Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[OH:14])=[CH:4][CH:3]=1.F[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[N+:22]([O-:24])=[O:23]>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[O:14][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[N+:22]([O-:24])=[O:23])=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: Cc1ccc(-c2ccccc2O)cc1
Product: Cc1ccc(-c2ccccc2Oc2ccccc2[N+](=O)[O-])cc1

Procedure:
Prepared from 4-methyl-2'-hydroxy-1,1'-biphenyl (Example 12, Step C) and 1-fluoro-2-nitrobenzene by the procedure described in Example 27, Step A. 1H NMR (200 MHz, CDCl3): 2.30 (s,3H), 6.74 (dd;2,8 Hz;1H), 6.9-7.5 (m,10H), 7.84 (dd;2, 8 Hz;1H).
Reaction SMILES: C[N:2]1CCCCC1.[CH:8]([O:11][C:12]([NH:14][C@H:15]([C:19]([OH:21])=O)[CH:16]([CH3:18])[CH3:17])=[O:13])([CH3:10])[CH3:9].ClC(OCC(C)C)=O.[F:30][C:31]1[CH:42]=[CH:41][C:34]2[N:35]=[C:36]([C@H:38](N)[CH3:39])[S:37][C:33]=2[CH:32]=1>C(Cl)Cl>[F:30][C:31]1[CH:42]=[CH:41][C:34]2[N:35]=[C:36]([C@H:38]([N:14]([C:12]([O:11][CH:8]([CH3:9])[CH3:10])=[O:13])[C@H:15]([C:19]([NH2:2])=[O:21])[CH:16]([CH3:17])[CH3:18])[CH3:39])[S:37][C:33]=2[CH:32]=1
Reactant: CC(C)OC(=O)N[C@H](C(=O)O)C(C)C
Reactant: CN1CCCCC1
Reactant: C[C@@H](N)c1nc2ccc(F)cc2s1
Agent: CC(C)COC(=O)Cl
Solvent: ClCCl
Product: CC(C)OC(=O)N([C@H](C)c1nc2ccc(F)cc2s1)[C@H](C(N)=O)C(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 63.3 %

Procedure:
0.4 g of N-methylpiperidine was added to a solution containing 0.8 g of N-isopropoxycarbonyl-L-valine dissolved in 25 ml of methylene chloride, at -20° C. After the mixture was stirred for 10 minutes at the same temperature, 0.6 g of isobutyl chloroformate was added to the mixture at -20° C., and stirred for 1 hour at -20° C.~-10° C. After 0.8 g of (R)-1-(6-fluoro-2-benzothiazolyl)ethylamine was added to this mixture at -60° C., the refrigerant was put off, and then the reaction mixture was warmed naturally to room temperature while being stirred. After completion of the reaction, the resulting mixture was washed successively with water, a 5% aqueous solution of sodium bicarbonate, and water. The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The obtained crude crystals were purified by column chromatography on silica gel, thus yielding 0.95 g of the desired product in the form of a white powder (yield: 63%).
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.C([C:11]1[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=1[NH2:13])CC.[C:18]1(C)[CH:23]=CC=C[CH:19]=1>>[CH2:19]([CH2:6][C:5]([NH:13][C:12]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:11]=1)=[O:7])[CH2:18][CH3:23]
Reactant: Cc1ccccc1
Reactant: CC(=O)OC(C)=O
Reactant: CCCc1ccccc1N
Product: CCCCC(=O)Nc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96 %

Procedure:
Acetic anhydride (7.5 ml) was added to a toluene (100 ml) solution of 2-propylaniline, and the mixture was stirred at room temperature for 2 hours. Crystals thus precipitated were collected by filtration and washed with hexane. The filtrate was concentrated under reduced pressure. After hexane was added thereto, tritulation was conducted. The deposited crystals were collected by filtration and washed with hexane. By the above crystallization steps, 2-propylacetanilide (13.0 g; yield, 96%) was obtained as white crystals.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8](=[O:13])[N:9]2[CH3:12])=[CH:4][CH:3]=1.C1C(=O)N([Br:21])C(=O)C1.O>CN(C=O)C.CCOC(C)=O>[Br:21][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:2]=1[F:1])[N:9]([CH3:12])[C:8](=[O:13])[CH2:7][CH2:6]2
Reactant: CN1C(=O)CCc2ccc(F)cc21
Reactant: O=C1CCC(=O)N1Br
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CN1C(=O)CCc2cc(Br)c(F)cc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 78 %

Procedure:
To an ice cold solution of 7-fluoro-1-methyl-3,4-dihydro-1H-quinolin-2-one (16.0 g, 89.4 mmol) in DMF (200 mL) was added NBS (16.0 g, 89.4 mmol). After the addition, the reaction mixture was warmed up to room temperature and stirred for 3 hr. After LC-MS analysis indicated the completion of reaction, the mixture was diluted with EtOAc (500 mL) and poured into water (500 mL). The aqueous layer was then extracted with EtOAc (200 mL, 3×) and the combined organic layers were washed with brine, dried over anhy. Na2SO4, filtered and concentrated in vacuo to give crude title compound as oil (18.0 g, 78% yield). It was used in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([Cl:11])[CH:5]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O.[C:44]([O:48][CH2:49][CH:50](O)[CH3:51])([CH3:47])([CH3:46])[CH3:45]>C1COCC1>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH:50]([CH3:51])[CH2:49][O:48][C:44]([CH3:47])([CH3:46])[CH3:45])=[C:6]([Cl:11])[CH:5]=1
Reactant: COC(=O)c1ccc(O)c(Cl)c1
Reactant: CC(O)COC(C)(C)C
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(OC(C)COC(C)(C)C)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1.5 g of 3-chloro-4-hydroxybenzoic acid methyl ester in 20 ml of THF, 1.8 ml of 1-tert-butoxy-2-propanol, 3.16 g of triphenylphosphine, and 1.9 ml of diethylazodicarboxylate were added, and the mixture was stirred at room temperature for 1 hour. After evaporation of the solvent under reduced pressure, the obtained residue was purified by silica gel column chromatography (eluent: hexane-EtOAc=100:1˜5:1) to obtain 2.3 g of 4-(1-tert-butoxy-2-propoxy)-3-chlorobenzoic acid methyl ester.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][C:6]([O:12][CH2:13][CH2:14][CH2:15][C:16]([N:18]([CH3:20])[CH3:19])=[O:17])=[CH:7][CH:8]=2)[CH2:3]1.C(N(CC)CC)C.[CH2:28]([O:35][C:36]1[CH:41]=[CH:40][C:39]([C:42](=[O:45])[CH2:43]Br)=[CH:38][CH:37]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.[BH4-].[Na+]>CN(C)C=O.C(O)C>[CH2:28]([O:35][C:36]1[CH:37]=[CH:38][C:39]([CH:42]([OH:45])[CH2:43][NH:1][C@H:2]2[CH2:11][CH2:10][C:9]3[C:4](=[CH:5][C:6]([O:12][CH2:13][CH2:14][CH2:15][C:16]([N:18]([CH3:20])[CH3:19])=[O:17])=[CH:7][CH:8]=3)[CH2:3]2)=[CH:40][CH:41]=1)[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: CN(C)C(=O)CCCOc1ccc2c(c1)C[C@@H](N)CC2
Reactant: O=C(CBr)c1ccc(OCc2ccccc2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCO
Product: CN(C)C(=O)CCCOc1ccc2c(c1)C[C@@H](NCC(O)c1ccc(OCc3ccccc3)cc1)CC2
Temperature: 0 °C
Yield: 26.5 %

Procedure:
(S)-4-(2-Amino-1,2,3,4-tetrahydronaphthalen-7-yloxy)-N,N-dimethylbutyramide (196 mg) and triethylamine (270 μl) were dissolved in N,N-dimethylformamide (3 ml), and a solution of 4'-benzyloxy-2-bromoacetophenone (195 mg) in N,N-dimethylformamide (2 ml) was added to the solution under ice-cooling with stirring. After reaction for 15 minutes, sodium borohydride (240 mg) and ethanol (3 ml) were added to the reaction mixture under ice-cooling with stirring. After reaction for 2 hours, the reaction mixture was poured into ice-water, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was removed in vacuo. To the resulting residue was added a solution of triethanolamine (200 mg) in tetrahydrofuran (5 ml), and the mixture was heated under reflux for 16 hours. After cooling, water was poured into the reaction mixture and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was removed in vacuo. Purification of the residue by medium pressure liquid column chromatography on silica gel (eluent: ethyl acetate/ethanol=6/1) gave 4-[(2S)-2-[[(2RS)-2-(4-benzyloxyphenyl)-2-hydroxyethyl]amino]-1,2,3,4-tetrahydronaphthalen-7-yloxy]-N,N-dimethylbutyramide (85 mg) as an amorphous.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][CH2:10][C:11]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)=[O:12])[CH2:4][CH2:3]1.[C:20]1([S:26](Cl)(=[O:28])=[O:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[C:20]1([S:26]([NH:1][CH:2]2[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][CH2:10][C:11]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)=[O:12])[CH2:4][CH2:3]2)(=[O:28])=[O:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: NC1CCN(CCCC(=O)c2ccc(Cl)cc2)CC1
Product: O=C(CCCN1CCC(NS(=O)(=O)c2ccccc2)CC1)c1ccc(Cl)cc1

Procedure:
Using an analogous procedure to Example 2 4-amino-1-(4-p-chlorophenyl-4-oxobutyl)piperidine may be reacted with benzenesulphonyl chloride to give the title compound.
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:16].[CH3:17][S:18][CH2:19][C:20](O)=[O:21]>>[CH3:17][S:18][CH2:19][C:20]([NH:1][N:2]1[N:11]=[C:10]([C:12]([F:15])([F:13])[F:14])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:16])=[O:21]
Reactant: Nn1nc(C(F)(F)F)c2ccccc2c1=O
Reactant: CSCC(=O)O
Product: CSCC(=O)Nn1nc(C(F)(F)F)c2ccccc2c1=O

Procedure:
The product from Example 11B and 2-(methylthio)acetic acid were treated using a method similar to that described in Example 57 to give the title compound 1H NMR (500 MHz, DMSO-d6/Deuterium Oxide) δ ppm 8.45 (ddd, J=8.0, 1.4, 0.7 Hz, 1H), 8.15 (td, J=7.7, 1.4 Hz, 1H), 8.04-8.11 (m, 2H), 3.37 (s, 2H), 2.24 (s, 3H); MS (ESI−) M/Z 316 (M−H)−.
Reaction SMILES: [CH3:1][O:2][P:3]([CH3:7])(=[O:6])[O:4][CH3:5].[Li+].CCC[CH2-].C[O:14][C:15]([C:17]1[CH:18]=[N:19][N:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:21]=1[CH3:22])=O>C1COCC1.CCCCCC>[CH3:1][O:2][P:3]([CH2:7][C:15]([C:17]1[CH:18]=[N:19][N:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:21]=1[CH3:22])=[O:14])(=[O:6])[O:4][CH3:5]
Reactant: COP(C)(=O)OC
Reactant: COC(=O)c1cnn(-c2ccccc2)c1C
Agent: [CH2-]CCC
Agent: [Li+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COP(=O)(CC(=O)c1cnn(-c2ccccc2)c1C)OC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 86.4 %

Procedure:
A solution of methyl-phosphonic acid dimethyl ester (2.1 g) in THF (20 mL) under an argon atmosphere was cooled to −78° C. and treated dropwise with 10.98 mL of a 1.6 M solution of N-butyllithium in hexane keeping the temperature of the reaction mixture below −65° C. After stirring for 15 minutes 5-methyl-1-phenyl-1H-pyrazole-4-carboxylic acid methyl ester (1.9 g in 2 ml THF) were added slowly and the mixture was stirred for 30 minutes (temperature below −65° C.). The reaction mixture was allowed to warm to 0° C., quenched with 1N aqueous HCl, and then partitioned between ACOEt and water. The layers were separated, the organic layer was washed with water, dried over MgSO4, filtered and evaporated to give [2-(5-Methyl-1-phenyl-1H-pyrazol-4-yl)-2-oxo-ethyl]-phosphonic acid dimethyl ester (2.34 g) as a dark brown oil that was used in the next reaction without further purification. MS (ESI): 309.1 (MH+).
Reaction SMILES: [OH-].[Na+].[N+:3]([CH3:6])([O-:5])=[O:4].[CH3:7][CH:8]([CH2:11][CH2:12][CH2:13]C)[CH:9]=[O:10].[CH2:15](O)C>O>[CH3:7][CH:8]([CH2:11][CH:12]([CH3:13])[CH3:15])[CH:9]([OH:10])[CH2:6][N+:3]([O-:5])=[O:4]
Reactant: CCCCC(C)C=O
Reactant: C[N+](=O)[O-]
Reactant: CCO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)CC(C)C(O)C[N+](=O)[O-]
Yield: 81.4 %

Procedure:
After dissolving 5.0 g of sodium hydroxide in 25 ml of water and 25 ml of ethanol at 4° C., 7.7 g of nitromethane and 7.2 g of 2,5-dimethylpentanal were added thereto. The temperature of the solution was allowed to rise to room temperature, and the solution was stirred for an hour. After concentrating the ethanol under reduced pressure, the solution was neutralized with 1 mol/l of hydrochloric acid so that the pH of the solution was approximately 7. Ethyl acetate was added to the solution, and the organic layer was washed with saturated saline. The organic layer was dried with magnesium sulfate and concentrated, and then purified by silica gel chromatography (hexane/ethyl acetate=8/1), thereby obtaining 9.0 g of 3,5-dimethyl-1-nitro-2-hexanol (yield: 81.4%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[C@@H:5]([OH:19])[CH2:6][C:7]([C:9]1[CH:18]=[CH:17][C:16]2[C:11](=CC=CC=2)[CH:10]=1)=[O:8])[CH3:2].[CH3:21]CCCCC.C[CH:28]([OH:30])C>>[CH2:1]([O:3][C:4](=[O:20])[C@@H:5]([OH:19])[CH:6]([CH3:21])[C:7]([C:9]1[CH:10]=[CH:11][C:16]([O:30][CH3:28])=[CH:17][CH:18]=1)=[O:8])[CH3:2]
Reactant: CCCCCC
Reactant: CC(C)O
Reactant: CCOC(=O)[C@@H](O)CC(=O)c1ccc2ccccc2c1
Product: CCOC(=O)[C@@H](O)C(C)C(=O)c1ccc(OC)cc1

Procedure:
1H NMR syn (CDCl3) δ=1.28 (t, 3H, J=7.1 Hz), 1.29 (d, 3H, J=7.1 Hz), 3.35 (br, 1H), 3.84-3.96 (m, 4H), 4.27 (q, 2H, J=7.1 Hz), 4.58 (t, 1H, J=4.2 Hz), 6.96 (apparent d, 2H, J=9.0 Hz), 7.30-7.45 (m, 5H) 7.95 (apparent d, 2H, J=8.8 Hz); anti (CDCl3) δ=1.19 (t, 3H, J=7.1 Hz), 1.36 (d, 3H, J=7.3 Hz), 3.75 (d, 1H, J=9.3 Hz), 3.88 (s, 3H), 3.94 (dq, 1H, J=4.6, 7.3 Hz), 4.15 (apparent dq, 2H, J=3.2, 7.1 Hz), 4.36 (dd, 1H, J=4.6, 9.3 Hz), 6.92-6.99 (m, 2H), 7.90-7.97 (m, 2H); 13C NMR syn (CDCl3) δ=12.3, 14.0, 43.7, 55.4, 61.8, 71.7, 113.9, 128.5, 130.7, 163.7, 173.1, 200.4; anti (CDCl3) δ=14.0, 14.6, 43.2, 55.5, 61.4, 73.4, 113.9, 128.7, 130.8, 163.8, 173.2, 201.9; IR (neat) syn 3477, 2979, 2935, 2850, 1730, 1670, 1600, 1573, 1510, 1463, 1420, 1308, 1261, 1173, 1125, 1027, 976, 843, 770, 604; anti 3478, 2979, 2941, 2843, 1738, 1671, 1599, 1580, 1510, 1457, 1419, 1370, 1308, 1257, 1216, 1172, 1092, 1026, 974, 841 cm−1; HRMS (FAB); Exact mass calcd for C14H19O5 [M+H]+, 267.1232, Found 267.1232.; HPLC, Daicel Chiralcel ADH, hexane/iPrOH=4/1, flow rate=0.2 mL/min: tR=60.5 min (2R, 3R), tR=65.4 min (2S, 2S), tR=75.2 min (2R, 3S), tR=78.9 min (2S, 3R).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([OH:7])[CH:2]=1.[H-].[Na+].Cl[C:11]1[C:12]2[N:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:13]=2[N:14]=[CH:15][N:16]=1>CN(C=O)C.O>[Cl:21][C:19]1[CH:18]=[CH:17][C:13]2[N:14]=[CH:15][N:16]=[C:11]([O:7][C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)[C:12]=2[N:20]=1
Reactant: Clc1ccc2ncnc(Cl)c2n1
Reactant: Oc1cccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Clc1ccc2ncnc(Oc3cccnc3)c2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69.6 %

Procedure:
To a solution of pyridin-3-ol (0.048 g, 0.500 mmol) in DMF (1.67 ml) was added NaH (0.027 g, 55% dispersion in mineral oil, 0.630 mmol) at 0° C. After stirring for 30 min at room temperature, the reaction mixture was cooled to 0° C. and 4,6-dichloropyrido[3,2-d]pyrimidine (Intermediate 1, step D) (0.1 g, 0.500 mmol) was added to the mixture. After stirring for 2 hours at room temperature, the reaction mixture was diluted with water, and extracted with EtOAc. The organic layers were dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on SiO2 (Hex:EtOAc=5:1) to give 6-chloro-4-(pyridin-3-yloxy)pyrido[3,2-d]pyrimidine (0.090 g, 70%) as a white solid. 1H-NMR (CDCl3, Varian 400 MHz) δ 7.46 (1H, dd, J=8.0 and 4.8 Hz), 7.66-7.69 (1H, m), 7.86 (1H, d, J=8.8 Hz), 8.31 (1H, d, J=8.8 Hz), 8.61 (1H, d, J=4.4 Hz), 8.65 (1H, d, J=2.8 Hz), 8.80 (1H, s).
Reaction SMILES: [CH2:1]([NH:5][C:6](=[O:31])[C:7]1[CH:12]=[CH:11][C:10]([C:13](=[N:28][OH:29])[CH:14]=[C:15]([C:20]2[CH:25]=[C:24]([Cl:26])[CH:23]=[C:22]([Cl:27])[CH:21]=2)[C:16]([F:19])([F:18])[F:17])=[CH:9][C:8]=1[CH3:30])[CH2:2][CH2:3][CH3:4].[Br:32]N1C(=O)CCC1=O>CN(C)C=O>[Br:32][CH:14]1[C:15]([C:20]2[CH:25]=[C:24]([Cl:26])[CH:23]=[C:22]([Cl:27])[CH:21]=2)([C:16]([F:18])([F:17])[F:19])[O:29][N:28]=[C:13]1[C:10]1[CH:11]=[CH:12][C:7]([C:6]([NH:5][CH2:1][CH2:2][CH2:3][CH3:4])=[O:31])=[C:8]([CH3:30])[CH:9]=1
Reactant: CCCCNC(=O)c1ccc(C(C=C(c2cc(Cl)cc(Cl)c2)C(F)(F)F)=NO)cc1C
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Product: CCCCNC(=O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2Br)cc1C
Temperature: 25 °C
Yield: 40 %

Procedure:
N-Butyl-4-[3-(3,5-dichloro-phenyl)-4,4,4-trifluoro-1-hydroxyimino-but-2-enyl]-2-methyl-benzamide (Example 3.1) (380 mg, 0.94 mmol) and N-bromosuccinimide (200 mg, 1.12 mmol) were heated in N,N-dimethylformamide (2 ml) at 120° C. for 7 minutes. The reaction mixture was allowed to cool to ambient temperature and then extracted with diethyl ether. The combined organic extracts were dried over magnesium sulfate and concentrated. The residue was purified by chromatography on silica gel (eluent: hexane/ethyl acetate 4:1) to give Compound No. A1 of Table A (210 mg, 40% yield) as a solid foam.
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH2:2][OH:3].C(=O)([O-])[O-].[K+].[K+].[I-].[K+].Cl[CH2:15][C:16]([O:18][C:19]1([CH3:29])[CH:26]2[CH2:27][CH:22]3[CH2:23][CH:24]([CH2:28][CH:20]1[CH2:21]3)[CH2:25]2)=[O:17]>C(OCC)C.CN(C)C=O>[CH3:29][C:19]1([O:18][C:16](=[O:17])[CH2:15][O:5][C:1](=[O:4])[CH2:2][OH:3])[CH:26]2[CH2:27][CH:22]3[CH2:23][CH:24]([CH2:28][CH:20]1[CH2:21]3)[CH2:25]2
Reactant: CC1(OC(=O)CCl)C2CC3CC(C2)CC1C3
Reactant: O=C(O)CO
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC1(OC(=O)COC(=O)CO)C2CC3CC(C2)CC1C3
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67.1 %

Procedure:
37.6 g (494 mmol) of glycolic acid, 700 mL of DMF, 86.5 g (626 mmol) of potassium carbonate, and 28.3 g (170 mmol) of potassium iodide were charged into a 2 L three-necked flask equipped with a thermometer, a cooling pipe, and a stirrer, followed by stirring at room temperature for 30 minutes. Then, 300 mL of a dimethylformamide solution containing 100 g (412 mmol) of 2-methyl-2-adamantyl chloroacetate was gradually added thereto. The resultant was heated to 40° C., and was then stirred for 4 hours. Following completion of the reaction, 2,000 mL of diethyl ether was added to the reaction mixture, followed by filtration of the resulting mixture. The obtained solution was washed three times with 500 mL of distilled water, followed by crystallization using a mixed solution containing 300 mL of toluene and 200 mL of heptane, thereby obtaining 78 g of an objective compound in the form of a colorless solid (yield: 67%, GC purity: 99%).
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][CH2:12][O:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][O:25][CH2:26][CH2:27]OS(C2C=CC(C)=CC=2)(=O)=O)(=O)=O)=CC=1.[Br:40][C:41]1[CH:42]=[C:43]([OH:47])[CH:44]=[CH:45][CH:46]=1.[C:48]([O-:51])([O-])=O.[K+].[K+]>CN(C=O)C>[Br:40][C:41]1[CH:42]=[C:43]([O:47][CH2:27][CH2:26][O:25][CH2:24][CH2:23][O:22][CH2:21][CH2:20][O:19][CH2:18][CH2:17][O:16][CH2:15][CH2:14][O:13][CH2:12][CH2:11][O:51][C:48]2[CH:44]=[CH:45][CH:46]=[C:41]([Br:40])[CH:42]=2)[CH:44]=[CH:45][CH:46]=1
Reactant: Oc1cccc(Br)c1
Reactant: O=C([O-])[O-]
Reactant: Cc1ccc(S(=O)(=O)OCCOCCOCCOCCOCCOCCOS(=O)(=O)c2ccc(C)cc2)cc1
Agent: [K+]
Solvent: CN(C)C=O
Product: Brc1cccc(OCCOCCOCCOCCOCCOCCOc2cccc(Br)c2)c1
Temperature: 60 °C
Reaction time: 8 h
Yield: 68.5 %

Procedure:
A synthesis of was published in Hargadon, M. T.; Davey, E. A.; McIntyre, T. B.; Gnanamgari, D.; Wynne, C. M.; Swift, R. C.; Zimbalist, J. R.; Fredericks, B. L.; Nicastro, A. J.; Goodson, F. E. Macromolecules 2008, 41, 741-750. A 250 mL round-bottomed flask was charged with 5.41 g (9.14 mmol) of hexaethylene glycol di(p-toluenesulfonate), 4.67 g (27.0 mmol) of 3-bromophenol, 12.8 g of K2CO3 (92.6 mmol), and 50 mL of DMF. The reaction was then left to stir overnight in a 60° C. oil bath, after which the solvent was removed via vacuum distillation. Dichloromethane was then added to the residue, and the resulting suspension was filtered to remove excess carbonate and salt byproducts. Afterwards, the solvent was removed with a rotary evaporator, and the residue was heated in a kugelrohr oven under a dynamic 5 mtorr vacuum to remove excess 3-bromophenol. The crude product was then chromatographed on silica with an eluent of hexanes/EtOAc adjusted to give an Rf for the product of 0.2-0.3. Hexaethylene glycol di(3-bromophenyl)ether (3.70 g, 6.26 mmol, 69% yield), was then isolated as a pale yellow oil after distillation at 200° C. (<1 mtorr): 1H NMR (300 MHz, CDCl3) δ 7.05-7.15 (multiple resonances, 6H); 6.84 (dm, Jd=8.1 Hz, 2H); 4.09 (t, J=4.5 Hz, 4H); 3.83 (t, J=4.8 Hz, 4H); 3.64-3.74 (multiple resonances, 8H); 3.65 (s, 8H); 13C NMR (75 MHz, CDCl3) δ 159.7, 130.4, 124.0, 122.7, 118.3, 113.8, 70.9, 70.7, 70.6, 69.6, 67.9, (one signal not resolved). Anal. Calcd. for C24H32Br2O7: C, 48.67; H, 5.44; Found: C, 48.83; H, 5.59.
Reaction SMILES: [C:1]1([NH:7][C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([N:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)=[O:18])=[CH:13][CH:12]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(C(C)C)C(C)C)C.Cl[CH2:35][C:36]1[CH:37]=[C:38]([CH:43]=[CH:44][C:45]=1[O:46][CH3:47])[C:39]([O:41][CH3:42])=[O:40]>C(#N)C>[CH3:47][O:46][C:45]1[CH:44]=[CH:43][C:38]([C:39]([O:41][CH3:42])=[O:40])=[CH:37][C:36]=1[CH2:35][N:22]1[CH2:23][CH2:24][N:19]([C:17](=[O:18])[C:14]2[CH:15]=[CH:16][C:11]([NH:10][C:8]([NH:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[O:9])=[CH:12][CH:13]=2)[CH2:20][CH2:21]1
Reactant: O=C(Nc1ccccc1)Nc1ccc(C(=O)N2CCNCC2)cc1
Reactant: COC(=O)c1ccc(OC)c(CCl)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COC(=O)c1ccc(OC)c(CN2CCN(C(=O)c3ccc(NC(=O)Nc4ccccc4)cc3)CC2)c1
Temperature: 45 °C
Reaction time: 8 h
Yield: 43 %

Procedure:
1-Phenyl-3-(4-(piperazin-1-carbonyl)phenyl)urea (439 mg, 1.0 mmol) was stirred in acetonitrile (8 mL) at room temperature for 1 hour, N-Ethyl-N-isopropylpropan-2-amine (697 μl, 4 mmol) was added, followed by a solution of methyl 3-(chloromethyl)4-methoxy-benzoate (215 mg, 1.0 mmol) in acetonitrile (5 mL). The mixture was heated to 45° C. and stirred overnight. The mixture was concentrated under vacuum, diluted with dichloromethane (40 mL) and washed with saturated aqueous ammonium chloride (25 mL) and saturated aqueous sodium chloride (25 mL). The organic phase was dried on magnesium sulfate, filtered and concentrated under vacuum. The residue was submitted to silica chromatography (0-10% methanol in dichloromethane as eluant) to give the title compound (216 mg). MS (ESI) m/z 503.1 [M+H]+
Reaction SMILES: Br[CH2:2][C:3]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:4]=1[C:5]#[N:6].[C:12]1(=[O:22])[NH:16][C:15](=[O:17])[C:14]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:13]12.C([O-])([O-])=O.[Cs+].[Cs+].C([O-])([O-])=O.[K+].[K+]>CN(C)C=O.O.CO.O>[O:17]=[C:15]1[C:14]2[C:13](=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:12](=[O:22])[N:16]1[CH2:2][C:3]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:4]=1[C:5]#[N:6]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: N#Cc1cc(F)ccc1CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CO
Product: N#Cc1cc(F)ccc1CN1C(=O)c2ccccc2C1=O
Reaction time: 1 h
Yield: 99.9 %

Procedure:
To a stirred solution of intermediate 104, 2-(bromomethyl)-5-fluorobenzonitrile (29.72 g, 139 mmol) and phthalimide (32.69 g, 222 mmol) in dimethylformamide (300 mL) was added Cs2CO3 (67.87 g, 208 mmol). After stirring vigorously for 1 h, the reaction mixture was poured into water (1.2 L). The precipitated product was filtered, washed with water (600 mL) and methanol (150 mL) to give a white solid. The solid was taken up into 1 L of water/methanol (2:1) to which was added K2CO3 (12 g) and the mixture stirred at 40° C. After 30 min., the mixture was cooled and filtered. The filter cake was washed with water (500 mL), and dried under vacuum to afford the title compound (38.91 g, 94% yield) as a white powder. 1H NMR (500 MHz, CDCl3) δ: 7.89 (2H, dd, J=5.5, 3.1 Hz), 7.76 (5.5, 3.1 Hz), 7.41 (1H, dd, J=8.6, 5.2 Hz), 7.38 (1H, dd, J=7.9, 2.8 Hz), 7.24 (1H, td, J=8.2, 2.8 Hz), 5.06 (2H, s). LCMS (M+H) calcd for C16H10FN2O2: 281.07. found: 281.15.