Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: OC1C2C(=O)C(OC)=CC(=O)C=2C(O)=C2C(=O)[C@]3(C4C(O)=C5C(C=C(/C=N/O[C@@H]6O[C@H](CO)[C@@H](O)[C@H](O)[C@H]6O)NC5=O)=CC=4CC3)C(=O)C=12.[CH3:50]/[CH:51]=[CH:52]/[CH:53]=[CH:54]/[C:55]1[NH:65][C:63](=[O:64])[C:62]2[C:57](=[CH:58][C:59]3[CH2:69][CH2:68][C:67]4([C:78](=[O:79])[C:77]5[C:72](=[C:73]([OH:89])[C:74]6[C:85](=[O:86])[CH:84]=[C:83](OC)[C:81](=[O:82])[C:75]=6[C:76]=5[OH:80])[C:70]4=[O:71])[C:60]=3[C:61]=2[OH:66])[CH:56]=1.[NH2:90][CH2:91][CH:92]1[CH2:97][CH2:96][NH:95][CH2:94][CH2:93]1>CN(C=O)C>[OH:80][C:76]1[C:75]2[C:81](=[O:82])[C:83]([NH:90][CH2:91][CH:92]3[CH2:97][CH2:96][NH:95][CH2:94][CH2:93]3)=[CH:84][C:85](=[O:86])[C:74]=2[C:73]([OH:89])=[C:72]2[C:70](=[O:71])[C@:67]3([C:60]4[C:61]([OH:66])=[C:62]5[C:57]([CH:56]=[C:55](/[CH:54]=[CH:53]/[CH:52]=[CH:51]/[CH3:50])[NH:65][C:63]5=[O:64])=[CH:58][C:59]=4[CH2:69][CH2:68]3)[C:78](=[O:79])[C:77]=12
Reactant: C/C=C/C=C/c1cc2cc3c(c(O)c2c(=O)[nH]1)C1(CC3)C(=O)c2c(O)c3c(c(O)c2C1=O)C(=O)C(OC)=CC3=O
Reactant: NCC1CCNCC1
Agent: COC1=CC(=O)c2c(O)c3c(c(O)c2C1=O)C(=O)[C@]1(CCc2cc4cc(/C=N/O[C@@H]5O[C@H](CO)[C@@H](O)[C@H](O)[C@H]5O)[nH]c(=O)c4c(O)c21)C3=O
Solvent: CN(C)C=O
Product: C/C=C/C=C/c1cc2cc3c(c(O)c2c(=O)[nH]1)[C@@]1(CC3)C(=O)c2c(O)c3c(c(O)c2C1=O)C(=O)C(NCC1CCNCC1)=CC3=O

Procedure:
Ten (10) mg (18.6 μmol) fredericamycin are dissolved in 1 ml DMF under argon, then 2.7 PI (22.3 μmol) 4-aminomethylpiperidine are added at room temperature. The reaction mixture is concentrated at high vacuum until dry after 24 h.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([C:8]2[C:9]([N:14]3[CH2:19][CH2:18][CH:17]([CH2:20][OH:21])[CH2:16][CH2:15]3)=[N:10][CH:11]=[CH:12][N:13]=2)[CH2:4][CH2:3]1.Cl[C:23]1[CH:32]=[CH:31][C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:24]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.O>[N:24]1[C:25]2[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:31]=[CH:32][C:23]=1[N:2]1[CH2:3][CH2:4][CH:5]([C:8]2[C:9]([N:14]3[CH2:19][CH2:18][CH:17]([CH2:20][OH:21])[CH2:16][CH2:15]3)=[N:10][CH:11]=[CH:12][N:13]=2)[CH2:6][CH2:7]1
Reactant: OCC1CCN(c2nccnc2C2CCNCC2)CC1
Reactant: Clc1ccc2ccccc2n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: OCC1CCN(c2nccnc2C2CCN(c3ccc4ccccc4n3)CC2)CC1
Temperature: 100 °C
Reaction time: 8 h
Yield: 70 %

Procedure:
To a solution of [1-(3-piperidin-4-yl-pyrazin-2-yl)-piperidin-4-yl]-methanol hydrochloride (156 mg, 0.5 mmol) and 2-chloro-quinoline (81.5 mg 0.5 mmol) in DMF (5 mL) was added Cs2CO3 (325 mg, 1 mmol). The reaction mixture was stirred at 100° C. overnight. The reaction mixture was diluted with water, extracted with EtOAc (2×20 mL). The combined organic extracts were washed with water (15 mL) and brine (15 mL), dried over Na2SO4 and filtered. The filtrate was evaporated in vacuo and the residue was purified by flash column chromatography on silica gel to give {1-[3-(1-quinolin-2-yl-piperidin-4-yl)-pyrazin-2-yl]-piperidin-4-yl}-methanol (142 mg, 0.35 mmol, yield 70.47%).
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]([C:14]2[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=2[C:16]([OH:18])=[O:17])=[O:13])=[C:4]1[CH3:23])[CH3:2].S(Cl)(Cl)=O.CO.N1C=CC=C[CH:31]=1>C(Cl)CCl>[CH3:31][O:13][C:12]1([C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[N:3]([CH2:1][CH3:2])[C:4]=2[CH3:23])[C:14]2[C:15](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:16](=[O:18])[O:17]1
Reactant: c1ccncc1
Reactant: CCn1c(C)c(C(=O)c2ccccc2C(=O)O)c2ccccc21
Solvent: O=S(Cl)Cl
Solvent: CO
Solvent: ClCCCl
Product: CCn1c(C)c(C2(OC)OC(=O)c3ccccc32)c2ccccc21

Procedure:
Proceeding in a manner similar to that described in Example 1 above, 5.1 g of 2-(1-ethyl-2-methylindol-3-yl)carbonylbenzoic acid, 1.2 ml of thionyl chloride and 5.0 ml of methyl alcohol were interacted in 30.0 ml of ethylene dichloride in the presence of 1.3 ml of pyridine to obtain 2.1 g of 3-methoxy-3-(1-ethyl-2-methylindol-3-yl)phthalide (Formula III: R0 =R=R1 =R2 =R8 =H; R6 =C2H5 ; R7 =Y=CH3 ; X=O), a dark brown-colored oil. Significant infrared maxima appeared at 1770 (C=O;s) and 740 cm-1 (C=O;s). Analysis by mass spectrum showed m/e peaks at 321 (M+) and 290 (M+ -OCH3). A toluene solution of the product spotted on an acidic clay-coated paper developed a red-purple-colored image.
Reaction SMILES: [OH:1][C:2]1[C:3]([N+:13]([O-])=O)=[CH:4][C:5]2[O:10][CH2:9][C:8](=[O:11])[NH:7][C:6]=2[CH:12]=1.[H][H]>CN(C=O)C.[Ni]>[OH:1][C:2]1[C:3]([NH2:13])=[CH:4][C:5]2[O:10][CH2:9][C:8](=[O:11])[NH:7][C:6]=2[CH:12]=1
Reactant: O=C1COc2cc([N+](=O)[O-])c(O)cc2N1
Reactant: [H][H]
Agent: [Ni]
Solvent: CN(C)C=O
Product: Nc1cc2c(cc1O)NC(=O)CO2

Procedure:
The 6-hydroxy-7-nitro-2H-1,4-benzoxazin-3-(4H)-one (17.5 g) in DMF (300 ml) was reduced under 60 Atm. hydrogen at 60° C. in the presence of Ni Raney catalyst in an autoclave. The resulting amine was not isolated.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([I:8])[C:3]=1[CH2:9][OH:10].[H-].[Na+].[CH2:13](Br)[CH:14]=[CH2:15]>C1COCC1>[CH2:15]([O:10][CH2:9][C:3]1[C:4]([I:8])=[CH:5][CH:6]=[CH:7][C:2]=1[F:1])[CH:14]=[CH2:13]
Reactant: C=CCBr
Reactant: OCc1c(F)cccc1I
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCOCc1c(F)cccc1I
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of (2-fluoro-6-iodophenyl)methanol (10 mmol) in 50 mL of THF was added NaH (12 mmol) in small portions at room temperature. After the addition, allylbromide (12 mmol) was added slowly via syringe. The reaction mixture was stirred 16 hours at room temperature. The resulting white heterogeneous mixture was quenched with water and then diluted with 100 mL of Et2O, followed by washing with water and brine. The organic layer was dried over MgSO4 and then concentrated to dryness in vacuo to offer 2.8 g of the title compound.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:22]=[C:23]([CH2:25][OH:26])[CH:24]=1)[O:6][CH2:7][CH2:8][CH2:9][N:10]([CH2:18][CH:19]([CH3:21])[CH3:20])[C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14].C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O>C(Cl)Cl>[CH:25]([C:23]1[CH:22]=[C:5]([CH:4]=[C:3]([CH:2]=[O:1])[CH:24]=1)[O:6][CH2:7][CH2:8][CH2:9][N:10]([CH2:18][CH:19]([CH3:21])[CH3:20])[C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:26]
Reactant: CC(C)CN(CCCOc1cc(CO)cc(CO)c1)C(=O)OC(C)(C)C
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CC(C)CN(CCCOc1cc(C=O)cc(C=O)c1)C(=O)OC(C)(C)C
Reaction time: 16 h
Yield: 52.9 %

Procedure:
tert-Butyl (3-(3,5-bis(hydroxymethyl)phenoxy)propyl)(isobutyl)carbamate (0.29 g, 0.78 mmol) and CH2Cl2 (20 mL) were added to a round-bottom flask. To the solution was added PCC (0.42 g, 1.94 mmol) and the reaction was stirred for 16 h. The reaction mixture was concentrated under reduced pressure. Purification by column chromatography (90% Hexanes/EtOAc) afforded the desired product (0.15 g, 20% 3 steps) as a white semi-solid, which was used without further purification.
Reaction SMILES: C([Li])CCC.[CH2:6]([O:13][CH2:14][O:15][CH2:16][Sn](CCCC)(CCCC)CCCC)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH3:30]/[C:31](/[CH2:35][CH2:36]/[CH:37]=[C:38](\[CH3:45])/[CH2:39][CH2:40][CH:41]=[C:42]([CH3:44])[CH3:43])=[CH:32]\[CH2:33]Br.O>C1COCC1>[CH3:30]/[C:31](/[CH2:35][CH2:36]/[CH:37]=[C:38](\[CH3:45])/[CH2:39][CH2:40][CH:41]=[C:42]([CH3:44])[CH3:43])=[CH:32]\[CH2:33][CH2:16][O:15][CH2:14][O:13][CH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CC(C)=CCC/C(C)=C/CC/C(C)=C/CBr
Reactant: CCCC[Sn](CCCC)(CCCC)COCOCc1ccccc1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CC(C)=CCC/C(C)=C/CC/C(C)=C/CCOCOCc1ccccc1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 54.5 %

Procedure:
n-Butyl lithium (1.6M in hexane, 8.6 mL, 13.8 mmol) was added under nitrogen to a stirred solution of (benzyloxymethoxy)methyl-tri-(n-butyl) tin (6.1 g, 13.8 mmol) in THF (56 mL) at -78° C. The resulting mixture was stirred at -78° C. for 10 min, then added a solution of (E,E)-3,7,11-trimethyl-2,6,10-dodecatrienylbromide (3.5 g, 12.3 mmol) in THF (4 mL) via a dropping funnel. The resulting mixture was stirred at -78° C. for 0.5 hours, then poured into cold water and extracted with ether. The ethereal extract was dried, filtered and evaporated to afford a residue, which was purified by flash chromatography on a silica gel column. Elution of the column with hexane:ether (25:1, v:v) provided the title compound as a colorless oil (2.39 g, 6.7 mmol, 54.5%).
Reaction SMILES: [C:1]([OH:11])(=O)/[CH:2]=[CH:3]/[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.ClN1C(OC)=NC(OC)=NC1.CN1CCOCC1.[CH2:30]([NH:34][C:35]([C@H:37]1[CH2:49][C:48]2[C:47]3[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=3)[NH:41][C:40]=2[C@@H:39]([C:50]2[CH:58]=[CH:57][C:53]3[O:54][CH2:55][O:56][C:52]=3[CH:51]=2)[NH:38]1)=[O:36])[CH2:31][CH2:32][CH3:33]>O1CCCC1>[CH2:30]([NH:34][C:35]([C@H:37]1[CH2:49][C:48]2[C:47]3[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=3)[NH:41][C:40]=2[C@@H:39]([C:50]2[CH:58]=[CH:57][C:53]3[O:54][CH2:55][O:56][C:52]=3[CH:51]=2)[N:38]1[C:1](=[O:11])[CH:2]=[CH:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)=[O:36])[CH2:31][CH2:32][CH3:33]
Reactant: CCCCNC(=O)[C@H]1Cc2c([nH]c3ccccc23)[C@@H](c2ccc3c(c2)OCO3)N1
Reactant: O=C(O)/C=C/c1ccccc1
Agent: COC1=NCN(Cl)C(OC)=N1
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CCCCNC(=O)[C@H]1Cc2c([nH]c3ccccc23)[C@@H](c2ccc3c(c2)OCO3)N1C(=O)C=Cc1ccccc1
Yield: 61.3 %

Procedure:
A mixture of trans-cinnamic acid (376 mg. 2.5 mmol), 2-chloro-3,5-dimethoxy-2,4,6-triazine (500 mg, 2.8 mmol), N-methylmorpholine (0.32 mL, 2.9 mmol), and tetrahydrofuran (20 mL) was stirred without cooling for 1.5 hours. Compound (XI) (1.0 g, 2.5 mmol) was added, then the reaction was stirred for an additional 18 hours. The solvent was evaporated, and the residue was dissolved in ethyl acetate, washed once with 1N hydrochloric acid, once with saturated sodium bicarbonate solution, dried (sodium sulfate), filtered, and concentrated in vacuo. Chromatography (silica gel, 30% ethyl acetate: 70% hexanes) of the residue provided 800 mg (61%) of Example 11 as a solid: mp 114–117° C.
Reaction SMILES: [Br:1][CH2:2][CH:3]([OH:13])[CH2:4][C:5]([NH:7][CH2:8][C:9]([O:11][CH3:12])=[O:10])=[O:6].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.[O:31]1[CH:36]=[CH:35][CH2:34][CH2:33][CH2:32]1>C(Cl)Cl>[Br:1][CH2:2][CH:3]([O:13][CH:32]1[CH2:33][CH2:34][CH2:35][CH2:36][O:31]1)[CH2:4][C:5]([NH:7][CH2:8][C:9]([O:11][CH3:12])=[O:10])=[O:6]
Reactant: COC(=O)CNC(=O)CC(O)CBr
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: COC(=O)CNC(=O)CC(CBr)OC1CCCCO1
Temperature: 25 °C
Reaction time: 20 h
Yield: 92 %

Procedure:
To a solution of 300 mg methyl 2-(4-bromo-3-hydroxybutanamido)acetate in 50 ml methylene chloride are added 30 mg pyridinium p-toluenesulphonate and 1 ml dihydropyran. After stirring at ambient temperature for 20 h, the solvent is evaporated in vacuo and the residue chromatographed on silica, eluting with ether. A colourless oil is obtained in 92% yield, Rf 0.33 (silica gel plates, thickness 0.25, eluent diethyl ether).
Reaction SMILES: [C:1]([O-])([O-])=O.[Cs+].[Cs+].[O:7]=[C:8]([CH2:14][CH3:15])[CH2:9][CH2:10][C:11]([OH:13])=[O:12].IC.CCOC(C)=O>CN(C=O)C.O>[O:7]=[C:8]([CH2:14][CH3:15])[CH2:9][CH2:10][C:11]([O:13][CH3:1])=[O:12]
Reactant: CCC(=O)CCC(=O)O
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Solvent: O
Solvent: CCOC(C)=O
Product: CCC(=O)CCC(=O)OC
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a stirring suspension of 8.15 g (25 mmol) of Cs2CO3 in DMF was added 5.79 g (44 mmol) of 4-oxohexanoic acid. After 5 minutes, 6.81 g (48 mmol) of iodomethane was added. The reaction mixture was stirred at ambient temperature for 16 hours. To the reaction was then added 250 mL of EtOAc and 250 mL of H2O. The layers were separated, and the organic layer was washed with 3×250 mL of H2O. The organic layer was then dried over Na2SO4 anhydrous, filtered, and concentrated under vacuum. The yield of methyl 4-oxohexanoate (16) was 4.15 g (65%), which was employed in Example 17 below.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][C@H:10]([CH3:14])[CH2:9]2)=[CH:4][C:3]=1[O:15][CH3:16].[NH:17]1[CH:21]=[CH:20][N:19]=[C:18]1[C:22]1[C:30]2[C:25](=[N:26][CH:27]=[CH:28][CH:29]=2)[N:24]([CH2:31][C:32](O)=[O:33])[N:23]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:32](=[O:33])[CH2:31][N:24]3[C:25]4=[N:26][CH:27]=[CH:28][CH:29]=[C:30]4[C:22]([C:18]4[NH:17][CH:21]=[CH:20][N:19]=4)=[N:23]3)[C@H:10]([CH3:14])[CH2:9]2)=[CH:4][C:3]=1[O:15][CH3:16]
Reactant: COc1cc(N2CCN[C@H](C)C2)ccc1Cl
Reactant: O=C(O)Cn1nc(-c2ncc[nH]2)c2cccnc21
Product: COc1cc(N2CCN(C(=O)Cn3nc(-c4ncc[nH]4)c4cccnc43)[C@H](C)C2)ccc1Cl

Procedure:
The title compound was prepared following Protocol A. (R)-1-(4-Chloro-3-methoxyphenyl)-3-methylpiperazine and [3-(1H-imidazol-2-yl)-pyrazolo[3,4-b]pyridin-1-yl]acetic acid were used as the coupling components. The crude product was purified by silica gel chromatography (1% to 7.5% MeOH in CH2Cl2) to provide 1-[(R)-4-(4-chloro-3-methoxyphenyl)-2-methylpiperazin-1-yl]-2-[3-(1H-imidazol-2-yl)-pyrazolo[3,4-b]pyridin-1-yl]ethanone as a tan solid: 1H NMR (CDCl3, 400 MHz) δ 8.75 (d, 0.6H), 8.66 (dd, 0.4H), 8.57-8.54 (m, 1H), 7.29-7.18 (m, 4H), 6.44-6.39 (m, 2H), 5.42 (br. s, 2H), 4.82 (br. s, 0.3H), 4.45 (br. s, 0.3H), 4.33 (br. s, 0.3H), 3.88 (s, 1.2H), 3.87 (s, 1.8H), 3.83 (br. s, 0.3H), 3.73-3.67 (m, 1H), 3.54-3.52 (m, 1H), 3.38 (br. s, 1H), 3.17-3.13 (m, 1H), 2.99 (br. s, 1H), 2.80 (br. s, 1H), 1.50-1.42 (m, 3H); LC/MS m/z (M+H)+ 466.4.
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]=[O:9])=[C:6]([Cl:10])[N:5]=[C:4]([S:11][CH3:12])[N:3]=1.[Cl:13][C:14]1[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=1[NH2:16]>>[Cl:10][C:6]1[C:7]([CH:8]=[O:9])=[C:2]([NH:16][C:15]2[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=2[Cl:13])[N:3]=[C:4]([S:11][CH3:12])[N:5]=1
Reactant: Nc1ccccc1Cl
Reactant: CSc1nc(Cl)c(C=O)c(Cl)n1
Product: CSc1nc(Cl)c(C=O)c(Nc2ccccc2Cl)n1

Procedure:
Prepared as described above in Example 1 starting from 4,6-dichloro-2-methylsulfanyl-pyrimidine-5-carbaldehyde and 2-chloroaniline to give the title compound 4-chloro-6-(2-chloro-phenylamino)-2-methylsulfanyl-pyrimidine-5-carbaldehyde. 1H-NMR: δ 2.55 (s, 3H), 7.17 (m, 1H), 7.29 (m, 2H), 7.44 (m, 1H), 10.37 (s, 1H), 11.49 (br s, 1H). LC MS (m/e)=315 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([O:14][C:15]3[S:16][C:17]4[CH:23]=[C:22]([C:24]5[CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26][CH:25]=5)[CH:21]=[CH:20][C:18]=4[N:19]=3)[CH2:10][CH2:9]2)=[N:6][CH:7]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:1][C:2]1[CH:7]=[N:6][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([O:14][C:15]3[S:16][C:17]4[CH:23]=[C:22]([C:24]5[CH2:29][CH2:28][NH:27][CH2:26][CH:25]=5)[CH:21]=[CH:20][C:18]=4[N:19]=3)[CH2:10][CH2:9]2)=[N:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ccc3nc(OC4CCN(c5ncc(F)cn5)CC4)sc3c2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Fc1cnc(N2CCC(Oc3nc4ccc(C5=CCNCC5)cc4s3)CC2)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.1 %

Procedure:
To a solution of tert-butyl 4-(2-(1-(5-fluoropyrimidin-2-yl)piperidin-4-yloxy)benzo[d]thiazol-6-yl)-5,6-dihydropyridine-1(2H)-carboxylate (1.27 g, 2.482 mmol) in CH2Cl2 (20 mL) was added TFA (1.9 mL, 24.8 mmol). The reaction mixture was stirred at rt overnight. The reaction mixture was diluted with CH2Cl2 (20 mL) and washed sequentially with aq. NaOH (1 N, 30 mL) and brine. The organic layer was dried (Na2SO4), filtered, and concentrated to afford 2-(1-(5-fluoropyrimidin-2-yl)piperidin-4-yloxy)-6-(1,2,3,6-tetrahydropyridin-4-yl)benzo[d]thiazole (1.01 g, 2.459 mmol, 99% yield) as a pale yellow solid. LCMS (m/z)=412 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:32])[CH2:4][O:5][C:6]1[CH:11]=[C:10]([O:12][CH3:13])[C:9]([S:14][CH2:15][CH2:16][CH2:17][NH:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:21][N:20]=2)=[CH:8][C:7]=1[CH3:31].[CH:33](=O)[CH3:34].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].ClC(Cl)C.Cl.C(=O)(O)[O-].[Na+]>C(O)(=O)C>[CH3:1][O:2][C:3](=[O:32])[CH2:4][O:5][C:6]1[CH:11]=[C:10]([O:12][CH3:13])[C:9]([S:14][CH2:15][CH2:16][CH2:17][N:18]([CH2:33][CH3:34])[C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)=[CH:21][N:20]=2)=[CH:8][C:7]=1[CH3:31]
Reactant: CC=O
Reactant: COC(=O)COc1cc(OC)c(SCCCNc2ccc(-c3ccccc3)cn2)cc1C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: CCN(CCCSc1cc(C)c(OCC(=O)OC)cc1OC)c1ccc(-c2ccccc2)cn1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Compound 64B (300 mg, 0.66 mmol), acetaldehyde (32 mg, 0.73 mmol), sodium triacetoxyborohydride (211 mg, 0.994 mmol), and 57 □l acetic acid were added to 5 ml dichloroethane and stirred at room temperature for 3 days. 1 eq more of aldehyde, sodium triacetoxyborohydride, and acetic acid were added and stirred 3 h more. 10 ml 2N HCl was added followed by saturated sodium bicarbonate to pH ca. 8. The product was extracted into 20 ml, dried over sodium sulfate, decanted, concentrated. Liquid chromatography give the title compound as a white solid. MS m/z 481 (M+1).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([OH:12])=O.C(Cl)(=O)C(Cl)=O.C1(C)C=CC=CC=1.[C:26]1([CH:32]2[CH:36]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[NH:35][NH:34][C:33]2=[O:43])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CN(C=O)C.C(Cl)Cl.N1C=CC=CC=1>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([N:35]1[CH:36]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH:32]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:33](=[O:43])[NH:34]1)=[O:12]
Reactant: O=C(O)c1cc2ccccc2[nH]1
Reactant: O=C1NNC(c2ccccc2)C1c1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C1NN(C(=O)c2cc3ccccc3[nH]2)C(c2ccccc2)C1c1ccccc1
Yield: 44.4 %

Procedure:
Indole-2-carboxylic acid (1.35 g, 8.38 mmol), oxalyl chloride (4 mL), and DMF (3 drops) were added in order to 50 mL toluene, and stirred until gas evolution subsided and a homogeneous solution was obtained (c.20 min). Solvent was removed in vacuo, the residue taken up in CH2Cl2, and added to a solution of 4,5-diphenyl-3-pyrazolidinone (2.0 g, 8.40 mmol, 1.00 eq.) in 50 mL CH2Cl2 and 5 mL pyridine. After stirring overnight, the solution was washed with 1N HC1, dried over Na2SO4, and solvent removed in vacuo. The residual solid was stirred with CH2Cl2, filtered, and recrystallized from DMF:H2O to give 1.42 g (44%) white solid: mp 248°-50° C.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[CH:12]=[CH:13][N:14]=[C:7]1[CH:6]=[CH:5]2.[F:15][C:16]1[CH:17]=[C:18]([C:23]2([C:29]#[N:30])[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[CH:19]=[C:20]([SH:22])[CH:21]=1.CCN(C(C)C)C(C)C.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:15][C:16]1[CH:17]=[C:18]([C:23]2([C:29]#[N:30])[CH2:24][CH2:25][O:26][CH2:27][CH2:28]2)[CH:19]=[C:20]([S:22][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]2[CH:12]=[CH:13][N:14]=[C:7]2[CH:6]=[CH:5]3)[CH:21]=1
Reactant: N#CC1(c2cc(F)cc(S)c2)CCOCC1
Reactant: Ic1ccc2c(ccc3nccn32)c1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: N#CC1(c2cc(F)cc(Sc3ccc4c(ccc5nccn54)c3)c2)CCOCC1
Temperature: 80 °C

Procedure:
1g (230 mg, 0.82 mmol) and 4-(3-Fluoro-5-mercapto-phenyl)-tetrahydro-pyran-4-carbonitrile (1h, 230 mg, 0.99 mmol) were dissolved in 1,4-dioxane (10 mL) and degassed with N2 for 10 minutes. iPr2NEt (0.35 mL, 2.0 mmol), Pd2dba3 (20 mg, 0.02 mmol), and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (24 mg, 0.04 mmol) were added, and the mixture was degassed with N2 for an additional 10 minutes. The reaction was heated to 80° C. overnight, then cooled to room temperature, concentrated, and purified by silica gel chromatography to give the desired product, 1k.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:11]([OH:13])=[O:12])=[C:4]2[NH:10][CH:9]=[N:8][C:5]2=[N:6][CH:7]=1.OS(O)(=O)=O.[CH3:19]O>>[Br:1][C:2]1[C:3]([C:11]([O:13][CH3:19])=[O:12])=[C:4]2[NH:10][CH:9]=[N:8][C:5]2=[N:6][CH:7]=1
Reactant: O=C(O)c1c(Br)cnc2nc[nH]c12
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1c(Br)cnc2nc[nH]c12
Reaction time: 10 h
Yield: 70 %

Procedure:
Absolute methanol (30 ml) is added to 6-bromo-1H-imidazo[4,5-b]pyridine-7-carboxylic acid x208 (Zerenex; 2.2 g, 9.1 mmol). Concentrated H2SO4 (4 ml) is added to the obtained suspension at 0° C. The reaction mixture is refluxed under protection from the air moisture and vigorous stirring for 10 h. The reaction mixture is then evaporated to half-volume in the vacuum of a rotary evaporator and neutralized under cooling with ice with aqueous ammonia to pH 8-9. The formed precipitate is quickly separated by filtration, washed with ice-cold water (2×30 ml), and dried over P2O5 at 1 mmHg overnight to afford methyl 6-bromo-1H-imidazo[4,5-b]pyridine-7-carboxylate x209 (1.63 g).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([N:12]([CH2:34][CH:35]([CH3:37])[CH3:36])[C@H:13]1[CH2:18][C@@H:17]([C:19]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[O:20])[CH2:16][N:15]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:14]1)=[O:11].CS(O[CH2:43][CH2:44][C:45]1[S:46][CH:47]=[CH:48][CH:49]=1)(=O)=O.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[CH3:36][CH:35]([CH3:37])[CH2:34][N:12]([C:10]([C:2]1[N:3]([CH2:43][CH2:44][C:45]2[S:46][CH:47]=[CH:48][CH:49]=2)[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[N:1]=1)=[O:11])[C@H:13]1[CH2:18][C@@H:17]([C:19]([N:21]2[CH2:22][CH2:23][O:24][CH2:25][CH2:26]2)=[O:20])[CH2:16][N:15]([C:27]([O:29][C:30]([CH3:31])([CH3:32])[CH3:33])=[O:28])[CH2:14]1
Reactant: CS(=O)(=O)OCCc1cccs1
Reactant: CC(C)CN(C(=O)c1nc2ccccc2[nH]1)[C@H]1C[C@@H](C(=O)N2CCOCC2)CN(C(=O)OC(C)(C)C)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)CN(C(=O)c1nc2ccccc2n1CCc1cccs1)[C@H]1C[C@@H](C(=O)N2CCOCC2)CN(C(=O)OC(C)(C)C)C1
Temperature: 65 °C
Reaction time: 0.5 h
Yield: 85.6 %

Procedure:
tert-Butyl (3S,5R)-3-{(1H-benzimidazol-2-ylcarbonyl)(2-methylpropyl)amino}-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate (150 mg) was dissolved in dimethylformamide (10 ml), 2-(thiophen-2-yl)ethyl methanesulfonate (90 mg) and cesium carbonate (190 mg) were added and the mixture was stirred at 65° C. for 30 min. 2-Thiophen-2-ylethyl methanesulfonate (90 mg) was added, and the mixture was further stirred for 1 hr. The reaction mixture was concentrated under reduced pressure, diluted with water, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel chromatography, and a fraction eluted with ethyl acetate-hexane (1:9)-ethyl acetate was concentrated under reduced pressure to give the object product (156 mg).
Reaction SMILES: [N:1]1[C:14]2[NH:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[S:6][C:5]=2[N:4]=[CH:3][CH:2]=1.[OH:15]O>C(O)(=O)C>[N:1]1[C:14]2[NH:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[S:6](=[O:15])[C:5]=2[N:4]=[CH:3][CH:2]=1
Reactant: c1ccc2c(c1)Nc1nccnc1S2
Reactant: OO
Solvent: CC(=O)O
Product: O=S1c2ccccc2Nc2nccnc21
Reaction time: 0.5 h

Procedure:
To 1,4-diaza-10H-phenothiazine (1 g, 5 mmoles) in acetic acid (15 ml) was added 50% hydrogen peroxide (1 ml). The mixture was stirred at 55° for 30 minutes. The mixture was evaporated to a small volume and the title compound crystallized out. The crystals were filtered, washed with acetic acid and air dried to yield 983 mg of the title compound, m.p. 261°-263°.