Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:6][C:5]23[CH2:16][CH:9]([C:10]4[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=4[C:4]2=[CH:3]1)[C:8]1[CH:17]=[CH:18][CH:19]=[CH:20][C:7]3=1.[H][H]>[Pd].C(O)(=O)C>[CH3:1][N:2]1[CH2:6][C:5]23[CH2:16][CH:9]([C:10]4[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=4[CH:4]2[CH2:3]1)[C:8]1[CH:17]=[CH:18][CH:19]=[CH:20][C:7]3=1
Reactant: CN1C=C2c3ccccc3C3CC2(C1)c1ccccc13
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Product: CN1CC2c3ccccc3C3CC2(C1)c1ccccc13
Yield: 100 %

Procedure:
A mixture of 13.6 g of 2-methyl-2,3-dihydro-8H-3a, 8-methanodibenzo[3,4:6,7]cyclohepta[1,2-c]pyrrole, 100 ml of acetic acid and 2 g of 10% palladium-on-charcoal catalyst is shaken under 40 psi hydrogen pressure at room temperature until the pressure remains constant. The filtered mixture is concentrated, the residue is made basic and extracted several times with methylene chloride. Removal of the solvent from the dried extracts gives 13.7 g of 2-methyl-2,3,8,12b-tetrahydro-1H-3a,8-methanodibenzo[3,4;6,7]-cyclohepta[1,2-c]pyrrole (1c) identical by nmr spectroscopy with the product obtained in Example 1.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.[Cl:34][C:35]1[CH:40]=[CH:39][C:38]([NH:41][C:42](=[O:47])[C:43]([F:46])([F:45])[F:44])=[C:37]([I:48])[CH:36]=1.[C:49]([O:53][C:54]([N:56]1[CH2:61][CH:60]=[C:59]([CH2:62]O)[CH2:58][CH2:57]1)=[O:55])([CH3:52])([CH3:51])[CH3:50]>O1CCCC1>[C:49]([O:53][C:54]([N:56]1[CH2:57][CH:58]=[C:59]([CH2:62][N:41]([C:38]2[CH:39]=[CH:40][C:35]([Cl:34])=[CH:36][C:37]=2[I:48])[C:42](=[O:47])[C:43]([F:45])([F:46])[F:44])[CH2:60][CH2:61]1)=[O:55])([CH3:52])([CH3:50])[CH3:51]
Reactant: CC(C)(C)OC(=O)N1CC=C(CO)CC1
Reactant: O=C(Nc1ccc(Cl)cc1I)C(F)(F)F
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC=C(CN(C(=O)C(F)(F)F)c2ccc(Cl)cc2I)CC1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 54.8 %

Procedure:
Triphenylphosphine (5.16 g) was dissolved in tetrahydrofuran (130 ml) and the solution was cooled to 0° C. under argon. Diisopropylazodicarboxylate (3.82 ml) was added dropwise over 10 min and the resulting mixture was stirred at 0° C. for 20 min (formation of a white precipitate). N-(4-Chloro-2-iodo-phenyl)-2,2,2-trifluoro-acetamide (5.5 g) was added as a solid, followed by 4-hydroxymethyl-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (J. Org. Chem. 2001, 66, 5545-5551, 3.4 g) dissolved in a minimum volume of tetrahydrofuran. The reaction mixture was allowed to warm to room temperature and stirred for 12 hours. The solution was then concentrated in vacuo and the residue subjected to silica gel chromatography (cyclohexane:ethyl acetate 9:1) to afford 4-{[(4-chloro-2-iodo-phenyl)-(2,2,2-trifluoro-acetyl)-amino]-methyl}-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (4.7 g). 1H NMR (600 MHz, CDCl3) 1.5 (s, 9H), 2.20 (m, 2H), 3.49 (m, 1H), 3.50 (d, J=17 Hz, 1H), 3.55 (m, 1H), 3.8-3.9 (m, 1H), 5.02 (d, J=17 Hz, 1H), 5.40 (s, 1H), 7.0 (m, 1H), 7.38 (dd, 1H), 7.92 (d, 1H); MS (ES+) 445/447 (M+H+—CO2-isobutene), 486/488 (M+H+-isobutene).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([CH3:15])=[CH:13][C:12]([OH:16])=[CH:11][C:10]=1[CH2:17][CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:26](Cl)(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.Cl>C(Cl)(Cl)Cl>[C:26]([O:16][C:12]1[CH:13]=[C:14]([CH3:15])[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[C:10]([CH2:17][CH3:18])[CH:11]=1)(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CCc1cc(O)cc(C)c1OCc1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCc1cc(OC(=O)c2ccccc2)cc(C)c1OCc1ccccc1
Temperature: 0 °C
Yield: 93.3 %

Procedure:
To a mixture of 6.3 g of 4-benzyloxy-3-ethyl-5-methylphenol, 3.2 g of triethylamine and 50 ml of chloroform was added dropwise 4.0 g of benzoyl chloride, while stirring at 0° C. After stirring at room temperature for 6 hours, the reaction mixture was concentrated under reduced pressure to give a residue. To the residue was added 100 ml of 10% hydrochloric acid, and the mixture was extracted with 100 ml of ethyl acetate. The ethyl acetate layer was successively washed 10% hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated saline solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure, which afforded 8.4 g of crude 4-benzyloxy-3-ethyl-5-methylphenyl benzoate (93% yield).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=1.[CH2:22]1[O:30][C:29]2[CH:28]=[CH:27][C:26]([CH2:31][C:32]#[N:33])=[CH:25][C:24]=2[O:23]1>>[O:30]1[C:29]2[CH:28]=[CH:27][C:26](/[C:31](=[CH:18]/[C:17]3[CH:20]=[CH:21][C:14]([O:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][OH:1])=[CH:15][CH:16]=3)/[C:32]#[N:33])=[CH:25][C:24]=2[O:23][CH2:22]1
Reactant: N#CCc1ccc2c(c1)OCO2
Reactant: O=Cc1ccc(OCCCCCCCCCCCO)cc1
Product: N#C/C(=C\c1ccc(OCCCCCCCCCCCO)cc1)c1ccc2c(c1)OCO2
Yield: 73 %

Procedure:
(2Z)-2-(1,3-benzodioxol-5-yl)-3-{4-[(11-hydroxyundecyl)oxy]phenyl}prop-2-enenitrile is prepared starting from 4-[(11-hydroxyundecyl)oxy]benzaldehyde and commercial [3,4-(methylenedioxy)phenyl]acetonitrile according the same procedure following for example 1 in 73% yield. This material proves chromatographically homogenous and displays spectral characteristics consistent with its assigned structure.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:10][CH:11]([CH3:13])[CH3:12])=[C:6]([CH:9]=1)[C:7]#[N:8].[CH3:14][Si:15]([CH3:19])([CH3:18])[C:16]#[CH:17]>O1CCCC1.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:11]([O:10][C:5]1[CH:4]=[CH:3][C:2]([C:17]#[C:16][Si:15]([CH3:19])([CH3:18])[CH3:14])=[CH:9][C:6]=1[C:7]#[N:8])([CH3:13])[CH3:12]
Reactant: CC(C)Oc1ccc(Br)cc1C#N
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Product: CC(C)Oc1ccc(C#C[Si](C)(C)C)cc1C#N

Procedure:
A solution of 5-bromo-2-isopropoxybenzonitrile (1.0 g, 4.16 mmol) in tetrahydrofuran was treated with copper (I) iodide (0.158 g, 0.83 mmol) and then purged with Argon for 5 minutes. Trimethyl silyl acetylene (2.85 g, 29.16 mmol) was then added followed by dichlorobis-(triphenylphosphine)palladium(II) (0.291 g, 0.41 mmol). The resultant mixture was heated at 80° C. overnight in a sealed tube. The mixture was evaporated and purified by column chromatography to give 2-isopropoxy-5-((trimethylsilyl)ethynyl)benzonitrile which was taken to the next step. 2-isopropoxy-5-((trimethylsilyl)ethynyl)benzonitrile (1.0 g, 3.8 mmol) in methanol (20 mL) was treated with potassium carbonate (1.07 g, 7.7 mmol) at room temperature overnight. The reaction was filtered and the filtrate was evaporated to give the crude product. The crude product was purified on a column (MPLC) using hexane:ethyl acetate and afforded Intermediate 1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:4]=1[CH2:5][NH:6][C:7]1[S:8][CH:9]=[CH:10][N:11]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Cl:28][C:29]1[C:38]2[C:33](=[CH:34][C:35]([S:39](OC3C(F)=C(F)C(F)=C(F)C=3F)(=[O:41])=[O:40])=[CH:36][CH:37]=2)[CH:32]=[CH:31][N:30]=1>O1CCCC1>[Cl:28][C:29]1[C:38]2[C:33](=[CH:34][C:35]([S:39]([N:6]([CH2:5][C:4]3[CH:12]=[CH:13][C:14]([O:16][CH3:17])=[CH:15][C:3]=3[O:2][CH3:1])[C:7]3[S:8][CH:9]=[CH:10][N:11]=3)(=[O:41])=[O:40])=[CH:36][CH:37]=2)[CH:32]=[CH:31][N:30]=1
Reactant: COc1ccc(CNc2nccs2)c(OC)c1
Reactant: O=S(=O)(Oc1c(F)c(F)c(F)c(F)c1F)c1ccc2c(Cl)nccc2c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(Cl)nccc3c2)c(OC)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of N-(2,4-dimethoxybenzyl)thiazol-2-amine (0.642 g, 2.56 mmol) in tetrahydrofuran (9.39 ml) was cooled in a dry ice-acetone bath for 5 min. Lithium bis(trimethylsilyl)amide (1M in THF) (2.68 ml, 2.68 mmol) was added drop wise, then the flask was removed from the cooling bath for 5 min. The flask was again cooled into a dry ice-acetone bath for 20 min, resulting in the formation of a thick slurry. A solution of perfluorophenyl 1-chloroisoquinoline-6-sulfonate (see Example 73, Step 1; 1.0 g, 2.441 mmol) in THF (5 mL) was added drop wise, and the reaction was stirred for 30 minutes. The reaction was warmed to room temperature and quenched with saturated ammonium chloride solution, diluted with ethyl acetate and washed with water. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were dried with sodium sulfate, filtered, and concentrated. The filtrate was purified by chromatography on an 80-g with 0 to 50% EtOAc/Heptane to afford 1-chloro-N-(2,4-dimethoxybenzyl)-N-(thiazol-2-yl)isoquinoline-6-sulfonamide (INTERMEDIATE OOO) as a white solid. (ESI) 498.2 (M+Na)+.
Reaction SMILES: [C:1]([Cl:4])(Cl)=[O:2].C([N:12]1[CH2:17][CH2:16][CH2:15][CH:14]([O:18][C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=2)[CH2:13]1)C1C=CC=CC=1>C(Cl)Cl>[Cl:26][C:21]1[CH:20]=[C:19]([CH:24]=[CH:23][C:22]=1[Cl:25])[O:18][CH:14]1[CH2:15][CH2:16][CH2:17][N:12]([C:1]([Cl:4])=[O:2])[CH2:13]1
Reactant: O=C(Cl)Cl
Reactant: Clc1ccc(OC2CCCN(Cc3ccccc3)C2)cc1Cl
Solvent: ClCCl
Product: O=C(Cl)N1CCCC(Oc2ccc(Cl)c(Cl)c2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 8 g (0.085 mole) of phosgene in 100 ml of methylene chloride at 5° C. under nitrogen gas was added slowly a solution of 27.1 g (0.081 mole) of 1-benzyl-3-(3,4-dichlorophenoxy)piperidine in 50 ml of methylene chloride. The reaction mixture was allowed to warm to room temperature over a 2 hr period and then concentrated to a light oil. The oil was triturated with hexane. Starting material, 1.6 g as fine white precipitate, was separated by filtration. The oil was triturated four more times with hexane to remove benzyl chloride. The remaining oil was taken up in 200 ml of benzene and 50 ml of pyridine was added. The mixture was allowed to stir overnight. Some quaternary benzyl chloride salt precipitated and was discarded. The title compound in solution was used in Example 12.
Reaction SMILES: CC(C)([O-])C.[K+].[N:7]#[C:8][NH2:9].CS([C:13]1[S:14][C:15]([C:18]2[CH:27]=[CH:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=2)=[N:16][N:17]=1)=O>C(O)(C)(C)C>[CH:19]1[C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:26]=[CH:27][C:18]=1[C:15]1[S:14][CH:13]([NH:9][C:8]#[N:7])[NH:17][N:16]=1
Reactant: N#CN
Reactant: CS(=O)c1nnc(-c2ccc3ccccc3c2)s1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: N#CNC1NN=C(c2ccc3ccccc3c2)S1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 38.6 %

Procedure:
To a stirred solution of potassium tert-butoxide (0.46 g, 4.08 mmol) in tert-butanol (25 ml) was added cyanamide (0.32 g, 7.65 mmol) and the resulting mixture was stirred for 15 min. at room temperature. To this mixture was added 2-methanesulfinyl-5-naphthalen-2-yl-[1,3,4]thiadiazole (0.7 g, 2.55 mmol) and the mixture was heated at reflux temperature for 15 min. followed by addition of an additional portion of cyanamide (0.2 g, 4.76 mmol). Heating was continued for an additional 2 h. The cooled reaction mixture was quenched by addition of 1 N sodium hydroxide (150 ml) and diluted by addition of diethyl ether. The organic phases were separated and the aqueous phase was acidified to pH=1 with concentrated hydrochloric acid. The precipitate was filtered off, washed with water (2×10 ml) and diethyl ether (2×10 ml) and dried at 50° C. which afforded 0.25 g (39%) of the title compound as a solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:15][CH3:16])=[C:6]([C:8]([CH3:14])([CH3:13])[CH2:9][C:10](=[O:12])[CH3:11])[CH:7]=1.[Br-:17].[Br-].[Br-].C([N+](C)(C)C)C1C=CC=CC=1.C([N+](C)(C)C)C1C=CC=CC=1.C([N+](C)(C)C)C1C=CC=CC=1>C(Cl)Cl.CO>[Br:17][CH2:11][C:10](=[O:12])[CH2:9][C:8]([C:6]1[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=1[O:15][CH3:16])([CH3:13])[CH3:14]
Reactant: [Br-]
Reactant: COc1ccc(F)cc1C(C)(C)CC(C)=O
Agent: C[N+](C)(C)Cc1ccccc1
Solvent: ClCCl
Solvent: CO
Product: COc1ccc(F)cc1C(C)(C)CC(=O)CBr
Reaction time: 0.5 h
Yield: 80 %

Procedure:
To a stirred solution of the above ketone (1.34 g, 6 mmol) in methylene chloride (35 mL) and MeOH (5 mL), benzyltrimethylammonium tribromide (2.57 g, 6.6 mmol) was added at ambient temperature. After 30 minutes, TLC (hexanes-EtOAc (9:1)) showed complete disappearance of the starting material. The reaction mixture was diluted with methylene chloride (50 mL), washed with two 50 mL portions of water, dried over anhydrous sodium sulfate, and concentrated in vacuo to give 1-bromo-4-(5-fluoro-2-methoxyphenyl)-4-methylpentan-2-one as a light brown liquid (80%) which was used for the next reaction without further purification.
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]([C:8]([OH:10])=O)=[C:5]([CH3:7])[N:6]=1.[NH2:11][CH2:12][C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[N:15]1[CH:16]=[CH:17][CH:18]=[C:13]([CH2:12][NH:11][C:8]([C:4]2[S:3][C:2]([Br:1])=[N:6][C:5]=2[CH3:7])=[O:10])[CH:14]=1
Reactant: NCc1cccnc1
Reactant: Cc1nc(Br)sc1C(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1nc(Br)sc1C(=O)NCc1cccnc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 96.1 %

Procedure:
To a solution of 2-bromo-4-methyl-thiazole-5-carboxylic acid (10.0 g, 45.0 mmol) in methylene chloride (200 mL) was added 3-(aminomethyl) pyridine (5.05 mL, 49.5 mmol), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP reagent, 21.9 g, 49.5 mmol) and N,N-diisopropylethylamine (15.7 mL, 90.1 mmol). The mixture was stirred under nitrogen at room temperature for 16 hr, then diluted with methylene chloride (300 mL), washed with water (300 mL) and brine (2×200 mL). The organic phase was dried (Na2SO4) and evaporated. The residue was purified by flash chromatography over silica gel (methylene chloride:methanol, 95:5) to provide 2-bromo-4-methyl-thiazole-5-carboxylic acid (pyridine-3-ylmethyl)-amide as a yellow solid (13.5 g, 96% yield). MS (M+H)+=313; Rt=1.01 min.
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)[C:4]=2[N:5]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:7]=1.[OH:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1.B(O)O>>[N:8]1([C:6]2[N:7]=[C:2]([C:28]3[CH:29]=[CH:30][C:25]([CH2:24][OH:23])=[CH:26][CH:27]=3)[C:3]3[CH2:16][CH2:15][N:14]([C:17]4[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=4)[C:4]=3[N:5]=2)[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1
Reactant: Clc1nc(N2CCOCC2)nc2c1CCN2c1ccncc1
Reactant: OCc1ccc(B(O)O)cc1
Agent: OBO
Product: OCc1ccc(-c2nc(N3CCOCC3)nc3c2CCN3c2ccncc2)cc1

Procedure:
In the same manner as Example 1-B-10, using 4-chloro-2-morpholin-4-yl-7-pyridin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine, and 4-(hydroxymethyl)phenylboronic acid as a boronic acid, the desired compound was obtained.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([CH:9]1[O:11][CH2:10]1)Br.[NH:12]([C:19]1[C:24]([Br:25])=[CH:23][N:22]=[C:21]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][C:28]=2[F:34])[N:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CN(C=O)C>[NH:12]([C:19]1[C:24]([Br:25])=[CH:23][N:22]=[C:21]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][CH2:7][CH:9]3[O:11][CH2:10]3)=[CH:29][C:28]=2[F:34])[N:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: BrCC1CO1
Reactant: Oc1ccc(Nc2ncc(Br)c(Nc3ccccc3)n2)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Fc1cc(OCC2CO2)ccc1Nc1ncc(Br)c(Nc2ccccc2)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 95.5 %

Procedure:
Potassium carbonate (1.1 g, 8.01 mmol) and epibromohydrin (402 mg, 2.94 mmol) were added to a solution of 4-anilino-5-bromo-2-(2-fluoro-4-hydroxyanilino)pyrimidine (Method 5; 1.0 g, 2.67 mmol) in DMF (3 ml), and the suspension was stirred at room temperature for 16 hours. Volatile material was removed by evaporation and the residue was stirred vigorously in water. The solid remaining was collected by filtration and dried under vacuum to give the product (1.1 g, 98%). MS (MH+): 431.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH:17]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH:18]([CH2:23][CH2:24][CH3:25])[C:19]([O:21]C)=[O:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.Cl>[OH-].[Na+].CO.CS(C)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH:17]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH:18]([CH2:23][CH2:24][CH3:25])[C:19]([OH:21])=[O:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: CCCC(C(=O)OC)C(c1ccccc1)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CO
Product: CCCC(C(=O)O)C(c1ccccc1)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Yield: 91 %

Procedure:
Methyl 2-((1-(4-fluorophenyl)-1H-indazol-5-yl)(phenyl)methyl)pentanoate was heated to 100° C. overnight in a mixture of 2 M NaOH/MeOH/DMSO (1:1:1). The next day, the reaction was cooled, acidified to pH 5 with HCl and extracted 2× EtOAc. The organic layers were washed with water×2, dried over MgSO4, filtered, concentrated in vacuo, and purified by HPLC to give 140 mg (91% yield) of acid 2-((1-(4-fluorophenyl)-1H-indazol-5-yl)(phenyl)methyl) pentanoic acid. MS found: (M+H)+=403.
Reaction SMILES: ClC1[C:7]([C:8](OCC)=[O:9])=C(C)N=C2N(CC)C=NC=12.[CH2:19]([N:23]1[C:27]2=[N:28][C:29]([CH3:38])=[C:30]([C:33]([O:35][CH2:36][CH3:37])=[O:34])[C:31](Cl)=[C:26]2[N:25]=[CH:24]1)[CH2:20][CH2:21][CH3:22]>>[CH2:19]([N:23]1[C:27]2=[N:28][C:29]([CH3:38])=[C:30]([C:33]([O:35][CH2:36][CH3:37])=[O:34])[C:31]([O:9][CH2:8][CH3:7])=[C:26]2[N:25]=[CH:24]1)[CH2:20][CH2:21][CH3:22]
Reactant: CCOC(=O)c1c(C)nc2c(ncn2CC)c1Cl
Reactant: CCCCn1cnc2c(Cl)c(C(=O)OCC)c(C)nc21
Product: CCCCn1cnc2c(OCC)c(C(=O)OCC)c(C)nc21
Yield: 81 %

Procedure:
By replacing 7-chloro-3-ethyl-5-methyl-3H-imidazo[4,5-b]pyridine-6-carboxylic acid, ethyl ester in Example 1 e with 3-butyl-7-chloro-5-methyl-3H-imidazo[4,5-b]pyridine-6-carboxylic acid, ethyl ester, 3-butyl-7-ethoxy-5-methyl-3H-imidazo[4,5-b]pyridine-6-carboxylic acid, ethyl ester is obtained. Yield 81%, b.p. 200°-210°/0.01. An equivalent of aqueous sodium hydroxide is added to an ethanol solution of the ethyl ester and refluxed for 1 hour. The reaction mixture is then taken to dryness, the residue is suspended in water and HCl to pH 4 is added. The precipitated solid is filtered off to obtain the free carboxylic acid. The sodium salt is obtained by dissolving this product in one equivalent of aqueous sodium hydroxide and freeze drying.
Reaction SMILES: CO[C:3](=[O:26])[C@@H:4]([CH2:22][CH:23]([CH3:25])[CH3:24])[N:5]([P:13]([CH3:21])([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:14])[CH2:6][C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1.Cl.[NH2:28][O:29][K]>>[OH:29][NH:28][C:3](=[O:26])[C@H:4]([N:5]([P:13]([CH3:21])([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:14])[CH2:6][C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1)[CH2:22][CH:23]([CH3:25])[CH3:24]
Reactant: NO[K]
Reactant: COC(=O)[C@@H](CC(C)C)N(Cc1cccnc1)P(C)(=O)c1ccccc1
Agent: Cl
Product: CC(C)C[C@H](C(=O)NO)N(Cc1cccnc1)P(C)(=O)c1ccccc1
Reaction time: 16 h

Procedure:
Methylphenylphosphinic chloride (12.23 g, 70 mmol) is taken up in dichloromethane (100 mL) and cooled to 0° C. To this is added a solution of N-(3-picolyl) D-leucine methyl ester (15.5 g, 65.6 mmol) and N-methyl morpholine (19.24 mL, 175 mmol) in dichloromethane (100 mL). A catalytic amount of 4-dimethylaminopyridine is added and the reaction stirs for 16 hours at room temperature. More methylphenylphosphinic chloride is added (2 g, 11.46 mmol). The reaction continues to stir for 24 hours until complete. By TLC, the diastereomers do not separate. The product is purified by silica gel flash chromatography (5:95 ethanol:ethyl acetate) to give N-((R/S)-methylphenyl-phosphinyl)-N-(3-picolyl) D-leucine methyl ester as an oil. To this ester is added a solution of NH2OK (250 mL, 1.76M in methanol) prepared as described in Fieser and Fieser, Vol. 1, p. 478. The reaction is stirred for 16 hours at which time TLC indicates completion. The reaction mixture is neutralized with 1M aqueous HCl and the volatiles are removed. The product is purified by silica gel flash chromatography (10:90 ethanol:ethyl acetate) to give 8.6 g of N-hydroxy-2(R)-[[(R/S)-methylphenylphosphinyl]3-picolylamino]-4-methylpentanamide as a 60 (R)/40 (S) mixture of diastereomers: MS-IS m/z 376 [M+H]+, 398[M+Na]+. (R1 =3-pyridyl methyl, R2 =isobutyl, R3 =methyl, R4 =phenyl).
Reaction SMILES: CS(O[CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1)(=O)=O.[F:19][C:20]([F:30])([F:29])[O:21][C:22]1[CH:27]=[CH:26][C:25]([SH:28])=[CH:24][CH:23]=1>>[F:30][C:20]([F:19])([F:29])[O:21][C:22]1[CH:23]=[CH:24][C:25]([S:28][CH:6]2[CH2:7][CH2:8][N:9]([C:12]([O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:13])[CH2:10][CH2:11]2)=[CH:26][CH:27]=1
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Reactant: FC(F)(F)Oc1ccc(S)cc1
Product: CC(C)(C)OC(=O)N1CCC(Sc2ccc(OC(F)(F)F)cc2)CC1
Yield: 41 %

Procedure:
The title compound was prepared in 41% yield (0.66 g, colorless oil) from tert-butyl 4-((methylsulfonyl)oxy)piperidine-1-carboxylate (1.20 g, 4.30 mmol) and 4-(trifluoromethoxy)benzenethiol (1.00 g, 5.15 mmol) by the similar manner in Step-1 of Intermediate-4.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:10]=[CH:9][S:8][CH:7]=1.C(O)(=O)C.C1C(=O)N([Br:22])C(=O)C1>C(Cl)(Cl)Cl>[Br:22][C:7]1[S:8][CH:9]=[CH:10][C:6]=1[CH2:5][CH2:4][CH2:3][CH2:2][Br:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: BrCCCCc1ccsc1
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: BrCCCCc1ccsc1Br
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 68 %

Procedure:
3-(4-bromobutyl)thiophene (8 g, 36.5 mmol) was dissolved in 250 ml CHCl3, and glacial acetic acid (250 ml) was added in the dark. NBS (6.5 g, 36.5 mmol) was added, and the mixture was stirred for 20 minutes at room temperature in the dark. The reaction mixture was washed with water, saturated NaHCO3, dried over magnesium sulfate and the solvent was removed under vacuum. Purification by column chromatography afforded the title compound (7.4 g, 68% yield) as a light yellow oil. 1H-NMR (ppm, CDCl3): 1.71-1.77 (2H, m), 1.85-1.89 (2H, m), 2.6 (2H, t, J=7.44 Hz), 3.43 (2H, t, J=7.32 Hz), 6.78 (1H, d, J=5.6 Hz), 7.19 (1H, d, J=5.6 Hz); 13C-NMR (ppm, CDCl3): 27.5, 29.4, 32.9, 33.9, 109.2, 125.5, 128.4, 141.8; GC-MS (m/z): 295.89.
Reaction SMILES: Cl.[CH3:2][N:3]1[CH2:7][CH2:6][CH2:5][C@H:4]1[CH2:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][N:10]1[CH2:15][C:16]([OH:18])=O.[NH2:19][C@@H:20]([CH2:38][O:39][CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C:21]([NH:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)=[CH:26][CH:25]=1)=[O:22]>>[CH2:40]([O:39][CH2:38][C@H:20]([NH:19][C:16](=[O:18])[CH2:15][N:10]1[CH2:11][CH2:12][CH2:13][CH2:14][CH:9]1[CH2:8][C@@H:4]1[CH2:5][CH2:6][CH2:7][N:3]1[CH3:2])[C:21]([NH:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)=[CH:26][CH:25]=1)=[O:22])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Reactant: CN1CCC[C@H]1CC1CCCCN1CC(=O)O
Agent: Cl
Product: CN1CCC[C@H]1CC1CCCCN1CC(=O)N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Yield: 43.3 %

Procedure:
Proceeding as in Example 1, but substituting 2-(2-(((S)-1-methylpyrrolidin-2-yl)methyl)piperidin-1-yl)acetic acid hydrochloride and (S)-2-amino-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)propanamide, gave Compound 113, (2S)-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)-2-(2-(2-(((S)-1-methylpyrrolidin-2-yl)methyl)piperidin-1-yl)acetamido)propanamide (20.9 mg, 43.3%). Major isomer: 1H-NMR (400 MHz, DMSO-D6): σ 10.27 (d, 1H), 8.51 (s, 1H), 7.67-7.64 (m, 2H), 7.31 (m, 5H), 7.21 (t, 2H), 7.03-6.98 (m, 4H), 4.72 (m, 1H), 4.52 (d, 2H), 4.16 (m, 1H), 4.04 (m, 1H), 3.77-3.73 (m, 4H), 3.38 (s, 2H), 2.99 (s, 2H), 2.79 (m, 1H), 2.43 (m, 2H), 2.32 (m, 2H), 2.18 (m, 1H), 1.99 (m, 2H), 1.75 (m, 1H), 1.51 (m, 4H), 1.37 (m, 2H). MS (EI) for C35H43FN4O4. found 603.7 (MH+).