Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][O:8][C:9]1[C:20]([O:21][CH3:22])=[CH:19][C:12]2[CH2:13][C:14](=O)[NH:15][CH:16]=[CH:17][C:11]=2[CH:10]=1.[Cl-].[NH4+]>O1CCOCC1>[CH3:22][O:21][C:20]1[C:9]([O:8][CH3:7])=[CH:10][C:11]2[CH2:17][CH2:16][NH:15][CH:14]=[CH:13][C:12]=2[CH:19]=1
Reactant: COc1cc2c(cc1OC)CC(=O)NC=C2
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: C1COCCO1
Product: COc1cc2c(cc1OC)CCNC=C2
Temperature: 0 °C

Procedure:
A boiling suspension of 0.8 gm of lithium aluminium hydride in 100 ml of absolute dioxane was mixed with 2.2 gm (0.01 mol) of 7,8-dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one, and the mixture was refluxed for 3 hours. Ammonium chloride solution (10%) was added while cooling with ice water, and the precipitate formed thereby was suction-filtered off. The filtrate was evaporated in vacuo to a volume of about 20 ml, and the resulting white precipitate was suction-filtered off and washed with a little dioxane.
Reaction SMILES: Br[C:2]1[CH:20]=[CH:19][C:5]2[N:6]=[C:7]([C@H:9]3[CH2:12][C@H:11]([N:13]4[CH2:17]C[CH2:15][C@H:14]4[CH3:18])[CH2:10]3)[S:8][C:4]=2[CH:3]=1.[CH3:21][C:22]1[CH:23]=[CH:24][C:25](=[O:28])[NH:26][N:27]=1.N1NC(=O)C=CC=1>>[CH:14]([N:13]([CH3:17])[C@H:11]1[CH2:12][C@H:9]([C:7]2[S:8][C:4]3[CH:3]=[C:2]([N:26]4[C:25](=[O:28])[CH:24]=[CH:23][C:22]([CH3:21])=[N:27]4)[CH:20]=[CH:19][C:5]=3[N:6]=2)[CH2:10]1)([CH3:18])[CH3:15]
Reactant: C[C@@H]1CCCN1[C@H]1C[C@H](c2nc3ccc(Br)cc3s2)C1
Reactant: Cc1ccc(=O)[nH]n1
Agent: O=c1cccn[nH]1
Product: Cc1ccc(=O)n(-c2ccc3nc([C@H]4C[C@H](N(C)C(C)C)C4)sc3c2)n1

Procedure:
The title compound was prepared according to the procedure described in Example 22, except for substituting the product of Example 52A for the product of Example 1E and substituting 6-methyl-3(2H)-pyridazinone for 3(2H)-pyridazinone. 1H NMR (400 MHz, CDCl3) δ ppm 8.12 (d, J=1.84 Hz, 1H) 8.01 (d, J=8.90 Hz, 1H) 7.67 (dd, J=8.59, 2.15 Hz, 1H) 7.16 (d, J=9.51 Hz, 1H) 7.00 (d, J=9.51 Hz, 1H) 3.49-3.66 (m, 1H) 3.12-3.28 (m, 1H) 2.91-3.06 (m, 1H) 2.61-2.75 (m, 2H) 2.40 (s, 3H) 2.29-2.40 (m, 2H) 2.14 (s, 3H) 1.03 (d, J=6.75 Hz, 6H). MS: (M+H)+=369.
Reaction SMILES: CC([O-])(C)C.[Na+].[C:7]1([CH3:13])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.ClC1C=CC(C)=CC=1.[CH2:22]([NH2:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CCOCC.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:22]([NH:29][C:10]1[CH:11]=[CH:12][C:7]([CH3:13])=[CH:8][CH:9]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: Cc1ccccc1
Reactant: NCc1ccccc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccc(Cl)cc1
Solvent: CCOCC
Product: Cc1ccc(NCc2ccccc2)cc1
Temperature: 100 °C
Yield: 89 %

Procedure:
An oven dried resealable Schlenk tube was purged with argon and charged with Pd2(dba)3 (4.6 mg, 0.005 mmol, 1.0 mol % Pd), 27 (7.4 mg, 0.015 mmol, 1.5 mol %), and NaOtBu (135 mg, 1.4 mmol). The tube was purged with argon and toluene (2 mL), 4-chlorotoluene (0.12 mL, 1.0 mmol), and benzylamine (0.165 mL, 1.5 mmol) were added through a rubber septum. The septum was replaced with a teflon screw cap, the tube was sealed, and the mixture was heated to 100° C. with stirring until the starting aryl chloride had been completely consumed as judged by GC analysis. A small amount of diarylated benzylamine was detected in the crude reaction mixture (GC ratio of product/diarylated benzylamine=16/1). The reaction mixture was cooled to room temperature, diluted with ether (20 mL), and extracted with 1 M HCl (5×40 mL). The organic phase was discarded and the combined aqueous extracts were basisified to pH 14 with 6M NaOH and extracted with ether (4×50 mL). The combined organic extracts were dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to give give 175 mg (89%) of a pale yellow oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([O:10][CH3:11])[N:3]=1.[CH:12]1[CH:17]=[C:16]([CH:18]=[O:19])[C:15]([OH:20])=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+].CS(C)=O>O>[CH3:11][O:10][C:4]1[CH:5]=[C:6]([O:8][CH3:9])[N:7]=[C:2]([O:20][C:15]2[CH:14]=[CH:13][CH:12]=[CH:17][C:16]=2[CH:18]=[O:19])[N:3]=1
Reactant: O=Cc1ccccc1O
Reactant: COc1cc(OC)nc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: COc1cc(OC)nc(Oc2ccccc2C=O)n1
Temperature: 120 °C
Reaction time: 3 h
Yield: 99.9 %

Procedure:
A 500-ml four-necked flask was charged with a mixture of 105 g (0.6 mole) of 2-chloro-4,6-dimethoxypyrimidine, 79.4 g (0.65 mole) of salicylic aldehyde, 48.3 g (0.35 mole) of potassium carbonate and 450 ml of dimethylsulfoxide. The mixture was gradually heated, and stirred at 120° C. for 3 hours. After the reaction mixture was cooled, it was poured into 2 l of water. Through the procedures of benzene extraction, washing with water, drying over anhydrous sodium sulfate and concentration, 156 g of the target product were obtained as a crude oil. It was purified further by silica gel chromatography to obtain 117.1 g of white crystals (yield: 75.0%). Melting point: 76.0° about 76.5° C.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][C:14]1[S:18][C:17]([C:19]([OH:21])=[O:20])=[CH:16][CH:15]=1.Br[CH2:23][CH2:24][CH:25]1[O:29][CH2:28][CH2:27][O:26]1>O1CCCC1.CCCCCC.C(#N)C>[O:26]1[CH2:27][CH2:28][O:29][CH:25]1[CH2:24][CH2:23][CH2:13][C:14]1[S:18][C:17]([C:19]([OH:21])=[O:20])=[CH:16][CH:15]=1
Reactant: Cc1ccc(C(=O)O)s1
Reactant: BrCCC1OCCO1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=C(O)c1ccc(CCCC2OCCO2)s1
Reaction time: 0.25 h
Yield: 88.5 %

Procedure:
To a solution of 64.8 g (640 mmol, 83.9 mL) of diisopropyl amine in 400 mL of tetrahydrofuran which had been cooled to −15° C. was added 400 mL (640 mmol) of 1.6M n-butyllithium in hexane dropwise over 25 minutes, maintaining the reaction temperature below −5° C. After a 15 minute stir time, a solution of 5-methyl-2-thiophenecarboxylic acid (41.4 g, 291 mmol) in 150 mL of tetrahydrofuran was added dropwise over 30 minutes, once again keeping the temperature below −5° C. The resultant dark green dianion solution was stirred at −15° C. to −10° C. for 90 minutes. To this solution was added 2-(2-bromoethyl)-1,3-dioxolane (57.9 g, 320 mmol) dropwise over 15 minutes and the magenta-colored mixture was stirred for 3 hours at −10° C. to −5° C. HPLC analysis (30% acetonitrile/70% 1% aqueous acetic acid solution, 2 mL/min, 30 cm C-18 column, λ=280 nm) at this time showed 9.0% 5-methyl-2-thiophenecarboxylic acid and 88.5% title compound. The reaction was quenched with 600 mL of water and acidified to pH 3 with 6N aqueous hydrochloric acid. The yellow mixture was extracted three times with 500 mL of t-butylmethyl ether and the combined organic extracts were dried over magnesium sulfate, filtered, and concentrated. The crude product was triturated with 300 mL of heptane and the solid was filtered, washed with heptane, and pulled dry on the filter to provide 58.21 g (82.5%) of the title compound which contained less than 3% starting material by 1H NMR. 1H NMR (300 MHz, CDCl3) δ 1.81 (m, 4H), 2.91 (t, J=7.4 Hz, 2H), 3.92 (m, 4H), 4.90 (t, J=4.4 Hz, 1H), 6.84 (d, J=3.7 Hz, 1H), 7.72 (d, J=3.7 Hz, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[C:12]([OH:14])=[O:13].[CH3:15][Si:16]([CH3:21])([CH3:20])[CH2:17][CH2:18]O.C1(N=C=NC2CCCCC2)CCCCC1>ClCCl.C1COCC1.CN(C)C1C=CN=CC=1>[CH3:15][Si:16]([CH3:21])([CH3:20])[CH2:17][CH2:18][O:13][C:12]([C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:10]=[CH:11][C:2]=1[OH:1])=[O:14]
Reactant: C[Si](C)(C)CCO
Reactant: O=C(O)c1c(O)ccc2ccccc12
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOC(=O)c1c(O)ccc2ccccc12
Temperature: 0 °C
Reaction time: 3 h
Yield: 94.6 %

Procedure:
To a solution of 2-hydroxynaphtoic acid (2.02 g, 10.7 mmol) in dichloromethane (45 mL) and THF (2 mL) were added 2-trimethylsilylethanol (4.6 mL, 32.2 mmol) and 4-dimethylaminopyridine (1.07 g, 8.9 mmol) under N2. The mixture was cooled to 0° C. and 1,3-dicyclohexylcarbodiimide (2.33 g, 11.3 mmol) was added. After removal of the ice bath, the mixture was stirred for 3 h at room temperature. 2N HCl was added to adjust the pH to 2, and the mixture was filtered to remove urea. After the separation of layers the organic phase was washed with water and brine, dried (Na2SO4), and concentrated to dryness. Purification by chromatography gave 2.92 g of 2-hydroxy-naphthalene-1-carboxylic acid 2-trimethylsilanyl-ethyl ester.
Reaction SMILES: [CH:1]1[C:6]2[CH2:7][CH2:8][CH2:9][CH2:10]/[C:11](=[CH:12]\[CH:13]=[CH:14]\[CH:15]=[O:16])/[C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:17]([O:23][CH3:24])(=[O:22])[CH2:18][C:19]([CH3:21])=[O:20]>>[CH:1]1[C:6]2[CH2:7][CH2:8][CH2:9][CH2:10]/[C:11](=[CH:12]\[CH:13]=[CH:14]\[CH:15]([OH:16])[CH2:21][C:19](=[O:20])[CH2:18][C:17]([O:23][CH3:24])=[O:22])/[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)CC(C)=O
Reactant: O=C/C=C/C=C1\CCCCc2ccccc21
Product: COC(=O)CC(=O)CC(O)/C=C/C=C1\CCCCc2ccccc21

Procedure:
By the method of Example 1 (E,E)-4-(8,9-Dihydro-6H,7H-benzocyclohepten-5-ylidene)-2-butenal (0.9 g, 4.2 mmol) was reacted with methyl acetoacetate to produce title product, 0.9 g.
Reaction SMILES: [C:1]([OH:12])(=O)/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH:13]1([NH2:19])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1>>[CH:13]1([NH:19][C:1](=[O:12])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: CCCCCCC/C=C/C(=O)O
Reactant: NC1CCCCC1
Product: CCCCCCC/C=C/C(=O)NC1CCCCC1

Procedure:
The same operation as in Example 1-1 or 1-2 was carried out using trans-2-decenoic acid and cyclohexylamine as starting materials to give the aimed compound.
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:11]2[CH:12]=[N:13][CH:14]=[C:15]([CH:19]=2)[C:16]([OH:18])=[O:17])[NH:3]1.[CH2:20]([N:22]([CH2:37][CH3:38])[CH2:23][CH2:24][NH:25][C:26]([C:28]1[C:32]([CH3:33])=[C:31]([CH:34]=O)[NH:30][C:29]=1[CH3:36])=[O:27])[CH3:21].N1CCCCC1>C(O)C>[CH2:37]([N:22]([CH2:20][CH3:21])[CH2:23][CH2:24][NH:25][C:26]([C:28]1[C:32]([CH3:33])=[C:31]([CH:34]=[C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][C:8]=3[C:11]3[CH:12]=[N:13][CH:14]=[C:15]([CH:19]=3)[C:16]([OH:18])=[O:17])[NH:3][C:2]2=[O:1])[NH:30][C:29]=1[CH3:36])=[O:27])[CH3:38]
Reactant: O=C1Cc2c(cccc2-c2cncc(C(=O)O)c2)N1
Reactant: CCN(CC)CCNC(=O)c1c(C)[nH]c(C=O)c1C
Solvent: C1CCNCC1
Solvent: CCO
Product: CCN(CC)CCNC(=O)c1c(C)[nH]c(C=C2C(=O)Nc3cccc(-c4cncc(C(=O)O)c4)c32)c1C
Temperature: 60 °C

Procedure:
A mixture of 5-(2-oxo-2,3-dihydro-1H-indol-4-yl)-nicotinic acid (381 mg, 1.5 mmol), 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylaminoethyl)-amide (398 mg, 1.5 mmol) and piperidine (1 mL) in ethanol (5 mL) was heated in a sealed tube at 60° C. for 10 hours. The reaction was concentrated, the residue was dissolved in a mixture of water and methanol and then acidified with 1N HCl. The resulted precipitate was collected by vacuum filtration, washed with methanol and dried to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:11]([CH:12]=O)=[C:10]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)[C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([CH3:21])[N:3]=1.[C:22]([O-])([O-])=O.[Cs+].[Cs+].[Si](C=[N+]=[N-])(C)(C)C>CO>[CH3:21][C:4]1[N:3]=[C:2]2[NH:1][CH:22]=[CH:12][C:11]2=[C:10]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)[C:5]=1[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1c(C)nc(N)c(C=O)c1-c1ccc(C)cc1
Reactant: O=C([O-])[O-]
Agent: C[Si](C)(C)C=[N+]=[N-]
Agent: [Cs+]
Solvent: CO
Product: COC(=O)c1c(C)nc2[nH]ccc2c1-c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89 %

Procedure:
A solution of methyl 6-amino-5-formyl-2-methyl-4-(p-tolyl)nicotinate (2.45 g, 8.62 mmol) and Cs2CO3 (5.62 g, 17.23 mmol) in methanol (70 ml) was treated with TMS-diazomethane (2M in hexane) (17.23 ml, 34.5 mmol) dropwise at 60° C. The mixture was stirred at 60° for 1 hour, cooled to rt, quenched with sat NH4Cl, extracted with EtOAc, washed with water, Brine, dried with Na2SO4, filtered, and concentrated to afford methyl 6-methyl-4-(p-tolyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (2.15 g, 7.67 mmol, 89% yield): 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 9.86 (br. s., 1 H), 7.40 (d, J=8.1 Hz, 2 H), 7.31-7.26 (m, 3 H), 6.43 (dd, J=2.0, 3.5 Hz, 1 H), 3.64 (s, 3 H), 2.71 (s, 3 H), 2.43 (s, 3 H); LCMS (m/z) ES+=281 (M+1).
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[N:6]([C:7](=[O:14])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[C@H:5]([CH:15]=[O:16])[CH2:4][O:3]1.[CH3:18][CH2:19][Mg+].[Br-]>CCOCC>[CH2:18]([CH:15]([C@@H:5]1[CH2:4][O:3][C:2]([CH3:1])([CH3:17])[N:6]1[C:7](=[O:14])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[OH:16])[CH3:19]
Reactant: CC[Mg+]
Reactant: CCCCCCC(=O)N1[C@H](C=O)COC1(C)C
Agent: [Br-]
Solvent: CCOCC
Product: CCCCCCC(=O)N1[C@H](C(O)CC)COC1(C)C
Reaction time: 1.5 h

Procedure:
A solution of 9a (108 mg, 0.44 mmol) in ether (1 mL) is added dropwise to a cold (5°) solution of EtMgBr (3M in ether, 0.36 mL). The cold bath is removed, a crystal of iodine is added to the mixture and stirring is continued for 1.5 h at room temperature. The resulting mixture is diluted with EtOAc and washed with saturated aqueous NH4Cl solution. The aqueous phase is reextracted and the combined organic solution dried and evaporated to yield crude 10a: NMR δ 0.88 (m, 3 H), 1.05 (m, 3 H), 1.30 (m, 6 H), 1.45 (m, 2 H), 1.57 (s, 3 H), 1.50-1.75 (m, 5 H), 2.10-2.60 (m, 2 H), 3.50-4.50 (m, 4 H); MS (EI) m/z 271 (M).
Reaction SMILES: [CH2:1]([O:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]2[C:22]([CH3:23])=[CH:21][CH:20]=[C:19]2[C:24]2[CH:43]=[CH:42][C:27]([O:28][C@H:29]([CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[C:30]([O:32]CC)=[O:31])=[CH:26][CH:25]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[OH-].[K+].Cl>C1COCC1.CO>[CH2:1]([O:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]2[C:22]([CH3:23])=[CH:21][CH:20]=[C:19]2[C:24]2[CH:25]=[CH:26][C:27]([O:28][C@H:29]([CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[C:30]([OH:32])=[O:31])=[CH:42][CH:43]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCCCOc1ccc(-n2c(C)ccc2-c2ccc(O[C@H](Cc3ccccc3)C(=O)OCC)cc2)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCCCCCCCCCOc1ccc(-n2c(C)ccc2-c2ccc(O[C@H](Cc3ccccc3)C(=O)O)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92 %

Procedure:
To a mixed solution of ethyl (2R)-2-{4-[1-(4-decyloxyphenyl)-5-methyl-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoate (870 mg, 1.49 mmol) in THF (30 ml) and methanol (15 ml) was added 1N aqueous potassium hydroxide solution(8 ml, 8 mmol) and the mixture was stirred for 1 hour at room temperature. The reaction solution was neutralized with 1N hydrochloric acid and extracted with ethyl acetate. The extract was washed with water and dried over magnesium sulfate anhydride, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to give the object compound as an oily substance. 760 mg (yield: 92.0%)
Reaction SMILES: C([CH2:8][NH:9][CH2:10][C@@H:11]([OH:18])[CH2:12][N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)C1C=CC=CC=1>CO.[C+4].[OH-].[Pd+2].[OH-].[OH-].[OH-].[OH-].[OH-]>[CH3:8][NH:9][CH2:10][C@H:11]([OH:18])[CH2:12][N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: O[C@H](CNCCc1ccccc1)CN1CCCC1
Agent: [Pd+2]
Agent: [C+4]
Agent: [OH-]
Solvent: CO
Product: CNC[C@H](O)CN1CCCC1
Reaction time: 4.5 h
Yield: 86.7 %

Procedure:
(2R)-1-(Benzylmethylamino)-3-(pyrrolidin-1-yl)-2-propanol (420 mg) was dissolved in methanol (10 ml). 10% Palladium hydroxide carbon (460 mg) was added thereto, followed by stirring under hydrogen atmosphere for 4.5 hours. The reaction mixture was filtered to remove the catalyst, and the catalyst was washed with methanol. The filtrate and the washings were combined and concentrated under reduced pressure to give a residue, which was dried under reduced pressure to provide the titled compound (232 mg, 87%) as a colorless oil.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][C:3]=1[C:15]1[CH:20]=[C:19]([CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:18]=[CH:17][C:16]=1[OH:28].[CH:29]1(Br)[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1.C(=O)([O-])[O-].[K+].[K+]>[Cu].CN(C=O)C>[CH:29]1([O:1][C:2]2[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][C:3]=2[C:15]2[CH:20]=[C:19]([CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:18]=[CH:17][C:16]=2[OH:28])[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: CCOC(=O)CCc1ccc(O)c(-c2cc(CCC(=O)OCC)ccc2O)c1
Reactant: BrC1CCCCC1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCc1ccc(O)c(-c2cc(CCC(=O)OCC)ccc2OC2CCCCC2)c1
Yield: 11.7 %

Procedure:
To 5 ml of a DMF solution containing 200 mg (0.5181 mmol) of 2,2'-dihydroxy-5,5'-bis (2-ethoxycarbonylethyl) biphenyl and 644.5 μl (5.181 mmol) of cyclohexyl bromide, there were added 85.8 mg (0.6217 mmol) of anhydrous potassium carbonate and a small amount of copper powder and the resulting mixture was agitated for 41 hours at room temperature, for a further 5 hours at 70° C. and for 8 hours at 100° C. The reaction mixture was filtered by suction through Celite to remove the solid matter and the filtrate was washed with ethyl acetate. After the solvent in the filtrate was evaporated off under reduced pressure, the evaporated residue was dissolved in chloroform. This solution was washed with dilute hydrochloric acid, dilute aqueous sodium bicarbonate, water and aqueous sodium chloride solution in this sequence and was dried by adding anhydrous sodium sulfate. The residue obtained after the solvent had been evaporated off was purified by silica gel column chromatography (with 20 g of WAKO-gel C-200, eluent: toluene and toluene/ethyl acetate of 1000/1 and 500/1) and further purified by silica-gel column chromatography (with 15 g of WAKO-gel C-200, eluent: hexane and hexane/ethyl acetate 50/1, 30/1, 15/1 and 12/1) to obtain 28.3 mg (0.0605 mmol, 12%) of 2-cyclohexyloxy-2'-hydroxy-5,5'-bis (2-ethoxycarbonylethyl) biphenyl as an oily product.
Reaction SMILES: [OH-].[Li+].[F:3][C:4]1[CH:5]=[C:6]([C:10]2[CH:18]=[C:17]3[C:13]([CH2:14][CH2:15][CH:16]3[N:19]([C:23]3[CH:24]=[C:25]([CH:32]=[CH:33][CH:34]=3)[O:26][CH2:27][C:28]([O:30]C)=[O:29])[C:20](=[O:22])[CH3:21])=[CH:12][CH:11]=2)[CH:7]=[CH:8][CH:9]=1>C1COCC1>[F:3][C:4]1[CH:5]=[C:6]([C:10]2[CH:18]=[C:17]3[C:13]([CH2:14][CH2:15][CH:16]3[N:19]([C:23]3[CH:24]=[C:25]([CH:32]=[CH:33][CH:34]=3)[O:26][CH2:27][C:28]([OH:30])=[O:29])[C:20](=[O:22])[CH3:21])=[CH:12][CH:11]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: COC(=O)COc1cccc(N(C(C)=O)C2CCc3ccc(-c4cccc(F)c4)cc32)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(=O)N(c1cccc(OCC(=O)O)c1)C1CCc2ccc(-c3cccc(F)c3)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.6 %

Procedure:
Aqueous lithium hydroxide (1 N, 1 mL, 1 mmol) was added to a solution of methyl 2-(3-(N-(6-(3-fluorophenyl)-2,3-dihydro-1H-inden-1-yl)acetamido)phenoxy)acetate (7 mg, 0.016 mmol) in THF (1 mL) in a scintillation vial. The vial was sealed and stirred overnight at room temperature. After 24 h, the reaction mixture was allowed to cool and the volatiles were concentrated. The residue was acidified with hydrochloric acid (1 N, 1 mL) and extracted with ethyl acetate (3×2 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated to afford 4 mg (59%) of the title compound.
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]=[C:5]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.Cl.[F:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]([CH:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)=[O:30])=[CH:25][CH:24]=1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[K+]>O.CC(C)CC(=O)C>[F:22][C:23]1[CH:24]=[CH:25][C:26]([C:29]([CH:31]2[CH2:36][CH2:35][N:34]([CH2:2][CH2:3][N:4]3[C:13](=[O:14])[C:12]4[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=4)[N:6]=[C:5]3[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:33][CH2:32]2)=[O:30])=[CH:27][CH:28]=1
Reactant: O=c1c2ccccc2nc(-c2ccccc2)n1CCCl
Reactant: O=C(c1ccc(F)cc1)C1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: O
Solvent: CC(=O)CC(C)C
Product: O=C(c1ccc(F)cc1)C1CCN(CCn2c(-c3ccccc3)nc3ccccc3c2=O)CC1
Yield: 69 %

Procedure:
A mixture of 5.5 parts of 3-(2-chloroethyl)-2-phenyl-4(3H)-quinazolinone, 4 parts of (4-fluorophenyl)(4-piperidinyl)methanone hydrochloride, 7 parts of sodium carbonate, 0.1 parts of potassium iodide and 200 parts of 4-methyl-2-pentanone is stirred and refluxed for 24 hours using a water-separator. The reaction mixture is filtered while hot. The filtrate is evaporated. The residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (95×5 by volume) as eluent. The pure fractions are collected and the eluent is evaporated. The residue is crystallized from a mixture of ethanol and 1,1'-oxybisethane. The product is filtered off and dried, yielding 5 parts (69%) of 3-[2-[4-(4-fluorobenzoyl)-1-piperidinyl]ethyl]-2-phenyl-4(3H)-quinazolinone; mp. 143.8° C.
Reaction SMILES: [Cl-].C[SiH](C)C.[Cl:6][C:7]1[C:14]([F:15])=[CH:13][CH:12]=[C:11]([F:16])[C:8]=1[CH2:9]Br.[Cl:17][C:18]1[CH:23]=[C:22](Cl)[N:21]=[CH:20][N:19]=1.O>O1CCCC1.BrC(Br)C.[Zn]>[Cl:17][C:18]1[CH:23]=[C:22]([CH2:9][C:8]2[C:11]([F:16])=[CH:12][CH:13]=[C:14]([F:15])[C:7]=2[Cl:6])[N:21]=[CH:20][N:19]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: Fc1ccc(F)c(CBr)c1Cl
Agent: CC(Br)Br
Agent: C[SiH](C)C
Agent: [Cl-]
Solvent: O
Solvent: C1CCOC1
Product: Fc1ccc(F)c(Cc2cc(Cl)ncn2)c1Cl
Reaction time: 0.33 h
Yield: 23.4 %

Procedure:
In 10 ml of tetrahydrofuran was suspended 1.3 g of zinc (powder), to which dibromoethane (2 drops) was added. The mixture was heated under reflux for 5 minutes, to which trimethylsilane chloride was added. The mixture was further heated under reflux for 5 minutes, to which a solution of 2.4 g of 2-chloro-3,6-difluorobenzyl bromide dissolved in 20 ml of tetrahydrofuran was slowly added with heating under reflux, followed by stirring for 20 minutes. (The solution thus obtained is referred to as solution P). In 10 ml of tetrahydrofuran were suspended 1.5 g of 4,6-dichloropyrimidine and 0.1 g of dichlorobistriphenylphosphine palladium, to which the above solution P was added, followed by heating under reflux for 3 hours and further stirring at room temperature for 12 hours. The reaction mixture was then poured into water and extracted three times with ethyl acetate. The organic layers were combined, washed with water, dried over anhydrous magnesium sulfate, and then concentrated. The residue was subjected to silica gel column chromatography to give 0.64 g of 4-chloro-6-(2-chloro-3,6-difluorobenzyl)pyrimidine.