Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([C:9]2[N:10]([CH2:18][CH3:19])[C:11]3[CH:16]=[CH:15][N:14]=[CH:13][C:12]=3[N:17]=2)[C:5]([NH2:8])=[N:6][CH:7]=1.B([C:23]1[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][CH:24]=1)(O)O.C([O-])([O-])=O.[K+].[K+]>CN(C)C=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:8][C:5]1[N:6]=[CH:7][C:2]([C:25]2[CH:24]=[CH:23][CH:31]=[CH:30][C:26]=2[C:27]([OH:29])=[O:28])=[N:3][C:4]=1[C:9]1[N:10]([CH2:18][CH3:19])[C:11]2[CH:16]=[CH:15][N:14]=[CH:13][C:12]=2[N:17]=1
Reactant: O=C(O)c1ccc(B(O)O)cc1
Reactant: CCn1c(-c2nc(Br)cnc2N)nc2cnccc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCn1c(-c2nc(-c3ccccc3C(=O)O)cnc2N)nc2cnccc21
Temperature: 200 °C
Reaction time: 0.13 h
Yield: 8.9 %

Procedure:
5-bromo-3-(1-ethyl-1H-imidazo[4,5-c]pyridin-2-yl)pyrazin-2-amine (0.032 g, 0.10 mmol) (made in example 2), 4-boronobenzoic acid (0.033 g, 0.20 mmol), Pd(PPh3)2Cl2 (0.0035 g, 0.005 mmol) and K2CO3 (0.050 g, 0.36 mmol) were combined in 0.5 mL of N,N-dimethylformamide and heated to 200° C. in the SmithSynthesizer microwave for 8 minutes and then for a further 8 minutes at 250° C. The reaction mixture was concentrated in vacuo and the residue purified by mass directed HPLC to give 0.0032 g of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[CH:16][C:3]=1[C:4]([N:6]([CH3:15])[NH:7]C(OC(C)(C)C)=O)=[O:5]>Cl.O1CCOCC1>[F:1][C:2]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[CH:16][C:3]=1[C:4]([N:6]([CH3:15])[NH2:7])=[O:5]
Reactant: CN(NC(=O)OC(C)(C)C)C(=O)c1ccc([N+](=O)[O-])cc1F
Agent: Cl
Solvent: C1COCCO1
Product: CN(N)C(=O)c1ccc([N+](=O)[O-])cc1F

Procedure:
A solution of 3.6 g (11.5 mmol) of tert-butyl 2-(2-fluoro-4-nitrobenzoyl)-2-methylhydrazinecarboxylate in 57 ml of 4-molar hydrochloric acid/dioxane solution was stirred at RT for 3 h. The reaction mixture was concentrated under reduced pressure and the residue was taken up in ethyl acetate and washed with saturated aqueous sodium bicarbonate solution. The organic phase was dried (sodium sulphate), filtered and concentrated under reduced pressure. Yield: 2.0 g (81% of theory)
Reaction SMILES: [C:1]([O:4][C:5](=[O:7])[CH3:6])(=O)[CH3:2].Cl.[C:9]([N:12]1[C:16]2[CH:17]=[CH:18][C:19]([Cl:21])=[CH:20][C:15]=2[S:14][CH:13]1[C:22]1[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:23]=1[O:30][CH2:31][CH2:32][CH2:33][N:34](CCO)[CH:35]([CH3:37])[CH3:36])(=[O:11])[CH3:10].N1C=CC=CC=1>C(=O)([O-])O.[Na+]>[ClH:21].[C:5]([O:4][CH2:1][CH2:2][N:34]([CH2:33][CH2:32][CH2:31][O:30][C:23]1[CH:24]=[CH:25][C:26]([O:28][CH3:29])=[CH:27][C:22]=1[CH:13]1[N:12]([C:9](=[O:11])[CH3:10])[C:16]2[CH:17]=[CH:18][C:19]([Cl:21])=[CH:20][C:15]=2[S:14]1)[CH:35]([CH3:36])[CH3:37])(=[O:7])[CH3:6]
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc(OCCCN(CCO)C(C)C)c(C2Sc3cc(Cl)ccc3N2C(C)=O)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: COc1ccc(OCCCN(CCOC(C)=O)C(C)C)c(C2Sc3cc(Cl)ccc3N2C(C)=O)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 171.3 %

Procedure:
Acetic anhydride (0.26 ml, 2.91 mmol) was added to a solution of 3-acetyl-6-chloro-2-[2-(3-(N-(2-hydroxyethyl)-N-isopropylamino)-propoxy)-5-methoxyphenyl]benzothiazoline hydrochloride (300 m g, 0.58 mmol) in pyridine (0.47 ml, 5.80 mmol) under ice-cooling, and then the mixture was stirred at room temperature for two hours. A saturated aqueous sodium hydrogencarbonate solution (50 ml) was added to the reaction mixture, and the whole was extracted with ethyl acetate (50 ml). The ethyl acetate layer was washed with saturated brine (50 ml) and dehydrated with anhydrous magnesium sulfate, and ethyl acetate was evaporated under reduced pressure. The obtained oily matter was dissolved in ethyl acetate (1 ml), and then a 4 N solution (0.5 ml) of hydrogen chloride in ethyl acetate. The mixture was concentrated under reduced pressure to give 277 mg (92%) of the target compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1.[Br:14][CH:15](O)[CH2:16][CH3:17].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[Br:14][CH2:15][CH2:16][CH2:17][O:12][C:9]1[CH:10]=[CH:11][C:6](/[CH:5]=[CH:4]/[C:3]([O:2][CH3:1])=[O:13])=[CH:7][CH:8]=1
Reactant: COC(=O)C=Cc1ccc(O)cc1
Reactant: CCC(O)Br
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)/C=C/c1ccc(OCCCBr)cc1
Reaction time: 8 h

Procedure:
To a solution 5 g (28.1 mmol) of 4-Hydroxycinnamic acid methyl ester, 4.9 g (35.1 mmol) of 4 bromopropanol, 9.2 g (35.1 mmol) of triphenylphosphine in 100 mL of THF are added 7.1 g (35.1 mmol) of diisopropylazodicarboxylate under inert atmosphere. The solution is heated up to reflux and allowed to stir overnight. After 20 hours, the reaction mixture is partitioned between EtOAc and water. The organic phase is washed repeatedly with water, dried over sodium sulphate, filtered and concentrated by rotary evaporation to give 7.5 g of (methyl (2E)-3-[4-(3-bromopropoxy)phenyl]prop-2-enoate.
Reaction SMILES: Cl[CH:2]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[F:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N+:21]([O-:23])=[O:22].Cl>CN(C=O)C.O>[F:14][C:15]1[CH:20]=[C:19]([CH:2]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH:18]=[CH:17][C:16]=1[N+:21]([O-:23])=[O:22]
Reactant: CCOC(=O)C(Cl)c1ccccc1
Reactant: O=[N+]([O-])c1ccccc1F
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(c1ccccc1)c1ccc([N+](=O)[O-])c(F)c1
Temperature: -45 °C
Reaction time: 0.33 h
Yield: 44.4 %

Procedure:
9.8 g of potassium tert. butylate were dissolved in 90 ml of DMF and cooled to −45° C. For this purpose, a mix of ethyl 2-chloro-2-phenylacetate (43.8 mmol, 8.7 g) and 1-fluoro-2-nitrobenzene (43.8 mmol, 4.6 ml) was carefully added dropwise and the mixture was stirred for a further 20 minutes. The reaction mix was set to pH 4 using 16% HCl, diluted with 25 ml of water and extracted with EE (3×50 ml). Once combined, the organic phases were washed with water and sat. aq. NaCl sol., dried over MgSO4 and concentrated under vacuum. The residue obtained was purified by column chromatography (silica gel: mesh 100-200, eluent: 10% EE in cyclohexane) and produced 5.9 g (44.9%) of product.
Reaction SMILES: [NH2:1][C:2]1[C:23]([Cl:24])=[CH:22][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][NH2:21])[CH2:12][CH2:11]2)=[O:7])=[C:4]([O:25][CH3:26])[CH:3]=1.[F:27][C:28]1[CH:35]=[CH:34][C:31]([CH:32]=O)=[CH:30][CH:29]=1>>[NH2:1][C:2]1[C:23]([Cl:24])=[CH:22][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][NH:21][CH2:32][C:31]3[CH:34]=[CH:35][C:28]([F:27])=[CH:29][CH:30]=3)[CH2:14][CH2:15]2)=[O:7])=[C:4]([O:25][CH3:26])[CH:3]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCN)CC1
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCNCc2ccc(F)cc2)CC1
Yield: 89.7 %

Procedure:
4-Amino-N-(1-(5-aminopentyl)piperidin-4-ylmethyl)-5-chloro-2-methoxybenzamide (2 g) as starting compound and 4-fluorobenzaldehyde (0.71 g) were reacted and treated in the same manner as in Example 121 to give 2.3 g of 4-amino-5-chloro-N-((1-(5-(4-fluorobenzylamino)pentyl)-piperidin-4-yl)methyl)-2-methoxybenzamide.
Reaction SMILES: [CH3:1][N:2](P(N(C)C)(N(C)C)=O)[CH3:3].CNC.CO[C:17]1[CH:26]=[CH:25][C:24]2[C:19](=[CH:20][CH:21]=[C:22]([C:27](=[O:39])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[CH:23]=2)[CH:18]=1>C1C=CC=CC=1>[CH3:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][C:27]([C:22]1[CH:21]=[CH:20][C:19]2[CH:18]=[C:17]([N:2]([CH3:3])[CH3:1])[CH:26]=[CH:25][C:24]=2[CH:23]=1)=[O:39]
Reactant: CN(C)P(=O)(N(C)C)N(C)C
Reactant: CCCCCCCCCCCC(=O)c1ccc2cc(OC)ccc2c1
Agent: CNC
Solvent: c1ccccc1
Product: CCCCCCCCCCCC(=O)c1ccc2cc(N(C)C)ccc2c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 66 %

Procedure:
Li (0.5 g, 70 mmol) was added to HMPA (20 ml) and benzene (30 ml), and then dimethylamine (3.5 g, 78 mmol) was added dropwise thereto. The mixture was violently stirred for one hour. To the resulting mixture was added 2-methoxy-6-dodecanoylnaphthalene (7.3 g, 22 mmol) prepared in Comparative Example 1-(1) all at one time. The mixture was stirred at room temperature for 5 hours. The reaction mixture was poured into ice-water, extracted with ether, evaporated to remove the solvents, and recrystallized from ethanol to give Laurdan (5.1 g, yield: 66%).
Reaction SMILES: [NH2:1][C:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([CH2:5]3)[CH2:3]1)[CH2:9]2.[CH2:12]([N:14]([CH2:43][C:44](O)=[O:45])[S:15]([C:18]([F:42])([F:41])[C:19]([F:40])([F:39])[C:20]([F:38])([F:37])[C:21]([F:36])([F:35])[C:22]([F:34])([F:33])[C:23]([F:32])([F:31])[C:24]([F:30])([F:29])[C:25]([F:28])([F:27])[F:26])(=[O:17])=[O:16])[CH3:13].ON1C(=O)CCC1=O>O1CCCC1>[C:2]12([NH:1][C:44](=[O:45])[CH2:43][N:14]([CH2:12][CH3:13])[S:15]([C:18]([F:42])([F:41])[C:19]([F:39])([F:40])[C:20]([F:37])([F:38])[C:21]([F:35])([F:36])[C:22]([F:33])([F:34])[C:23]([F:31])([F:32])[C:24]([F:29])([F:30])[C:25]([F:28])([F:27])[F:26])(=[O:17])=[O:16])[CH2:3][CH:4]3[CH2:10][CH:8]([CH2:7][CH:6]([CH2:5]3)[CH2:11]1)[CH2:9]2
Reactant: NC12CC3CC(CC(C3)C1)C2
Reactant: CCN(CC(=O)O)S(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: O=C1CCC(=O)N1O
Solvent: C1CCOC1
Product: CCN(CC(=O)NC12CC3CC(CC(C3)C1)C2)S(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 0 °C
Reaction time: 2 h

Procedure:
30.95 g (150 mmol) of N,N-dicyclohexylcarbodiimide is added at 0° C. to 15.12 g (100 mmol) of 1-aminoadamantane, 58.52 g (100 mmol) of N-(ethyl)N-(perfluorooctylsulfonyl)-aminoacetic acid and 11.51 g (100 mmol) of N-hydroxysuccinimide, dissolved in 300 ml of tetrahydrofuran. It is stirred for 2 hours at 0° C., then for 6 hours at room temperature. Precipitated urea is filtered out, the filtrate is evaporated to the dry state, and the residue is chromatographed on silica gel (mobile solvent: dichloromethane/acetone=30:1).
Reaction SMILES: [CH2:1]([N:8]([CH2:12][C@H:13]1[NH:17][C:16](=[O:18])[CH2:15][CH2:14]1)[CH2:9][CH2:10][OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>C(O)C.C(Cl)Cl>[CH2:1]([N:8]([CH2:12][C@@H:13]1[CH2:14][CH2:15][C:16](=[O:18])[NH:17]1)[CH2:9][CH2:10][O:11][S:20]([CH3:19])(=[O:22])=[O:21])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CC[C@@H](CN(CCO)Cc2ccccc2)N1
Reactant: CS(=O)(=O)Cl
Solvent: CCO
Solvent: ClCCl
Product: CS(=O)(=O)OCCN(Cc1ccccc1)C[C@@H]1CCC(=O)N1
Temperature: 25 °C
Reaction time: 20 h
Yield: 63 %

Procedure:
To a solution of (S)-(+)-5-((benzyl(2-hydroxyethyl)amino)methyl)pyrrolidin-2-one (3.5 g, 14.1 mmol) in ethanol-free CHCl3 (55 ml), TEA (2.85 g, 28.22 mmol) and methanesulfonyl chloride (3.23 g, 28.22 mmol, in 10 ml of CHCl3) were added at 0° C. The mixture was allowed to warm to room temperature and left stirring for 20 hours, then it was diluted with DCM (60 ml) and washed with a saturated solution of NaHCO3 (3×50 ml). After drying (Na2SO4) and removal of the solvent, the crude was purified by flash chromatography (DCM/abs EtOH/Petroleum Ether/33% NH4OH/Et2O 300/180/900/9.9/360 respectively) to afford the title compound (2.9 g, 63% yield).
Reaction SMILES: [ClH:1].[NH2:2][C@H:3]([C:21]([OH:23])=[O:22])[CH2:4][CH2:5][C:6]([NH:8][C@@H:9]([C:14]([NH:16][CH2:17][C:18]([OH:20])=[O:19])=[O:15])[C:10]([SH:13])([CH3:12])[CH3:11])=[O:7].[N:24](OCC)=[O:25].Cl.CO>CO.C(O)C>[ClH:1].[NH2:2][C@H:3]([C:21]([OH:23])=[O:22])[CH2:4][CH2:5][C:6]([NH:8][C@H:9]([C:14]([NH:16][CH2:17][C:18]([OH:20])=[O:19])=[O:15])[C:10]([S:13][N:24]=[O:25])([CH3:11])[CH3:12])=[O:7]
Reactant: CC(C)(S)[C@@H](NC(=O)CC[C@H](N)C(=O)O)C(=O)NCC(=O)O
Reactant: CCON=O
Agent: Cl
Solvent: CO
Solvent: CCO
Product: CC(C)(SN=O)[C@H](NC(=O)CC[C@H](N)C(=O)O)C(=O)NCC(=O)O
Reaction time: 0.5 h

Procedure:
To the solution of (N-γ-L-glutamyl-D-penicillamyl)glycine hydrochloride (0.5 g) in methanol (5 ml), was added at 0° C. the solution of ethyl nitrite in ethanol (10%) (1.1 ml). At the same temperature a drop of 4N-hydrochloric acid-methanol solution was added, and the mixture was stirred for 30 minutes. The solvent was evaporated off under reduced pressure, and the resultant crystals were washed with diethyl ether, to give (N-γ-L-glutamyl-S-nitroso-L-penicillamyl)glycine hydrochloride (0.5 g).
Reaction SMILES: [OH:1][C@@H:2]([C@@H:9]([N:14]1[C:18](=[O:19])[C:17]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:16]2[C:15]1=[O:24])[CH2:10][CH:11]([CH3:13])[CH3:12])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:25]1(C)C=CC(S(OC)(=O)=O)=CC=1.[H-].[Na+]>C1(C)C=CC=CC=1>[CH3:25][O:1][C@@H:2]([C@@H:9]([N:14]1[C:15](=[O:24])[C:16]2=[CH:23][CH:22]=[CH:21][CH:20]=[C:17]2[C:18]1=[O:19])[CH2:10][CH:11]([CH3:13])[CH3:12])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: COS(=O)(=O)c1ccc(C)cc1
Reactant: CC(C)C[C@@H]([C@H](O)c1ccccc1)N1C(=O)c2ccccc2C1=O
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CO[C@H](c1ccccc1)[C@H](CC(C)C)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C

Procedure:
To a solution of N-[1-(S)-[α-(R)-hydroxybenzyl]-3-methylbutyl]phthalimide (30.4 g, 94.0 mmol.) in toluene (380 mL) were successively added methyl p-toluenesulfonate (19.2 g, 103 mmol.) and 60% sodium hydride (4.13 g, 103 mmol.). The resulting mixture was heated under reflux for 18 hours under stirring, cooled to room temperature, successively washed with water and aqueous saturated sodium chloride solution, dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by middle pressure column chromatography (n-hexane/ethyl acetate=5/1), to give N-[1-(S)-[α-(R)-methoxybenzyl]-3-methylbutyl]phthalimide as a white crystalline product (25.6 g, yield: 81%).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][OH:9])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[C:11]1[CH:12]=[CH:13][C:14]([N+:33]([O-:35])=[O:34])=[C:15]([CH:32]=1)[C:16]([NH:18][C:19]1[CH:24]=[C:23]([C:25]([NH:27][CH:28]2[CH2:30][CH2:29]2)=[O:26])[CH:22]=[CH:21][C:20]=1[CH3:31])=[O:17]>>[CH:28]1([NH:27][C:25]([C:23]2[CH:22]=[CH:21][C:20]([CH3:31])=[C:19]([NH:18][C:16](=[O:17])[C:15]3[CH:32]=[C:11]([N:4]4[CH2:5][CH2:6][N:1]([CH2:7][CH2:8][OH:9])[CH2:2][CH2:3]4)[CH:12]=[CH:13][C:14]=3[N+:33]([O-:35])=[O:34])[CH:24]=2)=[O:26])[CH2:30][CH2:29]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1cc(Cl)ccc1[N+](=O)[O-]
Reactant: OCCN1CCNCC1
Product: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1cc(N2CCN(CCO)CC2)ccc1[N+](=O)[O-]

Procedure:
Using an analogous procedure to that described paragraph (B) in the portion of Example 1 which is concerned with the preparation of starting materials, N-piperazine ethanol was reacted with 5-chloro-N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-2-nitrobenzamide to give N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-5-[4-(2-hydroxyethyl)piperazine-1-yl)-2-nitrobenzamide; NMR Spectrum: (DMSOd6) 0.57 (m, 2H), 0.68 (m, 2H), 2.30 (s, 3H), 2.44 (t, 2H), 2.54 (m, 4H), 2.83 (m, 1H), 3.50 (m, 6H), 4.46 (s, 1H), 7.05 (m, 2H), 7.28 (d, 1H), 7.56 (d, 1H), 7.96 (s, 1H), 8.04 (d, 1H), 8.35 (d, 1H), 9.90 (s, 1H); Mass Spectrum: M+H+ 468.
Reaction SMILES: [CH2:1]1[CH2:13][O:12][C:11]2[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH2:8])=[CH:4][C:3]=2[O:2]1.Cl[C:15]1[C:16]2[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[S:27][C:17]=2[N:18]=[C:19]([C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)[N:20]=1>>[N:23]1[CH:24]=[CH:25][CH:26]=[C:21]([C:19]2[N:20]=[C:15]([NH:8][CH2:7][CH2:6][C:5]3[CH:9]=[CH:10][C:11]4[O:12][CH2:13][CH2:1][O:2][C:3]=4[CH:4]=3)[C:16]3[CH:29]=[C:28]([C:30]([F:33])([F:31])[F:32])[S:27][C:17]=3[N:18]=2)[CH:22]=1
Reactant: FC(F)(F)c1cc2c(Cl)nc(-c3cccnc3)nc2s1
Reactant: NCCc1ccc2c(c1)OCCO2
Product: FC(F)(F)c1cc2c(NCCc3ccc4c(c3)OCCO4)nc(-c3cccnc3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of 3,4-ethylenedioxyphenethylamine with 4-chloro-2-(pyridin-3-yl)-6-trifluoromethyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-3-yl)-4-(3,4-ethylenedioxyphenethylamino)-6-trifluoromethyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: Cl.[F:2][C@@H:3]1[CH2:7][NH:6][C@H:5]([C:8]([NH2:10])=O)[CH2:4]1.[Cl:11][CH2:12][C:13](Cl)=[O:14]>>[Cl:11][CH2:12][C:13]([N:6]1[CH2:7][C@@H:3]([F:2])[CH2:4][C@H:5]1[C:8]#[N:10])=[O:14]
Reactant: NC(=O)[C@@H]1C[C@H](F)CN1
Reactant: O=C(Cl)CCl
Agent: Cl
Product: N#C[C@@H]1C[C@H](F)CN1C(=O)CCl

Procedure:
According to the process for producing (2S,4S)-1-(2-bromoacetyl)-4-fluoropyrrolidine-2-carbonitrile described in the publication of WO 02/38541, (2S,4S)-4-fluoropyrrolidine-2-carboxamide hydrochloride (5.00 g) and chloroacetylchloride (2.60 mL) were used to give (2S,4S)-1-(2-chloroacetyl)-4-fluoropyrrolidine-2-carbonitrile (4.96 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17](I)[CH:16]=1.[F:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14]([C:15]1[CH:16]=[C:17]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[F:23])[CH:18]=[CH:19][CH:20]=1)=[O:22]
Reactant: OB(O)c1ccccc1F
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1cccc(I)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1cccc(-c2ccccc2F)c1
Yield: 73.8 %

Procedure:
N-(2-(5-chloro-1H-indol-3-yl)ethyl)-2′-fluorobiphenyl-3-carboxamide was prepared according to method B with N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3-iodobenzamide (0.075 g; 0.176 mmol), 2-fluorophenylboronic acid (0.026 g; 0.180 mmol), tetrakis(triphenylphosphine)palladium (0.010 g; 0.009 mmol), sodium carbonate (0.037 g; 0.353 mmol), in dimethoxyethane (3 mL) and water (1 mL), irradiated in a microwave oven at 130° C. for 15 minutes. Flash chromatography on silica gel (eluent 2 to 20% ethyl acetate in dichloromethane) furnished 0.051 g (73%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-2′-fluorobiphenyl-3-carboxamide as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]([Br:12])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].Cl.[N:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][C:21](O)=[O:22])[CH:15]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C)C=O>[Br:12][C:9]1[CH:10]=[CH:11][C:2]([NH:1][C:21](=[O:22])[CH2:20][C:16]2[CH:15]=[N:14][CH:19]=[CH:18][CH:17]=2)=[C:3]([CH:8]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cc(Br)ccc1N
Reactant: O=C(O)Cc1cccnc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Br)ccc1NC(=O)Cc1cccnc1
Temperature: 20 °C
Reaction time: 8 h

Procedure:
Into a 250-mL round-bottom flask was placed a solution of methyl 2-amino-5-bromobenzoate (5 g, 21.73 mmol, 100%), 2-(pyridin-3-yl)acetic acid hydrochloride (4.5 g, 25.92 mmol), HATU (10 g, 26.30 mmol 100%) and DIEA (8.5 g, 65.77 mmol, 100%) in N,N-dimethylformamide (100 mL). The resulting solution was stirred overnight at 20° C. The reaction was then quenched by the addition of 100 mL of water. The resulting solution was extracted with 3×100 mL of dichloromethane and the organic layers combined and dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:2-1:1) to provide the title compound as a yellow solid.
Reaction SMILES: [SH:1][C:2]1[NH:3][C:4]2[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.Cl.Cl[CH2:14][C:15]1[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=1[NH2:17]>>[CH3:11][C:10]1[C:4]2[N:3]=[C:2]([S:1][CH2:14][C:15]3[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=3[NH2:17])[NH:6][C:5]=2[CH:7]=[CH:8][CH:9]=1
Reactant: Cc1cccc2nc(S)[nH]c12
Reactant: Nc1ccccc1CCl
Agent: Cl
Product: Cc1cccc2[nH]c(SCc3ccccc3N)nc12
Yield: 23.1 %

Procedure:
The title compound was prepared by the method of Example 1 using 3.52 g of 2-mercapto-4-methylbenzimidazole instead of 2-mercaptobenzimidazole and 3.52 g of 2-(chloromethyl) aniline hydrochloride instead of 2-(chloromethyl)-N,N-dimethylaniline. Recrystallization from diethyl ether gave 1.23 g of the title compound: m.p. 125-127° C. Anal. Calc'd. for C15H15N3S: C, 66.89; H, 5.61; N,15.60; S, 11.90. Found: C, 66.76; H, 5.62; N, 15.41; S, 11.87.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([O:31][S:32]([CH3:35])(=[O:34])=[O:33])[C:28]=1[O:29][CH3:30])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([CH2:13][CH2:14]OS(C)(=O)=O)[CH2:9]1)=[O:7].[CH2:36]([O:38][CH2:39][CH2:40][N:41]1[C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][C:44]=2[N:43]=[C:42]1[NH:50][CH:51]1[CH2:56][CH2:55][NH:54][CH2:53][CH2:52]1)[CH3:37]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([O:31][S:32]([CH3:35])(=[O:34])=[O:33])[C:28]=1[O:29][CH3:30])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:13][CH2:14][N:54]2[CH2:55][CH2:56][CH:51]([NH:50][C:42]3[N:41]([CH2:40][CH2:39][O:38][CH2:36][CH3:37])[C:45]4[CH:46]=[CH:47][CH:48]=[CH:49][C:44]=4[N:43]=3)[CH2:52][CH2:53]2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:9]1)=[O:7]
Reactant: CCOCCn1c(NC2CCNCC2)nc2ccccc21
Reactant: COc1cc(C(=O)N2CCC(CCOS(C)(=O)=O)(c3ccccc3)C2)cc(OS(C)(=O)=O)c1OC
Product: CCOCCn1c(NC2CCN(CCC3(c4ccccc4)CCN(C(=O)c4cc(OC)c(OC)c(OS(C)(=O)=O)c4)C3)CC2)nc2ccccc21

Procedure:
Prepare by the method of Example 1.6 using 1-(3,4-dimethoxy-5-methanesulfonyloxybenzoyl)-3-phenyl-3-(2-methanesulfonyloxyethyl)pyrrolidine and (1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)(piperidin-4-yl)amine to give the title compound.
Reaction SMILES: N(C(OC(C)C)=O)=NC(OC(C)C)=O.[C:15]([O:19][C:20](=[O:35])[NH:21][C@H:22]([C:26]1[CH:31]=[C:30]([F:32])[C:29]([F:33])=[C:28]([F:34])[CH:27]=1)[C@@H:23]([OH:25])[CH3:24])([CH3:18])([CH3:17])[CH3:16].[N+:36]([C:39]1[CH:47]=[CH:46][C:42]([C:43](O)=[O:44])=[CH:41][CH:40]=1)([O-:38])=[O:37].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[C:15]([O:19][C:20]([NH:21][C@H:22]([C:26]1[CH:31]=[C:30]([F:32])[C:29]([F:33])=[C:28]([F:34])[CH:27]=1)[C@H:23]([O:25][C:43](=[O:44])[C:42]1[CH:41]=[CH:40][C:39]([N+:36]([O-:38])=[O:37])=[CH:47][CH:46]=1)[CH3:24])=[O:35])([CH3:16])([CH3:17])[CH3:18]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Reactant: C[C@H](O)[C@H](NC(=O)OC(C)(C)C)c1cc(F)c(F)c(F)c1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C[C@@H](OC(=O)c1ccc([N+](=O)[O-])cc1)[C@H](NC(=O)OC(C)(C)C)c1cc(F)c(F)c(F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.4 %

Procedure:
In nitrogen atmosphere, diisopropyl azodicarboxylate (6 mL) was dropwise added to a THF solution (100 mL) of [(1R,2S)-2-hydroxy-1-(3,4,5-trifluorophenyl)propyl]carbamic acid tert-butyl ester (5.88 g), 4-nitrobenzoic acid (4.84 g), and triphenylphosphine (7.59 g) under ice-cooling. This reaction solution was stirred at room temperature for 2 hr and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (toluene:ethyl acetate=97:3) to give a powder. The obtained powder was triturated with toluene-hexane to give 6.69 g of the title compound. The physical property values of this compound were as follows: