Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][C:8]=2[CH2:16][CH3:17])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1>CO.[Pd]>[CH:1]1([C:7]2[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][C:8]=2[CH2:16][CH3:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCc1cc(C(=O)O)ccc1C1=CCCCC1
Agent: [Pd]
Solvent: CO
Product: CCc1cc(C(=O)O)ccc1C1CCCCC1
Yield: 97.7 %

Procedure:
4-(1-Cyclohexen-1-yl)-3-ethylbenzoic acid (D12) (803 mg, 3.49 mmol) was dissolved in methanol (70 mL) and hydrogenated on an H-Cube using a palladium on carbon cartridge. The product solution was concentrated in vacuo to give the title compound as a white solid (792 mg, 3.41 mmol). δH (methanol-d4, 400 MHz): 7.82-7.68 (2H, m), 7.33 (1H, d), 2.83 (1H, m), 2.73 (2H, q), 1.87 (2H, m), 1.85-1.70 (3H, m), 1.58-1.30 (5H, m), 1.22 (3H, t).
Reaction SMILES: [CH3:1][N:2]([CH3:43])[CH2:3][CH2:4][NH:5][C:6]([C@@H:8]([NH:20][C:21]([C:23]1[CH:42]=[CH:41][C:26]2[N:27]([CH:35]3[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]3)[C:28]([C:30]3[CH:34]=[CH:33][O:32][CH:31]=3)=[N:29][C:25]=2[CH:24]=1)=[O:22])[CH2:9][C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([OH:19])[CH:17]=2)[NH:12][CH:11]=1)=[O:7].N[CH2:45][CH2:46]N1CCCC1>>[OH:19][C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]=[C:10]2[CH2:9][C@H:8]([NH:20][C:21]([C:23]1[CH:42]=[CH:41][C:26]2[N:27]([CH:35]3[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40]3)[C:28]([C:30]3[CH:34]=[CH:33][O:32][CH:31]=3)=[N:29][C:25]=2[CH:24]=1)=[O:22])[C:6](=[O:7])[NH:5][CH2:4][CH2:3][N:2]1[CH2:1][CH2:46][CH2:45][CH2:43]1
Reactant: NCCN1CCCC1
Reactant: CN(C)CCNC(=O)[C@H](Cc1c[nH]c2ccc(O)cc12)NC(=O)c1ccc2c(c1)nc(-c1ccoc1)n2C1CCCCC1
Product: O=C(N[C@@H](Cc1c[nH]c2ccc(O)cc12)C(=O)NCCN1CCCC1)c1ccc2c(c1)nc(-c1ccoc1)n2C1CCCCC1

Procedure:
The carboxylic acid of example 133 was coupled to 1-(2-aminoethyl)pyrrolidine under standard TBTU conditions to yield the title compound of example 137.
Reaction SMILES: C([Li])CCC.[CH2:6]([O:11][CH:12]1[NH:16][C:15](=[O:17])[CH2:14][CH2:13]1)[CH2:7][CH2:8][CH2:9][CH3:10].[C:18](Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CCCCCC.O1CCCC1>[C:18]([N:16]1[CH:12]([O:11][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH2:13][CH2:14][C:15]1=[O:17])(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CCCCCOC1CCC(=O)N1
Reactant: O=C(Cl)c1ccccc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCCCOC1CCC(=O)N1C(=O)c1ccccc1
Reaction time: 0.25 h
Yield: 62.3 %

Procedure:
15.56 cm3 of a 1.5M solution of n-butyllithium in hexane is added at -60° C. to a solution of 4 g of 5-(1-pentyloxy) pyrrolidin-2-one in 80 cm3 of tetrahydrofuran. Agitation is carried out for 15 minutes at -60° C. and then under these conditions a solution of 3.28 g of benzoyl chloride in 20 cm3 of tetrahydrofuran is added. After allowing the temperature to return to ambient, the solvent is evaporated under reduced pressure. The residue is chromatographed on silica (eluent: ethyl acetate-n-hexane 1-3) and 4 g of sought product is obtained.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][CH:6]=1.[Mg].[C:8]([O:14][CH3:15])(=[O:13])[C:9](OC)=[O:10].S(=O)(=O)(O)O>C(OCC)C>[CH3:15][O:14][C:8](=[O:13])[C:9]([OH:10])([C:2]1[S:3][CH:4]=[CH:5][CH:6]=1)[C:2]1[S:3][CH:4]=[CH:5][CH:6]=1
Reactant: Brc1cccs1
Reactant: COC(=O)C(=O)OC
Agent: O=S(=O)(O)O
Agent: [Mg]
Solvent: CCOCC
Product: COC(=O)C(O)(c1cccs1)c1cccs1
Temperature: 35 °C
Reaction time: 3 h
Yield: 60 %

Procedure:
2-Bromothiophene (9.68 mL, 0.1 mol) was slowly added to a stirred mixture of magnesium turnings (2.7 g, 0.11 mol) in diethyl ether (100 mL) under a nitrogen atmosphere at 0° C. The reaction mixture was stirred at 35° C. for 3 h and then dimethyl oxalate (5.9 g, 0.05 mol) in diethyl ether (150 mL) was added dropwise. The reaction mixture was heated at reflux (45° C.) for 45 min and then the mixture was allowed to cool to ambient temperature and 1.25 M sulfuric acid (150 mL) was added. The reaction mixture was stirred at ambient temperature for 1 h and then the organic layer was separated and washed with dilute aqueous sodium bicarbonate solution (100 mL), water (100 mL), dried with sodium sulfate, filtered and concentrated under reduced pressure. The resulting solid residue was recrystallized from tetrachloromethane (˜1 g/3 mL) to yield the title compound (7.68 g, 30 mmol, 60%).
Reaction SMILES: [F:1][C:2]1[C:7]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:6][CH:5]=[C:4]([F:15])[C:3]=1[CH:16]([O:31][CH3:32])[C:17]([NH:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27](=[NH:30])[NH:28]O)=[CH:23][CH:22]=1)=[O:18].C([OH:35])C>C(O)(=O)C.[Ni]>[C:16]([OH:31])(=[O:35])[CH3:17].[C:27]([C:24]1[CH:23]=[CH:22][C:21]([CH2:20][NH:19][C:17](=[O:18])[CH:16]([C:3]2[C:4]([F:15])=[CH:5][CH:6]=[C:7]([NH:8][C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:2]=2[F:1])[O:31][CH3:32])=[CH:26][CH:25]=1)(=[NH:28])[NH2:30]
Reactant: CCO
Reactant: COC(C(=O)NCc1ccc(C(=N)NO)cc1)c1c(F)ccc(Nc2ccccc2)c1F
Agent: [Ni]
Solvent: CC(=O)O
Product: COC(C(=O)NCc1ccc(C(=N)N)cc1)c1c(F)ccc(Nc2ccccc2)c1F
Temperature: 25 °C
Reaction time: 23 h

Procedure:
To a stirred solution of (RS)-2-(2,6-difluoro-3-phenylamino-phenyl)-N-[4-(N-hydroxycarbamimidoyl)-benzyl]-2-methoxy-acetamide (106 mg) at rt in ethanol (5 ml) under an argon atmosphere were added 5 drops of acetic acid and and a catalytic amount of Raney-Nickel. The mixture was then stirred at rt under a hydrogen atmosphere for 23 h. The catalyst was filtered off and the filtrate was concentrated. The crude product was purified using flash chromatography (EtOAc/acetone/H2O/HOAc 6:2:1:1) to give (RS)-N-(4-carbamimidoyl-benzyl)-2-(2,6-difluoro-3-phenylamino-phenyl)-2-methoxy-acetamide acetate (92 mg) as on off-white solid. MS 425.5 ([M+H]+)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([O:10][CH2:11][C:12]2[C:17]([O:18][CH3:19])=[CH:16][CH:15]=[C:14]([F:20])[C:13]=2[F:21])=[CH:4][C:3]=1[N:22]1[C:30](=[O:31])[NH:29][C:28]2[C:23]1=[N:24][C:25]([C:32]#[N:33])=[N:26][CH:27]=2.[OH-].[Na+].OO.S([O-])([O-])=[O:39].[Na+].[Na+]>CS(C)=O>[C:32]([C:25]1[N:24]=[C:23]2[C:28]([NH:29][C:30](=[O:31])[N:22]2[C:3]2[CH:4]=[C:5]([O:10][CH2:11][C:12]3[C:17]([O:18][CH3:19])=[CH:16][CH:15]=[C:14]([F:20])[C:13]=3[F:21])[C:6]([O:8][CH3:9])=[CH:7][C:2]=2[Cl:1])=[CH:27][N:26]=1)(=[O:39])[NH2:33]
Reactant: COc1cc(Cl)c(-n2c(=O)[nH]c3cnc(C#N)nc32)cc1OCc1c(OC)ccc(F)c1F
Reactant: O=S([O-])[O-]
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: COc1cc(Cl)c(-n2c(=O)[nH]c3cnc(C(N)=O)nc32)cc1OCc1c(OC)ccc(F)c1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 9-[2-chloro-5-(2,3-difluoro-6-methoxybenzyloxy)-4-methoxyphenyl]-2-cyano-7,9-dihydro-8H-purin-8-one (43 mg) in dimethyl sulfoxide (2 mL) were added 2 mol/L aqueous sodium hydroxide solution (0.14 mL) and 30% aqueous hydrogen peroxide solution (0.02 mL), and the mixture was stirred at room temperature for 1 hour. To the reaction mixture was added 10% aqueous sodium sulfite solution, and the resulting mixture was stirred at room temperature for 10 minutes, and extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residual solids were suspended in a mixed solvent (n-hexane/ethyl acetate=1/1), and collected by filtration. The collected solids were washed with the same solvent, and dried under reduced pressure to give the title compound (3 mg).
Reaction SMILES: [C:1]([N:8]([CH3:28])[CH:9]1[CH2:14][CH2:13][CH:12]([NH:15][CH2:16][C:17]2[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][C:22]=2[O:23][CH3:24])[CH2:11][CH2:10]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].FC(F)(F)S(O[C:35]1[CH:36]=[N:37][C:38]([CH3:41])=[CH:39][CH:40]=1)(=O)=O>>[CH3:24][O:23][C:22]1[CH:21]=[CH:20][C:19]([C:35]2[CH:36]=[N:37][C:38]([CH3:41])=[CH:39][CH:40]=2)=[CH:18][C:17]=1[CH2:16][NH:15][CH:12]1[CH2:13][CH2:14][CH:9]([N:8]([CH3:28])[C:1](=[O:2])[O:3][C:4]([CH3:7])([CH3:6])[CH3:5])[CH2:10][CH2:11]1
Reactant: COc1ccc(B(O)O)cc1CNC1CCC(N(C)C(=O)OC(C)(C)C)CC1
Reactant: Cc1ccc(OS(=O)(=O)C(F)(F)F)cn1
Product: COc1ccc(-c2ccc(C)nc2)cc1CNC1CCC(N(C)C(=O)OC(C)(C)C)CC1

Procedure:
Boronic acid 4 (1.6 g, 4.08 mmol) is coupled to pyridyl triflate 67 (982 mg, 4.08 mmol) using Method A to give the title compound.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[CH:8][C:7]=2/[CH:14]=[CH:15]/[C:16]2[N:17]=[C:18]3[S:26][CH:25]=[CH:24][N:19]3[C:20](=[O:23])[C:21]=2I)[CH2:3][CH2:2]1.[CH:27](=O)C1C=CC=CC=1.[H-].[Na+]>CS(C)=O>[CH3:2][C:1]([CH3:3])([CH3:27])[CH2:4][O:5][C:6]1[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[CH:8][C:7]=1/[CH:14]=[CH:15]/[C:16]1[N:17]=[C:18]2[S:26][CH:25]=[CH:24][N:19]2[C:20](=[O:23])[CH:21]=1
Reactant: O=Cc1ccccc1
Reactant: COc1cccc(/C=C/c2nc3sccn3c(=O)c2I)c1OCC1CC1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1cccc(/C=C/c2cc(=O)n3ccsc3n2)c1OCC(C)(C)C
Yield: 177 %

Procedure:
This compound was prepared using Step 2 intermediate from Intermediate 2 (1.00 g, 2.160 mmol), [2-(2,2-dimethylpropoxy)-3-methoxy)]benzaldehyde (527 mg, 2.316 mmol) and NaH (92 mg, 2.685 mmol) in dry DMSO (10 ml) according to the procedure outlined in Intermediate 2, Step 3 to yield a crude residue which was purified by column chromatography using 2% ethyl acetate in chloroform to afford the 1.416 g of the desired compound as a white solid: 1H NMR (300 MHz, DMSO-d6) 1.08 (s, 9H), 3.56 (s, 2H), 3.79 (s, 3H), 6.26 (s, 1H), 7.01-7.17 (m, 2H), 7.33-7.35 (m, 1H), 7.46 (d, J=4.8 Hz, 1H), 7.97 (d, J=4.8 Hz, 1H), 8.11-8.16 (m, 1H); ESI-MS (m/z) 371.52 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][N:9]=[CH:10][C:11](=O)[C:12]([F:15])([F:14])[F:13])=[CH:4][CH:3]=1.[CH3:17][CH:18](C(O)=O)[C:19](O)=[O:20].N1CCCCC1.C(O)(=O)C>N1C=CC=CC=1.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:19](=[O:20])[C:18]([CH3:17])=[C:11]([C:12]([F:15])([F:14])[F:13])[CH:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=C(C=NNc1ccc(Cl)cc1)C(F)(F)F
Reactant: CC(C(=O)O)C(=O)O
Solvent: CC(=O)O
Solvent: O
Solvent: c1ccncc1
Product: Cc1c(C(F)(F)F)cnn(-c2ccc(Cl)cc2)c1=O
Temperature: 80 °C
Reaction time: 4 h
Yield: 52.1 %

Procedure:
First, 0.25 g of 3,3,3-trifluoro-2-oxopropanal 1-(4-chlorophenylhydrazone), compound 3-11 was dissolved in 2 ml of pyridine. To this solution were added 0.24 g of methylmalonic acid and 0.09 g of piperidine, and the mixture was stirred at 80° C. for 4 hours. Then, 2.0 ml of acetic acid was added, and the mixture was stirred at 80° C. for 6.5 hours and further at 120° C. for 4 hours. After completion of the reaction, the reaction solution was poured into water, and this mixture was extracted with diethyl ether. The organic layer was washed with water and then with diluted hydrochloric acid, dried with anhydrous magnesium sulfate, and evaporated to remove the diethyl ether. The residue was subjected to silica gel column chromatography to give 0.15 g of 2-(4-chlorophenyl)-4-methyl-5-trifluoromethylpyridazin-3-one, compound 5-12, m.p., 80.8° C.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:8]3[N:9]([CH:13]=[C:14]([CH:16]4[CH2:19][N:18]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:17]4)[N:15]=3)[CH:10]=[CH:11][N:12]=2)[CH2:3][CH2:2]1.C1C(=O)N([Br:34])C(=O)C1>>[Br:34][C:10]1[N:9]2[CH:13]=[C:14]([CH:16]3[CH2:19][N:18]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:17]3)[N:15]=[C:8]2[C:7]([N:4]2[CH2:3][CH2:2][O:1][CH2:6][CH2:5]2)=[N:12][CH:11]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)OC(=O)N1CC(c2cn3ccnc(N4CCOCC4)c3n2)C1
Product: CC(C)(C)OC(=O)N1CC(c2cn3c(Br)cnc(N4CCOCC4)c3n2)C1

Procedure:
Compound 29a was brominated with NBS using the methods described in Example 1, Step E to obtain compound 29b. Mass Spectrum (LCMS, ESI pos.): Calcd. for C18H24BrN5O3: 438.1 (M+H). found: 438.2.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:11])[C:5](=[CH:9][CH:10]=1)[C:6]([OH:8])=[O:7].C(=O)([O-])O.[Na+].[CH2:17]([O:25][C:26](Cl)=[O:27])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].Cl>O.CO>[CH2:17]([O:25][C:26]([NH:1][C:2]1[CH:3]=[C:4]([OH:11])[C:5](=[CH:9][CH:10]=1)[C:6]([OH:8])=[O:7])=[O:27])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCCCCCCCOC(=O)Cl
Reactant: Nc1ccc(C(=O)O)c(O)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCCCCCCCOC(=O)Nc1ccc(C(=O)O)c(O)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.1 %

Procedure:
To 700 ml of methanol suspended 153 g of 4-aminosalicylic acid and 84 g of sodium hydrogen carbonate, 193 g of n-octylchloroformate was dropwise added over 2 hours at room temperature. After finishing dropwise addition, the mixture was further stirred for 2 hours at room temperature. An aqueous solution containing 30 g of concentrated hydrochloric acid and 1200 ml of water was added to the reaction mixture. Precipitated crystals were filtered and dried to obtain 300 g of desired 4-(n-octyloxycarbonylamino)salicylic acid as colorless crystals. Yield was 97%.
Reaction SMILES: [O:1]=[C:2]1[C:10](=[C:11]2[C:19]3[C:14](=[CH:15][C:16]([CH2:20][CH2:21][CH2:22]OS(C)(=O)=O)=[CH:17][CH:18]=3)[CH2:13][O:12]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1.[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1.O>CN(C=O)C>[N:28]1([CH2:22][CH2:21][CH2:20][C:16]2[CH:15]=[C:14]3[C:19](=[CH:18][CH:17]=2)[C:11](=[C:10]2[C:9]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[NH:3][C:2]2=[O:1])[O:12][CH2:13]3)[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1
Reactant: CS(=O)(=O)OCCCc1ccc2c(c1)COC2=C1C(=O)Nc2ccccc21
Reactant: C1COCCN1
Solvent: O
Solvent: CN(C)C=O
Product: O=C1Nc2ccccc2C1=C1OCc2cc(CCCN3CCOCC3)ccc21
Temperature: 90 °C
Yield: 98.3 %

Procedure:
A mixture of methanesulfonic acid 3-[1-(2-oxo-1,2-dihydro-indol-3-ylidene)-1,3-dihydro-isobenzofuran-5-yl]-propyl ester (400 mg, 1.04 mmol) and morpholine (1.5 ml, 17.2 mmol) in DMF (5 ml) was heated at 90° C. for 1.5 hours. The mixture was cooled, and poured into water (125 ml) with stirring. The solid was filtered, washed with water and dried under vacuum to give 3-[5-(3-morpholin-4-yl-propyl)-3H-isobenzofuran-1-ylidene]-1,3-dihydro-indol-2-one as a yellow solid (385 mg, 98%).
Reaction SMILES: C(N(CC)CC)C.[C:8]1([CH3:18])[CH:13]=[CH:12][C:11]([S:14](Cl)(=[O:16])=[O:15])=[CH:10][CH:9]=1.Cl.CN(C)C.[CH3:24][C:25]([CH2:31][CH2:32][CH2:33][CH:34]([CH3:46])[CH2:35][CH2:36][CH2:37][CH:38]([CH3:45])[CH2:39][CH2:40][CH2:41][CH:42]([CH3:44])[CH3:43])=[CH:26][CH2:27][CH2:28][CH2:29][OH:30].CN(C)CCCN>C(Cl)Cl.CCCCCC.C(OCC)(=O)C>[CH3:24][C:25]([CH2:31][CH2:32][CH2:33][CH:34]([CH3:46])[CH2:35][CH2:36][CH2:37][CH:38]([CH3:45])[CH2:39][CH2:40][CH2:41][CH:42]([CH3:44])[CH3:43])=[CH:26][CH2:27][CH2:28][CH2:29][O:30][S:14]([C:11]1[CH:12]=[CH:13][C:8]([CH3:18])=[CH:9][CH:10]=1)(=[O:16])=[O:15]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(=CCCCO)CCCC(C)CCCC(C)CCCC(C)C
Agent: CN(C)C
Agent: CN(C)CCCN
Agent: Cl
Solvent: CCCCCC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=CCCCOS(=O)(=O)c1ccc(C)cc1)CCCC(C)CCCC(C)CCCC(C)C
Reaction time: 1 h
Yield: 92.5 %

Procedure:
Under a nitrogen atmosphere, 55 mL (0.39 mol) of triethylamine, 59.9 g (0.314 mol) of p-toluenesulfonyl chloride, and 2.5 g (26 mmol) of trimethylamine hydrochloride were added to a solution of 85.0 g (0.262 mol) of 5,9,13,17-tetramethyloctadec-4-en-1-ol in dry methylene chloride (0.26 L) at 0° C., sequentially. After being stirred for 1 hour, 9.9 mL (79 mmol) of N,N-dimethyl-1,3-propanediamine was added to the reaction solution at 0° C. After being stirred for 1 hour, the mixture was diluted with a mixed solvent of hexane/ethyl acetate. The resulting solution was washed with water, 3M hydrochloric acid (twice), saturated sodium bicarbonate aqueous solution, and saturated brine, successively, and dried over magnesium sulfate. After filtration, the filtrate was concentrated, and the resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate=90:10) to obtain 116 g of (5,9,13,17-tetramethyloctadec-4-enyl)tosylate (93% yield).
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:20].[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][C:29](O)=[O:30])=[CH:24][CH:23]=1>>[Cl:19][C:16]1[CH:15]=[CH:14][C:13]([CH2:12][C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3](=[O:20])[N:2]([NH:1][C:29](=[O:30])[CH2:28][C:25]3[CH:26]=[CH:27][C:22]([Cl:21])=[CH:23][CH:24]=3)[N:11]=2)=[CH:18][CH:17]=1
Reactant: O=C(O)Cc1ccc(Cl)cc1
Reactant: Nn1nc(Cc2ccc(Cl)cc2)c2ccccc2c1=O
Product: O=C(Cc1ccc(Cl)cc1)Nn1nc(Cc2ccc(Cl)cc2)c2ccccc2c1=O

Procedure:
The product of Example 144A and 2-(4-chlorophenyl)acetic acid were treated using a method similar to that described in Example 17C to give the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.63 (s, 1H), 8.30 (d, J=8.3 Hz, 1H), 7.95-7.99 (m, 1H), 7.90-7.95 (m, 1H), 7.84-7.89 (m, 1H), 7.37-7.44 (m, 4H), 7.31-7.38 (m, 4H), 4.32-4.32 (bs, 2H), 3.70 (s, 2H); LC/MS (APCI) M/Z 438 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:16][O:17][CH2:18][CH2:19]Br.[I-].[Na+].C(=O)(O)[O-].[Na+].FC(F)(F)C(O)=O>O.CCOCC.C(OCC)(=O)C.CC#N.O.CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]([CH2:19][CH2:18][O:17][CH3:16])[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COCCBr
Reactant: CCOC(=O)CNc1ccc(Cl)c(Cl)c1
Agent: O=C([O-])O
Agent: [I-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)CN(CCOC)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 19.8 %

Procedure:
Ethyl N-(3,4-dichlorophenyl)glycinate (3.0 g, 12.1 mmol) was suspended in 2-bromoethyl methyl ether (9.09 mL, 96.7 mmol) and treated with sodium iodide (1.81 g, 12.1 mmol), sodium bicarbonate (1.02 g, 12.1 mmol), and 10 mL of DMF. The reaction was stirred for 20 hours at room temperature, but HPLC (Eclipse XDB-C18, 4.6×250 mm, 5 micron, 1-99% CH3CN/H2O with 0.1% trifluoroacetic acid) indicated that only starting material (Rt=8.0 min) was present and that no reaction had taken place. The reaction was heated to 125° C. for 24 hours, after which time HPLC showed that all of the starting material was gone and that a new product peak had formed (Rt=8.7 min). The reaction mixture was poured into 200 mL of ethyl acetate, 100 mL of ether, and 250 mL of water and shaken vigorously. The layers were separated and the organic layer was washed with water (1×400 mL), dried over magnesium sulfate, filtered, and concentrated to a black oil. The oil was adsorbed onto approximately 50 g of silica gel and purified by column chromatography (300 g silica gel 40 um, gradient elution from 10% ethyl acetate/90% hexanes to 100% ethyl acetate over 110 minutes) to give ethyl N-(3,4-dichlorophenyl)-N-[2-(methyloxy)ethyl]glycinate (0.73 g, 2.39 mmol, 20%) as a brown oil. MS (ES) m/e 306 [M+H]+.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5]1(=[O:11])[O:10][C:8](=[O:9])[CH2:7][CH2:6]1.C([C:14]1([CH:22]([CH3:26])C([O-])=O)[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]1[CH3:21])C.Cl>C(Cl)Cl>[Cl:20][C:17]1[CH:16]=[C:15]([CH3:21])[C:14]([CH2:22][CH2:26][C:8]([O:10][CH2:5][CH3:6])=[O:9])=[CH:19][C:18]=1[C:8](=[O:9])[CH2:7][CH2:6][C:5]([OH:10])=[O:11]
Reactant: O=C1CCC(=O)O1
Reactant: CCC1(C(C)C(=O)[O-])C=CC(Cl)=CC1C
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCOC(=O)CCc1cc(C(=O)CCC(=O)O)c(Cl)cc1C
Temperature: 25 °C
Reaction time: 24 h
Yield: 166.9 %

Procedure:
Aluminum chloride (5.87 g; 0.044 mole) was added portionwise (5 minutes) to a mixture of succinic anhydride (1.1 g; 0.011 mole) and 1-ethyl-4-chloro-2-methylphenylpropionate (2.27 g; 0.01 mole) in CH2Cl2 (20 ml) with cooling (ice bath). The reaction mixture was stirred at room temperature for 24 hours, poured into ice and 10 ml concentrated HCl and extracted with ether. The ether solution was dried and evaporated to give a yellow brown oil, which was purified by flash column chromatography (silica gel and 2% HOAc-10% acetone-90% CH2Cl2) to give the product as a yellow oil (3.0 g; 92% yield).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[C:5]1[CH:10]=[CH:9][C:8](F)=[C:7]([N+:12]([O-:14])=[O:13])[CH:6]=1)[CH3:2].CN(C=O)C.C(=O)([O-])[O-].[K+].[K+].[NH2:27][CH:28]([CH2:31][CH3:32])[CH2:29][CH3:30]>O>[CH2:1]([O:3][C:4](=[O:15])[C:5]1[CH:10]=[CH:9][C:8]([NH:27][CH:28]([CH2:31][CH3:32])[CH2:29][CH3:30])=[C:7]([N+:12]([O-:14])=[O:13])[CH:6]=1)[CH3:2]
Reactant: CCC(N)CC
Reactant: CCOC(=O)c1ccc(F)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1ccc(NC(CC)CC)c([N+](=O)[O-])c1
Reaction time: 2 h
Yield: 99.8 %

Procedure:
To a solution of 25.0 g of 4-fluoro-3-nitro-benzoic acid ethyl ester in 100 ml of abs. DMF was added 24.3 g of potassium carbonate, followed by 11.6 g of 3-aminopentane. After 2 h at rt, the mixture was poured into water, and extracted with ethyl acetate three times. The combined organic phases were dried over magnesium sulphate and concentrated to yield 32.8 g (100%) of 4-(1-Ethyl-propylamino)-3-nitro-benzoic acid ethyl ester as a yellow oil.
Reaction SMILES: [C:1]1([N:7]2[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:10][CH:9]=[C:8]2[C:18]2[CH:19]=[C:20]3[C:25](=[CH:26][CH:27]=2)[CH:24]=[C:23]([OH:28])[CH:22]=[CH:21]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:30][C:31]([O:33][CH3:34])=[O:32].C(=O)([O-])[O-].[Cs+].[Cs+]>>[C:1]1([N:7]2[C:11]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)=[CH:10][CH:9]=[C:8]2[C:18]2[CH:19]=[C:20]3[C:25](=[CH:26][CH:27]=2)[CH:24]=[C:23]([O:28][CH2:30][C:31]([O:33][CH3:34])=[O:32])[CH:22]=[CH:21]3)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)CBr
Reactant: Oc1ccc2cc(-c3ccc(-c4ccccc4)n3-c3ccccc3)ccc2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: COC(=O)COc1ccc2cc(-c3ccc(-c4ccccc4)n3-c3ccccc3)ccc2c1
Yield: 91.8 %

Procedure:
In a similar manner as described in step 6 of Example 1, the title compound was prepared from 6-(1,5-diphenyl-1H-pyrrol-2-yl)-2-naphthol (0.200 g, 0.553 mmol), prepared in step 2 of Example 11, methyl bromoacetate (0.102 g, 0.664 mmol) and cesium carbonate (0.900 g, 2.77 mmol) with the exception that the product was extracted with methylene chloride. Purification on a Biotage Horizon™ system with a KP-Sil Flash 40+M column (100 g Silica Gel, 60 Å) using 55% to 95% methylene chloride in hexane as the eluent gave methyl {[6-(1,5-diphenyl-1H-pyrrol-2-yl)-2-naphthyl]oxy}acetate as an off-white solid (0.22 g, 92%), mp 188–189° C. Elemental Analysis for C29H23NO3.0.16 CH2Cl2 Calc'd: C, 78.34; H, 5.26; N, 3.13. Found: C, 77.73; H, 5.08; N, 3.07.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[C:9]([Cl:10])=[CH:8][CH:7]=[C:6]([C:11](Cl)=[N:12][OH:13])[C:5]=1[F:15].[F:17][C:18]([F:27])([F:26])[C:19]1[CH:20]=[C:21]([CH:23]=[CH:24][CH:25]=1)[NH2:22].NC1C=CC=CC=1>C1COCC1>[Cl:10][C:9]1[C:4]([C:3]([O:2][CH3:1])=[O:16])=[C:5]([F:15])[C:6]([C:11](=[N:12][OH:13])[NH:22][C:21]2[CH:23]=[CH:24][CH:25]=[C:19]([C:18]([F:17])([F:26])[F:27])[CH:20]=2)=[CH:7][CH:8]=1
Reactant: COC(=O)c1c(Cl)ccc(C(Cl)=NO)c1F
Reactant: Nc1cccc(C(F)(F)F)c1
Solvent: C1CCOC1
Solvent: Nc1ccccc1
Product: COC(=O)c1c(Cl)ccc(C(=NO)Nc2cccc(C(F)(F)F)c2)c1F
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a solution of methyl-6-chloro-3-(chloro(hydroxyimino)methyl)-2-fluorobenzoate (1.2 g, 4.3 mmol) in THF (10 ml) at 0° C. was added 3-(trifluoromethyl)aniline (2.7 ml, 22 mmol). After stirring at 0° C. for 10 min, the reaction was allowed to warm to RT and stir for 3 h, then heat at 50° C. in an oil bath overnight. Added more of the aniline (5 mL) and heated at 50° C. for another 5 h. After cooling to RT, the solvent was evaporated and solid formed was filtered off. The filtrate was dissolved in DCM and purified by chromatography through a Redi-Sep® pre-packed silica gel column (120 g), eluting with a gradient of 5% to 25% EtOAc in hexane, to provide methyl 6-chloro-2-fluoro-3-(N′-hydroxy-N-(3-(trifluoromethyl)phenyl)carbamimidoyl)benzoate as off-white solid.