Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH:2]1[CH2:11][CH2:10][C:5]2([O:9][CH2:8][CH2:7][O:6]2)[CH2:4][CH2:3]1.[F:12][C:13]([F:23])([F:22])[C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH:17]=[O:18].[Cl-].[NH4+].C(OCC)C>O1CCCC1>[O:9]1[C:5]2([CH2:10][CH2:11][CH:2]([C:15]3[C:14]([C:13]([F:23])([F:22])[F:12])=[CH:21][CH:20]=[CH:19][C:16]=3[CH2:17][OH:18])[CH2:3][CH2:4]2)[O:6][CH2:7][CH2:8]1
Reactant: O=Cc1cccc(C(F)(F)F)c1
Reactant: BrC1CCC2(CC1)OCCO2
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: OCc1cccc(C(F)(F)F)c1C1CCC2(CC1)OCCO2
Temperature: 0 °C

Procedure:
This compound is prepared in a manner analogous to that of Step B of Example 6, using 22.1 grams (0.09 mole) of the Grignard reagent of 8-bromo-1,4-dioxaspiro[4.5]decane and 17.4 grams (0.10 mole) of 3-trifluoromethylbenzaldehyde in tetrahydrofuran. Upon completion of the reaction, the reaction mixture is poured into a mixture of 100 grams of ice, 100 mL of an aqueous solution saturated with ammonium chloride, and 200 mL of diethyl ether. This mixture is filtered and the organic layer is separated. The organic layer is concentrated under reduced pressure, yielding [(1,4-dioxaspiro[4.5]decan-8-yl)(3-trifluoromethylphenyl)]methanol.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:11])=[C:6]([CH:10]=1)[C:7](O)=O.[C:12]1([NH2:19])[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[NH2:18].CS(O)(=O)=O>[OH-].[Na+]>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:11])=[C:6]([C:7]2[NH:19][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:18]=2)[CH:10]=1
Reactant: O=C(O)c1cc(Br)ccc1Cl
Reactant: Nc1ccccc1N
Agent: CS(=O)(=O)O
Agent: [Na+]
Agent: [OH-]
Product: Clc1ccc(Br)cc1-c1nc2ccccc2[nH]1
Temperature: 170 °C
Reaction time: 5 h

Procedure:
Method 2—Step a Into a one necked round bottomed flask equipped with a magnetic stirrer, 5-bromo-2-chlorobenzoic acid (70.0 g, 297.3 mmol), o-phenylenediamine (64.3 g, 594.6 mmol) and methansulfonic acid (140 mL) were placed and heated to 170° C. in order to melt the solids. The system was stirred 5 h at this temperature, then left to come rt. The blue solid was treated with NaOH 35% (200 mL) obtaining a violet suspension (pH 5) that was filtered and washed with NaOH 0.5 M (2 L) and H2O (2 L). The product was dried under vacuum (60° C.), to give 61.6 g of a pure violet solid. (67%).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH2:9]([O:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][C:21]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:20]2)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>CN(C)C=O>[CH2:9]([O:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][C:21]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[C:20]2[Br:1])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: CCOC(=O)c1cc2cc(OCc3ccccc3)ccc2[nH]1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Product: CCOC(=O)c1[nH]c2ccc(OCc3ccccc3)cc2c1Br
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 87.9 %

Procedure:
A solution of N-bromosuccinimide (7.83 g, 44.0 mmol) in N,N-dimethylformamide (30 mL) was added dropwise (40 min) to a cooled (0 ° C.) and stirred solution of ethyl 5-(benzyloxy)-1H-indole-2-carboxylate (10.0 g, 39.2 mmol) in N,N-dimethylformamide (20 mL). The cold bath was removed and stirring was continued for an additional 1.5 h. The reaction was poured over ice water (600 mL) and the resulting precipitate was collected by vacuum filtration. The precipitate was washed with water and dried to give 12.9 g (98%) of crude product. This material was used in the next reaction without further purification or analysis.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[C:12](=[N:16]\[O:17][CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)/[C:13]([OH:15])=O)[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].[CH3:23][O:24][C:25]1[CH:34]=[CH:33][C:28]2[N:29]=[C:30]([NH2:32])[S:31][C:27]=2[CH:26]=1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4](/[C:12](=[N:16]\[O:17][CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)/[C:13]([NH:32][C:30]2[S:31][C:27]3[CH:26]=[C:25]([O:24][CH3:23])[CH:34]=[CH:33][C:28]=3[N:29]=2)=[O:15])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:9])=[O:10]
Reactant: CS(=O)(=O)c1ccc(/C(=N\OC2CCCC2)C(=O)O)cc1Cl
Reactant: COc1ccc2nc(N)sc2c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc2nc(NC(=O)/C(=N/OC3CCCC3)c3ccc(S(C)(=O)=O)c(Cl)c3)sc2c1
Reaction time: 2 h
Yield: 55 %

Procedure:
(E)-(3-Chloro-4-methanesulfonyl-phenyl)-cyclopentyloxyimino-acetic acid (prepared as in Example 1, 84 mg, 0.24 mmol), 6-methoxy-2-aminobenzothiazole (44 mg, 0.24 mmol) and N,N-diisopropylethylamine (127 μL, 0.73 mmol) were combined in methylene chloride (2 mL) and cooled in an ice bath. O-(7-Azabenzotriazole-1-yl)-N,N,N′N′-tetramethyluronium hexafluorophosphate (92 mg, 0.24 mmol) was added and the ice bath was removed. After stirring 2 h, the reaction mixture was evaporated in vacuo. The residue was treated with saturated aqueous sodium bicarbonate solution (1 mL) and extracted with chloroform (2×3 mL). The combined organic phases were dried over sodium sulfate and evaporated in vacuo. The residue was purified by flash column chromatography (Merck silica gel 60, 40-63 μm; 40% ethyl acetate/hexanes) to afford (E)-2-(3-chloro-4-methanesulfonyl-phenyl)-2-cyclopentyloxyimino-N-(6-methoxy-benzothiazol-2-yl)-acetamide (67 mg, 54%) as a faintly yellow solid after lyophilization from aqueous acetonitrile: LC-MS (ESI) m/e calcd for C22H22ClN3O5S2 [M+] 507.07, found 508 [M+H+]; H1-NMR (400 MHz, CDCl3) δ ppm 1.67 (m, 4 H, 2×CH2), 1.90 (m, 4 H, 2×CH2), 3.32 (s, 3 H, SO2CH3), 3.89 (d, 3 H, OCH3), 4.96 (m, 1 H, OCH), 7.07 (dd, Jo=8.9, Jm=2.5 Hz, 1 H, Ar), 7.31 (d, Jm=2.5 Hz, 1 H, Ar), 7.61 (dd, Jo=8.2, Jm=1.5 Hz, 1 H, Ar), 7.70 (d, Jo=8.9 Hz, 1 H, Ar), 7.71 (d, Jm=1.5 Hz, 1 H, Ar), 8.22 (d, Jo=8.2 Hz, 1 H, Ar), 10.11 (s, 1 H, NH).
Reaction SMILES: [NH2:1][C@H:2]([C:4](OC)=[O:5])[CH3:3].Cl.[NH:9]1[CH2:16][CH2:15][CH2:14][C@H:10]1[C:11]([OH:13])=[O:12]>O>[NH2:1][C@H:2]([C:4]([N:9]1[CH2:16][CH2:15][CH2:14][C@H:10]1[C:11]([OH:13])=[O:12])=[O:5])[CH3:3]
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: COC(=O)[C@H](C)N
Agent: Cl
Solvent: O
Product: C[C@H](N)C(=O)N1CCC[C@H]1C(=O)O
Temperature: 37 °C
Reaction time: 72 h

Procedure:
L-Ala-OMe.HCl was added to the L-Pro-TBP prepared by the conversion of L-Pro into its ionic liquid form according to the method disclosed in Example 1 so as to control the concentration of the L-Ala-OMe.HCl to 1.000 mmol per unit mass (1 kg) of the L-Pro-TBP (the amount of water relative to the total mass of the reaction system: 2% by mass). The mixture was stirred enough to ensure the mixture uniform, and then, the reaction of these components was initiated while stirring the reaction system in a water bath and warming the same at 37° C. or 50° C. The reaction was finished 72 hours after the initiation of the reaction, and the samples, which were collected at appropriate intervals of time during the reaction, were analyzed according to the HPLC technique to confirm the formation of the desired dipeptide, i.e., L-Ala-Pro. The results are summarized in the following Table 1.
Reaction SMILES: [C:1]([C:3]1[CH:16]=[CH:15][C:6]([O:7][CH:8]([CH2:12][CH2:13][CH3:14])[C:9]([OH:11])=O)=[CH:5][C:4]=1[C:17]([F:20])([F:19])[F:18])#[N:2].ON1C2C=CC=CC=2N=N1.C1C=CC2N(O)N=NC=2C=1.CN(C)CCCN=C=NCC.CCN=C=NCCCN(C)C.Cl.CN1CCOCC1.Cl.[CH3:72][O:73][C:74]1[CH:85]=[C:84]2[C:77]([NH:78][CH:79]=[C:80]2[CH2:81][CH2:82][NH2:83])=[CH:76][CH:75]=1>CN(C=O)C>[CH3:72][O:73][C:74]1[CH:85]=[C:84]2[C:77](=[CH:76][CH:75]=1)[NH:78][CH:79]=[C:80]2[CH2:81][CH2:82][NH:83][C:9](=[O:11])[CH:8]([O:7][C:6]1[CH:15]=[CH:16][C:3]([C:1]#[N:2])=[C:4]([C:17]([F:20])([F:19])[F:18])[CH:5]=1)[CH2:12][CH2:13][CH3:14]
Reactant: COc1ccc2[nH]cc(CCN)c2c1
Reactant: CCCC(Oc1ccc(C#N)c(C(F)(F)F)c1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CCCC(Oc1ccc(C#N)c(C(F)(F)F)c1)C(=O)NCCc1c[nH]c2ccc(OC)cc12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
The compound was prepared in the following manner. To 0.25 gm (0.87 mmol) of 2-(4-cyano-3-trifluoromethyl-phenoxy)-pentanoic acid in dimethylformamdie “DMF” (15 mL) were added 0.14 gm (1.09 mmol) of 1-Hydroxy-benzotriazole HOBT, 0.2 gm (1.09 mmol) of (3-(dimethylamino)propyl)ethylcarbodiimide EDCl, 0.23 gm (2.39 mmol) N-methyl morpholine, and approximately 246 mg of 5-methoxytryptamine hydrochloride (1.09 mmol). The resultant mixtures were stirred at room temperature for approximately 18 hours. The reactions were quenched with sodium bicarbonate (20 mL) and extracted with ethyl acetate (3 times 20 mL). The solvent was removed in vacuo to obtain oils that were then purified by HPLC.
Reaction SMILES: C([O:8][C:9]1[C:10]2[N:11]([CH:15]=[C:16]([CH3:18])[N:17]=2)[CH:12]=[CH:13][CH:14]=1)C1C=CC=CC=1.[H][H]>CO>[CH3:18][C:16]1[N:17]=[C:10]2[C:9](=[O:8])[CH2:14][CH2:13][CH2:12][N:11]2[CH:15]=1
Reactant: [H][H]
Reactant: Cc1cn2cccc(OCc3ccccc3)c2n1
Solvent: CO
Product: Cc1cn2c(n1)C(=O)CCC2
Temperature: 25 °C
Reaction time: 22 h

Procedure:
60 g (251.8 mmol) of 8-benzyloxy-2-methylimidazo[1,2-a]pyridine (Kaminski et al, J. Med. Chem. 1985, 28, 876–892) are hydrogenated on Pd-carbon in 400 ml of methanol at a hydrogen pressure of 55 bar and 70° C. After completion of the hydrogenation, the catalyst is filtered off and the filtrate is concentrated. The residue (38 g) is taken up in dichloromethane and the solution is treated in portions at room temperature with manganese dioxide (109.5 g). The reaction mixture is stirred at room temperature for 22 h and then filtered through silica gel. The filtrate is concentrated to a residue and the crystallizate is dried in vacuo at 60° C. 25.13 g (66% of theory) of the title compound are obtained.
Reaction SMILES: [N:1]1([C:6]([CH2:8][N:9]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[N:13]([CH2:20][C:21]([N:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)=[O:22])[C:12](=[O:28])[CH:11]([NH:29][C:30]([NH:32][C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([CH2:39][O:40][C:41](=[O:50])[NH:42][CH2:43][CH2:44][CH2:45][C:46]([O:48]C)=[O:47])[CH:34]=3)=[O:31])[C:10]2=[O:51])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.O.[OH-].[Li+]>CO.O>[N:23]1([C:21]([CH2:20][N:13]2[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[N:9]([CH2:8][C:6]([N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[O:7])[C:10](=[O:51])[CH:11]([NH:29][C:30]([NH:32][C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([CH2:39][O:40][C:41](=[O:50])[NH:42][CH2:43][CH2:44][CH2:45][C:46]([OH:48])=[O:47])[CH:34]=3)=[O:31])[C:12]2=[O:28])=[O:22])[CH2:24][CH2:25][CH2:26][CH2:27]1
Reactant: COC(=O)CCCNC(=O)OCc1cccc(NC(=O)NC2C(=O)N(CC(=O)N3CCCC3)c3ccccc3N(CC(=O)N3CCCC3)C2=O)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)CCCNC(=O)OCc1cccc(NC(=O)NC2C(=O)N(CC(=O)N3CCCC3)c3ccccc3N(CC(=O)N3CCCC3)C2=O)c1
Temperature: 25 °C
Reaction time: 7 h
Yield: 94.1 %

Procedure:
To a solution of Compound 9a (243 mg, 0.344 mmol) in methanol (3.5 ml) is added a solution of lithium hydroxide monohydrate (35 mg, 0.834 mmol) in water (0.6 ml) and the mixture is stirred at room temperature for 7 hr. After the addition of water, the mixture is washed with chloroform. After acidifying with 10% HCl, the mixture is extracted with chloroform containing 10% methanol. The extract is washed with water, dried over sodium sulfate, and distilled under reduced pressure to remove the solvent to obtain Compound 11a (224 mg, 94.1%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.[C:23]([OH:27])(=[O:26])[CH:24]=[CH2:25]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[C:23]([CH2:24][CH2:25][N:8]([CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:21][CH:22]=1)[C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)([OH:27])=[O:26]
Reactant: C=CC(=O)O
Reactant: COC(=O)c1ccc(OCCCNc2ccc(Cl)cc2)cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(OCCCN(CCC(=O)O)c2ccc(Cl)cc2)cc1
Temperature: 100 °C
Reaction time: 24 h

Procedure:
Methyl 4-[3-[N-[4-chlorophenyl)amino]propoxy]benzoate (2.0 g) was dissolved in toluene (6 ml), and thereto was added acrylic acid (2.24 ml), and the mixture was heated with stirring at 100° C. for 24 hours. The reaction mixture was diluted with ethyl acetate, and washed successively with aqueous sodium bicarbonate solution 2 times and water once, and it was concentrated under reduced pressure. The residue was subjected to column chromatography on silica gel and eluted with a mixed solvent of chloroform/methanol [60:1 (v/v)] to give the oily desired product (1.64 g).
Reaction SMILES: C([N:4]1[CH2:8][CH2:7][N:6]([C:9]2[CH:14]=[C:13](Cl)[CH:12]=[CH:11][C:10]=2[C:16]([N:18]2[CH2:23][CH2:22][N:21]([C:24]3[C:29]([CH3:30])=[CH:28][C:27]([CH3:31])=[C:26]([CH3:32])[N:25]=3)[CH2:20][CH2:19]2)=[O:17])[C:5]1=[O:33])(=O)C.[NH:34]1[CH2:38][CH2:37][CH2:36][C:35]1=[O:39]>>[O:39]=[C:35]1[CH2:36][CH2:37][CH2:38][N:34]1[C:13]1[CH:12]=[CH:11][C:10]([C:16]([N:18]2[CH2:19][CH2:20][N:21]([C:24]3[C:29]([CH3:30])=[CH:28][C:27]([CH3:31])=[C:26]([CH3:32])[N:25]=3)[CH2:22][CH2:23]2)=[O:17])=[C:9]([N:6]2[CH2:7][CH2:8][NH:4][C:5]2=[O:33])[CH:14]=1
Reactant: CC(=O)N1CCN(c2cc(Cl)ccc2C(=O)N2CCN(c3nc(C)c(C)cc3C)CC2)C1=O
Reactant: O=C1CCCN1
Product: Cc1cc(C)c(N2CCN(C(=O)c3ccc(N4CCCC4=O)cc3N3CCNC3=O)CC2)nc1C
Yield: 48.8 %

Procedure:
Using 1-acetyl-3-{5-chloro-2-[4-(3,5,6-trimethylpyridin-2-yl)piperazine-1-carbonyl]phenyl}imidazolidin-2-one (188 mg) described in Preparation Example 258 and pyrrolidin-2-one (51 mg) and by the reaction and treatment in the same manner as in Example 649, the title compound (93 mg) was obtained.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:19]2[O:23][N:22]=[C:21]([C:24]([N:26]([CH2:28][CH2:29][N:30]([CH3:32])[CH3:31])[CH3:27])=[O:25])[N:20]=2)[CH2:11][C:12]([O:14]C(C)(C)C)=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.FC(F)(F)C(O)=O>ClCCl>[CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:19]2[O:23][N:22]=[C:21]([C:24]([N:26]([CH2:28][CH2:29][N:30]([CH3:32])[CH3:31])[CH3:27])=[O:25])[N:20]=2)[CH2:11][C:12]([OH:14])=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CN(C)CCN(C)C(=O)c1noc([C@H](CCCC2CCCCC2)CC(=O)OC(C)(C)C)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(C)CCN(C)C(=O)c1noc([C@H](CCCC2CCCCC2)CC(=O)O)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 82 %

Procedure:
A solution of tert-butyl (3R)-6-cyclohexyl-3-(3-{[[2-(dimethylamino)ethyl](methyl)amino]carbonyl}-1,2,4-oxadiazol-5-yl)hexanoate (Preparation 81) (630 mg, 1.40 mmol) in dichloromethane (5 ml) was treated with trifluoroacetic acid (5 ml) and stirred at room temperature for 4 hours. The solvent was removed under reduced pressure and the residue azeotroped from dichloromethane. The residue was purified by column chromatography on silica gel eluting with a gradient system of 100:0 (dichloromethane:methanol) gradually changing to 90:10 (dichloromethane:methanol) to afford the title compound as a colourless gum (453 mg).
Reaction SMILES: S(Cl)([Cl:4])(=O)=O.[CH3:6][NH:7][C:8]([N:10]1[C:14]([CH3:15])=[CH:13][C:12]([O:16][C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][C:18]=2[C:26]([F:29])([F:28])[F:27])=[N:11]1)=[O:9]>C(O)(=O)C>[CH3:6][NH:7][C:8]([N:10]1[C:14]([CH3:15])=[C:13]([Cl:4])[C:12]([O:16][C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][C:18]=2[C:26]([F:29])([F:28])[F:27])=[N:11]1)=[O:9]
Reactant: CNC(=O)n1nc(Oc2ccc([N+](=O)[O-])cc2C(F)(F)F)cc1C
Reactant: O=S(=O)(Cl)Cl
Solvent: CC(=O)O
Product: CNC(=O)n1nc(Oc2ccc([N+](=O)[O-])cc2C(F)(F)F)c(Cl)c1C
Temperature: 25 °C
Reaction time: 4 h
Yield: 71.3 %

Procedure:
Sulfuryl chloride (0.16 g, 1.2 mmol) was added to a solution of N-methyl-5-methyl-3-(4-nitro-2-trifluoromethylphenyloxy)pyrazole-1-carboxamide (0.34 g, 1.0 mmol) in acetic acid (5 ml), and the mixture was stirred at room temperature for 4 hours. After completion of the reaction, the reaction mixture was poured into ice water and extracted with ethyl acetate (10 ml×3). An organic layer was washed with water, dried over anhydrous magnesium sulfate and filtered to remove a desiccant. 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=1/10), to give a white solid of N-methyl-4-chloro-5-methyl-3-(4-nitro-2-trifluoromethylphenyloxy)pyrazole-1-carboxamide (0.27 g, yield: 71.2%). mp: 157-158° C.; 1H-NMR (CDCl3, TMS, ppm): δ 2.66 (s, 3H), 2.96 (d, J=5.0 Hz, 3H), 6.70-6.95 (m, 1H), 7.31 (d, J=9.2 Hz, 1H), 8.41 (dd, J=2.7 and 9.2 Hz, 1H), 8.62 (d, J=2.7 Hz, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][CH:8]=[CH:9][C:10]=1[CH3:11])=[O:5])[CH3:2].[F:12][C:13]([F:25])([F:24])[C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21](Cl)=[O:22])=[CH:16][CH:15]=1>>[CH2:1]([O:3][C:4]([C:6]1[NH:7][CH:8]=[C:9]([C:21](=[O:22])[CH2:20][C:17]2[CH:16]=[CH:15][C:14]([C:13]([F:24])([F:12])[F:25])=[CH:19][CH:18]=2)[C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1[nH]ccc1C
Reactant: O=C(Cl)Cc1ccc(C(F)(F)F)cc1
Product: CCOC(=O)c1[nH]cc(C(=O)Cc2ccc(C(F)(F)F)cc2)c1C

Procedure:
3-Methyl-4-[2-(4-trifluoromethylphenyl)acetyl]-1H-pyrrole-2-carboxylic acid ethyl ester (100) was synthesized from 3-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (84) and (4-trifluoromethylphenyl)-acetyl chloride following the procedure described in Example 32. Crude yield: 96%. 1H-NMR (400 MHz, CDCl3): δ 1.38 (t, 3H), 2.61 (s, 3H), 4.11 (s, 2H), 4.35 (q, 2H), 7.37 (m, 2H), 7.51 (d, 1H), 7.58 (m, 2H), 9.29 (s broad, 1H) ppm. 13C-NMR (100 MHz, CDCl3): δ 11.71, 14.41, 46.90, 60.78, 123.70, 124.70, 125.49, 126.75, 129.41, 129.85, 130.00, 161.98, 193.49 ppm. DEPT (100 MHz, CDCl3): CH3 carbons: 11.71, 14.41; CH2 carbons: 46.90, 60.78; CH carbons: 123.70, 124.70, 125.49, 126.75, 129.41, 129.85, 130.00 ppm. LC/MS: 73.23%, m/z=339.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[CH3:11][NH:12][CH2:13][CH2:14][OH:15]>CN1CCCC1=O>[CH3:11][N:12]([CH2:13][CH2:14][OH:15])[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CNCCO
Reactant: O=[N+]([O-])c1ccc(F)cc1
Solvent: CN1CCCC1=O
Product: CN(CCO)c1ccc([N+](=O)[O-])cc1
Temperature: 85 °C
Yield: 79 %

Procedure:
A mixture of 4-fluoronitrobenzene (2.8 g, 20 mmol) and 2-(methylamino)ethanol (8.9 g, 120 mmol) in N-methylpyrrolidinone (80 mL) is heated for 19 hours in a 85° C. oil bath. After cooling to room temperature, the reaction mixture is partitioned between ethyl acetate and water. The organic phase is washed five times with water and with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to give 2-(methyl-4-nitroanilino)ethanol (3.1 g, 79%) as a yellow solid.
Reaction SMILES: Br[CH:2]1[CH2:7][CH2:6][O:5][C:3]1=[O:4].[Na+].[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([S:16]([O-:18])=[O:17])=[CH:12][CH:11]=1>C(O)C>[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([S:16]([CH:2]2[CH2:7][CH2:6][O:5][C:3]2=[O:4])(=[O:18])=[O:17])=[CH:12][CH:11]=1
Reactant: O=C1OCCC1Br
Reactant: O=S([O-])c1ccc(Cl)cc1
Agent: [Na+]
Solvent: CCO
Product: O=C1OCCC1S(=O)(=O)c1ccc(Cl)cc1
Temperature: 65 °C
Yield: 63 %

Procedure:
A mixture of α-bromo-γ-butyrolactone (1.58 g; 9.62 mmol) and 4-chlorobenzenesulfinic acid sodium salt (2.39 g; 12.03 mmol) in ethanol (75 mL) was heated at 65° C. for 10 hours and the volatiles removed in vacuo. The residue was diluted with ethyl acetate and filtered. Removal of the volatiles from the filtrate provided as residue which was purified by silica gel chromatography using ethyl acetate and hexanes as the eluent. Removal of the volatiles from the product-rich fractions provided 1.58 g of the desired product. 1H NMR (CDCl3) δ 7.89 (d, 2H), 7.58 (d, 2H), 4.54 (m, 1H), 4.42 (m, 1H), 4.03 (dd, 1H), 3.07 (m, 1H), 2.77 (m, 1H).
Reaction SMILES: [O:1]=[S:2]1(=[O:23])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:16]=[CH:15][C:10]([C:11](OC)=[O:12])=[C:9]([N:17]2[CH2:21][CH2:20][CH2:19][C:18]2=[O:22])[CH:8]=1.[CH3:24][C:25]1[C:26]([N:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)=[N:27][CH:28]=[C:29]([CH3:31])[CH:30]=1>>[CH3:24][C:25]1[C:26]([N:32]2[CH2:33][CH2:34][N:35]([C:11]([C:10]3[CH:15]=[CH:16][C:7]([N:3]4[CH2:4][CH2:5][CH2:6][S:2]4(=[O:1])=[O:23])=[CH:8][C:9]=3[N:17]3[CH2:21][CH2:20][CH2:19][C:18]3=[O:22])=[O:12])[CH2:36][CH2:37]2)=[N:27][CH:28]=[C:29]([CH3:31])[CH:30]=1
Reactant: Cc1cnc(N2CCNCC2)c(C)c1
Reactant: COC(=O)c1ccc(N2CCCS2(=O)=O)cc1N1CCCC1=O
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4CCCS4(=O)=O)cc3N3CCCC3=O)CC2)c(C)c1
Yield: 2.3 %

Procedure:
Using methyl 4-(1,1-dioxo-1λ6-isothiazolidin-2-yl)-2-(2-oxopyrrolidin-1-yl)benzoate (148 mg) described in Preparation Example 33 and 1-(3,5-dimethylpyridin-2-yl)piperazine (84 mg) described in Preparation Example 79 and by the reaction and treatment in the same manner as in Example 109, the title compound (5 mg) was obtained.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]([NH:6][C:7]([C:9]1[CH:10]=[C:11]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)[CH:12]=[C:13]([N:15]=[N+:16]=[N-:17])[CH:14]=1)=[O:8])[CH3:5].[C:25]([Si](C)(C)C)#[CH:26]>CN(C=O)C>[CH3:1][O:2][CH2:3][CH:4]([NH:6][C:7]([C:9]1[CH:10]=[C:11]([C:18]2[CH:19]=[CH:20][C:21]([CH3:24])=[CH:22][CH:23]=2)[CH:12]=[C:13]([N:15]2[CH:26]=[CH:25][N:17]=[N:16]2)[CH:14]=1)=[O:8])[CH3:5]
Reactant: COCC(C)NC(=O)c1cc(N=[N+]=[N-])cc(-c2ccc(C)cc2)c1
Reactant: C#C[Si](C)(C)C
Solvent: CN(C)C=O
Product: COCC(C)NC(=O)c1cc(-c2ccc(C)cc2)cc(-n2ccnn2)c1
Yield: 49.8 %

Procedure:
A solution of 5-azido-4′-methyl-biphenyl-3-carboxylic acid (2-methoxy-1-methyl-ethyl)-amide (488 mg, 1.5 mmol), ethynyltrimethylsilane (4.5 mmol, 0.64 mL) in DMF (6 mL) was heated to 110° C. for 16 hours. The mixture was cooled and filtered, and the filtrate was purified by preparative HPLC to afford 262 mg of 4′-methyl-5-[1,2,3]triazol-1-yl-biphenyl-3-carboxylic acid (2-methoxy-1-methyl-ethyl)-amide as white solid (50%). MS (M+H)=351.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:8][N:9]2[C:13]3=[N:14][CH:15]=[CH:16][CH:17]=[C:12]3[CH:11]=[C:10]2[C:18]([O:20]CC)=O)[CH:5]=[CH:6][CH:7]=1.[NH2:23][C:24]1[CH:34]=[CH:33][C:27]2[N:28]([CH3:32])[C:29]([CH3:31])=[N:30][C:26]=2[CH:25]=1>>[CH3:32][N:28]1[C:27]2[CH:33]=[CH:34][C:24]([NH:23][C:18]([C:10]3[N:9]([CH2:8][C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=4)[C:13]4=[N:14][CH:15]=[CH:16][CH:17]=[C:12]4[CH:11]=3)=[O:20])=[CH:25][C:26]=2[N:30]=[C:29]1[CH3:31]
Reactant: CCOC(=O)c1cc2cccnc2n1Cc1cccc(F)c1
Reactant: Cc1nc2cc(N)ccc2n1C
Product: Cc1nc2cc(NC(=O)c3cc4cccnc4n3Cc3cccc(F)c3)ccc2n1C
Yield: 86.1 %

Procedure:
The process is performed according to the method described in Example 11, starting with 0.4 g (1.34 mmol) of ethyl 1-[(3-fluorophenyl)methyl]-1H-pyrrolo[2,3-b]pyridine-2-carboxylate (Example 5.3) and 0.25 g (1.61 mmol) of 5-amino-1,2-dimethylbenzimidazole. 0.477 g of expected compound is isolated.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([CH:10]([OH:35])[C:11]2[N:12]=[CH:13][N:14]([C:16]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:15]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].N1C=CC=CC=1.[C:42](OC(=O)C)(=[O:44])[CH3:43]>CN(C=O)C>[C:4]([C:3]1[CH:6]=[CH:7][C:8]([CH:10]([O:35][C:42](=[O:44])[CH3:43])[C:11]2[N:12]=[CH:13][N:14]([C:16]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:15]=2)=[CH:9][C:2]=1[F:1])#[N:5]
Reactant: CC(=O)OC(C)=O
Reactant: N#Cc1ccc(C(O)c2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)cc1F
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CC(=O)OC(c1ccc(C#N)c(F)c1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1

Procedure:
2-Fluoro-4-[hydroxy-(1-trityl-1H-imidazol-4-yl)-methyl]-benzonitrile (4.05 g, 8.81 mmol), pyridine (2.14 mL, 26.4 mmol), and acetic anhydride (12.5 mL, 132 mmol) were stirred in anhydrous DMF (60 mL) for 3 h under Ar. The reaction was concentrated in uacuo, diluted with EtOAc (250 mL), washed with H2O (2×), brine, dried (MgSO4) and concentrated to give the title compound.