Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][N:9]=[C:10]([CH2:16][CH3:17])[CH2:11][C:12]([O:14][CH3:15])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Se](=O)=[O:19].O>ClC1C=CC=CC=1>[CH2:1]([O:8][N:9]=[C:10]([CH2:16][CH3:17])[C:11](=[O:19])[C:12]([O:14][CH3:15])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCC(CC(=O)OC)=NOCc1ccccc1
Reactant: O=[Se]=O
Solvent: Clc1ccccc1
Solvent: O
Product: CCC(=NOCc1ccccc1)C(=O)C(=O)OC
Temperature: 120 °C
Reaction time: 8 h
Yield: 62.5 %

Procedure:
To a solution of 47.06 g (0.2 mol) of methyl 3-benzyloxyiminovalerate in 150 ml of chlorbenzene, 24.41 g (0.22 mol) of selenium dioxide was added and the mixture was stirred for 8 hours at 120° C. After adding 200 ml of water and filtering through Celite, the filtrate was extracted three times with 200 ml of diethylether. After washing with water and a saturated aqueous sodium chloride followed by drying over with anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to obtain a residue, which was purified by a column chromatography on a silica gel (n-hexane/ethyl acetate) to obtain 31.15 g (yield 62%) of methyl 3-benzyloxyimino-2-oxovalerate as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:12]Br)=[C:6]([CH:11]=1)[C:7]([O:9]C)=O.Cl.[NH2:15][C@@H:16]1[CH2:21][CH2:20][CH2:19][CH2:18][C@H:17]1[OH:22].C(N(C(C)C)C(C)C)C.C(=O)(O)[O-].[Na+]>CN(C=O)C>[Br:1][C:2]1[CH:11]=[C:6]2[C:5]([CH2:12][N:15]([C@@H:16]3[CH2:21][CH2:20][CH2:19][CH2:18][C@H:17]3[OH:22])[C:7]2=[O:9])=[CH:4][CH:3]=1
Reactant: COC(=O)c1cc(Br)ccc1CBr
Reactant: N[C@@H]1CCCC[C@H]1O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C1c2cc(Br)ccc2CN1[C@@H]1CCCC[C@H]1O
Temperature: 80 °C
Reaction time: 3 h
Yield: 43.7 %

Procedure:
To a solution of methyl 5-bromo-2-(bromomethyl)benzoate (0.50 g) in DMF (5.00 mL) were added trans-2-aminocyclohexanol hydrochloride (0.37 g) and N-ethyldiisopropylamine (1.42 mL), and the mixture was stirred at 80° C. for 3 hr. To the reaction mixture was added 5% aqueous sodium bicarbonate, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (0.22 g).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([CH:8]=[O:9])[CH2:4][CH2:3]1.[H-].[Na+].C1OCCOCCOCCOCCOC1.Cl[CH:28]([F:30])[F:29]>O1CCCC1>[F:29][CH:28]([F:30])[O:1][CH:2]1[CH2:7][CH2:6][N:5]([CH:8]=[O:9])[CH2:4][CH2:3]1
Reactant: FC(F)Cl
Reactant: O=CN1CCC(O)CC1
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=CN1CCC(OC(F)F)CC1
Reaction time: 0.5 h
Yield: 18 %

Procedure:
4-hydroxypiperidine-1-carbaldehyde (10.8 g, 83.62 mmol) was dissolved in tetrahydrofuran (150 mL). To this was added sodium hydride (5.22 g, 108.70 mmol) and the reaction was stirred for 30 minutes. 15-crown-5 (9.21 g, 41.81 mmol) was added and the reaction was stirred for a further 30 minutes before the slow addition of chlorodifluoromethane (8.68 g, 100.34 mmol), after the addition the reaction was stirred for 30 minutes. The reaction mixture was quenched with saturated brine (75 mL), extracted with diethyl ether (3×100 mL), the organic layer was dried over MgSO4, filtered and evaporated to afford a yellow liquid. The crude product was purified by distillation at 0.8 mBar, collecting fractions that distilled at 80° C. to afford the desired material as a colourless liquid (2.70 g, 18.02%); 1H NMR (400.132 MHz, CDCl3) δ 1.93-1.70 (4H, m), 3.32-3.26 (1H, m), 3.60-3.47 (2H, m), 3.74-3.67 (1H, m), 4.50 (1H, septet), 6.28 (1H, t), 8.03 (1H, s).
Reaction SMILES: [CH3:1][O:2][N:3]=[CH:4][CH2:5][NH:6][C:7]([C:9]1[CH:31]=[CH:30][CH:29]=[CH:28][C:10]=1[C:11]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:26])([F:25])[C:21]([F:24])([F:23])[F:22])=[CH:16][C:15]=1[CH3:27])=[O:12])=[O:8].BrN1C(=O)CCC1=O.[I:40]N1C(=O)CCC1=O>>[I:40][C:31]1[C:9]([C:7]([NH:6][CH2:5][CH:4]=[N:3][O:2][CH3:1])=[O:8])=[C:10]([CH:28]=[CH:29][CH:30]=1)[C:11]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:25])([F:26])[C:21]([F:24])([F:23])[F:22])=[CH:16][C:15]=1[CH3:27])=[O:12]
Reactant: CON=CCNC(=O)c1ccccc1C(=O)Nc1ccc(C(F)(F)C(F)(F)F)cc1C
Reactant: O=C1CCC(=O)N1I
Agent: O=C1CCC(=O)N1Br
Product: CON=CCNC(=O)c1c(I)cccc1C(=O)Nc1ccc(C(F)(F)C(F)(F)F)cc1C
Yield: 53 %

Procedure:
2-(2-(N-methoxyimino)ethylaminocarbonyl)-2′-methyl-4′-pentafluoroethylbenzanilide was treated in the same manner as in Example 36, except that the N-bromosuccinimide was replaced with N-iodosuccinimide, to obtain 3-iodo-2-(2-(N-methoxyimino)ethylaminocarbonyl)-2′-methyl-4′-pentafluoroethylbenzanilide (yield 53%, melting point 110° C.). Regioselectivity of iodination into the 3-position was 100%.
Reaction SMILES: [C:1]([O:5][CH:6]([C:11]1[N:16]([CH3:17])[C:15](=[O:18])[C:14]2[NH:19][CH:20]=[CH:21][C:13]=2[C:12]=1[C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=1)[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].[F:29][C:30]1[CH:37]=[CH:36][C:35]([F:38])=[CH:34][C:31]=1[CH2:32]Br>>[C:1]([O:5][CH:6]([C:11]1[N:16]([CH3:17])[C:15](=[O:18])[C:14]2[N:19]([CH2:32][C:31]3[CH:34]=[C:35]([F:38])[CH:36]=[CH:37][C:30]=3[F:29])[CH:20]=[CH:21][C:13]=2[C:12]=1[C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=1)[C:7]([OH:9])=[O:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)C(OC(C)(C)C)c1c(-c2ccc(Cl)cc2)c2cc[nH]c2c(=O)n1C
Reactant: Fc1ccc(F)c(CBr)c1
Product: Cn1c(C(OC(C)(C)C)C(=O)O)c(-c2ccc(Cl)cc2)c2ccn(Cc3cc(F)ccc3F)c2c1=O

Procedure:
The title compound was prepared in a manner similar to that described in Example 2 from methyl 2-(tert-butoxy)-2-(4-(4-chlorophenyl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)acetate and 2,5-difluorobenzyl bromide. 1H NMR (400 MHz, CHLOROFORM-d) ppm 7.65-7.60 (m, 1H), 7.50-7.45 (m, 2H), 7.44-7.38 (m, 1H), 7.13-7.10 (m, 1H), 7.07-6.99 (m, 2H), 6.97-6.89 (m, 1H), 6.03-5.99 (m, 1H), 5.93-5.82 (m, 2H), 5.35-5.32 (m, 1H), 3.66 (s, 3H), 1.02 (s, 9H); LCMS (m/z) ES+=515 (M+1).
Reaction SMILES: C[O:2][C:3](=[O:34])[C@@H:4]([O:31][CH2:32][CH3:33])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]2[N:15]=[C:16]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH:27]([CH3:29])[CH3:28])=[CH:22][CH:21]=3)[O:17][C:18]=2[CH3:19])=[CH:8][C:7]=1[CH3:30].[Li+].[OH-]>>[CH2:32]([O:31][C@@H:4]([CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]2[N:15]=[C:16]([C:20]3[CH:21]=[CH:22][C:23]([O:26][CH:27]([CH3:29])[CH3:28])=[CH:24][CH:25]=3)[O:17][C:18]=2[CH3:19])=[CH:8][C:7]=1[CH3:30])[C:3]([OH:34])=[O:2])[CH3:33]
Reactant: CCO[C@@H](Cc1ccc(OCc2nc(-c3ccc(OC(C)C)cc3)oc2C)cc1C)C(=O)OC
Agent: [Li+]
Agent: [OH-]
Product: CCO[C@@H](Cc1ccc(OCc2nc(-c3ccc(OC(C)C)cc3)oc2C)cc1C)C(=O)O

Procedure:
In analogy to the procedure described in example 1 g], (S)-2-ethoxy-3-{4-[2-(4-isopropoxy-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2-methyl-phenyl}-propionic acid methyl ester was treated with LiOH to obtain (S)-2-ethoxy-3-{4-[2-(4-isopropoxy-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2-methyl-phenyl}-propionic acid as colorless solid.
Reaction SMILES: [C:1]1([CH3:33])[CH:6]=[CH:5][C:4]([N:7]([CH:15]2[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][C:23]3([CH2:29][C:30](O)=[O:31])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)[CH2:17][CH2:16]2)[C:8]([C:10]2[O:11][CH:12]=[CH:13][CH:14]=2)=[O:9])=[CH:3][CH:2]=1.C(Cl)(=O)C(Cl)=O.C(N(CC)CC)C.[NH2:47][C:48]1[CH:53]=[N:52][CH:51]=[CH:50][N:49]=1>ClCCl.CN(C)C=O>[N:49]1[CH:50]=[CH:51][N:52]=[CH:53][C:48]=1[NH:47][C:30]([CH2:29][C:23]1([CH2:22][CH2:21][N:18]2[CH2:19][CH2:20][CH:15]([N:7]([C:4]3[CH:5]=[CH:6][C:1]([CH3:33])=[CH:2][CH:3]=3)[C:8]([C:10]3[O:11][CH:12]=[CH:13][CH:14]=3)=[O:9])[CH2:16][CH2:17]2)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]1)=[O:31]
Reactant: Nc1cnccn1
Reactant: Cc1ccc(N(C(=O)c2ccco2)C2CCN(CCC3(CC(=O)O)CCCCC3)CC2)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(N(C(=O)c2ccco2)C2CCN(CCC3(CC(=O)Nc4cnccn4)CCCCC3)CC2)cc1
Reaction time: 1.5 h
Yield: 49.3 %

Procedure:
To a solution of [1-[2-[4-[N-(p-tolyl)-2-furancarboxamido]piperidin-1-yl]ethyl]cyclohexyl]acetic acid (synthesized in Example 3B-1) (201 mg) dissolved in dichloromethane (6 mL) was added N,N-dimethylformamide (2 drops). Oxalyl chloride (0.060 mL) was then added to the solution dropwise under ice cooling. The solution was stirred for 1.5 hours. After addition of triethylamine (0.12 mL) at that temperature, the solution was stirred for 20 minutes. 2-Aminopyrazine (128 mg) was then added to the solution and it was stirred at that temperature. The temperature was allowed to rise to room temperature and the solution was stirred for 16 hours. NH Silica gel was added to the reaction solution, and it was concentrated under reduced pressure. The resulting residue was purified by chromatography [at the first stage; NH silica gel, hexane-ethyl acetate (2:1) and at the second stage; silica gel, chloroform-methanol (10:1)] to give the title compound (116 mg).
Reaction SMILES: [CH3:1][N:2]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][CH2:14][CH2:15][CH2:16]Cl)[CH:11]=2)[CH2:6][CH2:5][C:3]1=[O:4].[CH2:18]([CH:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(=O)([O-])O.[Na+].CC(C)=O.[C:40]([OH:45])(=[O:44])[C:41]([OH:43])=[O:42]>CC(C)=O.CN(C)C=O.C(N(CC)CC)C>[C:40]([OH:45])(=[O:44])[C:41]([OH:43])=[O:42].[CH3:1][N:2]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][CH2:14][CH2:15][CH2:16][N:28]3[CH2:29][CH2:30][CH:25]([CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH2:26][CH2:27]3)[CH:11]=2)[CH2:6][CH2:5][C:3]1=[O:4]
Reactant: CN1C(=O)CCc2ccc(OCCCCl)cc21
Reactant: c1ccc(CC2CCNCC2)cc1
Agent: O=C(O)C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: CN1C(=O)CCc2ccc(OCCCN3CCC(Cc4ccccc4)CC3)cc21
Yield: 86 %

Procedure:
4.9 Grams of 1-methyl-7-(3-chloropropoxy)-3,4-dihydrocarbostyril, 4.2 g of 4-benzylpiperidine and 3 g of triethylamine were mixed with 60 ml of dimethylformamide. The mixture was heated at 70°-80° C. for 8 hours. After the reaction was completed, the reaction mixture was concentrated under a reduced pressure to dryness. To the residue thus obtained was added 5%-sodium hydrogencarbonate aqueous solution and extracted with chloroform. The chloroform layer was washed with water and dried, then chloroform was removed by distillation. The residue thus obtained was dissolved in 30 ml of acetone, and under stirring condition a 5%-oxalic acid acetone solution was added thereto to make pH 4.5 then was allowed to stand. Precipitates thus formed were obtained by filtration, washed with acetone, then recrystallized from ethanol-ether to obtain 7.9 g (yield: 86%) of 1-methyl-7-[3-(4-benzyl-1-piperidyl)propoxy]-3,4-dihydrocarbostyril monooxalate as in the form of colorless powder. Melting point: 175°-177° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH:8]=[O:9])[C:5]2[C:10]([I:32])=[N:11][N:12]([C:13]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:4]=2[CH:3]=1.[BH4-].[Na+]>C(Cl)Cl.CO>[Cl:1][C:2]1[N:7]=[C:6]([CH2:8][OH:9])[C:5]2[C:10]([I:32])=[N:11][N:12]([C:13]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:4]=2[CH:3]=1
Reactant: O=Cc1nc(Cl)cc2c1c(I)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: OCc1nc(Cl)cc2c1c(I)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 68.9 %

Procedure:
6-Chloro-3-iodo-1-trityl-1H-pyrazolo[4,3-c]pyridine-4-carbaldehyde (10.26 g, 18.66 mmol) was dissolved in DCM (250 mL) and methanol (125 mL). The reaction mixture was then cooled to 0° C. and sodium borohydride (0.706 g, 18.66 mmol) was added. The reaction mixture was stirred at room temperature for 15 min. The reaction was quenched with water and extracted with DCM. The combined organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo while loading on silica gel. Purification by flash chromatography (2-10% DCM/EtOAc) gave (6-chloro-3-iodo-1-trityl-1H-pyrazolo[4,3-c]pyridin-4-yl)methanol (7.09 g, 12.85 mmol, 69%). MS ESI calc'd. for C26H19ClN3O [M+H]+ 552. found 552.
Reaction SMILES: [H-].[Na+].[CH2:3]([CH:10]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([OH:20])[CH:18]=2)[O:13][CH2:12][CH:11]1[NH:21][C:22](=[O:26])[O:23][CH2:24][CH3:25])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Br[CH2:28][CH2:29][NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34].C(=O)([O-])O.[Na+]>CC(N(C)C)=O>[CH2:24]([O:23][C:22](=[O:26])[NH:21][CH:11]1[CH:10]([CH2:3][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH2:28][CH2:29][NH:30][C:31]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:37])[CH:18]=2)[O:13][CH2:12]1)[CH3:25]
Reactant: CC(C)(C)OC(=O)NCCBr
Reactant: CCOC(=O)NC1COc2ccc(O)cc2C1Cc1ccccc1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CCOC(=O)NC1COc2ccc(OCCNC(=O)OC(C)(C)C)cc2C1Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.3 %

Procedure:
150 mg (3.75 mmol, 60% in mineral oil) of sodium hydride were suspended under nitrogen atmosphere in 2 m dry dimethyl acetamide. 488 mg (1.5 mmol) of ethyl 4-benzyl-6-hydroxychroman-3-ylcarbamate dissolved in 8 ml dry dimethyl acetamide were added dropwise at room temperature and stirred for 1 h. Then 1.0 g (4.47 mmol) of tert-butyl 2-bromoethylcarbamate dissolved in 2 ml acetate amide were added slowly. The reaction mixture was allowed to warm to room temperature and stirred for 84 h. Then additional 50 mg (1.4 mmol) sodium hydride were added and the mixture was stirred for 30 min before additional 350 mg of tert-butyl 2-bromoethylcarbamate were added and the mixture was stirred for additional 72 h. The reaction mixture was poured onto diluted sodium hydrogencarbonate solution and extracted with ether (2×). The combined organic phases were washed with water (2×), dried over MgSO4 and concentrated (1.5 g of crude). The crude material was purified by flash chromatography to give 587 mg (1.25 mmol, 84%) of the desired product.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:6][CH:5]=1.Br[CH2:17][C:18]([OH:20])=[O:19].Cl>O.CN(C=O)C>[C:7]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][C:4]([O:3][CH2:17][C:18]([OH:20])=[O:19])=[CH:9][CH:8]=1
Reactant: Oc1ccc(-c2ccccc2)cc1
Reactant: O=C(O)CBr
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)COc1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65.8 %

Procedure:
Sodium hydride (60% dispersion in oil; 0.8 g) was added portionwise to a DMF (10 ml) solution of 4-hydroxybiphenyl (1.7 g) under ice-cooling. The reaction mixture was stirred at room temperature for 30 minutes, to which was added bromoacetic acid (1.4 g). The reaction mixture was further stirred at room temperature for 18 hours, which was poured into water. 2N hydrochloric acid was added to the mixture to adjust the pH to 4, which was extracted with ethyl acetate. The organic layer was washed with water, then dried and concentrated. The residue was purified by silica gel column chromatography (eluent: ethyl acetate/hexane=1/1), and the crude crystals were recrystallized from IPE to obtain the entitled compound (1.5 g).
Reaction SMILES: S(Cl)([Cl:3])=O.[CH2:5]([O:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:29]=[CH:28][C:27]([C:30](O)=[O:31])=[CH:26][CH:25]=2)=[CH:20][C:19]=1[F:33])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]>N1C=CC=CC=1>[CH2:5]([O:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([Cl:3])=[O:31])=[CH:26][CH:25]=2)=[CH:20][C:19]=1[F:33])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCOc1ccc(-c2ccc(C(=O)O)cc2)cc1F
Reactant: O=S(Cl)Cl
Solvent: c1ccncc1
Product: CCCCCCCCCCCCOc1ccc(-c2ccc(C(=O)Cl)cc2)cc1F

Procedure:
Thionyl chloride (8.5 g) was added to 4.0 g of the 4'-dodecyloxy-3'-fluorobiphenyl-4-carboxylic acid synthesized by the method shown in Example 1, and one drop of pyridine was added. The mixture was refluxed for 6 hours. After the reaction, the reaction mixture was concentrated to obtain 4'-dodecyloxy-3'-fluorobiphenyl-4-carbonyl chloride. To the product was added 2.15 g of 4-hydroxyphenyl (s)-2-ethoxypropionate. Furthermore, 10 ml of dry pyridine was added, and the mixture was stirred at room temperature for 20 hours. After the reaction, the reaction mixture was poured into a large amount of ethyl acetate, and the mixture was washed twice with a dilute aqueous solution of hydrochloric acid, and three times with water. The ethyl acetate layer was dried over anhydrous sodium sulfate, and concentrated to give 6.05 g of crude crystals. The desired product was separated by silica gel chromatography using ethyl acetate/hexane as an eluent. Recrystallization from ethanol gave 4.01 g (yield 67%) of the desired product.
Reaction SMILES: COCCOC[O:7][C:8]1[C:17]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][N:20]=2)=[CH:16][CH:15]=[CH:14][C:9]=1[C:10]([O:12][CH3:13])=[O:11]>CO>[CH3:13][O:12][C:10](=[O:11])[C:9]1[CH:14]=[CH:15][CH:16]=[C:17]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][N:20]=2)[C:8]=1[OH:7]
Reactant: COCCOCOc1c(Nc2ccc(OC)cn2)cccc1C(=O)OC
Solvent: CO
Product: COC(=O)c1cccc(Nc2ccc(OC)cn2)c1O
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 91.2 %

Procedure:
To a solution of methyl 2-[(2-methoxyethoxy)methoxy]-3-(5-methoxypyridin-2-ylamino)benzoate 1.0 g (2.8 mmol) of step 3 in methanol 20 mL was added 6NHCl 2 mL, followed by stirring at 40° C. for 30 min. The reaction mixture was cooled to room temperature, concentrated in a vacuum, diluted with ethylacetate, washed with distilled water, and a saturated NaCl solution. After drying over magnesium sulfate and concentration in a vacuum, purification by column chromatography (developing solvent: ethylacetate/hexane=1/2) afforded 0.70 g of the title compound (yield 90%).
Reaction SMILES: [C:1]12([C:11]3[CH:31]=[CH:30][C:14]([O:15]/[CH:16]=[CH:17]/[C:18]([NH:20][C:21]4[CH:22]=[C:23]([CH:27]=[CH:28][CH:29]=4)[C:24]([OH:26])=[O:25])=[O:19])=[CH:13][CH:12]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH3:32][N:33]([CH3:37])[CH2:34][CH2:35]Cl.Cl.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:32][N:33]([CH3:37])[CH2:34][CH2:35][O:25][C:24](=[O:26])[C:23]1[CH:27]=[CH:28][CH:29]=[C:21]([NH:20][C:18](=[O:19])/[CH:17]=[CH:16]/[O:15][C:14]2[CH:30]=[CH:31][C:11]([C:1]34[CH2:2][CH:3]5[CH2:4][CH:5]([CH2:6][CH:7]([CH2:9]5)[CH2:8]3)[CH2:10]4)=[CH:12][CH:13]=2)[CH:22]=1
Reactant: CN(C)CCCl
Reactant: O=C(/C=C/Oc1ccc(C23CC4CC(CC(C4)C2)C3)cc1)Nc1cccc(C(=O)O)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(C)CCOC(=O)c1cccc(NC(=O)/C=C/Oc2ccc(C34CC5CC(CC(C5)C3)C4)cc2)c1
Temperature: 60 °C
Reaction time: 12 h
Yield: 10.6 %

Procedure:
(E)-3-(3-(4-Adamantan-1-yl-phenoxy)acrylamido)benzoic acid (60 mg, 0.144 mmol) and 2-(dimethylamino)ethylchloride.HCl (31.1 mg, 0.216 mmol) were dissolved in DMF (3 ml), to which K2CO3 (39.8 mg, 0.288 mmol) was added, followed by stirring at 60° C. for 12 hours. The reaction mixture was extracted with ethylacetate and NaHCO3 solution, thereafter the organic layer was washed with NaCl solution and water, dried over anhydrous MgSO4, and concentrated. The residue was purified by Prep-TLC (n-Hexane:EtOAc=10:1) to give the target compound as a white solid (21.5 mg, yield: 10.6%).
Reaction SMILES: O[C:2]1([C:15]2[C:16](=[O:31])[NH:17][C:18](=[O:30])[N:19]([CH:29]=2)[C@@H:20]2[O:28][C@H:25]([CH2:26][OH:27])[C@@H:23]([OH:24])[C@H:21]2[OH:22])[C:14]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[CH:13]1[C:14]2[CH:2]([C:15]3[C:16](=[O:31])[NH:17][C:18](=[O:30])[N:19]([CH:29]=3)[C@@H:20]3[O:28][C@H:25]([CH2:26][OH:27])[C@@H:23]([OH:24])[C@H:21]3[OH:22])[C:3]3[C:8](=[CH:7][CH:6]=[CH:5][CH:4]=3)[C:9]=2[CH:10]=[CH:11][CH:12]=1
Reactant: O=c1[nH]c(=O)n([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)cc1C1(O)c2ccccc2-c2ccccc21
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=c1[nH]c(=O)n([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)cc1C1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 36 h
Yield: 33.6 %

Procedure:
The product of step (ii) (3.37 g) was dissolved in dichloromethane (100 ml) and triethylsilane (1.39 ml) and treated with trifluoroacetic acid (6.23 ml). The mixture was stirred at room temperature for 36 hours. The solvent was evaporated under reduced pressure and the residue azeotroped three times with toluene. The remaining residue was purified by flash chromatography on silica-gel eluting with 15% methanol in ethyl acetate to give 5-(9H-fluoren-9-yl)uridine as white powder (1.09 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:11].C1(C)C=CC=CC=1.[C:19](OC(=O)C)(=[O:21])[CH3:20]>C(O)(=O)C>[C:19]([NH:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:11])(=[O:21])[CH3:20]
Reactant: Nc1cc([N+](=O)[O-])ccc1O
Reactant: CC(=O)OC(C)=O
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: CC(=O)Nc1cc([N+](=O)[O-])ccc1O
Temperature: 80 °C

Procedure:
A mixture of 10 g. (0.065 mol) of 2-amino-4-nitrophenol, 125 ml. of dry toluene and 25 ml. of glacial acetic acid is heated to affect solution. Acetic anhydride (7.57 g., 0.074 mol) is added dropwise over a period of twenty minutes and the resulting mixture is heated at about 80° C. for two hours. The reaction mixture is filtered and the solid is washed with toluene, then recrystallized from methanol to give 2-acetamido-4-nitrophenol, m.p. 283°-284° C.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[CH:15]=[CH:14][C:13]3[N:12]=[C:11]([CH3:16])[NH:10][C:9](=[O:17])[C:8]=3[C:7]=2[CH:18]=1.[NH2:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[C:25](=[O:29])[N:24]([C@@H:30]([CH2:36][CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39])[C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH2:23]2.C([O-])(O)=O.[Na+].C(O)(=O)C>CN(C=O)C.C(O)C>[CH3:16][C:11]1[NH:10][C:9](=[O:17])[C:8]2[C:7]3[CH:18]=[C:3]([CH2:2][NH:19][C:20]4[CH:21]=[C:22]5[C:26](=[CH:27][CH:28]=4)[C:25](=[O:29])[N:24]([C@@H:30]([CH2:36][CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39])[C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH2:23]5)[CH:4]=[CH:5][C:6]=3[CH:15]=[CH:14][C:13]=2[N:12]=1
Reactant: Cc1nc2ccc3ccc(CBr)cc3c2c(=O)[nH]1
Reactant: CCOC(=O)CC[C@@H](C(=O)OCC)N1Cc2cc(N)ccc2C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)CC[C@@H](C(=O)OCC)N1Cc2cc(NCc3ccc4ccc5nc(C)[nH]c(=O)c5c4c3)ccc2C1=O
Yield: 49 %

Procedure:
A solution of crude 9-bromomethyl-3-methylbenzo[f]quinazolin-1(2H)-one (4.32 g), (S)-diethyl 2-(5-amino-1-oxo-2-isoindolinyl)glutarate (4.0 g, 12 mmol), and NaHCO3 (2.0 g, 24 mmol) in DMF (30 ml) was stirred under nitrogen at 105° C. for 1.5 hours. After cooling, acetic acid (1 ml, 17 mmol) was added, the reaction mixture transferred to a larger round bottom flask with ethanol, and then concentrated in vacuo onto silica gel (30 g). The absorbed material was purified by chromatography on silica gel eluting with methanol:methylene chloride (1:24) and then precipitation of the solid from methylene chloride (˜20 ml) with ethyl acetate (˜45 ml) and methanol (˜5 ml). The white solid was filtered under nitrogen and dried under high vacuum to give diethyl(S)-2-(5-(((1,2-dihydro-3-methyl-1-oxobenzo[f]-quinazolin-9-yl)-methyl)amino)-1-oxo-2-isoindolinyl)glutarate (3.27 g). 1H NMR (DMSO-d6, 300 MHz, δ: 1.10 (t, J=7 Hz, 3H, ester CH3), 1.15 (t, J=7 Hz, 3H, ester CH3), 1.93-2.33 (m, 4H, glu CH2CH2), 2.43 (s, 3H, C3—CH3), 3.87-4.03 (m, 2H, ester CH2), 4.09 (q, J=7 Hz, 2H, ester CH2), 4.25 (very strongly coupled AB pair, 2H, glu NCH2Ar), 4.58 (d, J=6 Hz, 2H, C9—CH2N), 4.74-4.83 (m, 1H, glu CH), 6.71 (br d, J=2 Hz, 1H, Ar), 6.74 (dd, J=8,2 Hz, 1H, Ar), 7.20 (t, J=6 Hz, 1H, ArNH), 7.37 (d, J=8 Hz, 1H, Ar), 7.59 (d, J=9 Hz, 1H, Ar), 7.63 (dd, J=8,2 Hz, 1H, Ar), 8.00 (d, J=8 Hz, 1H, Ar), 8.21 (d, J=9 Hz, 1H, Ar), 9.87 (s, 1H, Ar), 12.54 (s, 1H, N2H). Mass spectrum (CI—CH4) 557 (M+1, 100%). Anal. Calculated for C31H32N4O6: C, 66.89; H, 5.79; N, 10.07. Found: C, 66.80; H, 5.82; N, 10.10.