Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(CCC[N:7]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[CH2:15][CH2:14][C:13]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]1=2)C.[CH:22]1[CH:23]=CC2[C:26](=CC(C(O)=O)=C(O)C=2CC2C(O)=C(C(O)=O)C=C3C=2C=CC=C3)[CH:27]=1>C1(C)C=CC=CC=1>[CH2:17]([NH2:7])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:23][CH2:22][CH2:27][CH3:26]
Reactant: O=C(O)c1cc2ccccc2c(Cc2c(O)c(C(=O)O)cc3ccccc23)c1O
Reactant: CN(C)CCCN1c2ccccc2CCc2ccccc21
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCCCCCCCN
Reaction time: 3 h
Yield: 100 %

Procedure:
To a 100 mL round-bottom flask equipped with a magnetic stir bar and addition funnel was charged 730 mg (0.769 mmol) imipramine pamoate, (2:1) salt (prepared as described in King, et al.) in 10.7 g toluene to form a suspension. A solution of 207.3 mg (0.769 mmol) octadecylamine in 12.5 g toluene was prepared and added dropwise to the above suspension over 1 hour. The suspension was stirred for an additional 3 hours and the solids collected by filtration through a medium fritted filter. The product was dried under vacuum to provide 600 mg (83%) of a white solid (2.5% water) which was characterized by DSC, FTIR (FIG. 63), PXRD (FIG. 64), 1H NMR (FIG. 65) and HPLC. The PXRD diffractogram indicated the isolated drug product was crystalline. The relative ratio of imipramine/pamoate was determined to be 1.2/1 by HPLC (and corroborated by 1H NMR). The relative ratio of stearylamine/pamoate was determined to be about 1/1 by 1H NMR. The filtrate from the above work-up was concentrated under reduced pressure and dried under vacuum to give 200 mg of a yellow oil which was characterized by FTIR and 1H NMR. The analyses were consistent with those obtained for imipramine free base described in U.S. Pat. No. 5,578,500. The DSC thermogram is provided in FIG. 62 wherein an endothermic phase change of at least 40 J/g is observed at a temperature above 70° C. and an endothermic phase change of at least 1 J/g is observed above 125° C.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][O:8][C:9]1[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[CH:28][C:10]=1[CH2:11][N:12]1[C:25](=O)[CH:24]([CH3:27])[N:15]2[CH2:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:22]=3[CH2:23][C@@H:14]2[CH2:13]1>C1COCC1>[CH3:7][O:8][C:9]1[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[CH:28][C:10]=1[CH2:11][N:12]1[CH2:25][CH:24]([CH3:27])[N:15]2[CH2:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:22]=3[CH2:23][C@@H:14]2[CH2:13]1
Reactant: COc1ccc(CN2C[C@H]3Cc4ccccc4CN3C(C)C2=O)c(OC)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(CN2CC(C)N3Cc4ccccc4C[C@@H]3C2)c(OC)c1
Temperature: 25 °C
Yield: 91.5 %

Procedure:
Lithium aluminum hydride (1 M in THF, 0.63 ml, 0.63 mmol) was added to a solution of (11aR)-1,2,11,11a-tetrahydro-2-(2,4-dimethoxybenzyl)-4-methyl-4H-pyrazino[1,2-b]isoquinolin-3(6H)-one (0.11 g, 0.31 mmol) in THF (1.8 ml) stirring in a room temperature bath under nitrogen. After stirring at 65° C. for 2 h, the reaction was cooled to room temperature and slowly quenched with water (0.18 ml). Sodium hydroxide (1N, 0.36 ml) followed by water (0.27 ml) were then added and the resultant gelatinous precipitate was filtered through Celite® rinsing THF. The filtrate after evaporation of the solvent was transferred to a separatory funnel with EtOAc. Washing with brine and drying with MgSO4 afforded crude product (0.10 g, 95% yield) after evaporation of the solvent. This material was used in the next step without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6](C)[CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])([O-:3])=[O:2].O(Cl)Cl.[C:17]([Cl:21])(Cl)([Cl:19])[Cl:18]>>[Cl:18][C:17]([Cl:21])([Cl:19])[C:6]1[CH:7]=[CH:8][C:9]([N+:10]([O-:12])=[O:11])=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1
Reactant: Cc1ccc([N+](=O)[O-])c([N+](=O)[O-])c1
Reactant: ClC(Cl)(Cl)Cl
Agent: ClOCl
Product: O=[N+]([O-])c1ccc(C(Cl)(Cl)Cl)cc1[N+](=O)[O-]
Yield: 96 %

Procedure:
3,4-Dinitrotoluene (2.49 g 0.0136 mole) and dichlorine monoxide (4.74 g, 0.055 mole) in carbon tetrachloride (50 ml) were heated in a Carrius tube from which air had been removed, as in Example 6 at 75° for 10 hrs. The reaction solution was filtered to remove a white solid (0.35 g) which was identified by its infrared spectra as 3,4-dinitrobenzoic acid. The filtrate was dried (MgSO4) and the solvent removed on a rotary evaporator to give 1-trichloromethyl-3,4-dinitrobenzene as a white crystalline solid (3.57 g, purity by HPLC 96% yield 89.2%). The product was recrystallized from carbon tetrachloride-petroleum ether to give essentially pure product (mp 69.5°-70.6°).
Reaction SMILES: C([O:4][C:5]1[C:6]([CH3:25])=[C:7]2[CH2:23][CH2:22][N:21]([CH3:24])[C:8]2=[N:9][C:10]=1[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])(=O)C.CC(C[AlH]CC(C)C)C.C(C(C(C([O-])=O)O)O)([O-])=O.[K+].[Na+].CO.C(Cl)Cl.[C:52]([OH:58])([C:54]([F:57])([F:56])[F:55])=[O:53]>C(Cl)Cl.CC#N>[F:55][C:54]([F:57])([F:56])[C:52]([OH:58])=[O:53].[CH3:24][N:21]1[C:8]2=[N:9][C:10]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[C:5]([OH:4])[C:6]([CH3:25])=[C:7]2[CH2:23][CH2:22]1
Reactant: CCCCCCCCCCc1nc2c(c(C)c1OC(C)=O)CCN2C
Agent: CC(C)C[AlH]CC(C)C
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Solvent: ClCCl
Product: CCCCCCCCCCc1nc2c(c(C)c1O)CCN2C
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of 19.0 mg (54.8 μmol) of 2b in 1 mL of CH2Cl2 was added 165 μL (165 μmol, 1.0 M in hexanes) of DIBAL-H at 78° C. The reaction mixture was stirred at −78° C. for 1 h and then 2 mL of sat aq sodium potassium tartrate was added slowly. The reaction mixture was slowly warmed to room temperature over a period of 30 min. The solution was extracted with three 5-mL portions of ethyl acetate. The combined organic layer was washed with brine, dried (MgSO4) and concentrated under diminished pressure to give the crude product as a yellow oil: silica gel TLC Rf 0.16 (1:9 MeOH/CH2Cl2). The residue was then dissolved in 1 mL of CH3CN and 1% aq TFA, frozen and lyophilized. The crude product was purified on a Prepex C8 reversed phase semi-preparative (250 mm×10 mm) HPLC column using a gradient of methanol and water. Linear gradients were employed using 1:4 methanol/water→4:1 methanol/water over a period of 20 min, and then 4:1 methanol/water→methanol over a period of 40 min, at a flow rate of 3.5 mL/min (monitoring at 260 nm). Fractions containing the desired product eluted at 28.2 min, and were collected, frozen, and lyophilized to give 1b as a light yellow solid: yield 13.0 mg (76%); 1H NMR (CD3CN) δ 0.89 (t, 3H, J=6.8 Hz), 1.27-1.31 (m, 16H), 1.54 (quint, 2H, J=7.6 Hz), 2.13 (s, 3H), 2.70 (t, 2H, J=8.0 Hz), 2.99 (t, 2H, J=8.4 Hz), 3.06 (s, 3H) and 3.72 (t, 2H, J=8.4 Hz); 13C NMR (CDCl3) δ 13.0, 13.4, 22.4, 24.41, 27.3, 28.6, 28.9, 29.00, 29.04, 29.3, 29.3, 31.6, 32.4, 53.1, 117.3, 126.1, 132.1, 140.3, 141.5 and 152.1; mass spectrum, m/z 304.3 (M)+ (theoretical 304.3); mass spectrum (APCI), m/z 305.2590 (M+H)+ (C19H33N2O requires 305.2593).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([C:7]([C:9]2[S:13][C:12]([NH2:14])=[N:11][C:10]=2[C:15]2[O:16][CH:17]=[CH:18][CH:19]=2)=[O:8])[CH2:3][CH2:2]1.[CH3:20][N:21]([CH3:31])[C:22]1[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][CH:23]=1.CCN=C=NCCCN(C)C.Cl.O.ON1C2C=CC=CC=2N=N1>CN(C=O)C.O>[CH3:20][N:21]([CH3:31])[C:22]1[CH:30]=[CH:29][C:25]([C:26]([NH:14][C:12]2[S:13][C:9]([C:7]([CH:4]3[CH2:5][CH2:6][O:1][CH2:2][CH2:3]3)=[O:8])=[C:10]([C:15]3[O:16][CH:17]=[CH:18][CH:19]=3)[N:11]=2)=[O:27])=[CH:24][CH:23]=1
Reactant: Nc1nc(-c2ccco2)c(C(=O)C2CCOCC2)s1
Reactant: CN(C)c1ccc(C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)c1ccc(C(=O)Nc2nc(-c3ccco3)c(C(=O)C3CCOCC3)s2)cc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 2.8 %

Procedure:
Compound 454 (125 mg, 0.450 mmol) was dissolved in DMF (2 mL), and 4-(dimethylamino)benzoic acid (296 mg, 1.80 mmol), EDC hydrochloride (344 mg, 1.80 mmol) and 1-hydroxybenzotriazole monohydrate (276 mg, 1.80 mmol) were added thereto, followed by stirring at 80° C. for 2 hours. Water (200 mL) was added to the reaction mixture, and the precipitated solid was collected by filtration. The resulting solid was purified through silica gel column chromatography (chloroform:methanol=9:1), followed by reslurrying with ethanol to afford the entitled Compound 465 (5.30 mg, 3%) as a pale brown solid.
Reaction SMILES: [CH3:1][C:2]1[NH:6][C:5]2[CH:7]=[C:8]([CH3:12])[C:9]([CH3:11])=[CH:10][C:4]=2[N:3]=1.[CH:13](=O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CCOCC>[CH3:11][C:9]1[C:8]([CH3:12])=[CH:7][C:5]2[NH:6][C:2](/[CH:1]=[CH:13]/[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[N:3][C:4]=2[CH:10]=1
Reactant: O=Cc1ccccc1
Reactant: Cc1nc2cc(C)c(C)cc2[nH]1
Solvent: CCOCC
Product: Cc1cc2nc(/C=C/c3ccccc3)[nH]c2cc1C
Temperature: 200 °C
Yield: 12.9 %

Procedure:
A mixture of 2,5,6-trimethyl-1H-benzimidazole (1.5 g, 9.4 mmol) and benzaldehyde (5.0 g, 47 mmol) was heated to 200° C. for 3 h in a sealed tube. The reaction mixture was cooled to room temperature and then ether (50 ml) was added. The precipitated solids were collected by filtration to afford 300 mg (13%) of (E)-5,6-dimethyl-2-styryl-1H-benzimidazole as light yellow solids. 1H-NMR (CDCl3) δ: 8.39-8.33 (1H, m), 7.58-7.47 (2H, m), 7.24-7.16 (5H, m), 6.82 (1H, d, J=16.5 Hz), 5.20 (1H, br.s), 2.13 (6H, s).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][O:11][C:12]1[CH:37]=[CH:36][C:15]2[N:16]([CH2:28][C:29]3[CH:34]=[CH:33][C:32](Br)=[CH:31][CH:30]=3)[C:17]([C@H:19]3[CH2:24][CH2:23][CH2:22][CH2:21][C@H:20]3[C:25]([OH:27])=[O:26])=[N:18][C:14]=2[CH:13]=1.[F:38][C:39]([F:50])([F:49])[C:40]1[N:45]=[CH:44][C:43](B(O)O)=[CH:42][CH:41]=1>>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][O:11][C:12]1[CH:37]=[CH:36][C:15]2[N:16]([CH2:28][C:29]3[CH:34]=[CH:33][C:32]([C:43]4[CH:44]=[N:45][C:40]([C:39]([F:50])([F:49])[F:38])=[CH:41][CH:42]=4)=[CH:31][CH:30]=3)[C:17]([C@H:19]3[CH2:24][CH2:23][CH2:22][CH2:21][C@H:20]3[C:25]([OH:27])=[O:26])=[N:18][C:14]=2[CH:13]=1
Reactant: O=C(O)[C@@H]1CCCC[C@@H]1c1nc2cc(OCc3nc4ccccc4s3)ccc2n1Cc1ccc(Br)cc1
Reactant: OB(O)c1ccc(C(F)(F)F)nc1
Product: O=C(O)[C@@H]1CCCC[C@@H]1c1nc2cc(OCc3nc4ccccc4s3)ccc2n1Cc1ccc(-c2ccc(C(F)(F)F)nc2)cc1

Procedure:
The title compound was prepared using analogous conditions described in Step A of Example 97 using racemic cis-2-(5-(benzo[d]thiazol-2-ylmethoxy)-1-(4-bromobenzyl)-1H-benzo[d]imidazol-2-yl)cyclohexanecarboxylic acid and (6-(trifluoromethyl)pyridin-3-yl)boronic acid. MS (ESI): mass calcd. for C35H29F3N4O3S, 642.71; m/z found, 643.1 [M+H]+. 1H NMR (400 MHz, CD3OD) δ 9.00-8.88 (d, J=2.2, 1H), 8.29-8.22 (dd, J=8.2, 2.2, 1H), 8.05-7.94 (m, 2H), 7.92-7.84 (d, J=8.2, 1H), 7.79-7.71 (m, 2H), 7.62-7.51 (m, 2H), 7.51-7.41 (m, 2H), 7.38-7.26 (m, 3H), 6.01-5.75 (q, J=17.2, 2H), 5.75-5.62 (d, J=1.3, 2H), 3.83-3.57 (m, 1H), 3.03-2.90 (d, J=4.5, 1H), 2.42-2.27 (td, J=13.8, 13.3, 9.5, 1H), 2.27-2.16 (m, 1H), 2.13-2.05 (d, J=12.7, 1H), 2.01-1.93 (m, 1H), 1.88-1.74 (dd, J=15.2, 10.3, 1H), 1.74-1.64 (s, 1H), 1.64-1.45 (q, J=11.0, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][C:10]2[N:11]=[CH:12][NH:13][CH:14]=2)=[CH:4][CH:3]=1.[CH:15](=O)[CH3:16].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCCl>[CH2:15]([N:8]([C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)[CH2:9][C:10]1[N:11]=[CH:12][NH:13][CH:14]=1)[CH3:16]
Reactant: Fc1ccc(NCc2c[nH]cn2)cc1
Reactant: CC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CCN(Cc1c[nH]cn1)c1ccc(F)cc1
Temperature: 40 °C
Reaction time: 16 h
Yield: 56.9 %

Procedure:
To a solution of (4-fluoro-phenyl)-(1H-imidazol-4-ylmethyl)-amine (0.20 g, 1.05 mmol) in 1,2-dichloroethane (6 ml) were added acetaldehyde (0.30 ml, 5.23 mmol), sodium triacetoxyborohydride (0.67 g, 3.14 mmol) and acetic acid (0.06 ml). The reaction mixture was stirred at 40° C. for 16 h. The reaction mixture was then concentrated in vacuo and the residue was purified using flash chromatography (column: Isolute® Flash-NH2 (Separtis); eluent: methanol/ethyl acetate/heptane gradient) to yield a white solid (131 mg, 57%); MS (ISP): 220.4 ((M+H)+.).
Reaction SMILES: Cl[C:2]1[N:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[CH3:11][NH:12][NH2:13].O>C1COCC1>[Cl:10][C:8]1[CH:7]=[CH:6][C:3]2[C:2](=[N:13][N:12]([CH3:11])[CH:4]=2)[N:9]=1
Reactant: CNN
Reactant: O=Cc1ccc(Cl)nc1Cl
Solvent: O
Solvent: C1CCOC1
Product: Cn1cc2ccc(Cl)nc2n1
Temperature: 120 °C
Reaction time: 16 h
Yield: 66.5 %

Procedure:
To a solution of 2,6-dichloronicotinaldehyde (600 mg, 3.41 mmol) in THF (5 mL) was added CH3NHNH2 (480 mg, 4.1 mmol) in a seal tube at 26° C. The mixture was stirred for 16 h at 120° C. until the reaction was complete. The mixture was then treated with water (20 ml) and extracted with ethyl acetate (3×20 ml) and the combined organic layers washed with brine (20 ml), dried over Na2SO4 and concentrated to get the crude material, which was purified by column chromatography to yield the desired compound as a yellow solid (380 mg, 72.4%) (420 mg, Yield 75%).
Reaction SMILES: C([Li])CCC.C(P([CH2:12][S:13]([O:16][CH2:17][CH3:18])(=[O:15])=[O:14])(CC)=O)C.[Cl:19][C:20]1[S:24][C:23]([CH:25]=O)=[CH:22][CH:21]=1>C1COCC1>[CH2:17]([O:16][S:13]([CH:12]=[CH:25][C:23]1[S:24][C:20]([Cl:19])=[CH:21][CH:22]=1)(=[O:14])=[O:15])[CH3:18]
Reactant: CCOS(=O)(=O)CP(=O)(CC)CC
Reactant: O=Cc1ccc(Cl)s1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOS(=O)(=O)C=Cc1ccc(Cl)s1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
n-Butyl lithium (1.6 mL of a 2.5 M solution in hexanes, 4.0 mmol) is added dropwise to a solution of ethyl diethylphosphorylmethanesulfonate (1.0 g, 3.8 mmol), prepared as described in Tetrahedron, 1987, 43(21), 5125, at −78° C. in THF (15 mL). The mixture is stirred for 20 min. then 5-chloro-2-thiophenecarboxaldehyde (0.45 mL, 4.2 mmol) is slowly added. The yellow mixture is stirred at −78° C. for 1 h then allowed to warm to room temperature overnight. The bulk of the solvents are evaporated and the residue is treated with water (2 mL) and extracted with CH2Cl2. The organic layer is washed with brine, dried over MgSO4, filtered and concentrated. The crude product is purified by column chromatography eluting with CH2Cl2 to give the title compound as a yellow solid.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([C:13](O)=[O:14])[CH2:10][C:9]1=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17](N1C=CN=C1)([N:19]1C=CN=C1)=O.CN>C(Cl)Cl>[CH3:17][NH:19][C:13]([CH:11]1[CH2:12][N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:9](=[O:16])[CH2:10]1)=[O:14]
Reactant: O=C(O)C1CC(=O)N(Cc2ccccc2)C1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CN
Solvent: ClCCl
Product: CNC(=O)C1CC(=O)N(Cc2ccccc2)C1
Reaction time: 1 h

Procedure:
0.2 mole of (1-benzyl-2-oxo-4-pyrrolidinyl)carboxylic acid (described in Journal of Organic Chemistry, 1961; 26: p 1519) is dissolved in 200 cm3 of methylene chloride. The mixture is treated with 32.4 g of carbonyldiimidazole. It is left in contact for 1 hour and then a solution consisting of 20 g of methylamine and 200 cm3 of methylene chloride is added. The mixture is left in contact for 12 hours at room temperature, washed with water and then dried over magnesium sulfate. An oil which is the expected compound is obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:15]1([CH3:24])[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1B(O)O.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>C(COC)OC.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:24][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][N:9]=2)[CH:3]=1
Reactant: Cc1ccc(-c2cccc(Br)c2)nc1
Reactant: Cc1ccccc1B(O)O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: Cc1ccc(-c2cccc(-c3ccccc3C)c2)nc1
Yield: 108.8 %

Procedure:
To a solution of 2-(3-bromophenyl)-5-methylpyridine (26.4 g, 106 mmol), o-tolylboronic acid (17.4 g, 128 mmol), palladium (II) acetate (0.60 g, 2.7 mmol), and triphenylphosphine (2.8 g, 10.7 mmol) in 215 mL of dimethoxyethane was added a solution of potassium carbonate (39.7 g, 287 mmol) in 145 mL of water. The reaction mixture was heated at reflux under a nitrogen atmosphere for 16 h and cooled. Ethyl acetate was added, and the aqueous phase was discarded. Evaporation of the organic phase after drying over magnesium sulfate yielded a yellow liquid that was then subjected to vacuum distillation at 160° C. to remove most of the impurities. Further distillation at 220° C. yielded 29.9 g of a colorless liquid that was further purified by silica gel column chromatography with 10/90 ethyl acetate/hexane as the eluent to give 22.5 g (81%) of pure 2-(2′-methylbiphenyl-3-yl)pyridine as a colorless, viscous liquid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[OH:16][C:17]1[CH:18]=[C:19]([CH:28]=[CH:29][CH:30]=1)[C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:21].C(=O)([O-])O.[Na+]>>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][CH:3]=[C:2]2[O:16][C:17]1[CH:18]=[C:19]([C:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:21])[CH:28]=[CH:29][CH:30]=1
Reactant: O=C(c1ccccc1)c1cccc(O)c1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Agent: O=C([O-])O
Agent: [Na+]
Product: COc1cc2nccc(Oc3cccc(C(=O)c4ccccc4)c3)c2cc1OC
Temperature: 170 °C
Yield: 65.3 %

Procedure:
4-Chloro-6,7-dimethoxyquinoline (112 mg) and 3-hydroxybenzophenone (297 mg) were mixed together, and the mixture was heated at 170° C. for 10 min. A saturated aqueous sodium hydrogencarbonate solution was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, was dried over sodium sulfate, and was then concentrated. The residue was subjected to separation and purification by column chromatography on silica gel using hexane-acetone as a solvent to give the title compound (126 mg, yield 65%).
Reaction SMILES: [CH3:1][C:2]1[CH:17]=[C:5]2[N:6]=[C:7]([NH2:16])[CH:8]=[C:9]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[N:4]2[N:3]=1.[F:18][C:19]([F:31])([F:30])[S:20][C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][CH:22]=1>N1C=CC=CC=1>[CH3:1][C:2]1[CH:17]=[C:5]2[N:6]=[C:7]([NH:16][C:25](=[O:26])[C:24]3[CH:28]=[CH:29][C:21]([S:20][C:19]([F:31])([F:18])[F:30])=[CH:22][CH:23]=3)[CH:8]=[C:9]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[N:4]2[N:3]=1
Reactant: Cc1cc2nc(N)cc(-c3ccccc3)n2n1
Reactant: O=C(Cl)c1ccc(SC(F)(F)F)cc1
Solvent: c1ccncc1
Product: Cc1cc2nc(NC(=O)c3ccc(SC(F)(F)F)cc3)cc(-c3ccccc3)n2n1
Reaction time: 2 h
Yield: 49.7 %

Procedure:
A solution of 2-methyl-7-phenylpyrazolo[1,5-a]pyrimidin-5-amine (10A, 62 mg, 0.276 mmol) and pyridine (0.69 mL) in a 20 mL scintillation vial was cooled to 0° C. then treated with 4-(trifluoromethylthio)benzoyl chloride (100 mg, 0.415 mmol). The reaction mixture was stirred for 2 h, partitioned between saturated aqueous sodium bicarbonate and ethyl acetate, and the organic layer subsequently washed with water and then brine. The organic layer was then dried over sodium sulfate, filtered, concentrated under reduced pressure, diluted with methanol, filtered, and purified via preparative HPLC (80-80% MeCN/H2O gradient+0.01% TFA). Lyophilization of the combined fractions gave the titled compound as a yellow solid (58.8 mg, 50%). Melting point (100.9-101.6° C.). 1H NMR (DMSO-d6) δ: 11.49 (s, 1H), 8.15 (d, J=8.6 Hz, 2H), 8.06 (dd, J=6.7, 2.9 Hz, 2H), 7.93 (s, 1H), 7.87 (d, J=8.3 Hz, 2H), 7.56-7.66 (m, 3H), 6.41 (s, 1H), 2.40 (s, 3H); ESI-MS: m/z 429.1 (M+H)+. Melting point (100.9-101.6° C.).
Reaction SMILES: [NH:1]([N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)[C@H:2]([C:11]([O:13]C(C)(C)C)=[O:12])[CH2:3][O:4][C:5]([O:7][CH2:8][CH:9]=[CH2:10])=[O:6].C(O)(C(F)(F)F)=O>C(Cl)(Cl)Cl>[NH:1]([N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)[C@H:2]([C:11]([OH:13])=[O:12])[CH2:3][O:4][C:5]([O:7][CH2:8][CH:9]=[CH2:10])=[O:6]
Reactant: C=CCOC(=O)OC[C@H](NN1CCOCC1)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: C=CCOC(=O)OC[C@H](NN1CCOCC1)C(=O)O

Procedure:
Morpholino-Ser(OAloc) was prepared from Ser(OtBu)-OtBu. Reaction of Ser(OtBu)-OtBu with 4-morpholinecarbonyl chloride in pyridine yielded morpholino-Ser(OtBu)-OtBu. Morpholino-Ser(OtBu)-OtBu was hydrolyzed with TFA to yield morpholino-Ser. Esterification of morpholino-Ser with isobutylene in the presence of a catalytic amount of H2SO4 afforded morpholino-Ser-OtBu. Reaction of morpholino-Ser-OtBu with allyl 1-benzotriazolyl carbonate yielded morpholino-Ser(OAloc)-OtBu. Morpholino-Ser(OAloc)-OtBu was hydrolyzed with TFA in CHCl3 (1:1) to yield morpholino-Ser(OAloc).
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9]([NH:11][CH2:12][CH2:13][CH2:14][O:15][CH3:16])[C:8]([C:17]([N:19]([CH2:42][CH:43]([CH3:45])[CH3:44])[C@H:20]2[CH2:25][C@@H:24]([C:26]([N:28]3[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]3)=[O:27])[CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21]2)=[O:18])=[CH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].C(OCC)(=O)C.[ClH:52]>C(OCC)(=O)C>[ClH:52].[ClH:52].[ClH:52].[C:1]([C:5]1[N:10]=[C:9]([NH:11][CH2:12][CH2:13][CH2:14][O:15][CH3:16])[C:8]([C:17]([N:19]([C@H:20]2[CH2:25][C@@H:24]([C:26]([N:28]3[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]3)=[O:27])[CH2:23][NH:22][CH2:21]2)[CH2:42][CH:43]([CH3:45])[CH3:44])=[O:18])=[CH:7][N:6]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: COCCCNc1nc(C(C)(C)C)ncc1C(=O)N(CC(C)C)[C@H]1C[C@@H](C(=O)N2CCN(C)CC2)CN(C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: CCOC(C)=O
Product: COCCCNc1nc(C(C)(C)C)ncc1C(=O)N(CC(C)C)[C@@H]1CNC[C@H](C(=O)N2CCN(C)CC2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
tert-Butyl (3S,5R)-3-[({2-tert-butyl-4-[(3-methoxypropyl)amino]pyrimidin-5-yl}carbonyl)(2-methylpropyl)amino]-5-[(4-methylpiperazin-1-yl)carbonyl]piperidine-1-carboxylate (87 mg) was dissolved in ethyl acetate (1 ml), 4 N hydrogen chloride-ethyl acetate solution (1 ml) was added, and the mixture was stirred at room temperature for 1 hr. The solvent was evaporated under reduced pressure, and the residue was dried under reduced pressure to give the object compound (87 mg).
Reaction SMILES: Br[C:2]1[N:6]([CH3:7])[CH:5]=[C:4]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:3]=1[CH3:13].[F:14][C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.O.C(Cl)Cl.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>[CH2:11]([O:10][C:8]([C:4]1[C:3]([CH3:13])=[C:2]([C:18]2[CH:19]=[CH:20][C:15]([F:14])=[CH:16][CH:17]=2)[N:6]([CH3:7])[CH:5]=1)=[O:9])[CH3:12]
Reactant: OB(O)c1ccc(F)cc1
Reactant: CCOC(=O)c1cn(C)c(Br)c1C
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: ClCCl
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(C)c(-c2ccc(F)cc2)c1C
Temperature: 110 °C
Reaction time: 18 h
Yield: 96.4 %

Procedure:
A mixture of ethyl 5-bromo-1,4-dimethyl-1H-pyrrole-3-carboxylate (246 mg, 1.0 mmol), 4-fluorophenyl-boronic acid (210 mg, 1.5 mmol), Na2CO3 (320 mg, 3.0 mmol) and Pd(PPh3)4 (116 mg, 0.10 mmol) in DMF/H2O (10:1, 10 mL) was sparged with nitrogen for 10 min. The reaction vial was sealed and heated at 110° C. with stirring. After 18 h, the reaction mixture was diluted with DCM and then filtered. The filtrate was concentrated under reduced pressure and then purified by column chromatography, eluting with EtOAc-Hex (0:100 to 50:50), to give 1,4-dimethyl-5-(4-fluorophenyl)-1H-pyrrole-3-carboxylic acid ethyl ester (252 mg, 96%) as a pale yellow solid. 1H-NMR (CDCl3): δ 7.30 (1H, s), 7.26-7.20 (2H, m), 7.15-7.10 (2H, m), 4.28 (2H, q), 3.48 (3H, s), 2.20 (3H, s), 1.36 (3H, t). MS (ESI): 262 (MH+). The title compound was prepared from 1,4-dimethyl-5-(4-fluorophenyl)-1H-pyrrole-3-carboxylic acid ethyl ester in a manner similar to that described for Examples 16C-D.