Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]12[C:10](=O)OC(=O)[C:2]=1[CH2:3][CH2:4][CH2:5][CH2:6]2.C12C(=O)O[C:18](=[O:19])[CH:13]1CCCC2.C1(=O)OC(=O)C=C1C.C12CC(CC1)C1C(OC(=O)C21)=O.ClC12C(Cl)(Cl)C(Cl)(C(Cl)=C1Cl)C1C(OC(=O)C21)=O.CC1CC2C(=O)OC(=O)C2CC=1.CC1C2CC(C=1)C1C(OC(=O)C21)=O.C12CC(C=C1)C1C(OC(=O)C21)=O>>[O:19]1[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=2[CH2:10][CH2:13][CH2:18]1
Reactant: O=C1OC(=O)C2CCCCC12
Reactant: O=C1OC(=O)C2=C1CCCC2
Agent: CC1=CC(=O)OC1=O
Agent: CC1=CC2CC1C1C(=O)OC(=O)C21
Agent: CC1=CCC2C(=O)OC(=O)C2C1
Product: c1ccc2c(c1)CCCO2

Procedure:
The same reaction and isolation procedures as Synthesis Example 85 were followed except that 1.52 g of 1-cyclohexene-1,2-dicarboxylic anhydride, 1.54 g of cyclohexane-1,2-dicarboxylic anhydride, 1.12 g of citraconic anhydride, 1.66 g of norbornane-2,3-dicarboxylic anhydride, 3.71 g of 1,4,5,6,7,7-hexachloro-5-norbornene-2,3-dicarboxylic anhydride, 1.66 g of 4-methyl-4-cyclohexene-1,2-dicarboxylic anhydride or 1.78 g of 5-methyl-5-norbornene-2,3-dicarboxylic anhydride was used in lieu of 1.64 g of 5-norbornene-2,3-dicarboxylic anhydride to give the corresponding 3,4-dihydro-2H-benzopyran derivative. The results are given in Table 12. ##STR109##
Reaction SMILES: CN(C)C=O.[OH:6][C:7]1[CH:8]=[CH:9][C:10]2[CH:14]=[C:13]([CH2:15][N:16]3[C:24](=[O:25])[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:17]3=[O:26])[S:12][C:11]=2[CH:27]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:34](Br)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>O.C(OCC)(=O)C>[CH2:34]([O:6][C:7]1[CH:8]=[CH:9][C:10]2[CH:14]=[C:13]([CH2:15][N:16]3[C:17](=[O:26])[C:18]4[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=4)[C:24]3=[O:25])[S:12][C:11]=2[CH:27]=1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: O=C1c2ccccc2C(=O)N1Cc1cc2ccc(O)cc2s1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: O=C1c2ccccc2C(=O)N1Cc1cc2ccc(OCc3ccccc3)cc2s1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 92.2 %

Procedure:
To an N,N-dimethylformamide (3 mL) solution of 2-(6-hydroxy-benzo[b]thiophen-2-ylmethyl)-isoindole-1,3-dione (121 mg, 0.391 mmol) were added potassium carbonate (162 mg, 1.17 mmol) and benzyl bromide (70 μL, 0.587 mmol). The mixture was stirred at 100° C. for 30 minutes. The reaction mixture was distributed between ethyl acetate and water. The organic layer was washed with water followed by drying over anhydrous magnesium sulfate and filtering. The filtrate was concentrated under a reduced pressure and the resulting residue was purified by silica gel chromatography (hexane:ethyl acetate=10:1 to 4:1 and then 1:1) to obtain the title compound (144 mg, 92%).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][OH:12])=[CH:3][CH:2]=1.ClC1C=CC=C(C(OO)=[O:21])C=1>C(Cl)Cl>[O-:21][N+:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][OH:12])=[CH:3][CH:2]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: OCc1ccnc2ccccc12
Solvent: ClCCl
Product: [O-][n+]1ccc(CO)c2ccccc21
Temperature: 0 °C
Reaction time: 17.5 h

Procedure:
To a solution of quinolin-4-ylmethanol (0.20 g, 1.26 mmol) dissolved in CH2Cl2 (10 mL), which was cooled to 0° C., was added m-chloroperbenzoic acid (57-86% w/w in H2O, 0.50 mg) in one portion. The reaction was allowed to slowly warm to room temperature while stirring. After 17.5 h, the resulting solid was filtered and washed with CH2Cl2 to yield (1-oxidoquinolin-4-yl)methanol as a white solid. MS (ES+): 176 [MH+].
Reaction SMILES: O=C1[CH:10]2[CH:5]([CH:6]3C[CH:9]2[CH:8]=[CH:7]3)[CH:4]([NH:12][CH:13]([CH2:17][CH:18]([CH3:20])[CH3:19])[C:14]([O-:16])=[O:15])O1.[ClH:21]>O>[ClH:21].[CH2:4]([NH:12][C@H:13]([C:14]([OH:16])=[O:15])[CH2:17][CH:18]([CH3:20])[CH3:19])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CC(C)CC(NC1OC(=O)C2C3C=CC(C3)C12)C(=O)[O-]
Agent: Cl
Solvent: O
Product: CC(C)C[C@H](NCc1ccccc1)C(=O)O
Temperature: 20 °C
Reaction time: 1 h

Procedure:
A mixture of 1 g of the product of Example 2, 8 ml of demineralized water and 0.8 ml of hydrochloric acid was stirred at 20° C. for one hour and was then heated at 60° C. for one hour and was cooled at 20° C. The mixture was diluted with 15 ml of water and was then extracted with methylene chloride. The organic phase was washed with aqueous N sodium hydroxide solution and with water until the wash water was neutral, dried and evaporated to dryness under reduced pressure. The residue was taken up in 10 ml of ether and a stream of hydrogen chloride was slowly bubbled therethrough. The mixture was vacuum filtered to obtain 350 mg of benzyl L-leucine hydrochloride melting at 135° C. and having a specific rotation of [α]D20 =-5.5°±1° (c=1% in 0.1N hydrochloric acid).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])C.[CH3:8][N:9]1[CH2:14][CH2:13][CH:12]([C:15]2[CH:21]=[CH:20][C:18]([NH2:19])=[C:17]([O:22][CH:23]([CH3:25])[CH3:24])[CH:16]=2)[CH2:11][CH2:10]1>C(O)=O>[CH3:8][N:9]1[CH2:14][CH2:13][CH:12]([C:15]2[CH:21]=[CH:20][C:18]([NH:19][CH:1]=[O:3])=[C:17]([O:22][CH:23]([CH3:25])[CH3:24])[CH:16]=2)[CH2:11][CH2:10]1
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)Oc1cc(C2CCN(C)CC2)ccc1N
Solvent: O=CO
Product: CC(C)Oc1cc(C2CCN(C)CC2)ccc1NC=O
Reaction time: 1 h
Yield: 74.9 %

Procedure:
A solution of 12.3 g of acetic anhydride is added slowly to 19 ml of formic acid at ambient temperature. After one hour of stirring, a solution of 6.0 g of 4-(1-methylpiperidin-4-yl)-2-(propan-2-yloxy)aniline in 28 ml of formic acid is added dropwise. The mixture is stirred at ambient temperature for 2 h and then concentrated under vacuum and taken up with water. The aqueous phase is neutralized with a saturated sodium bicarbonate solution and extracted three times with 100 ml of dichoromethane. The organic phases are dried over magnesium sulfate, filtered and concentrated under vacuum. The crude product is triturated with ethyl ether and the solid is filtered off, so as to obtain 5.0 g of N-[4-(1-methylpiperidin-4-yl)-2-(propan-2-yloxy)phenyl]formamide.
Reaction SMILES: C[C@@H](NC)[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O[C@H]3OC[C@@](O)(C)[C@H](NC)[C@H]3O)[C@H](N)C[C@@H]2N)[C@H](N)CC1.[CH:34]1[C:39](N=C=S)=[CH:38][C:37]2[C:43]([O:45][C:46]3([C:56]4[CH:57]=[CH:58][C:59]([OH:61])=[CH:60][C:55]=4[O:54][C:48]4[CH:49]=[C:50]([OH:53])[CH:51]=[CH:52][C:47]3=4)[C:36]=2[CH:35]=1)=[O:44]>C(=O)([O-])[O-].[Na+].[Na+].C(=O)(O)[O-]>[CH:34]1[CH:39]=[CH:38][C:37]([C:43]([OH:45])=[O:44])=[C:36]([C:46]2[C:47]3[CH:52]=[CH:51][C:50]([OH:53])=[CH:49][C:48]=3[O:54][C:55]3[C:56]=2[CH:57]=[CH:58][C:59]([CH:60]=3)=[O:61])[CH:35]=1
Reactant: O=C1OC2(c3ccc(O)cc3Oc3cc(O)ccc32)c2ccc(N=C=S)cc21
Agent: CN[C@@H]1[C@@H](O)[C@@H](O[C@@H]2[C@@H](O)[C@H](O[C@H]3O[C@H]([C@@H](C)NC)CC[C@H]3N)[C@@H](N)C[C@H]2N)OC[C@]1(C)O
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Product: O=C(O)c1ccccc1-c1c2ccc(=O)cc-2oc2cc(O)ccc12
Reaction time: 2 h

Procedure:
Gentamicin (1mM) and fluorescein isothiocyanate (FITC) (1.25mM) were allowed to react in 0.05M sodium carbonate/bicarbonate buffer, pH 9.0, for 2 hours at room temperature. 2ml of the reaction mixture was applied to a column (1 × 97cm) of G-15 grade Sephadex and eluted with carbonate/bicarbonate buffer as above, with a flow rate of 1.8ml/h. Column fractions (1.8ml) were assayed for gentamicin content by radio-immunoassay and for fluorescein content by fluorimetry. FIG. 1 of the accompanying drawings shows the result. Unreacted gentamicin left the column first. The FTC-G product exited next, well separated from the gentamicin peak. Unreacted FITC was very strongly held on the G-15 column and was not eluted.
Reaction SMILES: C1(C2C3C(=CC=CC=3)C=CC=2)C2C(=CC=CC=2)C=CC=1.O1CCN=C1.[CH3:26][C:27](=[C:36]([CH3:38])[CH3:37])[CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[OH:35].C1(=O)C=CC(=O)C=C1>[Pd].CO>[C:36]([C@:27]1([CH3:26])[CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[O:35]1)([CH3:38])=[CH2:37]
Reactant: CC(C)=C(C)Cc1ccccc1O
Agent: [Pd]
Agent: C1=NCCO1
Agent: O=C1C=CC(=O)C=C1
Solvent: CO
Product: C=C(C)[C@]1(C)Cc2ccccc2O1
Temperature: 60 °C
Reaction time: 20 h

Procedure:
A polymer-carrying optically active binaphthyl type oxazoline compound-palladium complex (palladium content, 0.02 mmol), 35.2 mg (0.2 mmol) of 2-(2,3-dimethyl-2-butenyl)-phenol and 86.4 mg (0.8 mmol) of benzoquinone were added to 1 ml of methanol and then stirred at 60° C. for 20 hours. After cooling to room temperature, the resin was filtered and washed twice with 1 ml of methanol. The solution was concentrated under a reduced pressure, and the resulting residue was purified by a silica gel column chromatography (hexane/ethyl acetate=95/5) to obtain (S)-2-isopropenyl-2-methyl-2,3-dihydrobenzofuran as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([CH3:26])[C:11]=1[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][O:21][CH3:22])=[C:15]([CH:23]([CH3:25])[CH3:24])[CH:14]=1)[C:5](OC)=[O:6].CC(C[AlH]CC(C)C)C>C1COCC1>[CH3:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([CH3:26])[C:11]=1[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][O:21][CH3:22])=[C:15]([CH:23]([CH3:24])[CH3:25])[CH:14]=1)[CH2:5][OH:6]
Reactant: COCOc1ccc(Cc2c(C)cc(C(=O)OC)cc2C)cc1C(C)C
Agent: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Product: COCOc1ccc(Cc2c(C)cc(CO)cc2C)cc1C(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 81.3 %

Procedure:
To a mixture of methyl 3,5-dimethyl-4-(3′-iso-propyl-4′-methoxymethoxybenzyl)benzoate (1.00 g, 2.81 mmol) in THF (11.3 mL) at 0° C. was added a solution of DIBAL-H (8.44 mL, 8.44 mmol, 1.0 M solution in hexanes). The reaction mixture was stirred at room temperature for 16 h, quenched with cold 1 N HCl and diluted with ethyl acetate. The organic layer was washed with 1 N HCl and brine, dried over Na2SO4, filtered and concentrated under reduced pressure to afford 3,5-dimethyl-4-(3′-iso-propyl-4′-methoxymethoxy-benzyl)benzyl alcohol as an off-white solid (0.75 g, 81.3%): 1H NMR (300 MHz, DMSO-d6): δ 7.54 (s, 2H), 6.81 (m, 2H), 6.40 (m, 1H), 5.51 (m, 1H), 4.54 (d, J=6.0 Hz, 2H), 3.75 (s, 3H), 3.21 (m, 1H), 1.13 (d, J=6.0 Hz, 6H); TLC conditions: Uniplate silica gel, 250 microns; Mobile phase=ethyl acetate-hexanes (15:85); Rf=0.27.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[C:4]1[CH:9]=[C:8]([OH:10])[C:7]([CH3:11])=[C:6](O)[C:5]=1[O:13][C:14]1[C:19]([CH:20]=[O:21])=[C:18]([OH:22])[CH:17]=[C:16]([CH3:23])[C:15]=1[C:24]([OH:26])=[O:25].C(OC(=O)C)(=O)C>>[CH3:1][O:2][C:3]([C:4]1[C:5]2[O:13][C:14]3[C:19]([CH:20]=[O:21])=[C:18]([OH:22])[CH:17]=[C:16]([CH3:23])[C:15]=3[C:24](=[O:25])[O:26][C:6]=2[C:7]([CH3:11])=[C:8]([OH:10])[CH:9]=1)=[O:27]
Reactant: COC(=O)c1cc(O)c(C)c(O)c1Oc1c(C=O)c(O)cc(C)c1C(=O)O
Solvent: CC(=O)OC(C)=O
Product: COC(=O)c1cc(O)c(C)c2c1Oc1c(C=O)c(O)cc(C)c1C(=O)O2
Temperature: 145 °C
Yield: 30 %

Procedure:
Dry 2-(3-methyl-6-formyl-2-carboxy-5-hydroxy-phenoxy)-3,5-dihydroxy-4-methyl-benzoic acid methyl ester (1 mmol) was added to acetic anhydride (15 ml) and the resulting mixture was refluxed for five hours at 145° C. The excess acetic anhydride was distilled out. The residue was added with crushed ice and then extracted with ethyl acetate. The combined extracts were washed successively with saturated NH4Cl solution and water, dried over anhydrous Na2SO4, concentrated and purified by column chromatography to afford 4-formyl-3,8-dihydroxy-1,9-dimethyl-11-oxo-11H-dibenzo[b,e][1,4]dioxepine-6-carboxylic acid methyl ester (30%).
Reaction SMILES: B(F)(F)F.CCOCC.[BH4-].[Na+].[CH3:12][O:13][C:14]([C:16]1[CH:21]=[CH:20][C:19]([C:22]2[O:23][C:24]([CH3:32])=[C:25]([CH2:27][CH2:28][C:29](O)=[O:30])[N:26]=2)=[CH:18][CH:17]=1)=[O:15]>O1CCCC1>[OH:30][CH2:29][CH2:28][CH2:27][C:25]1[N:26]=[C:22]([C:19]2[CH:18]=[CH:17][C:16]([C:14]([O:13][CH3:12])=[O:15])=[CH:21][CH:20]=2)[O:23][C:24]=1[CH3:32]
Reactant: COC(=O)c1ccc(-c2nc(CCC(=O)O)c(C)o2)cc1
Agent: FB(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: COC(=O)c1ccc(-c2nc(CCCO)c(C)o2)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
Boron trifluoride etherate (4 g) was added dropwise with stiffing to a mixture of sodium borohydride (720 mg, 19.03 mmol, 2.02 equiv) in tetrahydrofuran (35 mL) maintained under nitrogen at 0° C. The resulting solution was warmed to room temperature and stirred for 2 h. The above mixture was cooled to 0° C. then 3-[2-[4-(methoxycarbonyl)-phenyl]-5-methyl-1,3-oxazol-4-yl]propanoic acid (2.72 g, 9.40 mmol, 1.00 equiv) was added in several batches. The reaction mixture was stirring at room temperature overnight and then quenched with 5 mL of methanol and 60 mL of water. The resulting solution was extracted with 50 mL of ethyl acetate. The organic layer was dried over anhydrous calcium chloride and concentrated under vacuum to give 2.2 g (85%) of methyl 4-[4-(3-hydroxypropyl)-5-methyl-1,3-oxazol-2-yl]benzoate as a white solid. LC-MS: (ES, m/z): 276 [M+H]+, 146, 115.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[C:12]([C:14]1[C:15]([N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)=[N:16][CH:17]=[C:18]([C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)[CH:19]=1)#[N:13]>C(Cl)(Cl)Cl>[C:12]([C:14]1[C:15]([N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)=[N:16][CH:17]=[C:18]([C:20]2[CH:21]=[CH:22][N+:23]([O-:9])=[CH:24][CH:25]=2)[CH:19]=1)#[N:13]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: N#Cc1cc(-c2ccncc2)cnc1N1CCOCC1
Solvent: ClC(Cl)Cl
Product: N#Cc1cc(-c2cc[n+]([O-])cc2)cnc1N1CCOCC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
1.1 g M-chloroperbenzoic acid is added at room temperature with stirring to a solution of 1.3 g 3-cyano-2-morpholino-5-(pyrid-4-yl)-pyridine in 20 ml chloroform. The reaction mixture is stirred for 48 hours at room temperature. Subsequently it is extracted with a bicarbonate solution and the chloroform phase is evaporated under vacuum. The residue is treated with water, filtered off with suction, dried at 110° C., and crystallized from a mixture of isopropanol and ethanol. Yield: 1.0 g (73% of the theoretical yield), with a melting point of 233° C.-235° C.
Reaction SMILES: [CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:29]([NH2:31])=[O:30])[CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([CH:27]=O)[CH:22]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2].[NH2:32][CH2:33][C:34]1[CH:35]=[C:36]([OH:41])[C:37]([OH:40])=[CH:38][CH:39]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClC(Cl)C>[OH:41][C:36]1[CH:35]=[C:34]([CH2:33][NH:32][CH2:27][C:23]2[CH:22]=[C:21]([C:18]3[CH:19]=[C:20]4[C:15](=[C:16]([C:29]([NH2:31])=[O:30])[CH:17]=3)[NH:14][CH:13]=[C:12]4[CH:9]3[CH2:10][CH2:11][N:6]([S:3]([CH2:1][CH3:2])(=[O:5])=[O:4])[CH2:7][CH2:8]3)[CH:26]=[CH:25][CH:24]=2)[CH:39]=[CH:38][C:37]=1[OH:40]
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cccc(C=O)c4)cc23)CC1
Reactant: NCc1ccc(O)c(O)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cccc(CNCc5ccc(O)c(O)c5)c4)cc23)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 15.1 %

Procedure:
To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-formylphenyl)-1H-indole-7-carboxamide (50 mg, 0.114 mmol) in dichloroethane (2 mL) was added 4-(aminomethyl)-1,2-benzenediol (12.1 mg, 0.087 mmol). The reaction solution was stirred at ambient temperature for 10 min prior to addition of NaBH(OAc)3 (58 mg, 0.261 mmol). The resulting mixture was shaken overnight at ambient temperature after which time the solvent was removed under reduced pressure. The crude product was purified by reverse phase HPLC (water/CH3CN, 0.1% TFA 10-90%) to give the title compound (7.4 mg, 12%).
Reaction SMILES: C(O[C:4](=[O:16])[CH2:5][N:6]1[CH2:11][CH2:10][N:9]([CH2:12][CH3:13])[C:8](=[O:14])[C:7]1=[O:15])C.O.[NH2:18][NH2:19]>C(O)C>[CH2:12]([N:9]1[CH2:10][CH2:11][N:6]([CH2:5][C:4]([NH:18][NH2:19])=[O:16])[C:7](=[O:15])[C:8]1=[O:14])[CH3:13]
Reactant: NN
Reactant: CCOC(=O)CN1CCN(CC)C(=O)C1=O
Solvent: CCO
Solvent: O
Product: CCN1CCN(CC(=O)NN)C(=O)C1=O
Yield: 77 %

Procedure:
As described for example 112a, (4-ethyl-2,3-dioxo-piperazin-1-yl)-acetic acid ethyl ester in ethanol was reacted with hydrazine hydrate (1.2 equivalents) and the resulting mixture heated under reflux for 16 h. The precipitated product was filtered off and dried to afford the title compound as a white solid (yield: 77%). MS: m/e=215.4 [M+H]+.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[CH:5][C:6]2[N:7]([C:9]([CH2:20]Cl)=[C:10]([C:12]3[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=3)[N:11]=2)[CH:8]=1.[Cl:22][C:23]1[CH:28]=[C:27]([CH3:29])[N:26]=[C:25]([NH2:30])[N:24]=1>>[Cl:2][C:3]1[CH:4]=[CH:5][C:6]2[N:7]([C:9]([CH2:20][NH:30][C:25]3[N:24]=[C:23]([Cl:22])[CH:28]=[C:27]([CH3:29])[N:26]=3)=[C:10]([C:12]3[CH:13]=[CH:14][C:15]([C:16]#[N:17])=[CH:18][CH:19]=3)[N:11]=2)[CH:8]=1
Reactant: Cc1cc(Cl)nc(N)n1
Reactant: N#Cc1ccc(-c2nc3ccc(Cl)cn3c2CCl)cc1
Agent: Cl
Product: Cc1cc(Cl)nc(NCc2c(-c3ccc(C#N)cc3)nc3ccc(Cl)cn23)n1

Procedure:
The title compound was prepared according to Method A and the experimentals described for compound 139 from 4-(6-chloro-3-(chloromethyl)imidazo[1,2-a]pyridin-2-yl)benzonitrile hydrochloride and 4-chloro-6-methylpyrimidin-2-amine. m/e+ 409.0, 411.0 for C20H14Cl2N6; H-NMR (400 MHz, CDCl3) 8.80 (s, 1H), 7.953 (d, J=8.277 Hz, 2H), 7.750 (d, J=8.093 Hz, 2H), 7.593 (d, J=9.533 Hz, 1H), 7.234 (d, J=9.551 Hz, 1H), 6.545 (s, 1H), 5.257 (s, NH), 5.03 (d, J=5.498 Hz, 2H, D, CH2), 2.311 (s, 6H, D, 2CH3) ppm.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:12][CH2:13][CH2:14][Cl:15])[CH:6]=1)=O.[NH2:16][C:17]1[CH:22]=[C:21]([CH3:23])[CH:20]=[CH:19][N:18]=1>C(O)C>[Cl:15][CH2:14][CH2:13][CH2:12][O:11][C:7]1[CH:6]=[C:5]([C:3]2[N:16]=[C:17]3[CH:22]=[C:21]([CH3:23])[CH:20]=[CH:19][N:18]3[CH:2]=2)[CH:10]=[CH:9][CH:8]=1
Reactant: Cc1ccnc(N)c1
Reactant: O=C(CBr)c1cccc(OCCCCl)c1
Solvent: CCO
Product: Cc1ccn2cc(-c3cccc(OCCCCl)c3)nc2c1
Temperature: 25 °C
Yield: 48.7 %

Procedure:
A solution of the product of Step B (2.6 g) and 2-amino-4-picoline (0.96 g) in ethanol (10 mL) was heated at 73° C. for 2 hours. The reaction mixture was cooled to ambient temperature and the solvent evaporated in vacuo. The residue was dissolved in dichloromethane (75 mL), washed with saturated sodium bicarbonate solution (2×75 mL), brine (75 mL), dried over magnesium sulfate, filtered and evaporated. The residue was purified via silica gel chromatography (ethyl acetate/hexane) to give the title compound (1.3 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4](=[CH:9][C:10]1[CH:11]=[C:12]2[C:16](=[C:17]([CH3:19])[CH:18]=1)[NH:15][N:14]=[CH:13]2)[CH2:5][C:6]([OH:8])=[O:7].C>C(OCC)(=O)C.CO>[CH3:1][O:2][C:3](=[O:20])[CH:4]([CH2:9][C:10]1[CH:11]=[C:12]2[C:16](=[C:17]([CH3:19])[CH:18]=1)[NH:15][N:14]=[CH:13]2)[CH2:5][C:6]([OH:8])=[O:7]
Reactant: COC(=O)C(=Cc1cc(C)c2[nH]ncc2c1)CC(=O)O
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)C(CC(=O)O)Cc1cc(C)c2[nH]ncc2c1
Yield: 100 %

Procedure:
A suspension of 2-(7-methyl-1H-indazol-5-ylmethylene)-succinic acid 1-methyl ester (0.4440 g, 1.62 mmol) and 10% palladized charcoal (0.04 g) in ethyl acetate (15 mL) and methanol (5 mL) was hydrogenated in a Parr apparatus overnight at 50 psi. The reaction mixture was filtered through a pad of celite and the filtrate evaporated to give the desired product as a yellow solid (100%). Mass spec.: 277 (MH)+.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7](C#C)=[CH:6][CH:5]=1)[CH2:2][CH3:3].[CH2:12](SC1C=CC(I)=CC=1)[CH2:13][CH2:14][CH2:15][CH3:16]>C(NCC)C.[Cu]I>[C:4]1([C:1]#[C:2][C:3]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: C#Cc1ccc(CCC)cc1
Reactant: CCCCCSc1ccc(I)cc1
Agent: [Cu]I
Solvent: CCNCC
Product: C(#Cc1ccccc1)c1ccccc1
Temperature: 20 °C
Reaction time: 16 h
Yield: 123.4 %

Procedure:
The product from step 2.4 (2.82 g) and the product from step 2.2 (6.0 g) were mixed in diethylamine (44 ml). Copper (I) iodide (0.026 g) and dichloro di(triphenylphosphine) palladium (0) (0.193 g) were then added and the mixture was then stirred at 20° C. under argon for 16 hrs. Purification by chromatography gave 4.3 g of tolane product, mpt. 43° C.
Reaction SMILES: [C:1]([O:4][CH:5]([CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:6][CH2:7][CH:8]1[CH2:12][CH2:11][CH2:10][C:9]1=[O:13])(=[O:3])[CH3:2].[C:19](OC(C)=C)(=[O:21])[CH3:20].C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)=O>[C:19]([O:13][C:9]1[CH2:10][CH2:11][CH2:12][C:8]=1[CH2:7][CH2:6][CH:5]([O:4][C:1](=[O:3])[CH3:2])[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])(=[O:21])[CH3:20]
Reactant: C=C(C)OC(C)=O
Reactant: CCCCCC(CCC1CCCC1=O)OC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Product: CCCCCC(CCC1=C(OC(C)=O)CCC1)OC(C)=O

Procedure:
2-(3-Acetoxyoctyl)cyclopentanone (85 g.) [prepared as described in (d) above], isopropenyl acetate (125 ml.) and p-toluenesulphonic acid (2 g.) were refluxed for 24 hours allowing the acetone formed during the reaction to slowly distil from the head of a Dufton column. The excess isopropenyl acetate was then distilled off and the residue cooled, shaken with 2N sodium carbonate solution and extracted with diethyl ether. The combined ether extracts were dried over anhydrous magnesium sulphate and the ether removed in vacuo. Distillation of the residue gave 1-acetoxy-2-(3-acetoxyoctyl)cyclopent-1-ene (85 g.), b.p. 108°-110° C./0.03 mm.Hg; nD26 = 1.459.
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]([C:9]1[CH:10]=[CH:11][C:12]2[O:16][C:15]([CH2:17][C:18]3[C:26]([O:27][CH3:28])=[CH:25][C:24]([CH3:29])=[C:23]4[C:19]=3[CH:20]=[CH:21][N:22]4[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])=[N:14][C:13]=2[CH:37]=1)#[N:8].C1OCCOCCOCCOCCOCCOC1.Br[CH2:57][C:58]([O:60][CH3:61])=[O:59]>C1COCC1>[C:7]([C:9]1[CH:10]=[CH:11][C:12]2[O:16][C:15]([CH:17]([C:18]3[C:26]([O:27][CH3:28])=[CH:25][C:24]([CH3:29])=[C:23]4[C:19]=3[CH:20]=[CH:21][N:22]4[C:30]([O:32][C:33]([CH3:34])([CH3:36])[CH3:35])=[O:31])[CH2:57][C:58]([O:60][CH3:61])=[O:59])=[N:14][C:13]=2[CH:37]=1)#[N:8]
Reactant: COC(=O)CBr
Reactant: COc1cc(C)c2c(ccn2C(=O)OC(C)(C)C)c1Cc1nc2cc(C#N)ccc2o1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)CC(c1nc2cc(C#N)ccc2o1)c1c(OC)cc(C)c2c1ccn2C(=O)OC(C)(C)C
Reaction time: 0.25 h

Procedure:
To a mixture of potassium tert-butoxide (108 mg, 0.958 mmol) in THF (0.715 mL) at −78° C. under nitrogen was added tert-butyl 4-((5-cyanobenzo[d]oxazol-2-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (Example 144-A) (200 mg, 0.479 mmol) in THF (4.3 mL) under nitrogen. After stirring for 15 min a solution of 18-crown-6 (12.66 mg, 0.048 mmol) in THF (1.430 mL) was added to the mixture at the same temperature and stirred for another 15 min. Then a solution of methyl bromoacetate (0.618 mL, 6.71 mmol) in THF (0.715 mL) was degassed and added dropwise and stirred at the same temp for 10 min. The reaction mixture was quenched with a saturated solution of ammonium chloride, extracted with EtOAc (2×), passed through a phase separator and concentrated to give the title compound. MS (ESI+) m/z 490.32 (M+H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[F:14][C:15]1[CH:16]=[CH:17][C:18]([CH3:25])=[C:19]([S:21](Cl)(=[O:23])=[O:22])[CH:20]=1>C(OCC)C.CCOC(C)=O.C([O-])(O)=O.[Na+]>[F:14][C:15]1[CH:16]=[CH:17][C:18]([CH3:25])=[C:19]([S:21]([N:1]2[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)(=[O:23])=[O:22])[CH:20]=1
Reactant: Cc1ccc(F)cc1S(=O)(=O)Cl
Reactant: C1CNCCN1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: Cc1ccc(F)cc1S(=O)(=O)N1CCNCC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 55.4 %

Procedure:
To a stirred suspension of piperazine (28.4 g, 288 mmol) in triethylamine (42 mL, 300 mmol) and diethyl ether (500 mL) that was cooled to 0° C. was added dropwise a solution of 5-fluoro-2-methylbenzene sulfonylchloride (30 g, 144 mmol) dissolved in diethyl ether (50 mL). The resulting mixture was stirred at room temp for 2 h then diluted with EtOAc and saturated aqueous NaHCO3. The organic phase was washed with water, brine and dried (Na2SO4). Concentration gave the title compound as a white solid (20.6 g, 55% yield). 1H NMR (300 MHz, CDCl3) δ: 7.57 (1H, dd, J=8.6, 2.7 Hz), 7.25 (1H, dd, J=8.4, 5.1 Hz), 7.12 (1H, td, J=8.1,2.8 Hz), 3.13-3.10 (4H, m), 2.98-2.85 (4H, m), 2.55 (3H, s), 1.69 (1H, bs). LCMS (M+H) calcd for C11H16FN2O2S: 259.09; found: 259.18.