown suspension was refluxed for ˜14 h. After this time, the hot reaction mixture was filtered through a pad of Celite, and solvent was removed under reduced pressure. The resulting residue was extracted with hot water, and the resulting aqueous suspension filtered through a pad of Celite. Solvent was removed under reduced pressure, and the residue extracted again with hot water. The resulting aqueous suspension was filtered through a pad of Celite. Solvent was removed to afford amine E3 as a brown-white crystalline solid (4.85 g, quantitative). 1H NMR [CD3)2SO]: 2.01 [s, 3H, ArCH3], 5.68 [s, 1H, ArNHAr], 5.88 [br s, 2H, ArNH2], 6.51 [ddd, J=9.67, 4.85, 2.94 Hz, 2H, ArH], 7.14 [d, J=8.52 Hz, 2H, ArH], 8.35 [s, 1H, ArH]. LCMS (APCI+): 216 (100%).