Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.C([Li])CCC.[Br:13][C:14]1[CH:19]=[CH:18][C:17]([C@H:20]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[CH3:34])[CH2:21][C:22](N(OC)C)=[O:23])=[CH:16][CH:15]=1.C(=O)([O-])O.[Na+]>O1CCCC1.C(OCC)(=O)C>[Br:13][C:14]1[CH:15]=[CH:16][C:17]([C@H:20]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[CH3:34])[CH2:21][C:22](=[O:23])[CH2:1][C:2]2[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=2)=[CH:18][CH:19]=1
Reactant: CON(C)C(=O)C[C@H](c1ccc(Br)cc1)c1ccccc1C
Reactant: Cc1ccncc1
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1ccccc1[C@H](CC(=O)Cc1ccncc1)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 51 %

Procedure:
To a solution of 4-methylpyridine (308 mg, 3.31 mmol) in tetrahydrofuran at −78° C. was added dropwise n-butyllithium solution (1.6 M in hexane, 2.07 mL, 3.31 mmol). The reaction mixture was stirred for 1 hour at room temperature and cooled down again to −78° C. (R)-3-(4-bromo-phenyl)-N-methoxy-N-methyl-3-o-tolyl-propionamide (example 142, step 1; 400 mg, 1.1 mmol) was added and the reaction mixture was stirred at room temperature for 3 hours. A saturated solution of sodium hydrogencarbonate and ethyl acetate were added, the phases were separated and the inorganic one was extracted with ethyl acetate (2×). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel (10% methanol in dichloromethane) to yield the title compound as a yellow oil (51%), MS (ESI+): m/z=394.0 ([M+H]+).
Reaction SMILES: C([O:3][C:4](=[O:20])[C@@H:5]([O:18][CH3:19])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]([OH:17])=O)=[CH:9][CH:8]=1)C.[O:21]([C:28]1[CH:33]=[CH:32][C:31]([NH2:34])=[CH:30][CH:29]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(O[C@@H](CC1C=CC(O[C@@H](C(=O)NCCC2C=CC(OC3C=CC=CC=3)=CC=2)C)=CC=1)C(O)=O)C>>[CH3:19][O:18][C@@H:5]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:14][C:15](=[O:17])[NH:34][C:31]2[CH:30]=[CH:29][C:28]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:33][CH:32]=2)=[CH:11][CH:12]=1)[C:4]([OH:3])=[O:20]
Reactant: CCOC(=O)[C@H](Cc1ccc(OCC(=O)O)cc1)OC
Reactant: Nc1ccc(Oc2ccccc2)cc1
Agent: CCO[C@@H](Cc1ccc(O[C@H](C)C(=O)NCCc2ccc(Oc3ccccc3)cc2)cc1)C(=O)O
Product: CO[C@@H](Cc1ccc(OCC(=O)Nc2ccc(Oc3ccccc3)cc2)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-(4-carboxymethoxy-phenyl)-2-methoxy-propionic acid ethyl ester (PREPARATION 3, step 2) and 4-phenoxy-phenylamine via the same procedure used for the preparation of (2S,1R)-2-ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionic acid (Example 1, step 3) to produce a colorless oil. MS (ES) for C24H23NO6 [M+H]+: 421.
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:11]([NH2:23])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH2:11]([NH:23][S:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:9])=[O:8])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CCCCCCCCCCCCN
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCNS(=O)(=O)c1ccccc1
Temperature: 40 °C
Yield: 82.8 %

Procedure:
Benzenesulfonyl chloride (353 g, 2 mol) was added dropwise to a toluene (2000 mL) solution of dodecylamine (371 g, 2 mol) and triethylamine (203 g, 2 mol) with ice bath cooling. During the one hour addition period, the temperature increased to about 40° C. After filtration of the triethylamine hydrochloride, the toluene solution was washed with dilute HCl, dilute NaOH and water. After drying over magnesium sulfate, the toluene was removed in vacuo and the precipitate slurried in hexane and filtered to give 539 g of product. Melting point 57-60° C. Calculated for C18H32NO2S 326, found 326. 1H NMR (CDCl3) δ0.88 (t, 3, CH3), 1.24 (d, 18, CH2), 1.45 (s, 2, CH2), 4.66 (sb, 1, NH), 7.49-7.84 (m, 5, arom.).
Reaction SMILES: COC1C=CC(C[N:8]2[C:12]3=[N:13][CH:14]=[C:15]4[C:19](=[O:20])[NH:18][C:17](=[O:21])[C:16]4=[C:11]3[CH:10]=[N:9]2)=CC=1.[CH2:24](O)[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1.FC(F)(F)C(O)=O>[CH2:24]([N:18]1[C:19](=[O:20])[C:15]2[C:16](=[C:11]3[CH:10]=[N:9][NH:8][C:12]3=[N:13][CH:14]=2)[C:17]1=[O:21])[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: OCCc1ccccc1
Reactant: COc1ccc(Cn2ncc3c4c(cnc32)C(=O)NC4=O)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: O=C1c2cnc3[nH]ncc3c2C(=O)N1CCc1ccccc1
Temperature: 65 °C
Reaction time: 6 h
Yield: 12.8 %

Procedure:
A solution of 3-(4-methoxybenzyl)pyrazolo[3,4-b]pyrrolo[3,4-d]pyridine-6,8(3H,7H)-dione (150 mg, 0.48 mmol), phenethylalcohol (70 μl, 0.58 mmol) and triphenylphosphine (191 mg, 0.73 mmol) in anhydrous tetrahydrofuran (6 ml) was treated with diisopropyl azodicarboxylate (141 μl, 0.73 mmol) at room temperature and stirred for 6 hours. The mixture was partitioned between ethyl acetate (100 ml) and water (100 ml). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford a brown oil. The oil was dissolved in trifluoroacetic acid (7 ml) and heated to 65° C. for 24 hours. The mixture was concentrated under reduced pressure and the product was partitioned between ethyl acetate (100 ml) and saturated aqueous sodium bicarbonate (50 ml). The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to afford a brown solid which was purified by flash column chromatography (12 g SiO2, 30% ethyl acetate in hexanes). Fractions containing the product were concentrated under reduced pressure. The solid was triturated in ethyl acetate, cooled to 0° C. and filtered to afford 7-phenethylpyrazolo[3,4-b]pyrrolo[3,4-d]pyridine-6,8(3H,7H)-dione as a white solid (18 mg, 13%). M.p.=237-239° C.; 400 MHz 1H NMR (DMSO-d6) δ: 9.00 (s, 1H), 8.51 (s, 1H), 7.23 (m, 6H), 3.85 (t, J=7.2 Hz, 2H), 2.95 (t, J=7.6 Hz, 2H); LCMS: 293 [M+H].
Reaction SMILES: [CH3:1][N:2]([CH2:9][C:10]1[CH:16]=[CH:15][C:13]([NH2:14])=[CH:12][CH:11]=1)[CH:3]1[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1.C(N(CC)CC)C.[C:24](OC(=O)C)(=[O:26])[CH3:25]>C1COCC1>[CH3:1][N:2]([CH2:9][C:10]1[CH:11]=[CH:12][C:13]([NH:14][C:24](=[O:26])[CH3:25])=[CH:15][CH:16]=1)[CH:3]1[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1
Reactant: CC(=O)OC(C)=O
Reactant: CN(Cc1ccc(N)cc1)C1CCOCC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)Nc1ccc(CN(C)C2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Into a solution of 4-[N-methyl-N-(tetrahydropyran-4-yl)aminomethyl]aniline (551 mg) in THF (50 ml) were added triethylamine (0.42 ml) and acetic anhydride (0.26 ml), and the resulting mixture was stirred at room temperature for 3 hours. After evaporation of THF, the residue was extracted with ethyl acetate. The extract was washed successively with an aqueous solution of sodium bicarbonate and an aqueous solution of sodium chloride, was dried with anhydrous magnesium sulfate and was then concentrated under reduced pressure. The residue was recrystallized from ethyl acetate/hexane to obtain N-[4-[N-methyl-N-(tetrahydropyran-4-yl)aminomethyl]phenyl]acetamide (472 mg) as light yellow crystals.
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.[CH3:12][C:13]1[C:17]([C:18]2[CH:19]=[C:20]([C@@H:24]([NH2:26])[CH3:25])[CH:21]=[CH:22][CH:23]=2)=[C:16]([CH3:27])[O:15][N:14]=1>>[CH3:12][C:13]1[C:17]([C:18]2[CH:19]=[C:20]([C@@H:24]([NH:26][C:1](=[O:11])[CH:2]=[CH:3][C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH3:25])[CH:21]=[CH:22][CH:23]=2)=[C:16]([CH3:27])[O:15][N:14]=1
Reactant: O=C(O)C=Cc1ccccc1
Reactant: Cc1noc(C)c1-c1cccc([C@H](C)N)c1
Product: Cc1noc(C)c1-c1cccc([C@H](C)NC(=O)C=Cc2ccccc2)c1

Procedure:
The title compound was prepared from cinnamic acid and (S)-1-[3-(3,5-dimethyl-isoxazol-4-yl)-phenyl]-ethylamine following the general procedures as described for Example 1.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH:13]2[CH2:18][CH2:17][C:16](=O)[CH2:15][CH2:14]2)=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([CH3:12])[CH2:7]2.[CH3:20][N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:13]2[CH2:18][CH2:17][C@H:16]([N:24]3[CH2:25][CH2:26][N:21]([CH3:20])[CH2:22][CH2:23]3)[CH2:15][CH2:14]2)=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([CH3:12])[CH2:7]2
Reactant: CN1CCNCC1
Reactant: CN1Cc2c(C3CCC(=O)CC3)ccc(N)c2C1=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CN1CCN([C@H]2CC[C@H](c3ccc(N)c4c3CN(C)C4=O)CC2)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of 7-amino-2-methyl-4-(4-oxocyclohexyl)-2,3-dihydro-1H-isoindol-1-one (100.0 mg, 0.3871 mmol) in 1,2-dichloroethane (2.0 mL) was charged with 1-methylpiperazine (58.16 mg, 0.5807 mmol) and sodium triacetoxyborohydride (164.1 mg, 0.7743 mmol). The reaction mixture was stirred at rt for 24 hours. The reaction mixture was quenched with NaHCO3 (10 mL) and extracted with EtOAc (20 mL). The organic layer was washed with brine (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to yield a light yellow oil. The crude material was purified and by silica gel chromatography on the combi-flash Rf system using DCM/7M NH3 in MeOH (100:0→90:10) as eluent to afford the cis isomer (76.5 mg, 58%, first eluting product) and the trans isomer (30.0 mg, 23%, second eluting product). Cis isomer: 1H NMR (CDCl3, 400 MHz): δ=1.42-1.56 (m, 4 H), 1.82-1.96 (m, 2 H), 2.06 (d, J=11.87 Hz, 2 H), 2.27 (br. s., 1 H), 2.34 (s, 3 H), 2.38-2.78 (m, 9 H), 3.14 (s, 3 H), 4.31 (s, 2 H), 5.08 (s, 2 H), 6.58 (d, J=8.34 Hz, 1 H), 7.18 (d, J=8.34 Hz, 1 H). MS (ES+): m/z 343.25 [MH+]. Trans isomer: 1H NMR (CDCl3, 400 MHz): δ=1.35-1.75 (m, 7 H), 1.91 (d, J=12.13 Hz, 2 H), 2.03-2.13 (m, 2 H), 2.34 (s, 3 H), 2.47-2.82 (m, 7 H), 3.14 (s, 3 H), 4.28 (s, 2 H), 5.09 (s, 2 H), 6.56 (d, J=8.34 Hz, 1 H), 7.09 (d, J=8.34 Hz, 1 H). MS (ES+): m/z 343.26 [MH+].
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:16][S:17][CH2:18][C@H:19]([O:35][C:36](=[O:48])[NH:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])[CH2:20][O:21][C:22](=[O:34])[NH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[C:13](O)=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:82][CH2:83][CH2:84][O:85][CH2:86][CH2:87][O:88][CH2:89][CH2:90][O:91][CH2:92][CH2:93][P:94](=[O:101])([O:98][CH2:99][CH3:100])[O:95][CH2:96][CH3:97]>C(Cl)Cl>[CH2:99]([O:98][P:94]([CH2:93][CH2:92][O:91][CH2:90][CH2:89][O:88][CH2:87][CH2:86][O:85][CH2:84][CH2:83][NH:82][C:13](=[O:14])[C@@H:12]([NH:11][C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:10])[CH2:16][S:17][CH2:18][C@H:19]([O:35][C:36](=[O:48])[NH:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])[CH2:20][O:21][C:22](=[O:34])[NH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])(=[O:101])[O:95][CH2:96][CH3:97])[CH3:100]
Reactant: CCOP(=O)(CCOCCOCCOCCN)OCC
Reactant: CCCCCCCCCCNC(=O)OC[C@H](CSC[C@H](NC(=O)OCc1ccccc1)C(=O)O)OC(=O)NCCCCCCCCCC
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCCCCCCCCNC(=O)OC[C@H](CSC[C@H](NC(=O)OCc1ccccc1)C(=O)NCCOCCOCCOCCP(=O)(OCC)OCC)OC(=O)NCCCCCCCCCC
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of (R)-2-(benzyloxycarbonylamino)-3-((R)-2,3-bis(decylcarbamoyloxy)propylthio) propanoic acid (15, 1 eq) and HBTU (1.2 eq) in DCM (0.06 M) was added DIEA (2.4 eq), followed by diethyl 2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)ethylphosphonate (1.2 eq, from example 18, step 4). The reaction was stirred at room temperature for 4 hours. The crude mixture was purified by flash chromatography on a COMBIFLASH® system (ISCO) using a gradient of 0-10% MeOH/DCM to afford the title compound as a clear viscous oil.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.[F:12][C:13]1([F:27])[CH2:17][CH2:16][C@@H:15]([NH:18][CH2:19][C:20]2([C:23]([O:25][CH3:26])=[O:24])[CH2:22][CH2:21]2)[CH2:14]1.C(=O)(O)[O-].[Na+]>ClCCl>[Cl:1][C:2]1[N:7]=[C:6]([N:18]([CH2:19][C:20]2([C:23]([O:25][CH3:26])=[O:24])[CH2:22][CH2:21]2)[C@@H:15]2[CH2:16][CH2:17][C:13]([F:12])([F:27])[CH2:14]2)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1
Reactant: COC(=O)C1(CN[C@@H]2CCC(F)(F)C2)CC1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)C1(CN(c2nc(Cl)ncc2[N+](=O)[O-])[C@@H]2CCC(F)(F)C2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 91.2 %

Procedure:
2,4-Dichloro-5-nitropyrimidine (2.16 g, 11.15 mmol) was added to a mixture of (R)-methyl 1-((3,3-difluorocyclopentylamino)methyl)cyclopropanecarboxylate (2.6 g, 11.15 mmol) and sodium bicarbonate (3.75 g, 44.64 mmol) in dichloromethane (15 mL) and petroleum ether (60 mL). The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with dichloromethane and dried over magnesium sulfate. The solids were filtered off, rinsing with more dichloromethane. The mother liquors were adsorbed on silica gel and concentrated in vacuo. The residue was purified by flash column chromatography to afford the desired product as a yellow solid (3.974 g, 91% yield).
Reaction SMILES: [NH:1]([C:17]([O:19][CH2:20][CH:21]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27]2[C:22]1=[CH:23][CH:24]=[CH:25][CH:26]=2)=[O:18])[C@H:2]([C:9]([O:11][CH2:12][C:13]([Cl:16])([Cl:15])[Cl:14])=[O:10])[CH2:3][O:4]C(C)(C)C>C(O)(C(F)(F)F)=O.O>[NH:1]([C:17]([O:19][CH2:20][CH:21]1[C:22]2[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:28]2[C:33]1=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:18])[C@H:2]([C:9]([O:11][CH2:12][C:13]([Cl:14])([Cl:15])[Cl:16])=[O:10])[CH2:3][OH:4]
Reactant: CC(C)(C)OC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)OCC(Cl)(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: O=C(N[C@@H](CO)C(=O)OCC(Cl)(Cl)Cl)OCC1c2ccccc2-c2ccccc21
Reaction time: 5 h

Procedure:
Fmoc-Ser(tBu)-OTce was dissolved in TFA-H2O (19:1, 10 mL) and allowed to stir for 5 h. The reaction mixture was concentrated in vacuo and purified by flash chromatography (EtOAc-Hexane, 3:7) to give Fmoc-Ser-OTce (0.83 g, 1.8 mmol, 69% overall yield for the two steps).
Reaction SMILES: [O:1]=[C:2]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4][CH2:3]1.[Br:16]Br.C(N(CC)CC)C.CC(OC(OC(OC(C)(C)C)=O)=O)(C)C>C(Cl)(Cl)Cl>[Br:16][CH:8]1[C:2](=[O:1])[CH2:3][CH2:4][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:6][CH2:7]1
Reactant: CC(C)(C)OC(=O)N1CCCC(=O)CC1
Reactant: BrBr
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N1CCC(=O)C(Br)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 26.5 %

Procedure:
To a solution tert-butyl 4-oxoazepane-1-carboxylate (compound 82.2, 11.0 g, 51.6 mmol) in chloroform (220 mL) at 0° C. was added drop-wise a solution of bromine (3.98 mL, 77.6 mmol) in chloroform (110 mL). The resulting mixture was stirred at room temperature overnight, then the solids that formed were collected by filtration and dissolved in dichloromethane (200 mL). Triethylamine (16.8 mL, 121 mmol) and (Boc)2O (8.70 g, 40.3 mmol) were added to the mixture at 0° C. and the resulting solution was stirred for 3 h at room temperature, and then concentrated under reduced pressure. The crude residue was purified by silica gel chromatography using ethyl acetate/petroleum ether (1:10) as the eluent to give 4.0 g (27%) of the title compound as a yellow oil.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([F:14])([F:13])[F:12])=[N:9][N:10]=2)[N:7]=1.[F:15][C:16]([F:28])([F:27])[O:17][C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1.C([O-])([O-])=O.[Na+].[Na+].COCCOC>C(OCC)(=O)C.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>[F:15][C:16]([F:27])([F:28])[O:17][C:18]1[CH:23]=[CH:22][C:21]([C:2]2[CH:3]=[CH:4][C:5]3[N:6]([C:8]([C:11]([F:14])([F:13])[F:12])=[N:9][N:10]=3)[N:7]=2)=[CH:20][CH:19]=1
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Reactant: FC(F)(F)c1nnc2ccc(Cl)nn12
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: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: FC(F)(F)Oc1ccc(-c2ccc3nnc(C(F)(F)F)n3n2)cc1

Procedure:
To a round bottom flask was added 6-chloro-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine (0.982 mmole), 4-(trifluoromethoxy)phenylboronic acid (1.18 mmole), tetrakis(triphenylphosphine)palladium (0.0491 mmole), 2M Na2CO3 (2 mL), and 1,2-dimethoxyethane (3 mL). The resulting reaction mixture was heated at 85 C for 2 hours. The reaction mixture was diluted with ethyl acetate and filtered through celite. The filtrate was washed with water. The organic extract was dried over Na2SO4 and evaporated in vacuo. The crude residue was purified by preparative HPLC to yield 6-(4-(trifluoromethoxy)phenyl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][C:11]([NH:13][NH:14][C:15]([C:17]2[CH:25]=[CH:24][C:20]3[N:21]=[CH:22][S:23][C:19]=3[CH:18]=2)=O)=[O:12])[CH:6]=[CH:7][CH:8]=1.C1(C)C=CC(S(Cl)(=O)=O)=CC=1>N1C=CC=CC=1.C(OCC)(=O)C>[F:27][C:2]([F:1])([F:26])[C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][C:11]2[O:12][C:15]([C:17]3[CH:25]=[CH:24][C:20]4[N:21]=[CH:22][S:23][C:19]=4[CH:18]=3)=[N:14][N:13]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: O=C(CCc1cccc(C(F)(F)F)c1)NNC(=O)c1ccc2ncsc2c1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: FC(F)(F)c1cccc(CCc2nnc(-c3ccc4ncsc4c3)o2)c1
Yield: 74.6 %

Procedure:
A solution of N′-[3-[3-(trifluoromethyl)phenyl]propionyl]benzothiazole-6-carbohydrazide (433 mg, 1.10 mmol) and p-toluenesulfonyl chloride (419 mg, 2.20 mmol) in pyridine (5 mL) was stirred under an argon atmosphere at 80° C. for 16 hr. After cooling, the reaction mixture was diluted with ethyl acetate, washed with 0.1M hydrochloric acid and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (hexane/ethyl acetate=1/1) and recrystallized from hexane/ethyl acetate to give the title compound (308 mg, yield 75%) as colorless crystals.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[Li]CCCC.[NH:13]1[C:17]2[CH:18]=[CH:19][S:20][C:16]=2[C:15]([C:21]2[NH:22][C:23]3[C:28]([CH:29]=2)=[CH:27][C:26]([C:30](=[O:33])[CH2:31][CH3:32])=[CH:25][CH:24]=3)=[N:14]1.CO>O1CCCC1>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:30]([C:26]1[CH:27]=[C:28]2[C:23](=[CH:24][CH:25]=1)[NH:22][C:21]([C:15]1[C:16]3[S:20][CH:19]=[CH:18][C:17]=3[NH:13][N:14]=1)=[CH:29]2)([OH:33])[CH2:31][CH3:32]
Reactant: Brc1ccccn1
Reactant: CCC(=O)c1ccc2[nH]c(-c3n[nH]c4ccsc34)cc2c1
Agent: [Li]CCCC
Solvent: CO
Solvent: C1CCOC1
Product: CCC(O)(c1ccc2[nH]c(-c3n[nH]c4ccsc34)cc2c1)c1ccccn1
Reaction time: 0.33 h
Yield: 96.5 %

Procedure:
To a solution of 2-bromopyridine (224 mg, 1.42 mmol) in anhydrous tetrahydrofuran (2 mL) is added n-BuLi (1.6 M in hexane, 0.95 mL, 1.52 mmol) at −78° C. under nitrogen. After stirring for 20 minutes, to it is added a solution of 1-[2-(1H-thieno[3,2-c]pyrazol-3-yl)-1H-indol-5-yl)-propan-1-one (140 mg, 0.473 mmol, Example 28) in anhydrous tetrahydrofuran (4 mL) drop wise. After 30 minutes, the cooling bath is removed and continued stirring at ambient temp for 30 minutes. The reaction is quenched by the addition of saturated ammonium chloride (4 mL) followed by water (4 mL). The reaction mixture is extracted with ethyl acetate (120 mL). Ethyl acetate phase is washed with water, brine and dried over sodium sulfate. Purification by chromatography (10 g silica gel cartridge, 30-60% ethyl acetate gradient in heptane) afforded product. It is then dissolved with minimum amount of methanol and triturated with water to give 1-pyridin-2-yl-1-[2-(1H-thieno[3,2-c]pyrazol-3-yl)-1H-indol-5-yl]-propan-1-ol (171 mg, 31%, Example 31) as a beige solid; 1H NMR [(CD3)2SO)]: δ 13.195 (1H, s), 11.417 (1H, s), 8.472 (1H, d), 7.742-7.661 (4H, m) 7.259-7.166 (4H, m), 6.59 (1H, s), 5.697 (1H, s, OH), 2.361 (2H, m), 0.785 (3H, t); LC/MS: 375 (M+H).
Reaction SMILES: O.[C:2]([C:10]([OH:12])=[O:11])(=[O:9])C1C=CC=CC=1.[CH2:13](O)[CH2:14][CH:15]=[CH2:16]>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[C:10]([O:12][CH2:16][CH2:15][CH:14]=[CH2:13])(=[O:11])[CH:2]=[O:9]
Reactant: C=CCCO
Reactant: O=C(O)C(=O)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: C=CCCOC(=O)C=O
Temperature: 110 °C
Yield: 85.9 %

Procedure:
In a flask with a water separator, a mixture of 11.02 g of benzoylformic acid (glyoxalic acid), 6.62 g of 3-buten-1-ol and 0.42 g of p-toluenesulfonic acid in 130 ml of toluene is heated at 110° C. for 22 hours. The solution is washed with saturated NaHCO3 solution and water. The organic phases are dried over sodium sulfate. Filtration, evaporation of the solvent and distillation (b.p.=85° C. at 0.035 mbar) give but-3-enyl glyoxalate (8.08 g, 54%) as a pale yellowish liquid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:22][C:23]([C:25]2[C:26](=[O:38])[N:27]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[N:28]([CH3:31])[C:29]=2[CH3:30])=[O:24])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([OH:21])=[C:16]([O:19][CH3:20])[CH:17]=2)[N:12]=[CH:11][CH:10]=1.CS(O[CH2:44][CH2:45][CH2:46][N:47]1[CH2:53][CH:52]([OH:54])[C:49]2([CH2:51][CH2:50]2)[CH2:48]1)(=O)=O.C([O-])([O-])=O.[Cs+].[Cs+]>CC(N(C)C)=O>[OH:54][CH:52]1[C:49]2([CH2:51][CH2:50]2)[CH2:48][N:47]([CH2:46][CH2:45][CH2:44][O:21][C:15]2[CH:14]=[C:13]3[C:18]([C:9]([O:8][C:7]4[CH:6]=[CH:5][C:4]([NH:22][C:23]([C:25]5[C:26](=[O:38])[N:27]([C:32]6[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=6)[N:28]([CH3:31])[C:29]=5[CH3:30])=[O:24])=[CH:3][C:2]=4[F:1])=[CH:10][CH:11]=[N:12]3)=[CH:17][C:16]=2[O:19][CH3:20])[CH2:53]1
Reactant: COc1cc2c(Oc3ccc(NC(=O)c4c(C)n(C)n(-c5ccccc5)c4=O)cc3F)ccnc2cc1O
Reactant: CS(=O)(=O)OCCCN1CC(O)C2(CC2)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: COc1cc2c(Oc3ccc(NC(=O)c4c(C)n(C)n(-c5ccccc5)c4=O)cc3F)ccnc2cc1OCCCN1CC(O)C2(CC2)C1
Temperature: 25 °C
Reaction time: 40 h
Yield: 65.8 %

Procedure:
To a solution of N-(3-fluoro-4-(7-hydroxy-6-methoxyquinolin-4-yloxy)phenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide (200 mg, 0.389 mmol) in DMA (2 mL) was added 3-(7-hydroxy-5-azaspiro[2.4]heptane-5-yl)propyl methanesulfonate (193 mg, 0.778 mmol) and Cs2CO3 (379 mg, 1.167 mmol). The reaction was then stirred at rt for 40 hrs. The solvent was removed and the residue was partioned between saturated NaHCO3 aqueous solution (10 mL) and CHCl3 (30 mL). The organic layer was separated, dried over anhydrous Na2SO4, filtered and concentrated in vacuo and the residue was purified by a silica gel column chromatography (100:15:1 (v/v/v) EtOAc/CH3OH/Et3N) to afford the desired compound as a pale yellow solid (171 mg, 66%).