Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH2:5][NH2:6].[Cl:12][C:13]1[N:14]=[C:15](Cl)[C:16]2[CH:21]=[C:20]([CH2:22][CH3:23])[S:19][C:17]=2[N:18]=1>>[Cl:12][C:13]1[N:14]=[C:15]([NH:6][CH2:5][C:4]2[CH:7]=[CH:8][C:9]([O:10][CH3:11])=[C:2]([Cl:1])[CH:3]=2)[C:16]2[CH:21]=[C:20]([CH2:22][CH3:23])[S:19][C:17]=2[N:18]=1
Reactant: COc1ccc(CN)cc1Cl
Reactant: CCc1cc2c(Cl)nc(Cl)nc2s1
Product: CCc1cc2c(NCc3ccc(OC)c(Cl)c3)nc(Cl)nc2s1

Procedure:
Following the procedure of Example 1, the reaction of 3-chloro-4-methoxybenzylamine with 2,4-dichloro-6-ethyl-thieno-[2,3-d]-pyrimidine yields 2-chloro-6-ethyl-4-(3-chloro-4-methoxybenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH:1]([PH:4][CH:5]([CH3:7])[CH3:6])([CH3:3])[CH3:2].CN([CH2:11][C-:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[CH2:17]N(C)C)C.[CH-:21]1[CH:25]=[CH:24][CH:23]=[CH:22]1.[Fe+2:26]>C(O)(=O)C>[CH:1]([P:4]([CH2:11][C-:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[CH2:17][P:4]([CH:25]([CH3:24])[CH3:21])[CH:1]([CH3:3])[CH3:2])[CH:5]([CH3:7])[CH3:6])([CH3:3])[CH3:2].[CH-:21]1[CH:25]=[CH:24][CH:23]=[CH:22]1.[Fe+2:26]
Reactant: CN(C)Cc1ccc[c-]1CN(C)C
Reactant: CC(C)PC(C)C
Agent: [Fe+2]
Agent: c1cc[cH-]c1
Solvent: CC(=O)O
Product: CC(C)P(Cc1ccc[c-]1CP(C(C)C)C(C)C)C(C)C

Procedure:
The title compound was prepared in accordance with the procedure of Example 10 employing di-iso-propylphosphine (Digital Speciality Chemicals 392 mg, 3.33 mmol), 1,2-bis(dimethylaminomethyl)ferrocene (0.5 g, 1.66 mmol) and anhydrous acetic acid (100 ml). Yield 0.262 g.
Reaction SMILES: [Cl:1][C:2]1[C:15]2[O:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:16])[C:6]=2[CH:5]=[CH:4][C:3]=1[OH:17].C(=O)([O-])[O-].[K+].[K+].Br[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27].CN(C=O)C>O>[Cl:1][C:2]1[C:15]2[O:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:16])[C:6]=2[CH:5]=[CH:4][C:3]=1[O:17][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27]
Reactant: CCOC(=O)CBr
Reactant: O=c1c2ccccc2oc2c(Cl)c(O)ccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)COc1ccc2c(=O)c3ccccc3oc2c1Cl
Reaction time: 3 h
Yield: 67.9 %

Procedure:
A mixture of 1.2 g of 4-chloro-3-hydroxy-9-oxo-9H-xanthene, 1.7 g of potassium carbonate, 2.1 g of ethyl bromoacetate and 30 ml of DMF was stirred at 60°-70° C. for 3 hours. After cooling the mixture, water was added and the resulting crystal was recovered by filtration, washed with water and dried. Recrystallization from ethanol gave 1.1 g of ethyl 4-chloro-9-oxo-9H-xanthene-3-yloxyacetate. m.p. 183°-185° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:8]O)[CH:5]=[N:6][CH:7]=1.P(Br)(Br)[Br:11]>ClCCl>[BrH:11].[Br:11][CH2:8][C:4]1[CH:5]=[N:6][CH:7]=[C:2]([F:1])[CH:3]=1
Reactant: OCc1cncc(F)c1
Reactant: BrP(Br)Br
Solvent: ClCCl
Product: Br
Product: Fc1cncc(CBr)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (5-fluoropyridin-3-yl)methanol (430 mg, 3.4 mmol) in anhydrous dichloromethane (30 mL) was added dropwise phosphorus tribromide (650 μL, 6.8 mmol). The mixture was stirred at room temperature overnight. Dichloromethane was evaporated. The residue was dried in vacuo, affording 3-(bromomethyl)-5-fluoropyridine hydrobromide. The product was used without further purification.
Reaction SMILES: [CH3:1][S:2][CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[NH:11][CH:10]=[CH:9]2.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20](O)[C:21]2[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][CH:22]=2)=[CH:16][CH:15]=1.FC1C=CC(C(C2C=CC(F)=CC=2)C2C3C(=C(CSC)C=CC=3)NC=2)=CC=1>>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([CH:20]([C:9]2[C:8]3[C:12](=[C:4]([CH2:3][S:2][CH3:1])[CH:5]=[CH:6][CH:7]=3)[NH:11][CH:10]=2)[C:21]2[CH:22]=[CH:23][C:24]([C:25]#[N:26])=[CH:27][CH:28]=2)=[CH:18][CH:19]=1
Reactant: N#Cc1ccc(C(O)c2ccc(Cl)cc2)cc1
Reactant: CSCc1cccc2cc[nH]c12
Agent: CSCc1cccc2c(C(c3ccc(F)cc3)c3ccc(F)cc3)c[nH]c12
Product: CSCc1cccc2c(C(c3ccc(Cl)cc3)c3ccc(C#N)cc3)c[nH]c12

Procedure:
The title compound was prepared starting from 750 mg (4.23 mmol) of the compound from Example 8A and 1.03 g (4.23 mmol) of the compound from Example 174A in analogy to the synthesis of the compound from Example 278. 248 mg (15% of theory) of the target compound were obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([I:11])[CH:10]=1)[C:5]([OH:7])=[O:6].O=S(Cl)Cl.[CH3:16]O>>[CH3:16][O:6][C:5](=[O:7])[C:4]1[CH:8]=[C:9]([I:11])[CH:10]=[C:2]([Br:1])[CH:3]=1
Reactant: CO
Reactant: O=C(O)c1cc(Br)cc(I)c1
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc(Br)cc(I)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 75 %

Procedure:
To a suspension of 3-bromo-5-iodo-benzoic acid (6.5 g, 20 mmol) in 25 mL of methanol was added SOCl2 (1.14 mL, 40 mmol) dropwise at 0° C. The mixture was then warmed to room temperature and stirred at room temperature for 2 days. The precipitates formed were collected by filtration to afford the desired product as white solid 5.12 g (75%). LC/MS m/e calcd. for C8H6BrIO2: 341, observed (M+H)+: 342.2.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][C:6]([NH:12][C:13]3[CH:18]=[C:17]([C:19]4[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=4)[N:16]=[CH:15][N:14]=3)=[CH:7][CH:8]=2)[N:3]=1.[CH3:29][NH2:30]>CCO>[ClH:1].[ClH:1].[CH3:29][NH:30][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][C:6]([NH:12][C:13]3[CH:18]=[C:17]([C:19]4[CH:24]=[CH:23][C:22]([C:25]([F:26])([F:27])[F:28])=[CH:21][CH:20]=4)[N:16]=[CH:15][N:14]=3)=[CH:7][CH:8]=2)[N:3]=1
Reactant: FC(F)(F)c1ccc(-c2cc(Nc3ccc4ccc(Cl)nc4c3)ncn2)cc1
Reactant: CN
Solvent: CCO
Product: CNc1ccc2ccc(Nc3cc(-c4ccc(C(F)(F)F)cc4)ncn3)cc2n1
Product: Cl
Temperature: 160 °C

Procedure:
(2-Chloroquinolin-7-yl)-[6-(4-trifluoromethyl-phenyl)pyrimidin-4-yl]amine, Example 13(b), (100 mg, 0.25 mmol) was dissolved in satd methylamine in EtOH [2 mL, prepared by bubbling methylamine (Aldrich) into EtOH at 0° C.]. The solution was heated in a microwave at 160° C. for 20 min. Additional satd methylamine in EtOH (2 mL) was added and the reaction mixture was heated again in a microwave at 160° C. for 20 min. The mixture was concentrated in vacuo, redissolved in satd methylamine in EtOH (2 mL), and heated for an additional 20 min at 160° C. The mixture was concentrated in vacuo and the residue suspended in 1 N HCl (20 mL) and EtOAc (50 mL). The suspension was shaken vigorously and the solid collected by filtration, washed with water (20 mL), EtOAc (20 mL), hexane (20 μL) and air-dried. The solid was dissolved in MeOH, and concentrated in vacuo to provide the title product as a yellow amorphous solid. MS (ESI, pos. ion) m/z: 396 (M+1).
Reaction SMILES: [F:1][C:2]1[C:10]([F:11])=[CH:9][C:8]([F:12])=[C:7]([F:13])[C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:16])=O>>[Cl:16][C:4]([C:3]1[C:2]([F:1])=[C:10]([F:11])[CH:9]=[C:8]([F:12])[C:7]=1[F:13])=[O:5]
Reactant: O=C(O)c1c(F)c(F)cc(F)c1F
Reactant: O=S(Cl)Cl
Product: O=C(Cl)c1c(F)c(F)cc(F)c1F

Procedure:
A mixture of 2,3,5,6-tetrafluorobenzoic acid (25 g) and thionyl chloride (40 cm3) was heated at the reflux temperature for 3 hours after which the excess thionyl chloride was removed by evaporation under reduced pressure to leave a residue of 1-chlorocarbonyl-2,3,5,6-tetrafluorobenzene. To this was added an excess of dry methanol and the mixture stirred for one hour at the ambient temperature. Removal of excess methanol by evaporation under reduced pressure gave methyl 2,3,5,6-tetrafluorobenzoate (19 g) as a mobile liquid.
Reaction SMILES: ClCCCC([O:11]C(=O)C)CCCCC.ClCCCC(OC(=O)C)CCCC(C)(C)C.C([O:34][CH:35]([CH2:53][CH2:54][CH2:55][C:56]([CH3:59])(C)[CH3:57])[CH2:36][CH2:37][CH2:38][N:39]([CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][C:48]([O:50]CC)=[O:49])[C:40]#[N:41])(=O)C>>[OH:34][C@H:35]([CH2:53][CH2:54][CH2:55][CH2:56][CH3:57])[C:36]#[C:37][CH2:38][N:39]([CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][C:48]([OH:50])=[O:49])[C:40]#[N:41].[OH:34][C@H:35]([CH2:53][CH2:54][CH2:55][CH2:56][CH3:59])[C:36]#[C:37][CH2:38][N:39]([CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][C:48]([OH:50])=[O:49])[C:40]([NH2:41])=[O:11]
Reactant: CCCCCC(CCCCl)OC(C)=O
Reactant: CCOC(=O)CCCCCCN(C#N)CCCC(CCCC(C)(C)C)OC(C)=O
Agent: CC(=O)OC(CCCCl)CCCC(C)(C)C
Product: CCCCC[C@@H](O)C#CCN(C#N)CCCCCCC(=O)O
Product: CCCCC[C@@H](O)C#CCN(CCCCCCC(=O)O)C(N)=O

Procedure:
The synthesis of this compound is carried out as described in Example 1 except that, in Step A, the 1-chloro-4-acetoxynonane is replaced by an equimolar amount of 1-chloro-4-acetoxy-8,8-dimethylnonane (Example D). The product of Step A is thus ethyl 7-[N-(4-acetoxy-8,8-dimethylnonyl)cyanamido]heptanoate. The subsequent steps yield 7-[N-(4-hydroxy-8,8-dimethylnonyl)cyanamido]-heptanoic acid (B) and 7-[1-(4-hydroxy-8,8-dimethylnonyl)ureido]heptanoic acid (C).
Reaction SMILES: [F:1][C:2]1[C:3]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([I:31])=[CH:27][C:26]=2[F:32])=[C:4]([CH:12]=[C:13]([CH2:16][NH:17][O:18][CH2:19][CH2:20][S:21]([CH3:23])=[O:22])[C:14]=1[F:15])[C:5]([NH:7][O:8][CH2:9][CH2:10][OH:11])=[O:6].CO.I([O-])(=O)(=O)=[O:36].[Na+]>O>[F:1][C:2]1[C:3]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([I:31])=[CH:27][C:26]=2[F:32])=[C:4]([CH:12]=[C:13]([CH2:16][NH:17][O:18][CH2:19][CH2:20][S:21]([CH3:23])(=[O:36])=[O:22])[C:14]=1[F:15])[C:5]([NH:7][O:8][CH2:9][CH2:10][OH:11])=[O:6]
Reactant: CS(=O)CCONCc1cc(C(=O)NOCCO)c(Nc2ccc(I)cc2F)c(F)c1F
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CS(=O)(=O)CCONCc1cc(C(=O)NOCCO)c(Nc2ccc(I)cc2F)c(F)c1F
Reaction time: 17 h
Yield: 12.7 %

Procedure:
To a solution of 3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(2-methanesulfinyl-ethoxyamino)-methyl]-benzamide (10 mg, 0.017 mmol) obtained in Example 10 in a mixed solvent of methanol (1.8 mL) and water (0.2 mL) was added sodium metaperiodate (6 mg, 0.026 mmol) at room temperature, and the mixture was stirred for 17 hours. After completion of the reaction, the reaction mixture was extracted with ethyl acetate, and the organic layer was washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resultant residue was purified by preparative TLC (No. 5744, Merck, 5% methanol/methylene chloride as a developing solvent) to give 3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(2-methanesulfonyl-ethoxyamino)-methyl]-benzamide (1.3 mg, 13%) as an off-white solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][CH2:8][C@H:9]1[CH2:14][CH2:13][C@@H:12]([CH2:15][NH:16]C(OC(C)(C)C)=O)[CH2:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2].Cl.CC(OC(OC(OC(C)(C)C)=O)=O)(C)C>C(Cl)Cl.CCOC(C)=O>[C:1]([O:5][C:6](=[O:24])[NH:7][CH2:8][C@H:9]1[CH2:10][CH2:11][C@@H:12]([CH2:15][NH2:16])[CH2:13][CH2:14]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC[C@H]1CC[C@@H](CNC(=O)OC(C)(C)C)CC1
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC[C@H]1CC[C@@H](CN)CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of cis-[4-(tert-butoxycarbonylamino-methyl)-cyclohexylmethyl]-carbamic acid tert-butyl ester (2.55 g, 7.45 mmol) in CH2Cl2 (40 mL) was added 4 M hydrogen chloride in EtOAc (4 mL). The reaction mixture was stirred at ambient temperature for 5 hr and concentrated. The residue was dissolved in 1,4-dioxane (20 mL) and 10% aqueous sodium hydroxide (40 mL) and the resulting solution was cooled on an ice-bath. (Boc)2O (829 mg, 3.80 mmol) was added dropwise and the mixture was stirred at ambient temperature for 3 h. The aqueous layer was extracted with CHCl3 (three times). The combined organic layer was dried over MgSO4, filtered and concentrated, and purified by flash chromatography (silica gel, 9% MeOH in CHCl3) to give cis-(4-aminomethyl-cyclohexylmethyl)-carbamic acid tert-butyl ester (255 mg, 14%) as a pale yellow oil.
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([C:13](O)=[O:14])[C:10]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]3[N:27]=[C:28]([C:32]4[O:33][CH:34]=[CH:35][CH:36]=4)[O:29][C:30]=3[CH3:31])=[CH:20][CH:19]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C([N:40]=C=NCCCN(C)C)C.CN(C)C=O>O>[CH2:1]([N:8]1[CH:12]=[C:11]([C:13]([NH2:40])=[O:14])[C:10]([O:16][CH2:17][C:18]2[CH:19]=[CH:20][C:21]([O:24][CH2:25][C:26]3[N:27]=[C:28]([C:32]4[O:33][CH:34]=[CH:35][CH:36]=4)[O:29][C:30]=3[CH3:31])=[CH:22][CH:23]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1oc(-c2ccco2)nc1COc1ccc(COc2nn(Cc3ccccc3)cc2C(=O)O)cc1
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: Cc1oc(-c2ccco2)nc1COc1ccc(COc2nn(Cc3ccccc3)cc2C(N)=O)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 100.2 %

Procedure:
A mixture of 1-benzyl-3-[(4{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}benzyl)oxy]-1H-pyrazole-4-carboxylic acid (1.10 g), 1-hydroxybenzotriazole ammonia complex (0.53 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.67 g) and N,N-dimethylformamide (50 mL) was stirred at room temperature for 3 days. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give 1-benzyl-3-[(4{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}benzyl)oxy]-1H-pyrazole-4-carboxamide as pale-yellow crystals (1.10 g, yield 99%). Recrystallization from ethyl acetate-hexane gave pale-yellow prism crystals. melting point: 139-140° C.
Reaction SMILES: C([C:3]1[CH:11]=[CH:10][C:9]2[N:8](CC)[C:7]3[CH2:14][CH2:15][CH2:16][C:6]=3[C:5]=2[CH:4]=1)#N.CC(C[AlH]C[CH:23]([CH3:25])C)C.[C:26](C(C(C([O-])=O)O)O)([O-])=[O:27].[K+].[Na+]>ClCCl>[CH2:23]([C:16]1[C:6]2[C:7]([N:8]=[C:9]3[C:5]=2[CH:4]=[CH:3][CH:11]=[C:10]3[CH:26]=[O:27])=[CH:14][CH:15]=1)[CH3:25]
Reactant: CC(C)C[AlH]CC(C)C
Reactant: CCn1c2c(c3cc(C#N)ccc31)CCC2
Reactant: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [K+]
Agent: [Na+]
Solvent: ClCCl
Product: CCC1=CC=C2N=c3c(C=O)cccc3=C12
Reaction time: 15 h

Procedure:
A solution of 7-cyano-4-ethyl-1,2,3,4-tetrahydrocyclopent[b]indole (0.28 g, 1.33 mmol) in dichloromethane (15 mL) was cooled in an ice-bath then treated with DIBAL-H (0.189 g, 1.33 mmol). The reaction was then allowed to reach room temperature and was stirred for 15 hours before diluting with dichloromethane and pouring into a saturated solution of sodium potassium tartrate. The organic layer was separated then washed with brine. The crude product was purified by column chromatography eluting with dichloromethane, to afford 0.2 g of title compound.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][C@H:8]2[CH2:10][C@@H:5]1[CH2:6][N:7]2[C:11]1[CH:17]=[CH:16][C:14]([NH2:15])=[CH:13][CH:12]=1)([CH3:3])[CH3:2].[Br:18][C:19]1[N:24]2[N:25]=[CH:26][N:27]=[C:23]2[C:22](Br)=[N:21][CH:20]=1>C(N(CC)CC)C>[Br:18][C:19]1[N:24]2[N:25]=[CH:26][N:27]=[C:23]2[C:22]([NH:15][C:14]2[CH:13]=[CH:12][C:11]([N:7]3[CH2:6][C@H:5]4[CH2:10][C@@H:8]3[CH2:9][N:4]4[CH:1]([CH3:3])[CH3:2])=[CH:17][CH:16]=2)=[N:21][CH:20]=1
Reactant: CC(C)N1C[C@H]2C[C@@H]1CN2c1ccc(N)cc1
Reactant: Brc1ncc(Br)n2ncnc12
Solvent: CCN(CC)CC
Product: CC(C)N1C[C@H]2C[C@@H]1CN2c1ccc(Nc2ncc(Br)n3ncnc23)cc1

Procedure:
To the solution obtained from step 2 is added 5,8-dibromo[1,2,4]triazolo[1,5-a]-pyrazine (1.6 g; 5.8 mmol) and triethylamine (3.4 mL). The resulting mixture was heated at reflux for 70 h, after which the reactor contents were cooled down and filtered to remove solids. The filter cake was washed with 2-MeTHF (2×5 mL) and the filtrate used as such in the next step.
Reaction SMILES: C([O:5][C:6](=O)/[C:7](=[CH:19]/[C:20]1[CH:25]=[CH:24][C:23]([N:26]2[CH:30]=[C:29]([CH3:31])[N:28]=[CH:27]2)=[C:22]([O:32][CH3:33])[CH:21]=1)/[CH2:8][CH2:9][NH:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=1)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[F:18][C:14]1[CH:13]=[C:12]([CH:17]=[CH:16][CH:15]=1)[CH2:11][N:10]1[CH2:9][CH2:8]/[C:7](=[CH:19]\[C:20]2[CH:25]=[CH:24][C:23]([N:26]3[CH:30]=[C:29]([CH3:31])[N:28]=[CH:27]3)=[C:22]([O:32][CH3:33])[CH:21]=2)/[C:6]1=[O:5]
Reactant: COc1cc(/C=C(\CCNCc2cccc(F)c2)C(=O)OC(C)(C)C)ccc1-n1cnc(C)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(/C=C2\CCN(Cc3cccc(F)c3)C2=O)ccc1-n1cnc(C)c1
Yield: 60.8 %

Procedure:
To a methylene chloride (0.5 mL) solution of (E)-4-(3-fluorobenzylamino)-2-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]butyric acid tert-butyl ester (4.50 mg), trifluoroacetic acid (500 μL) was added. After agitating reaction solution at room temperature for 1.5 hours and agitating that materials disappeared, reaction solution was concentrated under reduced pressure as it was. The residue was dissolved in DMF (0.5 mL), IPEA (17.0 μL), EDC (5.58 mg), and HOBT (3.93 mg) were added to the reaction solution one by one, and the reaction solution was agitated at room temperature for 1.5 hours. After confirming disappearance of the starting materials, water and ethyl acetate were added to the reaction solution, and the organic layer was partitioned. After the obtained organic layer was washed with a saturated saline solution, it was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent: ethyl acetate->ethyl acetate:ethanol=20:1), and 2.30 mg of the title compound was obtained.
Reaction SMILES: Br[C:2]1[C:3]2[C:4]3[CH:17]=[CH:16][S:15][C:5]=3[C:6](=[O:14])[NH:7][C:8]=2[CH:9]=[CH:10][C:11]=1[O:12][CH3:13].[F:18][C:19]1[CH:24]=[C:23](B2OC(C)(C)C(C)(C)O2)[CH:22]=[CH:21][C:20]=1[CH:34]([CH3:44])[CH2:35][NH:36][C:37](=[O:43])[O:38][C:39]([CH3:42])([CH3:41])[CH3:40]>>[F:18][C:19]1[CH:24]=[C:23]([C:2]2[C:3]3[C:4]4[CH:17]=[CH:16][S:15][C:5]=4[C:6](=[O:14])[NH:7][C:8]=3[CH:9]=[CH:10][C:11]=2[O:12][CH3:13])[CH:22]=[CH:21][C:20]=1[CH:34]([CH3:44])[CH2:35][NH:36][C:37](=[O:43])[O:38][C:39]([CH3:41])([CH3:40])[CH3:42]
Reactant: CC(CNC(=O)OC(C)(C)C)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1F
Reactant: COc1ccc2[nH]c(=O)c3sccc3c2c1Br
Product: COc1ccc2[nH]c(=O)c3sccc3c2c1-c1ccc(C(C)CNC(=O)OC(C)(C)C)c(F)c1
Yield: 49.4 %

Procedure:
Following General Procedure B, 9-bromo-8-methoxythieno[2,3-c]quinolin-4(5H)-one (1.2 g, 3.8 mmol) was reacted with tert-butyl 2-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propylcarbamate (2.2 g, 5.8 mmol) to afford the desired product (905 mg, 51%) as a brown solid: ESI MS m/z 483 [C26H27FN2O4S+H]+.
Reaction SMILES: [CH:1](NC(C)C)(C)C.C([Li])CCC.[CH3:13][O:14][C:15]([CH:17]1[CH2:22][CH2:21][CH:20]([C:23]([OH:25])=[O:24])[CH2:19][CH2:18]1)=[O:16].IC>C1COCC1>[CH3:13][O:14][C:15]([C:17]1([CH3:1])[CH2:22][CH2:21][CH:20]([C:23]([OH:25])=[O:24])[CH2:19][CH2:18]1)=[O:16]
Reactant: CC(C)NC(C)C
Reactant: COC(=O)C1CCC(C(=O)O)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CI
Product: COC(=O)C1(C)CCC(C(=O)O)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
N,N-Diisopropylamine (1.18 mL, 8.35 mmol) was added dropwise to a 2M solution of n butyllithium (4.18 mL, 8.4 mmol) at −78° C. under nitrogen. After 15 min at this temperature the solution was raised to and held at 0° C. for 15 min prior to re-cooloing to −78° C. and treatment with a solution of 4-(methoxycarbonyl)cyclohexanecarboxylic acid (0.62 g, 3.34 mmol) in THF (8 mL). After 30 min., iodomethane (0.31 mL, 5 mmol) was added dropwise and the mixture was allowed to warm to rt over 2 hr. The mixture was cooled to at 0° C., quenched with 2 N HCl (10 mL) then was extracted with EtOAc (2×10 mL), washed with brine (3×15 mL), and dried over anhydrous magnesium sulfate. Concentration of the combined organic extracts afforded a yellow solid. NMR (CDCl3) consistent with crude, desired product.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[CH2:3][NH:4][C:5]([C:7]1([CH2:20][CH2:21][CH2:22][CH2:23]Br)[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6].[C:27]1([N:33]2[C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=3[N:35]=[C:34]2[N:42]2[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[F:1][C:2]([F:26])([F:25])[CH2:3][NH:4][C:5]([C:7]1([CH2:20][CH2:21][CH2:22][CH2:23][N:45]2[CH2:46][CH2:47][N:42]([C:34]3[N:33]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[C:37]4[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=4[N:35]=3)[CH2:43][CH2:44]2)[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6]
Reactant: c1ccc(-n2c(N3CCNCC3)nc3ccccc32)cc1
Reactant: O=C(NCC(F)(F)F)C1(CCCCBr)c2ccccc2-c2ccccc21
Product: O=C(NCC(F)(F)F)C1(CCCCN2CCN(c3nc4ccccc4n3-c3ccccc3)CC2)c2ccccc2-c2ccccc21

Procedure:
Prepared analogously to Example 10 from 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-(2,2,2-trifluoro-ethyl)-amide and 1-phenyl-2-(piperazin-1-yl)-1H-benzimidazole.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1B(O)O.Br[C:12]1[C:17]([O:18][CH3:19])=[CH:16][C:15]([NH:20]C(=O)C)=[C:14]([CH3:24])[CH:13]=1.CC1C=C(C=CC=1C1C=NC=CC=1C)N>>[CH3:19][O:18][C:17]1[C:12]([C:3]2[CH:4]=[N:5][CH:6]=[CH:7][C:2]=2[CH3:1])=[CH:13][C:14]([CH3:24])=[C:15]([CH:16]=1)[NH2:20]
Reactant: COc1cc(NC(C)=O)c(C)cc1Br
Reactant: Cc1ccncc1B(O)O
Agent: Cc1cc(N)ccc1-c1cnccc1C
Product: COc1cc(N)c(C)cc1-c1cnccc1C

Procedure:
Intermediate 22 was prepared from Intermediate 1A and Intermediate 22B by the procedures described for the preparation of Intermediate 1, and was obtained as a pale yellow solid (55% yield). MS (ES): m/z=229.3 [M+H]+. Intermediate 22 was used in the synthesis of Example 20.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:16]([O:17][CH3:18])=[CH:15][C:6]([CH2:7][O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]=[CH2:14])=[C:5]([N+:19]([O-:21])=[O:20])[CH:4]=1.[CH3:22][O:23][SiH:24]([O:27][CH3:28])[O:25][CH3:26]>[H+].[H+].O.O.O.O.O.O.Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl>[CH3:22][O:23][Si:24]([O:27][CH3:28])([O:25][CH3:26])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][O:8][CH2:7][C:6]1[CH:15]=[C:16]([O:17][CH3:18])[C:3]([O:2][CH3:1])=[CH:4][C:5]=1[N+:19]([O-:21])=[O:20]
Reactant: C=CCCCCOCc1cc(OC)c(OC)cc1[N+](=O)[O-]
Reactant: CO[SiH](OC)OC
Agent: Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl
Agent: [H+]
Solvent: O
Product: COc1cc(COCCCCCC[Si](OC)(OC)OC)c([N+](=O)[O-])cc1OC
Temperature: 37 °C
Reaction time: 0.5 h
Yield: 33.5 %

Procedure:
A 20-ml eggplant type flask was purged with nitrogen, and charged with 2.95 g (10.0 mmol) of 5-hexenyl 4,5-dimethoxy-2-nitrobenzyl ether, 1.47 g (12 mmol) of trimethoxysilane, and an infinitesimal amount of hydrogen hexachloroplatinate(IV) hexahydrate (H2PtCl6·6H2O), followed by stirring at 37° C. for 30 minutes. Thereafter, the bath temperature was raised to 100° C., and the reaction was completed in 2 hours. The reaction mixture was purified by silica gel column chromatography using a medium-pressure column. Using a mixture of hexane, ethyl acetate and tetramethoxysilane (in a volume ratio of 100:20:1) as the eluent, 1.4 g (3.35 mmol) of the desired product was obtained in a 34% yield. Its Rf value (for the aforesaid eluent) was 0.1.
Reaction SMILES: Br[CH:2]([C:13]1[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][CH:14]=1)[C:3]([C:5]1[CH:10]=[CH:9][C:8]([S:11][CH3:12])=[CH:7][CH:6]=1)=O.[C:20]([NH2:23])(=[S:22])[CH3:21]>C(O)C>[Br:19][C:16]1[CH:17]=[CH:18][C:13]([C:2]2[S:22][C:20]([CH3:21])=[N:23][C:3]=2[C:5]2[CH:10]=[CH:9][C:8]([S:11][CH3:12])=[CH:7][CH:6]=2)=[CH:14][CH:15]=1
Reactant: CC(N)=S
Reactant: CSc1ccc(C(=O)C(Br)c2ccc(Br)cc2)cc1
Solvent: CCO
Product: CSc1ccc(-c2nc(C)sc2-c2ccc(Br)cc2)cc1
Yield: 56.1 %

Procedure:
A mixture of 2-bromo2-(4-bromophenyl)-1-(4-methylthiophenyl)ethanone (7.6 g, 0.018 mol) and thioacetamide 1.4 g, 0.018 mol) in ethanol (150 mL) was refluxed for 1 day. The mixture was concentrated and the solid was purified by flash chromatography eluting with CH2Cl2/hexane (2/1) to give title compound (3.8 g, 56%).