Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1B(O)O)=[O:2].Br[C:15]1[S:16][C:17]([CH3:20])=[CH:18][N:19]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O.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>[CH3:10][O:9][C:7]1[CH:6]=[CH:5][C:4]([C:15]2[S:16][C:17]([CH3:20])=[CH:18][N:19]=2)=[C:3]([CH:8]=1)[CH:1]=[O:2]
Reactant: Cc1cnc(Br)s1
Reactant: COc1ccc(B(O)O)c(C=O)c1
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: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(-c2ncc(C)s2)c(C=O)c1
Temperature: 120 °C
Reaction time: 0.25 h
Yield: 61.8 %

Procedure:
To a solution of 2-formyl-4-methoxyphenylboronic acid (200 mg, 1.11 mmol) in DMF (10 mL) and H2O (2 mL) are added 2-bromo-5-methylthiazole (217 mg, 1.22 mmol), Pd(PPh3)4 (128 mg, 0.11 mmol) and K2CO3 (230 mg, 1.67 mmol) at room temperature. The solution is heated to 120° C. for 1 hour in a microwave reactor. The solution is cooled down and 3-mercaptopropyl-functionalized silica gel (500 mg) is added. The solution is stirred for 15 minutes and filtered. The filtrate is washed with H2O (15 mL) and is extracted with EtOAc (3×15 mL). The combined organic layer is dried with MgSO4 and is filtered. The filtrate is concentrated and the residue is purified by silica gel flash chromatography eluting with 50% EtOAc in heptane to afford 5-methoxy-2-(5-methyl-thiazol-2-yl)-benzaldehyde (160 mg, 63%) as a white foam.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[C:9]([NH2:19])=[N:10][N:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:12]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][N:23]=1>N1C=CC=CC=1.C(Cl)Cl>[Cl:21][C:22]1[N:23]=[CH:24][C:25]([C:26]([NH:19][C:9]2[C:8]([NH:7][C:6](=[O:20])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:12][N:11]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:10]=2)=[O:27])=[CH:29][CH:30]=1
Reactant: O=C(Cl)c1ccc(Cl)nc1
Reactant: CC(C)(C)OC(=O)Nc1cn(-c2ccccc2)nc1N
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)Nc1cn(-c2ccccc2)nc1NC(=O)c1ccc(Cl)nc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of t-butyl(3-amino-1-phenyl-1H-pyrazol-4-yl)carbamate (100 mg, 0.364 mmol) in pyridine (500 μL) was added 6-chloronicotinoyl chloride (53 mg, 0.304 mmol) in CH2Cl2 (2 mL). After 6 hours of stirring at room temperature, the reaction mixture was filtered and the solvent concentrated. Formation of t-butyl(3-([(6-chloropyridin-3-yl)carbonyl]amino)-1-phenyl-1H-pyrazol-4-yl)carbamate (J) was confirmed by MS (ESI+): cal'd [M+H]+ 414.1, obs'd 414.1.
Reaction SMILES: N[C@H:2]([C:11]([O:13]CC=C)=[O:12])[CH2:3][CH2:4][C:5]([O:7]CC=C)=O.ClC(Cl)([O:20]C(=O)OC(Cl)(Cl)Cl)Cl.CCN(CC)CC.N[C@H:37]([C:43](O)=O)[CH2:38][CH2:39]CCN>C(Cl)Cl>[CH:37]1[CH:43]=[C:4]2[C:5]([C:11]([OH:12])([OH:13])[C:2](=[O:20])[C:3]2=[CH:39][CH:38]=1)=[O:7]
Reactant: C=CCOC(=O)CC[C@H](N)C(=O)OCC=C
Reactant: NCCCC[C@H](N)C(=O)O
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1c2ccccc2C(=O)C1(O)O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a stirred solution of diallyl glutamate (3.96 g, 15 mmol) and triphosgene (1.47 g, 4.95 mmol) in CH2Cl2 (143 mL) at −78° C. was added Et3N (6.4 mL, 46 mmol) in CH2Cl2 (28 mL). The reaction mixture was allowed to warm to room temperature and stirred for 1.5 h. The Lysine derivative (2.6 g, 9.09 mmol) in a solution of CH2Cl2 (36 mL) was then added at −78° C. and the reaction was stirred at room temperature for 12 h. The solution was diluted with CH2Cl2, washed twice with H2O, dried over MgSO4 (anh.) and purified by column chromatography (Hexane:AcOEt 3:1→2:1→AcOEt) to give 4 g (82%) (TLC in CH2Cl2:MeOH 20:1 Rf=0.3, revealed with ninhydrin). 1H-NMR (CDCl3, 300 MHz) δ 5.97-5.84 (m, 3H, 3-CH2CHCH2), 5.50 (bt, 2H, 2NHurea), 5.36-5.20 (m, 6H, 3-CH2CHCH2), 4.81 (bs, 1H, NHBoc), 4.68-4.40 (m, 8H, 3-CH2CHCH2, CH(Lys), CH(glu)), 3.09-3.05 (m, 2H, CH2NHBoc), 2.52-2.39 (m, 2H, CH2(glu.)), 2.25-2.14 and 2.02-1.92 (2m, 2H, CH2(glu.)), 1.87-1.64 (m, 4H, 2CH2(Lys)), 1.51-1.35 (m, 2H, CH2(Lys)), 1.44 (s, 9H, Boc).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[O:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]1[CH2:13][CH:14]3[NH:19][CH:18]([C:7]2=1)[CH2:17][CH2:16][CH2:15]3.[CH3:22][C:23]1[CH:28]=[CH:27][C:26]([CH:29]=[CH2:30])=[CH:25][N:24]=1>>[CH3:22][C:23]1[N:24]=[CH:25][C:26]([CH2:29][CH2:30][N:9]2[C:10]3[C:6](=[CH:5][C:4]([O:3][C:2]([F:1])([F:20])[F:21])=[CH:12][CH:11]=3)[C:7]3[CH:18]4[NH:19][CH:14]([CH2:13][C:8]2=3)[CH2:15][CH2:16][CH2:17]4)=[CH:27][CH:28]=1
Reactant: C=Cc1ccc(C)nc1
Reactant: FC(F)(F)Oc1ccc2[nH]c3c(c2c1)C1CCCC(C3)N1
Product: Cc1ccc(CCn2c3c(c4cc(OC(F)(F)F)ccc42)C2CCCC(C3)N2)cn1

Procedure:
The coupling of 2-trifluoromethoxy-6,7,8,9,10,11-hexahydro-5H-7,11-epiminocycloocta[b]indole (148 mg, 0.500 mmol; Example 140A) and 2-methyl-5-vinylpyridine (119 mg, 1.00 mmol; IBScreen) was performed according to the procedure described in Example 114B to afford the title compound: 1H NMR (500 MHz, pyridine-d5) δ ppm 1.09-1.22 (m, 1H), 1.29-1.39 (m, J=7, 7 Hz, 1H), 1.46 (d, J=14 Hz, 1H), 1.75 (d, J=14 Hz, 1H), 2.26-2.44 (m, 3H), 2.48 (s, 3H), 2.95-3.04 (m, 1H), 3.05-3.13 (m, 1H), 3.47 (dd, J=18, 7 Hz, 1H), 4.22-4.31 (m, 1H), 4.34-4.43 (m, 2H), 5.29 (s, 1H), 6.99 (d, J=8 Hz, 1H), 7.23-7.31 (m, 2H), 7.51 (d, J=9 Hz, 1H), 7.60 (s, 1H), 8.37 (d, J=2 Hz, 1H); MS (DCI/NH3) m/z 416 (M+H)+.
Reaction SMILES: [CH2:1]1[CH2:6][CH2:5][CH:4]([N:7]=[C:8]=[N:9][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[CH2:3][CH2:2]1.[O:16]1CCCC1>N1C=CC=CC=1.CN(C1C=CN=CC=1)C>[C:8]([NH:7][CH:4]1[CH2:3][CH2:2][CH2:1][CH2:6][CH2:5]1)([NH:9][CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)=[O:16]
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: C1CCOC1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: O=C(NC1CCCCC1)NC1CCCCC1
Temperature: 25 °C
Reaction time: 60 h

Procedure:
Poly(ethoxylated fluoroalkyl acrylate)-block-polystyrene (IV). One gram of poly(acrylic acid)-block-polystyrene (2.19 mmol acrylic acid) was dissolved in 5 mL of anhydrous pyridine. DCC (6.57 mmol), DMAP (0.823 mmol), and Zonyl FSO-100 (6 g) were dissolved in tetrahydrofuran and added drop-wise to the polymer solution. The reaction mixture was stirred at room temperature for about 2.5 days. Dicyclohexylurea formed during the reaction was removed by filtration. After concentration under reduced pressure, the polymer solution was poured into excess methanol. Further purification was achieved by precipitating the polymer from tetrahydrofuran into methanol.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]([OH:16])=[O:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:17](=O)([O-])[O-].[K+].[K+].IC>CN(C)C=O.O>[CH3:17][O:15][C:14]([CH:10]1[O:11][CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9]1)=[O:16]
Reactant: CC(C)(C)OC(=O)N1CCOC(C(=O)O)C1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C1CN(C(=O)OC(C)(C)C)CCO1
Temperature: 25 °C
Reaction time: 18 h
Yield: 78.8 %

Procedure:
A solution of morpholine-2,4-dicarboxylic acid 4-tert-butyl ester (supplied by NeoMPS, Inc.), (5.78 g, 25.0 mmol) in N,N-dimethylformamide (30 mL) was subsequently treated with potassium carbonate (4.14 g, 30.0 mmol) and iodomethane (7.10 g, 3.1 mL, 50.0 mmol). After stirring at room temperature for 18 h, the reaction mixture was diluted with water and the aqueous layer was extracted with ethyl acetate. The organic extracts were combined, washed with water (4×) and brine then filtered through a hydrophobic frit and the volatiles were removed in vacuo. The residue was purified by silica gel chromatography using a gradient of iso-hexanes/ethyl acetate 3:1 to 1:3 to afford the title compound (4.83 g, 79%) as a white solid. 1H NMR (300 MHz, CDCl3) δ 1.49 (s, 9H), 3.06-3.15 (m, 2H), 3.56-3.64 (m, 1H), 3.75-3.79 (m, 1H), 3.81 (s, 3H), 4.00-4.14 (m, 3H). LCMS (m/z) 268.1 [M+Na], Tr=1.94 min.
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[CH2:3][CH2:4][CH2:5][OH:6].[CH3:9][S:10](Cl)(=[O:12])=[O:11]>C(Cl)Cl>[CH3:9][S:10]([O:6][CH2:5][CH2:4][CH2:3][C:2]([F:8])([F:7])[F:1])(=[O:12])=[O:11]
Reactant: CS(=O)(=O)Cl
Reactant: OCCCC(F)(F)F
Solvent: ClCCl
Product: CS(=O)(=O)OCCCC(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 0.3 %

Procedure:
To a solution of 4,4,4-trifluorobutan-1-ol (100 mg, 83 mmol) in dry DCM (2 mL) was added methanesulfonyl chloride (107.3 mg, 72 mmol) and then by TEA (158 mg, 216 mmol) at 0° C. The reaction was stirred at room temperature for 1 h. The reaction was partitioned between ethyl acetate and water. The organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated to give a yellow oil product (50 mg, 31.1% yield), which was used without purification. Product tlc [petroleum ether/ethyl acetate (3:1) Rf 0.4]
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C[Si](C)(C)[N-][Si](C)(C)C.[Na+].[CH2:29](Br)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C1COCC1.C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C:10]([C:14]([O:16][CH2:17][CH3:18])=[O:15])([CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)C1CCCN(C(=O)OC(C)(C)C)C1
Reactant: BrCc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCOC(=O)C1(Cc2ccccc2)CCCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 56.1 %

Procedure:
To a stirring solution of N-(t-butoxycarbonyl)-3-(carboethoxy)-piperidine (800 mg, 3.11 mmol) in dry THF (10 mL) at −78° C. was added a 0.6M solution of sodium hexamethyldisilazide in toluene (5.7 mL). The reaction was stirred for 1 h when benzyl bromide (559 mg, 3.27 mmol) was added. After 1 h, the reaction was warmed to room temperature for 15 h. The reaction was quenched by the addition of 1M HCl (10 mL). The reaction was extracted with EtOAc (4×20 mL). The organic layers were combined, washed with brine, dried over Na2SO4, and conc. in vacuo to an oil. The oil was purified by flash chromatography (SiO2, 5–15% EtOAc in hexanes) to yield 606 mg of the product as a colorless oil. MS (ESI) 348 (M+H).
Reaction SMILES: [F:1][C:2]([F:22])([C:6]([F:21])([F:20])[C:7]([F:19])([F:18])[C:8]([F:17])([F:16])[C:9]([F:15])([F:14])[C:10]([F:13])([F:12])[F:11])[CH2:3][CH:4]=[CH2:5].[CH:23]1[CH2:27][CH:26]=[CH:25][CH:24]=1.C([O:32]O)(C)(C)C>C1(C)C=CC=CC=1>[O:32]1[CH:23]2[CH:24]1[CH:25]1[CH2:26][CH:27]2[CH:4]([CH2:3][C:2]([F:22])([F:1])[C:6]([F:20])([F:21])[C:7]([F:18])([F:19])[C:8]([F:16])([F:17])[C:9]([F:14])([F:15])[C:10]([F:13])([F:12])[F:11])[CH2:5]1
Reactant: CC(C)(C)OO
Reactant: C1=CCC=C1
Reactant: C=CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Solvent: Cc1ccccc1
Product: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)CC1CC2CC1C1OC21
Reaction time: 2 h

Procedure:
10.7 g (25 mmol) of the Diels-Alder product of 4,4,5,5,6,6,7,7,8,8,9,9,9-tridecafluoro-1-nonene (perfluorohexyl-1-propene) and cyclopentadiene are mixed in 10 ml of dry toluene with 326 mg (1 mmol) of molybdenum acetylacetonate, and 13 ml of a2.9 molar solution of t-butyl hydroperoxide in toluene (37.5 mmol) are added dropwise at 22° C. within 30 minutes. During this period, thetemperature rises to 60° C. The solution is then held at 60° C. for another 2 hours. The low-boiling components are distilled off underreduced pressure at 40° C., and the residue is chromatographed on silica gel. The mobile solvent used is a mixture of hexane/methylene chloride/diethyl ether (10:10:0.5 parts by volume). The product-containingfractions are combined. After the mobile solvent is distilled off, 7.3 g ofa white solid remain behind.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]2[NH:9][CH:8]=[C:7]([CH2:10][CH2:11][OH:12])[C:5]=2[CH:6]=1.[C:13]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])(=O)[CH2:14][CH3:15].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH2:21]([O:20][C:18](=[O:19])[CH2:17][C:13]1([CH2:14][CH3:15])[C:8]2[NH:9][C:4]3[C:5]([C:7]=2[CH2:10][CH2:11][O:12]1)=[CH:6][CH:1]=[CH:2][CH:3]=3)[CH3:22]
Reactant: OCCc1c[nH]c2ccccc12
Reactant: CCOC(=O)CC(=O)CC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: CCOC(=O)CC1(CC)OCCc2c1[nH]c1ccccc21
Yield: 67.6 %

Procedure:
A mixture of tryptophol (1.612 g, 10 mmol), ethyl propionylacetate (1.730 g, 12 mmol), and p-toluenesulfonic acid monohydrate (0.20 g) in benzene (70 mL) was heated to reflux for 5 hours. It was quenched with ethyl acetate and washed with saturated sodium bicarbonate. The organic layer was dried over magnesium sulfate, evaporated to dryness. Flash chromatography on silica gel provided 1.943 g (68%) of the title compound as a solid. mp<80° C. 1H NMR (300 MHz, CDCl3) δ 9.06 (br, 1H), 7.50 (d, 1H), 7.36 (d, 1H), 7.14 (t, 1H), 7.12 (t, 1H), 4.18 (q, 2H), 4.03 (m, 1H), 3.94 (m, 1H), 2.99 (d, 1H), 2.88 (d, 1H), 2.78 (m, 2H), 2.14 (m, 1H), 2.01 (m, 1H), 1.25 (t, 3H), 0.82 (t, 3H); ESI (+) MS m/e=288 (MH+), ESI (−) MS m/e=286 (MH−).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[O:10][C:9]([CH3:12])=[CH:8][C:7]=2[C:6]([NH2:13])=[CH:5][CH:4]=1.C1N=CN([C:19](N2C=NC=C2)=[S:20])C=1>C(Cl)Cl>[N:13]([C:6]1[C:7]2[CH:8]=[C:9]([CH3:12])[O:10][C:11]=2[C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)=[C:19]=[S:20]
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: COc1ccc(N)c2cc(C)oc12
Solvent: ClCCl
Product: COc1ccc(N=C=S)c2cc(C)oc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82.1 %

Procedure:
7-Methoxy-2-methyl-4-nitro-benzofuran (1.24 g, 6.0 mmol) was hydrogenated using Pd/C (10%, dry, 700 mg) and H2 balloon in EtOH (30 mL) at r.t. for 2 h. The reaction mixture was filtered. Purification of the concentrated filtrate by column chromatography (EtOAc:Hexane=2.5:7.5) afforded 7-methoxy-2-methyl-benzofuran-4-ylamine as a brown oil (620 mg, 58%). 7-Methoxy-2-methyl-benzofuran-4-ylamine (620 mg, 3.5 mmol) was dissolved in CH2Cl2 (10 mL). TCDI (thiocarbodiimidazole, 686 mg, 3.9 mmol) was added to the solution and the reaction mixture was stirred at r.t. for 30 min. Silica gel was added to the reaction mixture and the solvent was removed under vacuum. Purification of the silica gel coated crude product by flash column chromatography (EtOAc:Hexane=2:8) afforded the title product as a pale yellow oil (630 mg, 82%).
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:5]2[C:6](O)=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.FC1C=CC(S(C)(=O)=O)=CC=1.CC(C)([O-])C.[K+]>CN(C)C(=O)C>[N:11]1[C:2]([NH2:1])=[N:3][N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: Nc1nc2c(O)cccn2n1
Agent: CC(C)(C)[O-]
Agent: CS(=O)(=O)c1ccc(F)cc1
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: Nc1nc2ccccn2n1
Temperature: 130 °C

Procedure:
A well stirred mixture of 2-amino-[1,2,4]triazolo[1,5-a]pyridine-8-ol (0.300 g, 2.00 mmol), 1-fluoro-4-methanesulfonyl-benzene (0.418 g, 2.40 mmol), N,N-dimethylacetamide (2 mL) and potassium tert-butoxide (0.448 g, 4.00 mmol) was heated at 130° C. for 18 h under an argon atmosphere. The reaction mixture was evaporated in vacuo and partitioned between dichloromethane and saturated aqueous sodium bicarbonate solution. The aqueous phase was extracted twice with dichloromethane and the combined organic layers were washed with brine, dried over sodium sulfate, filtered, and evaporated in vacuo to furnish a crude product. The crude product was purified by preparative Gilson HPLC method to yield a pure product, which was triturated from a mixture of dichloromethane, methanol, ether and hexane. 8-(4-Methanesulfonyl-phenoxy)-[1,2,4-triazolo[1,5-a]pyridin-2-ylamine was isolated as a white solid (125 mg, 20%). MP=245-247° C. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 8.53 (d, J=6.56 Hz, 1H), 7.87 (d, J=8.77 Hz, 2H), 7.36 (d, J=7.73 Hz, 1H), 7.15 (d, J=8.76 Hz, 2H), 6.92 (t, J=7.28 Hz, 1H), 6.13 (s, 1H), 3.19 (s, 3H). MS=305 (MH)+.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[Cl:15][C:16]1[CH:17]=[C:18]([C:23]2[N:24]=[C:25]([C:28]3[CH:29]=[CH:30][C:31]([N:34]4[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]4)=[N:32][CH:33]=3)[NH:26][CH:27]=2)[CH:19]=[CH:20][C:21]=1[Cl:22].C(O)(=O)C.[CH:44](=O)[CH:45]([CH3:47])[CH3:46]>C1COCC1.[OH-].[Na+].C(OCC)(=O)C>[Cl:15][C:16]1[CH:17]=[C:18]([C:23]2[NH:24][C:25]([C:28]3[CH:29]=[CH:30][C:31]([N:34]4[CH2:39][CH2:38][N:37]([CH2:44][CH:45]([CH3:47])[CH3:46])[CH2:36][CH2:35]4)=[N:32][CH:33]=3)=[N:26][CH:27]=2)[CH:19]=[CH:20][C:21]=1[Cl:22]
Reactant: CC(C)C=O
Reactant: Clc1ccc(-c2c[nH]c(-c3ccc(N4CCNCC4)nc3)n2)cc1Cl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)CN1CCN(c2ccc(-c3ncc(-c4ccc(Cl)c(Cl)c4)[nH]3)cn2)CC1

Procedure:
Sodium triacetoxyborohydride (20.2 g) was added to a suspension of 1-{5-[4-(3,4-dichloro-phenyl)-1H-imidazol-2-yl]-pyridin-2-yl}-piperazine (23.8 g), acetic acid (5.1 mL), and isobutyraldehyde (6.35 mL) in THF (250 mL). The resultant suspension was stirred at ambient temperature for 18 hours, and then the reaction mixture was diluted with 1 N NaOH (1000 mL) and ethyl acetate (450 mL). The layers were separated, and the organic phase was diluted with hexanes (1000 mL). The resultant precipitate was collected by filtration, and the mother liquors were concentrated to 400 mL. The second crop of precipitate was collected and combined with the first crop to provide 1-{5-[5(3,4,-dichloro-phenyl)-1H-imidazol-2-yl]-pyridin-2-yl}-4-isobutyl-piperazine (22.5 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:10][CH2:9][CH2:8][O:7][C:6]=2[CH:11]=1.[Br:12][CH2:13][CH2:14][CH2:15]Br.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:10]([CH2:15][CH2:14][CH2:13][Br:12])[CH2:9][CH2:8][O:7][C:6]=2[CH:11]=1
Reactant: Fc1ccc2c(c1)OCCN2
Reactant: BrCCCBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Fc1ccc2c(c1)OCCN2CCCBr
Temperature: 70 °C
Yield: 47.3 %

Procedure:
A mixture of 7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazine (1.3 g, 1 eq, 8.49 mmol) obtained in step (iii) above, 1,3-dibromo propane (8.6 ml, 10 eq, 84.9 mmol) and anhydrous sodium carbonate (2.7 g, 3 eq, 25.4 mmol) in dry DMF (85 ml) was heated at 70° C. for 16 h. The reaction was diluted with ethyl acetate and washed with water and brine. The residue was chromatographed using ethyl acetate and hexane to afford the title compound (1.1 g, yield 47%) as viscous oil.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:15]=[CH:14][C:10]3[O:11][CH2:12][O:13][C:9]=3[C:8]=2[C:16]2[C:17]3[NH:24][C:23]([CH3:25])=[C:22]([C:26]([NH:28][C@H:29]4[C@H:33]([OH:34])[CH2:32][NH:31][CH2:30]4)=[O:27])[C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:4][CH2:3]1.[C:35](Cl)(=[O:37])[CH3:36]>>[C:35]([N:31]1[CH2:32][C@@H:33]([OH:34])[C@H:29]([NH:28][C:26]([C:22]2[C:18]3[N:19]=[CH:20][N:21]=[C:16]([C:8]4[C:9]5[O:13][CH2:12][O:11][C:10]=5[CH:14]=[CH:15][C:7]=4[O:6][CH2:5][CH:2]4[CH2:4][CH2:3]4)[C:17]=3[NH:24][C:23]=2[CH3:25])=[O:27])[CH2:30]1)(=[O:37])[CH3:36]
Reactant: CC(=O)Cl
Reactant: Cc1[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc2c1C(=O)N[C@@H]1CNC[C@H]1O
Agent: Cl
Product: CC(=O)N1C[C@@H](O)[C@H](NC(=O)c2c(C)[nH]c3c(-c4c(OCC5CC5)ccc5c4OCO5)ncnc23)C1

Procedure:
Starting from 4-[5-(cyclopropylmethoxy)-1,3-benzodioxol-4-yl]-N-[(3R*,4R*)-4-hydroxypyrrolidin-3-yl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f5) and commercially available acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[CH:5][C:6]([O:9][C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[N:7][CH:8]=1.Br[CH:20]([CH3:27])[CH:21]=[CH:22][C:23]([O:25][CH3:26])=[O:24].C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C.C(OCC)C>[F:18][C:2]([F:1])([F:17])[C:3]1[CH:4]=[CH:5][C:6]([O:9][C:10]2[CH:11]=[CH:12][C:13]([O:16][CH:20]([CH3:27])[CH:21]=[CH:22][C:23]([O:25][CH3:26])=[O:24])=[CH:14][CH:15]=2)=[N:7][CH:8]=1
Reactant: COC(=O)C=CC(C)Br
Reactant: Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: CCOCC
Product: COC(=O)C=CC(C)Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Temperature: 25 °C
Reaction time: 32 h
Yield: 83.8 %

Procedure:
In 50 ml of methyl ethyl ketone, 2.0 g (0.0078 mole) of 4-[5-(trifluoromethyl)-2-pyridinyloxy]phenol, 3.2 g of methyl 4-bromo-2-pentenoate, and 2.0 g of potassium carbonate were refluxed with constant stirring for 32 hours. Upon cooling to room temperature, the suspension was filtered through celite and the insoluble material washed with 75 ml of acetone. The filtrate was concentrated under reduced pressure to give an oily residue which was dissolved in 125 ml of ethyl ether and transferred to a separatory funnel. After washing with saturated sodium bicarbonate and water, the ether layer was dried over magnesium sulfate and charcoal filtered. Under reduced pressure, the solvent was evaporated and traces of volatile impurities removed at 0.4 mm Hg. (50° for 2 hours) to yield 2.4 g (84% ) of product, ND25 1.520.
Reaction SMILES: [C:1]([OH:4])(=[O:3])[CH3:2].[CH2:5]([O:12][C:13]1[CH:14]=[C:15]([CH2:19][CH2:20][CH2:21][CH2:22][NH:23][CH2:24][CH2:25][CH2:26][CH2:27]O)[CH:16]=[CH:17][CH:18]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>O>[C:1]([O:4][CH2:27][CH2:26][CH2:25][CH2:24][NH:23][CH2:22][CH2:21][CH2:20][CH2:19][C:15]1[CH:16]=[CH:17][CH:18]=[C:13]([O:12][CH2:5][C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:14]=1)(=[O:3])[CH3:2]
Reactant: OCCCCNCCCCc1cccc(OCc2ccccc2)c1
Reactant: CC(=O)O
Solvent: O
Product: CC(=O)OCCCCNCCCCc1cccc(OCc2ccccc2)c1
Temperature: 80 °C
Yield: 88 %

Procedure:
To 10 ml of anhydrous acetic acid was added 2.7 g (8.2 mmol) of 4-[(3-benzyloxyphenyl)butylamino]-1-butanol and the mixture was stirred with heating at 80° C. for 1 hour. The reaction mixture was poured into 150 ml of water and subjected to extraction with ethyl acetate. Washing was performed with a saturated sodium bicarbonate solution and then with a saturated saline solution. Drying over anhydrous sodium sulfate and concentration were performed. The residue was purified by silica gel column chromatography to give 2.68 g of a colorless oily matter (yield: 88.0%).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]1[N:14]=[C:15]2[CH:20]=[CH:19][C:18]([C:21]([OH:23])=O)=[CH:17][N:16]2[CH:24]=1.CC1ON=C(C2C=CC=CC=2)C=1C1N=[C:39]2[CH:44]=[C:43](C(O)=O)[CH:42]=[CH:41][N:40]2C=1>>[CH:41]1([NH:40][C:21]([C:18]2[CH:19]=[CH:20][C:15]3[N:16]([CH:24]=[C:13]([C:3]4[C:4]([C:7]5[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=5)=[N:5][O:6][C:2]=4[CH3:1])[N:14]=3)[CH:17]=2)=[O:23])[CH2:42][CH2:43][CH2:44][CH2:39]1
Reactant: Cc1onc(-c2ccccc2)c1-c1cn2ccc(C(=O)O)cc2n1
Reactant: Cc1onc(-c2ccccc2)c1-c1cn2cc(C(=O)O)ccc2n1
Product: Cc1onc(-c2ccccc2)c1-c1cn2cc(C(=O)NC3CCCC3)ccc2n1
Yield: 85 %

Procedure:
As described for Example 15, 2-(5-methyl-3-phenyl-isoxazol-4-yl)-imidazo[1,2-a]pyridine-6-carboxylic acid (96 mg, 0.3 mmol), instead of 2-(5-methyl-3-phenyl-isoxazol-4-yl)-imidazo[1,2-a]pyridine-7-carboxylic acid, was converted to the title compound (98 mg, 85%) which was obtained as a light yellow foam. MS: m/e=387.3 [M+H]+.