Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH:13]1([CH2:16][N:17]2[C:22](=[O:23])[C:21]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([C:31]4[C:32]([C:37]#[N:38])=[CH:33][CH:34]=[CH:35][CH:36]=4)=[CH:27][CH:26]=3)=[C:20]([CH2:39][CH2:40][CH3:41])[N:19]3[N:42]=[CH:43][N:44]=[C:18]23)[CH2:15][CH2:14]1>C(OCC)(=O)C>[CH:13]1([CH2:16][N:17]2[C:22](=[O:23])[C:21]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=4[C:37]4[NH:3][C:4](=[O:7])[O:5][N:38]=4)=[CH:27][CH:26]=3)=[C:20]([CH2:39][CH2:40][CH3:41])[N:19]3[N:42]=[CH:43][N:44]=[C:18]23)[CH2:14][CH2:15]1
Reactant: O=C([O-])O
Reactant: [NH3+]O
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(CC2CC2)c2ncnn12
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n(CC2CC2)c2ncnn12
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 27.6 %

Procedure:
A mixture of hydroxylammonium chloride (1.3 g), sodium hydrogen carbonate (2.2 g) and dimethyl sulfoxide (15 mL) was stirred at 40° C. for 30 min, 4′-{[4-(cyclopropylmethyl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (0.54 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in tetrahydrofuran (15 mL). N,N′-Carbonyldiimidazole (0.25 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.21 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogensulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.17 g, 27%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[NH:7][CH2:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:20]=[C:19]([C:21](=[O:29])[NH:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:18]=[CH:17][C:16]=2[N+:30]([O-])=O)[CH2:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2].C(OCC)(=O)C.O.[Cl-].[NH4+]>C(O)C.[Fe]>[C:1]([O:5][C:6](=[O:33])[NH:7][CH2:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:20]=[C:19]([C:21](=[O:29])[NH:22][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:18]=[CH:17][C:16]=2[NH2:30])[CH2:11][CH2:10]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCC1CCN(c2cc(C(=O)Nc3ccccc3)ccc2[N+](=O)[O-])CC1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NCC1CCN(c2cc(C(=O)Nc3ccccc3)ccc2N)CC1
Temperature: 80 °C
Yield: 98.8 %

Procedure:
To a solution of [1-(2-nitro-5-phenylcarbamoyl-phenyl)-piperidin-4-ylmethyl]-carbamic acid tert-butyl ester (0.13 g, 0.286 mmol) in a mixture of ethanol (8 mL), ethyl acetate (3 mL) and water (3 mL) were added ammonium chloride (0.12 g, 7.6 mmol) and iron powder (0.12 g, 7.5 mmol) and the resulting mixture was heated at 80° C. for 4 hours. The reaction mixture was filtered through a CELITE™ pad, the filter cake was washed with ethyl acetate. The filtrate was washed with and aqueous solution of sodium bicarbonate (5%) and with brine, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to afford 0.12 g (quantitative yield) of [1-(2-amino-5-phenylcarbamoyl-phenyl)-piperidin-4-ylmethyl]-carbamic acid tert-butyl ester as light yellow foam.
Reaction SMILES: [Cl:1][CH2:2][C:3]([O:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:15])[CH3:14])=[CH:8][CH:7]=1)=[O:4].[N:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(OCC)(=O)C>[Cl-:1].[C:13]([NH:12][C:9]1[CH:10]=[CH:11][C:6]([O:5][C:3](=[O:4])[CH2:2][N+:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:7][CH:8]=1)(=[O:15])[CH3:14]
Reactant: c1ccncc1
Reactant: CC(=O)Nc1ccc(OC(=O)CCl)cc1
Solvent: CCOC(C)=O
Product: CC(=O)Nc1ccc(OC(=O)C[n+]2ccccc2)cc1
Product: [Cl-]
Temperature: 25 °C
Yield: 97 %

Procedure:
4-Acetamidophenyl 2-chloroacetate [2] (1.138 g, 5 mmol) and pyridine (0.475 g, 6 mmol) were suspended in 50 ml of anhydrous ethyl acetate and refluxed for 48 hrs. After cooling to room temperature the white precipitate was filtered, washed with ethylacetate and diethylether and dried under reduced pressure to give [5] in 97% yield. The product was pure according to 1H NMR and was directly subjected to the next step without further purification. The desired compound is isolated as a colourless powder. 1H-NMR (300 MHz, d6-DMSO) δ(ppm)=10.31 (s, 1H), 9.27 (d, J=6.5 Hz, 2H), 8.76 (t, 7.9 Hz, 1H), 8.29 (t, 7.2 Hz, 2H), 7.71 (d, J=9.7 Hz, 2H), 7.11 (d, J=9.7 Hz, 2H), 4.69 (s, 2H), 2.08 (s, 3H). mp 199° C. (dec), T5%onset 198° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[OH:11])[C:5](O)=[O:6].C1CC[CH:15]([N:18]=[C:19]=NC2CCCCC2)CC1.C1C=CC2N(O)N=NC=2C=1.CNC>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[OH:11])[C:5]([N:18]([CH3:19])[CH3:15])=[O:6]
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: O=C(O)c1ccc(O)c(Cl)c1
Agent: CNC
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CN(C)C(=O)c1ccc(O)c(Cl)c1
Yield: 76.2 %

Procedure:
3-Chloro-4-hydroxy-benzoic acid (800 mg, 4.6 mmol), DCC (856 mg, 5.4 mmol), and HOBt (540 mg, 5.4 mmol) were mixed in DMF (10 mL). N,N-dimethyl amine (2M in THF, 4.6 mL) was added to the mixture at 0° C. The reaction was stirred over night and purified by silica gel chromatography (70%–90% EtOAc/Hexane) to provide the title compound (700 mg, 87.5%). MS (DCI) m/z 200, 202 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.Br[C:12]1[CH:17]=[CH:16][C:15]([C:18](=[O:25])[CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])=[CH:14][CH:13]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.ClCCl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:12]2[CH:13]=[CH:14][C:15]([C:18](=[O:25])[CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])=[CH:16][CH:17]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)CCC(=O)c1ccc(Br)cc1
Reactant: Cc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COC(=O)CCC(=O)c1ccc(-c2ccc(C)cc2)cc1
Yield: 69.4 %

Procedure:
To a stirred mixture of (4-methylphenyl)boronic acid (0.818 g, 0.00602 mol) and 4-(4-bromo-phenyl)-4-oxo-butyric acid, methyl ester (1.3556 g, 0.00500 mol) in toluene (10 mL) was added tetrakis(triphenylphosphine)palladium(0) (0.173 g, 0.000150 mol) and 2.0 M aqueous sodium carbonate (5.0 mL, 0.010 mol), and the mixture was heated at reflux under nitrogen for 12 hours and allowed to cool. The mixture was diluted with toluene and dichloromethane (10 mL/10 mL), and filtered through a pad of Celite. The Celite was washed with additional toluene and dichloromethane. Filtrate and washings were combined and washed with 2.0 M aqueous sodium carbonate, brine, 3% aqueous ammonium hydroxide, water, and brine. The organics were dried (Na2SO4) and rotary evaporated. The residue was dissolved in chloroform and purified by column chromatography on silica gel (144 g, 230-400 mesh), eluting with hexanes-acetone (6:1, 17×125 mL) to give 0.98 g of 4-(4′-methyl-biphenyl-4-yl)-4-oxo-butyric acid, methyl ester as a white solid; mp 121-122° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7](=[S:9])[NH2:8].Br[CH2:11][C:12](=O)[C:13]([O:15][CH2:16][CH3:17])=[O:14]>C(O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[S:9][CH:11]=[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:8]=1
Reactant: CCOC(=O)C(=O)CBr
Reactant: NC(=S)c1ccccn1
Solvent: CCO
Product: CCOC(=O)c1csc(-c2ccccn2)n1
Temperature: 25 °C
Yield: 35.4 %

Procedure:
A solution of the product of Example 3H (25.4 mmol) in ethanol (50 mL) was treated with ethyl bromopyruvate (3 mL, 23.9 mmol) and molecular sieves (10 g, 3 Å), heated at reflux for 16 hours, cooled to 25° C., filtered and concentrated. The concentrate was partitioned between ethyl acetate and saturated NaHCO3, and the organic phase was washed with brine, dried over MgSO4, filtered and concentrated. The residue was chromatographed on silica gel eluting with 0-25% ethyl acetate in dichloromethane to give the title compound (1.98 g, 33% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([NH:11][C@H:12]([C:14]([OH:16])=[O:15])[CH3:13])=[O:10])[CH:5]=[CH:6][CH:7]=1.[CH3:17][C:18]1([CH2:21]O)[CH2:20][CH2:19]1>>[CH3:17][C:18]1([CH2:21][O:15][C:14](=[O:16])[C@H:12]([CH3:13])[NH:11][C:9](=[O:10])[CH2:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[CH2:20][CH2:19]1
Reactant: CC1(CO)CC1
Reactant: C[C@H](NC(=O)Cc1cccc(Cl)c1)C(=O)O
Product: C[C@H](NC(=O)Cc1cccc(Cl)c1)C(=O)OCC1(C)CC1

Procedure:
Following General Procedure C above, and using N-(3-chlorophenylacetyl alanine (from Example D above) and (1-methylcyclopropyl)methanol (Aldrich) the title compound can be prepared. The reaction was monitored by tlc on silica gel and purification was by liquid chromatography using 3:7 EtOAc:hexane as the eluant.
Reaction SMILES: C[O:2][C:3]([C:5]1([OH:28])[CH2:10][C@@H:9]([O:11][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13])[C:8](=[CH2:19])[C@H:7]([O:20][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22])[CH2:6]1)=O.C1COCC1>>[Si:12]([O:11][C@H:9]1[C:8](=[CH2:19])[C@H:7]([O:20][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22])[CH2:6][C:5]([CH2:3][OH:2])([OH:28])[CH2:10]1)([C:15]([CH3:17])([CH3:18])[CH3:16])([CH3:14])[CH3:13]
Reactant: C=C1[C@H](O[Si](C)(C)C(C)(C)C)CC(O)(C(=O)OC)C[C@H]1O[Si](C)(C)C(C)(C)C
Solvent: C1CCOC1
Product: C=C1[C@H](O[Si](C)(C)C(C)(C)C)CC(O)(CO)C[C@H]1O[Si](C)(C)C(C)(C)C
Reaction time: 6 h

Procedure:
(i) To a stirred solution of the ester 3 (90 mg, 0.21 mmol) in anhydrous THF (8 mL) lithium aluminum hydride (60 mg, 1.6 mmol) was added at 0° C. under argon. The cooling bath was removed after 1 h and the stirring was continued at 6° C. for 12 h and at room temperature for 6 h. The excess of the reagent was decomposed with saturated aq. Na2SO4, and the mixture was extracted with ethyl acetate and ether, dried (MgSO4) and evaporated. Flash chromatography of the residue with hexane/ethyl acetate (9:1) afforded unreacted substrate (12 mg) and a pure, crystalline diol 4 (35 mg, 48% based on recovered ester 3): 1H NMR (CDCl3+D20) δ 0.079, 0.091, 0.100, and 0.121 (each 3H, each s, 4× SiCH3), 0.895 and 0.927 (9H and 9H, each s, 2× Si-t-Bu), 1.339 (1H, t, J˜12 Hz), 1.510 (1H, dd, J=14.3, 2.7 Hz), 2.10 (2H, m), 3.29 and 3.40 (1H and 1H, each d, J=11.0 Hz), 4.66 (1H, t, J˜2.8 Hz), 4.78 (1H, m), 4.92 (1H, t, J=1.7 Hz), 5.13 (1H, t, J=2.0 Hz); MS m/z (relative intensity) no M+, 345 (M+-t-Bu, 8), 327 (M+-t-Bu-H2O, 22), 213 (28), 195 (11), 73 (100).
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[C:11]3=[CH:12][N:13]=[C:14]([C:16]([OH:18])=O)[CH:15]=[C:10]3[C:9]([CH2:19][O:20][CH2:21][CH2:22][O:23][CH3:24])=[CH:8]2)=[CH:4][CH:3]=1.CN1CCOCC1.Cl.[CH3:35][NH:36][OH:37]>CN(C=O)C.CCOC(C)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:11]3=[CH:12][N:13]=[C:14]([C:16]([N:36]([OH:37])[CH3:35])=[O:18])[CH:15]=[C:10]3[C:9]([CH2:19][O:20][CH2:21][CH2:22][O:23][CH3:24])=[CH:8]2)=[CH:25][CH:26]=1
Reactant: CNO
Reactant: COCCOCc1cn(Cc2ccc(F)cc2)c2cnc(C(=O)O)cc12
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: COCCOCc1cn(Cc2ccc(F)cc2)c2cnc(C(=O)N(C)O)cc12
Reaction time: 1.5 h
Yield: 37 %

Procedure:
To a solution of 1-(4-fluorobenzyl)-3-[(2-methoxyethoxy)methyl]-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid (200 mg 0.5581 mmol) in anhydrous DMF (10 mL) was added CDMT (118 mg 0.6695 mmol 1.2 eq.) and NMM (N-methyl morpholine) (0.074 mL 0.67 mmol 1.2 eq.). The mixture, under nitrogen, was stirred for 1.5 hours, during which it slowly darkened to a deep orange. N-Methylhydroxylamine hydrochloride (233 mg 2.79 mmol 5.0 eq) was added and stirring continued for 10 hours. The reaction was judged to be complete by HPLC-MS analysis and the volatiles were removed in vacuo (ca. 2 torr) to give a golden yellow oil. This oil was dissolved in EtOAc (30 mL) and washed with water (3×20 mL) and brine (20 mL). The organic phase was separated, dried (Na2SO4), and concentrated in vacuo to afford the crude product. Which was purified by chromatography on a column of silica gel (40 mm OD, 100 g, 230-400 mesh, packed with CH2Cl2, eluted with CH2Cl2—MeOH—NH3 97:2:1 v/v, 2.0 L, 25 mL fractions) using the flash technique. Fractions were combined to afford 0.080 g (37%) of 1-(4-fluorobenzyl)-N-hydroxy-3-[(2-methoxyethoxy)methyl]-N-methyl-1H-pyrrolo[2,3-c]pyridine-5-carboxamide. LC-MS (Eclipse XDB-C8, 0.8 mL/min, gradient 80:20 to 5:95H2O (+0.1% HOAc):CH3CN—5 minutes, ESI, +mode): RT -2.062 min, m/e=388.1 (M+H+, base). 1H-NMR (300 MHz, CDCl3): o=3.38 (s, 3H), 3.47 (s, 3H), 3.57 (m, 2H), 3.68 (m, 2H), 4.78 (s, 2H), 5.37 (s, 2H), 7.04 (m, 2H), 7.13 (m, 2H), 7.42 (s, 1H), 8.46 (s, 1H), 8.64 (s, 1H). Found: C, 61.79; H, 5.83; N, 10.7%. C20H22FN3O4; 0.08H2O, requires C, 61.78; H, 5.74; N, 10.81%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([CH3:14])=[C:12]([C:15](OC)=[O:16])[C:11]([C:19](OC)=[O:20])=[C:10]2[CH3:23])=[CH:5][CH:4]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[H-].O>ClCCl.CCOCC>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([CH3:14])=[C:12]([CH2:15][OH:16])[C:11]([CH2:19][OH:20])=[C:10]2[CH3:23])=[CH:5][CH:4]=1
Reactant: COC(=O)c1c(C(=O)OC)c(C)n(-c2ccc(OC)cc2)c1C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Solvent: ClCCl
Product: COc1ccc(-n2c(C)c(CO)c(CO)c2C)cc1
Yield: 91 %

Procedure:
A solution of dimethyl N-(4-methoxyphenyl)-2,5-dimethylpyrrole-3,4-dicarboxylate (0.04 mol) in dry dichloromethane (50 mL) was added dropwise over a 15-min period to a mechanically stirred mixture of lithium aluminum hydride (3.4 g, 0.08 mol) in anhydrous ether (100 mL) heated under reflux (50°-55° C. bath). The stirred mixture was heated under reflux for 1 h after the addition was complete and then cooled in an ice bath. The excess hydride was carefully decomposed with small additions of wet ether and then with water until the salts were white. The mixture was filtered (medium-porosity sintered-glass funnel) and the inorganic residue was washed with several portions of hot dichloromethane (about 30 mL) until the total filtrate volume was about 400 mL. The filtrate was concentrated in vacuo to a volume of about 125 mL, warmed to boiling, and diluted with slow portionwise addition of petroleum ether (about 100 mL) to yield 91% of N-(4-methoxyphenyl)-2,5-dimethyl-3,4-bis(hydroxymethyl)pyrrole: mp 143°-145° C. (dec).
Reaction SMILES: C(OC(=O)C)(C)(C)C.[C:9]([O:13][C:14](=[O:25])[CH2:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH:23]=O)[CH:18]=1)([CH3:12])([CH3:11])[CH3:10].NO.Cl.[N:29]1C=CC=CC=1>CO>[C:9]([O:13][C:14](=[O:25])[CH2:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][NH2:29])[CH:18]=1)([CH3:12])([CH3:11])[CH3:10]
Reactant: CC(C)(C)OC(=O)COc1cccc(C=O)c1
Reactant: c1ccncc1
Agent: Cl
Agent: NO
Solvent: CO
Solvent: CC(=O)OC(C)(C)C
Product: CC(C)(C)OC(=O)COc1cccc(CN)c1
Reaction time: 2 h

Procedure:
(3-Hydroxyimino-methyl)-phenoxy)-acetic acid tert-butyl ester. To a solution of (3-formyl-phenoxy)-acetic acid tert-butyl ester prepared of Preparation 20, Step A (2.05 g, 8.68 mmol) in MeOH (30 mL) was added NH2OH.HCl (0.66 g, 9.54 mmol) and pyridine (3.5 mL, 43.4 mmol) and the reaction was stirred for 2 hours. The MeOH was removed in vacuo and the residue was diluted with EtOAc and 1N HCl. The layers were separated and the aqueous solution was washed with EtOAc. The combined organic layers were dried over MgSO4, filtered and concentrated in vacuo to afford the title compound of Step B (1.99 g). 1H NMR (400 MHz, CDCl3) δ 8.07 (s, 1H), 7.23-7.28 (m, 2H), 7.12 (m, 1H), 6.93 (d, 1H), 4.51 (s, 2H), 1.46 (s, 9H).
Reaction SMILES: CO[CH:3](OC)[N:4]([CH3:6])[CH3:5].[F:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C:17](=[O:24])[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:12][CH:11]=1.[C:25](OCCCC)(=O)C>>[CH2:6]([N:4]1[CH:3]=[C:16]([C:13]2[CH:12]=[CH:11][C:10]([F:9])=[CH:15][CH:14]=2)[C:17](=[O:24])[C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:5]1)[CH3:25]
Reactant: CCOC(=O)CC(=O)Cc1ccc(F)cc1
Reactant: CCCCOC(C)=O
Reactant: COC(OC)N(C)C
Product: CCOC(=O)c1cn(CC)cc(-c2ccc(F)cc2)c1=O
Temperature: 90 °C
Reaction time: 5 h

Procedure:
N,N-Dimethylformamide dimethylacetal (3.9 ml) was added to a solution of ethyl 4-(4-fluorophenyl)-3-oxobutanoate (1310 mg) in n-butyl acetate (15 ml) at room temperature, and the mixture was stirred at 90° C. for five hours. The solvent was distilled off under reduced pressure, and ethanol (20 ml) was added, followed by addition of ethylamine (2 M solution in THF, 4.4 ml). After stirring at 60° C. for two hours, ethylamine (2 M solution in THF, 3.0 ml) was added and the mixture was further stirred at 60° C. for two hours. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography [chloroform:methanol=300:1->70:1 (v/v)] to give 985 mg of the title compound as an oily substance.
Reaction SMILES: [CH3:1][NH:2][S:3]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[CH2:9]2)(=[O:5])=[O:4].[CH2:16]([O:18][C:19](=[O:32])[CH2:20][NH:21][C:22]([C:24]1[C:28]([CH3:29])=[C:27]([CH:30]=O)[NH:26][CH:25]=1)=[O:23])[CH3:17]>N1CCCCC1.C(O)C>[CH2:16]([O:18][C:19](=[O:32])[CH2:20][NH:21][C:22]([C:24]1[C:28]([CH3:29])=[C:27]([CH:30]=[C:9]2[C:8]3[C:12](=[CH:13][CH:14]=[C:6]([S:3](=[O:5])(=[O:4])[NH:2][CH3:1])[CH:7]=3)[NH:11][C:10]2=[O:15])[NH:26][CH:25]=1)=[O:23])[CH3:17]
Reactant: CNS(=O)(=O)c1ccc2c(c1)CC(=O)N2
Reactant: CCOC(=O)CNC(=O)c1c[nH]c(C=O)c1C
Solvent: C1CCNCC1
Solvent: CCO
Product: CCOC(=O)CNC(=O)c1c[nH]c(C=C2C(=O)Nc3ccc(S(=O)(=O)NC)cc32)c1C
Temperature: 90 °C
Yield: 35.6 %

Procedure:
A mixture of 5-methylaminosulfonyl-2-oxindole (0.06 g, 0.22 mmol), [(5-formyl-4-methyl-1H-pyrrole-3-carbonyl)-amino]-acetic acid ethyl ester (0.075 g, 0.27 mmol) and piperidine (2 drops) in ethanol (5 mL) was heated in a sealed tube at 90° C. for 12 hrs. After cooling, the precipitate was collected by vacuum filtration, washed with ethanol, triturated with dichloromethane/ether and dried to give 0.035 g (36%) of the title compound as a yellowish brown solid.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:16]2[CH2:15][CH2:14][C@H:13]([N:17]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH3:18])[CH2:12][C:11]=2[CH:10]=[CH:9][CH:8]=1)(=O)=O.[CH3:28][N:29]1[C:33]([CH3:34])=[C:32](B2OC(C)(C)C(C)(C)O2)[C:31]([CH3:44])=[N:30]1.C([O-])([O-])=O.[K+].[K+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:19]([N:17]([CH3:18])[C@H:13]1[CH2:14][CH2:15][C:16]2[C:11](=[CH:10][CH:9]=[CH:8][C:7]=2[C:32]2[C:31]([CH3:44])=[N:30][N:29]([CH3:28])[C:33]=2[CH3:34])[CH2:12]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Cc1nn(C)c(C)c1B1OC(C)(C)C(C)(C)O1
Reactant: CN(Cc1ccccc1)[C@H]1CCc2c(cccc2OS(=O)(=O)C(F)(F)F)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: Cc1nn(C)c(C)c1-c1cccc2c1CC[C@H](N(C)Cc1ccccc1)C2
Reaction time: 3 h

Procedure:
(6S)-6-[Benzyl(methyl)amino]-5,6,7,8-tetrahydronaphthalen-1-yl trifluoromethanesulfonate (5.0 g, 12.517 mmol), 1,3,5-trimethyl-1H-pyrazole-4-boronic acid pinacol ester (3.60 g, 15.246 mmol) and Pd(PPh3)4 (1.70 g, 1.471 mmol) were added to a solution of K2CO3 (3.31 g, 23.95 mmol) in a mixture of 1,2,-dimethoxyethane (120 mL) and H2O (15 mL). The reaction mixture was purged with N2 (g) for 10 min, and warmed up to reflux. The reaction was completed in 3 h (TLC analysis). It was allowed to reach room temperature, diluted with H2O (150 mL) and extracted with AcOEt (300 mL). The organic layer was filtered through Celite (washing with AcOEt), dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by flash chromatography on silica gel (0-10-20% Et3N/AcOEt) to afford the desired product as a brown-colored oil. The material was dissolved in CH2Cl2 (100 mL) and acidified with HCl aqueous solution (6 N). The organic layer was discarded, and the aqueous layer was taken to pH>13 with NaOH aqueous solution (6 N). It was extracted with CH2Cl2 (3×200 mL), and the organic layer was dried over anhydrous Na2SO4, filtered and concentrated, to give 3.67 g of the coupling product (Rf=0.3 (AcOEt), pale yellow oil, 81% yield).
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][C:7]2[C:16]3[C:11](=[C:12]([NH2:17])[CH:13]=[CH:14][CH:15]=3)[N:10]=[CH:9][CH:8]=2)=[CH:4][C:3]=1[C:20]([F:23])([F:22])[F:21].[Cl:24][C:25]1[C:30]([C:31](O)=[O:32])=[C:29]([F:34])[C:28]([CH2:35][NH:36][C:37](=[O:42])[C:38]([CH3:41])([CH3:40])[CH3:39])=[CH:27][CH:26]=1.C(Cl)(=O)C(Cl)=O.CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)Cl>[Cl:24][C:25]1[C:30]([C:31]([NH:17][C:12]2[CH:13]=[CH:14][CH:15]=[C:16]3[C:11]=2[N:10]=[CH:9][CH:8]=[C:7]3[O:6][C:5]2[CH:18]=[CH:19][C:2]([F:1])=[C:3]([C:20]([F:23])([F:21])[F:22])[CH:4]=2)=[O:32])=[C:29]([F:34])[C:28]([CH2:35][NH:36][C:37](=[O:42])[C:38]([CH3:40])([CH3:39])[CH3:41])=[CH:27][CH:26]=1
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)O)c1F
Reactant: Nc1cccc2c(Oc3ccc(F)c(C(F)(F)F)c3)ccnc12
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)Nc2cccc3c(Oc4ccc(F)c(C(F)(F)F)c4)ccnc23)c1F
Yield: 32.8 %

Procedure:
The title compound was prepared following the procedure described in Example-1 using 4-(4-fluoro-3-(trifluoromethyl)phenoxy)quinolin-8-amine (Intermediate-44, 60 mg, 0.18 mmol), 6-chloro-2-fluoro-3-(pivalamidomethyl)benzoic acid (Intermediate-2, 80 mg, 0.27 mmol), oxalyl chloride (52 mg, 0.41 mmol), DMF (1 drop) and DIPEA (70 mg, 0.54 mmol) in CH2Cl2 (2 mL) to afford 35 mg of the title product. 1H NMR (300 MHz, DMSO-d6): δ 10.75 (s, 1H), 8.79 (d, J=7.5 Hz, 1H), 8.71 (d, J=5.1 Hz, 1H), 8.16 (t, 1H), 8.09 (d, J=8.7 Hz, 1H), 7.88 (m, 1H), 7.75-7.70 (m, 3H), 7.38 (m, 2H), 6.83 (d, J=5.4 Hz, 1H), 4.32 (d, J=5.1 Hz, 2H), 1.14 (s, 9H); MS (m/z): 592.29 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[CH:10]=2)[CH:5]=[C:4]([C:18]([O:20][CH3:21])=[O:19])[CH:3]=1.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]([C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=2)(O)[C:31]#[CH:32])=[CH:26][CH:25]=1>C1(C)C=CC=CC=1>[CH3:41][O:40][C:37]1[CH:36]=[CH:35][C:34]([C:30]2([C:27]3[CH:26]=[CH:25][C:24]([O:23][CH3:22])=[CH:29][CH:28]=3)[O:1][C:2]3[C:11]4[C:6]([CH:5]=[C:4]([C:18]([O:20][CH3:21])=[O:19])[C:3]=3[CH:32]=[CH:31]2)=[CH:7][CH:8]=[C:9]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[CH:10]=4)=[CH:39][CH:38]=1
Reactant: C#CC(O)(c1ccc(OC)cc1)c1ccc(OC)cc1
Reactant: COC(=O)c1cc(O)c2cc(N3CCOCC3)ccc2c1
Solvent: Cc1ccccc1
Product: COC(=O)c1cc2ccc(N3CCOCC3)cc2c2c1C=CC(c1ccc(OC)cc1)(c1ccc(OC)cc1)O2
Yield: 14.9 %

Procedure:
A solution of methyl 4-hydroxy-6-morpholino-2-naphthoate (1.0 g, 3.5 mmol) and 1,1-di(4-methoxyphenyl)prop-2-yn-1-ol (0.94 g, 3.5 mmol) in toluene (45 cm3) containing acidic alumina (Brockmann 1), (5.0 g) was refluxed for 100 minutes. The cooled solution was filtered and the alumina was washed well with EtOAc (200 cm3). The organic filtrate was washed with aqueous sodium hydroxide (2M, 2×50 cm3) and water (100 cm3). Removal of the dried (Na2SO4) EtOAc gave an oil which was flash chromatographed over silica using 35% EtOAc in hexane as the eluent to afford a pale yellow solid. Recrystallisation from EtOAc/hexane gave methyl 2,2-bis(4-methoxyphenyl)-9-morpholino-2H-naphtho [1,2-b]pyran-5-carboxylate (yield=0.28 g, theoretical yield=1.87 g 15%, m.p.=153.5-155° C. (uncorrected)).