Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([CH2:18][OH:19])[CH2:9][C:10]1[CH:15]=[C:14]([F:16])[CH:13]=[C:12]([F:17])[CH:11]=1)(C)(C)C.[F:21][C:22]([F:27])([F:26])[C:23]([OH:25])=[O:24]>ClCCl>[F:21][C:22]([F:27])([F:26])[C:23]([OH:25])=[O:24].[NH2:7][C@@H:8]([CH2:9][C:10]1[CH:11]=[C:12]([F:17])[CH:13]=[C:14]([F:16])[CH:15]=1)[CH2:18][OH:19]
Reactant: CC(C)(C)OC(=O)N[C@H](CO)Cc1cc(F)cc(F)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N[C@H](CO)Cc1cc(F)cc(F)c1

Procedure:
Dissolve [2-(3,5-difluorophenyl)-1-(S)-hydroxymethyl-ethyl]-carbamic acid tert-butyl ester (4.57 g, 15.9 mmol) in dichloromethane (20 mL). Add trifluoroacetic acid (20 mL) and stir 45 min and concentrate to give the title compound as a thick residue.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([CH2:12][C:13]([NH2:15])=[NH:14])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].O.[NH2:17]N.[C:19]([NH:22][CH:23]([CH2:31][CH3:32])[C:24](=O)[C:25](OCC)=[O:26])(=[O:21])[CH3:20]>>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH2:12][C:13]1[NH:15][C:25](=[O:26])[C:24]([CH:23]([NH:22][C:19](=[O:21])[CH3:20])[CH2:31][CH3:32])=[N:17][N:14]=1
Reactant: NN
Reactant: COc1ccc(CC(=N)N)cc1OC
Reactant: CCOC(=O)C(=O)C(CC)NC(C)=O
Agent: Cl
Solvent: O
Product: CCC(NC(C)=O)c1nnc(Cc2ccc(OC)c(OC)c2)[nH]c1=O

Procedure:
Analogously to Example 10A, 9.75 g (42.3 mmol) of 2-(3,4-dimethoxyphenyl)ethanamidine hydrochloride are reacted with 2.54 g (50.7 mmol) of hydrazine hydrate and 12.8 g (63.4 mmol) of ethyl 3-(acetylamino)-2-oxopentanoate to give N-{1-[3-(3,4-dimethoxybenzyl)-5-oxo-4,5-dihydro-1,2,4-triazin-6-yl]propyl}acetamide.
Reaction SMILES: [C:1]([N:4]([CH3:20])[C:5]1[N:10]=[CH:9][C:8]([NH:11][C:12](=[O:19])OCC(Cl)(Cl)Cl)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[C:21]1([C:27]2[N:31]=[C:30]([N:32]3[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]3)[S:29][N:28]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(N(C(C)C)CC)(C)C.CS(C)=O>O>[C:1]([N:4]([CH3:20])[C:5]1[N:10]=[CH:9][C:8]([NH:11][C:12]([N:35]2[CH2:36][CH2:37][N:32]([C:30]3[S:29][N:28]=[C:27]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[N:31]=3)[CH2:33][CH2:34]2)=[O:19])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)N(C)c1ccc(NC(=O)OCC(Cl)(Cl)Cl)cn1
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)cc1
Solvent: O
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N(C)c1ccc(NC(=O)N2CCN(c3nc(-c4ccccc4)ns3)CC2)cn1
Yield: 39.3 %

Procedure:
A solution of 2,2,2-trichloroethyl {6-[acetyl(methyl)amino]pyridin-3-yl}carbamate (200 mg, 0.587 mmol), 1-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine (145 mg, 0.587 mmol), diisopropylethylamine (0.102 ml, 0.587 mmol) and dimethylsulfoxide (4 ml) was stirred at 70° C. for 12 hours, the reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was recrystallized from a mixed solvent of ethyl acetate and hexane to obtain the desired product (101 mg, 39.3%) as a solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[NH:11][C:10]([C:14]3[CH:15]=[C:16]([CH:24]=[CH:25][C:26]=3[Cl:27])[CH2:17][NH:18][C:19]([CH:21]3[CH2:23][CH2:22]3)=[O:20])=[N:9]2)=[CH:4][C:3]=1[O:28][CH3:29].[CH:30]1([C:33](Cl)=[O:34])[CH2:32][CH2:31]1.CCN(C(C)C)C(C)C>C1COCC1>[Cl:27][C:26]1[CH:25]=[CH:24][C:16]([CH2:17][NH:18][C:19]([CH:21]2[CH2:23][CH2:22]2)=[O:20])=[CH:15][C:14]=1[C:10]1[NH:11][C:12](=[O:13])[N:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:1][C:33]([CH:30]3[CH2:32][CH2:31]3)=[O:34])=[C:3]([O:28][CH3:29])[CH:4]=2)[N:9]=1
Reactant: COc1cc(-n2nc(-c3cc(CNC(=O)C4CC4)ccc3Cl)[nH]c2=O)ccc1N
Reactant: O=C(Cl)C1CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1cc(-n2nc(-c3cc(CNC(=O)C4CC4)ccc3Cl)[nH]c2=O)ccc1NC(=O)C1CC1
Yield: 25.9 %

Procedure:
The title compound was prepared by following the procedure as described for step-2 of Intermediate-30 by using N-(3-(1-(4-amino-3-methoxyphenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)-4-chlorobenzyl)cyclopropanecarboxamide (Intermediate-37, 0.050 g, 0.120 mmol), cyclopropylcarbonyl chloride (0.018 g, 0.180 mmol), DIPEA (2.0 mL) and THF (5 mL) to afford 0.015 g of desired product. 1H NMR (300 MHz, DMSO d6): δ 0.69 (s, 4H), 0.77 (s, 4H), 1.60 (m, 1H), 2.08 (m, 1H), 3.88 (s, 3H), 4.33 (d, J=5.4 Hz, 2H), 7.45 (m, 2H), 7.62 (s, 2H), 7.96 (d, J=8.4 Hz, 1H), 8.69 (m, 1H), 9.49 (s, 1H), 12.54 (s, 1H); MS (m/z): 482.10 (M+H)+.
Reaction SMILES: [C:1]([CH2:4][C:5]1[CH:22]=[CH:21][C:8]([C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH2:17][C:18]([OH:20])=[O:19])=O)=[CH:7][CH:6]=1)([OH:3])=[O:2].Cl.O.[OH-].[Na+]>CO>[C:1]([CH2:4][C:5]1[CH:22]=[CH:21][C:8]([CH2:9][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH2:17][C:18]([OH:20])=[O:19])=[CH:7][CH:6]=1)([OH:3])=[O:2]
Reactant: O=C(O)Cc1ccc(C(=O)c2ccccc2CC(=O)O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)Cc1ccc(Cc2ccccc2CC(=O)O)cc1
Yield: 46.1 %

Procedure:
A solution of 3.8 g of 2-(4-carboxymethylbenzoyl)phenylacetic acid in 15 ml of methanol was added to 9.0 g of zinc amalgam, 17.5 ml of conc. hydrochloric acid and 7.5 ml of water. The mixture was heated under reflux for 5 hours with stirring. After the reaction, the reaction mixture was cooled, and the zinc amalgam was removed by decantation. Water (100 ml) was added, and the mixture was extracted with ether. The ethereal layer was washed with a saturated aqueous solution of sodium chloride. The ether was distilled off to afford a yellow oily product. Methanol (20 ml) was added to dissolve it. Then, 60 ml of a 10% sodium hydroxide solution was added to the solution, and the solution was heated under reflux for 3 hours with stirring. After the reaction, the reaction mixture was cooled, acidified with conc. hydrochloric acid, and extracted with ether. The ethereal layer was washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate. The ether was then distilled off. The residue was chromatographed on a silica gel column using a mixture of chloroform and methanol (95:5) as an eluent. A solid was obtained from the eluate. Recrystallization from ether afforded 1.67 g of 2-(4-carboxymethylbenzyl)phenylacetic acid as colorless plate-like crystals having a melting point of 155° to 156° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])[CH:5]=[C:6]([C:9]([CH3:12])([CH3:11])[CH3:10])[C:7]=1[OH:8].[Cl-].[Al+3].[Cl-].[Cl-].CC1C=CC=C(C(C)(C)C)C=1[OH:37].Cl.[CH2:39](Cl)[CH2:40]Cl>>[CH3:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([C:9]([CH3:12])([CH3:10])[CH3:11])[C:7]=1[OH:8])[C:13]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([O:21][CH2:39][CH3:40])=[O:20])=[O:37]
Reactant: Cc1cc(CCCCCCC(=O)O)cc(C(C)(C)C)c1O
Reactant: ClCCCl
Reactant: Cc1cccc(C(C)(C)C)c1O
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: CCOC(=O)CCCCCC(=O)c1cc(C)c(O)c(C(C)(C)C)c1
Temperature: -5 °C
Reaction time: 5 h

Procedure:
7-(3-methyl-5-t-butyl-4-hydroxyphenyl)heptanoic acid. To a cooled (-5° C.) solution of 103 parts of ethyl 6-chloroformyl hexanoate in 100 parts by volume of ethylene chloride is rapidly added with stirring 133 parts of granular anhydrous aluminum chloride. To this mixture is next added a solution of 88 parts of 2-methyl-6-t-butylphenol in 500 parts by volume of ethylene chloride. The reaction mixture is stirred at -5° C. for 5 hours and then allowed to slowly attain room temperature overnight. At the end of this time the material is poured over ice, rendered acidic with 6 N hydrochloric acid and extracted with ether. The combined extracts are successively washed with water, dilute aqueous sodium bicarbonate solution and saturated aqueous sodium bicarbonate solution. After drying over sodium sulfate, the solvent is removed under reduced pressure to yield ethyl 6-(3-methyl-5-t-butyl-4-hydroxybenzoyl)hexanoate, which is saponified with excess potassium hydroxide in methanol. After acidification of the reaction mixture, the solid, comprising 6 -(3-methyl-5-t-butyl-4-hydroxybenzoyl)hexanoic acid, is subjected to a Clemmenson reduction as modified by Martin [J.A.C.S. 58, 1438 (1936)]to yield 7-(3-methyl-5-t-butyl-4-hydroxyphenyl)heptanoic acid which is esterified with ethanol and p-toluenesulfonic acid to yield the corresponding ethyl ester.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]([CH3:27])[CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[N:18]([CH2:22][C:23]([O:25][CH3:26])=[O:24])[CH:17]=[CH:16]3)[C:5]([F:28])=[CH:4][N:3]=1.O.C(=O)([O-])[O-].[Na+].[Na+].[CH3:36][O:37][C:38]1[CH:43]=[CH:42][C:41](B(O)O)=[CH:40][CH:39]=1>C1(C)C=CC=CC=1.O1CCOCC1>[F:28][C:5]1[C:6]([N:8]([CH3:27])[CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[N:18]([CH2:22][C:23]([O:25][CH3:26])=[O:24])[CH:17]=[CH:16]3)=[N:7][C:2]([C:41]2[CH:42]=[CH:43][C:38]([O:37][CH3:36])=[CH:39][CH:40]=2)=[N:3][CH:4]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: COC(=O)Cn1ccc2cc(OCCCN(C)c3nc(Cl)ncc3F)ccc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)Cn1ccc2cc(OCCCN(C)c3nc(-c4ccc(OC)cc4)ncc3F)ccc21
Temperature: 80 °C
Yield: 92 %

Procedure:
To a solution of methyl (5-{3-[(2-chloro-5-fluoro-4-pyrimidinyl)(methyl)amino]propoxy}-1H-indol-1-yl)acetate (Example 84, 0.1 g, 0.25 mmol) in toluene (3.75 mL), dioxane (0.75 mL), and water (0.88 mL) were added sodium carbonate (0.26 g, 2.46 mmol), 4-methoxyphenyl boronic acid (0.15 g, 0.98 mmol), and PdCl2(dppf)(CH2Cl2) (0.04 g, 0.05 mmol). The mixture was heated at 80° C. for 4 h and then concentrated under reduced pressure. The product (0.11 g, 94%) was obtained after column chromatography (67% hexanes in EtOAc). 1H NMR (300 MHz, CD2Cl2) δ 8.31 (d, 2H), 8.06 (d, 1H), 7.12-7.07 (m, 3H), 6.95-6.87 (m, 3H), 6.41 (d, 1H), 4.85 (s, 2H), 4.11 (t, 2H), 3.94 (t, 2H), 3.86 (s, 3H), 3.76 (s, 3H), 3.35 (d, 3H), 2.26-2.20 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1([Cl:14])[CH2:8][CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[NH:4][C:3]1=[O:13].Br[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18].[H-].[Na+]>O1CCCC1>[Cl:14][C:2]1([Cl:1])[CH2:8][CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[N:4]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:3]1=[O:13]
Reactant: O=C1Nc2ccccc2CCC1(Cl)Cl
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)CN1C(=O)C(Cl)(Cl)CCc2ccccc21
Reaction time: 2 h

Procedure:
A solution of 3,3-dichloro-2,3,4,5-tetrahydro-1H-[1]benzazepin-2-one (1.0 g, 4.32 mmol) and ethyl bromoacetate (0.51 ml) in of tetrahydrofuran (30 ml) was added dropwise with stirring during 15 minutes to a solution of sodium hydride (4.76 mmol) in tetrahydrofuran (20 ml) at room temperature under a nitrogen atmosphere. Stirring was continued for an additional 2 hours. The solution was quenched by addition of saturated aqueous ammonium chloride and the solvents were removed under reduced pressure. The residue was extracted with ether (3×20 ml), and the combined ether solutions washed with saturated brine (20 ml) and dried over magnesium sulfate. Removal of the solvent under reduced pressure gave 3,3-dichloro-1-ethoxycarbonylmethyl-2,3,4,5-tetrahydro-1H-[1]benzazepin-2-one. NMR(CDCl3):δ1.27 (t, 3H); 3.22 (m, 4H); 4.25 (q, 2H); 4.65 (s, 2H), 7.3 (m, 4H).
Reaction SMILES: [C:1]([BH3-])#[N:2].[Na+].N[CH:6]1[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[CH:14]=[CH:15][N:16]3[C:21]=2[C:20]([NH:22][C:23]2[CH:24]=[C:25]4[C:29](=[CH:30][CH:31]=2)[N:28]([CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[CH:34]=2)[N:27]=[CH:26]4)=[N:19][CH:18]=[N:17]3)[CH2:8][CH2:7]1.[C:40](O)(=O)C.C=O>C(Cl)Cl>[CH3:40][N:2]([CH3:1])[CH:6]1[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[CH:14]=[CH:15][N:16]3[C:21]=2[C:20]([NH:22][C:23]2[CH:24]=[C:25]4[C:29](=[CH:30][CH:31]=2)[N:28]([CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[CH:34]=2)[N:27]=[CH:26]4)=[N:19][CH:18]=[N:17]3)[CH2:8][CH2:7]1
Reactant: NC1CCN(Cc2ccn3ncnc(Nc4ccc5c(cnn5Cc5cccc(F)c5)c4)c23)CC1
Reactant: CC(=O)O
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: ClCCl
Product: CN(C)C1CCN(Cc2ccn3ncnc(Nc4ccc5c(cnn5Cc5cccc(F)c5)c4)c23)CC1
Reaction time: 0.5 h
Yield: 8 %

Procedure:
Sodium cyanoborohydride (5 mg, 2 equiv.) was added to a solution of [5-(4-amino-piperidin-1-ylmethyl)-pyrrolo[2,1-f][1,2,4]triazin-4-yl]-[1-(3-fluoro-benzyl)-1H-indazol-5-yl]-amine (20 mg, 0.042 mmole), acetic acid (3 uL), and 37% formaldehyde (7 uL, 2 equiv.) in DCM (0.3 ml) at 0° C. After 0.5 h, the reaction was removed from the ice-bath and, after an additional 4 h, was diluted with DCM and made alkaline with saturated NaCO3 solution. The organic layer was dried (Na2SO4) and the solvent was removed. The title compound (4 mg, 8%) was isolated by preparative HPLC. MS: 499 (M+H)+; HPLC Ret Time: 1.04 min (YMC ODS-A C18 S7 3.0×50 mm column, 2 min gradient, 5 ml/min).
Reaction SMILES: C[O:2][C:3](=[O:35])[C@H:4]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][C:25]([C:27]2[C:32]([Cl:33])=[CH:31][CH:30]=[CH:29][C:28]=2[Cl:34])=[O:26])=[CH:20][CH:19]=1)[NH:5][C:6]([C:8]1([CH2:13][CH2:14][O:15][CH3:16])[CH2:12][CH2:11][CH2:10][CH2:9]1)=[S:7].[OH-].[Na+].Cl.C(OCC)(=O)C>CO.O>[Cl:33][C:32]1[CH:31]=[CH:30][CH:29]=[C:28]([Cl:34])[C:27]=1[C:25]([NH:24][C:21]1[CH:22]=[CH:23][C:18]([CH2:17][C@@H:4]([C:3]([OH:35])=[O:2])[NH:5][C:6]([C:8]2([CH2:13][CH2:14][O:15][CH3:16])[CH2:12][CH2:11][CH2:10][CH2:9]2)=[S:7])=[CH:19][CH:20]=1)=[O:26]
Reactant: COCCC1(C(=S)N[C@@H](Cc2ccc(NC(=O)c3c(Cl)cccc3Cl)cc2)C(=O)OC)CCCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: O
Product: COCCC1(C(=S)N[C@@H](Cc2ccc(NC(=O)c3c(Cl)cccc3Cl)cc2)C(=O)O)CCCC1
Reaction time: 2 h
Yield: 78.3 %

Procedure:
To a solution of 4-[[(2,6-dichlorophenyl)carbonyl]amino]-N-[[1-(2-methoxyethyl) cyclopentyl]thioxomethyl]-L-phenylalanine methyl ester (4.00 g, 7.44 mmol) in methanol (18 mL) was added a solution of NaOH (421 mg, 10.5 mmol) in water (3 mL). The mixture was stirred for 2 h and then acidified (pH˜1-2) with 0.5N HCl. The reaction mixture was poured into a separatory funnel containing ethyl acetate (150 mL) and water (25 mL). The separated aqueous layer was back-extracted with ethyl acetate (2×50 mL). The combined organic layers was washed with brine, dried over MgSO4, filtered and concentrated in vacuo. Purification of the residual material by RP-HPLC (15-95% acetonitrile-water gradient over 25 min) provided 4-[[(2,6-dichlorophenyl)carbonyl]amino]-N-[[1-(2-methoxyethyl)cyclopentyl]thioxomethyl]-L-phenylalanine (3.05 g, 78%). HR MS: Obs. mass, 545.1043. Calcd. mass, 545.1045 (M+Na).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:32])[CH:19]([O:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]#[N:31])[CH:25]=2)[CH2:20][CH2:21][CH3:22])=[CH:13][CH:12]=1)(=[O:4])=[O:3].Cl.[Cl-].[OH:35][NH3+:36].C(N(CC)CC)C>CO.O>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH:12]=[CH:13][C:14]([NH:17][C:18](=[O:32])[CH:19]([O:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30](=[NH:31])[NH:36][OH:35])[CH:25]=2)[CH2:20][CH2:21][CH3:22])=[CH:15][CH:16]=1)(=[O:3])=[O:4]
Reactant: CCCC(Oc1cccc(C#N)c1)C(=O)Nc1ccc(-c2ccccc2S(C)(=O)=O)cc1
Reactant: [NH3+]O
Agent: Cl
Agent: [Cl-]
Solvent: CO
Solvent: O
Solvent: CCN(CC)CC
Product: CCCC(Oc1cccc(C(=N)NO)c1)C(=O)Nc1ccc(-c2ccccc2S(C)(=O)=O)cc1
Temperature: 60 °C
Reaction time: 18 h

Procedure:
A solution of 1.40 g (3.12 mmol) of 2-(3-cyanophenoxy)pentanoic acid (2′-methanesulfonylbiphenyl-4-yl)amide in 50 ml of methanol is treated with 695 mg (10.0 mmol) of hydroxylammonium chloride hydrochloride and 1.01 g (10.0 mmol) of triethylamine and stirred at 60° C. for 18 hours. It is allowed to cool, the solvent is stripped off, the residue is taken up in water and the resulting precipitate is filtered off. A colourless solid is obtained; FAB 482
Reaction SMILES: [C:1]1(=[O:24])[N:5]([CH:6]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=2)[CH2:7][C:8](O)=[O:9])[C:4](=[O:19])[C:3]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:2]12.C(N1C=CN=C1)([N:27]1C=CN=C1)=O.[OH-].[NH4+].CCOCC>O1CCCC1.CN(C)C1C=CN=CC=1>[C:1]1(=[O:24])[N:5]([CH:6]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=2)[CH2:7][C:8]([NH2:27])=[O:9])[C:4](=[O:19])[C:3]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:2]12
Reactant: O=C(O)CC(c1ccc(Cl)c(Cl)c1)N1C(=O)c2ccccc2C1=O
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CN(C)c1ccncc1
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: NC(=O)CC(c1ccc(Cl)c(Cl)c1)N1C(=O)c2ccccc2C1=O
Reaction time: 0.17 h
Yield: 35.6 %

Procedure:
To a stirred solution of 3-phthalirnido-3-(3,4-dichlorophenyl)propionic acid (1.10 g, 3.02 mmol) in 20 mL of tetrahydrofuran at room temperature under nitrogen was added carbonyldiimidazole (0.51 g, 3.17 mmol) and a catalytic amount of 4-dimethylaminopyridine. The mixture was stirred for 45 in and then concentrated ammonium hydroxide (0.21 nL, 3.2 mmol) was added. The reaction mixture was stirred for 10 minutes and then the tetrahydrofuran was removed under reduced pressure. To the resulting mixture was added 20 mL of water, a light yellow oil was formed. To the mixture was added 3 mL of ether, the mixture was stirred at room temperature for 1 hour. The resulting slurry was filtered, the solid was washed with water and air-dried to afford 0.73 g of the crude product as a white solid. The crude product was purified by flash chromatography (silica gel, hexane/methylene chloride, 22-0% (v/v)) to afford 0.39 g (36%) of 3-phthaiimido-3-(3,4-dichlorophenyl)propionamide as a white powder: 1H NMR (DMSO-d6, 250 MHz) δ7.83 (m, 4H, Ar), 7.35-7.75 (m, 4H), 6.93 (br s, 1H), 5.72 (t, 1H, J=8 Hz), 3.25 (dd, 1H, J1=8 Hz, J2=15 Hz), 3.14 (dd, 1H, J1=8 Hz, J2=15 Hz); 13C NMR (DMSO-d6) δ170.8, 167.6, 140.2, 134.6, 131.2, 131.0, 130.7, 130.3, 129.2, 127.7, 123.2, 49.3, 36.5. Anal. Calcd for C17H12N2O3Cl2. Theoretical C, 54.69; H, 3.54; N, 7.53. Found C, 54.69; H, 3.38; N, 7.15.
Reaction SMILES: Cl.Cl.[CH:3]1([O:8][C:9]2[CH:10]=[C:11]([N:17]3[CH2:22][CH2:21][NH:20][C@@H:19]([CH2:23][N:24]4[CH2:28][CH2:27][CH2:26][CH2:25]4)[CH2:18]3)[CH:12]=[CH:13][C:14]=2[O:15][CH3:16])[CH2:7][CH2:6][CH2:5][CH2:4]1.C(N(C(C)C)CC)(C)C.[CH3:38][C:39]1[NH:43][N:42]=[C:41]([CH2:44][C:45](O)=[O:46])[N:40]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl.CN(C=O)C>[CH:3]1([O:8][C:9]2[CH:10]=[C:11]([N:17]3[CH2:22][CH2:21][N:20]([C:45](=[O:46])[CH2:44][C:41]4[N:40]=[C:39]([CH3:38])[NH:43][N:42]=4)[C@@H:19]([CH2:23][N:24]4[CH2:25][CH2:26][CH2:27][CH2:28]4)[CH2:18]3)[CH:12]=[CH:13][C:14]=2[O:15][CH3:16])[CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: Cc1nc(CC(=O)O)n[nH]1
Reactant: COc1ccc(N2CCN[C@@H](CN3CCCC3)C2)cc1OC1CCCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc(N2CCN(C(=O)Cc3n[nH]c(C)n3)[C@@H](CN3CCCC3)C2)cc1OC1CCCC1
Reaction time: 16 h
Yield: 64 %

Procedure:
A solution of (S)-1-(3-(cyclopentyloxy)-4-methoxyphenyl)-3-(pyrrolidin-1-ylmethyl)piperazine, dihydrochloride (Example 40, Compound 128) (173 mg, 0.40 mmol) in CH2Cl2 (1 mL) and DMF (1 mL) was treated with diisopropylethylamine (348 uL, 2.0 mmol), 2-(5-methyl-1H-1,2,4-triazol-3-yl)acetic acid CAS [720706-28-5] (68 mg, 0.48 mmol) followed by HBTU (162 mg, 0.48 mmol). The reaction mixture was stirred for 16 h after which time the mixture was partitioned between CH2Cl2 (3 mL) and a saturated aqueous solution of NaHCO3 (2 mL). The organic portion was further washed with NaHCO3 (2×3 mL) followed by brine (3 mL). The organic portion was then dried over MgSO4, filtered, and evaporated to afford quenched with evaporated and the residue purified by silica gel flash chromatography with 5% MeOH/EtOAc the 10% MeOH/EtOAc containing 1% NH4OH as eluant to afford product as a foam (123 mg, 64%). LC/MS (Method B) 2.18 min, [M+1]+ 483. Potency class C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[N:16]([CH3:20])[N:15]=[CH:14]3)=[C:6]([CH:9]=1)[C:7]#[N:8].[ClH:21]>CO.[OH-].[OH-].[Pd+2]>[ClH:21].[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[N:16]([CH3:20])[N:15]=[CH:14]3)=[C:6]([CH:9]=1)[CH2:7][NH2:8]
Reactant: Cn1ncc2cc(Oc3ccc(F)cc3C#N)ccc21
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CO
Product: Cn1ncc2cc(Oc3ccc(F)cc3CN)ccc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of (4t) (0.32 g, 1.22 mmol) in MeOH (20 mL) was purged with nitrogen and treated with 20% Pd(OH)2/C catalyst (15% wt, 180 mg) followed by concentrated HCl (0.3 mL, 3.6 mmol). After purging further with nitrogen, a balloon containing hydrogen was placed on top of the flask. After stirring at room temperature for 18 hours, the LC indicated no more starting material was present. The catalyst was filtered through a plug of silica gel/celite/sand and washed with MeOH. The solvent was evaporated in vacuo and the residue co-evaporated from ether. The resulting pale yellow foam (5t) was stored under N2, 0.34 g (91% isolated yield). 1H NMR (400 MHz, CDCl3) 7.38 (d, J=7.8 Hz, 1H), 7.17 (dd, J=7.8, 1.6 Hz, 1H), 7.13 (d, J=1.6 Hz, 1H), 5.19-5.18 (m, 1H), 4.51-4.44 (m, 1H), 4.434.36 (m, 1H), 2.53-2.45 (m, 1H), 2.36-2.30 (m, 1H); MS (ESI+) m/z 272 (M+H) detected.
Reaction SMILES: C([O:8][C:9]1[C:10](=[O:26])[N:11]([CH2:15][C:16](=[O:25])[NH:17][O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:12]=[CH:13][CH:14]=1)C1C=CC=CC=1.[H][H]>CCO.[Pd].[Fe+3]>[OH:8][C:9]1[C:10](=[O:26])[N:11]([CH2:15][C:16](=[O:25])[NH:17][O:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:12]=[CH:13][CH:14]=1
Reactant: [H][H]
Reactant: O=C(Cn1cccc(OCc2ccccc2)c1=O)NOc1ccccc1
Agent: [Fe+3]
Agent: [Pd]
Solvent: CCO
Product: O=C(Cn1cccc(O)c1=O)NOc1ccccc1
Yield: 57 %

Procedure:
17 (350 mg, 0.8 mmol) was suspended in 175 mL of EtOH. 10% (w/w, 38 mg) of 10% Pd/C catalyst was added to the hydrogenation flask (500 mL Pyrex® Parr reaction bottle tested to 120 psi, max. working pressure of 60 psi). The Parr hydrogenation system located in the VanNieuwenhze lab was used for the deprotection reactions. The hydrogen pressure was set to 35 psi with agitation, and the process went on for 41 h. A white precipitate was present even after the reaction was stopped, but this white product reacted with iron(III) to give a reddish product instead of no reaction as seen with the protected starting material. The catalyst was removed by vacuum filtration and separated from the product by dissolving the white precipitate in 125 mL hot CH2Cl2 and MeOH and THF. The clear solution was concentrated by rotary evaporation to yield a white solid. The solid was washed with MeOH to remove residual DCU to yield a white, feathery microcrystalline solid. Yield: 57%. 1H NMR (d6-DMSO, 400 MHz, 25° C.): δ 4.75 (s, 2H, —CH2—), 6.11 (t, J=7.0 Hz, 1H, Ar—H), 6.72 (d, J=7.2 Hz, 1H, Ar—H), 6.97 (m, 4H, Phenoxy-H), 7.11 (m, 2H, Ar—H, Phenoxy-H), 7.36 (t, J=7.2 Hz, 2H, Phenoxy-H), 7.58 (d, J=6.8 Hz, 2H, Phenoxy-H), 9.03 (s, 1H, —OH), 10.36 (s, 1H, —NH—). APCI-MS: m/z 336.9 [M+H]+. Anal. Calcd for C19H16N2O4: C, 67.85; H, 4.79; N, 8.33. Found: C, 67.75; H, 5.07; N, 8.49.