Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[N:6][C:7]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=3[Cl:25])=[C:8]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=3)[CH:9]=2)[O:4][C:3]=1[C:26](=[O:28])[CH3:27].[CH3:29][S:30](Cl)(=[O:32])=[O:31].C(N(CC)CC)C>C(Cl)Cl>[C:26]([C:3]1[O:4][C:5]2=[N:6][C:7]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=3[Cl:25])=[C:8]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=3)[CH:9]=[C:10]2[C:2]=1[N:1]([S:30]([CH3:29])(=[O:32])=[O:31])[S:30]([CH3:29])(=[O:32])=[O:31])(=[O:28])[CH3:27]
Reactant: CS(=O)(=O)Cl
Reactant: CC(=O)c1oc2nc(-c3ccc(Cl)cc3Cl)c(-c3ccc(Cl)cc3)cc2c1N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)c1oc2nc(-c3ccc(Cl)cc3Cl)c(-c3ccc(Cl)cc3)cc2c1N(S(C)(=O)=O)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 0.030 g (0.0696 mmol)of the product from Example 5 in CH2Cl2 (1 mL) cooled to 0° C. was treated with methanesulfonyl chloride (5 μL; 0.0696 mmol), followed by triethylamine (30 μL; 0.209 mmol). The reaction mixture was allowed to warm to room temperature and stirred for 2 h. The reaction was quenched with saturated NaHCO3 solution. The reaction mixture was partitioned between ethyl acetate and saturated NaHCO3 solution. The organic layer was washed twice with saturated NaHCO3 solution, brine, dried (Na2SO4), filtered, and concentrated in vacuo. Purification by MPLC (silica gel; 0% to 20% ethyl acetate:hexane gradient) gave the title compound. HPLC/MS: 586.9 (M+1), 588.9 (M+3); Rt=4.16 min.
Reaction SMILES: C1C=CC2N(O)N=NC=2C=1.Cl.Cl.[CH3:13][O:14][C:15]1[CH:16]=[C:17](/[CH:27]=[CH:28]/[C:29]([NH:31][NH2:32])=[O:30])[CH:18]=[CH:19][C:20]=1[N:21]1[CH:25]=[C:24]([CH3:26])[N:23]=[CH:22]1.[F:33][C:34]1[CH:35]=[C:36]([CH:40]=[CH:41][CH:42]=1)[C:37](O)=[O:38].C(N(C(C)C)CC)(C)C>CN(C=O)C.O.C(OCC)(=O)C.C(Cl)CCl>[CH3:13][O:14][C:15]1[CH:16]=[C:17](/[CH:27]=[CH:28]/[C:29]([NH:31][NH:32][C:37](=[O:38])[C:36]2[CH:40]=[CH:41][CH:42]=[C:34]([F:33])[CH:35]=2)=[O:30])[CH:18]=[CH:19][C:20]=1[N:21]1[CH:25]=[C:24]([CH3:26])[N:23]=[CH:22]1
Reactant: COc1cc(/C=C/C(=O)NN)ccc1-n1cnc(C)c1
Reactant: O=C(O)c1cccc(F)c1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(/C=C/C(=O)NNC(=O)c2cccc(F)c2)ccc1-n1cnc(C)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 62.7 %

Procedure:
HOBT (70 mg) and EDC (100 mg) were added to a solution of (E)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylic acid hydrazide dihydrochloride (120 mg), 3-fluorobenzoic acid (49 mg) and IPEA (0.37 mL) in DMF, and the reaction solution was stirred at room temperature for 12 hours. Ethyl acetate and water were added to the reaction solution, and the precipitated solid was collected by filtration to obtain 86 mg of the title compound. The property value of the compound as follows.
Reaction SMILES: [N:1]12[CH2:16][CH:5]([C:6](=[C:8]([C:14]#[N:15])[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:7]1)[CH2:4][CH2:3][CH2:2]2.[H][H]>[Pd].C(O)C>[N:1]12[CH2:16][CH:5]([CH:6]([CH:8]([C:14]#[N:15])[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:7]1)[CH2:4][CH2:3][CH2:2]2
Reactant: CCOC(=O)C(C#N)=C1CN2CCCC1C2
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C(C#N)C1CN2CCCC1C2

Procedure:
A solution of ethyl (1-azabicyclo[3.2.1]octan-6-ylidene)cyanoacetate (41 g, 0.19 mol) in abs. ethanol (500 ml) was treated with 10% palladium on carbon (5 g) and hydrogen in a Parr shaker at 30 psi for 5 h. Filtration and evaporation gave the title compound in 36 g yield.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[CH2:11][CH:10]([NH:15][CH3:16])[CH2:9]2)(=[O:4])=[O:3].Cl[CH2:18][C:19]1[CH:28]=[CH:27][C:26]2[C:21](=[CH:22][CH:23]=[C:24]([NH:29][S:30]([CH3:33])(=[O:32])=[O:31])[CH:25]=2)[N:20]=1.C(=O)(O)[O-].[Na+]>C(#N)C>[CH3:1][S:2]([NH:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[CH2:11][CH:10]([N:15]([CH2:18][C:19]1[CH:28]=[CH:27][C:26]3[C:21](=[CH:22][CH:23]=[C:24]([NH:29][S:30]([CH3:33])(=[O:32])=[O:31])[CH:25]=3)[N:20]=1)[CH3:16])[CH2:9]2)(=[O:4])=[O:3]
Reactant: CNC1Cc2ccc(NS(C)(=O)=O)cc2C1
Reactant: CS(=O)(=O)Nc1ccc2nc(CCl)ccc2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: CN(Cc1ccc2cc(NS(C)(=O)=O)ccc2n1)C1Cc2ccc(NS(C)(=O)=O)cc2C1

Procedure:
5-Methanesulphonamido-2-methylaminoindane (0.09 g), 2-chloromethyl-6-methanesulphonamidoquinoline (0.1 g) and sodium bicarbonate (0.2 g) were heated under reflux in acetonitrile (10 ml) for 11/2 hours. The solvent was then removed by evaporation in vacuo and the residue was taken up in methylene chloride, washed with aqueous sodium bicarbonate, dried (MgSO4) and evaporated in vacuo. The residue was purified by column chromatography on silica eluting with methylene chloride containing methanol (0% up to 2%) and the product-containing fractions were combined and evaporated to give the title compound as a foam, yield 0.09 g. A sample was crystallised from deuterochloroform, m.p. 189°-191°.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[CH3:12][S:13](Cl)(=[O:15])=[O:14]>ClCCl>[O:11]=[C:6]1[CH2:5][C:4]2[C:8](=[CH:9][CH:10]=[C:2]([NH:1][S:13]([CH3:12])(=[O:15])=[O:14])[CH:3]=2)[NH:7]1
Reactant: Nc1ccc2c(c1)CC(=O)N2
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Product: CS(=O)(=O)Nc1ccc2c(c1)CC(=O)N2
Temperature: -30 °C
Yield: 90 %

Procedure:
A stirred solution of 5-amino-1,3-dihydro-indol-2-one (2 g, 13.5 mmol, prepared according to U.S. Pat. No. 6,114,371) in 30 ml of dichloromethane was added with tirethylamine (1.9 ml). The solution was cooled down to −30° C. in an acetone-dry ice bath and added with methanesulfonyl chloride (1 ml, 13.5 mmol) dropwise. Upon the completion of the addition, the resulting mixture was heated at 45° C. for 1 hour until precipitate was formed. The solid was filtered, washed with water (50 ml×3) and dried in vacuo to give N-(2-oxo-2,3-dihydro-1H-indol-5-yl)-methanesulfonamide (2.7 g, 90%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[C:10]2[N:9]=[C:8]([CH:11]([F:13])[F:12])[N:7]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:16]=3[CH3:22])[C:6]=2[CH:5]=[C:4]([NH2:23])[CH:3]=1.[OH-].[Na+].Br[CH2:27][CH2:28][O:29][CH2:30][CH2:31]Br>[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[Br:1][C:2]1[C:10]2[N:9]=[C:8]([CH:11]([F:13])[F:12])[N:7]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:16]=3[CH3:22])[C:6]=2[CH:5]=[C:4]([N:23]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)[CH:3]=1
Reactant: Cc1c(Cl)cccc1Cn1c(C(F)F)nc2c(Br)cc(N)cc21
Reactant: BrCCOCCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Agent: [Na+]
Product: Cc1c(Cl)cccc1Cn1c(C(F)F)nc2c(Br)cc(N3CCOCC3)cc21
Reaction time: 2.5 h
Yield: 33.7 %

Procedure:
The crude product from the previous reaction 4-bromo-1-(3-chloro-2-methylbenzyl)-2-(difluoromethyl)-1H-benzo[d]imidazol-6-amine (2.25 g, 5.62 mmol) was stirred in 6M sodium hydroxide (30 mL, 180 mmol) solution with 1-bromo-2-(2-bromoethoxy)ethane (1.5 mL, 12.03 mmol) and tetrabutylammonium iodide (0.207 g, 0.562 mmol) at 110° C. After stirring for 2.5 hr the mixture was cooled and the aqueous was decanted and the remaining sticky solid was dissolved in EtOAc. The organic was washed with H2O and brine, and dried over MgSO4 and concentrated to leave a residue that was purified by column chromatography. The residue was loaded onto a 25 g Silica column and eluted with EtOAc/Hex 10% to 40% over 15 minutes. The cleanest fractions containing desired product were combined and concentrated in-vacuo to afford 892 mg (34% yield) of the titled compound. LC/MS: MS (ES+) m/e 471.8 [M+H]+; 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.22-7.37 (m, 3H), 6.81-7.14 (m, 2H), 6.31-6.42 (m, 2H), 5.51 (s, 2H), 3.76-3.89 (m, 4H), 3.03-3.20 (m, 4H), 2.48 (s, 3H)
Reaction SMILES: [CH:1]1([N:4]([CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[C:5](=[O:18])[C:6]2[CH:11]=[CH:10][C:9]([C:12]3[O:16][CH:15]=[N:14][CH:13]=3)=[C:8]([F:17])[CH:7]=2)[CH2:3][CH2:2]1.Cl[C:26]1[N:31]=[CH:30][C:29]([CH2:32][CH3:33])=[CH:28][N:27]=1>>[CH:1]1([N:4]([CH:19]2[CH2:24][CH2:23][N:22]([C:26]3[N:31]=[CH:30][C:29]([CH2:32][CH3:33])=[CH:28][N:27]=3)[CH2:21][CH2:20]2)[C:5](=[O:18])[C:6]2[CH:11]=[CH:10][C:9]([C:12]3[O:16][CH:15]=[N:14][CH:13]=3)=[C:8]([F:17])[CH:7]=2)[CH2:2][CH2:3]1
Reactant: O=C(c1ccc(-c2cnco2)c(F)c1)N(C1CCNCC1)C1CC1
Reactant: CCc1cnc(Cl)nc1
Product: CCc1cnc(N2CCC(N(C(=O)c3ccc(-c4cnco4)c(F)c3)C3CC3)CC2)nc1

Procedure:
The title compound is prepared from N-cyclopropyl-3-fluoro-4-oxazol-5-yl-N-piperidin-4-yl-benzamide and 2-chloro-5-ethyl-pyrimidine following a procedure analogous to that described in Example 19. LC (method 1): tR=1.16 min; Mass spectrum (ESI+): m/z=436 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[CH2:10][N:11]2[CH2:16][CH2:15][N:14]([C:17]3[N:18]([CH3:26])[N:19]=[C:20]([CH3:25])[C:21]=3[N+:22]([O-])=O)[CH2:13][CH2:12]2)=[CH:4][CH:3]=1.O.[Sn](Cl)Cl.O.O.O.C([O-])(=O)C.[Na+]>O1CCCC1.CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[CH2:10][N:11]2[CH2:16][CH2:15][N:14]([C:17]3[N:18]([CH3:26])[N:19]=[C:20]([CH3:25])[C:21]=3[NH2:22])[CH2:13][CH2:12]2)=[CH:4][CH:3]=1
Reactant: Cc1nn(C)c(N2CCN(C/C=C/c3ccc(Cl)cc3)CC2)c1[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: Cc1nn(C)c(N2CCN(C/C=C/c3ccc(Cl)cc3)CC2)c1N
Temperature: 25 °C
Reaction time: 34 h
Yield: 69.3 %

Procedure:
To a solution of the product obtained in Step B (800 mg) in tetrahydrofuran (8 ml) and methanol (8 ml) at room temperature under nitrogen was added tin(II) chloride monohydrate (2.9 g) and sodium acetate trihydrate (3.5 g). The resulting mixture was stirred at room temperature for 34 hours. The reaction mixture was partitioned between 1M sodium hydroxide and ethyl acetate, stirred for 10 min, the organic layer was separated, dried over sodium sulfate and concentrated. 1-[(E)-3-(4-Chlorophenyl)-allyl]-4-(2,5-dimethyl-4-amino-2H-pyrazol-3-yl)-piperazine (510 mg) was obtained as a red solid. 1H NMR (400 MHz, CDCl3) 2.3 (s, 3H), 2.8 (m, 4H), 3.3 (m, 4H), 3.4 (d, J=9 Hz, 2H), 3.8 (s, 3H), 6.4 (dt, J=18, 9 Hz, 1H), 6.7 (d, J=18 Hz, 1H), 7.3-7.4 (m, 4H); MS (ES+) 151/153 (cinnamyl), 196(M-cinnamyl), 346/348 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[C:11]([NH:13][CH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1)=[O:12].[C:20]1([CH2:26][CH2:27]Br)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[C:11]([NH:13][CH:14]1[CH2:19][CH2:18][N:17]([CH2:27][CH2:26][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:16][CH2:15]1)=[O:12]
Reactant: BrCCc1ccccc1
Reactant: O=C(NC1CCNCC1)c1c[nH]c2ccc(F)cc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: O=C(NC1CCN(CCc2ccccc2)CC1)c1c[nH]c2ccc(F)cc12
Temperature: 0 °C

Procedure:
To a solution of 0.6 g of 5-fluoro-N-(4-piperidyl)indole-3-carboxamide in a mixture of 50 ml of toluene and 10 ml of dimethylformamide were added 0.43 g of 2-phenylethylbromide and 1 g of potassium carbonate, and the whole mixture was stirred while heating and refluxing for 7 hours. After cooling, to the reaction mixture was added 50 ml of ice-cold water and stirred for 1 hour. The precipitated crystals were filtered, and washed with water and ethyl acetate. An organic layer was separated from the filtrate, dried over magnesium sufate and concentrated under reduced pressure. The residue was treated with a small amount of ethyl acetate to crystallize, and the crystals were filtered and combined with the crystals obtained as above. All of the crystals were recrystallized from methanol to give 5-fluoro-N-[1-(2-phenylethyl)-4-piperidyl]indole-3-carboxamide, melting at 238°-240° C.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:8]=[C:7]([CH3:9])[NH:6][N:5]=1.[N+:10]([C:13]1[C:14](F)=[C:15]([C:22]([F:25])([F:24])[F:23])[CH:16]=[C:17]([N+:19]([O-:21])=[O:20])[CH:18]=1)([O-:12])=[O:11].Cl>CN(C=O)C>[N+:19]([C:17]1[CH:18]=[C:13]([N+:10]([O-:12])=[O:11])[CH:14]=[C:15]([C:22]([F:23])([F:24])[F:25])[C:16]=1[O:3][C:4]1[CH:8]=[C:7]([CH3:9])[NH:6][N:5]=1)([O-:21])=[O:20]
Reactant: Cc1cc(O)n[nH]1
Reactant: O=[N+]([O-])c1cc([N+](=O)[O-])c(F)c(C(F)(F)F)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(Oc2c([N+](=O)[O-])cc([N+](=O)[O-])cc2C(F)(F)F)n[nH]1
Temperature: 70 °C
Yield: 34.9 %

Procedure:
Sodium hydride (60% in oil, 0.2 g, 5.5 mmol) was added to a solution of 3-hydroxy-5-methylpyrazole (0.49 g, 5.0 mmol) and 3,5-dinitro-2-fluorobenzotrifluoride (1.35 g, 5.0 mmol) in DMF (10 ml), and the mixture was stirred under heating at 70° C. for 6 hours. After completion of the reaction, the reaction mixture was poured into 2N hydrochloric acid (30 ml) and extracted with ethyl acetate (20 ml×3). An organic layer was washed with water, dried over anhydrous magnesium sulfate and filtered to remove a desiccant, and the solvent was distilled off from the filtrate under reduced pressure. The resultant crude product was purified with a silica gel column (ethyl acetate/hexane=1/7), to give a yellowish solid of 3-(2,4-dinitro-6-trifluoromethylphenyloxy)-5-methylpyrazole (0.58 g, yield: 34.9%). mp: 145-147° C.; 1H-NMR (CDCl3, TMS, ppm): δ 2.29 (s, 3H), 5.84 (s, 1H), 8.82 (m, 2H), 9.01 (d, J=2.7 Hz, 1H).
Reaction SMILES: [CH3:1][N:2]1[C:7]([CH3:9])([CH3:8])[CH2:6][CH:5]([OH:10])[CH2:4][C:3]1([CH3:12])[CH3:11].[C:13](Cl)(=[O:25])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22](Cl)=[O:23].Cl.[CH3:28][N:29]1[C:34]([CH3:36])([CH3:35])[CH2:33][CH:32]([OH:37])[CH2:31][C:30]1([CH3:39])[CH3:38]>C1C=CC=CC=1>[CH3:1][N:2]1[C:7]([CH3:8])([CH3:9])[CH2:6][CH:5]([O:10][C:13](=[O:25])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([O:37][CH:32]2[CH2:31][C:30]([CH3:38])([CH3:39])[N:29]([CH3:28])[C:34]([CH3:36])([CH3:35])[CH2:33]2)=[O:23])[CH2:4][C:3]1([CH3:12])[CH3:11]
Reactant: O=C(Cl)CCCCCCCCC(=O)Cl
Reactant: CN1C(C)(C)CC(O)CC1(C)C
Agent: Cl
Solvent: c1ccccc1
Product: CN1C(C)(C)CC(OC(=O)CCCCCCCCC(=O)OC2CC(C)(C)N(C)C(C)(C)C2)CC1(C)C

Procedure:
A solution of 17.10 parts of 1,2,2,6,6-pentamethylpiperidin-4-ol in 50 parts of dry benzene was stirred at 15°-20° C. whilst adding 6.0 parts of sebacoyl chloride dropwise over 15 minutes. The mixture was stirred for a further 12 hours at room temperature after which the 1,2,2,6,6-pentamethylpiperidin-4-ol hydrochloride formed during the reaction was filtered off. The benzene was removed by distillation under reduced pressure to give a yellow oil, which was distilled under reduced pressure to give bis-(1,2,2,6,6-pentamethyl-4-piperidinyl)sebacate as a colourless oil having a boiling point of 218°-20° C. at 0.4 mm of Hg and the following elemental analysis by weight:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:14]2[S:15][C:16]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:17]([CH3:19])[N:18]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]([CH3:13])([CH3:12])[CH3:11].[I-:25].[Li+]>CN1CCCC1=O>[I:25][C:2]1[CH:3]=[C:4]([C:14]2[S:15][C:16]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:17]([CH3:19])[N:18]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]([CH3:13])([CH3:12])[CH3:11]
Reactant: CCOC(=O)c1sc(-c2ccc(OCC(C)(C)C)c(Br)c2)nc1C
Reactant: [I-]
Agent: [Li+]
Solvent: CN1CCCC1=O
Product: CCOC(=O)c1sc(-c2ccc(OCC(C)(C)C)c(I)c2)nc1C
Temperature: 150 °C
Yield: 71.1 %

Procedure:
120 mg of Ethyl 2-(3-bromo-4-neopentyloxyphenyl)-4-methyl-5-thiazolecarboxylate, 100 mg of cuprous iodide and 80 mg of lithium iodide were suspended in 2 ml of N-methyl pyrrolidone, and the suspension was heated at 150° C. for 4 hours with stirring. After completion of the reaction, the product was extracted with ethyl acetate, and the organic layer was concentrated to give a crude crystal. The resulting crystal was purified by silica gel chromatography to give 95 mg of ethyl 2-(3-iodo-4-neopentyloxyphenyl)-4-methyl-5-thiazolecarboxylate. The product was hydrolyzed by a conventional process, followed by recrystallization from hexane-ether to give 63 mg of 2-(3-iodo-4-neopentyloxyphenyl)-4-methyl-5-thiazolecarboxylic acid (yield: 58%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([O:15][C:16]2[C:25]3[C:20](=[CH:21][C:22]([OH:28])=[C:23]([O:26][CH3:27])[CH:24]=3)[N:19]=[CH:18][CH:17]=2)[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)=[N:6][C:7]=1[CH3:8].C(=O)([O-])[O-].[K+].[K+].Br[CH2:36][CH2:37][CH2:38][OH:39]>CN(C)C=O>[CH3:1][C:2]1[CH:3]=[C:4]([O:15][C:16]2[C:25]3[C:20](=[CH:21][C:22]([O:28][CH2:36][CH2:37][CH2:38][OH:39])=[C:23]([O:26][CH3:27])[CH:24]=3)[N:19]=[CH:18][CH:17]=2)[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)=[N:6][C:7]=1[CH3:8]
Reactant: COc1cc2c(Oc3cc(C)c(C)nc3-c3ccccn3)ccnc2cc1O
Reactant: OCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3cc(C)c(C)nc3-c3ccccn3)ccnc2cc1OCCCO
Temperature: 25 °C
Reaction time: 8 h
Yield: 42 %

Procedure:
4-(5,6-Dimethyl-[2,2′]bipyridin-3-yloxy)-6-methoxy-quinolin-7-ol (compound 338) (45 mg) was suspended in N,N-dimethylformamide (5 ml), potassium carbonate (50 mg) and 3-bromo-1-propanol (0.03 ml) were added to the suspension, and the mixture was stirred at room temperature overnight. The solvent was removed by distillation under the reduced pressure, water was then added to the residue, and the mixture was extracted with chloroform. The chloroform layer was washed with saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-acetone to give the title compound (22 mg, yield 42%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[S:12][C:11]([CH:13]=[CH:14][C:15]([OH:17])=[O:16])=[CH:10][CH:9]=1.[CH3:18]O>[Pd]>[CH3:18][O:16][C:15](=[O:17])[CH2:14][CH2:13][C:11]1[S:12][C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])=[CH:9][CH:10]=1
Reactant: CO
Reactant: O=C(O)C=Cc1ccc(-c2ccccc2F)s1
Agent: [Pd]
Product: COC(=O)CCc1ccc(-c2ccccc2F)s1
Reaction time: 168 h

Procedure:
100 mg of 5% palladium on carbon were added to a solution of 5 g (20.1 mmol) of 3-[5-(2-fluoro-phenyl)-thiophen-2-yl]-acrylic acid in 200 ml of methanol, and the reaction mixture was hydrogenated at atmospheric pressure and room temperature for 7 days. The mixture was filtered and evaporated. The product was purified by silica gel chromatography. Yield: 2.9 g.
Reaction SMILES: O[CH2:2][CH2:3][C:4]1[CH:18]=[CH:17][C:7]([O:8][C:9]([CH3:16])([CH3:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][CH:5]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:39]>ClCCl>[Br:39][CH2:2][CH2:3][C:4]1[CH:18]=[CH:17][C:7]([O:8][C:9]([CH3:16])([CH3:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][CH:5]=1
Reactant: BrC(Br)(Br)Br
Reactant: CCOC(=O)C(C)(C)Oc1ccc(CCO)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCOC(=O)C(C)(C)Oc1ccc(CCBr)cc1
Reaction time: 0.67 h
Yield: 84.4 %

Procedure:
To a stirred solution of ethyl 2-[4-(2-hydroxyethyl)-phenoxy]-2-methylpropionate (474 mg) and triphenylphosphine (591 mg) in dichloromethane (10 ml) was added carbon tetrabromide (748 mg) under ice-cooling, and the mixture was stirred for 40 minutes. Rough purification of the reaction mixture by flash column chromatography on silica gel (eluent: diethylether) and further purification of the fraction by medium pressure liquid column chromatography on silica gel (eluent: hexane/diethyl ether=10/1) gave ethyl 2-[4-(2-bromoethyl)phenoxy]-2-methylpropionate (500 mg). 1H-NMR (CDCl3) δ ppm: 1.25 (3H, t, J=7.1 Hz), 1.59 (6H, s), 3.09 (2H, t, J=7.8 Hz), 3.52 (2H, t, J=7.8 Hz), 4.23 (2H, q, J=7.1 Hz) 6.79 (2H, d, J=8.7 Hz), 7.07 (2H, d, J=8.7 Hz)
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][CH:6]=1)=O.[Br:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([NH2:19])=[O:18])=[CH:15][CH:14]=1.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[Br:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]2[O:18][CH:2]=[C:3]([C:5]3[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][CH:6]=3)[N:19]=2)=[CH:15][CH:14]=1
Reactant: NC(=O)c1ccc(Br)cc1
Reactant: Cc1ccc(C(=O)CBr)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: Cc1ccc(-c2coc(-c3ccc(Br)cc3)n2)cc1
Temperature: 160 °C

Procedure:
A mixture of 2-bromo-4′-methylacetophenone (152 mg, 0.7 mmol) and 4-bromobenzamide (200 mg, 1.0 mmol) was heated to 160° C. for 3 hours, cooled to room temperature, dissolved in ethyl acetate (20 mL), and treated with 5% sodium bicarbonate (20 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (2×10 mL). The combined extracts were dried (MgSO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 50% ethyl acetate/hexanes to provide the desired product. MS (DCI) m/e 314, 316 (M−H)−, (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ8.70 (s, 1H), 8.00-7.97 (m, 2H), 7.79-7.76 (m, 2H), 7.77-7.74 (m, 2H), 7.29-7.27 (m, 2H), 2.34 (s, 3H).
Reaction SMILES: [CH:1]1([C:6]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]([S:15]([C:18]3[CH:26]=[CH:25][C:21]([C:22]([OH:24])=O)=[CH:20][CH:19]=3)(=[O:17])=[O:16])[CH:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.CN1CCOCC1.ClC1N=C(OC)N=C(OC)N=1.[NH2:45][CH2:46][CH:47]1[CH2:52][CH2:51][O:50][CH2:49][CH2:48]1.Cl>C1COCC1.C(Cl)Cl>[CH:1]1([C:6]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]([S:15]([C:18]3[CH:26]=[CH:25][C:21]([C:22]([NH:45][CH2:46][CH:47]4[CH2:52][CH2:51][O:50][CH2:49][CH2:48]4)=[O:24])=[CH:20][CH:19]=3)(=[O:16])=[O:17])[CH:7]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: NCC1CCOCC1
Reactant: O=C(O)c1ccc(S(=O)(=O)n2cc(C3CCCC3)c3ccccc32)cc1
Agent: COc1nc(Cl)nc(OC)n1
Agent: Cl
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Solvent: ClCCl
Product: O=C(NCC1CCOCC1)c1ccc(S(=O)(=O)n2cc(C3CCCC3)c3ccccc32)cc1
Temperature: 5 °C
Reaction time: 1 h

Procedure:
Stir a stir solution of 4-(3-cyclopentyl-indole-1-sulfonyl)-benzoic acid (19.0 g, 51.43 mmol) in anhydrous THF (250 mL) cool to 5° C. under N2 add N-methylmorpholine (5.8 mL, 52.72 mmol) and 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT) (9.0 g, 51.34 mmol). Stir the mixture for 1 h and add a solution of 4-aminomethyltetrahydropyran (6.6 g, 57.34 mmol) in dry THF (75 mL) by dropping funnel. Warm the mixture to room temperature and stir for 3 h. Cool the mixture to 5° C., add 1N HCl (250 mL) and partition the resulting solution with ethyl acetate (250 mL). Extract the organic layer with aqueous saturated sodium bicarbonate (250 mL), brine (250 mL), and dry over sodium sulfate. Concentrate to give a foam, dissolve in minimum methylene chloride and add to a flash 65 M cartridge. Elute with 3:2 hexanes/ethyl acetate to give the major product as a solid, filter from hexanes, and dry (20 mm Hg, 40° C.) to give the homogeneous white solid (20.5 g, 85%); MS(ESI) m/z 467 (m+H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[OH:9].C([O-])(O)=O.[Na+].Cl[CH2:16][C:17](Cl)=[O:18]>O.COCCOC>[Br:8][C:5]1[CH:6]=[CH:7][C:2]2[NH:1][C:17](=[O:18])[CH2:16][O:9][C:3]=2[CH:4]=1
Reactant: Nc1ccc(Br)cc1O
Reactant: O=C(Cl)CCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: O=C1COc2cc(Br)ccc2N1
Temperature: 15 °C
Reaction time: 0.5 h
Yield: 95.9 %

Procedure:
To a mixture of 2-amino-5-bromophenol (51.3 g, 273 mmol) and NaHCO3 (68.8 g, 819 mmol) in water (200 mL) and DME (200 mL) was added 2-chloroacetyl chloride (46.2 g, 409 mmol) at 0° C. and the reaction mixture was stirred at 15° C. for 0.5 h then heated at 80° C. for 18 h. The reaction mixture was cooled to ambient temperature. The precipitate was collected by suction, washed with water and dried in vacuo to give 7-bromo-4H-benzo[1,4]oxazin-3-one (59.7 g, 96%) as a brown solid. 1H NMR (400 MHz, DMSO-d6) δ 10.83 (br s, 1H), 7.17 (s, 1H), 7.12 (d, J=8.4 Hz, 1H), 6.83 (d, J=8.4 Hz, 1H), 4.59 (s, 2H).