Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([CH2:13][CH2:14][C:15]([OH:17])=[O:16])[O:11][CH:12]=2)=[CH:4][CH:3]=1.[C:18]1([C:24](O)([CH3:26])[CH3:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C1(N=C=NC2CCCCC2)CCCCC1>C(#N)C.CN(C)C1C=CN=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]([CH2:13][CH2:14][C:15]([O:17][C:24]([CH3:26])([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH3:25])=[O:16])[O:11][CH:12]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)CCc1nc(-c2ccc(Cl)cc2)co1
Reactant: CC(C)(O)c1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CC#N
Product: CC(C)(OC(=O)CCc1nc(-c2ccc(Cl)cc2)co1)c1ccccc1
Temperature: 25 °C
Reaction time: 65 h
Yield: 40.4 %

Procedure:
To a solution of 4-(4-chlorophenyl)-2-oxazolepropionic acid (0.5 g) in acetonitrile (20 ml) were added 2-phenyl-2-propanol (0.325 g), dicyclohexylcarbodiimide (0.49 g) and 4-dimethylaminopyridine (0.025 g), followed by stirring for 65 hours at room temperature. 2-Phenyl-2-propanol (0.325 g), dicyclohexylcarbodiimide (0.49 g) and 4-dimethylaminopyridine (0.025 g) were further added to the reaction mixture, followed by stirring for 2 hours at 50° C. The reaction mixture was filtered to remove an insoluble substance, and the filtrate was then concentrated. The oily residue was subjected to a silica gel column chromatography. Crystals of 1-methyl-1-phenylethyl 4-(4-chlorophenyl)-2-oxazolepropionate (0.297 g, 38%) were obtained from the fraction eluted with ethyl acetate-hexane (1:4, V/V). Recrystallization from hexane gave colorless prism crystals of mp 94°-95° C.
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.[F-].F[C:20]1[C:21]([O:33][CH3:34])=[C:22]2[C:26](=[CH:27]C=1)N(C)C=C2CCO.[N:35]([CH2:38][CH2:39][C:40]1[C:48]2[C:43](=[CH:44][CH:45]=[C:46]([F:57])[C:47]=2[O:49][CH2:50][C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[NH:42][CH:41]=1)=[N+:36]=[N-:37]>>[N:35]([CH2:38][CH2:39][C:40]1[C:48]2[C:43](=[CH:44][CH:45]=[C:46]([F:57])[C:47]=2[O:49][CH2:50][C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[N:42]([CH2:20][CH:21]2[CH2:22][CH2:26][CH2:27][CH2:34][O:33]2)[CH:41]=1)=[N+:36]=[N-:37]
Reactant: COc1c(F)ccc2c1c(CCO)cn2C
Reactant: [N-]=[N+]=NCCc1c[nH]c2ccc(F)c(OCc3ccccc3)c12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: [N-]=[N+]=NCCc1cn(CC2CCCCO2)c2ccc(F)c(OCc3ccccc3)c12
Yield: 82 %

Procedure:
Following the procedure (step 5, scheme 17, TBAF deprotection step unnecessary) used to prepare compound 17-6, compound 19-1 gave compound 19-2 in 82% yield as a colorless oil. 1H NMR (CDCl3, 300 MHz) (ppm): 7.25-7.47 (m, 5H), 6.91-6.97 (m, 3H), 3.91-4.04 (m, 3H), 3.58 (m, 1H), 3.36-3.43 (m, 3H), 2.97 (t, J=6.9 Hz, 2H), 1.23-1.48 (m, 6H).
Reaction SMILES: [Cl:1][C:2]1[C:21]([Cl:22])=[CH:20][C:5]2[N:6]([C:11]3[CH:16]=[CH:15][C:14]([CH2:17][CH2:18]O)=[CH:13][CH:12]=3)[C:7]([CH2:9][CH3:10])=[N:8][C:4]=2[CH:3]=1.[C:23]([O:27][C:28]([NH:30][O:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])=[O:29])([CH3:26])([CH3:25])[CH3:24].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[C:23]([O:27][C:28]([N:30]([O:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:18][CH2:17][C:14]1[CH:13]=[CH:12][C:11]([N:6]2[C:5]3[CH:20]=[C:21]([Cl:22])[C:2]([Cl:1])=[CH:3][C:4]=3[N:8]=[C:7]2[CH2:9][CH3:10])=[CH:16][CH:15]=1)=[O:29])([CH3:26])([CH3:25])[CH3:24]
Reactant: CCc1nc2cc(Cl)c(Cl)cc2n1-c1ccc(CCO)cc1
Reactant: CC(C)(C)OC(=O)NOC(=O)OC(C)(C)C
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCc1nc2cc(Cl)c(Cl)cc2n1-c1ccc(CCN(OC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a stirred mixture of 2-[4-(5,6-dichloro-2-ethyl-1H-benzimidazol-1-yl)phenyl]ethanol (Example 96, 100 mg, 0.3 mmol), N,O-Bis-tert-butoxycarbonylhydroxylamine (Baillie, L. C.; Batsanov, A.; Bearder, J. R.; Whiting, D. A. J. Chem. Soc. Perkin Trans. 1, 1998, 20, 3471., 140 mg, 0.6 mmol) and triphenylphosphine (158 mg, 0.6 mmol) in THF (10 mL) was added diethyl azodicarboxylate (DEAD) (0.1 mL, 0.6 mmol). The mixture was stirred under nitrogen atmosphere at room temperature for 2.5 h. The solvent was removed and the residue was purified by flash column chromatography on silica gel eluting with hexane/ethyl acetate (1:1) to afford 174 mg (quant.) of the title compound as yellow amorphous: 1H-NMR (CDCl3) δ 7.84 (1H, s), 7.46 (2H, d, J=8.4 Hz), 7.25 (2H, d, J=8.4 Hz), 7.16 (1H, s), 3.92 (2H, t, J=6.7 Hz), 3.05 (2H, t, J=6.7 Hz), 2.76 (2H, q, J=7.6 Hz), 1.56 (9H, s), 1.46 (9H, s), 1.33 (3H, t, J=7.6 Hz).
Reaction SMILES: Cl[CH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[CH3:13].[CH3:14][O:15][P:16]([O:19]C)[O:17][CH3:18]>>[CH3:13][C:4]1[CH:5]=[CH:6][C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:2][P:16](=[O:19])([O:17][CH3:18])[O:15][CH3:14]
Reactant: Cc1ccc2ccccc2c1CCl
Reactant: COP(OC)OC
Product: COP(=O)(Cc1c(C)ccc2ccccc12)OC
Yield: 59.1 %

Procedure:
A solution of 1-chloromethyl-2-methylnaphthalene (9.50 g, 0.050 M) in trimethylphosphite (15 mL, 15.8 g, 0.13 M) is heated at reflux temperature for 48 hours. Excess trimethylphosphite is removed under reduced pressure, giving a yellow oil which is chromatographed over silica gel (40-63 μ, 400 g, 50 mL fractions) using ethyl acetate for elution of the column. Fractions 18-21 are pooled and after concentration gave a white solid (7.78 g). Recrystallization from ether-pentane gave title compound (6.94 g) as colorless crystals, mp 54°-57° C.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:16]=[CH:15][C:14]([CH:17]=[CH:18][CH:19]3[CH2:24][CH2:23][CH:22]([CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH2:21][CH2:20]3)=[CH:13][CH:12]=2)[CH2:7][CH2:6]1)=[O:4]>C1(C)C=CC=CC=1.C(O)C.[Pd]>[CH3:1][O:2][C:3]([CH:5]1[CH2:6][CH2:7][CH:8]([C:11]2[CH:12]=[CH:13][C:14]([CH2:17][CH2:18][CH:19]3[CH2:20][CH2:21][CH:22]([CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH2:23][CH2:24]3)=[CH:15][CH:16]=2)[CH2:9][CH2:10]1)=[O:4]
Reactant: CCCCCC1CCC(C=Cc2ccc(C3CCC(C(=O)OC)CC3)cc2)CC1
Agent: [Pd]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCCCCC1CCC(CCc2ccc(C3CCC(C(=O)OC)CC3)cc2)CC1
Yield: 87.9 %

Procedure:
6.9 g (17.4 mmol) of 4-{4-[2-(4-pentyl-cyclohexyl)-vinyl]-phenyl}cyclohexane carboxylic acid methyl ester produced in Example 6-1 was dissolved in a mixture of toluene and ethanol (1:1 by volume %). 0.4 g of Pd/C was added to 200 mL of the resultant solution and reacted in hydrogenation reactor for 12 hours. After reaction, Pd/C was removed by filtration, concentrated under reduced pressure and recrystallized from chloroform and ethanol to obtain 6.1 g (88%) of 4-{4-[2-(4-pentyl-cyclohexyl)-ethyl]-phenyl}-cyclohexane carboxylic acid methyl ester.
Reaction SMILES: Cl.[C:2]([C:4]1[CH:30]=[CH:29][C:7]([CH2:8][N:9]2[C:13]([CH2:14][CH2:15][NH:16][C:17]([C@@H:19]3[CH2:28][C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH2:21][NH:20]3)=[O:18])=[CH:12][N:11]=[CH:10]2)=[CH:6][CH:5]=1)#[N:3].CCN(CC)CC.[CH:38](=O)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.C([BH3-])#N.[Na+]>CO>[C:2]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][N:9]2[C:13]([CH2:14][CH2:15][NH:16][C:17]([C@@H:19]3[CH2:28][C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH2:21][N:20]3[CH2:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)=[O:18])=[CH:12][N:11]=[CH:10]2)=[CH:29][CH:30]=1)#[N:3]
Reactant: N#Cc1ccc(Cn2cncc2CCNC(=O)[C@@H]2Cc3ccccc3CN2)cc1
Reactant: O=Cc1ccccc1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CCN(CC)CC
Product: N#Cc1ccc(Cn2cncc2CCNC(=O)[C@@H]2Cc3ccccc3CN2Cc2ccccc2)cc1
Reaction time: 18 h

Procedure:
1,2,3,4-Tetrahydro-isoquinoline-3(S)-carboxylic acid {2-[3-(4-cyanobenzyl)-3H-imidazol-4-yl]-ethyl}-amide hydrochloride (0.15 g, 0.33 mmol) was dissolved in MeOH (7 mL). Et3N was added to this solution dropwise until the pH=5. To the solution was added benzaldehyde (0.069 mL, 0.65 mmol) and sodium cyanoborohydride (0.041 g, 0.65 mmol). After stirring for 18 hr. the mixture was evaporated in vacuo and the residue was partitioned between EtOAc (50 mL) and saturated NaHCO3 (30 mL). The organic layer was washed with saturated NaCl solution (30 mL) and dried (MgSO4). Filtration and concentration to dryness gave the title compound after purification on silica gel eluting with CH2Cl2 :
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:21])=[C:4]([C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([Br:20])[CH:18]=3)[NH:13][CH:12]=2)=[O:10])[C:5]([F:8])=[CH:6][CH:7]=1.C(N(CC)CC)C.[Cl:29][C:30]1[CH:38]=[CH:37][CH:36]=[C:35]([Cl:39])[C:31]=1[C:32](Cl)=[O:33]>CN(C)C1C=CN=CC=1.CC1CCCO1>[NH2:1][C:2]1[C:3]([F:21])=[C:4]([C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([Br:20])[CH:18]=3)[N:13]([C:32](=[O:33])[C:31]3[C:30]([Cl:29])=[CH:38][CH:37]=[CH:36][C:35]=3[Cl:39])[CH:12]=2)=[O:10])[C:5]([F:8])=[CH:6][CH:7]=1
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Reactant: Nc1ccc(F)c(C(=O)c2c[nH]c3ncc(Br)cc23)c1F
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: CC1CCCO1
Product: Nc1ccc(F)c(C(=O)c2cn(C(=O)c3c(Cl)cccc3Cl)c3ncc(Br)cc23)c1F
Temperature: 9.300000190734863 °C
Yield: 92.93 %

Procedure:
Compound 4 (2.5 kg, 7.114 mol) obtained from Example 2 was added into a 50-liter flask and cooled to 9.3° C. To compound 4 in the 50-liter flask was added triethylamine (0.864 kg, 8.537 mol), followed by 4-dimethylaminopyridine (DMAP) (0.087 kg, 0.7114 mol) and 2,6-dichlorobenzoyl chloride (1.34 kg, 6.40 mol) in 2-methyl-THF (25 L) over a period of 2 hrs. The reaction was quenched with methanol (0.30 L at room temperature and added an aqueous NaCl solution (12.5 L, 15%) and celite (0.5 kg). The mixture was stirred and filtered through celite. The filtrate was concentrated and added 5 volumes of heptanes. The resulting solution was stirred for about 1 hr and dried with sodium sulfate (1 kg) and filtered. Compound 5 was isolated by removing the solvents under vacuum (3.47 kg, 92.93% yield). MS (ESI): M+H+=524, 525.8, 527.8. 1H NMR (DMSO-d6, δ ppm): 5.36 (2H, s), 7.01 (2H, m), 7.68 (3H, s), 8.34 (1H, brs), 8.61 (1H, brs), 8.72 (1H, d J=2.3 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH:16]3[CH2:17][CH2:18][CH2:19][CH:12]2[C:13](=[CH:21]O)[C:14](=O)[CH2:15]3)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH2:23][C:24]1[N:28]=[C:27]([S:29][CH3:30])[NH:26][N:25]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH:16]3[CH2:17][CH2:18][CH2:19][CH:12]2[C:13]2[CH:21]=[N:23][C:24]4[N:25]([C:14]=2[CH2:15]3)[N:26]=[C:27]([S:29][CH3:30])[N:28]=4)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=C1CC2CCCC(C1=CO)N2S(=O)(=O)c1ccc(Cl)cc1
Reactant: CSc1nc(N)n[nH]1
Product: CSc1nc2ncc3c(n2n1)CC1CCCC3N1S(=O)(=O)c1ccc(Cl)cc1

Procedure:
Prepared as described in Example 5 using 9-(4-chlorophenylsulfonyl)-2-(hydroxymethylene)-9-azabicyclo[3.3.1]nonan-3-one which was prepared as described in Example 34 and 3-amino-5-methylthio-1,2,4-triazole.
Reaction SMILES: C(N(CC)CC)C.Cl.[CH3:9][C:10]1[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[C:11]=1[O:12][CH:13]1[CH2:16][NH:15][CH2:14]1.[C:22](Cl)(=[O:24])[CH3:23]>O1CCCC1>[C:22]([N:15]1[CH2:14][CH:13]([O:12][C:11]2[C:17]([CH3:21])=[CH:18][CH:19]=[CH:20][C:10]=2[CH3:9])[CH2:16]1)(=[O:24])[CH3:23]
Reactant: CC(=O)Cl
Reactant: Cc1cccc(C)c1OC1CNC1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)N1CC(Oc2c(C)cccc2C)C1
Temperature: 0 °C
Reaction time: 8 h
Yield: 96.1 %

Procedure:
Triethylamine (10.8 g, 106 mmol) was added to a stirred slurry of 3-(2,6-dimethylphenoxy)azetidine monohydrochloride (9.10 g, 42.7 mmol) in tetrahydrofuran (500 mL). After 10 minutes the reaction mixture was cooled to 0° C., and a solution of acetyl chloride (5.03 g, 64.1 mmol) in 50 mL of tetrahydrofuran was added dropwise. The reaction mixture was allowed to come to ambient temperature and was stirred overnight. The reaction mixture was then filtered and the filtrate concentrated in vacuo. The residue was chromatographed (flash, SiO2) eluting with methylene chloride/methanol (9:1) to give 9.00 g (99%) of yellow powder with a melting point of 40.0°-42.5° C.
Reaction SMILES: Cl[C:2]1[C:18]([Cl:19])=[C:17]([OH:20])[CH:16]=[CH:15][C:3]=1[C:4](=[N:13][OH:14])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:6]=1[CH3:12].[H-].[Na+].Br[CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26].O>CN(C=O)C>[CH2:28]([O:27][C:25](=[O:26])[CH2:24][O:20][C:17]1[CH:16]=[CH:15][C:3]2[C:4]([C:5]3[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:6]=3[CH3:12])=[N:13][O:14][C:2]=2[C:18]=1[Cl:19])[CH3:29]
Reactant: CCOC(=O)CBr
Reactant: Cc1cccc(C(=NO)c2ccc(O)c(Cl)c2Cl)c1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)COc1ccc2c(-c3cccc(C)c3C)noc2c1Cl
Temperature: 130 °C
Reaction time: 7 h

Procedure:
To a solution of 5 g of 2,3-dichloro-4-hydroxy-2',3'-dimethylbenzophenone oxime in 70 ml of DMF, 0.96 g of NaH is added. The internal temperature is held between 95°-120° C. for seven hours, then the mixture is heated at 130° C. for 1.5 hours. The reaction mixture is cooled and 2.94 g of ethyl bromoacetate is added dropwise. The mixture is stirred one hour and water is added dropwise. The product which forms is filtered off and recrystallized from 95% ethanol to yield ethyl-{[7-chloro-3-(2,3-dimethylphenyl)-1,2-benzisoxazol-6-yl]oxy}acetate, mp 89°-91° C.
Reaction SMILES: [Br:1][C:2]1[CH:13]=[CH:12][C:5]([C:6](N(OC)C)=[O:7])=[C:4]([Cl:14])[CH:3]=1.[CH3:15][Mg]Cl>C1COCC1>[Br:1][C:2]1[CH:13]=[CH:12][C:5]([C:6](=[O:7])[CH3:15])=[C:4]([Cl:14])[CH:3]=1
Reactant: C[Mg]Cl
Reactant: CON(C)C(=O)c1ccc(Br)cc1Cl
Solvent: C1CCOC1
Product: CC(=O)c1ccc(Br)cc1Cl
Temperature: -78 °C
Reaction time: 1 h
Yield: 79.9 %

Procedure:
To a solution of 4-bromo-2-chloro-N-methoxy-N-methylbenzamide (2.27 g, 8.15 mmol) in THF at −78° C. was added methylmagnesium chloride (4.07 ml, 3M solution in THF, 12.23 mmol) dropwise. The reaction mixture was stirred at −78° C. for 1 h and then warmed to rt slowly and stirring was continued at rt overnight. The reaction mixture was quenched with 1N HCl and extracted with ether. The organic layer was washed with water, and brine, dried (MgSO4), filtered and concentrated in vacuo to give a residue which was purified by flash column chromatography (1:4 ether:pentane) to give 1-(4-bromo-2-chlorophenyl)-ethanone (1.52 g, 80%) as a yellow oil. 1H NMR (CDCl3, 300 MHz): δ 7.61 (m, 1H), 7.50-7.44 (m, 2H), 2.64 (s, 3H).
Reaction SMILES: [OH-].[Na+].[O:3]1[CH:7]=[CH:6][C:5]([CH:8]=O)=[CH:4]1.[CH:10](=[O:12])[CH3:11]>O.CCOCC>[O:3]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:11][CH:10]=[O:12])=[CH:4]1
Reactant: CC=O
Reactant: O=Cc1ccoc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Product: O=CC=Cc1ccoc1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 40.9 %

Procedure:
To a solution of 2N NaOH (115 mL) was added 3-furaldehyde (4.5 mL, 52.0 mmol) dropwise. The solution was stirred until homogeneous (approximately five minutes) and then cooled to 0° C. and acetaldehyde (1.65 mL, 57.2 mmol) in 5 mL water was added. The reaction was stirred at 0° C. for 30 min and was then diluted with ether. The mixture was separated and the aqueous layer was extracted with ether (3×50 mL). The combined organic extract was washed with brine, dried over MgSO4, filtered and evaporated to yield 4.56 g of crude product. Chromatography (silica gel ,30% ether/hexanes) yielded 2.6 g (41%) of 3-(furan-3-yl)propenal.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]3[C@H:14]([CH2:15][C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[NH:13][CH:12]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH2:11][N:10]3[CH:28]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:29][O:30][CH2:31][C:32](Cl)=[O:33]>C(Cl)(Cl)Cl>[CH3:29][O:30][CH2:31][C:32]([N:13]1[CH:12]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:11][N:10]2[CH:28]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[N:8]=[C:9]2[C@@H:14]1[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:33]
Reactant: COCC(=O)Cl
Reactant: c1ccc(C[C@@H]2NC(c3ccccc3)Cn3cc(-c4ccccc4)nc32)cc1
Solvent: ClC(Cl)Cl
Product: COCC(=O)N1C(c2ccccc2)Cn2cc(-c3ccccc3)nc2[C@@H]1Cc1ccccc1
Reaction time: 2 h
Yield: 68 %

Procedure:
To a solution of 5,6,7,8-tetrahydro-2,6-diphenyl-8(S)-phenylmethyl-imidazo[1,2-a]pyrazine (29 mg) in chloroform were successively added morpholinomethylpolystyrene resin (Novabiochem, loading=3.51 mmol/g, 50 mg, 2 eq) and methoxyacetylchloride (10 mL, 1.3 eq). After about 3 hours of stirring at about 20° C. chloroform was added to the mixture followed by aminomethylpolystyrene resin (Novabiochem, loading=1.2 mmol/g, 132 mg, 2 eq). The reaction mixture was stirred for another 2 hours and then filtered. The filtrate was concentrated under reduced pressure to afford 23 mg of the title compound (yield=68%). NMR (1H, 100 MHz, CDCl3): 7.9-7.0 (m, 16H, arom, H), 6.6 (m, 1H, H1), 5.3 (m, 1H, H1), 4.6 (dd, 1H, 2J=13 Hz, H5), 4.35 (dd, 1H, 2J=13 Hz, 3J=5 Hz, H5′), 3.7-2.9 (m, 5H, CH2Ph, OCH3).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[F:7][C:8]([F:35])([F:34])[C:9]1[CH:33]=[CH:32][C:12]([O:13][C:14]2[CH:31]=[CH:30][C:17]([O:18][CH:19]([CH3:29])[C:20]([O:27][CH3:28])=[CH:21][C:22](OCC)=[O:23])=[CH:16][CH:15]=2)=[CH:11][CH:10]=1.[H-].O>CCOCC>[F:7][C:8]([F:34])([F:35])[C:9]1[CH:10]=[CH:11][C:12]([O:13][C:14]2[CH:31]=[CH:30][C:17]([O:18][CH:19]([CH3:29])[C:20]([O:27][CH3:28])=[CH:21][CH2:22][OH:23])=[CH:16][CH:15]=2)=[CH:32][CH:33]=1
Reactant: CCOC(=O)C=C(OC)C(C)Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Product: COC(=CCO)C(C)Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1
Reaction time: 0.17 h

Procedure:
To a slurry of LiAlH4 (400 mg) in anhydrous ether (20 ml) is added dropwise at 0°, a solution of ethyl 4-[4-(4-trifluoromethylphenoxy)phenoxy]-3-methoxy-2-pentenoate (1.2 g) in ether (10 ml). After addition is complete, the reaction mixture is stirred for about 10 minutes. Excess hydride is decomposed with wet ether and water. After filtration, the filtrate is concentrated to give the alcohol, 4-[4-(4-trifluoromethylphenoxy)phenoxy]-3-methoxy-2-penten-1-ol.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[CH:15]=[C:14]([Cl:16])[CH:13]=[C:12]([Cl:17])[CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CN(C)CCN(C)C.C([Li])CCC.CCCCCC.[Cl:37][C:38]1[CH:46]=[CH:45][C:41]([C:42](Cl)=[O:43])=[CH:40][CH:39]=1>O1CCCC1>[Si:1]([O:8][CH2:9][C:10]1[CH:15]=[C:14]([Cl:16])[C:13]([C:42]([C:41]2[CH:45]=[CH:46][C:38]([Cl:37])=[CH:39][CH:40]=2)=[O:43])=[C:12]([Cl:17])[CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: CC(C)(C)[Si](C)(C)OCc1cc(Cl)cc(Cl)c1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCc1cc(Cl)c(C(=O)c2ccc(Cl)cc2)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 16.6 %

Procedure:
A stirred -55° C. solution of 3,5-dichlorobenzyl t-butyldimethylsilyl ether (1.46 g, 5.00 mmol) and tetramethylethylenediamine (0.755 mL, 0.581 g, 5.01 mmol) in tetrahydrofuran (5 mL) under nitrogen atmosphere was treated dropwise over 10 minutes with a 1.6 M solution of n-butyllithium in hexane (3.3 mL, 5.25 mmol). After 30 minutes at -55° C., a solution of p-chlorobenzoyl chloride (0.875 g, 5.00 mmol) in tetrahydrofuran (1.0 mL) was added over 15 minutes. The resulting mixture was stirred 2 hours at -55° to -30° C. and 1.5 hours at ambient temperature. The reaction was quenched by addition of saturated aqueous ammonium chloride (1.1 mL) and stirred 30 minutes. The mixture was treated with sodium sulfate (1.1 g), stirred 1 hour, and decanted. The residual solid was washed well with diethyl ether. The combined solution and washes were extracted twice with water, once with 10% aqueous citric acid, and once with brine, dried over anhydrous magnesium sulfate, and evaporated under vacuum to provide 1.93 g of crude brown oil. A total of 585 mg of oil was chromatographed on eight 1000μ 20 cm×20 cm silica gel preparative thick layer chromatography plates developed with 5:1 (v/v) hexane-ethyl acetate to provide 356 mg (60%) 4-(t-butyldimethylsilyloxymethyl)-2,4',6-trichlorobenzophenone; NMR (CDCl3): 0.14 s (6H), 0.95 s (9H), 4.72 s (2H), 7.27 s (2H), 7.35 d (J=9Hz, 2H), 7.70 d (J=9Hz, 2H).
Reaction SMILES: [CH2:1]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][N:13]=2)[C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([OH:21])[CH:16]=2)=[C:7]([NH:22][C:23]([NH:25][C:26]2[C:31]([CH:32]([CH3:34])[CH3:33])=[CH:30][CH:29]=[CH:28][C:27]=2[CH:35]([CH3:37])[CH3:36])=[O:24])[C:6]1=[O:38])[CH2:2][CH2:3][CH3:4].Cl.[CH2:40]([N:47]([CH2:50][CH2:51]Cl)[CH2:48][CH3:49])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.CC(C)([O-])C.[K+].O>CS(C)=O>[CH2:1]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][N:13]=2)[C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:51][CH2:50][N:47]([CH2:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[CH2:48][CH3:49])[CH:16]=2)=[C:7]([NH:22][C:23]([NH:25][C:26]2[C:27]([CH:35]([CH3:37])[CH3:36])=[CH:28][CH:29]=[CH:30][C:31]=2[CH:32]([CH3:33])[CH3:34])=[O:24])[C:6]1=[O:38])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1c(=O)c(NC(=O)Nc2c(C(C)C)cccc2C(C)C)c(-c2cccc(O)c2)c2cccnc21
Reactant: CCN(CCCl)Cc1ccccc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CCCCn1c(=O)c(NC(=O)Nc2c(C(C)C)cccc2C(C)C)c(-c2cccc(OCCN(CC)Cc3ccccc3)c2)c2cccnc21
Temperature: 25 °C
Reaction time: 5 h
Yield: 82.1 %

Procedure:
To a solution of N-[1-butyl-4-(3-hydroxyphenyl)-1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl]-N'-(2,6-diisopropylphenyl)urea (200 mg, 0.39 mmol) in DMSO (8 ml) were added 2-(N-benzyl-N-ethylamino)ethyl chloride hydrochloride (182 mg, 0.78 mmol) and potassium t-butoxide (132 mg, 1.17 mmol), and the mixture was stirred at room temperature for five hours. The mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water, washed with a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The resultant was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to give the title compound (218 mg, 0.32 mmol).
Reaction SMILES: [CH:1]([Mg]Cl)=[CH2:2].[Br:5][C:6]1[CH:19]=[C:18]2[C:9]([O:10][C:11]3[C:12]([F:23])=[CH:13][C:14]([O:21][CH3:22])=[CH:15][C:16]=3[C:17]2=[O:20])=[CH:8][CH:7]=1>C1COCC1>[Br:5][C:6]1[CH:19]=[C:18]2[C:9]([O:10][C:11]3[C:12]([F:23])=[CH:13][C:14]([O:21][CH3:22])=[CH:15][C:16]=3[C:17]2([CH:1]=[CH2:2])[OH:20])=[CH:8][CH:7]=1
Reactant: COc1cc(F)c2oc3ccc(Br)cc3c(=O)c2c1
Reactant: C=C[Mg]Cl
Solvent: C1CCOC1
Product: C=CC1(O)c2cc(Br)ccc2Oc2c(F)cc(OC)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
To a solution of vinylmagnesium chloride (55.9 ml, 89.4 mmol) at −78° C. was added dropwise of a solution of 7-bromo-4-fluoro-2-methoxy-9H-xanthen-9-one (8.0 g, 24.76 mmol) in THF (99 mL). After 30 min, the reaction was allowed to slowly warm to rt, then quenched with 240 mL of saturated aqueous NH4Cl. The mixture was extracted with EtOAc. The organic layer was dried over magnesium sulfate, filtered and concentrated to yield 7-bromo-4-fluoro-2-methoxy-9-vinyl-9H-xanthen-9-ol (8.69 g, 24.76 mmol, 100% yield) as yellow solid.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[O:9][CH2:8][O:7][C:6]=2[CH:5]=[CH:4][C:3]=1[C:11]([O:13]C)=[O:12].C1COCC1.O[Li].O.Cl>O>[Cl:1][C:2]1[C:10]2[O:9][CH2:8][O:7][C:6]=2[CH:5]=[CH:4][C:3]=1[C:11]([OH:13])=[O:12]
Reactant: COC(=O)c1ccc2c(c1Cl)OCO2
Agent: Cl
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccc2c(c1Cl)OCO2
Temperature: 70 °C
Reaction time: 2 h

Procedure:
To a vial containing methyl 4-chlorobenzo[d][1,3]dioxole-5-carboxylate (395.8 mg, 1.8 mmol, 1 equiv.) in 3:1 THF:H2O (15 mL) was added LiOH.H2O (153.3 mg, 3.7 mmol, 2 equiv.). The vial was capped and the mixture was stirred at 70° C. for 2 h, diluted with water, acidified with 1M HCl to pH <3, and extracted with ethyl acetate. The combined organic layers was dried over anhydrous Na2SO4, filtered and the solvent was removed under vacuum to give a quantitative yield of 4-chlorobenzo[d][1,3]dioxole-5-carboxylic acid as a white solid.