Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([C@@H:15]3[O:20][CH2:19][CH2:18][N:17]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:16]3)=[CH:11][CH:10]=2)=[O:7])=[N:2]1.[Cl:28][C:29]1[C:34](Cl)=[N:33][CH:32]=[CH:31][N:30]=1.C(=O)([O-])[O-].[K+].[K+].O>CC(N(C)C)=O>[Cl:28][C:29]1[C:34]([N:1]2[CH:5]=[CH:4][C:3]([C:6]([NH:8][C:9]3[CH:14]=[CH:13][C:12]([C@@H:15]4[O:20][CH2:19][CH2:18][N:17]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:16]4)=[CH:11][CH:10]=3)=[O:7])=[N:2]2)=[N:33][CH:32]=[CH:31][N:30]=1
Reactant: Clc1nccnc1Cl
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(NC(=O)c3cc[nH]n3)cc2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(NC(=O)c3ccn(-c4nccnc4Cl)n3)cc2)C1
Reaction time: 16 h
Yield: 41.2 %

Procedure:
(S)-tert-Butyl 2-(4-(1H-pyrazole-3-carboxamido)phenyl)morpholine-4-carboxylate (90 mg, 0.24 mmol) and 2,3-dichloropyrazine (43 mg, 0.29 mmol) were dissolved in dimethylacetamide (2 ml) and potassium carbonate (67 mg, 0.48 mmol) was added. The reaction mixture was placed on a Büchi shaker for 16 hours at 80° C. To complete the reaction an additional amount of 2,3-dichloropyrazine (10 mg) was added and heating was continued for another 2 h at 120° C. After cooling the mixture, water was added followed by extraction with ethyl acetate twice. The combined organic layers was dried over MgSO4 and evaporated. The crude material was purified by flash chromatography (silica gel, 10 g, 25% to 50% EtOAc in heptane) to yield an off-white gum (48 mg, 42%). MS (ISP): 429.3 (100%, [M−tBu+H]+), 485.4 (10%, [M+H]+).
Reaction SMILES: O[C:2]1C2C(=CC(OC)=CC=2)N=C(C2SC=C(C(C)C)N=2)C=1.C(O)(=O)CCCCCC=C.N1CCC[C@H]1C(O)=O.[CH:40]([C:43]1[N:44]=[C:45]([C:48]2[CH:57]=[C:56]([O:58][CH:59]3[CH2:77][CH:76]4[N:61]([C:62](=[O:82])C[CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH:69]=[CH:70][CH:71]5[C:73]([C:79]([OH:81])=[O:80])([NH:74][C:75]4=[O:78])[CH2:72]5)[CH2:60]3)[C:55]3[C:50](=[CH:51][C:52]([O:83][CH3:84])=[CH:53][CH:54]=3)[N:49]=2)[S:46][CH:47]=1)([CH3:42])[CH3:41]>>[CH:40]([C:43]1[N:44]=[C:45]([C:48]2[CH:57]=[C:56]([O:58][CH:59]3[CH2:77][CH:76]4[N:61]([C:62](=[O:82])[CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH:69]=[CH:70][CH:71]5[C:73]([C:79]([OH:81])=[O:80])([NH:74][C:75]4=[O:78])[CH2:72]5)[CH2:60]3)[C:55]3[C:50](=[C:51]([CH3:2])[C:52]([O:83][CH3:84])=[CH:53][CH:54]=3)[N:49]=2)[S:46][CH:47]=1)([CH3:42])[CH3:41]
Reactant: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)O)CC5C=CCCCCCCC(=O)N4C3)cc(-c3nc(C(C)C)cs3)nc2c1
Reactant: COc1ccc2c(O)cc(-c3nc(C(C)C)cs3)nc2c1
Agent: C=CCCCCCC(=O)O
Agent: O=C(O)[C@@H]1CCCN1
Product: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)O)CC5C=CCCCCCC(=O)N4C3)cc(-c3nc(C(C)C)cs3)nc2c1C

Procedure:
The title compound was prepared from 4-hydroxy-2-(4-isopropylthiazol-2-yl)-7-methoxyquinoline, oct-7-enoic acid and intermediate 5 following the procedure (Step D-H) reported for 18-[2-[4-(isopropyl)thiazol-2-yl]-7-methoxyquinolin-4-yloxy]-2,15-dioxo-3,16-diazatricyclo[14.3.0.04,6]nonadec-7-ene-4-carboxylic acid 10: m/z=619 (M+H)+.
Reaction SMILES: CCOCC.C([O:10][CH2:11][CH:12]([O:30][CH3:31])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]/[CH:20]=[CH:21]\[CH2:22]/[CH:23]=[CH:24]\[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])(C)(C)C>C(OC(=O)C)(=O)C>[CH3:31][O:30][CH:12]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]/[CH:20]=[CH:21]\[CH2:22]/[CH:23]=[CH:24]\[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH2:11][OH:10]
Reactant: CCCCC/C=C\C/C=C\CCCCCCCC(COC(C)(C)C)OC
Solvent: CC(=O)OC(C)=O
Solvent: CCOCC
Product: CCCCC/C=C\C/C=C\CCCCCCCC(CO)OC

Procedure:
(Z,Z)-(±)-1-t-butoxy-10,13-nonadecadiene-2-ol, from Example 1, was reacted with methyl iodide under Williamson conditions as in Example 1 to yield the mixed ether (Z,Z)-(±)-1-t-butoxy-2-methoxy-10,13-nonadecadiene; and the ether on the C-1 hydroxyl was cleaved by ferric chloride in acetic anhydride to yield (Z,Z)-(±)-2-methoxy-10,13-nonadecadien-1-ol having the following characteristics.
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:10][C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[N:14][C:15]([O:21][CH2:22][CH2:23][N:24]([CH3:26])[CH3:25])=[CH:16][CH:17]=2)[N:12]=1.O>C(OCC)(=O)C>[CH3:25][N:24]([CH3:26])[CH2:23][CH2:22][O:21][C:15]1[N:14]=[C:13]2[C:18]([CH:19]=[CH:20][C:11]([NH:10][C:1](=[O:9])[C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[N:12]2)=[CH:17][CH:16]=1
Reactant: O=C(O)c1ccccc1
Reactant: CN(C)CCOc1ccc2ccc(N)nc2n1
Solvent: O
Solvent: CCOC(C)=O
Product: CN(C)CCOc1ccc2ccc(NC(=O)c3ccccc3)nc2n1
Temperature: 4 °C
Yield: 29.7 %

Procedure:
The procedure is similar to that described in Example 1, but starting with benzoic acid (5.5 g), N,N'-carbonyldiimidazole (8.1 g) and 2-amino-7-(2-dimethylaminoethoxy)-1,8-naphthyridine (11.6 g), heating for 5 hours under reflux. The reaction mixture is poured into water (1500 cc) and extracted with ethyl acetate (2×1000 cc). After concentration of the organic phases to dryness under reduced pressure (4 kPa), the oily residue obtained (9.2 g) is dissolved in boiling ethyl acetate (25 cc). Then, after 2 hours' cooling at 4° C., the crystallized solid is separated by filtration, washed with ethyl acetate (3 cc) and dried at 40° C. under reduced pressure (0.07 kPa). N-[7-(2-Dimethylaminoethoxy)-1,8-naphthyridin-2-yl]benzamide (4.5 g), m.p. 109° C., is obtained.
Reaction SMILES: C[C:2]([O:5][C:6]([C@@H:8]([NH:14]C(OCC1C=CC=CC=1)=O)[CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[O:7])([CH3:4])C.C1CCC(NC2CCCCC2)CC1.C1[O:40][CH:39]1CO.C(Cl)CCl.C(Cl)CCl.CN(C1C=CN=CC=1)C>ClCCl.CN(C1C=CN=CC=1)C>[CH2:2]([O:5][C:6](=[O:7])[C@H:8]([CH2:9][CH2:10][C:11]([OH:13])=[O:12])[NH2:14])[CH:4]1[O:40][CH2:39]1
Reactant: CC(C)(C)OC(=O)[C@H](CCC(=O)O)NC(=O)OCc1ccccc1
Reactant: OCC1CO1
Agent: C1CCC(NC2CCCCC2)CC1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: ClCCl
Product: N[C@@H](CCC(=O)O)C(=O)OCC1CO1
Yield: 141.4 %

Procedure:
A solution of 1720 mg (3.38 mmol) of Z-Glu-OtBu DCHA in 17 mL of dichloromethane was cooled to 0° C. and treated with 0.448 mL (6.75 mmol, 2.0 equiv) of glycidol, 41.2 mg (0.338 mmol, 0.1 equiv) of DMAP and 970 mg (5.06 mmol, 1.5 equiv) of EDC according to the general procedure for EDC/DMAP esterification. Purification by flash chromatography (30×150 mm silica gel, 35% ethyl acetate/hexane) gave 971 mg (73%) of the title compound: 1H NMR (300 MHz, CD3OD) δ7.38-7.24 (m, 5H), 5.09 (s, 2H), 4.41 (dd, J=2.9, 12.4 Hz, 1H), 4.13-4.09 (overlapping dd, 1H), 3.91-3.84 (overlapping dd, 1H), 3.32-3.16 (m, 1H), 2.80-2.78 (overlapping t, 1H), 2.64-2.61 (overlapping dd, 1H), 2.47 (t, J=7.6 Hz, 2H), 2.20-2.08 (m, 1H), 1.97-1.84 (m, 1H), 1.45 (s, 9H); MS(FAB) 394 (M+1), 338, 294, 260.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4](Cl)[N:3]=1.[NH2:17][C@@H:18]1[CH2:23][CH2:22][C@H:21]([OH:24])[CH2:20][CH2:19]1>C(N(CC)CC)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4]([NH:17][C@H:18]2[CH2:23][CH2:22][C@@H:21]([OH:24])[CH2:20][CH2:19]2)[N:3]=1
Reactant: Clc1nc(Cl)c2ncn(C3CCCC3)c2n1
Reactant: N[C@H]1CC[C@@H](O)CC1
Solvent: CCN(CC)CC
Product: O[C@H]1CC[C@@H](Nc2nc(Cl)nc3c2ncn3C2CCCC2)CC1

Procedure:
Cis-2-chloro-6-[(4-hydroxy)cyclohexylamino]-9-cyclopentylpurine is prepared from 2,6-dichloro-9-cyclopentylpurine, cis-4-(amino)cyclohexanol, and triethylamine essentially as described above in Example 1, Scheme A, step b.
Reaction SMILES: N#N.[C:3]([Si:7]([CH3:19])([CH3:18])[O:8][CH:9]([C:11]1[O:12][C:13]([CH2:16]O)=[CH:14][N:15]=1)[CH3:10])([CH3:6])([CH3:5])[CH3:4].CCN(CC)CC.S([Cl:31])(C)(=O)=O>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:3]([Si:7]([CH3:19])([CH3:18])[O:8][CH:9]([C:11]1[O:12][C:13]([CH2:16][Cl:31])=[CH:14][N:15]=1)[CH3:10])([CH3:6])([CH3:5])[CH3:4]
Reactant: CS(=O)(=O)Cl
Reactant: CC(O[Si](C)(C)C(C)(C)C)c1ncc(CO)o1
Agent: CN(C)c1ccncc1
Agent: N#N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(O[Si](C)(C)C(C)(C)C)c1ncc(CCl)o1
Temperature: 0 °C

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 2-[1-(tert-butyl-dimethyl-silanyloxy)-ethyl]-oxazol-5-yl-methanol (760 mg, 2.95 mmol) in dry CH2Cl2 (15 mL) was treated at 0° C. with Et3N (0.53 mL, 3.82 mmol) followed by DMAP (36 mg, 0.30 mmol) and Ms-Cl (0.30 mL, 3.73 mmol). After stirring at 0° C. until reaction completion, the reaction was quenched with water (50 mL). The org. layer was dried over Na2SO4, filtered, and the solvents were removed under reduced pressure to give crude 2-[1-(tert-butyl-dimethyl-silanyloxy)-ethyl]-5-chloromethyl-oxazole as a yellow oil. The crude material (2.95 mmol) was dissolved in dry DMF (15 mL) and treated with NaN3 (205 mg, 3.01 mmol) at 80° C. for 40 h. The reaction mixture was then cooled down to rt and partitioned between EA and water. The layers were separated and the org. layer dried over MgSO4, filtered and concentrated under reduced pressure to give crude 5-azidomethyl-2-[1-(tert-butyl-dimethyl-silanyloxy)-ethyl]-oxazole as a yellow oil. LC-MS-conditions 02: tR=1.12 min; [M+H]+=283.55.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:10])[C@:4]([CH2:8][OH:9])([CH3:7])[CH:5]=[CH2:6].[F:11][C:12]([F:20])(S(F)(=O)=O)C(O)=O.O>C(#N)C.[Cu]I>[CH3:1][O:2][C:3](=[O:10])[C@:4]([CH2:8][O:9][CH:12]([F:20])[F:11])([CH3:7])[CH:5]=[CH2:6]
Reactant: C=C[C@](C)(CO)C(=O)OC
Reactant: O=C(O)C(F)(F)S(=O)(=O)F
Agent: [Cu]I
Solvent: O
Solvent: CC#N
Product: C=C[C@](C)(COC(F)F)C(=O)OC
Temperature: 25 °C
Yield: 50.2 %

Procedure:
A solution of (R)-2-hydroxymethyl-2-methyl-but-3-enoic acid methyl ester (288 mg, 2.0 mmol) in acetonitrile (8 mL) was stirred at room temperature under nitrogen. Copper(I) iodide (80 mg, 0.4 mmol) was added followed by difluoro-fluorosulfonyl-acetic acid (356 mg, 0.2 mL, 2.0 mmol) and the reaction mixture was heated at reflux for 30 minutes. The reaction mixture was cooled to room temperature, water was added and the mixture was extracted with ethyl acetate. The organic extracts were combined and washed with brine. The organic solution was filtered through a hydrophobic frit and the filtrate was evaporated. The residue was purified by silica gel chromatography using a gradient of pentane/diethyl ether 10:1 to 5:1 to afford the title compound (195 mg, 50%) as a clear oil. 1H NMR (300 MHz, CDCl3) δ 1.40 (s, 3H), 3.75 (s, 3H), 3.86 (d, J=9.4 Hz, 1H), 4.10 (d, J=9.4 Hz, 1H), 5.24 (d, J=17.4 Hz, 1H), 5.24 (dd, J=10.9 Hz, 1H), 5.95 (dd, J=17.4, 10.9 Hz, 1H), 6.22 (t, J=74.3 Hz, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:10][C@@H:9]2[CH:11]=[CH2:12])=[CH:4][CH:3]=1.BrC1C=CC([C@H]2C[C@@H]2C[OH:24])=CC=1>CCCCCC.C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:10][C@H:9]2[CH2:11][CH2:12][OH:24])=[CH:4][CH:3]=1
Reactant: C=C[C@H]1C[C@@H]1c1ccc(Br)cc1
Reactant: OC[C@H]1C[C@@H]1c1ccc(Br)cc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: OCC[C@@H]1C[C@H]1c1ccc(Br)cc1

Procedure:
The alkene intermediate from Example 29F (1.64 g, 7.35 mmol) was converted to the alcohol by the method of Example 26F, followed by chromatography (7.3 hexane/ethyl acetate) provided the title compound. 1H NMR (300 MHz, CDCl3): δ 0.96-0.79 (m, 2H), 1.00-1.14 (m, 1H), 1.54-1.76 (m, 3H), 4.91-4.97 (m, 1H), 3.76 (t, J=6 Hz, 2H), 6.92 (d, J=9 Hz, 2H), 7.35 (d, J=9 Hz, 2H). MS (DCl—NH3) m/z 258 (M+NH4)+.
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[CH:12][N:11]=[N:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(O)=[O:16]>>[C:2]1([C:1]([C:8]2[CH:13]=[CH:12][N:11]=[N:10][CH:9]=2)=[O:16])[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)O
Reactant: c1ccc(Cc2ccnnc2)cc1
Product: O=C(c1ccccc1)c1ccnnc1
Temperature: 100 °C
Yield: 91 %

Procedure:
A solution of 4-benzylpyridazine (1.0 g, 5.9 mmol) in AcOH (28 mL) was added dropwise to a stirring suspension of SeO2 (3.2 g, 29.5 mmol) in AcOH (28 mL), the resulting mixture was heated to 100° C. for 1 h. TLC showed the starting material had disappeared, then the reaction solution was filtrated, the filtration was concentrated under reduced pressure, and Sat.aq Na2CO3 was added to adjust PH=9-10, then, extracted with DCM (50 mL×3), washed by brine, dried over Na2SO4 and concentrated to get the phenyl(pyridazin-4-yl)methanone (1.0 g, yield: 91%). 1H NMR (CDCl3 400 MHz): δ9.50-9.45 (m, 2H), 7.83 (d, J=7.6 Hz, 2H), 7.78-7.74 (dd, J=5.2, 2.4 Hz, 1H), 7.74-7.68 (m, 1H), 7.57 (t, J=7.2 Hz, 2H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([OH:23])[CH:12]=[CH:13][C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[OH-].[K+].[CH2:27]([CH:29]1[O:31][CH2:30]1)Cl>C(O)C>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:12]=[CH:13][C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[O:23][CH2:27][CH:29]1[O:31][CH2:30]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: ClCC1CO1
Reactant: Oc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: c1ccc(COc2ccc(OCC3CO3)cc2OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a stirred solution of 6.1 g. of 3,4-dibenzyloxyphenol in 10 ml. of water and 1.53 g. of potassium hydroxide pellets is added 5.6 g. of epichlorohydrin in 60 ml. of ethanol. The solution is stirred at room temperature for 24 hours and then concentrated in vacuo. The residue is suspended in water and the mixture extracted with ether. The ether extracts are dried to yield 3-(3,4-dibenzyloxyphenoxy)-1,2-epoxypropane.
Reaction SMILES: [C:1]1([CH3:9])[CH:6]=[CH:5][C:4]([Mg]Br)=[CH:3][CH:2]=1.C1C=CC=CC=1.Cl[C:17]([C:19]1[N:23]([CH3:24])[C:22]([CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:21][CH:20]=1)=[O:18].Cl>CCOCC.[Cl-].[Cd+2].[Cl-]>[CH3:24][N:23]1[C:19]([C:17]([C:4]2[CH:5]=[CH:6][C:1]([CH3:9])=[CH:2][CH:3]=2)=[O:18])=[CH:20][CH:21]=[C:22]1[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27]
Reactant: CCOC(=O)Cc1ccc(C(=O)Cl)n1C
Reactant: Cc1ccc([Mg]Br)cc1
Agent: Cl
Agent: [Cd+2]
Agent: [Cl-]
Solvent: c1ccccc1
Solvent: CCOCC
Product: CCOC(=O)Cc1ccc(C(=O)c2ccc(C)cc2)n1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 0.0516 mole of p-tolyl magnesium bromide in ether (40 ml.) is added 5.0 g. (0.0274 mole) of cadmium chloride. The mixture is refluxed for 20 minutes, 50 ml. of dry benzene is added and the ether is distilled off. To this solution of di-(p-tolyl) cadmium is added dropwise 5.9 g. (0.0258 mole) of ethyl 5-chlorocarbonyl-1-methylpyrrole-2-acetate in 25 ml. of benzene. The mixture is stirred at room temperature for 1 hour and poured into dilute HCl. The mixture is extracted with ether. The ether extract is washed successively with dimethylaminopropylamine solution, dilute HCl. and brine and then dried (anhydrous MgSO4). The solvent is evaporated in vacuo. The residue is crystallized from methyl cyclohexane and recrystallized from ethanol to give white crystalline ethyl 1-methyl-5-p-toluoylpyrrole-2-acetate, m.p. 70°-71°C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][CH2:10][CH2:9][C:8](=[O:12])[NH:7][C:6]=2[CH:13]=1.Cl[C:15]1[N:20]=[C:19]([NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[S:28]([N:31]2[CH2:35][CH2:34][CH2:33][CH2:32]2)(=[O:30])=[O:29])[C:18]([Cl:36])=[CH:17][N:16]=1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.C(=O)(O)[O-].[Na+]>C(O)(C)C.O>[Cl:36][C:18]1[C:19]([NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[S:28]([N:31]2[CH2:35][CH2:34][CH2:33][CH2:32]2)(=[O:30])=[O:29])=[N:20][C:15]([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[CH2:11][CH2:10][CH2:9][C:8](=[O:12])[NH:7][C:6]=3[CH:13]=2)=[N:16][CH:17]=1
Reactant: Nc1ccc2c(c1)NC(=O)CCC2
Reactant: O=S(=O)(c1ccccc1Nc1nc(Cl)ncc1Cl)N1CCCC1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Product: O=C1CCCc2ccc(Nc3ncc(Cl)c(Nc4ccccc4S(=O)(=O)N4CCCC4)n3)cc2N1
Yield: 60.5 %

Procedure:
8-Amino-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (0.037 g, 0.21 mmol), (2,5-Dichloro-pyrimidin-4-yl)-[2-(pyrrolidine-1-sulfonyl)-phenyl]-amine (0.072 g, 0.19 mmol) and 10-Camphorsulfonic acid (0.0045 g, 0.019 mmol) in Isopropyl alcohol (1 mL) was irradiated in a CEM microwave (120° C., 30 min). One mL Sodium bicarbonate and 1 mL water were added to the reaction mixture, which was then filtered and the resulting ppt was washed first with water then three times with 1 mL of Isopropyl alcohol. The solid was then purified by silica gel chromatography (ISCO, 0-100% EtOAc) to afford 8-{5-Chloro-4-[2-(pyrrolidine-1-sulfonyl)-phenylamino]-pyrimidin-2-ylamino}-1,3,4,5-tetrahydro-benzo[b]azepin-2-one as a white powder (59 mg, 60%). MP 249-251° C.; LCMS: 513 (M+H); 1H-NMR (DMSO): 9.56 (s, 1H), 9.45 (s, 1H), 9.41 (s, 1H), 8.61 (s, 1H), 8.29 (s, 1H), 7.86 (d, J=8.0 Hz, 1H), 7.67 (dd, J=8.0 Hz, 1H), 7.34 (d, J=8.0 Hz, 1H), 7.31 (s, 1H), 7.27 (s, 1H), 7.09 (d, J=8.0 Hz, 1H), 3.14 (t, J=4.0 Hz, 4H), 2.62 (t, J=8.0 Hz, 2H), 2.15 (t, J=8.0 Hz, 2H), 2.07 (m, 2H), 1.68 (m, 4H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12](/[CH:13]=[CH:14]/[C:15]3[S:16][C:17]([C:20]([OH:22])=O)=[CH:18][N:19]=3)=[C:11]([CH3:23])[O:10][N:9]=2)=[N:6][CH:7]=1.[NH2:24][C:25]([CH3:29])([CH3:28])[CH2:26][OH:27]>>[OH:27][CH2:26][C:25]([NH:24][C:20]([C:17]1[S:16][C:15](/[CH:14]=[CH:13]/[C:12]2[C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][N:6]=3)=[N:9][O:10][C:11]=2[CH3:23])=[N:19][CH:18]=1)=[O:22])([CH3:29])[CH3:28]
Reactant: CC(C)(N)CO
Reactant: Cc1onc(-c2ccc(F)cn2)c1/C=C/c1ncc(C(=O)O)s1
Product: Cc1onc(-c2ccc(F)cn2)c1/C=C/c1ncc(C(=O)NC(C)(C)CO)s1
Yield: 46 %

Procedure:
As described for example 77c, 2-{(E)-2-[3-(5-fluoro-pyridin-2-yl)-5-methyl-isoxazol-4-yl]-vinyl}-thiazole-5-carboxylic acid (83 mg, 0.25 mmol) was converted, using 2-amino-2-methyl-1-propanol instead of 4-aminotetrahydropyran, to the title compound (46 mg, 46%) which was obtained as an off white solid after recrystallization from heptane/ethyl acetate. MS: m/e=403.3 [M+H]+.
Reaction SMILES: [CH:1]1([NH:7][C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11](=[O:18])[C:10](=[O:19])[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.S(OC)(O[CH3:24])(=O)=O>[OH-].[Na+]>[CH:1]1([N:7]=[C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11](=[O:18])[C:10]([O:19][CH3:24])=[CH:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C1C=C(NC2CCCCC2)c2ccccc2C1=O
Reactant: COS(=O)(=O)OC
Agent: [Na+]
Agent: [OH-]
Product: COC1=CC(=NC2CCCCC2)c2ccccc2C1=O
Reaction time: 6 h

Procedure:
A solution of 9.0 g of 4-(cyclohexylamino)-1,2-naphthoquinone in 200 ml of dimethyl sulfate and 460 ml of 30% aqueous sodium hydroxide is heated slowly to reflux. The reaction mixture is stirred for 6 hours, washed with 300 ml of water and dried at 80° C. under vacuo to yield 4-cyclohexylimino-1-oxo-2-methoxy-1,4-dihydronaphthalene, m.p. 145°-147° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:27])=[C:6]([C:8]2[CH:17]=[C:16]3[C:11]([CH:12]=[C:13]([NH:18][C:19]([CH:21]4[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]4)=[O:20])[N:14]=[CH:15]3)=[CH:10][CH:9]=2)[CH:7]=1.CN(C)C=O.[CH:33](N(CC)C(C)C)(C)[CH3:34].ICC>>[CH2:33]([N:24]1[CH2:25][CH2:26][CH:21]([C:19]([NH:18][C:13]2[N:14]=[CH:15][C:16]3[C:11]([CH:12]=2)=[CH:10][CH:9]=[C:8]([C:6]2[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=2[CH3:27])[CH:17]=3)=[O:20])[CH2:22][CH2:23]1)[CH3:34]
Reactant: Cc1ccc(F)cc1-c1ccc2cc(NC(=O)C3CCNCC3)ncc2c1
Reactant: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCI
Product: CCN1CCC(C(=O)Nc2cc3ccc(-c4cc(F)ccc4C)cc3cn2)CC1
Temperature: 25 °C
Reaction time: 19 h
Yield: 41.4 %

Procedure:
To a solution of N-(7-(5-fluoro-2-methylphenyl)isoquinolin-3-yl)piperidine-4-carboxamide (110.6 mg, 0.1936 mmol) in N,N-dimethylformamide (2.0 mL, 26 mmol) was added N,N-diisopropylethylamine (0.1 mL, 0.574 mmol) and iodoethane (19.0 uL, 0.238 mmol). The reaction was stirred at room temperature for 19 hours, and then N,N-diisopropylethylamine (0.1 mL) and iodoethane (30 uL, 0.375 mmol) were added. After an additional 4 hours, the mixture was evaporated in vacuo. The crude product was purified via reverse phase HPLC and lyophilized to yield 31.4 mg (41%) of 1-ethyl-N-(7-(5-fluoro-2-methylphenyl)isoquinolin-3-yl)piperidine-4-carboxamide. LCMS (ESI): RT (Min)=4.370, M+H=392.1, method=E; 1H NMR (400 MHz, DMSO-d6) δ 10.76 (s, 1H), 9.19 (s, 1H), 8.53 (s, 1H), 8.06 (s, 1H), 7.96 (d, J=8.6 Hz, 1H), 7.73 (d, J=8.5 Hz, 1H), 7.39 (s, 1H), 7.18 (d, J=8.9 Hz, 2H), 3.53 (unresolved, 2H), 3.08 (unresolved, 2H), 2.83 (unresolved, 3H), 2.25 (s, 3H), 2.07 (unresolved, 2H), 1.90 (unresolved, 2H), 1.22 (unresolved, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:29]2[NH:33][N:32]=[N:31][N:30]=2)[N:5]([C:7]2[CH:28]=[CH:27][C:10]([CH2:11][N:12]3[C:16]4=[N:17][CH:18]=[CH:19][C:20]([CH3:21])=[C:15]4[N:14]=[C:13]3S(CC)(=O)=O)=[CH:9][CH:8]=2)[CH:6]=1.[O-:34][CH2:35][CH3:36].[Na+].Cl(O)(=O)=O>C(O)C.ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C:29]2[NH:30][N:31]=[N:32][N:33]=2)[N:5]([C:7]2[CH:8]=[CH:9][C:10]([CH2:11][N:12]3[C:16]4=[N:17][CH:18]=[CH:19][C:20]([CH3:21])=[C:15]4[N:14]=[C:13]3[O:34][CH2:35][CH3:36])=[CH:27][CH:28]=2)[CH:6]=1
Reactant: CCS(=O)(=O)c1nc2c(C)ccnc2n1Cc1ccc(-n2cc(Cl)cc2-c2nnn[nH]2)cc1
Reactant: CC[O-]
Agent: [Na+]
Agent: [O-][Cl+2]([O-])O
Solvent: CCO
Solvent: ClCCl
Product: CCOc1nc2c(C)ccnc2n1Cc1ccc(-n2cc(Cl)cc2-c2nnn[nH]2)cc1

Procedure:
To a stirred solution of 3-[4-[4-chloro-2-(1H-tetrazol-5-yl)-1-pyrrolyl]benzyl]-2-ethylsulfonyl-7-methyl-3H-imidazo[4,5-b]pyridine (209 mg) in ethanol(2 ml) was added 1N sodium ethoxide solution in ethanol (1.02 ml) and dichloromethane(30 ml) at room temperature and the resulting mixture was heated under reflux for two hours. After cooling, the mixture was treated with 7% aqueous hydrogenchloric acid and the organic phase was washed with water and dried over anhydrous magnesium sulfute. After filtration the solvent was removed in vauo and the residue was purified by preparative thin layer chromatography eluting with dichloromethane-methanol(8:1 v/v) to give 3-[4-[4-chloro-2-(1H-tetrazol-5-yl)-1-pyrrolyl]benzyl]-2-ethoxy-7-methyl-3H-imidazo[4,5-b]pyridine(97 mg) as a amorphous solid which was powderized by treating with diethylether.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Cl[C:11]1[C:16]([N+:17]([O-:19])=[O:18])=[C:15]([NH:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[C:14]([CH3:34])=[C:13]([CH3:35])[N:12]=1.[O-]C1C=CC=CC=1.[Na+]>O1CCCC1.C(OCC)(=O)C>[CH3:35][C:13]1[C:14]([CH3:34])=[C:15]([NH:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[C:16]([N+:17]([O-:19])=[O:18])=[C:11]([O:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:12]=1
Reactant: Cc1nc(Cl)c([N+](=O)[O-])c(NCCOCCNC(=O)OC(C)(C)C)c1C
Reactant: Oc1ccccc1
Agent: [H-]
Agent: [Na+]
Agent: [O-]c1ccccc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1nc(Oc2ccccc2)c([N+](=O)[O-])c(NCCOCCNC(=O)OC(C)(C)C)c1C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 83.6 %

Procedure:
Phenol (5.33 g, 56.63 mmol) was added in small portions over a period of 10 minutes to a chilled (0°) suspension of sodium hydride (2.39 g of 60%, 59.75 mmol) in anhydrous tetrahydrofuran (100 mL). After the addition was complete, the reaction was allowed to stir at 0° for 30 minutes. A solution tert-butyl 2-{2-[(2-chloro-5,6-dimethyl-3-nitropyridin-4-yl)amino]ethoxy}ethylcarbamate (20.67 g, 53.16 mmol) in tetrahydrofuran (100 mL) was added over a period of 1 hour while maintaining the temperature at 0° C. The ice bath was removed and the reaction mixture was heated to reflux. At 46 and 52 hours additional fresh sodium phenoxide (11.3 mmol) was added. Refluxing was continued for 2 hours after the second addition. The reaction mixture was diluted with ethyl acetate (500 mL); washed sequentially with water (3×100 mL), 1N sodium hydroxide (2×100 mL), and brine; dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by column chromatography (450 g of silica gel eluting with 1/1 hexanes/ethyl acetate) to provide 19.85 g of tert-butyl 2-{2-[(2,3-dimethyl-5-nitro-6-phenoxypyridin-4-yl)amino]ethoxy}ethylcarbamate.