Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]1[C:8]([S:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[F:16])=[CH:7][CH:6]=[CH:5][C:4]=1[CH:17]([CH3:20])[C:18]#N.C(O)(=[O:23])C>I>[CH3:18][CH:17]1[C:4]2[CH:5]=[CH:6][CH:7]=[C:8]([S:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[F:16])[C:3]=2[O:2][C:20]1=[O:23]
Reactant: COc1c(Sc2ccccc2F)cccc1C(C)C#N
Reactant: CC(=O)O
Agent: I
Product: CC1C(=O)Oc2c(Sc3ccccc3F)cccc21

Procedure:
A solution of 2-[2-methoxy-3-(2-fluorophenylthio)phenyl]propionitrile (3.2 g) in hydriodic acid (58%, 20 ml) and acetic acid (40 ml) was refluxed under heating for 20 hours, and acetic acid was distilled off under reduced pressure. To the residue were added water and aqueous sodium bicarbonate, and the mixture was extracted with diethyl ether. The extract was washed with dil. aqueous sodium hydrogen sulfite and water in turn, dried and evaporated under reduced pressure. The oily residue (2 g) was purified by column chromatography (silica gel 40 g, toluene) to give oily 3-methyl-7-(2-fluorophenylthio)-2,3-dihydrobenzofuran-2-one (1.3 g).
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[C:8]([CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[CH:7]=[CH:6][C:5]=1[OH:16])[CH2:2][CH3:3].C(=O)([O-])[O-].[K+].[K+].Br[CH2:24][CH2:25][CH2:26][O:27][C:28]1[CH:29]=[C:30]([CH:38]=[CH:39][CH:40]=1)[CH:31]([OH:37])[C:32]([O:34][CH2:35][CH3:36])=[O:33]>CN(C=O)C>[CH2:1]([C:4]1[CH:9]=[C:8]([CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[CH:7]=[CH:6][C:5]=1[O:16][CH2:24][CH2:25][CH2:26][O:27][C:28]1[CH:29]=[C:30]([CH:38]=[CH:39][CH:40]=1)[CH:31]([OH:37])[C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:2][CH3:3]
Reactant: CCCc1cc(C2CCCCC2)ccc1O
Reactant: CCOC(=O)C(O)c1cccc(OCCCBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCc1cc(C2CCCCC2)ccc1OCCCOc1cccc(C(O)C(=O)OCC)c1

Procedure:
A solution of 2-propyl-4-cyclohexylphenol (0.9 g) (as prepared in Step A), potassium carbonate (0.69 g) and ethyl 3-(3-bromopropoxy)mandelate (1.18 g) in DMF (30 mL) was stirred at 40° C. for 30 h. The reaction mixture was partitioned between ethyl acetate and 1.0 N HCl. The organic layer was washed twice with water, once with brine and then dried over sodium sulfate. The organic layer was then filtered and the solvent remove in vacuo. The resulting oil was chromatographed on silica gel, using ethyl acetate/hexane to yield the titled compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].C[Al](C)C.C([O:15][C:16]([C:18]1[CH:23]=[C:22]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)[CH:21]=[C:20]([CH3:31])[N:19]=1)=O)C>O1CCOCC1.CCCCCC>[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][C:16]([C:18]2[CH:23]=[C:22]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)[CH:21]=[C:20]([CH3:31])[N:19]=2)=[O:15])[CH:6]=[CH:7][CH:8]=1
Reactant: CCOC(=O)c1cc(-c2ccc(F)cc2)cc(C)n1
Reactant: Nc1cccc(Cl)c1
Agent: C[Al](C)C
Solvent: CCCCCC
Solvent: C1COCCO1
Product: Cc1cc(-c2ccc(F)cc2)cc(C(=O)Nc2cccc(Cl)c2)n1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 73.9 %

Procedure:
To a solution of 113 μl (138 mg, 1.08 mmol, 4.0 equiv.) of 3-Chloroaniline in 7 ml of dry dioxane were added 540 μl (1.08 mmol, 4.0 equiv.) of a 2M solution of trimethylaluminium in hexane. The solution was stirred for 45 min at room temperature. Then a solution of 70.0 mg (0.27 mmol) of 4-(4-Fluoro-phenyl)-6-methyl-pyridine-2-carboxylic acid ethyl ester in 1 ml of dry dioxane was added and the reaction was heated to 100° C. for 1 h. The reaction was quenched by cautious addition of 0.7 ml of water. Then approximately 1 g of anhydrous sodium sulfate were added to bind the water and the mixture was stirred vigorously for 5 min. The mixture was diluted by addition of 10 ml of methylenene chloride and filtered over Speedex filter aid which was washed with methylene chloride. The filtrate was concentrated in vaccuo and the residue (248 mg orange solid) was purified by flash chromatography (heptane/ethyl acetate 4:1) to yield the title compound (68.0 mg, 74%) as a crystalline white solid, MS (ISP): m/e=341.0, 343.0 (M+H)+.
Reaction SMILES: [CH2:1]([C:5]1[C:6](=[O:23])[O:7][C:8]2[CH:15]=[C:14]([O:16][CH3:17])[C:13]([O:18][CH2:19][CH2:20][CH2:21]Cl)=[CH:12][C:9]=2[C:10]=1[CH3:11])[CH2:2][CH2:3][CH3:4].[C:24]1([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(O)(C)C.C([O-])(=O)/C=C/C([O-])=O>O.CC(C)=O.CC(OC)(C)C>[CH2:1]([C:5]1[C:6](=[O:23])[O:7][C:8]2[CH:15]=[C:14]([O:16][CH3:17])[C:13]([O:18][CH2:19][CH2:20][CH2:21][N:33]3[CH2:34][CH2:35][N:30]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH2:31][CH2:32]3)=[CH:12][C:9]=2[C:10]=1[CH3:11])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1c(C)c2cc(OCCCCl)c(OC)cc2oc1=O
Reactant: c1ccc(N2CCNCC2)cc1
Agent: O=C([O-])/C=C/C(=O)[O-]
Solvent: COC(C)(C)C
Solvent: O
Solvent: CC(C)=O
Product: CCCCc1c(C)c2cc(OCCCN3CCN(c4ccccc4)CC3)c(OC)cc2oc1=O
Yield: 72 %

Procedure:
Method B (60 h at 50° C.); starting materials: 3-butyl-6-(3-chloropropoxy)-7-methoxy-4-methyl-2H-1-benzopyran-2-one (example 77) and 1-phenylpiperazine; yield 72%; fusion point 130°-131° C. (from isopropanol and TBME). Fumarate: method E; yield 57%; fusion point 205°-208° C. (from acetone and water).
Reaction SMILES: Cl.Cl.[CH2:3]([C:7]1[N:8]=[N:9][C:10]([O:26][CH:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[CH:11][C:12]=1[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)=[CH:15][CH:14]=1)[CH2:4][CH2:5][CH3:6].C=O.O.[C:36](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.C(O)(=O)C.O.CCOC(C)=O.C([O-])(O)=O.[Na+]>[CH2:3]([C:7]1[N:8]=[N:9][C:10]([O:26][CH:27]2[CH2:32][CH2:31][N:30]([CH3:36])[CH2:29][CH2:28]2)=[CH:11][C:12]=1[C:13]1[CH:14]=[CH:15][C:16]([O:19][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)=[CH:17][CH:18]=1)[CH2:4][CH2:5][CH3:6]
Reactant: CCCCc1nnc(OC2CCNCC2)cc1-c1ccc(OC2CCCCC2)cc1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: Cl
Agent: O=C([O-])O
Solvent: CC(=O)O
Solvent: O
Solvent: ClCCl
Product: CCCCc1nnc(OC2CCN(C)CC2)cc1-c1ccc(OC2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-butyl-4-(4-cyclohexyloxy-phenyl)-6-(piperidin-4-yloxy)-pyridazine dihydrochloride (0.2 mmol, 82 mg) in DCM (2 mL) was added formaldehyde solution in water (37%, 2 mmol, 0.2 mL), and 1 drop of acetic acid. Then sodium triacetoxyborohydride (2 mmol, 424 mg) was added, and the mixture was stirred at room temperature for 0.5 hour then condensed. It was then diluted with water/EtOAc and neutralized with NaHCO3 powder. The organic layers were combined and dried over Na2SO4. The solvent was removed in vacuo and the residue was purified by silica gel chromatography (DCM to DCM+10% 2N ammonia in MeOH) to provide 3-butyl-4-(4-cyclohexyloxy-phenyl)-6-(1-methyl-piperidin-4-yloxy)-pyridazine. The solid was dissolved in 1 mL DCM, 2N HCl in ether (1 mL) was added, kept at room temperature for 10 min, condensed, triturated with hexanes to provide the title compound (79 mg). LCMS: m/z 425 [M+1]. 1H NMR (400 MHz, CD3OD): δ 7.78 and 7.86 (1H, s), 7.45-7.50 (2H, m), 7.11-7.15 (2H, m), 5.35-5.53 (1H, m), 4.42-4.49 (1H, m), 3.24-3.69 (4H, m), 3.12-3.17 (2H, m), 2.94 (3H, s), 1.90-2.58 (6H, m), 1.78-1.86 (2H, m), 1.34-1.64 (8H, m), 1.25-1.32 (2H, m), 0.82 (3H, t).
Reaction SMILES: C([O:9][C:10]1[C:19]2[N:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13](=[O:20])[NH:12][C:11]=1[C:21]([O:23][CH3:24])=[O:22])(=O)C1C=CC=CC=1.N1C=CC=CC=1.[O:31](S(C(F)(F)F)(=O)=O)[S:32]([C:35]([F:38])([F:37])[F:36])(=O)=[O:33]>ClCCl>[OH:9][C:10]1[C:11]([C:21]([O:23][CH3:24])=[O:22])=[N:12][C:13]([O:20][S:32]([C:35]([F:38])([F:37])[F:36])(=[O:33])=[O:31])=[C:14]2[C:19]=1[N:18]=[CH:17][CH:16]=[CH:15]2
Reactant: COC(=O)c1[nH]c(=O)c2cccnc2c1OC(=O)c1ccccc1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1nc(OS(=O)(=O)C(F)(F)F)c2cccnc2c1O
Temperature: 0 °C

Procedure:
To a stirring suspension of the compound of Step 2 (25 g, 77 mmol) in dry dichoromethane (150 ml) under argon was added pyridine (31 ml, 385 mmol). The suspension was then cooled to 0° C. and Tf2O (32.6 g, 19.4 ml, 116 mmol) was added dropwise which caused the formation of a red color. The ice bath was then removed and after 1 hour the red solution was poured into a saturated aqueous solution of NaHCO3 (200 ml). The organic phase was separated and the aqueous phase was extracted three times with chloroform. The combined organics were dried over sodium sulfate, filtered and concentrated to give a green solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:38])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:31]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)=[CH:30][N:21]4[N:22]=[C:23]5[C:28]([CH:27]=[CH:26][CH:25]=[C:24]5Br)=[C:20]4[N:19]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH3:39][O:40][C:41](=[O:44])[CH:42]=[CH2:43].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C.[Cl-].[NH4+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.ClCCl.O>[CH3:39][O:40][C:41](=[O:44])/[CH:42]=[CH:43]/[C:24]1[C:23]2[C:28](=[C:20]3[N:19]=[C:18]([C:15]4[CH:16]=[CH:17][C:12]([C:8]5([NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:38])[CH2:11][CH2:10][CH2:9]5)=[CH:13][CH:14]=4)[C:31]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)=[CH:30][N:21]3[N:22]=2)[CH:27]=[CH:26][CH:25]=1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c5cccc(Br)c5nn4cc3-c3ccccc3)cc2)CCC1
Reactant: C=CC(=O)OC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: COC(=O)/C=C/c1cccc2c1nn1cc(-c3ccccc3)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)nc21
Temperature: 110 °C
Reaction time: 1 h

Procedure:
200 mg (0.351 mmol) {1-[4-(7-Bromo-3-phenylpyrimido[1,2-b]indazol-2-yl)phenyl]-cyclobutyl}carbamic acid tert-butyl ester (intermediate example Int-2-1), 60.5 mg (0.7 mmol) acrylic acid methyl ester, 18.2 mg (0.06 mmol) tri-2-tolylphosphane and 7.9 mg (0.035 mmol) palladium(II) acetate were given in 2.47 mL degassed acetonitrile. After addition of 40.5 mg (0.4 mmol) triethylamine the reaction mixture was stirred in the microwave for one hour at 110° C. Due to an incomplete reaction additional acrylic acid methyl ester (30 mg) and catalyst (4 mg) were added and stirring was continued for two hours at 110° C. The reaction mixture was poured on a mixture of water (10 mL), saturated ammonium chloride (60 mL) and dichloromethane (150 mL). After vigorous stirring the organic phase was separated and the water phase was reextracted with dichloromethane (50 mL). The combined organic extracts were washed with brine and dried (sodium sulfate). After removal of the solvent the crude product (275 mg, >100%) was used in the next step without further purification.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([C:12]([OH:14])=[O:13])([CH3:11])[CH3:10])=[CH:4][CH:3]=1.C([Li])CCC.[B:20](OC)([O:23]C)[O:21]C>O1CCCC1.CCCCCC>[C:12]([C:9]([CH3:11])([CH3:10])[CH2:8][C:5]1[CH:6]=[CH:7][C:2]([B:20]([OH:23])[OH:21])=[CH:3][CH:4]=1)([OH:14])=[O:13]
Reactant: COB(OC)OC
Reactant: CC(C)(Cc1ccc(Br)cc1)C(=O)O
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(Cc1ccc(B(O)O)cc1)C(=O)O
Temperature: -70 °C
Reaction time: 0.33 h

Procedure:
1-bromo-4-(2-carboxy-2-methylpropyl)benzene (1.93 g) was dissolved in anhydrous tetrahydrofuran (20 ml) and cooled to -70° C. A 1.25M solution of n-butyl lithium in hexane (18 ml) was added dropwise with stirring under an argon atmosphere, such that the temperature did not exceed -65° C. After a further 20 minutes, trimethyl borate was slowly added at -65° C. and the reaction mixture was allowed to attain -15° C. The reaction was quenched by the addition of a saturated aqueous solution of ammonium chloride (50 ml) and the mixture acidified by the addition of 2M hydrochloric acid. The organic phase was separated and the aqueous layer was extracted with ethyl acetate (2×50 ml). The combined organic phase was washed with brine (15 ml) and evaporated and the residue was triturated with hexane to give 4-(2-carboxy-2-methylpropyl)benzeneboronic acid (1.2 g); 1H NMR (DMSO-d6): 1.06 (s, 6 H), 2.78 (s, 2 H), 7.11 (d, 2 H), 7.67 (d, 2 H), 7.9 (br s, 2 H), 12.2 (br s, 1 H); mass spectrum (-ve ESP) 221 (M-H)-.
Reaction SMILES: Br[C:2]1[N:3]([CH:21]([CH2:25][CH2:26][CH3:27])[CH2:22][CH2:23][CH3:24])[C:4]2[C:9]([C:10](=[O:12])[CH:11]=1)=[C:8]([C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][C:14]=1[CH3:20])[CH:7]=[CH:6][CH:5]=2.[CH3:28]B(O)O.C(=O)([O-])[O-].[K+].[K+].O>O1CCOCC1.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>[CH3:20][C:14]1[CH:15]=[C:16]([CH3:19])[CH:17]=[CH:18][C:13]=1[C:8]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:9]=1[C:10](=[O:12])[C:11]([CH3:28])=[CH:2][N:3]2[CH:21]([CH2:25][CH2:26][CH3:27])[CH2:22][CH2:23][CH3:24]
Reactant: CB(O)O
Reactant: CCCC(CCC)n1c(Br)cc(=O)c2c(-c3ccc(C)cc3C)cccc21
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: C1COCCO1
Solvent: O
Product: CCCC(CCC)n1cc(C)c(=O)c2c(-c3ccc(C)cc3C)cccc21
Temperature: 90 °C
Reaction time: 8 h
Yield: 43 %

Procedure:
3 Bromo-5-(2,4-dimethylphenyl)-1-(1-propylbutyl)quinolin-4(1H)-one was then charged with methylboronic acid (0.19 g, 3.2 mmol), potassium carbonate (0.22 g, 1.6 mmol), tetrakis(triphenylphosphine)palladium(0) (0.18 g, 0.16 mmol) and diluted with dioxane (8 mL) under nitrogen gas. Water (29 μL, 1.6 mmol) was added last. The reaction was stirred at 90° C. overnight. The solution was cooled and concentrated. Flash chromatography (40% ethyl acetate/hexanes) gave 0.049 g (43% yield) of the title compound as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH2:23]([C@@H:27]1[O:29][C@H:28]1[CH2:30]O)[CH2:24][CH2:25][CH3:26]>C(Cl)(Cl)Cl>[CH2:23]([C@@H:27]1[O:29][C@H:28]1[CH2:30][O:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1)[CH2:24][CH2:25][CH3:26]
Reactant: CCCC[C@@H]1O[C@H]1CO
Reactant: CCCCCCCCOc1cnc(-c2cccc(O)c2)nc1
Solvent: ClC(Cl)Cl
Product: CCCCCCCCOc1cnc(-c2cccc(OC[C@@H]3O[C@H]3CCCC)c2)nc1

Procedure:
The synthesis is carried out analogously to Example 11 from 2-(3-hydroxyphenyl)-5-octyloxypyrimidine and (2S,3S)-3-butyloxiran-2-ylmethanol. ##STR45## [α]D20 (CHCl3)=-14.74
Reaction SMILES: [N+](C1C=CC=CC=1O)([O-])=O.[C:11]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:16]=[CH:15][C:14]([CH2:17][C:18]([OH:20])=O)=[CH:13][CH:12]=1.CC(C)N=C=NC(C)C.[N:36]1([CH:41]2[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]2)[CH2:40][CH2:39][CH2:38][CH2:37]1.[ClH:47]>ClCC(Cl)C.CN(C=O)C.C(O)C>[ClH:47].[C:11]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:12]=[CH:13][C:14]([CH2:17][C:18]([N:44]2[CH2:45][CH2:46][CH:41]([N:36]3[CH2:40][CH2:39][CH2:38][CH2:37]3)[CH2:42][CH2:43]2)=[O:20])=[CH:15][CH:16]=1
Reactant: O=C(O)Cc1ccc(-c2ccccc2)cc1
Reactant: C1CCN(C2CCNCC2)C1
Agent: CC(C)N=C=NC(C)C
Agent: Cl
Agent: O=[N+]([O-])c1ccccc1O
Solvent: CCO
Solvent: CN(C)C=O
Solvent: CC(Cl)CCl
Product: O=C(Cc1ccc(-c2ccccc2)cc1)N1CCC(N2CCCC2)CC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 29 %

Procedure:
To the polymeric nitrophenol (1.5 g, approx. 1 mmol) was added a filtered solution of 4-biphenylylacetic acid (1.10 g, 5.18 mmol) in a mixture of 1,2-dichloropropane (18 ml) and DMF (2 ml), followed by the addition of a solution of DIC (0.63 g, 4.99 mmol) in 1,2-dichloropropane (5 ml). The mixture was shaken at room temperature for 15 hours, filtered, and the polymer was extensively washed with DCM, DMF, and 1,2-dichloropropane. To the polymer was added 1,2-dichloropropane (5 ml) and a solution of 4-(1-pyrrolidinyl)piperidine (0.123 g, 0.80 mmol) in 1,2-dichloropropane (10 ml). The resulting mixture was shaken at room temperature for 21 hours and then at 60° C. for one hour, filtered, and the polymer was carefully washed with DCM and methanol. The combined filtrates were concentrated to yield the crude product, which was mixed with ethanol and 1 molar aqueous hydrochloric acid, concentrated, and the residual hydrochloride was recrystallized from ethanol. 90 mg (29%) of the title compound was obtained.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:12])=[N:7]2.[CH3:13][O:14][C:15]([C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[C:19]([NH2:29])[CH:18]=1)=[O:16]>>[CH3:13][O:14][C:15]([C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[C:19]([NH:29][C:2]2[C:3]3[C:8](=[N:7][C:6]([CH3:12])=[CH:5][CH:4]=3)[N:9]=[CH:10][CH:11]=2)[CH:18]=1)=[O:16]
Reactant: Cc1ccc2c(Cl)ccnc2n1
Reactant: COC(=O)c1ccc(-c2ccccc2)c(N)c1
Product: COC(=O)c1ccc(-c2ccccc2)c(Nc2ccnc3nc(C)ccc23)c1

Procedure:
The product from Example 1d (0.0552 g, 0.309 mmol) was reacted with the product from Example 212c (0.070 g, 0.309 mmol) for 92 h following the procedure of Example 1g giving the crude title compound, which was purified by HPLC with AA. The resulting solid was triturated with 4N HCl in dioxane to generate the hydrochloride salt which was collected by vacuum filtration (0.0747 g, 55%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 2.72 (s, 3H) 3.91 (s, 3H) 6.27 (d, J=6.99 Hz, 1H) 7.30 (m, J=6.99 Hz, 3H) 7.52 (m, 2H) 7.74 (d, J=8.82 Hz, 1H) 7.79 (d, J=8.09 Hz, 1H) 8.09 (d, J=1.47 Hz, 1H) 8.16 (dd, J=7.91, 1.65 Hz, 1H) 8.30 (d, J=6.99 Hz, 1H) 9.15 (d, J=8.82 Hz, 1H) 11.54 (s, 1H); MS (ESI+) m/z 369.9 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([CH2:16][C:17]([O:19]C)=[O:18])=[N:8]2)=[C:4]([F:23])[CH:3]=1.[OH-].[K+]>CO>[Br:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([CH2:16][C:17]([OH:19])=[O:18])=[N:8]2)=[C:4]([F:23])[CH:3]=1
Reactant: COC(=O)Cc1nn(Cc2ccc(Br)cc2F)c2ccccc12
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)Cc1nn(Cc2ccc(Br)cc2F)c2ccccc12
Reaction time: 16 h

Procedure:
A solution of methyl 1-(4-bromo-2-fluorobenzyl)-1H-indazole-3-acetate (0.30g) in methanol (5 ml) containing 10% aqueous KOH (1 ml) was stirred at roomtemperature for 16 hours. It was then concentrated to a low volume, and then diluted with ethyl acetate (10 ml) and sufficient 10% HCl added to adjust the pH to about 4.0. The ethyl acetate layer was washed with water (5 ml), dried and then evaporated to a white solid (yield: 0.21 g; m.p. 167°-168° C.).
Reaction SMILES: C1C2C(COC([NH:18][CH2:19][C:20]([NH:22][CH2:23][CH:24]3[CH2:29][CH2:28][N:27]([CH2:30][C:31]4[CH:36]=[CH:35][C:34]([S:37][CH3:38])=[CH:33][CH:32]=4)[CH2:26][CH2:25]3)=[O:21])=O)C3C(=CC=CC=3)C=2C=CC=1.N1CCCCC1>CN(C=O)C>[NH2:18][CH2:19][C:20]([NH:22][CH2:23][CH:24]1[CH2:29][CH2:28][N:27]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([S:37][CH3:38])=[CH:33][CH:32]=2)[CH2:26][CH2:25]1)=[O:21]
Reactant: CSc1ccc(CN2CCC(CNC(=O)CNC(=O)OCC3c4ccccc4-c4ccccc43)CC2)cc1
Solvent: C1CCNCC1
Solvent: CN(C)C=O
Product: CSc1ccc(CN2CCC(CNC(=O)CN)CC2)cc1

Procedure:
A DMF (4 mL) solution of 4-[[N-(9-fluorenylmethyloxycarbonyl)glycyl]aminomethyl]-1-(4-methylthiobenzyl)piperidine (590 mg) and piperidine (1 mL) was stirred at 60° C. for 2 hours. After concentrating, the obtained crude product was purified by column chromatography (SiO2,triethylamine/methanol/dichloromethane=1:1:9) to thereby afford 4-[(glycylamino)methyl]-1-(4-methylthiobenzyl)piperidine (365 mg) as a white solid. 1H NMR (CDCl3, 270 MHz) δ 1.25 (dd, J=12 Hz, 4.1 Hz, 2H), 1.34 (dd, J=12 Hz, 4.1 Hz, 2H), 1.51 (br-s, 2H), 1.66 (d, J=12 Hz, 2H), 1.77 (d, J=7.3 Hz, 1H), 1.94 (t, J=9.5 Hz, 2H), 2.48 (s, 3H), 2.80 (d, J=12 Hz, 2H), 3.18 (t, J=6.2 Hz, 2H), 3.35 (s, 2H), 3.45 (s, 2H), 7.18-7.29 (m, 4H), 7.35 (br-s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][NH2:6].C([O:14][C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23]1[CH:28]=[CH:27][C:26]([CH2:29][N:30]2[C:38]3[C:33](=[CH:34][C:35]([C:39](O)=[O:40])=[CH:36][CH:37]=3)[C:32]([CH3:42])=[C:31]2[CH3:43])=[CH:25][CH:24]=1)=[O:16])(C)(C)C>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][NH:6][C:39]([C:35]1[CH:34]=[C:33]2[C:38](=[CH:37][CH:36]=1)[N:30]([CH2:29][C:26]1[CH:25]=[CH:24][C:23]([C:18]3[C:17]([C:15]([OH:16])=[O:14])=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:28][CH:27]=1)[C:31]([CH3:43])=[C:32]2[CH3:42])=[O:40]
Reactant: NCc1cccc(Cl)c1
Reactant: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c2ccc(C(=O)O)cc12
Product: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)O)cc2)c2ccc(C(=O)NCc3cccc(Cl)c3)cc12

Procedure:
The title compound was prepared following the same general protocol as described in Steps 8-9, Example 1, using 3-chlorobenzylamine and 1-((2′-(tert-butoxycarbonyl)biphenyl-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:4][C:3]=1[C:19]([OH:21])=[O:20].[CH:22]1[C:27]([N+:28]([O-:30])=[O:29])=[CH:26][CH:25]=[C:24](O)[CH:23]=1.S(Cl)(Cl)=O>C1(C)C=CC=CC=1>[N+:28]([C:27]1[CH:22]=[CH:23][C:24]([O:20][C:19]([C:3]2[CH:4]=[C:5]([O:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:2]=2[OH:1])=[O:21])=[CH:25][CH:26]=1)([O-:30])=[O:29]
Reactant: CCOC(=O)COc1cc(C(=O)O)c(O)c2ccccc12
Reactant: O=[N+]([O-])c1ccc(O)cc1
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: CCOC(=O)COc1cc(C(=O)Oc2ccc([N+](=O)[O-])cc2)c(O)c2ccccc12
Yield: 65.9 %

Procedure:
335 g (1.15 mol) of 1-hydroxy-4-ethoxycarbonylmethyloxy-2-naphthoic acid and 160 g (1 mol) of p-nitrophenol were added to 1 liter of toluene, and the mixture was stirred while keeping the temperature at 80° C. 130 mols of thionyl chloride were added dropwise over 30 minutes. After stirring for 30 minutes more, the mixture was cooled. The precipitated crystals were filtered off and dried to obtain 271 g (57% yield) of 1-hydroxy-4-ethoxycarbonylmethyloxy-2-naphthoic acid 4-nitrophenyl ester. Melting point: 165°-167° C.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([F:19])[CH:18]=[C:13]3[CH:12]=[C:11]2[C:20](OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:21][CH:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:38][O:39][C:40](=[O:57])[C:41]1[CH:46]=[CH:45][C:44](B2OC(C)(C)C(C)(C)O2)=[CH:43][C:42]=1[F:56].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:38][O:39][C:40](=[O:57])[C:41]1[CH:46]=[CH:45][C:44]([C:20]([C:11]2[N:10]([S:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)(=[O:9])=[O:8])[C:14]3=[N:15][CH:16]=[C:17]([F:19])[CH:18]=[C:13]3[CH:12]=2)=[CH:21][CH:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)=[CH:43][C:42]=1[F:56]
Reactant: COC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1F
Reactant: Cc1ccc(S(=O)(=O)OC(=CC2CCCC2)c2cc3cc(F)cnc3n2S(=O)(=O)c2ccccc2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COC(=O)c1ccc(C(=CC2CCCC2)c2cc3cc(F)cnc3n2S(=O)(=O)c2ccccc2)cc1F
Yield: 83.2 %

Procedure:
To a mixture of toluene-4-sulfonic acid 1-(1-benzenesulfonyl-5-fluoro-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-cyclopentyl-vinyl ester (prepared as in Example 88, 3 g, 5.75 mmol), 2-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoic acid methyl ester (prepared as in Example 95, 3.9 g, 13.9 mmol) and dichlorobis(triphenylphosphine)palladium (II) (390 mg, 0.6 mmol) in dioxane (24 mL) was added an aqueous sodium carbonate solution (2 M, 6.93 mL). The resulting mixture was subjected to microwave irradiation for 2 h at 100° C. The mixture was diluted with ethyl acetate (200 mL), washed with a saturated aqueous sodium bicarbonate solution (3×50 mL), brine, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company, 25% ethyl acetate/hexanes) afforded 4-[1-(1-benzenesulfonyl-5-fluoro-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-cyclopentyl-vinyl]-2-fluoro-benzoic acid methyl ester (2.50 g, 86%) as a white solid: LC/MS m/e calcd for C28H24F2N2O4S [M+H]+ 523.58, observed 522.7.