Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[CH3:11][O:12][C:13](=[O:38])[C:14](=[O:37])[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][CH2:24][CH:25]([OH:36])[C:26]2[CH:35]=[CH:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=2)=[CH:17][CH:16]=1.CC(C)=O.C(=O)=O>ClCCl.C(N(CC)CC)C>[CH3:11][O:12][C:13](=[O:38])[C:14](=[O:37])[C:15]1[CH:16]=[CH:17][C:18]([O:21][CH2:22][CH2:23][CH2:24][C:25]([C:26]2[CH:35]=[CH:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=2)=[O:36])=[CH:19][CH:20]=1
Reactant: COC(=O)C(=O)c1ccc(OCCCC(O)c2ccc3ccccc3c2)cc1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C=O
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C(=O)c1ccc(OCCCC(=O)c2ccc3ccccc3c2)cc1
Temperature: 178 °C
Reaction time: 0.5 h
Yield: 84.4 %

Procedure:
A solution of dimethylsulfoxide (0.079 g) in dichloromethane (2 mL) was added over 20 minutes to a stirred solution of oxalyl chloride (0.123 g) in dry dichloromethane (4 mL) maintained throughout at 178° C. by using an acetone-dry ice bath. After 30 minutes at -78° C., a solution of rac-4-[4-hydroxy-4-(2-naphthalenyl)butoxy]-alpha-oxobenzeneacetic acid methyl ester (0.356 g) in dichloromethane (3 mL) was added over 30 minutes and the reaction mixture was stirred for 30 minutes in the acetone-dry ice bath, then triethylamine (0.144 mL) was added. The cooling bath was removed and the reaction was allowed to equilibrate to room temperature, then water was added and the phases were separated. After the aqueous layer was extracted with dichlormethane (2×7 mL), the combined organic layers were washed with brine, then were dried (MgSO4) and evaporated. The residue was purified by flash chromatography over silica gel (ethyl acetate-hexane; 1:3) and then crystallized from ethyl acetate-hexane to furnish in two crops, 0.299 g of 4-[[4-(2-naphthalenyl)-4-oxobutyl]oxy]-alpha-oxobenzeneacetic acid methyl ester, mp 86°-87° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8]Br)[C:3]=1[CH2:10][CH3:11].[P:12]([O:19]CC)([O:16][CH2:17][CH3:18])[O:13][CH2:14][CH3:15]>C1(C)C=CC=CC=1>[Br:1][C:2]1[C:3]([CH2:10][CH3:11])=[C:4]([CH2:8][P:12](=[O:19])([O:16][CH2:17][CH3:18])[O:13][CH2:14][CH3:15])[CH:5]=[CH:6][CH:7]=1
Reactant: CCc1c(Br)cccc1CBr
Reactant: CCOP(OCC)OCC
Solvent: Cc1ccccc1
Product: CCOP(=O)(Cc1cccc(Br)c1CC)OCC
Temperature: 130 °C
Yield: 99.9 %

Procedure:
To a solution of 1-bromo-3-(bromomethyl)-2-ethylbenzene (D134) (1.3 g, 4.68 mmol) in Toluene (10 mL) was added triethyl phosphite (0.818 mL, 4.68 mmol). The reaction solution was heated in a sealed tube at 130° C. for 2 days. The solvent was removed in vacuo to afford diethyl [(3-bromo-2-ethylphenyl)methyl]phosphonate (D135) (1.567 g), which was used directly without further purification. MS (ES): C13H20BrO3P requires 334.0. found 335.0 (M+H+).
Reaction SMILES: [CH3:1][CH:2]([CH3:8])/[CH:3]=[CH:4]/[C:5]([OH:7])=O.C(Cl)(=O)C(Cl)=O.Cl.Cl.[CH3:17][C:18]1[CH:23]=[CH:22][N:21]=[C:20]([N:24]2[CH2:30][CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH:19]=1.CCN(C(C)C)C(C)C>ClCCl.CN(C=O)C>[CH3:8][CH:2]([CH3:1])/[CH:3]=[CH:4]/[C:5]([N:27]1[CH2:28][CH2:29][CH2:30][N:24]([C:20]2[CH:19]=[C:18]([CH3:17])[CH:23]=[CH:22][N:21]=2)[CH2:25][CH2:26]1)=[O:7]
Reactant: Cc1ccnc(N2CCCNCC2)c1
Reactant: CC(C)/C=C/C(=O)O
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccnc(N2CCCN(C(=O)/C=C/C(C)C)CC2)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 31.3 %

Procedure:
(E)-4-Methylpent-2-enoic acid (26 mg, 0.23 mmol) was dissolved in dichloromethane (1 ml), oxalyl chloride (20 μl, 0.23 mol) and one drop of DMF were added and the resulting solution was stirred at room temperature for 15 minutes. This solution was added to a solution of 1-(4-methyl-2-pyridyl)-1,4-diazepane dihydrochloride (40 mg, 0.15 mmol) in DCM (2 ml). DIPEA (80 μl, 0.5 mmol) was added and the resulting mixture was stirred at room temperature overnight. The mixture was concentrated under reduced pressure and the resulting residue was purified by preparative HPLC (Waters XBridge, gradient of water containing 0.1% NH3 and acetonitrile) to yield 13 mg of a solid (0.047 mmol, 20%).
Reaction SMILES: [OH-].[Li+].[OH:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([OH:10])[C:5]=1[C:11](=[O:13])[CH3:12].[Cl:14][C:15]1[CH:23]=[CH:22][C:18]([C:19](Cl)=O)=[CH:17][CH:16]=1.Cl>C1COCC1>[Cl:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]2[O:3][C:4]3[C:5]([C:11](=[O:13])[CH:12]=2)=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=3)=[CH:17][CH:16]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: CC(=O)c1c(O)cccc1O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=c1cc(-c2ccc(Cl)cc2)oc2cccc(O)c12
Temperature: -10 °C
Reaction time: 2 h

Procedure:
Dry, pulverulent lithium hydroxide (51 mmol, 4 equivalents) is added in one portion to a well-stirred solution of 2′,6′-dihydroxyacetophenone (12.8 mmol) in dry THF (40 ml) under an argon atmosphere at −78° C. The reaction mixture is stirred at −78° C. for one hour and subsequently at −10° C. for two hours. After the mixture has been re-cooled to −78° C., a solution of 4-chlorobenzoyl chloride (13.97 mmol) in THF (20 ml) is added in one portion. The mixture is stirred at −78° C. for one hour and at room temperature for 4 hours until the starting material has disappeared. The reaction mixture is emptied into a mixture of ice (400 g) and concentrated HCl (16 ml) and extracted with dichloromethane (3×50 ml). The solvents are removed from the dried extracts, and the residue is dried under reduced pressure for 24 hours. Glacial acetic acid (100 ml) and sulfuric acid (0.5 ml) are added to the residue, and the mixture is heated at 95–100° C. for from 30 minutes to one hour under an argon atmosphere. Approximately one third of the acetic acid is stripped off, and the residue is emptied into water. The precipitated product is filtered, washed and dried and recrystallised in methanol, giving 4′-chloro-5-hydroxyflavone. 1H NMR (250 MHz, CDCl3): δ=6.7–8.0 (m, 7H), 12.5 (s, 10 H); EI-MS (70 eV) m/e (rel. abund.)=272; UV (2-propanol): λ=213 nm, 301 nm, 275 nm, 338 nm.
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([S:13]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:17]=1[O:24][C:25]([F:28])([F:27])[F:26])(=[O:15])=[O:14])[C:8](=[O:29])[C:7]2([N:46]1[CH2:55][C@H:54]([OH:56])[CH2:53][C@H:47]1[C:48]([N:50]([CH3:52])[CH3:51])=[O:49])[C:30]1[CH:35]=[C:34]([CH:36](O)[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH:33]=[CH:32][C:31]=1[O:44][CH3:45].[OH-].[Na+]>C(O)(C(F)(F)F)=O.O>[CH2:36]([C:34]1[CH:33]=[CH:32][C:31]([O:44][CH3:45])=[C:30]([C:7]2([N:46]3[CH2:55][C@H:54]([OH:56])[CH2:53][C@H:47]3[C:48]([N:50]([CH3:52])[CH3:51])=[O:49])[C:6]3[C:10](=[CH:11][CH:12]=[C:4]([Cl:3])[CH:5]=3)[N:9]([S:13]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:17]=3[O:24][C:25]([F:26])([F:27])[F:28])(=[O:15])=[O:14])[C:8]2=[O:29])[CH:35]=1)[C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1
Reactant: COc1ccc(S(=O)(=O)N2C(=O)C(c3cc(C(O)c4ccccc4)ccc3OC)(N3C[C@H](O)C[C@H]3C(=O)N(C)C)c3cc(Cl)ccc32)c(OC(F)(F)F)c1
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: COc1ccc(S(=O)(=O)N2C(=O)C(c3cc(Cc4ccccc4)ccc3OC)(N3C[C@H](O)C[C@H]3C(=O)N(C)C)c3cc(Cl)ccc32)c(OC(F)(F)F)c1
Yield: 91.9 %

Procedure:
A solution of 5 mg of NaBH4 in TFA (1 ml) was stirred for 15 minutes at room temperature, then, a solution of 28.1 mg of the compound obtained in Example 249 in TFA (3 ml) was added dropwise over 10 minutes. Two hours later, the solution was diluted with water, neutralized with NaOH, and the resulting mixture was extracted with CHCl3. The organic layer was washed with water and with saturated brine and dried over MgSO4, then, the drying agent was separated by filtration and the solvent was evaporated under reduced pressure. The obtained residue was purified by column chromatography (silicagel 60; mobile phase: MeOH/CHCl3=2/98; v/v) to obtain 25.3 mg of the title compound (colorless amorphous).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([OH:12])=O)=[CH:9][C:4]=2[N:3]=[CH:2]1.[CH3:13][O:14][C:15]1[CH:35]=[CH:34][C:18]([CH2:19][C:20]2[C:25]3[C@@H:26]4[C@H:31]([CH2:32][CH2:33][C:24]=3[CH:23]=[CH:22][CH:21]=2)[NH:30][CH2:29][CH2:28][CH2:27]4)=[CH:17][CH:16]=1>>[NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([N:30]3[C@@H:31]4[C@@H:26]([C:25]5[C:20]([CH2:19][C:18]6[CH:34]=[CH:35][C:15]([O:14][CH3:13])=[CH:16][CH:17]=6)=[CH:21][CH:22]=[CH:23][C:24]=5[CH2:33][CH2:32]4)[CH2:27][CH2:28][CH2:29]3)=[O:12])=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: O=C(O)c1ccc2[nH]cnc2c1
Reactant: COc1ccc(Cc2cccc3c2[C@H]2CCCN[C@H]2CC3)cc1
Product: COc1ccc(Cc2cccc3c2[C@H]2CCCN(C(=O)c4ccc5[nH]cnc5c4)[C@H]2CC3)cc1
Yield: 17 %

Procedure:
The title compound is prepared from 1H-benzoimidazole-5-carboxylic acid and cis-10-(4-methoxy-benzyl)-1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinoline following a procedure analogous to that described in Example 1. Yield: 17% of theory; LC (method 1): tR=3.21 min; Mass spectrum (ESI+): m/z=452 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([NH:13][S:14]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]3[C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[N:28]=[C:27]([CH3:35])[CH:26]=3)=[CH:19][CH:18]=2)(=[O:16])=[O:15])[C@H:10]([C:36](O)=[O:37])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:39][OH:40]>>[OH:40][NH:39][C:36]([C@H:10]1[C@@H:11]([NH:13][S:14]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]3[C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[N:28]=[C:27]([CH3:35])[CH:26]=3)=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH2:12][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:9]1)=[O:37]
Reactant: NO
Reactant: Cc1cc(COc2ccc(S(=O)(=O)N[C@H]3CN(C(=O)OC(C)(C)C)C[C@H]3C(=O)O)cc2)c2ccccc2n1
Product: Cc1cc(COc2ccc(S(=O)(=O)N[C@H]3CN(C(=O)OC(C)(C)C)C[C@H]3C(=O)NO)cc2)c2ccccc2n1
Yield: 81 %

Procedure:
According to the procedure of Example 17, Step 5, the reaction of 122 mg of cis-1-(tert-butoxycarbonyl)-4-[({4-[(2-methylquinolin-4-yl)methoxy]phenyl}sulfonyl)amino]pyrrolidine-3-carboxylic acid with hydroxylamine provided 104 mg (81% yield) of tert-butyl cis-3-[(hydroxyamino)carbonyl]-4-[({4-[(2-methylquinolin-4-yl)methoxy]phenyl}sulfonyl)amino]pyrrolidine-1-carboxylate. MS: 557.3 (M+H)+
Reaction SMILES: [O:1]=[C:2]1[C:11](=[O:12])[NH:10][C:9]2[C:4](=[CH:5][C:6]([N+:14]([O-:16])=[O:15])=[C:7](F)[CH:8]=2)[N:3]1[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19].[NH:23]1[CH:27]=[CH:26][N:25]=[CH:24]1>CN(C=O)C>[O:1]=[C:2]1[C:11](=[O:12])[NH:10][C:9]2[C:4](=[CH:5][C:6]([N+:14]([O-:16])=[O:15])=[C:7]([N:23]3[CH:27]=[CH:26][N:25]=[CH:24]3)[CH:8]=2)[N:3]1[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: CCOC(=O)Cn1c(=O)c(=O)[nH]c2cc(F)c([N+](=O)[O-])cc21
Reactant: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1c(=O)c(=O)[nH]c2cc(-n3ccnc3)c([N+](=O)[O-])cc21
Yield: 96.1 %

Procedure:
By using 2.02 g of ethyl 2-(2,3-dioxo-6-fluoro-7-nitro-1,2,3,4-tetrahydroquinoxalin-1-yl)acetate, 1.33 g of imidazole and 15 ml of DMF, 2.24 g (96%) of ethyl 2-[2,3-dioxo-6-(1H-imidazol-1-yl)-7-nitro-1,2,3,4-tetrahydroquinoxalin-1-yl]acetate was obtained.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[CH3:9][O:10][C:11]1[CH:12]=[CH:13][C:14]([CH2:17][OH:18])=[CH:15][CH:16]=1>>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([O:18][CH2:17][C:14]2[CH:13]=[CH:12][C:11]([O:10][CH3:9])=[CH:16][CH:15]=2)=[N:3][CH:4]=1
Reactant: Brc1ccc(Br)nc1
Reactant: COc1ccc(CO)cc1
Product: COc1ccc(COc2ccc(Br)cn2)cc1

Procedure:
Synthesized as described in Example 53A from 2,5-dibromopyridine and p-methoxybenzyl alcohol with the following exceptions: the reaction was heated at reflux for 90 min, and the title compound was purified by flash chromatography (EtOAc/hexanes): 1H NMR (400 MHz, CDCl3) δ 8.21 (dd, J=2.6, 0.6 Hz, 1H), 7.64 (dd, J=8.8, 2.6 Hz, 1H), 7.38 (m, 2H, AA′XX′), 6.91 (m, 2H, AA′XX′), 6.69 (dd, J=8.9, 0.6 Hz, 1H), 5.26 (s, 2H), 3.81 (s, 3H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:13]=[CH:12][N:11]=[C:10]([NH:14][CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)[N:9]=2)[CH:5]=[CH:4][N:3]=1.[Cl:21][C:22]1[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[C:23]=1[NH2:24].C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:21][C:22]1[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[C:23]=1[NH:24][C:2]1[N:7]=[C:6]([C:8]2[N:13]=[CH:12][N:11]=[C:10]([NH:14][CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)[N:9]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Clc1nccc(-c2ncnc(NC3CCOCC3)n2)n1
Reactant: Cc1cccc(Cl)c1N
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: Cc1cccc(Cl)c1Nc1nccc(-c2ncnc(NC3CCOCC3)n2)n1
Temperature: 25 °C

Procedure:
To a solution of 4-(2-chloro-4-pyrimidinyl)-N-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-amine (i.e., the product of Step A) (125 mg, 0.42 mmol) in toluene (4.0 mL) under nitrogen was added 2-chloro-6-methylaniline (180 mg, 1.27 mmol), cesium carbonate (273 mg, 0.84 mmol), tris(dibenzylideneacetone)dipalladium(0) (20 mg, 0.022 mmol), and ((±)-BINAP) (28 mg, 0.044 mmol), and the resulting mixture was stirred and heated at reflux for 6 h. After cooling to room temperature, the mixture was concentrated and purified using column chromatography on silica gel eluted with 40% acetone in hexanes to give 57 mg of the title compound as a yellow solid.
Reaction SMILES: N[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([Cl:11])[CH:3]=1.N([O-])=[O:13].[Na+].O>S(=O)(=O)(O)O>[Cl:11][C:4]1[CH:3]=[C:2]([OH:13])[CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7]
Reactant: Nc1ccc(C(=O)O)c(Cl)c1
Reactant: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: O=C(O)c1ccc(O)cc1Cl
Temperature: 70 °C
Reaction time: 1 h

Procedure:
4-Amino-2-chlorobenzoic acid (10.01 g) was homogeneously dissolved in 12.5% sulfuric acid (400 ml) by heating the mixture to 70° C. and cooled with ice. An aqueous solution of sodium nitrite (4.24 g/water 12 ml) was dropwise added to this suspension over 5 min at a temperature of not more than 8° C. Five minutes later, this solution was gradually poured into water (500 ml) at 80° C., upon which vigorous bubbling occurred and the solution turned red. The reaction mixture was further stirred at 80° C. for 1 hr. After cooling, the resulting product was extracted three times with ether. The organic layers were combined, washed successively with diluted hydrochloric acid, water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated and a small amount of diisopropyl ether was added to allow crystallization, whereby the objective compound (6.32 g) was obtained as an orange powder.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([CH2:18][NH:19][CH:20]3[CH2:25][CH2:24][CH:23]([N:26]([CH3:34])[C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:22][CH2:21]3)[CH:11]=2)=[CH:6][CH:5]=1)(=[O:3])[NH2:2].[Cl:35][C:36]1[C:37]2[CH:47]=[CH:46][CH:45]=[CH:44][C:38]=2[S:39][C:40]=1[C:41](Cl)=[O:42]>>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([CH2:18][N:19]([C:41]([C:40]3[S:39][C:38]4[CH:44]=[CH:45][CH:46]=[CH:47][C:37]=4[C:36]=3[Cl:35])=[O:42])[CH:20]3[CH2:25][CH2:24][CH:23]([N:26]([CH3:34])[C:27](=[O:33])[O:28][C:29]([CH3:31])([CH3:30])[CH3:32])[CH2:22][CH2:21]3)[CH:11]=2)=[CH:8][CH:9]=1)(=[O:3])[NH2:2]
Reactant: COc1ccc(-c2ccc(C(N)=O)cc2)cc1CNC1CCC(N(C)C(=O)OC(C)(C)C)CC1
Reactant: O=C(Cl)c1sc2ccccc2c1Cl
Product: COc1ccc(-c2ccc(C(N)=O)cc2)cc1CN(C(=O)c1sc2ccccc2c1Cl)C1CCC(N(C)C(=O)OC(C)(C)C)CC1

Procedure:
Biaryl amine 55 (267 mg, 0.57 mmol) is treated with 3-chloro-benzo[b]thiophene-2-carbonyl chloride (158 mg, 0.69 mmol) using Method D to give the title compound.
Reaction SMILES: COC(CC(CC(OC)=O)=O)=O.CO.Cl.CN([C:21]1[CH:30]=[C:29]2[C:24]([C:25](CC([O-])=O)=[CH:26][C:27](=[O:31])[O:28]2)=[CH:23][CH:22]=1)CCO>[Cl-].[Zn+2].[Cl-].O>[O:28]1[C:29]2[C:24](=[CH:23][CH:22]=[CH:21][CH:30]=2)[CH:25]=[CH:26][C:27]1=[O:31]
Reactant: CN(CCO)c1ccc2c(CC(=O)[O-])cc(=O)oc2c1
Agent: COC(=O)CC(=O)CC(=O)OC
Agent: Cl
Agent: [Cl-]
Solvent: CO
Solvent: O
Product: O=c1ccc2ccccc2o1
Temperature: 0 °C

Procedure:
Dimethyl acetonedicarboxylate (13.9 g), 13.6 grams of the product from the previous step, 3.0 grams of anhydrous zinc chloride and 35 mL of methanol were refluxed for 23.5 hours. After cooling, the solution was poured over 60 g of ice, 20 mL of water and 3 mL of concentrated hydrochloric acid. The purple oil which separated was extracted into methylene chloride. The methylene chloride solution was washed once with cold water, dried over sodium sulfate, filtered and evaporated (yield 13.6 g of semi-solid). After 2 days at room temperature the solid was filtered from the liquid, washed twice with -20° C. methanol, and dried. Yield 1.34 g, MP 150°-154° C. This material was then recrystallized from methanol to give yellow-orange plates, MP 158.5°-160° C. The 1H NMR spectrum for this compound was consistent with that expected formethyl 7-[N-methyl-N-(2-hydroxyethyl)amino]coumarin-4-acetate. Elemental analysis for nitrogen: for C15H17NO5, %N expected: 4.81; found: 4.93.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.Cl.[C:15]([O:19][C:20](=[O:32])[C@H:21]([CH2:23][CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[NH2:22])([CH3:18])([CH3:17])[CH3:16].ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O.CO>[N+:11]([C:9]1[CH:8]=[CH:7][C:3]([C:4]([NH:22][C@H:21]([C:20]([O:19][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:32])[CH2:23][CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:29])[CH3:30])=[O:26])=[O:6])=[C:2]([F:1])[CH:10]=1)([O-:13])=[O:12]
Reactant: CC(C)(C)OC(=O)CC[C@H](N)C(=O)OC(C)(C)C
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1F
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CO
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CC[C@H](NC(=O)c1ccc([N+](=O)[O-])cc1F)C(=O)OC(C)(C)C
Reaction time: 0.25 h

Procedure:
A solution of 2-fluoro-4-nitrobenzoic acid (6.26 g, 33.8 mmoles), (L)-glutamate di-tert-butyl ester hydrochloride (10.0 g, 33.8 mmoles), and 1-hydroxybenzotriazole (4.57 g, 33.8 mmoles) in dry dimethylformamide (150 mL) was stirred under nitrogen while triethylamine (3.42 g, 4.71 mL, 33.8 mmoles) was added in one portion. After 15 minutes, 1.3-dicyclohexylcarbodiimide (7.67 g, 37.2 mmoles) was added in portions during 1 minute. The reaction mixture was filtered after 20 hours and the solids rinsed with dichloromethane (1×50 mL). The filtrate was spin evaporated to an amber residue that was partitioned between dichloromethane and saturated bicarbonate solution (200 mL each). The organic phase was washed successively with saturated bicarbonate, 5% citric acid, and brine (1×200 mL each). The organic phase was then dried (MgSO4), filtered, spin evaporated, and dried (high vacuum) to an oily yellow solid (11.9 g, 83%) that showed a major spot on tlc (silica, 2:1 hexane/ethyl acetate, Rf =0.5). The product was purified by the flash chromatography technique to give a light green gum; yield, 9.7 g (67%); 1H-NMR (CDCl3) δ 1.42 (s, 9H), 1.50 (s, 9H), 2.02-2.41 (m, 4H), 4.72 (m, 1H), 7.44 (br t, 1H), 8.0-8.3 (m, 3H); uv (MeOH) 260 nm max (11000), 225 min (4710), 215 sh (7680); mass spec (CI) m/e 427 (24%), 371 (20), 315 (100).
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:35]([O:37][CH3:38])=[O:36])=[CH:12][C:13]=3[N:14]3[CH:20]=[C:19]([C:21]([O:23]CC4C=CC=CC=4)=[O:22])[CH2:18][C:17]4[CH:31]=[CH:32][CH:33]=[CH:34][C:16]=4[C:15]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>[Pd].C1COCC1.CO>[CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:35]([O:37][CH3:38])=[O:36])=[CH:12][C:13]=3[N:14]3[CH2:20][CH:19]([C:21]([OH:23])=[O:22])[CH2:18][C:17]4[CH:31]=[CH:32][CH:33]=[CH:34][C:16]=4[C:15]=23)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)C=C(C(=O)OCc1ccccc1)Cc1ccccc1-3
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(C(=O)O)Cc1ccccc1-3
Temperature: 22 °C
Reaction time: 18 h
Yield: 92.1 %

Procedure:
Method A: The intermediate ester (14, R=H, 53 mg, 0.13 mmol) in a 1:1 mixture of THF/MeOH (2 mL) was treated with a catalytic amount of Pd (10% on C) under hydrogen (balloon pressure). The mixture was stirred at 22° C. for 18 hr. The catalyst was removed by filtration through a fine pad of celite and the solution was concentrated in vacuo to afford the title compound as a pale tan solid (50 mg, 92%). ESI-MS m/z 418 (MH+).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[N:7][C:8]2[C:13]([C:14]=1[O:15][CH3:16])=[CH:12][C:11](I)=[CH:10][CH:9]=2)=[O:4].[OH-].[Na+].[C:20](O)(=[O:22])C>CO.O>[CH:20]([C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[N:7]=[CH:6][C:5]([C:3]([OH:2])=[O:4])=[C:14]2[O:15][CH3:16])=[O:22]
Reactant: COC(=O)c1cnc2ccc(I)cc2c1OC
Reactant: CC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1c(C(=O)O)cnc2ccc(C=O)cc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To the suspension of 6-iodo-4-methoxy-quinoline-3-carboxylic acid methyl ester (example 1d) (5.91 g, 17.2 mmol) in methanol (20 mL) was slowly added the solution of sodium hydroxide (2.76 g, 69 mmol) in water (10 mL). The mixture was stirred at room temperature for 3 hours. The solution was adjusted pH=5.0 using aqueous acetic acid solution. After adding more water, the solid was collected by filtration, washed with water and dried to obtain 6-formyl-4-methoxy-quinoline-3-carboxylic acid. LC-MS m/e 330 (MH+)
Reaction SMILES: [OH:1][CH2:2][CH:3]([NH:8][C:9]([C:11]1[CH:20]=[CH:19][C:14]2[NH:15][C:16](=[O:18])[NH:17][C:13]=2[CH:12]=1)=[O:10])[C:4]([O:6]C)=[O:5].[OH-].[Na+]>CO>[OH:1][CH2:2][CH:3]([NH:8][C:9]([C:11]1[CH:20]=[CH:19][C:14]2[NH:15][C:16](=[O:18])[NH:17][C:13]=2[CH:12]=1)=[O:10])[C:4]([OH:6])=[O:5]
Reactant: COC(=O)C(CO)NC(=O)c1ccc2[nH]c(=O)[nH]c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(NC(CO)C(=O)O)c1ccc2[nH]c(=O)[nH]c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.7 %

Procedure:
The methyl ester adduct benzimidazol-2-one-5-carboxy-(L-serine)-amide (9) (100 mg, 0.3584 mmol) was suspended in methanol (10 mL) and on addition of 1M aq NaOH (0.68 mL, 0.680 mmol) readily dissolved. The disappearance of starting material was monitored with TLC and complete after stirring overnight at room temperature. The volume was increased by addition of further methanol (30 mL) and the pH carefully adjusted from 10 to 5 by the addition of Dowex 50 W-X8(H+) resin. The resin was rapidly filtered off and washed with further methanol (4×20 mL) and the combined filtrates rotary evaporated to dryness to give benzimidazol-2-one-5-carboxy-(L-serine)-amide (10) (91 mg, 96% yield) as a white powder;
Reaction SMILES: [CH2:1]1[O:9][C:8]2[C:3]3([O:18][CH2:17][O:16][C:15]4[CH:14]=[CH:13][CH:12]=[C:11]([C:19]([NH2:21])=O)[C:10]=4[C:7]=2[C:6]([C:22]([NH2:24])=O)=[CH:5][CH2:4]3)[O:2]1>P(Cl)(Cl)(Cl)=O>[CH2:1]1[O:9][C:8]2[C:3](=[CH:4][CH:5]=[C:6]([C:22]#[N:24])[C:7]=2[C:10]2[C:11]([C:19]#[N:21])=[CH:12][CH:13]=[C:14]3[O:18][CH2:17][O:16][C:15]=23)[O:2]1
Reactant: NC(=O)C1=CCC23OCOC2=C1c1c(cccc1C(N)=O)OCO3
Solvent: O=P(Cl)(Cl)Cl
Product: N#Cc1ccc2c(c1-c1c(C#N)ccc3c1OCO3)OCO2
Temperature: 0 °C
Yield: 91.8 %

Procedure:
5,6-Methylenedioxy-5,6' -methylenedioxy-2,2'-biphenyldicarboxamide (8 g) is refluxed in phosphorus oxychloride (70 ml) for 4 hours. The reaction mixture is cooled and then poured into ice water. The precipitated crystals are separated by filtration and dissolved in chloroform. The solution is washed with water, dried and distilled to remove the solvent to give 5,6-methylenedioxy-5',6'-methylenedioxy-2,2'-biphenyldicarbonitrile (6.5 g) as colorless crystal. M.p. 213°-215° C.