Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH2:2][C:3]([N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:6]1)=[O:4].[Cl:20]Cl.O>C(O)(=O)C>[Cl:1][CH2:2][C:3]([N:5]1[C:13]2[C:8](=[CH:9][C:10]([Cl:20])=[CH:11][CH:12]=2)[CH:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:6]1)=[O:4]
Reactant: ClCl
Reactant: O=C(CCl)N1CC(c2ccccc2)c2ccccc21
Solvent: CC(=O)O
Solvent: O
Product: O=C(CCl)N1CC(c2ccccc2)c2cc(Cl)ccc21
Temperature: 15 °C

Procedure:
2.7 G of N-chloracetyl-3-phenylindoline was added with vigorous stirring to a solution of 0.77 g of chlorine in 10 ml of glacial acetic acid which had been cooled to 15° C. The temperature of the mixture which rose to 33° C was cooled down to room temperature and the mixture stirred for a further hour. The resulting solution was poured into 100 ml of cold water. The liquid was decanted from the gummy residue, which was subsequently crystallized from ethanol to give 1.9 g of crystalline N-chloracetyl-3-phenyl-5-chloroindoline having a melting point of 107°-9° C.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]([OH:9])=O)[CH:4]=[N:3]1.C1C=CC2N(O)N=NC=2C=1.[NH:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>C(Cl)Cl.O>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)=[O:9])[CH:4]=[N:3]1
Reactant: C1COCCN1
Reactant: Cn1cc(C(=O)O)cn1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Product: Cn1cc(C(=O)N2CCOCC2)cn1
Reaction time: 0.5 h

Procedure:
To a solution of 1-methyl-1H-pyrazole-4-carboxylic acid (2.00 g, 15.9 mmol) in DCM (100 ml) and TEA (8.80 ml, 63.5 mmol), EDCHCl (3.65 g, 19.0 mmol) and HOBt (2.57 g, 19.0 mmol) were added under a nitrogen atmosphere at rt and stirred for 30 min. Morpholine (1.68 ml, 19.0 mmol) was then added to the reaction mixture and stirring was continued for 18 h. On completion of reaction (monitored by TLC), the reaction mixture was diluted with water and DCM. The organic layer was separated, dried over Na2SO4 and concentrated to get the crude product. Column chromatography afforded the desired product as off white solid. Yield: 1.20 g (39%); MS: m/z=196.4 ([M+H]+)
Reaction SMILES: [OH-].[K+].[Cl:3][C:4]([Cl:24])=[C:5]([C:15]1[CH:20]=[CH:19][C:18]([O:21]C#N)=[CH:17][CH:16]=1)[C:6]1[CH:11]=[CH:10][C:9]([O:12]C#N)=[CH:8][CH:7]=1.ClC(Cl)(Cl)C(C1C=CC(O)=CC=1)C1C=CC(O)=CC=1.Cl>O.CO>[Cl:3][C:4]([Cl:24])=[C:5]([C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1)[C:6]1[CH:7]=[CH:8][C:9]([OH:12])=[CH:10][CH:11]=1
Reactant: N#COc1ccc(C(=C(Cl)Cl)c2ccc(OC#N)cc2)cc1
Agent: Cl
Agent: Oc1ccc(C(c2ccc(O)cc2)C(Cl)(Cl)Cl)cc1
Agent: [K+]
Solvent: CO
Solvent: O
Product: Oc1ccc(C(=C(Cl)Cl)c2ccc(O)cc2)cc1
Temperature: 20 °C

Procedure:
A 4-necked 5-liter flask, equipped with a mechanical stirrer, a thermometer, and a condenser, is charged with methanol (800 g). Potassium hydroxide (440 g) is added in portions to the methanol solution. After the addition, the solution is cooled to 20° C. To this stirring solution, 1,1,1-trichloro-2,2-bis(4-hydroxyphenyl)ethane (420 g) is added in portions. The reaction temperature is kept below 40° C. After the addition, the temperature is raised to 50° C. and maintained for 2.5 hours. The reaction mixture is cooled to 20° C. and neutralized with 25% HCl solution. After the neutralization, the mixture is heated to reflux and water (480 g) is added. The mixture is allowed to cool to the room temperature. The precipitates are filtered and dried to afford 1,1-dichloro-2,2-bis(4-hydroxyphenyl)ethene as white solids with slight tan color.
Reaction SMILES: [Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH:15][C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)=[O:17])[CH:11]=[CH:12][C:13]=1[OH:14].O[CH2:27][CH2:28][C:29]1[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=1.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:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH:15][C:16]([NH:18][C:19]2[CH:20]=[CH:21][C:22]([Cl:25])=[CH:23][CH:24]=2)=[O:17])[CH:11]=[CH:12][C:13]=1[O:14][CH2:27][CH2:28][C:29]1[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=1
Reactant: Cn1ncc(Br)c1-c1cc(NC(=O)Nc2ccc(Cl)cc2)ccc1O
Reactant: OCCc1ccncc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cn1ncc(Br)c1-c1cc(NC(=O)Nc2ccc(Cl)cc2)ccc1OCCc1ccncc1
Reaction time: 2 h
Yield: 44 %

Procedure:
To a solution of 1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-hydroxy-phenyl]-3-(4-chloro-phenyl)-urea (0.1 g, 0.24 mmol), 4-(2-hydroxyethyl)-pyridine (0.0443 g, 0.36 mmol), and triphenylphosphine (0.0944 g, 0.36 mmol) in 10 mL of dry THF was added diisopropylazo-dicarboxylate (0.0728 g, 0.36 mmol) at ambient temperature. The mixture was stirred for 2 hours. Next, additional triphenylphosphine (0.0944 g, 0.36 mmol), 4-(2-hydroxyethyl)-pyridine (0.0443 g, 0.36 mmol), and diisopropylazodicarboxylate were added and the reaction mixture further stirred at room temperature overnight. The solvent from the reaction mixture was evaporated and the crude residue was dissolved in 5.0 mL of DMSO and purified by RP-HPLC. The proper fractions were collected and concentrated to ¼ volume. The aqueous solution was neutralized with 1N NaOH and extracted with ethyl acetate (2×, 59 mL). The organic layer was dried with sodium sulfate, filtered and evaporated to dryness to afford 1-[3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-pyridin-4-yl-ethoxy)-phenyl]-3-(4-chloro-phenyl)-urea as a brown solid in 44% yield. LCMS m/z (%)=526 (M+H 79Br, 100), 528 (M+H 81Br, 67). 1H NMR (DMSO-d6) δ: 9.33 (bs, 1H), 9.24 (bs, 1H), 8.39 (dd, J=4.44 and 1.48 Hz, 2H), 7.63 (d, J=7.28 Hz, 1H), 7.59 (s, 1H), 7.56 (dd, J=8.94 and 2.71 Hz, 2H), 7.48 (m, 1H), 7.34 (d, J=2.67, 1H), 7.31 (d, J=2.67, 1H), 7.28 (dd, J=6.88 and 4.87 Hz, 2H), 7.14 (d, J=9.05 Hz, 1H), 7.09 (d, J=5.93 Hz, 1H), 4.01-4.2 (m, 2H), 3.48 (s, 3H), 2.96-2.91 (m, 2H).
Reaction SMILES: O1CCCC1.[F:6][C:7]1[CH:8]=[C:9]([CH:22]=[CH:23][CH:24]=1)[O:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18](Cl)=[N:19][OH:20])=[CH:13][CH:12]=1.[C:25]([C:27]1[C:28]([NH2:33])=[N:29][CH:30]=[CH:31][CH:32]=1)#[CH:26].C(N(CC)CC)C>O>[F:6][C:7]1[CH:8]=[C:9]([CH:22]=[CH:23][CH:24]=1)[O:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18]2[CH:26]=[C:25]([C:27]3[C:28]([NH2:33])=[N:29][CH:30]=[CH:31][CH:32]=3)[O:20][N:19]=2)=[CH:13][CH:12]=1
Reactant: ON=C(Cl)Cc1ccc(Oc2cccc(F)c2)cc1
Reactant: C#Cc1cccnc1N
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: Nc1ncccc1-c1cc(Cc2ccc(Oc3cccc(F)c3)cc2)no1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 25.3 %

Procedure:
To a tetrahydrofuran (5.00 mL) solution of (4-(3-fluoro-phenoxy)-phenyl)-acetohydroximoyl chloride (290 mg, 1.04 mmol) described in Manufacturing Example 81-1-2 and 3-ethynyl-pyridin-2-ylamine described in Manufacturing Example 1-2-3 (50.0 mg, 0.423 mmol) was added triethylamine (177 μL, 1.27 mmol) at room temperature, which was stirred for 30 minutes at 60° C. Water was added to the reaction solution at room temperature, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was evaporated under a reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate:heptane=1:5) to obtain the title compound (38.7 mg, 25.3%).
Reaction SMILES: Br[C:2]1[O:6][C:5]([C:7]2[O:8][C:9]([C:12]3[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=3)=[CH:10][CH:11]=2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[Na+].[Na+].[C:26]([C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1)#[N:27]>C1(C)C=CC=CC=1.CO.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>[C:26]([C:28]1[CH:33]=[CH:32][C:31]([C:2]2[O:6][C:5]([C:7]3[O:8][C:9]([C:12]4[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=4)=[CH:10][CH:11]=3)=[CH:4][CH:3]=2)=[CH:30][CH:29]=1)#[N:27]
Reactant: N#Cc1ccc(-c2ccc(-c3ccc(Br)o3)o2)cc1
Reactant: N#Cc1ccc(B(O)O)cc1
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: CO
Solvent: Cc1ccccc1
Product: N#Cc1ccc(-c2ccc(-c3ccc(-c4ccc(C#N)cc4)o3)o2)cc1
Temperature: 80 °C
Yield: 52 %

Procedure:
Method (i): Referring now to Scheme 4, to a stirred solution of 4 (1.256 g, 4 mmol), and tetrakis(triphenylphosphine)palladium (230 mg) in toluene (8 mL) under a nitrogen atmosphere was added 4 mL of a 2 M aqueous solution of Na2CO3 followed by 4-cyanophenyl boronic acid (658 mg, 4.8 mmol) in 4 mL of methanol. The vigorously stirred mixture was warmed to 80° C. for 24 h, then cooled, and the precipitate was filtered. The precipitate was partitioned between methylene chloride (250 mL) and 2 M aqueous Na2CO3 (20 mL) containing 2.4 mL of concentrated ammonia. The organic layer was dried (Na2SO4), and then concentrated to dryness under reduced pressure to afford 15 in 52% yield; mp 298-299° C. (DMF). 1H NMR (DMSO-d6); δ 7.09 (d, J=3.6 Hz, 2H), 7.39 (d, J=3.6 Hz, 2H), 7.89 (d, J=8.1 Hz, 4H), 7.97 (d, J=8.1 Hz, 4H). 13C NMR; δ 151.1, 145.8, 133.3, 132.7, 123.8, 118.6, 111.4, 109.45, 109.40. MS (m/z, rel.int.); 336 (M+, 100), 307 (5), 279 (5), 206 (15), 168 (15). High resolution calcd for C22H12N2O2 ms 336.08988. Observed 336.08978. Calcd for C22H12N2O2-0.75H2O: C, 75.52; H, 3.86; N, 8.00. Found. C, 75.12; H, 3.48; N, 7.74
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[CH3:11][N:12]1[CH:16]=[C:15]([C:17]2[C:25]3[C:20](=[N:21][CH:22]=[C:23]([NH2:26])[CH:24]=3)[NH:19][CH:18]=2)[CH:14]=[N:13]1>N1C=CC=CC=1>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:26][C:23]2[CH:24]=[C:25]3[C:17]([C:15]4[CH:14]=[N:13][N:12]([CH3:11])[CH:16]=4)=[CH:18][NH:19][C:20]3=[N:21][CH:22]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: Cn1cc(-c2c[nH]c3ncc(N)cc23)cn1
Reactant: O=C(Cl)c1ccc(F)cc1
Solvent: c1ccncc1
Product: Cn1cc(-c2c[nH]c3ncc(NC(=O)c4ccc(F)cc4)cc23)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 12.7 %

Procedure:
4-Fluorobenzoyl chloride (100 μL, 0.84 mmol) was added to a solution of 54 (20.0 mg, 93.7 μmol) in pyridine (2 mL). The mixture was stirred at r.t. overnight, concentrated and separated by means of LCMS (column LUNA 10 μ C18(2) 00G-4253-V0 250×50 mm) using water—MeCN (0.1% AcOH) as eluent (in gradient; flow 80 mL/min) to afford 55 (3.99 mg, 13%). 1H NMR (400 MHz; DMSO-d6) δ 3.87 (s, 3H), 7.38 (t, J=8.8 Hz, 2H), 7.66 (s, 1H), 7.75 (s, 1H), 8.00 (s, 1H), 8.08 (dd, J=8.7, 5.4 Hz, 2H), 8.48 (dd, J=7.0, 2.2 Hz, 2H); MS (ES) m/z 377 (MH++MeCN).
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C@H:12]3[O:17][CH2:16][C@@H:15]4[CH2:18][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:20][CH2:21][N:14]4[CH2:13]3)[CH:9]=2)[C:4](=[O:29])[O:3]1.C[C@@H]1CC2C(=CC=C([C@@H]3OC[C@@H]4CN(C(OC(C)(C)C)=O)CCN4C3)C=2)C(=O)O1.BrC1C=C2C(=CC=1)C(=O)O[C@H](C)C2.OC[C@@H]1NCCN(C(OC(C)(C)C)=O)C1>>[CH3:1][C@@H:2]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C@@H:12]3[O:17][CH2:16][C@H:15]4[CH2:18][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:20][CH2:21][N:14]4[CH2:13]3)[CH:9]=2)[C:4](=[O:29])[O:3]1
Reactant: C[C@@H]1Cc2cc([C@@H]3CN4CCN(C(=O)OC(C)(C)C)C[C@H]4CO3)ccc2C(=O)O1
Agent: CC(C)(C)OC(=O)N1CCN[C@@H](CO)C1
Agent: C[C@@H]1Cc2cc(Br)ccc2C(=O)O1
Agent: C[C@@H]1Cc2cc([C@H]3CN4CCN(C(=O)OC(C)(C)C)C[C@H]4CO3)ccc2C(=O)O1
Product: C[C@@H]1Cc2cc([C@H]3CN4CCN(C(=O)OC(C)(C)C)C[C@@H]4CO3)ccc2C(=O)O1

Procedure:
8G and 8H were prepared in a similar manner as 8A and 8B except (3R)-6-Bromo-3-methyl-3,4-dihydro-1H-isochromen-1-one and tert-butyl (3R)-3-(hydroxymethyl)piperazine-1-carboxylate were used as the starting materials. The cis/trans mixture was purified via chiral HPLC (20% 2:1 MeOH:MeCN/CO2) on OJ column. The slower eluting diastereomer was the trans isomer: 8G LC-MS: (M+1)+ 403; 8H: LC-MS: (M+1)+ 403.
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:7])[CH2:4][CH2:5][SH:6].[H-].[Na+].C1COCC1.Cl[C:16]1[CH:21]=[N:20][CH:19]=[C:18]([C:22]#[N:23])[N:17]=1>O.C(OCC)(=O)C>[C:22]([C:18]1[CH:19]=[N:20][CH:21]=[C:16]([S:6][CH2:5][CH2:4][N:3]([CH3:7])[CH3:2])[N:17]=1)#[N:23]
Reactant: CN(C)CCS
Reactant: N#Cc1cncc(Cl)n1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CN(C)CCSc1cncc(C#N)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 48 %

Procedure:
2-Dimethylaminoethanethiol hydrochloride salt (1.46 g, 10.0 mmol) and sodium hydride (60% in oil, 0.88 g, 22.0 mmol) were added to THF (50 ml), and 2-chloro-6-cyanopyrazine (1.40 g, 10.0 mmol) was added thereto. The mixture was stirred at room temperature for 18 hrs. The reaction mixture was combined with ethyl acetate and water. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was recrystallized from n-hexane-ethyl acetate to give the titled compound (1.00 g, 48%) as pale yellow crystals.
Reaction SMILES: [CH:1]([C:3]1[S:7][C:6]([NH:8][C@@H:9]([CH:17]([CH3:19])[CH3:18])[C:10]([O:12]C(C)(C)C)=[O:11])=[N:5][CH:4]=1)=[O:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:1]([C:3]1[S:7][C:6]([NH:8][C@@H:9]([CH:17]([CH3:19])[CH3:18])[C:10]([OH:12])=[O:11])=[N:5][CH:4]=1)=[O:2]
Reactant: CC(C)[C@H](Nc1ncc(C=O)s1)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)[C@H](Nc1ncc(C=O)s1)C(=O)O
Yield: 200.1 %

Procedure:
Following the procedure described in Example 3, except using the material from Example 19 (2.99 g, 10.51 mmol), CH2Cl2 (200 mL) and TFA (51 mL, 662 mmol), 4.8 g (quantitative yield) of the title compound is obtained as a tan syrup as a bis TFA salt. LC/MS (Condition A): ret. T=2.33 min, (M+H)+ 229.04.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][C:20]([O:22]C)=[O:21])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].CO.C(Cl)Cl.Cl>[OH-].[K+]>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21])[CH2:14][CH2:15]2)=[CH:8][CH:9]=1)(=[O:3])[CH3:2]
Reactant: COC(=O)CCCCN1CCN(c2ccc(C(C)=O)cc2)CC1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: CC(=O)c1ccc(N2CCN(CCCCC(=O)O)CC2)cc1
Temperature: 100 °C
Yield: 47.9 %

Procedure:
4-(4-Acetylphenyl)-1-piperazinevaleric acid, methyl ester (15.3 mg) is suspended in 0.1 mL of potassium hydroxide solution (33.2 mg/mL). After heating at 100° C. for 150 min, the starting material is completely dissolved and absent by TLC (10% MeOH/CH2Cl2). After acidifying the reaction solution to pH 4 by adding 0.2N HCl, the aqueous solution is extracted with methylene chloride. After evaporation of the organic layer to dryness, the residue is dissolved in methylene chloride and filtered. Evaporation of the organic layer gives 7 mg of 4-(4-acetylphenyl)-1-piperazinevaleric acid as a white solid. 1H-NMR (CDCl3) spectrum is consistent with the assigned structure. MS (FAB) m/e 305 (M+ +H), 327 (M+ +Na), 348 (M+ +2Na--H).
Reaction SMILES: F[C:2]1[CH:19]=[CH:18][C:5]([C:6]([CH:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]([OH:17])=[O:16])[CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1.[OH-].[Na+].Cl.[CH2:23]([OH:25])[CH3:24]>O>[CH2:23]([O:25][C:2]1[CH:19]=[CH:18][C:5]([C:6]([CH:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]([OH:17])=[O:16])[CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1)[CH3:24]
Reactant: CCO
Reactant: O=C(O)CN1CCC(C(=O)c2ccc(F)cc2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCOc1ccc(C(=O)C2CCN(CC(=O)O)CC2)cc1
Temperature: 80 °C

Procedure:
To a solution of 2-(4-(4-fluorobenzoyl)piperidin-1-yl)acetic acid (600 mg, 2.26 mmol) in ethanol (20 mL) was added sodium hydroxide (400 mg, 10.0 mmol) in water (2 mL) and heated at 80° C. for 24 h. The reaction mixture was neutralized with aqueous hydrochloric acid (1 N), the solvent was evaporated under reduced pressure and used to the next step directly. MS m/z 292.3 (M+1), retention time=0.99 min.
Reaction SMILES: CN1CCC(=C)CC1.BrC1C=C(NC(=O)C)C=C(C(F)(F)F)C=1.[N:24]1([CH2:30][CH2:31][CH2:32][C:33]2[CH:34]=[C:35]([NH:43][C:44](=[O:46])[CH3:45])[CH:36]=[C:37]([C:39]([F:42])([F:41])[F:40])[CH:38]=2)[CH2:29]CC[CH2:26][CH2:25]1>>[CH3:29][N:24]1[CH2:25][CH2:26][CH:32]([C:33]2[CH:34]=[C:35]([NH:43][C:44](=[O:46])[CH3:45])[CH:36]=[C:37]([C:39]([F:40])([F:41])[F:42])[CH:38]=2)[CH2:31][CH2:30]1
Reactant: CC(=O)Nc1cc(CCCN2CCCCC2)cc(C(F)(F)F)c1
Agent: C=C1CCN(C)CC1
Agent: CC(=O)Nc1cc(Br)cc(C(F)(F)F)c1
Product: CC(=O)Nc1cc(C2CCN(C)CC2)cc(C(F)(F)F)c1

Procedure:
N-[3-(1-Methylpiperidin-4-yl)-5-trifluoromethyl-phenyl]-acetamide was prepared from 1-methyl-4-methylene-piperidine and N-(3-bromo-5-trifluoromethyl-phenyl)-acetamide similar to that described in the preparation of N-[3-(3-piperidin-1-yl-propyl)-5-trifluoromethyl-phenyl]-acetamide.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1.S(=O)(=O)(O)O.O[CH2:19][NH:20][C:21](=[O:24])[CH2:22][Cl:23].[OH-].[K+]>C(O)(=O)C>[Cl:23][CH2:22][C:21]([NH:20][CH2:19][C:7]1[CH:8]=[CH:9][C:4]([O:3][C:2]([F:11])([F:12])[F:1])=[CH:5][C:6]=1[OH:10])=[O:24]
Reactant: Oc1cccc(OC(F)(F)F)c1
Reactant: O=C(CCl)NCO
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Product: O=C(CCl)NCc1ccc(OC(F)(F)F)cc1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 33.8 %

Procedure:
3-(Trifluoromethoxy)phenol (4.827 g, 27 mmol) was dissolved in glacial acetic acid (20 mL). The mixture was cooled in an ice bath between 14–17° C. and concentrated sulfuric acid (2 mL) was slowly added keeping the temperature below 20° C. The mixture was cooled below 10° C. and N-hydroxymethyl-2-chloroacetamide (3.52 g, 28.5 mmol) was added. The mixture was warmed slowly to room temperature and stirred overnight. The mixture was then poured slowly into ice (200 mL) and the pH was adjusted to ˜4–5 with KOH pellets, keeping the temperature below 5° C. The reaction mixture was warmed to room temperature and extracted twice with ethyl acetate (150 mL). The organic layer was collected and washed with NaHCO3 (sat., 30 mL). The organic layer was dried over MgSO4, filtered and the solvent removed to dryness. The mixture was purified by column chromatography (SiO2, 700 mL) using an eluent of hexane/ethyl acetate (10/2). Recovery: 2.42 g (33.8% yield). 1H NMR (DMSO) δ=10.23 (1H, s), 8.56 (1H, st), 7.16–7.14 (1H, sd), 6.71–6.70 (2H, br), 4.18–4.17 (2H, d), 4.08 (2H, s).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]([F:23])([F:22])[F:21])[CH:14]=1)[C:7]([C:24]([OH:26])=O)=[CH:6]2)#[N:2].Cl.[NH2:28][C@@H:29]1[CH2:33][CH2:32][CH2:31][C@H:30]1[OH:34]>>[OH:34][C@@H:30]1[CH2:31][CH2:32][CH2:33][C@H:29]1[NH:28][C:24]([C:7]1[N:8]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]([F:21])([F:23])[F:22])[CH:14]=2)[C:9]2[C:5]([CH:6]=1)=[CH:4][C:3]([C:1]#[N:2])=[CH:11][CH:10]=2)=[O:26]
Reactant: N[C@@H]1CCC[C@H]1O
Reactant: N#Cc1ccc2c(c1)cc(C(=O)O)n2Cc1cccc(OC(F)(F)F)c1
Agent: Cl
Product: N#Cc1ccc2c(c1)cc(C(=O)N[C@@H]1CCC[C@H]1O)n2Cc1cccc(OC(F)(F)F)c1

Procedure:
The title compound was prepared using 5-cyano-1-(3-trifluoromethoxybenzyl)-1H-indole-2-carboxylic acid [prepared from 3-(trifluoromethoxy)benzyl bromide and ethyl 5-cyanoindole-2-carboxylate] and trans-2-aminocyclopentanol hydrochloride in a manner similar to that described in Example 11.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[F:15][C:16]([F:21])([F:20])[C:17]([OH:19])=[O:18].FC(F)(F)C(O)=O.[Cl:29][C:30]1[CH:31]=[N:32][C:33]2[NH:34][C:35]3[CH:36]=[N:37][CH:38]=[C:39]([CH:60]=3)[CH2:40][CH2:41][C:42]3[CH:50]=[C:46]([NH:47][C:48]=1[N:49]=2)[CH:45]=[CH:44][C:43]=3[NH:51][CH2:52][CH2:53][CH:54]1[CH2:59][CH2:58][NH:57][CH2:56][CH2:55]1.[CH3:61][C:62]1[O:66][N:65]=[C:64]([C:67](Cl)=[O:68])[CH:63]=1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[F:15][C:16]([F:21])([F:20])[C:17]([OH:19])=[O:18].[Cl:29][C:30]1[CH:31]=[N:32][C:33]2[NH:34][C:35]3[CH:36]=[N:37][CH:38]=[C:39]([CH:60]=3)[CH2:40][CH2:41][C:42]3[CH:50]=[C:46]([NH:47][C:48]=1[N:49]=2)[CH:45]=[CH:44][C:43]=3[NH:51][CH2:52][CH2:53][CH:54]1[CH2:55][CH2:56][N:57]([C:67]([C:64]2[CH:63]=[C:62]([CH3:61])[O:66][N:65]=2)=[O:68])[CH2:58][CH2:59]1
Reactant: Cc1cc(C(=O)Cl)no1
Reactant: Clc1cnc2nc1Nc1ccc(NCCC3CCNCC3)c(c1)CCc1cncc(c1)N2
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C(=O)N2CCC(CCNc3ccc4cc3CCc3cncc(c3)Nc3ncc(Cl)c(n3)N4)CC2)no1
Yield: 55 %

Procedure:
The desired compound was prepared according to the procedure of Example D94 using 6-chloro-N-(2-piperidin-4-ylethyl)-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-amine tetrakis(trifluoroacetate) and 5-methylisoxazole-3-carbonyl chloride as the starting materials in 55% yield. LCMS for C29H32ClN8O2 (M+H)+: m/z=559.2.
Reaction SMILES: [OH-].[Na+].C(O[C:6]([C:8]1[NH:9][C:10]([CH3:37])=[C:11]([C:14]2[NH:15][C:16]3[CH:22]=[C:21]([S:23][C:24]4[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=4)[C:20]([O:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[CH:19][C:17]=3[N:18]=2)[C:12]=1[CH3:13])=[O:7])C.[CH2:38]([N:40]=[C:41]=NCCCN(C)C)C.CNC>CN(C)C=O.C(O)C>[CH3:38][N:40]([CH3:41])[C:6]([C:8]1[NH:9][C:10]([CH3:37])=[C:11]([C:14]2[NH:15][C:16]3[CH:22]=[C:21]([S:23][C:24]4[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=4)[C:20]([O:30][C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=4)=[CH:19][C:17]=3[N:18]=2)[C:12]=1[CH3:13])=[O:7]
Reactant: CCN=C=NCCCN(C)C
Reactant: CCOC(=O)c1[nH]c(C)c(-c2nc3cc(Oc4ccccc4)c(Sc4ccncc4)cc3[nH]2)c1C
Agent: CNC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CN(C)C=O
Product: Cc1[nH]c(C(=O)N(C)C)c(C)c1-c1nc2cc(Oc3ccccc3)c(Sc3ccncc3)cc2[nH]1
Temperature: 60 °C
Reaction time: 17 h
Yield: 34.3 %

Procedure:
Five milliliters of ethanol and 3.5 ml (3.5 mmol) of a 1 N sodium hydroxide aqueous solution were added to 0.48 g (1.0 mmol) of the 4-(5-(4-pyridylsulfenyl)-6-phenoxybenzimidazole-2-yl)-3,5-dimethylpyrrole-2-carboxylic acid ethyl ester obtained in Comparative Example 1, and the reaction mixture was stirred at 60° C. for 17 hours. The reaction mixture was allowed to cool and concentrated, and the insoluble material was filtered off by adding water. The filtrate was neutralized with a 2 N hydrochloric acid solution, and the precipitate was collected by filtration, washed with water, and dried at reduced pressure to afford crude carboxylic acid (0.22 g). 0.2 g (0.4 mmol) of the crude carboxylic acid was dissolved in 3 ml of N,N-dimethylformamide, and then 92 mg (0.5 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide and 0.25 ml (2.2 mmol) of a 40% dimethylamine aqueous solution were added to the solution. The reaction mixture was stirred at 60° C. for 18 hours. The reaction mixture was allowed to cool to room temperature, and the solvent was evaporated at reduced pressure. The obtained residue was purified using medium pressure silica gel flash column chromatography (methanol:chloroform=1:100 to 1:10) to afford (N,N-dimethyl)-4-(5-(4-pyridylsulfenyl)-6-phenoxybenzimidazole-2-yl)-3,5-dimethylpyrrole-2-carboxamide (83 mg, 43%) as an amorphous.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH3:20])[NH:12][C:11]([C:21]2[C:26]([Cl:27])=[CH:25][CH:24]=[CH:23][N:22]=2)=[N:10]1.C1C(=O)N([Br:35])C(=O)C1>>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH2:20][Br:35])[NH:12][C:11]([C:21]2[C:26]([Cl:27])=[CH:25][CH:24]=[CH:23][N:22]=2)=[N:10]1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)C1=C(C)NC(c2ncccc2Cl)=NC1c1ccc(F)cc1Br
Product: CCOC(=O)C1=C(CBr)NC(c2ncccc2Cl)=NC1c1ccc(F)cc1Br
Yield: 49.1 %

Procedure:
Ethyl 4-(2-bromo-4-fluorophenyl)-2-(3-chloropyridin-2-yl)-6-methyl-1,4-dihydropyrimidine-5-carboxylate (6.07 g, 13.4 mmol) (The compound was synthesized according to the procedure as described in WO0058302) was reacted with NBS (2.87 g, 16.1 mmol) according to the procedure as described in Example 1, Step B to give the title compound as a yellow solid (3.5 g, 49%). The compound was characterized by the following spectroscopic data: