Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:21])[CH2:5][CH:6]([C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)[C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1)C>C1C=CC=CC=1.CCCCCC>[F:13][C:10]1[CH:9]=[CH:8][C:7]([CH:6]([C:14]2[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=2)[CH2:5][C:4]([OH:21])=[O:3])=[CH:12][CH:11]=1
Reactant: CCOC(=O)CC(c1ccc(F)cc1)c1ccc(F)cc1
Solvent: CCCCCC
Solvent: c1ccccc1
Product: O=C(O)CC(c1ccc(F)cc1)c1ccc(F)cc1

Procedure:
Saponification of Intermediate 80A as described in the preparation of Intermediate 1B gave the title acid as white needles: mp 106-107° C. (benzene-hexane). 1HNMR 400 MHz (CDCl3) δ (ppm): 3.05 (2H, d, J=8.1 Hz, CH2), 4.51 (1H, t, J=8.1 Hz, CH), 7.0 (4H, m, aromatics), 7.18 (4H, m, aromatics). Anal. Calcd for C15H12F2O2: C, 68.69; H, 4.61. Found: C, 68.71; H, 4.63.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[CH2:6]([O:13][C:14]1[CH:23]=[C:22]2[C:17]([C:18](O)=[C:19]([N+:24]([O-:26])=[O:25])[CH:20]=[N:21]2)=[CH:16][CH:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>CN(C=O)C.ClCCl>[CH2:6]([O:13][C:14]1[CH:23]=[C:22]2[C:17]([C:18]([Cl:3])=[C:19]([N+:24]([O-:26])=[O:25])[CH:20]=[N:21]2)=[CH:16][CH:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=[N+]([O-])c1cnc2cc(OCc3ccccc3)ccc2c1O
Reactant: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cnc2cc(OCc3ccccc3)ccc2c1Cl
Temperature: 100 °C
Reaction time: 0.42 h
Yield: 94.2 %

Procedure:
N,N-Dimethylformamide (100 mL) (DMF) was cooled to 0° C., and phosphorous oxychloride (27.5 mL, 0.295 mol) was added dropwise. The resulting solution was stirred for 25 minutes and then added dropwise to a mixture of 7-benzyloxy-3-nitroquinolin-4-ol (72.87 g, 0.2459 mol) in DMF (400 mL). Following the addition, the reaction was heated at 100° C. for 5 minutes, cooled to ambient temperature, and poured into ice water with stirring. A tan precipitate formed, which was isolated by filtration and dissolved in dichloromethane. The resulting solution was dried over magnesium sulfate, filtered, and concentrated under reduced pressure to yield 72.9 g of 7-benzyloxy-4-chloro-3-nitroquinoline as a light brown solid.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:24])[C:13](=[O:23])[N:14]([C:15]4[C:16]([CH3:22])=[N:17][N:18]([CH2:20][CH3:21])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[CH2:25]([O:27][C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[CH3:26]>>[CH2:25]([O:27][C:28]1[CH:29]=[C:30]([C:2]2[CH:11]=[CH:10][C:9]3[N:8]=[CH:7][C:6]4[N:12]([CH3:24])[C:13](=[O:23])[N:14]([C:15]5[C:16]([CH3:22])=[N:17][N:18]([CH2:20][CH3:21])[CH:19]=5)[C:5]=4[C:4]=3[CH:3]=2)[CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[CH3:26]
Reactant: CCOc1cc(B(O)O)ccc1OC
Reactant: CCn1cc(-n2c(=O)n(C)c3cnc4ccc(Br)cc4c32)c(C)n1
Product: CCOc1cc(-c2ccc3ncc4c(c3c2)n(-c2cn(CC)nc2C)c(=O)n4C)ccc1OC

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1-ethyl-3-methyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate F, 39 mg, 0.100 mmol) and 3-ethoxy-4-methoxyphenylboronic acid (Combi-Blocks, San Diego, USA, 25.5 mg, 0.130 mmol) to give the title compound as an off-white foam. (HPLC: tR 2.86 min (Method A); M+H=458 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 8.92 (s, 1H), 8.16 (s, 1H), 8.08-8.01 (m, 1H), 7.93-7.87 (m, 1H), 7.52-7.46 (m, 1H), 7.06-6.96 (m, 3H), 4.20-4.03 (m, 4H), 3.77 (s, 3H), 3.57 (s, 3H), 1.97 (s, 3H), 1.45-1.33 (m, 6H))
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[C:14](=O)[NH:13][C:12]([C:16]([OH:18])=[O:17])=[C:11]([CH3:19])[CH:10]=2)[CH:3]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:21]>N1C=CC=CC=1>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[C:14](=[S:21])[NH:13][C:12]([C:16]([OH:18])=[O:17])=[C:11]([CH3:19])[CH:10]=2)[CH:3]=1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: Cc1cc(Nc2cc(N)ncn2)c(=O)[nH]c1C(=O)O
Solvent: c1ccncc1
Product: Cc1cc(Nc2cc(N)ncn2)c(=S)[nH]c1C(=O)O
Temperature: 25 °C

Procedure:
To a solution of 5-((6-aminopyrimidin-4-yl)amino)-3-methyl-6-oxo-1,6-dihydropyridine-2-carboxylic acid (4, 0.5 g, 1.91 mmol) in pyridine (10 mL) is added phosphorus pentasulfide (1.27 g, 5.73 mmol). The reaction is refluxed overnight. The resulting mixture is cooled to room temperature and concentrated. The crude is purified via column chromatography to afford 5-((6-aminopyrimidin-4-yl)amino)-3-methyl-6-thioxo-1,6-dihydropyridine-2-carboxylic acid (5).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]([CH:8]1[CH2:27][C:11]2[NH:12][C:13]3[CH:14]=[CH:15][C:16]([O:19][CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[CH:17][C:18]=3[C:10]=2[CH2:9]1)=[O:7])[CH3:4].[CH3:28]I.O>CN(C)C=O>[CH2:3]([O:5][C:6]([CH:8]1[CH2:27][C:11]2[N:12]([CH3:28])[C:13]3[CH:14]=[CH:15][C:16]([O:19][CH2:20][C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)=[CH:17][C:18]=3[C:10]=2[CH2:9]1)=[O:7])[CH3:4]
Reactant: CCOC(=O)C1Cc2[nH]c3ccc(OCc4ccccc4)cc3c2C1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C1Cc2c(n(C)c3ccc(OCc4ccccc4)cc23)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 102.2 %

Procedure:
To a suspension of sodium hydride (60% in oil, 3.0 g, 0.075 mole) in 25 ml of dry dimethylformamide, was added a solution of 1,2,3,4-tetrahydro-7-phenylmethoxycyclopent[b]indole-2-carboxylic acid ethyl ester (23.5 g, 0.07 mole) in 100 ml of dry dimethylformamide. After stirring at ambient temperature for two hours, a solution of methyl iodide (4.7 ml, 0.075 mole) in 20 ml of dimethylformamide was added, and the mixture was stirred at 70° C. for five hours. After cooling, the mixture was poured into 500 ml of water, stirred for five minutes, and then extracted with ethyl acetate (3×). The organic layer was washed successively with water and saturated sodium chloride solution, and dried over anhydrous MgSO4. After filtering, the solvent was evaporated to afford a brown oil (~25 g), which was eluted on a silica gel column with 5% ethyl acetate/dichloromethane via HPLC. The desired fraction was concentrated to a thick brown oil, 20.6 g, which solidified on cooling, m.p. 90°-95° C. A sample of this material was recrystallized from ethanol to give the product as an off-white solid, m.p. 109°-110° C.
Reaction SMILES: C(OC([NH:11][C:12]1[CH:26]=[CH:25][C:15]([O:16][CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[CH:14][CH:13]=1)=O)C1C=CC=CC=1.C(O)(=O)C.[H][H]>C(O)C.[Pd]>[C:18]([OH:20])(=[O:19])[CH3:17].[NH2:11][C:12]1[CH:13]=[CH:14][C:15]([O:16][CH2:17][C:18]([O:20][C:21]([CH3:22])([CH3:24])[CH3:23])=[O:19])=[CH:25][CH:26]=1
Reactant: CC(C)(C)OC(=O)COc1ccc(NC(=O)OCc2ccccc2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Product: CC(C)(C)OC(=O)COc1ccc(N)cc1
Yield: 126.1 %

Procedure:
To a solution of the product of step (b) (5 g) in ethanol (300 ml) containing glacial acetic acid (0.8 ml) under argon was added 10% Pd on C (250 mg). The argon was replaced by hydrogen and the reaction mixture was stirred under a blanket of hydrogen for 4 hours. The catalyst was filtered off through a pad of diatomaceous earth and washed with ethanol, and the combined filtrate and washings were evaporated to dryness to yield t-butyl 4-aminophenoxyacetate, acetate salt (2.5 g) as brown oil: NMR Spectrum (DMSO-d6) 1.41 (9H, s), 1.86 (3H, s), 4.43 (2H, s), 5.12 (2H, s), 6.49 (2H, d), 6.60 (2H, m).
Reaction SMILES: [C:1]([O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][N:15]1[C:23]2[C:22](Cl)=[N:21][CH:20]=[N:19][C:18]=2[CH:17]=[CH:16]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:25][C:26]1[CH:45]=[CH:44][C:29]([O:30][CH:31]2[CH2:36][CH2:35][N:34]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:33][CH2:32]2)=[C:28]([Cl:46])[CH:27]=1>C(O)(C)C>[C:1]([O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][N:15]1[C:23]2[C:22]([NH:25][C:26]3[CH:45]=[CH:44][C:29]([O:30][CH:31]4[CH2:32][CH2:33][N:34]([C:37]([O:39][C:40]([CH3:42])([CH3:43])[CH3:41])=[O:38])[CH2:35][CH2:36]4)=[C:28]([Cl:46])[CH:27]=3)=[N:21][CH:20]=[N:19][C:18]=2[CH:17]=[CH:16]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OCCOCCn1ccc2ncnc(Cl)c21)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(N)cc2Cl)CC1
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(Nc3ncnc4ccn(CCOCCOC(=O)c5ccccc5)c34)cc2Cl)CC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 73.8 %

Procedure:
A mixture of 2-[2-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethoxy]ethyl benzoate (3.46 g), tert-butyl 4-(4-amino-2-chlorophenoxy)piperidine-1-carboxylate (3.27 g) and isopropyl alcohol (50 mL) was stirred at 80° C. overnight. The reaction mixture was concentrated under reduced pressure, water and saturated aqueous sodium hydrogen carbonate solution were added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was subjected to silica gel column chromatography (eluent, methanol:ethyl acetate=0:100→10:90). The object fraction was concentrated under reduced pressure. The residue was crystallized from ethyl acetate-diisopropyl ether to give the title compound (4.70 g) as a white powder.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10][C:11]2[C:19]3[C:14](=[CH:15][C:16](Br)=[CH:17][CH:18]=3)[N:13]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:12]=2[CH3:28])[CH:5]=1.[CH2:30](B1OC(C)(C)C(C)(C)O1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[CH3:1][O:2][C:3](=[O:29])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10][C:11]2[C:19]3[C:14](=[CH:15][C:16]([CH2:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[CH:17][CH:18]=3)[N:13]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:12]=2[CH3:28])[CH:5]=1
Reactant: CC1(C)OB(Cc2ccccc2)OC1(C)C
Reactant: COC(=O)c1cccc(Sc2c(C)n(Cc3ccccc3)c3cc(Br)ccc23)c1
Product: COC(=O)c1cccc(Sc2c(C)n(Cc3ccccc3)c3cc(Cc4ccccc4)ccc23)c1

Procedure:
Prepared according to the procedure described in Example 11, Step 1, using the following starting materials: 3-(1-benzyl-6-bromo-2-methyl-1H-indol-3-ylsulfanyl)-benzoic acid methyl ester and benzylboronic acid pinacol ester.
Reaction SMILES: C[O:2][C:3](=[O:16])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][CH2:14]Br)=[CH:7][CH:6]=1.[CH3:17][N:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]([CH:27]=[N:28][OH:29])=[C:19]1[CH3:30].[OH-].[Na+]>>[CH3:17][N:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20](/[CH:27]=[N:28]/[O:29][CH2:14][CH2:13][CH2:12][O:11][C:8]2[CH:9]=[CH:10][C:5]([CH2:4][C:3]([OH:2])=[O:16])=[CH:6][CH:7]=2)=[C:19]1[CH3:30]
Reactant: COC(=O)Cc1ccc(OCCCBr)cc1
Reactant: Cc1c(C=NO)c2ccccc2n1C
Agent: [Na+]
Agent: [OH-]
Product: Cc1c(/C=N/OCCCOc2ccc(CC(=O)O)cc2)c2ccccc2n1C
Temperature: 25 °C
Yield: 48.1 %

Procedure:
To a solution [4-(3-bromo-propoxy)-phenyl]-acetic acid methyl ester (0.47 g, 1.64 mmol) and 1,2-dimethyl-1H-indole-3-carbaldehyde oxime (0.32 g, 1.73 mmol) in 10/5/3 tetrahydrofuran/ethanol/water (21 mL) was added 2.5 M sodium hydroxide solution (6 mL). This mixture was heated to reflux for 2.5 hours and then allowed to cool back to room temperature. The mixture was partitioned between ethyl acetate and water. The aqueous layer was acidified to approximately pH 5 using 1 N hydrochloric acid. The layers were then separated. The aqueous layer was extracted with one additional portion of ethyl acetate. The organics were combined, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash chromatography through silica gel using ethyl acetate/hexanes (20/80 with 1% formic acid) to give {4-[3-({[(1E)-(1,2-dimethyl-1H-indol-3-yl)methylidene]amino}oxy)propoxy]phenyl}acetic acid (0.30 g, 48%) as a white solid. mp=106.5-107.5° C. 1H NMR (400 MHz, DMSO-d6); δ 12.20 (bs, 1H), 8.45 (s, 1H), 7.95 (d, 1H), 7.43 (d, 1H), 7.16 (t, 1H), 7.14 (d, 2H), 7.07 (t, 1H), 6.88 (d, 2H), 4.23 (t, 2H), 4,09 (t, 2H), 3.67 (s, 3H), 3.46 (s, 2H), 2.47 (s, 3H), 2.13 (m, 2H). Mass spec; (ES+) m/z 381.2 Elemental analysis; Calculated for C22H24N2O4: C, 69.46; H, 6.36; N, 7.36. Found: C, 69.25; H, 6.23; N, 7.27.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][C:16]([C:18]2[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=2)=[O:17])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:26]1[C:31]([CH2:32][CH3:33])=[CH:30][N:29]=[CH:28][N:27]=1.Cl.C[O-].[Na+].CO>C(O)C>[CH2:32]([C:31]1[C:26]([NH:22][C:21]2[CH:20]=[CH:19][C:18]([C:16](=[O:17])[CH2:15][CH2:14][CH:11]3[CH2:12][CH2:13][N:8]([CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[CH2:9][CH2:10]3)=[CH:24][CH:23]=2)=[N:27][CH:28]=[N:29][CH:30]=1)[CH3:33]
Reactant: CCc1cncnc1Cl
Reactant: Nc1ccc(C(=O)CCC2CCN(Cc3ccccc3)CC2)cc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: CCO
Product: CCc1cncnc1Nc1ccc(C(=O)CCC2CCN(Cc3ccccc3)CC2)cc1
Yield: 58.9 %

Procedure:
To 10 ml of ethanol were added 0.23 g of 4-[3-(1-benzylpiperidin-4-yl)propanoyl]aniline and 0.13 g of 4-chloro-5-ethylpyrimidine, and after adding 2 ml of an ethanol solution of hydrochloric acid (containing 0.071 g of hydrochloric acid), the mixture was reacted under reflux for 2 hours. After cooling, a 28% sodium methylate-methanol solution was added to the reaction mixture to make it alkaline, and then the mixture was condensed under reduced pressure. The obtained residue was applied to silica gel column chromatography to obtain 0.18 g of the title compound as pale yellow crystal.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[O:8][C:9]3[C:18]([CH3:19])=[CH:17][C:16]([C:20]([OH:22])=[O:21])=[CH:15][C:10]=3[S:11](=[O:14])(=[O:13])[CH2:12][C:6]=2[CH:5]=[C:4]([S:23](Cl)(=[O:25])=[O:24])[CH:3]=1.[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1.O>C(OCC)(=O)C>[Cl:1][C:2]1[C:7]2[O:8][C:9]3[C:18]([CH3:19])=[CH:17][C:16]([C:20]([OH:22])=[O:21])=[CH:15][C:10]=3[S:11](=[O:14])(=[O:13])[CH2:12][C:6]=2[CH:5]=[C:4]([S:23]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)(=[O:25])=[O:24])[CH:3]=1
Reactant: C1COCCN1
Reactant: Cc1cc(C(=O)O)cc2c1Oc1c(Cl)cc(S(=O)(=O)Cl)cc1CS2(=O)=O
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1cc(C(=O)O)cc2c1Oc1c(Cl)cc(S(=O)(=O)N3CCOCC3)cc1CS2(=O)=O

Procedure:
A mixture of Example 49j (0.2 g, 0.45 mm) and morpholine (0.08 mL, 0.9 mmol) in dry ethyl acetate (25 mL) was stirred overnight at room temperature, treated with water and extracted with ethyl acetate. The organic layer was washed with 10% aqueous HCl (50 mL), water, brine, concentrated and purified using flash chromatography (silica gel, methanol/chloroform) to obtain the title compound. Yield: 0.19 g, (86%); 1H NMR (DMSO-d6): δ 2.80 (s, 3H, CH3), 3.0 (t, 4H, 2CH2), 3.7 (s, 4H, 2CH2), 5.5 (s, 2H, CH2), 8.0 (s, 1H, Ar), 8.1 (s, 1H, Ar), 8.2 (s, 2H, Ar). MS: m/e (EI+) 487 (M+).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[C:4]1[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=1[C:6](=[O:12])[NH:7]2.[F:17][C:18]([F:27])([F:26])[C:19]1[CH:20]=[C:21]([CH:23]=[CH:24][CH:25]=1)[NH2:22]>>[F:17][C:18]([F:26])([F:27])[C:19]1[CH:20]=[C:21]([NH:22][C:2]2[CH:11]=[CH:10][N:9]=[C:8]3[C:3]=2[C:4]2[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=2[C:6](=[O:12])[NH:7]3)[CH:23]=[CH:24][CH:25]=1
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: O=c1[nH]c2nccc(Cl)c2c2ccccc12
Product: O=c1[nH]c2nccc(Nc3cccc(C(F)(F)F)c3)c2c2ccccc12
Yield: 34 %

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 188 using Compound 83 (100 mg, 0.43 mmol) and 3-(trifluoromethyl)aniline (140 mg, 0.87 mmol) to provide 194 (52 mg, 34% yield) as a white solid. LC-MS (M+H=356, obsd.=356).
Reaction SMILES: [Si:1]([O:8][C@@H:9]([C@@H:11]1[C@@H:14]([C@@H:15]([CH3:26])[C:16](=[O:25])[C:17]([CH3:24])([O:19][Si](C)(C)C)[CH3:18])[NH:13][C:12]1=[O:27])[CH3:10])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].O.O.C(O)(=O)C(O)=O>CO>[Si:1]([O:8][C@@H:9]([C@@H:11]1[C@@H:14]([C@@H:15]([CH3:26])[C:16](=[O:25])[C:17]([OH:19])([CH3:24])[CH3:18])[NH:13][C:12]1=[O:27])[CH3:10])([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N[C@@H]1[C@@H](C)C(=O)C(C)(C)O[Si](C)(C)C
Agent: O=C(O)C(=O)O
Solvent: CO
Solvent: O
Product: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N[C@@H]1[C@@H](C)C(=O)C(C)(C)O
Reaction time: 1 h
Yield: 99.9 %

Procedure:
To a solution of (3S,4R)-3-[(1R)-1-(t-butyldimethylsilyloxy)ethyl]-4-[(1R)-1,3-dimethyl-3-(trimethylsilyloxy)-2-oxobutyl]-2-azetidinone (132 mg) in methanol (6 ml) was added oxalic acid dihydrate (200 mg) at room temperature and the mixture was stirred for 1 hour. The reaction mixture was evaporated, and diethyl ether (30 ml) and saturated aqueous sodium bicarbonate (10 ml) were slowly added to the residue. The solution was extracted twice with diethyl ether, and the extracts were combined and washed in turn with saturated aqueous sodium bicarbonate and brine. The organic layer was dried over magnesium sulfate and evaporated to give (3S,4R)-3-[(1R)-1-(t-butyldimethylsilyloxy)ethyl]-4-[(1R)-3-hydroxy-1,3-dimethyl-2-oxobutyl]-2-azetidinone (109 mg).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[CH:9]([CH2:11][C:12]([OH:14])=[O:13])[O:8][B:7]([OH:15])[C:6]=2[CH:5]=[C:4]([OH:16])[CH:3]=1.[OH-].[Na+].Cl[C:20]([O:22][CH2:23][CH3:24])=[O:21].Cl>O>[Cl:1][C:2]1[C:10]2[CH:9]([CH2:11][C:12]([OH:14])=[O:13])[O:8][B:7]([OH:15])[C:6]=2[CH:5]=[C:4]([O:16][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:3]=1
Reactant: CCOC(=O)Cl
Reactant: O=C(O)CC1OB(O)c2cc(O)cc(Cl)c21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCOC(=O)Oc1cc(Cl)c2c(c1)B(O)OC2CC(=O)O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 21.5 %

Procedure:
To the suspension of the crude 2-(4-chloro-1,6-dihydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-3-yl)acetic acid (180 mg, 0.74 mmol) and NaOH (30 mg, 0.74 mmol) in 8 mL H2O was added ethyl chloroformate (96 mg, 0.89 mol) dropwise at 0° C. The reaction mixture was stirred at room temperature for 30 min and acidified to pH=5.0 using 1N HCl. The resulting mixture was extracted with EtOAc (3×10 mL) and the combined organic layers were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by prep HPLC to give the title compound as an off-white powder (50 mg, yield: 21.5%, two steps). 1H NMR (400 MHz, DMSO) δ12.43 (s, 1H), 9.50 (s, 1H), 7.55 (d, J=2.4 Hz, 1H), 7.50 (d, J=2.4 Hz, 1H), 5.52 (m, 1H), 4.28 (m, 2H), 3.19 (m, 1H), 2.36 (m, 1H), 1.31 (t, J=7.0 Hz, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[N:8][CH:9]=1)([O-])=O.[H][H]>C(OCC)(=O)C.[Pd]>[N:10]1([C:7]2[N:8]=[CH:9][C:4]([NH2:1])=[CH:5][CH:6]=2)[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1
Reactant: O=[N+]([O-])c1ccc(N2CCOCC2)nc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Nc1ccc(N2CCOCC2)nc1
Yield: 86.3 %

Procedure:
The solution of 4-(5-nitro-pyridin-2-yl)-morpholine (1.5 g, 7.18 mmol) in ethyl acetate (20 mL) in the presence of 10% palladium on carbon (0.75 g) was shaken under the hydrogen with a pressure of 50 psi at room temperature for 3 hr. After the reaction, the reaction mixture was filtered through a plug of celite and the filtration pad was washed with ethyl acetate. The organic layer was collected, concentrated, and dried to give 6-morpholin-4-yl-pyridin-3-ylamine (1.11 g, crude) as a light red solid, which was directly used in the next step reaction without further purification. LCMS calcd for C9H14N3O (m/e) 179, obsd 180 (M+H).
Reaction SMILES: [CH2:1]1[CH:12]2[CH:4]([NH:5][C:6]3[C:7]([C:13]([NH:15][C@H:16]([CH3:20])[C:17](O)=[O:18])=[O:14])=[CH:8][CH:9]=[CH:10][C:11]=32)[CH2:3][CH2:2]1>C(O)(=O)C>[CH3:20][C@H:16]1[NH:15][C:13](=[O:14])[C:7]2=[C:6]3[C:11](=[CH:10][CH:9]=[CH:8]2)[CH:12]2[CH2:1][CH2:2][CH2:3][CH:4]2[N:5]3[C:17]1=[O:18]
Reactant: C[C@@H](NC(=O)c1cccc2c1NC1CCCC21)C(=O)O
Solvent: CC(=O)O
Product: C[C@H]1NC(=O)c2cccc3c2N(C1=O)C1CCCC31

Procedure:
Following the procedure of method 7E, (2R)-2-[(1,2,3,3a,4,8b-hexahydrocyclopenta[b]indol-5-ylcarbonyl)amino]propanoic acid was cyclized by refluxing in acetic acid (50 mL). Purification by flash chromatography through silica gel (elution with 5% methanol-chloroform) provided each diastereomer: less polar product (1.5 mmol, 0.39 g, 56% over 2 steps) arbitrarily assigned as the R,R configuration and more polar product (0.47 mmol, 0.11 g, 17% over 2 steps) assigned as the S,S configuration.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:12]([O:14][CH3:15])=[O:13])[CH:5]=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[CH2:16]([CH:26]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[C:27](Cl)=[O:28])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25].O>O1CCCC1>[CH2:16]([CH:26]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[C:27]([NH:1][C:2]1[CH:11]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[CH:5]=[C:4]([CH:3]=1)[C:12]([O:14][CH3:15])=[O:13])=[O:28])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: COC(=O)c1cc(N)cc(C(=O)OC)c1
Reactant: CCCCCCCCCCCCC(CCCCCCCCCC)C(=O)Cl
Solvent: O
Solvent: C1CCOC1
Product: CCCCCCCCCCCCC(CCCCCCCCCC)C(=O)Nc1cc(C(=O)OC)cc(C(=O)OC)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Dimethyl 5-aminoisophthalate (Aldrich, 4.40 g, 21.0 mmol) is suspended in dry tetrahydrofuran (100 mL) in a 250 mL round bottom flask under an inert atmosphere. The dimethyl 5-aminoisophthalate suspension is cooled to 0° C. for at least 30 min., and an ice cold suspension of 2-decyltetradecanoyl chloride in of dry tetrahydrofuran (80 mL) is added slowly, dropwise. The reaction is then allowed to slowly warm to room temperature and stir overnight. Deionized water (10 mL) is added and the tetrahydrofuran is removed by rotary evaporation. The crude residue is then dissolved in 250 mL of ethyl acetate, and is washed with 3 successive 100 mL portions of deionized water. The ethyl acetate is then removed from the organic phase by rotary evaporation and the product is dried in vacuo to give crude dimethyl 5-(2′-decyltetradecanamido)isophthalate (12.56 g) as a pale yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH2:9][C:10]2([CH3:14])[CH3:13])=[CH:5][C:4]=1[CH3:15].C(O)(=[O:18])C>O>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6](=[CH:5][C:4]=1[CH3:15])[C:7](=[O:18])[CH2:8][CH2:9][C:10]2([CH3:13])[CH3:14]
Reactant: CC(=O)O
Reactant: COc1cc2c(cc1C)CCCC2(C)C
Solvent: O
Product: COc1cc2c(cc1C)C(=O)CCC2(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 72 %

Procedure:
To a solution of 7-methoxy-1,1,6-trimethyl-1,2,3,4-tetrahydronaphthalene (Compound 29, 14.7 g, 72.1 mmol) and 30 mL of glacial acetic acid at 0° C. was added a cold solution of CrO3 (14.5 g, 144.2 mmol) in 30 mL of glacial acetic acid and 15 mL of water. The resulting dark solution was stirred at 0° C. for 1 h, then quenched with NaOH 2N, extracted with diethyl ether, washed with brine, dried over MgSO4, and filtered. The solvent was removed to give 11.3 g (72%) of the title compound as a dark brown solid. PNMR (300 MHz, CDCl3) δ 1.38 (s, 6H), 1.98 (t, 2H, J=7.5 Hz), 2.10 (s, 3H), 2.68 (t, 2H, J=7.5 Hz), 3.90 (s, 3H), 6.76 (s, 1H), 7.83 (d, 1H).
Reaction SMILES: [C:1]([O:9][C:10]1[CH:15]=[CH:14][C:13](O)=[C:12]([N+:17]([O-:19])=[O:18])[CH:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:21][C:22]([O:24][CH3:25])=[O:23].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[C:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:21][C:22]([O:24][CH3:25])=[O:23])=[C:12]([N+:17]([O-:19])=[O:18])[CH:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)CBr
Reactant: O=C(Oc1ccc(O)c([N+](=O)[O-])c1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)Cc1ccc(OC(=O)c2ccccc2)cc1[N+](=O)[O-]
Yield: 63436.2 %

Procedure:
A mixture of 4-hydroxy-3-nitrophenyl benzoate (48.8 g, 0.19 mol), methyl bromoacetate (28.8 g, 0.19 mmol), anhydrous potassium carbonate (33.8 g, 0.24 mol) and acetone (700 mL) was heated at reflux for 24 h. The mixture was evaporated in vacuo and the residue partitioned between aqueous NaOH (1 M, 1 L) and dichloromethane (3×200 mL). The combined organic extracts were washed with aqueous NaOH (1 M, 500 mL), water (500 mL) and brine (250 mL), then dried (Na2SO4) and evaporated in vacuo to give a solid. Crystallisation from methanol with charcoal treatment gave the title compound (38 g, 61%) as pale yellow needles.