Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1.[CH:25]1([NH:28][CH:29]2[CH2:34][CH2:33][N:32]([C:35]3[C:40]([F:41])=[CH:39][C:38]([C:42]([F:45])([F:44])[F:43])=[CH:37][N:36]=3)[CH2:31][CH2:30]2)[CH2:27][CH2:26]1.[CH3:46][C:47]1[N:48]([C:52]2[CH:60]=[CH:59][C:55]([C:56](O)=[O:57])=[CH:54][CH:53]=2)[CH:49]=[CH:50][N:51]=1.C(#N)C.O.FC(F)(F)C(O)=O>CN(C)C=O.C(N(CC)CC)C>[CH:25]1([N:28]([CH:29]2[CH2:34][CH2:33][N:32]([C:35]3[C:40]([F:41])=[CH:39][C:38]([C:42]([F:44])([F:43])[F:45])=[CH:37][N:36]=3)[CH2:31][CH2:30]2)[C:56](=[O:57])[C:55]2[CH:54]=[CH:53][C:52]([N:48]3[CH:49]=[CH:50][N:51]=[C:47]3[CH3:46])=[CH:60][CH:59]=2)[CH2:26][CH2:27]1
Reactant: Cc1nccn1-c1ccc(C(=O)O)cc1
Reactant: Fc1cc(C(F)(F)F)cnc1N1CCC(NC2CC2)CC1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: Cc1nccn1-c1ccc(C(=O)N(C2CC2)C2CCN(c3ncc(C(F)(F)F)cc3F)CC2)cc1
Reaction time: 2 h

Procedure:
Bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (PyBrOP, 14 mg) in N,N-dimethylformamide (0.1 mL) is added to a solution of cyclopropyl-(3′-fluoro-5′-trifluoromethyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-amine (6 mg), 4-(2-methyl-imidazol-1-yl)-benzoic acid (6 mg), and triethylamine (0.015 mL) in N,N-dimethylformamide (0.4 mL) at room temperature. The solution is stirred for 2 h and then submitted to chromatography on reversed phase (HPLC, acetonitrile/water/trifluoroacetic acid) to give the pure title compound. LC (method 19): tR=4.33 min; Mass spectrum (ESI+): m/z=488 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:16]=[C:15]([CH2:17][C:18]([NH:20][CH:21]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[N:31]2[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]2)[CH2:22][CH2:23][CH3:24])=[O:19])[CH:14]=[CH:13][C:5]=1[CH:6]=[CH:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH3:2].[H][H]>C(O)C.[Pd]>[CH2:1]([O:3][C:4]1[CH:16]=[C:15]([CH2:17][C:18]([NH:20][CH:21]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[N:31]2[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]2)[CH2:22][CH2:23][CH3:24])=[O:19])[CH:14]=[CH:13][C:5]=1[CH2:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH3:2]
Reactant: CCCC(NC(=O)Cc1ccc(C=CC(=O)OCC)c(OCC)c1)c1ccccc1N1CCCCC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCCC(NC(=O)Cc1ccc(CCC(=O)OCC)c(OCC)c1)c1ccccc1N1CCCCC1

Procedure:
A solution of ethyl 2-ethoxy-4-[N-(1-(2-piperidinophenyl)-1-butyl)-aminocarbonylmethyl]-cinnamate (0.54 g, 1.1 mmol) in ethanol (15 ml) is hydrogenated for 1 hour at ambient temperature and under 3 bars of hydrogen on 10% palladium/charcoal (0.1 g). The mixture is filtered, concentrated by evaporation in vacuo and the evaporation residue is crystallized from petroleum ether.
Reaction SMILES: [CH2:1]([C:3]1[S:4][CH:5]=[C:6](/[CH:8]=[CH:9]/[C:10]2[C:11]([O:21][CH2:22][C:23]3[CH:46]=[CH:45][C:26]([O:27][CH2:28][C:29]4[N:30]=[C:31]([C:35]5[O:39][C:38]([C:40]([O:42]CC)=[O:41])=[CH:37][CH:36]=5)[O:32][C:33]=4[CH3:34])=[C:25]([O:47][CH3:48])[CH:24]=3)=[N:12][N:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:14]=2)[N:7]=1)[CH3:2].O1CCCC1.[OH-].[Na+].Cl>O.C(O)C>[CH2:1]([C:3]1[S:4][CH:5]=[C:6](/[CH:8]=[CH:9]/[C:10]2[C:11]([O:21][CH2:22][C:23]3[CH:46]=[CH:45][C:26]([O:27][CH2:28][C:29]4[N:30]=[C:31]([C:35]5[O:39][C:38]([C:40]([OH:42])=[O:41])=[CH:37][CH:36]=5)[O:32][C:33]=4[CH3:34])=[C:25]([O:47][CH3:48])[CH:24]=3)=[N:12][N:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:14]=2)[N:7]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(-c2nc(COc3ccc(COc4nn(-c5ccccc5)cc4/C=C/c4csc(CC)n4)cc3OC)c(C)o2)o1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: CCc1nc(/C=C/c2cn(-c3ccccc3)nc2OCc2ccc(OCc3nc(-c4ccc(C(=O)O)o4)oc3C)c(OC)c2)cs1
Temperature: 60 °C
Reaction time: 1 h
Yield: 70.4 %

Procedure:
To a mixture of ethyl 5-[4-({4-[([4-[(E)-2-(2-ethyl-1,3-thiazol-4-yl)ethenyl]-1-phenyl-1H-pyrazol-3-yl}oxy)methyl]-2-methoxyphenoxy}methyl)-5-methyl-1,3-oxazol-2-yl]-2-furancarboxylate (0.46 g), tetrahydrofuran (2 mL) and ethanol (2 mL) was added 1N aqueous sodium hydroxide solution (1.5 mL), and the mixture was stirred at 60° C. for 1 hr. To the reaction mixture were added 1N hydrochloric acid (2 mL) and water, and the precipitated crystals were collected by filtration to give 5-[4-({4-[({4-[(E)-2-(2-ethyl-1,3-thiazol-4-yl)ethenyl]-1-phenyl-1H-pyrazol-3-yl}oxy)methyl]-2-methoxyphenoxy}methyl)-5-methyl-1,3-oxazol-2-yl]-2-furancarboxylic acid as colorless crystals (0.31 g, yield 84%). Recrystallization from acetone-hexane gave colorless prism crystals. melting point: 154-155° C.
Reaction SMILES: N1C=CN=C1.[C:6]([O:10][C:11]([C@:13]1([C:24]([O-:26])=[O:25])[CH2:15][C@:14]1([CH2:22][OH:23])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:12])([CH3:9])([CH3:8])[CH3:7].[Na+].[Si:28](Cl)([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C1(C)C=CC=CC=1.CO.O>[C:6]([O:10][C:11]([C@:13]1([C:24]([OH:26])=[O:25])[CH2:15][C@:14]1([CH2:22][O:23][Si:28]([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:12])([CH3:9])([CH3:7])[CH3:8]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(C)(C)OC(=O)[C@]1(C(=O)[O-])C[C@]1(CO)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)[C@]1(C(=O)O)C[C@]1(CO[Si](C)(C)C(C)(C)C)c1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 98.4 %

Procedure:
Imidazol (18 g, 0.27 mol) was added to a suspension of sodium (1R*,2S*)-1-t-butoxycarbonyl-2-hydroxymethyl-2-phenyl-cyclopropanecarboxylate (38 g, 0.11 mol) obtained in the above-mentioned Example a) in N,N-dimethylformamide (190 mL) under argon atmosphere at 0° C., and t-butyldimethylsilyl chloride (35 g, 0.24 mol) was further added in 2 portions. After warming to room temperature, the mixture was stirred for 12 hours. Then water (76 mL) and methanol (76 mL) were added to the mixture at 0° C., which was followed by addition of potassium carbonate (30 g, 0.21 mol). After the obtained suspension was stirred for 3 hours at room temperature, toluene (190 mL) was added and the mixture was separated into layers using 10% aqueous citric acid solution (400 mL) while adjusting pH to about 5. The aqueous layer was extracted twice with toluene, and the combined organic layer was sequentially washed with 10% aqueous citric acid solution and saturated aqueous sodium chloride solution, and dried over sodium sulfate. After filtration and evaporation, the product was azeotroped with xylene to remove t-butyldimethylsilanol. The title compound (44 g) was obtained as white crystals. The obtained product was used in the next step without purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:48]=[CH:47][C:6]([CH2:7][N:8]([CH2:38][C:39]2[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][CH:40]=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][N:27]([C:30]([NH:32][CH2:33][CH2:34][C:35]([OH:37])=O)=[O:31])[C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:11][N:10]=2)=[CH:5][CH:4]=1.[Cl-].[NH4+].C([N:53](C(C)C)C(C)C)C.C1C=CC2N(O)N=NC=2C=1>O.CN(C=O)C>[C:35]([CH2:34][CH2:33][NH:32][C:30]([N:27]1[C:17]2[N:18]=[C:19]([N:21]3[CH2:22][CH2:23][O:24][CH2:25][CH2:26]3)[N:20]=[C:15]([C:12]3[CH:11]=[N:10][C:9]([N:8]([CH2:38][C:39]4[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][CH:40]=4)[CH2:7][C:6]4[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:48][CH:47]=4)=[N:14][CH:13]=3)[C:16]=2[CH2:29][CH2:28]1)=[O:31])(=[O:37])[NH2:53]
Reactant: CCN(C(C)C)C(C)C
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4C(=O)NCCC(=O)O)cn2)cc1
Agent: On1nnc2ccccc21
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4C(=O)NCCC(N)=O)cn2)cc1
Temperature: 80 °C
Reaction time: 3 h
Yield: 84 %

Procedure:
To a DMF solution (1 ml) of 3-[(4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidine-7-carbonyl)-amino]-propionic acid (40 mg) obtained in Step A, ammonium chloride (6.5 mg), N-ethyldiisopropylamine (53 μl), HOBt (8.3 mg) and WSCI (17.6 mg) were added, followed by stirring at 80° C. for 3 hours. To this, water was added and the resulting solid was filtered, to obtain a crude product of the desired compound (33.5 mg, 84%).
Reaction SMILES: C([O:3][C:4]([C:6]1([C:10]#[N:11])[CH2:9][CH2:8][CH2:7]1)=[O:5])C.[OH-].[Na+]>CO>[C:10]([C:6]1([C:4]([OH:5])=[O:3])[CH2:9][CH2:8][CH2:7]1)#[N:11]
Reactant: CCOC(=O)C1(C#N)CCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: N#CC1(C(=O)O)CCC1

Procedure:
20 g (0.131 mol) of 1-cyano-1-cyclobutanecarboxylic acid ethyl ester are dissolved in 60 ml of methanol and saponified with 40 ml of 4 N NaOH for about 12 hours at 23° C.
Reaction SMILES: Cl[CH2:2][CH2:3][NH:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[C:10](=[C:14]1[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:16][C:15]1=[O:23])[O:9][CH2:8]2.[NH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>>[N:24]1([CH2:2][CH2:3][NH:4][C:5]2[CH:6]=[C:7]3[C:11](=[CH:12][CH:13]=2)[C:10](=[C:14]2[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[NH:16][C:15]2=[O:23])[O:9][CH2:8]3)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: O=C1Nc2ccccc2C1=C1OCc2cc(NCCCl)ccc21
Reactant: C1CCNCC1
Product: O=C1Nc2ccccc2C1=C1OCc2cc(NCCN3CCCCC3)ccc21
Temperature: 110 °C
Yield: 89.3 %

Procedure:
A mixture of 3-[5-(2-chloro-ethylamino)-3H-isobenzofuran-1-ylidene]-1,3-dihydro-indol-2-one (1.10 g, 3.37 mmol) and piperidine (8 ml, 80.9 mmol) was heated at 110° C. for 4 hours. After cooled to room temperature, the mixture was poured into an ice water (150 ml) with stirring. The solid was filtered, washed with water and dried to give a crude product. Trituration of the crude product with CHCl3/hexanes afforded 3-[5-(2-piperidin-1-yl-ethylamino)-3H-isobenzofuran-1-ylidene]-1,3-dihydro-indol-2-one as a yellow solid (1.13 g, 89%).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([N:14]1[C:18]([CH2:19][CH2:20][CH3:21])=[C:17]([C:22](OCC)=[O:23])[CH:16]=[N:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+].CCCCCC>O1CCCC1>[CH2:7]([N:14]1[C:18]([CH2:19][CH2:20][CH3:21])=[C:17]([CH2:22][OH:23])[CH:16]=[N:15]1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CCCc1c(C(=O)OCC)cnn1Cc1ccccc1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: O
Product: CCCc1c(CO)cnn1Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.8 %

Procedure:
Lithium aluminium hydride (2.58 g) was added to a solution of ethyl 1-benzyl-5-propyl-1H-pyrazole-4-carboxylate (18.50 g) in tetrahydrofuran (300 ml) at 0° C., and the mixture was stirred at room temperature for one hour. Sodium sulfate decahydrate (21.88 g) and hexane (100 ml) were added to the reaction mixture and the mixture was stirred at room temperature for 30 minutes. After the precipitate was removed by filtration, the filtrate was concentrated to obtain (1-benzyl-5-propyl-1H-pyrazol-4-yl)methanol (14.99 g, yield: 96%) as a colorless oily substance.
Reaction SMILES: [Cl:1][C:2]1([Cl:13])[CH2:4][CH:3]1[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[O:11]C.B(Br)(Br)Br>>[Cl:1][C:2]1([Cl:13])[CH2:4][CH:3]1[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[OH:11]
Reactant: COc1ccccc1C1CC1(Cl)Cl
Agent: BrB(Br)Br
Product: Oc1ccccc1C1CC1(Cl)Cl

Procedure:
o-(2,2-Dichlorocyclopropyl)phenol was prepared from 7.8 g. of o-(2,2-dichlorocyclopropyl)anisole and 5.3 g. of boron tribromide according to the procedure described above in Example 1, part (c), affording 7.1 g. of oil used directly in the following reaction.
Reaction SMILES: [NH2:1][C:2]1[NH:3][CH:4]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=2)[N:6]=1.[C:16](OC(=O)C)(=[O:18])[CH3:17]>>[C:16]([NH:1][C:2]1[NH:3][CH:4]=[C:5]([C:7]2[CH:8]=[CH:9][C:10]([N+:13]([O-:15])=[O:14])=[CH:11][CH:12]=2)[N:6]=1)(=[O:18])[CH3:17]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1nc(-c2ccc([N+](=O)[O-])cc2)c[nH]1
Product: CC(=O)Nc1nc(-c2ccc([N+](=O)[O-])cc2)c[nH]1
Temperature: 100 °C

Procedure:
A mixture of 2-amino-4-(4-nitro-phenyl)-1H-imidazole (17.3 g) and acetic anhydride (100 ml) was heated at 100° C. for one hour. The resulting solution was evaporated to dryness, and the residue was treated with ether, filtered off and dried to give 18.9 g of the title compound.
Reaction SMILES: F[C:2]1[C:3]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:4]([CH3:19])[C:5]([C:17]#[N:18])=[C:6]2[C:10]=1[O:9][C:8]([N:11]1[CH2:14][C:13]([OH:16])([CH3:15])[CH2:12]1)=[N:7]2.C(N(CC)CC)C.[CH3:33][N:34]([CH3:40])[C@H:35]1[CH2:39][CH2:38][NH:37][CH2:36]1>CS(C)=O>[CH3:33][N:34]([CH3:40])[C@H:35]1[CH2:39][CH2:38][N:37]([C:2]2[C:3]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[C:4]([CH3:19])[C:5]([C:17]#[N:18])=[C:6]3[C:10]=2[O:9][C:8]([N:11]2[CH2:14][C:13]([OH:16])([CH3:15])[CH2:12]2)=[N:7]3)[CH2:36]1
Reactant: Cc1c(-c2ccccc2)c(F)c2oc(N3CC(C)(O)C3)nc2c1C#N
Reactant: CN(C)[C@H]1CCNC1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: Cc1c(-c2ccccc2)c(N2CC[C@H](N(C)C)C2)c2oc(N3CC(C)(O)C3)nc2c1C#N
Temperature: 150 °C
Reaction time: 4 h
Yield: 10.9 %

Procedure:
7-Fluoro-2-(3-hydroxy-3-methylazetidin-1-yl)-5-methyl-6-phenyl-1,3-benzoxazole-4-carbonitrile (I-193) (230 mg, 0.68 mmol) was dissolved in DMSO (5 ml), then triethylamine (195 μl, 1.36 mmol) and (3S)-3-(dimethylamino)pyrrolidine (181 μl, 1.43 mmol) were added, followed by stirring at 150° C. for 4 hours. After cooling, concentration under reduced pressure, dilution with ethyl acetate and washing with water, the organic layer was dried over anhydrous magnesium sulfate, then the solvent was evaporated away under reduced pressure. The resulting residue was subjected to silica gel column chromatography, and the eluate with chloroform/methanol (10:1, v/v) gave the entitled compound (32 mg, 11%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[C:6]1[O:7][C:8]2[C:13]([C:14](=[O:16])[CH:15]=1)=[CH:12][CH:11]=[C:10]([OH:17])[CH:9]=2.[H-].[Na+].[CH2:25]([CH:27]1[O:29][CH2:28]1)Cl>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[C:6]1[O:7][C:8]2[C:13]([C:14](=[O:16])[CH:15]=1)=[CH:12][CH:11]=[C:10]([O:17][CH2:25][CH:27]1[O:29][CH2:28]1)[CH:9]=2
Reactant: ClCC1CO1
Reactant: COc1ccc(-c2cc(=O)c3ccc(O)cc3o2)cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(-c2cc(=O)c3ccc(OCC4CO4)cc3o2)cc1OC

Procedure:
Reaction of 3′,4′-dimethoxy-7-hydroxy-flavone, 27 (6 g, 20 mol), 50% sodium hydride (2.4 g, 100 mmol) and epichlorohydrin (3.9 mL, 50 mmol) in dry dimethyl formamide (200 mL) using identical procedure as described for 28 furnished 33. Yield 5.3 g (74%); mp 148-149° C.; MS (FAB) 355 (M++1); IR (KBr) 1632; 1H NMR (200 MHz, CDCl3) δ 8.13 (d, J=9.5 Hz, 1H), 7.73 (dd, J=8.5 Hz, 2.0 Hz, 1H), 7.35 (d, J=1.9 Hz, 1H), 7.00 (dd, J=7.1 Hz, 2.3 Hz, 1H), 6.99 (d, J=2.2 Hz, 1H), 6.97 (d, J=8.5 Hz, 1H), 6.68 (s, 1H), 4.39 (dd, J=11.1 Hz, 2.9 Hz, 1H), 4.05 (dd, J=11.1 Hz, 5.8 Hz, 1H), 3.98 (s, 3H), 3.96 (s, 3H), 3.44-3.40 (m, 1H), 2.96 (t, J=4.5 Hz, 4.5 Hz, 1H), 2.81 (dd, J=4.8 Hz, 2.6 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[N:9][CH:10]=1)[N:7]([CH2:11][CH3:12])[C:6](=[O:13])[CH2:5]2.[O:14]1[CH:18]=[CH:17][CH:16]=[C:15]1[C:19](Cl)=[O:20]>CN(C)C1C=CN=CC=1.CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[N:9][CH:10]=1)[N:7]([CH2:11][CH3:12])[C:6](=[O:13])[CH:5]2[C:19]([C:15]1[O:14][CH:18]=[CH:17][CH:16]=1)=[O:20]
Reactant: O=C(Cl)c1ccco1
Reactant: CCN1C(=O)Cc2cc(Cl)cnc21
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Product: CCN1C(=O)C(C(=O)c2ccco2)c2cc(Cl)cnc21

Procedure:
The title compound was prepared from 5-chloro-1-ethyl-7-azaoxindole (Example 53D) according to the procedure of Example 53E, using 5-chloro-1-ethyl-7-azaoxindole (405 mg, 2.06 mmol), 4-dimethylaminopyridine (500 mg, 4.09 mmol), 2-furoyl chloride (0.22 mL, 2.23 mmol) and DMF (10 mL). The solid product obtained following chromatography was recrystallized from hexane. The yield was 110 mg (18%).
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5](=[O:7])/[C:4](=[CH:8]\[C:9]2[CH:28]=[CH:27][C:12]([O:13][CH2:14][CH2:15][O:16][C:17]3[CH:26]=[CH:25][C:20]([C:21]([O:23]C)=[O:22])=[CH:19][CH:18]=3)=[CH:11][CH:10]=2)/[S:3]1.CO.O.[OH-].[Li+].Cl>C1COCC1.O>[O:1]=[C:2]1[NH:6][C:5](=[O:7])/[C:4](=[CH:8]\[C:9]2[CH:10]=[CH:11][C:12]([O:13][CH2:14][CH2:15][O:16][C:17]3[CH:26]=[CH:25][C:20]([C:21]([OH:23])=[O:22])=[CH:19][CH:18]=3)=[CH:27][CH:28]=2)/[S:3]1
Reactant: COC(=O)c1ccc(OCCOc2ccc(/C=C3/SC(=O)NC3=O)cc2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C1NC(=O)/C(=C\c2ccc(OCCOc3ccc(C(=O)O)cc3)cc2)S1
Temperature: 60 °C
Yield: 22.6 %

Procedure:
To a solution of methyl ester 356 (647 mg, 1.62 mmol) in THF (15 mL) was added methanol (2 mL), water (2 mL) and lithium hydroxide monohydrate (340 mg, 8.11 mmol). The mixture was heated at 60° C. for 1 hour, acidified with 10% HCl solution and extracted with ethyl acetate. The organic extract was dried over MgSO4, filtered, and evaporated to afford the title compound (141 mg, 22%). 1H NMR: (MeOD-d4) δ (ppm): 7.97 (d, J=8.8 Hz, 2H), 7.75 (s, 1H), 7.53 (d, J=8.8 Hz, 2H), 7.12 (d, J=8.8 Hz, 2H), 7.04 (d, J=8.8 Hz, 2H), 4.44 (4H, bs). LRMS (ESI): (calc.) 385.4; (found) 392.3 (MLi)+.
Reaction SMILES: [C:1]([O:8][CH2:9][CH3:10])(=[O:7])[C:2]([O:4][CH2:5][CH3:6])=O.O[CH2:12][C:13]([C:15]1C=C[CH:18]=[CH:17][CH:16]=1)=[O:14].[O-]CC.[Na+].S(=O)(=O)(O)O>C1(C)C=CC=CC=1.C(O)C.O>[O:4]1[C:5]2[C:15](=[CH:16][CH:17]=[CH:18][CH:6]=2)[C:13](=[O:14])[CH:12]=[C:2]1[C:1]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCOC(=O)C(=O)OCC
Reactant: O=C(CO)c1ccccc1
Agent: CC[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cc(=O)c2ccccc2o1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 189.8 %

Procedure:
Into a solution of 12.0 g of diethyl oxalate in 180 g of toluene is added 30 g of 2-hydroxyacetophenone, then dropwise added 65.0 g of 20% sodium ethoxide in ethanol. After the reaction is complete, 13 g of 98% sulfuric acid is added, and the mixture stirred at 60° C. for about 30 min. After adding 140 g of water, the organic fraction is separated. The organic fraction is concentrated and 55.0 g of hexane is added. Filtering below 10° C. affords about 34.0 g of ethyl chromone-2-carboxylate (about 95% yield).
Reaction SMILES: [C:1]12([C:11]3[CH:20]=[C:19]4[C:14]([CH:15]=[CH:16][C:17](B(O)O)=[CH:18]4)=[CH:13][C:12]=3[O:24][CH2:25][O:26][CH2:27][CH2:28][O:29][CH3:30])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[OH:31][C:32]1[CH:41]=[C:40](I)[CH:39]=[CH:38][C:33]=1[C:34]([O:36][CH3:37])=[O:35]>>[OH:31][C:32]1[CH:41]=[C:40]([C:17]2[CH:16]=[CH:15][C:14]3[C:19](=[CH:20][C:11]([C:1]45[CH2:10][CH:5]6[CH2:4][CH:3]([CH2:9][CH:7]([CH2:6]6)[CH2:8]4)[CH2:2]5)=[C:12]([O:24][CH2:25][O:26][CH2:27][CH2:28][O:29][CH3:30])[CH:13]=3)[CH:18]=2)[CH:39]=[CH:38][C:33]=1[C:34]([O:36][CH3:37])=[O:35]
Reactant: COCCOCOc1cc2ccc(B(O)O)cc2cc1C12CC3CC(CC(C3)C1)C2
Reactant: COC(=O)c1ccc(I)cc1O
Product: COCCOCOc1cc2ccc(-c3ccc(C(=O)OC)c(O)c3)cc2cc1C12CC3CC(CC(C3)C1)C2
Yield: 81.3 %

Procedure:
Following the procedure of Example 1(c), but reacting 2.25 g (5.5 mmol) of 7-(1-adamantyl)-6-methoxyethoxymethoxy-2-naphthylboronic acid with 1.39 g (5 mmol) of methyl 2-hydroxy-4-iodobenzoate, 2.1 g (81%) of the expected ester were obtained, which ester had a melting point of 101°-2° C.
Reaction SMILES: C(Cl)(Cl)Cl.[OH:5][CH2:6][C:7]1[CH:16]=[C:15]2[C:10]([CH2:11][CH2:12][C:13](=[O:17])[NH:14]2)=[CH:9][CH:8]=1.[CH3:18][C:19](OC(C)=O)=[O:20].C([O-])(O)=O.[Na+]>CN(C1C=CN=CC=1)C.CCN(CC)CC>[C:19]([O:5][CH2:6][C:7]1[CH:16]=[C:15]2[C:10]([CH2:11][CH2:12][C:13](=[O:17])[NH:14]2)=[CH:9][CH:8]=1)(=[O:20])[CH3:18]
Reactant: CC(=O)OC(C)=O
Reactant: O=C1CCc2ccc(CO)cc2N1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(=O)OCc1ccc2c(c1)NC(=O)CC2
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a CHCl3 (30.0 mL) solution, the compound (670 mg) obtained in Step 52-1, Ac2O (536 μL), DMAP (20.0 mg) and Et3N (1.05 mL) were added under ice cooling and the mixture was stirred at room temperature for 45 minutes. To the reaction mixture, a saturated aqueous NaHCO3 solution was added and the solution was extracted three times with CHCl3. The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel 60 N, mobile phase: MeOH/CHCl3=0/100 to 10/90; v/v) to obtain (2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)methyl acetate (767 mg, a light yellow solid).
Reaction SMILES: C[O:2][C:3](=[O:26])[C:4](=[O:25])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][O:14][CH:15]2[CH2:24][CH2:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:16]2)=[CH:7][CH:6]=1.[OH-].[Na+]>CO.O1CCCC1.O>[O:25]=[C:4]([C:5]1[CH:6]=[CH:7][C:8]([O:11][CH2:12][CH2:13][O:14][CH:15]2[CH2:24][CH2:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:16]2)=[CH:9][CH:10]=1)[C:3]([OH:26])=[O:2]
Reactant: COC(=O)C(=O)c1ccc(OCCOC2CCc3ccccc3C2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C(O)C(=O)c1ccc(OCCOC2CCc3ccccc3C2)cc1
Yield: 86.8 %

Procedure:
A mixture of rac.-alpha-oxo-4-[[2-(1,2,3,4-tetrahydro-2-naphthalenyloxy)ethyl]oxy]benzeneacetic acid methyl ester (0.69 g) in hot methanol (10 mL) plus enough tetrahydrofuran to dissolve the solids, was treated with 1N sodium hydroxide (4 mL) and diluted with water. The organic solvent was removed under vacuum and the residue was mixed with water, acidified with excess hydrochloric acid, and extracted with dichloromethane. The organic layer was dried (Na2SO4), filtered, and evaporated to give crude product. Crystallization from diethyl ether-hexane provided 0.575 g of rac.-alpha-oxo-4-[[2-(1,2,3,4-tetrahydro-2-naphthalenyloxy)ethyl]oxy]benzeneacetic acid as a colorless solid, mp 119°-120° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:38])[C@H:4]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:24]([NH:26][C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=4)=[O:25])=[CH:19][CH:18]=3)=[CH:13][CH:14]=2)[C:9]1=[O:37])[CH:5]([CH3:7])[CH3:6].Br[C:40]1[CH:48]=C2C(CN([C@@H](C3C=CC=CC=3)C(OC)=O)C2=O)=C[CH:41]=1.CC1(C)C(C)(C)OB(C2C=CC(NC(NC3C=CC=C(C(F)(F)F)C=3)=O)=CC=2)O1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[O:37]=[C:9]1[C:10]2[C:15](=[CH:14][CH:13]=[C:12]([C:17]3[CH:18]=[CH:19][C:20]([NH:23][C:24]([NH:26][C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:34])([F:36])[F:35])[CH:28]=4)=[O:25])=[CH:21][CH:22]=3)[CH:11]=2)[CH2:16][N:8]1[C@@H:4]([C:5]1[CH:7]=[CH:48][CH:40]=[CH:41][CH:6]=1)[C:3]([O:2][CH3:1])=[O:38]
Reactant: COC(=O)[C@@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)Nc4cccc(C(F)(F)F)c4)cc3)cc2C1=O
Reactant: COC(=O)[C@H](c1ccccc1)N1Cc2ccc(Br)cc2C1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC1(C)OB(c2ccc(NC(=O)Nc3cccc(C(F)(F)F)c3)cc2)OC1(C)C
Solvent: ClCCl
Product: COC(=O)[C@H](c1ccccc1)N1Cc2ccc(-c3ccc(NC(=O)Nc4cccc(C(F)(F)F)c4)cc3)cc2C1=O

Procedure:
The compound of example 345 was prepared analogous to compound of example 330 by reaction of the compound of example 344, compound of example 327 and Pd(dppf)Cl2: CH2Cl2.