Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:9][C:10]([C:12]1[CH:13]=[C:14]([C:34]2[CH:39]=[C:38]([CH:40]([CH3:42])[CH3:41])[CH:37]=[CH:36][C:35]=2[O:43][CH3:44])[C:15]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:16][C:17]=1[O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=O)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.P(Cl)(Cl)(Cl)(Cl)Cl.[Si]([N:55]=[N+:56]=[N-:57])(C)(C)C>ClCCl>[CH2:19]([O:18][C:17]1[CH:16]=[C:15]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:14]([C:34]2[CH:39]=[C:38]([CH:40]([CH3:42])[CH3:41])[CH:37]=[CH:36][C:35]=2[O:43][CH3:44])=[CH:13][C:12]=1[C:10]1[N:9]([CH2:1][CH2:2][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:57]=[N:56][N:55]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: COc1ccc(C(C)C)cc1-c1cc(C(=O)NCCc2ccccc2)c(OCc2ccccc2)cc1OCc1ccccc1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClCCl
Product: COc1ccc(C(C)C)cc1-c1cc(-c2nnnn2CCc2ccccc2)c(OCc2ccccc2)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 89 %

Procedure:
4,6-Bis-benzyloxy-5′-isopropyl-2′-methoxy-biphenyl-3-carboxylic acid phenethyl-amide (193 mg, 0.33 mmole) was dissolved in anhydrous dichloromethane (5 ml), then phosphorus pentachloride (104 mg, 0.5 mmol) was added and the resulting solution was stirred at r.t. for 3 hr. TMSN3 (0.3 ml, neat) was added and the resulting mixture was stirred at r.t. for 3 hr. After quenching the reaction with sodium bicarbonate solution, the mixture was extracted with dichloromethane (3×20 ml). The combined organic were dried over Na2SO4. After filtration and concentration, the residue was purified by flash chromatography on silica gel to give 5-(4,6-bis-benzyloxy-5′-isopropyl-2′-methoxy-biphenyl-3-yl)-1-phenethyl-1H-tetrazole (201 mg, 89%). M.p.: 118-120° C.; 400 MHz 1H NMR (CDCl3, δ: 7.32-7.23 (m, 8H), 7.19-7.07 (m, 8H), 6.92 (s, 1H), 6.90 (s, 1H), 6.87 (d, J=8.0 Hz, 1H), 6.68 (s, 1H), 5.05 (s, 2H), 4.99 (s, 2H), 4.43 (t, J=7.6 Hz, 2H), 3.70 (s, 3H), 3.11 (t, J=7.6 Hz, 2H), 2.92-2.84 (m, 1H), 1.24 (d, J=7.2 Hz, 6H); LCMS: 611 [M+H].
Reaction SMILES: [C:1]([CH:3]1[CH2:9][CH2:8][CH2:7][N:6]2[CH:10]=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:12]=[C:5]2[C:4]1=O)#[N:2].O.[NH2:20][NH2:21].C(O)(=O)C>C(O)C>[NH2:2][C:1]1[C:3]2[CH2:9][CH2:8][CH2:7][N:6]3[CH:10]=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:12]=[C:5]3[C:4]=2[NH:21][N:20]=1
Reactant: CCOC(=O)c1cc2n(c1)CCCC(C#N)C2=O
Reactant: NN
Solvent: CC(=O)O
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1cc2n(c1)CCCc1c(N)n[nH]c1-2
Yield: 78.4 %

Procedure:
To ethyl 8-cyano-9-oxo-6,7,8,9-tetrahydro-5H-pyrrolo[1,2-a]azepine-2-carboxylate (12 g, 49 mmol) in ethanol a solution of hydrazine monohydrate (6.5 g, 130 mmol) and acetic acid (9 g, 150 mmol) was added. The reaction was refluxed for 62 hours and concentrated under reduced pressure. The residue was dissolved in ethyl acetate and washed with water and NH3. The organic phase was dried on Na2SO4. 10 g of a pale yellow solid were obtained (yield 78%).
Reaction SMILES: [C:1]([O:5][C:6]([C@@H:8]([C@@H:12]([C:16]1[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=1)/[CH:13]=[CH:14]/[CH3:15])[C:9]([OH:11])=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].CO.[Si](C=[N+]=[N-])(C)(C)[CH3:29].CCCCCC>C1C=CC=CC=1>[C:1]([O:5][C:6]([C@@H:8]([C@@H:12]([C:16]1[CH:17]=[CH:18][C:19]([C:22]([F:23])([F:24])[F:25])=[CH:20][CH:21]=1)/[CH:13]=[CH:14]/[CH3:15])[C:9]([O:11][CH3:29])=[O:10])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: C/C=C/[C@H](c1ccc(C(F)(F)F)cc1)[C@@H](C(=O)O)C(=O)OC(C)(C)C
Solvent: CO
Solvent: CCCCCC
Solvent: c1ccccc1
Product: C/C=C/[C@H](c1ccc(C(F)(F)F)cc1)[C@@H](C(=O)OC)C(=O)OC(C)(C)C
Yield: 98 %

Procedure:
(2S,3S,E)-2-(tert-butoxycarbonyl)-3-(4-(trifluoromethyl)phenyl)hex-4-enoic acid (5.3 g, 14 mmol) was taken up in 70 mL of 3.5:1 benzene:MeOH. TMS diazomethane, 2M in hexane (7.8 mL, 16 mmol) was added slowly to the mixture. Bubbling ensued. Approximately 2 mL excess TMS diazomethane reagent was added, presumably due to loss of titer of the reagent. The bubbling was monitored, and the addition was stopped when the bubbling ceased. The solvent was removed under reduced pressure. The mixture was triturated twice with 50 mL of 10% ether:hexanes, affording (2S,3S,E)-methyl 2-(tert-butoxycarbonyl)-3-(4-(trifluoromethyl)phenyl)hex-4-enoate (5.4 g, 98% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 7.59 (d, J=8.22 Hz, 2H) 7.34 (d, J=8.22 Hz, 2H) 5.75-5.59 (m, 2H) 4.92-4.84 (m, 1H) 4.70-4.63 (m, 1H) 3.78-3.72 (m, 1H) 3.68 (s, 3H) 1.72 (d, J=5.28 Hz, 3H) 1.37 (s, 9H).
Reaction SMILES: [C:1]1([C:7]2[C:11]([CH2:12][CH2:13][C:14]([O:16]CC)=[O:15])=[CH:10][N:9]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([NH:28][CH2:29][CH2:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=4)=[O:27])[CH:21]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].C(O)C.Cl>O1CCCC1>[C:1]1([C:7]2[C:11]([CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:10][N:9]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([NH:28][CH2:29][CH2:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=4)=[O:27])[CH:21]=3)[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)CCc1cn(Cc2cccc(C(=O)NCCc3ccccn3)c2)nc1-c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(O)CCc1cn(Cc2cccc(C(=O)NCCc3ccccn3)c2)nc1-c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.4 %

Procedure:
A mixture of ethyl 3-[3-phenyl-1-[3-[2-(2-pyridyl)ethylaminocarbonyl]benzyl]-1H-pyrazol-4-yl]propionate (450 mg), 1 N aqueous sodium hydroxide solution (2 ml), ethanol (2 ml), and tetrahydrofuran (2 ml) was stirred at room temperature for one hour. After 1 N hydrochloric acid (2 ml) was added to the reaction mixture, the reaction mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The obtained crystals were collected by filtration, and 3-[3-phenyl-1-[3-[2-(2-pyridyl)ethylaminocarbonyl]benzyl]-1H-pyrazol-4-yl]propionic acid (400 mg, yield: 95%) was obtained. This was recrystallized from tetrahydrofuran-hexane. Melting point: 166–167° C.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][N:3]=1.N1C=CC=CC=1.[C:17](OC(=O)C)(=[O:19])[CH3:18].Cl>C(#N)C>[C:17]([N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:2]([CH3:1])=[N:3]1)(=[O:19])[CH3:18]
Reactant: Cc1n[nH]c2ccccc12
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: CC#N
Solvent: c1ccncc1
Product: CC(=O)n1nc(C)c2ccccc21
Temperature: 20 °C
Reaction time: 1 h
Yield: 85.9 %

Procedure:
290 g (2.20 mol) of 3-methylindazole and an acetonitrile solution (400 ml) of pyridine (4.34 mol) were stirred as the mixture was cooled on a water bath, and 310 ml (3.30 mol) of acetic anhydride was added dropwise thereto. Upon addition, the reaction temperature rose from 15° C. to 43° C. After the conclusion of the dropwise addition, the reaction solution was warmed to from 55° to 60° C., and stirred at this temperature for one hour. After cooling to 20° C., the reaction solution was poured into 1.5 kg of ice-cold water containing 500 ml of aqueous hydrochloric acid. The crystals deposited were filtered off, and washed with water. Thus, 328 g (1.89 mol) of 1-acetyl-3-methylindazole was obtained.
Reaction SMILES: [C:1]([NH:3][C:4]([NH:9][CH2:10][C:11]#[CH:12])=[N:5][CH2:6][CH2:7][SH:8])#[N:2].[Na].[CH3:14][C:15]1[N:16]=[CH:17][NH:18][C:19]=1[CH2:20]Cl.Cl>C(O)C>[C:1]([NH:3][C:4]([NH:5][CH2:6][CH2:7][S:8][CH2:20][C:19]1[NH:18][CH:17]=[N:16][C:15]=1[CH3:14])=[N:9][CH2:10][C:11]#[CH:12])#[N:2]
Reactant: C#CCNC(=NCCS)NC#N
Reactant: Cc1nc[nH]c1CCl
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: C#CCN=C(NC#N)NCCSCc1[nH]cnc1C
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
The ethanol solution of the product of step B, above, (about 10 m moles) was added to a solution of 0.46 sodium (0.02 g-atoms) in 10 ml ethanol at 4° C. under nitrogen. After 5 minutes, a solution of 1.67 g (10 m moles) of 4-methyl-5-chloromethylimidazole.HCl in 14 ml ethanol was added and the mixture was stirred at room temperature under nitrogen for 70 minutes. The reaction mixture was filtered through a bed of celite filter aid to remove the inorganic salts and the celite was washed with ethanol. The filtrate was evaporated to dryness and the product was purified by chromatography on a silica gel column (20 g silica, 3.2×4.5 cm bed) with ethanol-chloroform mixtures as the solvent. The ethanol content was gradually increased from 2 to 15%. The eluant was evaporated to dryness to give 1.906 g of crystalline product. Recrystallization from 2-propanol gave 1.49 g (54%) of the title product, m.p. 144°-145° C.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([N:15]([CH3:25])[CH:16]([CH2:21][CH2:22][CH2:23]Cl)[C:17]([O:19][CH3:20])=[O:18])(=[O:14])=[O:13])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4].[I-:26].[Na+]>CC(C)=O>[CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([N:15]([CH3:25])[CH:16]([CH2:21][CH2:22][CH2:23][I:26])[C:17]([O:19][CH3:20])=[O:18])(=[O:14])=[O:13])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4]
Reactant: CC#CCOc1ccc(S(=O)(=O)N(C)C(CCCCl)C(=O)OC)cc1
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: CC#CCOc1ccc(S(=O)(=O)N(C)C(CCCI)C(=O)OC)cc1

Procedure:
Step 2 A solution of 4.80 g of methyl 2-[{[4-(2-butynyloxy)phenyl]-sulfonyl}(methyl)amino]-5-chloropentanoate of Step 1 and 15 g of sodium iodide in 25 ml of acetone was stirred at room temperature for 3 days. Solvent was removed under reduced pressure, and the residue was washed with water. The product was dried to give methyl 2-[{[4-(2-butynyloxy)phenyl]-sulfonyl}(methyl)amino]-5-iodopentanoate as a pale yellow solid, Electrospray Mass Spec 480.2 (M+H)+
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[CH2:18][CH:17]([CH3:19])[O:16][CH:15]([CH3:20])[CH2:14]1.[H-].[Na+].[Cl:23][C:24]1[CH:32]=[CH:31][C:27]([CH2:28][C:29]#[N:30])=[CH:26][CH:25]=1.C1(C)C=CC=CC=1>CN(C=O)C>[Cl:23][C:24]1[CH:32]=[CH:31][C:27]([CH:28]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH:17]([CH3:19])[O:16][CH:15]([CH3:20])[CH2:14]2)[C:29]#[N:30])=[CH:26][CH:25]=1
Reactant: N#CCc1ccc(Cl)cc1
Reactant: CC1CN(CCCCCCCCCCCCl)CC(C)O1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CC1CN(CCCCCCCCCCCC(C#N)c2ccc(Cl)cc2)CC(C)O1

Procedure:
This intermediate (900 mg.) was prepared using the procedure described in Example 2a except using 3.9 g. (0.013 mole) of 4-(11-chloroundecyl)-2,6-dimethylmorpholine, 0.62 g. (0.014 mole) of sodium hydride, 1.97 g. (0.013 mole) of 4-chlorobenzyl cyanide, and 75 ml. of a 2 to 1 mixture of toluene and DMF.
Reaction SMILES: [CH2:1]([N:8]1[C:16]([OH:17])=[N:15][C:14]2[C:9]1=[N:10][C:11]([CH2:19][C:20]#N)=[N:12][C:13]=2[NH2:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-:22].[Na+].Cl.[CH3:25][OH:26]>>[CH2:1]([N:8]1[C:16]([OH:17])=[N:15][C:14]2[C:9]1=[N:10][C:11]([CH2:19][C:20]([O:26][CH3:25])=[O:22])=[N:12][C:13]=2[NH2:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#CCc1nc(N)c2nc(O)n(Cc3ccccc3)c2n1
Reactant: [OH-]
Reactant: CO
Agent: Cl
Agent: [Na+]
Product: COC(=O)Cc1nc(N)c2nc(O)n(Cc3ccccc3)c2n1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
After sodium cyanide (0.20 g, 4.08 mmol) and 9-benzyl-2-chloromethyl-8-hydroxyadenine (0.20 g, 0.69 mmol) were added to DMF (10 ml), the mixture was stirred at 80° C. for 7 hours. After removing the solvent, the residue was poured into water and the solution was neutralized with concentrated hydrochloric acid. The solution was extracted with dichloromethane, and the organic layer was dried over anhydrous magnesium sulfate and concentrated. The residue was purified by column chromatography (SiO2 20 g, eluting solvent: CHCl3/MeOH=100/1˜50/1) and washed with methanol to give 9-benzyl-2-cyanomethyl-8-hydroxyadenine (0.16 g, 0.57 mmol) as a pale yellow solid. Thus obtained 9-benzyl-2-cyanomethyl-8-hydroxyadenine (0.08 g, 0.29 mmol) was added to a mixed solvent of 5% sodium hydroxide solution (20 ml) and methanol (10 ml), and the mixture was stirred at 60° C. for 8 hours. After the mixture was neutralized with concentrated hydrochloric acid, the solvent was removed. The residue and sulfuric acid (1 ml) were added to methanol (50 ml), and the mixture was refluxed for 3 hours under stirring. After being neutralized with saturated sodium hydrogencarbonate solution in an ice bath, the solution was extracted with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate and concentrated. The residue was purified with column chromatography (SiO2 20 g, eluting solvent: CHCl3/MeOH=100/1˜30/1) and washed with methanol to give the captioned compound (0.02 g, 0.06 mmol) as a white solid.
Reaction SMILES: ClC(Cl)(Cl)[CH2:3][CH:4](Cl)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.S(=O)(=O)(O)O.Cl.[C]=O.[CH:22]([OH:24])=[O:23]>>[C:22]([OH:24])(=[O:23])[CH:3]=[CH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: ClC(CC(Cl)(Cl)Cl)c1ccccc1
Reactant: O=CO
Agent: Cl
Agent: O=S(=O)(O)O
Agent: [C]=O
Product: O=C(O)C=Cc1ccccc1
Yield: 86.9 %

Procedure:
A mixture of 103.2 g of 1,1,1,3-tetrachloro-3-phenylpropane, 114 g of 85% formic acid and 4.2 g of 93% sulphuric acid is refluxed under stirring at a temperature in the range 100° to 110° C. for 6 h with evolution of hydrogen chloride and carbon monoxide. The reaction mixture is cooled, the crystals so precipitated are filtered off and washed with water to give 51.5 g of cinnamic acid in total yield of 98 per cent (melting point 127° to 133° C., min. 98% purity).
Reaction SMILES: [C:1]1([N:7]2[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:10]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:9]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH:29](Br)[CH3:30])[C:8]2=[O:32])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[P:33]([O:40][CH2:41][CH3:42])([O:37]CC)[O:34]CC.[C:43]1(C)C(C)=CC=CC=1>>[PH:33](=[O:34])([OH:40])[OH:37].[CH2:30]([CH:29]([CH2:41][CH3:42])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][N:9]1[C:10]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:8]1=[O:32])[CH3:43]
Reactant: CCOP(OCC)OCC
Reactant: Cc1ccccc1C
Reactant: CC(Br)CCCCCn1c(-c2ccccc2)c(-c2ccccc2)n(-c2ccccc2)c1=O
Product: CCC(CC)CCCCCn1c(-c2ccccc2)c(-c2ccccc2)n(-c2ccccc2)c1=O
Product: O=[PH](O)O

Procedure:
A solution of 1,4,5-triphenyl-3-(6-bromoheptyl)-imidazol-2-one (1.43 g) and triethyl phosphite (2.49 g) in xylene (8 ml) was heated at reflux temperature for 65 hours. The solution was evaporated to an oil and chromatographed on silica gel (ethyl acetate/ethanol). The resulting oil was taken up in diethyl ether, filtered and evaporated to the titled compound as a clear oil (1.15 g; 72%) Found: C, 69.67; H, 7.13; N, 5.43%; C31H37N2O4P; Requires: C, 69.91; H, 7.00; N, 5.26%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10]O)=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:31]N1C(=O)CCC1=O>C(Cl)Cl>[Br:31][CH2:10][CH2:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: OCCCc1ccc(Cl)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Clc1ccc(CCCBr)cc1
Yield: 95 %

Procedure:
3-(4-Chlorophenyl)-1-propanol (1.00 g) was dissolved in methylene chloride (30 ml), triphenylphosphine (1.66 g) and N-bromosuccinimide (1.11 g) were added under ice-cooling, and the mixture was stirred under ice-cooling for 6 hr. The reaction mixture was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. Diethyl ether (50 ml) was added, and the precipitated triphenylphosphine oxide was filtered off. The concentrate of the filtrate was purified by silica gel column chromatography (hexane alone) to give the object product (1.30 g) as a colorless oil.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([C:12]1[CH:17]=[CH:16][C:15]([O:18][C:19]2[C:24](Cl)=[N:23][CH:22]=[CH:21][N:20]=2)=[CH:14][CH:13]=1)=[O:11].P([O-])([O-])([O-])=O.[K+].[K+].[K+].[F:34][C:35]([F:46])([F:45])[C:36]1[CH:41]=[C:40](B(O)O)[CH:39]=[CH:38][N:37]=1>C(COC)OC>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([C:12]1[CH:17]=[CH:16][C:15]([O:18][C:19]2[C:24]([C:40]3[CH:39]=[CH:38][N:37]=[C:36]([C:35]([F:46])([F:45])[F:34])[CH:41]=3)=[N:23][CH:22]=[CH:21][N:20]=2)=[CH:14][CH:13]=1)=[O:11]
Reactant: O=C(c1ccc(Oc2nccnc2Cl)cc1)c1nc2ccccc2[nH]1
Reactant: OB(O)c1ccnc(C(F)(F)F)c1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: O=C(c1ccc(Oc2nccnc2-c2ccnc(C(F)(F)F)c2)cc1)c1nc2ccccc2[nH]1
Temperature: 80 °C

Procedure:
A mixture of (1H-benzo[d]imidazol-2-yl)(4-(3-chloropyrazin-2-yloxy)phenyl)methanone (300 mg, 0.855 mmol), potassium phosphate (545 mg, 2.57 mmol), 2-(trifluoromethyl)pyridin-4-ylboronic acid (490 mg, 2.57 mmol), and Bis-[4-(di-tert-butylphosphino)-N,N-dimethylbenzenamine]palladium dichloride (121 mg, 0.171 mmol) in dimethoxyethane was heated to 80° C. Following complete reaction, the mixture was cooled to room temperature which caused a solid to precipitate which was collected by filtration and dried to give (1H-benzo[d]imidazol-2-yl)(4-(3-(2-(trifluoromethyl)pyridin-4-yl)pyrazin-2-yloxy)phenyl)methanone. MS (ESI, pos. ion) m/z: 461.0 (M+1). IC50 (uM) +++++.
Reaction SMILES: O1CCCC1.Cl[C:7]1[N:12]=[C:11]([Cl:13])[N:10]=[CH:9][N:8]=1.C(=O)([O-])[O-].[Na+].[Na+].Cl.[F:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH2:32][CH2:31][C@@H:30]([NH2:33])[CH2:29]2)=[CH:24][CH:23]=1>C(OCC)(=O)C.O>[Cl:13][C:11]1[N:10]=[CH:9][N:8]=[C:7]([NH:33][C@@H:30]2[CH2:31][CH2:32][N:28]([C:25]3[CH:26]=[CH:27][C:22]([F:21])=[CH:23][CH:24]=3)[CH2:29]2)[N:12]=1
Reactant: Clc1ncnc(Cl)n1
Reactant: N[C@@H]1CCN(c2ccc(F)cc2)C1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: Fc1ccc(N2CC[C@@H](Nc3ncnc(Cl)n3)C2)cc1

Procedure:
To a tetrahydrofuran solution (2.0 mL)-water (0.80 mL) solution of 2,4-dichloro-1,3,5-triazine (166 mg, 1.11 mmol) and sodium carbonate (141 mg, 1.33 mmol), (R)-1-(4-fluorophenyl)pyrrolidin-3-amine hydrochloride (200 mg, 1.11 mmol) synthesized in Reference Synthesis Example 30 was added at 0° C. and the resultant mixture was stirred for 3 hours. After completion of the reaction, water was added to the reaction solution and extraction from the resultant mixture with ethyl acetate was performed. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain the title compound as a crude product.
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH3:22])[C:4](=[O:21])[C:5]2[C:10]([C:11]3[C:16]([CH3:17])=[CH:15][C:14]([CH3:18])=[CH:13][C:12]=3[CH3:19])=[CH:9][N:8]([CH3:20])[C:6]=2[N:7]=1.CN(C)C=O.[H-].[Na+].[CH3:30][O:31][CH2:32][CH2:33]Br>O>[C:12]1([CH3:19])[CH:13]=[C:14]([CH3:18])[CH:15]=[C:16]([CH3:17])[C:11]=1[C:10]1[C:5]2[C:4](=[O:21])[N:3]([CH3:22])[C:2]([NH:1][CH2:33][CH2:32][O:31][CH3:30])=[N:7][C:6]=2[N:8]([CH3:20])[CH:9]=1
Reactant: COCCBr
Reactant: Cc1cc(C)c(-c2cn(C)c3nc(N)n(C)c(=O)c23)c(C)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COCCNc1nc2c(c(-c3c(C)cc(C)cc3C)cn2C)c(=O)n1C
Reaction time: 0.5 h
Yield: 23.5 %

Procedure:
To a solution of 2-amino-5-mesityl-3,7-dimethyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one (55 mg, 0.18 mmol) and N,N-dimethylformamide (2 ml) was added sodium hydride (60% in oil, 24 mg, 0.60 mmol) at 0° C. and stirred for 0.5 hour. After stirring at room temperature for 0.5 hour, to the mixture was added a solution of 2-methoxyethylbromide (232 mg, 0.60 mmol) and N,N-dimethylformamide (1 ml) at 0° C. and stirred for 0.5 hour. After stirring at room temperature for 2 hours and heating under reflux for 2 hours, the mixture was diluted with water (20 ml) and extracted with ethyl acetate (50 ml×2). The extracts were combined, washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with hexane/ethyl acetate (9:1) to give 15 mg (23%) of the title compound as an oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][C:11]([C:18](=O)[CH2:19]Br)=[C:12]([F:17])[CH:13]=2)[N:8]([CH2:22][CH3:23])[CH:7]=1)=[O:5])[CH3:2].[C:24]([O:27][CH2:28][CH2:29][N:30]([CH2:34][C:35]([NH2:37])=[S:36])[C:31](=[O:33])[CH3:32])(=[O:26])[CH3:25]>C(O)C>[CH2:1]([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][C:11]([C:18]3[N:37]=[C:35]([CH2:34][N:30]([CH2:29][CH2:28][O:27][C:24](=[O:26])[CH3:25])[C:31](=[O:33])[CH3:32])[S:36][CH:19]=3)=[C:12]([F:17])[CH:13]=2)[N:8]([CH2:22][CH3:23])[CH:7]=1)=[O:5])[CH3:2]
Reactant: CC(=O)OCCN(CC(N)=S)C(C)=O
Reactant: CCOC(=O)c1cn(CC)c2cc(C(=O)CBr)c(F)cc2c1=O
Solvent: CCO
Product: CCOC(=O)c1cn(CC)c2cc(-c3csc(CN(CCOC(C)=O)C(C)=O)n3)c(F)cc2c1=O

Procedure:
According to example 30, by reacting 7-bromoacetyl-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid ethyl ester with 2-[N-(2-acetoxyethyl)-N-acetylamino]thioacetamide in ethanol gave 1-ethyl-6-fluoro-1,4-dihydro-7-[2-[[N-(2-acetoxyethyl)-N-acetylamino]methyl]-4-thiazolyl]-4-oxo-3-quinolinecarboxylic acid ethyl ester, mp 148°-152° C., resolidified and melted 164°-165° C., which was hydrolyzed with refluxing 6N hydrochloric acid to afford the titled compound, mp 290° C. (dec).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[C:10]1([CH2:16][CH2:17][CH2:18][Mg]Br)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]([OH:5])[CH2:18][CH2:17][CH2:16][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Br[Mg]CCCc1ccccc1
Reactant: O=Cc1ccccc1Br
Product: OC(CCCc1ccccc1)c1ccccc1Br

Procedure:
Prepared according to the procedure described in Example 5, Step 1, using the following starting materials: 2-bromo-benzaldehyde and 3-phenyl-propyl magnesium bromide.
Reaction SMILES: [CH:1]([N:14]1[C:22]2[C:17](=[CH:18][C:19]([Cl:23])=[CH:20][CH:21]=2)[C:16]([CH2:24][CH2:25][O:26][C:27]2[CH:37]=[CH:36][C:30]([C:31]([O:33]CC)=[O:32])=[C:29]([F:38])[CH:28]=2)=[C:15]1[CH2:39][CH2:40][NH:41][S:42]([CH2:45][C:46]1[CH:51]=[CH:50][C:49]([Cl:52])=[C:48]([Cl:53])[CH:47]=1)(=[O:44])=[O:43])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1COCC1.[OH-].[Na+]>CO>[CH:1]([N:14]1[C:22]2[C:17](=[CH:18][C:19]([Cl:23])=[CH:20][CH:21]=2)[C:16]([CH2:24][CH2:25][O:26][C:27]2[CH:37]=[CH:36][C:30]([C:31]([OH:33])=[O:32])=[C:29]([F:38])[CH:28]=2)=[C:15]1[CH2:39][CH2:40][NH:41][S:42]([CH2:45][C:46]1[CH:51]=[CH:50][C:49]([Cl:52])=[C:48]([Cl:53])[CH:47]=1)(=[O:44])=[O:43])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1ccc(OCCc2c(CCNS(=O)(=O)Cc3ccc(Cl)c(Cl)c3)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1F
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1ccc(OCCc2c(CCNS(=O)(=O)Cc3ccc(Cl)c(Cl)c3)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1F
Yield: 93.2 %

Procedure:
Ethyl 4-{2-[1-benzhydryl-5-chloro-2-(2-{[(3,4-dichlorobenzyl)sulfonyl]amino)-ethyl)-1H-indol-3-yl]ethoxy}-2-fluorobenzoate (0.11 g, 0.14 mmol), THF (0.5 mL), MeOH (0.5 mL), and 1 N NaOH (0.5 mL) were stirred together overnight. Solvents were removed and the resulting residue was taken up in water. The solution was acidified with 1N HCl and extracted with ethyl acetate. The extract was dried over sodium sulfate, and evaporated. The resulting residue was triturated with a mixture of ether and hexanes to give 0.10 g of 4-{2-[1-benzhydryl-5-chloro-2-(2-{[(3,4-dichlorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}-2-fluorobenzoic acid as a white solid; mp 117-119° C.; HRMS: calcd for C39H32Cl3FN2O5S, 764.1082; found (ESI+), 787.09794