Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC1C=C(C=CC=1C1SC=CC=1)[NH2:6].[C:15]1(=O)[O:20][C:18](=[O:19])[C:17]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:16]12.O>C(O)(=O)C>[C:18]1(=[O:19])[C:17]2[C:16](=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:15](=[O:20])[NH:6]1
Reactant: COc1cc(N)ccc1-c1cccs1
Reactant: O=C1OC(=O)c2ccccc21
Solvent: CC(=O)O
Solvent: O
Product: O=C1NC(=O)c2ccccc21

Procedure:
A stirred mixture of 5.1 g (0.025 mole) of 3-methoxy-4-(thien-2-yl)aniline (prepared in Example 4) and 4.1 g (0.03 mole) of phthalic anhydride in 20 ml of glacial acetic acid was heated at reflux for approximately 18 hours. The hot reaction mixture was poured into 700 ml of distilled water forming a precipitate. The precipitate was collected by filtration and the filter cake dissolved in methylene chloride. The methylene chloride solution was washed first with a 10% aqueous potassium carbonate solution and then with an aqueous sodium chloride solution. The washed organic solution was dried over anhydrous sodium sulfate and filtered. The solvent was removed from the filtrate by evaporation under reduced pressure to yield 8.2 g of 2-[4-thien-2-yl)-3-methoxyphenyl]-1H-isoindol-1,3-(2H)-dione as a solid (mp 153°-155° C.).
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:10]1[N:11]=[C:12]([NH:15][C:16]([O:18][CH2:19][C:20]([Cl:23])([Cl:22])[Cl:21])=[O:17])[S:13][CH:14]=1)[C:5]([O:7]CC)=[O:6].[OH-].[K+].O>C(O)C>[CH3:1][O:2][N:3]=[C:4]([C:10]1[N:11]=[C:12]([NH:15][C:16]([O:18][CH2:19][C:20]([Cl:23])([Cl:21])[Cl:22])=[O:17])[S:13][CH:14]=1)[C:5]([OH:7])=[O:6]
Reactant: CCOC(=O)C(=NOC)c1csc(NC(=O)OCC(Cl)(Cl)Cl)n1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CON=C(C(=O)O)c1csc(NC(=O)OCC(Cl)(Cl)Cl)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 8.1 g. of ethyl α-methoxyimino-[2-(β,β,β-trichloroethoxycarbonylamino)thiazol-4-yl]acetate in 50 ml. of ethanol is added a solution of 11.2 g. of KOH in a mixture of 30 ml. of water and 150 ml. of ethanol. The whole mixture is stirred at room temperature for 1 hour, and then concentrated under reduced pressure. The residue is extracted with ethyl acetate. The water layer is made acidic with 10% aq. HCl and the separated solid is collected. Recrystallization of the solid from aq. methanol gives α-methoxyimino-[2-(β,β,β-trichloroethoxycarbonylamino)thiazol-4-yl]acetic acid. 4.1 g. Melting point: 162°-163° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([C:12]=1[CH3:13])[C:7]([O:9]CC)=O.[Li+].CC([N-]C(C)C)C.[C:22]([O:26][CH3:27])(=[O:25])[CH:23]=[CH2:24].CC(O)=O>C1COCC1>[Br:1][C:2]1[C:12]2[CH2:13][CH2:24][CH:23]([C:22]([O:26][CH3:27])=[O:25])[C:7](=[O:9])[C:6]=2[CH:5]=[N:4][CH:3]=1
Reactant: C=CC(=O)OC
Reactant: CCOC(=O)c1cncc(Br)c1C
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COC(=O)C1CCc2c(Br)cncc2C1=O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 95.3 %

Procedure:
Ethyl 5-bromo-4-methylnicotinate (7.04 g, 28.8 mmol) in THF (28.8 mL) was added over a period of 20 min to a solution of LDA (31.7 mmol) [generated from N,N-diisopropylamine (4.52 ml, 31.7 mmol) and n-butyllithium (19.8 mL, 31.7 mmol, 1.6M in hexane) in 144 mL THF] at −78° C. The resulting dark red solution was stirred for 20 min, then methyl acrylate (6.21 g, 72.1 mmol) in THF (28.8 mL) was added over 15 min. The reaction was stirred an additional 1.5 h, then aq. 10% AcOH was added (resulting pH=4-5) and the reaction was allowed to warm to room temperature. After evaporation, the residue was poured on aq. sat. NaHCO3 and extracted with EtOAc (3×). The combined organic layers were dried (Na2SO4) and concentrated to afford the title compound (7.80 g, 95% in 70% purity with 30% starting material) as brown solid. MS: 284.0 (M+H+, 1Br).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:10]([CH3:11])=[C:9]([CH:12]=[O:13])[NH:8][C:7]=1[CH3:14])=[O:5])C.[OH-].[K+].Cl>CO.O>[CH:12]([C:9]1[NH:8][C:7]([CH3:14])=[C:6]([C:4]([OH:5])=[O:3])[C:10]=1[CH3:11])=[O:13]
Reactant: CCOC(=O)c1c(C)[nH]c(C=O)c1C
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1[nH]c(C=O)c(C)c1C(=O)O
Temperature: 25 °C
Yield: 95.7 %

Procedure:
5-Formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid ethyl ester (2 g, 10 mmol) was added to a solution of potassium hydroxide (3 g, 53 mmol) dissolved in methanol (3 mL) and water (10 mL). The mixture was refluxed for 3 hours, cooled to room temperature and acidified with 6 N hydrochloric acid to pH 3. The solid was collected by filtration, washed with water and dried in a vacuum oven overnight to give 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (1.6 g , 93%). 1H NMR (300 MHz, DMSO-d6) δ12.09 (s, br, 2H, NH & COOH), 9.59 (s, 1H, CHO), 2.44 (s, 3H, CH3), 2.40 (s, 3H, CH3).
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]([F:24])([F:23])[F:22])[CH:15]=2)[N:8]=1)=O.[C:26]1([CH3:34])[CH:31]=[CH:30][C:29]([NH:32]N)=[CH:28][CH:27]=1>>[C:26]1([CH3:34])[CH:31]=[CH:30][C:29]([N:32]2[C:5]([C:7]3[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]4[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]([F:24])([F:23])[F:22])[CH:15]=4)[N:8]=3)=[CH:4][CH:3]=[N:2]2)=[CH:28][CH:27]=1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(OC(F)(F)F)c2)ccc1=O
Reactant: Cc1ccc(NN)cc1
Product: Cc1ccc(-n2nccc2-c2nn(-c3cccc(OC(F)(F)F)c3)ccc2=O)cc1

Procedure:
Reaction of 3-((E)-3-Dimethylamino-acryloyl)-1-(3-trifluoromethoxy-phenyl)-1H-pyridazin-4-one (A-6) and p-tolyl-hydrazine according to example 43 gave the desired product. MS: M=413.3 (M+H)+
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:6]2[CH2:7][CH:8]3[CH:12]([NH2:13])[C:11]([CH3:14])([C:5]=2[CH:4]=1)[CH:10]=[CH:9]3.[H][H]>[Pt]=O.C(O)C>[CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:6]2[CH2:7][CH:8]3[CH:12]([NH2:13])[C:11]([CH3:14])([C:5]=2[CH:4]=1)[CH2:10][CH2:9]3
Reactant: [H][H]
Reactant: COc1ccc2c(c1)C1(C)C=CC(C2)C1N
Agent: O=[Pt]
Solvent: CCO
Product: COc1ccc2c(c1)C1(C)CCC(C2)C1N

Procedure:
A solution of 8,9-dihydro-3-methoxy-5-methyl-5,8-methano-5H-benzocyclohepten-10-amine [1.0 g. of α,β-amine mixture (9:1)] in 100 ml. of ethanol is hydrogenated over 150 mg. of platinum oxide catalyst under 48 psi hydrogen pressure in a Parr apparatus. Uptake of hydrogen is complete in one-half hour. The catalyst is filtered and the filtrate is concentrated. Gas chromatography of the residue identified it as a 9:1 mixture of α/β 6,7,8,9-tetrahydro-3-methoxy-5-methyl-5,8-methano-5H-benzocycloheptene-10-amine.
Reaction SMILES: O(P(O[C:18]1[N:19]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:21][O:22][CH:23]=1)(OC1C=CC=CC=1)=O)C1C=CC=CC=1.CC1(C)C(C)(C)OB([C:39]2[CH:44]=[CH:43][C:42]([NH:45][C:46](=[O:48])[CH3:47])=[CH:41][CH:40]=2)O1>>[C:46]([NH:45][C:42]1[CH:43]=[CH:44][C:39]([C:18]2[N:19]([C:24]([O:26][C:27]([CH3:28])([CH3:29])[CH3:30])=[O:25])[CH2:20][CH2:21][O:22][CH:23]=2)=[CH:40][CH:41]=1)(=[O:48])[CH3:47]
Reactant: CC(C)(C)OC(=O)N1CCOC=C1OP(=O)(Oc1ccccc1)Oc1ccccc1
Reactant: CC(=O)Nc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Product: CC(=O)Nc1ccc(C2=COCCN2C(=O)OC(C)(C)C)cc1
Yield: 44 %

Procedure:
This compound was prepared from tert-butyl 5-((diphenoxyphosphoryl)oxy)-2H-1,4-oxazine-4(3H)-carboxylate and N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetamide using a procedure similar to that described in Example 2 (Steps 1-3a) above. The product was isolated as a white solid (44% yield); 1H-NMR (d6-DMSO) 1.07 (9H, s), 2.02 (3H, s), 3.66 (2H, t), 4.08 (2H, t), 6.32 (1H, s), 7.09 (2H, d), 7.49 (2H, d), 9.88 (1H, s); MS ES(+) 263.0 (M+-tBu); HRMS m/z calcd for C17H22N2O4+H+ 319.1658 [M+H+]. Found 319.1658. IR λmax=1694 cm−1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:8]1[C@@H:13]([OH:14])[CH2:12][CH2:11][N:10]([CH3:15])[CH2:9]1.[F:16][C:17]1[CH:22]=[CH:21][C:20](O)=[CH:19][CH:18]=1>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:8]1[C@H:13]([O:14][C:20]2[CH:21]=[CH:22][C:17]([F:16])=[CH:18][CH:19]=2)[CH2:12][CH2:11][N:10]([CH3:15])[CH2:9]1
Reactant: CN1CC[C@H](O)[C@H](c2ccccc2F)C1
Reactant: Oc1ccc(F)cc1
Product: CN1CC[C@@H](Oc2ccc(F)cc2)[C@H](c2ccccc2F)C1

Procedure:
The procedure of Example 53 is repeated with cis-3-(2-fluorophenyl)-1-methyl-4-piperidinol and 4-fluorophenol to yield trans-3-(2-fluorophenyl)-4-(4-fluorophenoxy)-1-methylpiperidine. This compound is treated with a solution of fumaric acid in ether containing to yield trans-4-(4-fluorophenoxy)-3-(2-fluorophenyl)-1-methylpiperidine fumarate, m.p. 205.5°-206.5° C. The crude salt is recrystallized from isopropanol to afford colorless crystals, m.p. 205.5-206.5.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][CH2:10][CH2:11][Cl:12])=[CH:4][CH:3]=1.C1C=C(Cl)C=C(C(OO)=[O:21])C=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([CH2:9][CH2:10][CH2:11][Cl:12])=[O:21])=[CH:6][CH:7]=1
Reactant: Fc1ccc(SCCCCl)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Product: O=S(CCCCl)c1ccc(F)cc1

Procedure:
Prepared by Procedure S and Scheme AA using 3-chloropropyl 4-fluorophenyl sulfide and 1 eq m-CPBA: 1H NMR (400 MHz, CDCl3) δ 7.65-7.62 (m, 2H), 7.28-7.21 (m, 2H), 3.65 (m, 2H), 2.94 (m, 2H), 2.28 (m, 1H), 2.06 (m, 1H); ESMS m/e: 220.9 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:15][CH2:16][CH3:17])[C:5]1[O:10][C:9](=O)[CH:8]=[C:7]([OH:12])[C:6]=1[CH2:13][CH3:14])[CH3:2].CO.[NH3:20]>>[CH2:1]([O:3][CH:4]([O:15][CH2:16][CH3:17])[C:5]1[NH:20][C:9](=[O:10])[CH:8]=[C:7]([OH:12])[C:6]=1[CH2:13][CH3:14])[CH3:2]
Reactant: N
Reactant: CCOC(OCC)c1oc(=O)cc(O)c1CC
Solvent: CO
Product: CCOC(OCC)c1[nH]c(=O)cc(O)c1CC
Temperature: 60 °C
Reaction time: 4 h
Yield: 7.5 %

Procedure:
A mixture of intermediate 19 (20 g; 82 mmol) in CH3OH/NH3 (150 ml) was stirred at 60° C. for 4 hours, evaporated till dryness and taken up in diisopropyl ether. The precipitate was filtered to yield 1.5 g of intermediate 20 (7.5%). The product was used without further purification in the next reaction step.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[CH3:9][C:10]1[NH:14][C:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:12][CH:11]=1.[OH-].[Na+]>C(Cl)(Cl)Cl>[Cl:1][C:11]1[CH:12]=[C:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[NH:14][C:10]=1[CH3:9]
Reactant: CCOC(=O)c1ccc(C)[nH]1
Reactant: O=C1CCC(=O)N1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1cc(Cl)c(C)[nH]1
Temperature: 40 °C
Reaction time: 4 h
Yield: 37.8 %

Procedure:
N-Chlorosuccinimide (0.67 g, 5.08 mmol) was added to a solution of ethyl 5-methyl-1H-pyrrole-2-carboxylate (Intermediate 29, 0.65 g, 4.23 mmol) in chloroform (20 ml). The reaction was warmed to 40° C. and stirred for 4 h, then poured to a beaker containing 2 N NaOH (20 ml) at 0° C. The layers were separated and the aqueous layer was extracted with chloroform 3 times. The combined organic extracts were dried over magnesium sulfate and concentrated. The resultant off-white solid was purified by flash chromatography (hexanes/EtOAc, 16:1) to give the title product as a white solid (0.3 g, 38%). MS (ES): 188 (M+1) for C8H10ClNO2; NMR (CDCl3): 1.34 (t, 3H), 2.27 (s, 3H), 4.30 (q, 2H), 6.76 (s, 1H), 9.07 (brs, 1H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:13]3=[CH:14][C:15]4[O:19][CH2:18][O:17][C:16]=4[CH:20]=[C:12]3[O:11][CH2:10]2)[C:2]1=[O:21].[Br:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27]Br)=[CH:25][CH:24]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CC(=O)CC.C(OCC)(=O)C>[Br:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27][N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]3([C:13]4=[CH:14][C:15]5[O:19][CH2:18][O:17][C:16]=5[CH:20]=[C:12]4[O:11][CH2:10]3)[C:2]2=[O:21])=[CH:25][CH:24]=1
Reactant: BrCc1ccc(Br)cc1
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCO3
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCC(C)=O
Solvent: CCOC(C)=O
Product: O=C1N(Cc2ccc(Br)cc2)c2ccccc2C12COc1cc3c(cc12)OCO3
Temperature: 25 °C
Reaction time: 16 h
Yield: 84.5 %

Procedure:
A mixture of spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one (1.05 g, 3.73 mmol), 4-bromobenzyl bromide (1.21 g, 4.84 mmol) and cesium carbonate (1.84 g, 5.65 mmol) in 2-butanone (25 mL) was stirred at ambient temperature for 16 h. The mixture was diluted with ethyl acetate and filtered through Celite. The filtrate was concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography with hexanes/ethyl acetate (9:1, increased to 1:1) to afford 1′-(4-bromobenzyl)spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one (1.42 g, 84%) as a colorless solid: mp 148-150° C. (hexanes); 1H NMR (300 MHz, CDCl3) δ7.48 (d, J=8.4 Hz, 2H), 7.25-7.17 (m, 4H), 7.05 (dd, J=7.5, 7.5 Hz, 1H), 6.77 (d, J=7.8 Hz, 1H), 6.53 (s, 1H), 6.12 (s, 1H), 5.89 (s, 1H), 5.88 (s, 1H), 5.02 (d, J=15.6 Hz, 1H), 4.97 (d, J=9.0 Hz, 1H), 4.78 (d, J=15.6 Hz, 1H), 4.70 (d, J=9.0 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 177.8, 156.1, 149.1, 142.5, 141.9, 134.9, 132.3, 132.2, 129.3, 129.1, 124.2, 123.8, 122.0, 119.4, 109.3, 103.1, 101.7, 93.8, 80.6, 58.4, 43.7; MS (ES+) m/z 452.0 (M+1), 450.0 (M+1).
Reaction SMILES: [O:1]1[CH2:4][CH:3]([N:5]2[CH:9]=[C:8]([C:10]3[N:15]=[C:14]([C:16]4[CH:17]=[N:18][N:19]([C:21]5([CH2:30][C:31]#[N:32])[CH2:24][N:23]([CH2:25][C:26]([F:29])([F:28])[F:27])[CH2:22]5)[CH:20]=4)[N:13]4[CH:33]=[CH:34][N:35]=[C:12]4[CH:11]=3)[CH:7]=[N:6]2)[CH2:2]1.C([O-])(O)=O.[Na+].C(Cl)[Cl:42]>>[Cl:42][C:33]1[N:13]2[C:14]([C:16]3[CH:17]=[N:18][N:19]([C:21]4([CH2:30][C:31]#[N:32])[CH2:24][N:23]([CH2:25][C:26]([F:29])([F:28])[F:27])[CH2:22]4)[CH:20]=3)=[N:15][C:10]([C:8]3[CH:7]=[N:6][N:5]([CH:3]4[CH2:2][O:1][CH2:4]4)[CH:9]=3)=[CH:11][C:12]2=[N:35][CH:34]=1
Reactant: ClCCl
Reactant: N#CCC1(n2cc(-c3nc(-c4cnn(C5COC5)c4)cc4nccn34)cn2)CN(CC(F)(F)F)C1
Agent: O=C([O-])O
Agent: [Na+]
Product: N#CCC1(n2cc(-c3nc(-c4cnn(C5COC5)c4)cc4ncc(Cl)n34)cn2)CN(CC(F)(F)F)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 28 %

Procedure:
2-(3-(4-(7-(1-(Oxetan-3-yl)-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-5-yl)-1H-pyrazol-1-yl)-1-(2,2,2-trifluoroethyl)azetidin-3-yl)acetonitrile (Example 105; 0.040 g, 0.08274 mmol) was suspended in DCM (3 mL) and saturated aqueous NaHCO3 (1 mL). n-Chlorosuccinimide (0.017 g, 0.124 mmol) was added in one portion and the reaction mixture stirred at ambient temperature overnight. Additional n-chlorosuccinimide (0.033 g, 0.248 mmol) was added and the reaction was allowed to stir at ambient temperature overnight. The reaction mixture was partitioned between saturated aqueous NaHCO3 and DCM. The combined organic extracts were washed with brine, dried (MgSO4), filtered and concentrated under reduced pressure to afford the crude material, which was purified by flash column chromatography, eluting with 1-2% (9:1 MeOH:NH4OH)/DCM to provide 2-(3-(4-(3-chloro-7-(1-(oxetan-3-yl)-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-5-yl)-1H-pyrazol-1-yl)-1-(2,2,2-trifluoroethyl)azetidin-3-yl)acetonitrile (0.012 g, 0.023 mmol, 28% yield). MS (apci) m/z=518.1 (M+H).
Reaction SMILES: [Cl:1][C:2](=[N:16][OH:17])[CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1.[CH3:18][S:19](Cl)(=[O:21])=[O:20].C(N(CC)CC)C>C(OCC)C>[Cl:1][C:2](=[N:16][O:17][S:19]([CH3:18])(=[O:21])=[O:20])[CH:3]1[CH2:4][CH2:5][N:6]([C:9]([O:11][C:12]([CH3:13])([CH3:14])[CH3:15])=[O:10])[CH2:7][CH2:8]1
Reactant: CC(C)(C)OC(=O)N1CCC(C(Cl)=NO)CC1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCC(C(Cl)=NOS(C)(=O)=O)CC1
Temperature: 25 °C
Yield: 53.7 %

Procedure:
tert-Butyl 4-(chloro(hydroxyimino)methyl)piperidine-1-carboxylate (2.3 g, 8.75 mmol) and methanesulfonyl chloride (0.68 mL, 8.75 mmol) were suspended in diethyl ether (200 mL). Triethylamine (1.22 mL, 8.75 mmol) was added and the reaction stirred at ambient temperature until consumption of starting material. The mixture was filtered and the filtrate was concentrated. The residue was purified by flash chromatography (using dichloromethane) to afford the title compound (1.6 g, 53% yield) as a clear oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH:10]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=1)[C:11](OC)=[O:12].[H-].[Al+3].[Li+].[H-].[H-].[H-]>CCOCC>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH:10]([C:15]1[CH:16]=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=1)[CH2:11][OH:12]
Reactant: COC(=O)C(Cc1ccc(Cl)cc1Cl)c1ccc(Cl)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: OCC(Cc1ccc(Cl)cc1Cl)c1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
To a solution of methyl 3-(2,4-dichlorophenyl)-2-(4-chlorophenyl)propionate (6.4 g, 8.6 mmol) in 50 mL ether at −40° C. was added lithium aluminum hydride (1.4 g, 37 mmol), and the reaction was allowed to warm to room temperature over 2 h. The reaction was quenched by addition of MeOH (3 mL) dropwise at −10° C., and the mixture was partitioned between 100 mL saturated ammonium chloride and EtOAc (100 mL). The organic layer was separated and the aqueous layer extracted with EtOAc (2×100 mL). The combined organic extracts were dried over anhydrous MgSO4, filtered, and concentrated to dryness to give the title compound, which was used without further purification. 1H NMR (400 M, CD3OD): δ 7.4-6.9 (m, 7H), 3.72 (m, 2H), 3.24 (dd, 1H), 3.16 (m, 1H), 2.85 (dd, 1H).
Reaction SMILES: [CH2:1]([OH:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].N1C=CC=CC=1.[N+:22]([C:25]1[CH:33]=[CH:32][C:28]([C:29](Cl)=[O:30])=[CH:27][CH:26]=1)([O-:24])=[O:23]>ClCCl>[N+:22]([C:25]1[CH:26]=[CH:27][C:28]([C:29]([O:15][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])=[O:30])=[CH:32][CH:33]=1)([O-:24])=[O:23]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: CCCCCCCCCCCCCCO
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCOC(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 30 °C
Yield: 47.2 %

Procedure:
Under a nitrogen atmosphere, a mixture of 1-tetradecanol (96.3 grams, 449 mmol), pyridine (40 milliliters), and dichloromethane (1000 milliliters) was heated to 30° C. 4-Nitrobenzoyl chloride (100 grams, 539 mmol) was added in portions over a twenty minute period. The reaction mixture was heated to reflux for sixteen hours. The reaction mixture was washed with water (2×500 milliliters). The organic layer was concentrated under reduced pressure to a yellow solid. 1000 milliliters of hexane was added and the mixture was heated to reflux. The mixture was cooled and filtered. The filtrate was concentrated to yield a yellow solid. The yellow solid was recrystallized twice from ethanol to obtain 77.0 grams of tetradecyl 4-nitrobenzoate as yellow crystals.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([O:20][C:21]2[CH:22]=[N:23][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:25][CH:26]=2)[CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]1[S:12][CH:13]([CH2:16][C:17]([OH:19])=O)[CH2:14][N:15]=1)=[CH:7]2.[NH2:31][CH2:32][C@@H:33]([OH:35])[CH3:34].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O.O>[OH:35][C@@H:33]([CH3:34])[CH2:32][NH:31][C:17](=[O:19])[CH2:16][CH:13]1[S:12][C:11]([C:8]2[NH:9][C:10]3[C:6]([CH:7]=2)=[CH:5][C:4]([O:20][C:21]2[CH:22]=[N:23][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:25][CH:26]=2)=[CH:3][C:2]=3[CH3:1])=[N:15][CH2:14]1
Reactant: Cc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc2cc(C3=NCC(CC(=O)O)S3)[nH]c12
Reactant: C[C@H](O)CN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc2cc(C3=NCC(CC(=O)NC[C@H](C)O)S3)[nH]c12
Reaction time: 15 h
Yield: 68 %

Procedure:
To a solution of [2-(7-methyl-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indol-2-yl)-4,5-dihydro-1,3-thiazol-5-yl]acetic acid (300 mg) and (S)-(+)-1-amino-2-propanol (78 mg) in N,N-dimethylformamide (20 mL)were added 1-hydroxybenzotriazole (137 mg) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (194 mg) under ice-cooling, and the mixture was stirred under ice-cooling and then at room temperature for 15 hr. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The obtained pale-yellow crystals were recrystallized from tetrahydrofuran-ethyl acetate to give the title compound (230 mg, yield 68%) as colorless crystals.
Reaction SMILES: C(OC([N:8]1[C:12]2=[N:13][C:14]([N:17]3[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]3)=[CH:15][CH:16]=[C:11]2[N:10]=[CH:9]1)=O)(C)(C)C.C[O:31][C:32](=O)[C:33]1[CH:38]=[CH:37][N:36]=[C:35]([Br:39])[CH:34]=1.C([N-]C(C)C)(C)C.[Li+]>O1CCCC1>[C:26]([O:25][C:23]([N:20]1[CH2:19][CH2:18][N:17]([C:14]2[N:13]=[C:12]3[NH:8][C:9]([C:32]([C:33]4[CH:38]=[CH:37][N:36]=[C:35]([Br:39])[CH:34]=4)=[O:31])=[N:10][C:11]3=[CH:16][CH:15]=2)[CH2:22][CH2:21]1)=[O:24])([CH3:27])([CH3:28])[CH3:29]
Reactant: COC(=O)c1ccnc(Br)c1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc3ncn(C(=O)OC(C)(C)C)c3n2)CC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc3nc(C(=O)c4ccnc(Br)c4)[nH]c3n2)CC1
Temperature: -78 °C
Reaction time: 2 h
Yield: 16.5 %

Procedure:
The mixture of 5-(4-tert-butoxycarbonyl-piperazin-1-yl)-imidazo[4,5-b]pyridine-3-carboxylic acid tert-butyl ester (600 mg, 1.49 mmole), methyl-2-bromo-isonicotinate (321 mg, 1.49 mmole), and tetrahydrofuran (5 ml) was cooled to −78° C. Lithium diisopropylamide (2N, 2.23 ml, 4.46 mmole) was added slowly. Reaction mixture was stirred at −78° C. for 2 hours. Reaction was quenched with water and extracted with EtOAc. EtOAc layer was concentrated and crude product was purified by using silica gel chromatography, eluting with 0% to 40% of EtOAc in CH2Cl2 to afford 4-[2-(2-bromo-pyridine-4-carbonyl)-3H-imidazo[4,5-b]pyridine-5-yl]-piperazine-1-carboxylic acid tert-butyl ester (120 mg, 16.6%). 1H NMR (400 MHz, CD2Cl2) δ 1.58 (s, 9H), 3.59 (m, 4H), 3.74 (m, 4H), 6.89 (d, J=9.03 Hz, 1H), 8.03 (d, J=9.03 Hz, 1H), 8.39 (d, J=5.03 Hz, 1H), 8.61 (d, J=5.02 Hz, 1H), 8.67 (s, 1H). MS(ESI) m/z 488 [M+1].
Reaction SMILES: [C:1]12([NH:11][C:12]3[CH:17]=[C:16](Cl)[N:15]=[C:14]([N:19]4[CH2:23][CH2:22][CH2:21][CH2:20]4)[N:13]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[NH:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1>>[C:1]12([NH:11][C:12]3[CH:17]=[C:16]([N:24]4[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]4)[N:15]=[C:14]([N:19]4[CH2:23][CH2:22][CH2:21][CH2:20]4)[N:13]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: C1CNCCN1
Reactant: Clc1cc(NC23CC4CC(CC(C4)C2)C3)nc(N2CCCC2)n1
Product: c1c(NC23CC4CC(CC(C4)C2)C3)nc(N2CCCC2)nc1N1CCNCC1
Yield: 49.7 %

Procedure:
4-(1-Adamantylamino)-6-chloro-2-pyrrolidinopyrimidine is reacted with piperazine as described in Example 4 to give the title compound in a yield of 49.7%, m.p.: 152°-156° C.