Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[O:6][CH:5]([CH2:7][NH2:8])[CH2:4][O:3]1.N1C=CC=CC=1.[CH3:16][S:17](Cl)(=[O:19])=[O:18]>C(OCC)C>[CH3:1][C:2]1([CH3:9])[O:6][CH:5]([CH2:7][NH:8][S:17]([CH3:16])(=[O:19])=[O:18])[CH2:4][O:3]1
Reactant: CC1(C)OCC(CN)O1
Reactant: CS(=O)(=O)Cl
Solvent: CCOCC
Solvent: c1ccncc1
Product: CC1(C)OCC(CNS(C)(=O)=O)O1
Reaction time: 2 h
Yield: 11.9 %

Procedure:
To a solution of the (2,2-dimethyl-1,3-dioxolan-4-yl)methanamine (4.616 g, 35.19 mmol) in diethylether (100 mL) was added pyridine (2.90 mL, 35.9 mmol). A solution of methanesulfonyl chloride (2.75 mL, 35.4 mmol) in diethylether (50 mL) was added to the amine solution over 30 minutes. After stirring for 2 h, the reaction was washed once with 25 mL water then twice with 25 mL brine. The organic layer was separated, dried over MgSO4, filtered, and evaporated to a residue. The residue was chromatographed over silica gel with 0-100% EtOAc in hexanes. The product fractions were evaporated in vacuo to give N-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)methanesulfonamide as a near-colorless oil (0.875 g, 4.18 mmol, 12% yield). 1H NMR (400 MHz, DMSO-d6): 7.17 (1H, t, J=6.4 Hz), 4.13-4.06 (1H, m), 3.98 (1H, dd, J=8.3 Hz, 6.4 Hz), 3.66 (1H, dd, J=8.3 Hz, 5.7 Hz), 3.09-2.98 (2H, m), 2.91 (3H, s), 1.33 (3H, s), 1.26 (3H, s).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:43]=[C:42]([O:44][CH3:45])[CH:41]=[CH:40][C:4]=1[CH2:5][NH:6][C:7]1[C:8]2[CH:15]=[CH:14][N:13]([C@H:16]3[C@@H:20]4[O:21][C:22]([CH3:25])([CH3:24])[O:23][C@@H:19]4[C@@H:18]([CH2:26][N:27]([CH:37]([CH3:39])[CH3:38])[CH:28]4[CH2:31][CH:30]([CH2:32][CH2:33][C:34]([OH:36])=O)[CH2:29]4)[CH2:17]3)[C:9]=2[N:10]=[CH:11][N:12]=1.C(N(CC)C(C)C)(C)C.[F:55][C:56]([F:67])([F:66])[O:57][C:58]1[CH:59]=[C:60]([NH2:65])[C:61]([NH2:64])=[CH:62][CH:63]=1.CN(C)C=O>>[NH2:65][C:60]1[CH:59]=[C:58]([O:57][C:56]([F:55])([F:66])[F:67])[CH:63]=[CH:62][C:61]=1[NH:64][C:34](=[O:36])[CH2:33][CH2:32][CH:30]1[CH2:29][CH:28]([N:27]([CH2:26][C@@H:18]2[C@@H:19]3[C@@H:20]([O:21][C:22]([CH3:25])([CH3:24])[O:23]3)[C@H:16]([N:13]3[C:9]4[N:10]=[CH:11][N:12]=[C:7]([NH:6][CH2:5][C:4]5[CH:40]=[CH:41][C:42]([O:44][CH3:45])=[CH:43][C:3]=5[O:2][CH3:1])[C:8]=4[CH:15]=[CH:14]3)[CH2:17]2)[CH:37]([CH3:39])[CH3:38])[CH2:31]1
Reactant: Nc1ccc(OC(F)(F)F)cc1N
Reactant: COc1ccc(CNc2ncnc3c2ccn3[C@@H]2C[C@H](CN(C(C)C)C3CC(CCC(=O)O)C3)[C@H]3OC(C)(C)O[C@H]32)c(OC)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc(CNc2ncnc3c2ccn3[C@@H]2C[C@H](CN(C(C)C)C3CC(CCC(=O)Nc4ccc(OC(F)(F)F)cc4N)C3)[C@H]3OC(C)(C)O[C@H]32)c(OC)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N,N,N′,N-Tetramethyl-0-(7-azabenzotriazol-1-yl)uronium Hexafluorophosphate (1.19 g, 3.14 mmol) added to a solution of 3-(3-((((3aR,4R,6R,6aS)-6-(4-((2,4-dimethoxybenzyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)methyl)(isopropyl)amino)cyclobutyl)propanoic acid (1.3 g, 2.1 mmol) and N,N-Diisopropylethylamine (1.20 mL, 6.90 mmol) and 4-(trifluoromethoxy)benzene-1,2-diamine (0.482 g, 2.51 mmol) in N,N-Dimethylformamide (13.0 mL, 167 mmol). The reaction was stirred overnight at RT and was partially concentrated to ca. 2 mls and then NaHCO3 (saturated) was added. The mixture was extracted with EtOAc (3×) and the combined organics were dried with MgSO4 filtered and concentrated. The residue was purified by flash chromatography (DCM/7N NH3 in MeOH 95:5) to the desired amide (1.4 g) as a solid.
Reaction SMILES: ClC(Cl)(Cl)[C:3]([NH:5][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:15]=1[N:14]=[CH:13][CH:12]=[CH:11]2)=[O:4].[C:18]([C:22]1[CH:31]=[C:30]2[C:25]([CH:26]([NH2:32])[CH2:27][CH2:28][O:29]2)=[CH:24][CH:23]=1)([CH3:21])([CH3:20])[CH3:19].N12CCCN=C1CCCCC2>C(#N)C>[C:18]([C:22]1[CH:31]=[C:30]2[C:25]([CH:26]([NH:32][C:3]([NH:5][C:6]3[CH:7]=[CH:8][CH:9]=[C:10]4[C:15]=3[N:14]=[CH:13][CH:12]=[CH:11]4)=[O:4])[CH2:27][CH2:28][O:29]2)=[CH:24][CH:23]=1)([CH3:21])([CH3:19])[CH3:20]
Reactant: O=C(Nc1cccc2cccnc12)C(Cl)(Cl)Cl
Reactant: CC(C)(C)c1ccc2c(c1)OCCC2N
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CC(C)(C)c1ccc2c(c1)OCCC2NC(=O)Nc1cccc2cccnc12
Yield: 14.4 %

Procedure:
A mixture of the product of Example 3A (145mg, 0.5 mmol), the product of Example 1C (103mg, 0.5 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 190 mg, 1.25 mmol) in acetonitrile (15 mL) was heated at reflux for 3.5 hours, cooled, and the acetonitrile removed under reduced pressure. The residue was taken up in ethyl acetate and washed with water. The isolated organic layer was dried with magnesium sulfate, filtered and the solvent removed under reduced pressure. The resulting residue was purified by reverse-phase HPLC (acetonitrile/water) to give 27 mg of the title compound (14% yield). 1H NMR (300 MHz, DMSO-d6) δ ppm 9.37 (s, 1H), 8.83 (dd, J=4.1 and 1.7 Hz, 1H), 8.54 (dd, J=7.3 and 1.9 Hz, 1H), 8.34 (dd, J=8.5 and 1.7 Hz, 1H), 7.91 (d, J=7.8 Hz, 1H), 7.55-7.60 (m, 1H), 7.46-7.53 (m, 2H), 7.22 (d, J=8.1 Hz, 1H), 6.94 (dd, J=8.1 and 2.0 Hz, 1H), 6.77 (d, J=2.0 Hz, 1H), 4.87-4.93 (m, 1H), 4.22-4.29 (m, 1H), 4.12-4.20 (m, 1H), 2.07-2.16 (m, 1H), 1.91-2.00 (m, 1H), 1.24 (s, 9H). MS (ESI) m/e 376 (M+H)+. Calcd. For C23H25N3O2.0.35CF3CO2H: C, 68.53; H, 6.15; N, 10.12. Found C, 68.33; H, 6.00; N, 10.00.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.[NH:9]1[CH:13]=[CH:12][N:11]=[CH:10]1>O1CCCC1>[Cl:8][C:6]1[N:5]=[CH:4][N:3]=[C:2]([N:9]2[CH:13]=[CH:12][N:11]=[CH:10]2)[CH:7]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: c1c[nH]cn1
Solvent: C1CCOC1
Product: Clc1cc(-n2ccnc2)ncn1
Yield: 78.4 %

Procedure:
In anhydrous tetrahydrofuran, 298 mg of 4,6-dichloro-pyrimidine was substituted with 136 mg of imidazole. The reaction mixture was treated according to the procedure of Example 5 to yield 283 mg of the 6-chloro-4-(1-imidazolyl)pyrimidine, recrystallized from a mixture of n-hexane and ethyl acetate, having a melting point of 131.5°-132° C.
Reaction SMILES: [CH:1]([C:4]1[C:9]([C:10]([F:13])([F:12])[F:11])=[C:8]([S:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:7]=[CH:6][C:5]=1[C:21]1[CH:26]=[CH:25][N+:24]([O-])=[CH:23][CH:22]=1)([CH3:3])[CH3:2]>O=P(Cl)(Cl)Cl>[CH:1]([C:4]1[C:9]([C:10]([F:13])([F:11])[F:12])=[C:8]([S:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:7]=[CH:6][C:5]=1[C:21]1[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1c(-c2cc[n+]([O-])cc2)ccc(Sc2ccccc2)c1C(F)(F)F
Solvent: O=P(Cl)(Cl)Cl
Product: CC(C)c1c(-c2ccncc2)ccc(Sc2ccccc2)c1C(F)(F)F
Yield: 89.6 %

Procedure:
Then, 2-chloro-4-(4-(2-isopropyl-phenylsulfanyl-3-trifluoromethyl-phenyl)-pyridine 76 was prepared as follows. Compound 75 (3.19 g, 8.19 mmol) was treated with POCl3 (50 mL) at 100° C. for 10 hours. The reaction mixture was concentrated on a rotovap, and the residue was treated with crushed ice (20 g). Water (100 mL) was added, the aqueous solution was then extracted with ethyl acetate (2×100 mL). The combined organic layers were washed with brine (3×100 mL), dried over MgSO4, filtered and concentrated. The crude product was purified by chromatography to give the title compound 76 as a brown oil (2.74 g, 82%). 1H-NMR (CDCl3, 400 MHz) δ 1.19 (d, J=6.8 Hz, 6H), 3.51 (heptet, J=6.8 Hz, 1H), 6.91 (d, J=8.5 Hz, 1H), 7.25-7.28 (m, 1H), 7.37 (dd, J=1.7 Hz, 5.1 Hz, 1H), 7.45-7.52 (m, 5H), 7.87 (d, J=2.0 Hz, 1H), 8.43 (d, J=5.4 Hz, 1H). MS (DCI) m/z 408, 409, 410 (M+H)+.
Reaction SMILES: [CH2:1]([S:8][C:9]1[CH:10]=[CH:11][C:12]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([Br:29])=[CH:25][C:24]=2[O:30][CH3:31])=[C:13](/[CH:15]=[CH:16]/[C:17]([O:19]CC)=O)[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.C[O-].[Na+]>C(Cl)Cl>[CH2:1]([S:8][C:9]1[CH:14]=[C:13]2[C:12](=[CH:11][CH:10]=1)[N:22]([C:23]1[CH:28]=[CH:27][C:26]([Br:29])=[CH:25][C:24]=1[O:30][CH3:31])[C:17](=[O:19])[CH:16]=[CH:15]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)/C=C/c1cc(SCc2ccccc2)ccc1Nc1ccc(Br)cc1OC
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: COc1cc(Br)ccc1-n1c(=O)ccc2cc(SCc3ccccc3)ccc21
Reaction time: 0.5 h
Yield: 68.6 %

Procedure:
A RBF was charged with (E)-ethyl 3-(5-(benzylthio)-2-((4-bromo-2-methoxyphenyl)amino)phenyl)acrylate (3.13 g, 6.28 mmol) and MeOH (31.4 ml) to give a yellow suspension. Sodium methoxide (25 wt % in MeOH) (0.271 ml, 1.256 mmol) was added. A reflux condenser was attached, and the flask was lowered into a 75° C. heating bath. The bath quickly spiked to ca. 80-85° C., but returned to 70-75° C. after 30 min. The reaction was stirred for 16 hrs, and the mixture was diluted with DCM and concentrated. The residue was purified by chromatography on silica gel (50-g SNAP Ultra column, 25-g silica gel loading column, 10-60% EtOAc/Heptane) to give 6-(benzylthio)-1-(4-bromo-2-methoxyphenyl)quinolin-2(1 H)-one (1.95 g, 4.31 mmol, 68.6% yield) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6) □=7.94 (d, J=9.5 Hz, 1 H), 7.78 (d, J=2.2 Hz, 1 H), 7.50 (d, J=2.1 Hz, 1 H), 7.43-7.16 (m, 8 H), 6.66 (d, J=9.6 Hz, 1 H), 6.47 (d, J=8.8 Hz, 1 H), 4.23 (s, 2 H), 3.69 (s, 3 H). m/z (ESI) 452.0 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][NH2:6])[CH3:2].S=[C:8]1[CH2:12][S:11][C:10](=[O:13])[NH:9]1>C(O)C>[CH2:1]([O:3][CH2:4][CH2:5][NH:6][C:8]1[CH2:12][S:11][C:10](=[O:13])[N:9]=1)[CH3:2]
Reactant: O=C1NC(=S)CS1
Reactant: CCOCCN
Solvent: CCO
Product: CCOCCNC1=NC(=O)SC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.6 %

Procedure:
To a solution of 2-ethoxyethanamine (4.07 g) in ethanol (100 mL) was added 4-thioxo-1,3-thiazolidin-2-one (4.05 g), and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (4.90 g).
Reaction SMILES: [Cl:1][CH2:2][C@@H:3]([OH:27])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([C:15]2[CH:26]=[CH:25][C:18]([O:19][CH2:20][C@H:21]([OH:24])[CH2:22][OH:23])=[CH:17][CH:16]=2)([CH3:14])[CH3:13])=[CH:8][CH:7]=1.CO[C:30](OC)([CH3:32])[CH3:31].C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)=O>[Cl:1][CH2:2][C@@H:3]([OH:27])[CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]([C:15]2[CH:16]=[CH:17][C:18]([O:19][CH2:20][C@H:21]3[CH2:22][O:23][C:30]([CH3:32])([CH3:31])[O:24]3)=[CH:25][CH:26]=2)([CH3:14])[CH3:13])=[CH:10][CH:11]=1
Reactant: CC(C)(c1ccc(OC[C@H](O)CO)cc1)c1ccc(OC[C@H](O)CCl)cc1
Reactant: COC(C)(C)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Product: CC1(C)OC[C@H](COc2ccc(C(C)(C)c3ccc(OC[C@H](O)CCl)cc3)cc2)O1
Reaction time: 14 h

Procedure:
To a solution of (R)-3-(4-(2-(4-((S)-3-chloro-2-hydroxypropoxy)phenyl)propan-2-yl)phenoxy)propane-1,2-diol (1000 mg, 2.53 mmol) in acetone (8.0 mL) was added 2,2-dimethoxypropane (630 μL, 5.06 mmol) and catalytic amounts of p-toluenesulfonic acid. After 14 h, the reaction mixture was quenched with an aqueous solution of sodium chloride and stirred for 15 min, and the resulting mixture was extracted twice with ethyl acetate. The organic phases were combined, dried over anhydrous magnesium sulfate and filtered. Solvents were evaporated, and the resulting crude material was purified by silica gel flash chromatography (eluent: 2% methanol in dichloromethane) to provide the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][C:9]([C:11]3[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=3[OH:18])=[N:8][C:7](=O)[C:6]=2[CH:20]=1.C(N(CC)CC)C.Cl.[NH:29]([CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[NH2:30]>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:10])=[C:6]([C:7]2[N:8]=[C:9]([C:11]3[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=3[OH:18])[N:29]([CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[N:30]=2)[CH:20]=1
Reactant: CCOC(=O)CNN
Reactant: O=c1nc(-c2cc(Cl)ccc2O)oc2ccc(Cl)cc12
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)Cn1nc(-c2cc(Cl)ccc2O)nc1-c1cc(Cl)ccc1O

Procedure:
6.0 g of chloro-2-(5-chloro-2-hydroxyphenyl)benz[e][1,3]oxazin-4-one (Example 16), 3.0 ml of triethylamine and 3.3 g of ethyl hydrazinoacetate hydrochloride are boiled under reflux for 2 h in 60 ml of ethanol. On cooling, the product precipitates in crystalline form. It is filtered off and washed with ethanol. After drying, ethyl [3,5-bis(5-chloro-2-hydroxyphenyl)-[1,2,4]triazol-1-yl]acetate is obtained as colorless crystals of m.p. 195-200° C.
Reaction SMILES: [C:1]1([CH:7]([CH3:11])[CH2:8][CH2:9][OH:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(C)C=CC=CC=1.[C:19](OC(=O)C)(=[O:21])[CH3:20].Cl>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[C:19]([O:10][CH2:9][CH2:8][CH:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH3:11])(=[O:21])[CH3:20]
Reactant: CC(=O)OC(C)=O
Reactant: CC(CCO)c1ccccc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CC(=O)OCCC(C)c1ccccc1
Yield: 98.8 %

Procedure:
Into a four-necked flask provided with a stirring means and a thermometer, 150 g (1 mol) of (+)-3-phenyl-1-butanol (XXVI-60), 500 ml of toluene and 200 ml of pyridine were charged, and 122.4 g (1.2 mol) of acetic acid anhydride and 1 g of 4-dimethylaminopyridine were further added thereto. The mixture was reacted for 4 hours while temperature being maintained at 40°-50° C. After completion of the reaction, the reaction mixture was poured into 500 ml of 4N hydrochloric acid, extracted and fractionated. The resulting organic layer was washed with 1N hydrochloric acid, water, 5% sodium bicarbonate aqueous solution ad water in the order. The thus-obtained organic layer was concentrated under a reduced pressure to obtain 190 g of (+)-1-acetoxy-3-phenylbutane (XXV-60) with yield of 99.0%.
Reaction SMILES: [C:1]1([C:7]2[C:16]([N:17]3[CH2:22][CH2:21][CH:20]([NH:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH2:19][CH2:18]3)=[N:15][C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:30]([O:32]C)=[O:31])[CH:13]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH3:36]I>O1CCCC1>[CH3:36][N:23]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH:20]1[CH2:19][CH2:18][N:17]([C:16]2[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[N:8][C:9]3[C:14]([N:15]=2)=[CH:13][C:12]([C:30]([OH:32])=[O:31])=[CH:11][CH:10]=3)[CH2:22][CH2:21]1
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(N3CCC(Nc4ccccc4)CC3)nc2c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(c1ccccc1)C1CCN(c2nc3cc(C(=O)O)ccc3nc2-c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 10.1 %

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of methyl 2-phenyl-3-(4-(phenylamino)piperidin-1-yl)quinoxaline-6-carboxylate (297.4 mg, 0.68 mmol, 1.00 equiv) in tetrahydrofuran (16 mL). Then sodium hydride (163 mg, 6.79 mmol, 10.00 equiv) and CH3I (964 mg, 6.79 mmol, 10.00 equiv) was added. The resulting solution was stirred for 2 days at room temperature. The reaction was then quenched by the addition of water. The resulting aqueous solution was extracted with 5×30 mL of dichloromethane. The organic layers were combined and concentrated under vacuum. The crude product (150 mg) was purified by Prep-HPLC with the following conditions (AGILENT Pre-HPLC (UV-Directed): Column, SunFire Prep C18, 19*150 mm 5 um; mobile phase, water with 0.05% TFA and CH3CN (25% CH3CN up to 60% in 6 min, up to 100% in 1 min); Detector, UV 254 nm 30 mg of product was obtained. This resulted in 30 mg (10%) of 3-(4-(methyl(phenyl)amino)piperidin-1-yl)-2-phenylquinoxaline-6-carboxylic acid as a yellow solid.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:8]([C:16]2[N:17]=[CH:18][NH:19][CH:20]=2)=[CH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[CH:6][CH:7]=1>CCO.[Pd]>[C:4]1([CH:8]([C:16]2[N:17]=[CH:18][NH:19][CH:20]=2)[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:3]=[CH:2][CH:7]=[CH:6][CH:5]=1
Reactant: Clc1cccc(C(=Cc2ccccc2)c2c[nH]cn2)c1
Agent: [Pd]
Solvent: CCO
Product: c1ccc(CC(c2ccccc2)c2c[nH]cn2)cc1

Procedure:
A mixture of 4-(1-(3-chlorophenyl)-2-phenylvinyl)-1H-imidazole (AGN-216677) (35 mg) in EtOH (10 mL) was reduced by the action of 10% Pd/C (20 mg) under H2 atmosphere forl 6 h at rt. The mixture was filtered through Celite and freed of solvent under reduced pressure. The residue was purified by chromatography on silica gel with 5% NH3-MeOH: CH2Cl2 to give 4-(1,2-diphenylethyl)-1H imidazole as a solid, (31 mg), AGN217242. 1H NMR (300 MHz, CD3OD): δ 7.38 (s, 1H), 7.10-7.26 (m, 8H), 7.08 (s, 1H), 4.41 (t, J=9 Hz, 3H), 3.43 (dd; J=9 Hz, 15 Hz, 1H), 3.27 (dd, J=6 Hz, 9 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[CH:4][C:3]=1[Br:12].[F:13][B-](F)(F)F.F[B-](F)(F)F.ClC[N+]12CC[N+](F)(CC1)CC2>C(#N)C>[NH2:1][C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[C:5]([F:13])=[CH:4][C:3]=1[Br:12]
Reactant: COC(=O)c1ccc(Br)c(N)n1
Reactant: F[B-](F)(F)F
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: CC#N
Product: COC(=O)c1nc(N)c(Br)cc1F

Procedure:
A mixture of methyl 6-amino-5-bromopyridine-2-carboxylate (19.8 g) (T. R. Kelly and F. Lang, J. Org. Chem. 61, 1996, 4623-4633) and 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (34.3 g) in acetonitrile (340 mL) under argon was heated to 40° C. for 1 hour, 60° C. for 1 hour and then 80° C. overnight. After partitioning between EtOAc and water (500 mL each) the aqueous fraction was re-extracted with EtOAc (300 mL) and the combined organic solution dried with MgSO4 and evaporated. Chromatography (20% then 30% EtOAc in hexane) separated various byproducts from the required ester (2.09 g); MS (+ve ion electrospray) m/z 249 and 251 (MH+, 100%)
Reaction SMILES: S(OC)(O[CH3:5])(=O)=O.[CH3:8][C:9]([CH3:25])([CH3:24])[C:10]([O:12][C:13]1[C:14]([C:20]([O:22][CH3:23])=[O:21])=[N:15][CH:16]=[N:17][C:18]=1[OH:19])=[O:11].C(=O)([O-])[O-].[Cs+].[Cs+]>>[CH3:8][C:9]([CH3:25])([CH3:24])[C:10]([O:12][C:13]1[C:18](=[O:19])[N:17]([CH3:5])[CH:16]=[N:15][C:14]=1[C:20]([O:22][CH3:23])=[O:21])=[O:11]
Reactant: COC(=O)c1ncnc(O)c1OC(=O)C(C)(C)C
Reactant: COS(=O)(=O)OC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: COC(=O)c1ncn(C)c(=O)c1OC(=O)C(C)(C)C

Procedure:
Dimethyl sulfate (1.5 eq.) was added to a solution of the product of Step 3 (1 eq.) in TBF containing cesium carbonate (1.5 eq.). The reaction was carried out at 50° C. for thirty minutes. The solvent was evaporated and the resulting oil was dissolved in ethyl acetate, washed with 1N HCl solution. The crude title compound was recovered as yellow solid and used in the next step without purification.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([C@H:12]2[CH2:17][CH2:16][C@H:15]([O:18][C:19]3[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=3)[CH2:14][CH2:13]2)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[C:40](=[N:43]O)([NH2:42])[CH3:41].[H-].[Na+]>C1COCC1>[CH:1]([N:4]1[CH2:5][CH2:6][N:7]([C:10]([C@H:12]2[CH2:13][CH2:14][C@H:15]([O:18][C:19]3[CH:20]=[CH:21][C:22]([C:23]4[O:24][N:43]=[C:40]([CH3:41])[N:42]=4)=[CH:26][CH:27]=3)[CH2:16][CH2:17]2)=[O:11])[CH2:8][CH2:9]1)([CH3:3])[CH3:2]
Reactant: CC(N)=NO
Reactant: CC(C)N1CCN(C(=O)[C@H]2CC[C@H](Oc3ccc(C(=O)O)cc3)CC2)CC1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1noc(-c2ccc(O[C@H]3CC[C@H](C(=O)N4CCN(C(C)C)CC4)CC3)cc2)n1

Procedure:
A mixture of 0.1 g (0.22 mmol) of trans-4-[4-(4-Isopropyl-piperazine-1-carbonyl)-cyclohexyloxy]-benzoic acid and 59 mg (0.36 mmol) of 1,1′-carbonyl-diimidazole in 2 ml THF was refluxed for 16 hr. After cooling down, 79 mg (1.1 mmol) of acetamide oxime was added and the mixture was refluxed for 48 hr. To the mixture, 29 mg (0.66 mmol, 55% purity) of sodium hydride was added and the mixture was refluxed for 16 hr. The mixture was evaporated. The mixture was diluted with AcOEt, washed with saturated NaHCO3 solution, dried over Na2SO4, and evaporated. The residue was purified by column chromatography on silica eluting with dichloromethane and methanol=from 98:2 to 9:1. The combined product fractions were evaporated to dryness to yield 40 mg (44%) of the title compound. MS (m/e): 413.2 (MH+).
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:11][N:10]([C:12]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:13]=3[C:14]#[N:15])[CH2:9][CH2:8][C:4]=2[N:5]=[CH:6][N:7]=1.[Si:21]([O:28][CH2:29][C@H:30]([C:32]1[CH:33]=[N:34][C:35]([O:38][CH3:39])=[N:36][CH:37]=1)[NH2:31])([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22]>C(#N)C.C(N(CC)C(C)C)(C)C>[Si:21]([O:28][CH2:29][C@@H:30]([NH:31][C:2]1[C:3]2[CH2:11][N:10]([C:12]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:13]=3[C:14]#[N:15])[CH2:9][CH2:8][C:4]=2[N:5]=[CH:6][N:7]=1)[C:32]1[CH:37]=[N:36][C:35]([O:38][CH3:39])=[N:34][CH:33]=1)([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22]
Reactant: COc1ncc([C@H](N)CO[Si](C)(C)C(C)(C)C)cn1
Reactant: Cc1ccc(N2CCc3ncnc(Cl)c3C2)c(C#N)c1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COc1ncc([C@@H](CO[Si](C)(C)C(C)(C)C)Nc2ncnc3c2CN(c2ccc(C)cc2C#N)CC3)cn1

Procedure:
A reaction mixture of 2-(4-chloro-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-5-methylbenzonitrile (500 mg, 1.76 mmol) and (S)-2-(tert-butyldimethylsilyloxy)-1-(2-methoxypyrimidin-5-yl)ethanamine (800 mg, 2.82 mmol) in acetonitrile (10 mL) and N,N-diisopropylethylamine (1 mL) was subjected to microwave irradiation at 185° C. for 3 h. The reaction mixture was concentrated and the residue was purified by silica-gel column to afford a light yellow solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([NH2:19])[C:9]=2[N:8]=[C:7]1[CH2:20][CH2:21][O:22][CH3:23].[N:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[N:27]=[CH:26][C:25]=1[C:34](O)=[O:35]>>[NH2:19][C:10]1[C:9]2[N:8]=[C:7]([CH2:20][CH2:21][O:22][CH3:23])[N:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:34]([C:25]3[CH:26]=[N:27][C:28]4[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=4)[N:24]=3)=[O:35])[C:18]=2[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:11]=1
Reactant: O=C(O)c1cnc2ccccc2n1
Reactant: COCCc1nc2c(N)nc3ccccc3c2n1CCCCN
Product: COCCc1nc2c(N)nc3ccccc3c2n1CCCCNC(=O)c1cnc2ccccc2n1
Yield: 12 %

Procedure:
Using the general method of Example 181 1-(4-aminobutyl)-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-4-amine (1.5 g, 4.78 mmol) was reacted with 2-quinoxalinecarboxylic acid (1.0 g, 5.74 mmol) to provide 270 mg of N-{4-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]butyl} quinoxaline-2-carboxamide as a yellow crystalline solid, m.p. 85-87° C. Analysis: Calculated for C26H27N7O2: % C, 66.51; % H, 5.80; % N, 20.88; Found: % C, 66.12; % H, 5.70; % N, 20.62.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[Cl:5][C:6]1[CH:7]=[C:8]([C:13]2[NH:17][C:16]([C:18]([F:21])([F:20])[F:19])=[N:15][C:14]=2[C:22]2[CH:27]=[CH:26][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:24][CH:23]=2)[CH:9]=[C:10]([CH3:12])[CH:11]=1.C(N(CC)CC)C>C(#N)C>[Cl:5][C:6]1[CH:7]=[C:8]([C:13]2[N:17]([C:1](=[O:3])[CH3:2])[C:16]([C:18]([F:21])([F:19])[F:20])=[N:15][C:14]=2[C:22]2[CH:23]=[CH:24][C:25]([S:28]([CH3:31])(=[O:29])=[O:30])=[CH:26][CH:27]=2)[CH:9]=[C:10]([CH3:12])[CH:11]=1
Reactant: CC(=O)Cl
Reactant: Cc1cc(Cl)cc(-c2[nH]c(C(F)(F)F)nc2-c2ccc(S(C)(=O)=O)cc2)c1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(=O)n1c(C(F)(F)F)nc(-c2ccc(S(C)(=O)=O)cc2)c1-c1cc(C)cc(Cl)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 10.9 %

Procedure:
Acetyl chloride (50 mg, 0.6 mmol) was added to a cold (5° C.), stirred solution of Example 54 (150 mg, 0.3 mmol) and triethylamine (80 mg, 0.8 mmol) in acetonitrile (3 ml). The reaction was warmed to room temperature and stirred for 4 hours. The solvent was removed and the residue was purified by chromatography on silica gel using 20% ethyl acetate in toluene as the eluent to give 15 mg of the desired product as a crystalline solid: mp 257° C. Anal. Calc'd. for C20H16N2O3ClF3S (MW 456.87): C, 52.58; H, 3.53; N, 6.13; S, 7.02. Found: C, 52.21; H, 3.61; N, 5.95; S, 7.30.