Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1NC=C2C=1[C:8](=[O:10])NC=N2.[CH2:11]([O:13][C:14]1[C:19]([C:20]2[NH:21][C:22](=[O:35])[C:23]3[N:28](CCOC)[N:27]=[C:26]([CH2:33][CH3:34])[C:24]=3[N:25]=2)=[CH:18][C:17]([S:36]([N:39]2[CH2:44][CH2:43][N:42]([CH2:45][CH3:46])[CH2:41][CH2:40]2)(=[O:38])=[O:37])=[CH:16][N:15]=1)[CH3:12].C(C1N([CH2:80][C:81]2[CH:86]=[CH:85][CH:84]=[CH:83][N:82]=2)N=C2C(=O)NC(C3C=C(S(N4CCN(CC)CC4)(=O)=O)C=CC=3OCCC)=NC=12)C>>[CH2:11]([O:13][C:14]1[C:19]([C:20]2[NH:21][C:22](=[O:35])[C:23]3[C:24](=[C:26]([CH2:33][CH3:34])[N:27]([CH2:80][C:81]4[CH:86]=[CH:85][CH:84]=[C:83]([O:10][CH3:8])[N:82]=4)[N:28]=3)[N:25]=2)=[CH:18][C:17]([S:36]([N:39]2[CH2:44][CH2:43][N:42]([CH2:45][CH3:46])[CH2:41][CH2:40]2)(=[O:38])=[O:37])=[CH:16][N:15]=1)[CH3:12]
Reactant: O=c1[nH]cnc2c[nH]nc12
Reactant: CCOc1ncc(S(=O)(=O)N2CCN(CC)CC2)cc1-c1nc2c(CC)nn(CCOC)c2c(=O)[nH]1
Reactant: CCCOc1ccc(S(=O)(=O)N2CCN(CC)CC2)cc1-c1nc2c(CC)n(Cc3ccccn3)nc2c(=O)[nH]1
Product: CCOc1ncc(S(=O)(=O)N2CCN(CC)CC2)cc1-c1nc2c(CC)n(Cc3cccc(OC)n3)nc2c(=O)[nH]1

Procedure:
5-[2-i-butoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-2,3-diethyl-2,6-dihydro-7H-pyrazolo[[4,3-d]pyrimidin-7-one; 5-[2-ethoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2-[1-pyridin-2-yl)ethyl]2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one; 5-[2-Ethoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-1-(2-methoxyethyl)-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one; 3-Ethyl-5-[5-(4-ethylpiperazin-1-ylsulphonyl)-2-propoxyphenyl]-2-(pyridin-2-yl)methyl-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one; 5-(2-ethoxy-5-(2-(4-morpholino)acetyl)phenyl)-1-methyl-3-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one or the pharmaceutically acceptable salts thereof.
Reaction SMILES: C(NC(C)C)(C)C.[Li].[CH2:9]([O:16][C:17]1[CH2:22][CH2:21][CH2:20][C:19](=[O:23])[CH:18]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[CH2:24]1[O:34][C:27]2([CH2:32][CH2:31][C:30](=[O:33])[CH2:29][CH2:28]2)[O:26][CH2:25]1.[Cl-].[NH4+]>O1CCCC1.ClCCl>[CH2:9]([O:16][C:17]1[CH2:22][CH2:21][CH:20]([C:30]2([OH:33])[CH2:31][CH2:32][C:27]3([O:34][CH2:24][CH2:25][O:26]3)[CH2:28][CH2:29]2)[C:19](=[O:23])[CH:18]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: O=C1C=C(OCc2ccccc2)CCC1
Agent: [Cl-]
Agent: [Li]
Agent: [NH4+]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: ClCCl
Product: O=C1C=C(OCc2ccccc2)CCC1C1(O)CCC2(CC1)OCCO2
Temperature: -78 °C
Reaction time: 0.58 h
Yield: 88.5 %

Procedure:
To a round-bottomed flask was added anhydrous tetrahydrofuran (600 ml) and diisopropylamine (38.1 ml). The stirred solution was cooled to −78° C. and nbutyl lithium (113.4 ml, 2.4 M in cyclohexanes) was added dropwise via syringe in 20 ml portions. The resulting yellow solution was stirred for 35 min at −78° C., then 3-benzyloxy-2-cyclohexen-1-one (50.0 g) was added as a solution in anhydrous tetrahydrofuran (100 ml). The solution was stirred for 1 hr prior to the addition of cyclohexane-1,4-dione monoethylene ketal (38.7 g) as a solution in anhydrous tetrahydrofuran (100 ml). The solution was stirred for 2 hr at −78° C., then allowed to warm slowly to room temperature over 1 hr. Saturated aqueous ammonium chloride (80 ml) was added, followed by dichloromethane (700 ml), and the mixture was stirred until no solids remained. The layers were separated and the aqueous phase extracted with dichloromethane (2×100 ml). The combined organic layers were washed with brine (50 ml), dried over magnesium sulfate, then concentrated in vacuo. Trituration of the resulting solid with methanol afforded the title compound (78.4 g, 88%). m/z (ES+) 359 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:20][CH3:21])[CH:16]=3)[CH:11]=2)=[C:7](N)[CH:8]=1.F[B-](F)(F)F.[H+].N(O[CH2:31][CH2:32][CH:33]([CH3:35])C)=O.[CH2:36]([O:38][CH2:39][CH3:40])[CH3:37]>O1CCCC1>[CH2:36]([O:38][C:39]1[CH:31]=[C:32]([C:7]2[CH:8]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=2[C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:20][CH3:21])[CH:16]=3)[CH:11]=2)[CH:33]=[CH:35][CH:40]=1)[C:37]1[CH:5]=[CH:4][CH:3]=[CH:8][CH:7]=1
Reactant: COc1ccc(-c2ccc3cc(OC)ccc3c2)c(N)c1
Reactant: CC(C)CCON=O
Reactant: CCOCC
Agent: F[B-](F)(F)F
Agent: [H+]
Solvent: C1CCOC1
Product: COc1ccc(-c2ccc3cc(OC)ccc3c2)c(-c2cccc(OCc3ccccc3)c2)c1
Temperature: -40 °C
Reaction time: 2 h

Procedure:
The title compound was synthesized by referring to Tetrahedron Lett., 1996, 37, 3857. To a solution of 5-methoxy-2-(6-methoxynaphthalen-2-yl)phenyl amine (340 mg) in tetrahydrofuran (8 ml) was added tetrafluoroboric acid (42% aqueous solution) (0.22 ml) under a nitrogen atmosphere, the solution was cooled at −40° C., isoamyl nitrite (2.4 ml) was then added dropwise thereto followed by stirring for 2 hours at −40° C. Diethyl ether (20 ml) was added thereto and the solid that was precipitated was filtered. A suspension of the resulting 5-methoxy-2-(6-methoxynaphthalen-2-yl)benzenediazonium tetrafluoroborate (320 mg), 3-benzyloxyphenylboronic acid (235 mg) and palladium(II) acetate (10 mg) in 1,4-dioxane (4 ml) was stirred overnight at room temperature under a nitrogen atmosphere. Water was added thereto followed by stirring, the solution was extracted with ethyl acetate, then sequentially washed with water and brine, dried over anhydrous magnesium sulfate, and then the solvent was evaporated in vacuo. The residue was purified by NH silica gel column chromatography (hexane-ethyl acetate system) to provide the title compound (181 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1/[CH:9]=[CH:10]/[C:11]1[CH:16]=[CH:15][C:14]([S:17]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]#N)[CH:21]=2)(=[O:19])=[O:18])=[CH:13][N:12]=1.[H-].C([Al+]CC(C)C)C(C)C.C[OH:39].Cl>ClCCl.C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1/[CH:9]=[CH:10]/[C:11]1[N:12]=[CH:13][C:14]([S:17]([C:20]2[CH:21]=[C:22]([CH:23]=[CH:24][CH:25]=2)[CH:26]=[O:39])(=[O:19])=[O:18])=[CH:15][CH:16]=1
Reactant: N#Cc1cccc(S(=O)(=O)c2ccc(/C=C/c3ccc(F)cc3F)nc2)c1
Reactant: CO
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: O=Cc1cccc(S(=O)(=O)c2ccc(/C=C/c3ccc(F)cc3F)nc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 46 %

Procedure:
A suspension of 2-[(E)-2-(2,4-difluorophenyl)vinyl]-5-[(3-cyanophenyl)-sulfonyl]pyridine (Example 33, 200 mg, 0.52 mmol) in dichloromethane (2 mL) and toluene (2 mL) was cooled in an ice-bath while stirring under nitrogen. Diisobutylaluminium hydride (1.5M in toluene, 0.38 mL, 0.57 mmol) was added and the reaction stirred at 0° C. then allowed to warm to room temperature over 3 hours. Methanol was added then 1N aqueous hydrochloric acid and the mixture left to stand overnight. The products were extracted into dichloromethane, dried over MgSO4 and concentrated in vacuo. Dry flash column chromatography using 3% methanol/dichloromethane followed by recrystallisation from methanol gave 3-({6-[(E)-2-(2,4-difluorophenyl)vinyl]pyridin-3-yl}sulfonyl)benzaldehyde (93 mg, 46%). δH (400 MHz, CDCl3): 9.07 (1H, d, J=2.2 Hz), 8.23-8.09 (3H, m), 7.89-7.81 (2H, m), 7.74-7.66 (1H, m), 7.61-7.55 (1H, m), 7.48-7.44 (1H, m), 7.25-7.16 (2H, m), 6.93-6.83 (2H, m); m/z (ES+) 386 [MH+].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][C:26]=1[F:27])[CH2:5][N:6]1[CH2:15][CH2:14][C:13]2[C:12]([C:16](N(C)C)=[O:17])=[N:11][C:10]([OH:21])=[C:9]([OH:22])[C:8]=2[C:7]1=[O:23].[CH3:28][O-:29].[Mg+2].C[O-].[CH2:33](Br)[CH:34]=[CH2:35].Cl>CO.CS(C)=O>[CH2:33]([N:11]1[C:10](=[O:21])[C:9]([OH:22])=[C:8]2[C:13]([CH2:14][CH2:15][N:6]([CH2:5][C:4]3[CH:24]=[CH:25][C:26]([F:27])=[C:2]([Cl:1])[CH:3]=3)[C:7]2=[O:23])=[C:12]1[C:16]([O:29][CH3:28])=[O:17])[CH:34]=[CH2:35]
Reactant: C=CCBr
Reactant: C[O-]
Reactant: CN(C)C(=O)c1nc(O)c(O)c2c1CCN(Cc1ccc(F)c(Cl)c1)C2=O
Agent: Cl
Agent: [Mg+2]
Solvent: CO
Solvent: CS(C)=O
Product: C=CCn1c(C(=O)OC)c2c(c(O)c1=O)C(=O)N(Cc1ccc(F)c(Cl)c1)CC2
Temperature: 60 °C
Reaction time: 8 h

Procedure:
A mixture of 6-(3-chloro-4-fluorobenzyl)-3,4-dihydroxy-N,N-dimethyl-5-oxo-5,6,7,8-tetrahydro-2,6-naphthyridine-1-carboxamide (3.99 g, 10.511 mmol; Example 1, step 9) and magnesium methoxide in methanol (52.4 mL, 6-10% methanol solution available from Aldrich) in DMSO (100 mL) was heated at 60° C. for 30 minutes. Methanol was exhaustively removed under vacuum over 45 minutes. The residual DMSO solution was treated with allyl bromide (3.810 g, 31.52 mmol) and stirred at room temperature under an atmosphere of nitrogen for overnight. The reaction mixture was treated dilute hydrochloric acid. The solid precipitated was filtered to provide the title compound. (ES MS M+1=421.2)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C@H:4]([CH3:21])[NH:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]#[N:20])=[CH:9][CH:8]=1.[CH3:23][CH2:24][CH2:25][C:26](Cl)=[O:27]>C(N(CC)CC)C>[CH3:1][O:2][C:3](=[O:22])[C@H:4]([CH3:21])[N:5]([C:26](=[O:27])[CH2:25][CH2:24][CH3:23])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]#[N:20])=[CH:9][CH:8]=1
Reactant: CCCC(=O)Cl
Reactant: COC(=O)[C@H](C)NCc1ccc(-c2ccccc2C#N)cc1
Solvent: CCN(CC)CC
Product: CCCC(=O)N(Cc1ccc(-c2ccccc2C#N)cc1)[C@@H](C)C(=O)OC

Procedure:
The starting material can be obtained, for example, analogously to Example 2: Reaction of 2.0 g of N-[(2'-cyanobiphenyl-4-yl)methyl]-(L)-alanine methyl ester, 1.23 ml of triethylamine and 0.92 ml of n-butyryl chloride yields N-butyryl-N-[(2'-cyanobiphenyl-4-yl)methyl]-(L)-alanine methyl ester. (TLC: N2) Rf : 0.5.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[C:6]([Cl:11])[C:3]=1[CH:4]=[O:5].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:31][C:32]1([CH3:39])[O:36][CH:35]([CH2:37]O)[CH2:34][O:33]1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[Cl:1][C:2]1[CH:9]=[C:8]([O:10][CH2:37][CH:35]2[CH2:34][O:33][C:32]([CH3:39])([CH3:31])[O:36]2)[CH:7]=[C:6]([Cl:11])[C:3]=1[CH:4]=[O:5]
Reactant: O=Cc1c(Cl)cc(O)cc1Cl
Reactant: CC1(C)OCC(CO)O1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC1(C)OCC(COc2cc(Cl)c(C=O)c(Cl)c2)O1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 6.64 g (35.0 mmol) A1, 10.03 g (38.0 mmol) triphenylphosphine and 5.06 g (38.0 mmol) (rac)-2,2-dimethyl-[1,3]-dioxolane-4-methanol in 100 ml dry tetrahydrofurane a solution of 6.48 g (37.0 mmol) diethyl azodicarboxylate in 20 ml dry tetrahydrofurane was added and the mixture was stirred at room temperature overnight. After removal of the solvent and column chromatography on SiGel (hexane/ethyl acetate 4:1) 6.12 g (57%) A8 were obtained as a colorless oil that solidified on ice standing.
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].[C:5]1(=O)[CH2:9][CH2:8][CH2:7][CH2:6]1.[Na].O>C(O)C>[CH:5]1([NH:4][CH2:3][CH2:1][OH:2])[CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: NCCO
Reactant: O=C1CCCC1
Agent: [Na]
Solvent: O
Solvent: CCO
Product: OCCNC1CCCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 35181.5 %

Procedure:
A mixture of ethanolamine (4 ml, 0.066 mmol) and cyclopentanone (6.85 ml, 0.08 mmol) in ethanol (60 ml) was stirred at ambient temperature for 30 minutes. The mixture was cooled in ice and then sodium borohydide (3.04 g, 0.08 mmol) was added slowly over 20 minutes. The mixture was stirred for 15 minutes before water (10 ml) was added. The mixture was evaporated under reduced pressure and the residue dissolved in dichloromethane and dried over magnesium sulphate and then evaporated under reduced pressure. The crude product was purified by vacuum distillation to give 2-(cyclopentylamino)ethanol (3 g, 35% yield) as a clear oil:
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([I:10])=[C:7]([OH:9])[CH:8]=1)[CH3:2].C(=O)([O-])[O-].[K+].[K+].I[CH:18]([CH3:20])[CH3:19]>O>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([I:10])=[C:7]([O:9][CH:18]([CH3:20])[CH3:19])[CH:8]=1)[CH3:2]
Reactant: CC(C)I
Reactant: CCc1ccc(I)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CCc1ccc(I)c(OC(C)C)c1
Temperature: 25 °C
Yield: 80.1 %

Procedure:
A mixture of 5-ethyl-2-iodophenol (1.0 g, 4 mmol), potassium carbonate (1.10 g, 8 mmol) and 2-iodopropane (0.80 mL, 8 mmol) was heated at reflux for 6 h. The reaction mixture was cooled to room temperature and water was added. The mixture was extracted with diethyl ether. The combined organic extracts were washed with brine and dried over anhydrous magnesium sulfate. The solid was then filtered off, and the filtrate was concentrated in vacuo. Purification of the residue by flash chromatography (Biotage system, KP-Sil™ 32-63 μm, 60 Å silica gel) eluting with hexanes, 5% ethyl acetate in hexanes yielded 4-ethyl-1-iodo-2-isopropoxy-benzene (0.93 g, 80%).
Reaction SMILES: [O:1]=[C:2]1[C:5]([CH3:6])=[C:4]([NH:7][CH2:8][C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[NH:14][CH:13]=[C:12]3[CH2:18][CH2:19][CH2:20][OH:21])[C:3]1=[O:22].C(N(CC)CC)C.[CH3:30][S:31](Cl)(=[O:33])=[O:32]>ClCCl.C1COCC1>[O:1]=[C:2]1[C:5]([CH3:6])=[C:4]([NH:7][CH2:8][C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[NH:14][CH:13]=[C:12]3[CH2:18][CH2:19][CH2:20][O:21][S:31]([CH3:30])(=[O:33])=[O:32])[C:3]1=[O:22]
Reactant: Cc1c(NCc2ccc3[nH]cc(CCCO)c3c2)c(=O)c1=O
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cc1c(NCc2ccc3[nH]cc(CCCOS(C)(=O)=O)c3c2)c(=O)c1=O
Temperature: -20 °C
Reaction time: 1.5 h
Yield: 83 %

Procedure:
To a solution of 5-(1,2-dioxo-4-methyl-3-cyclobuten-3-yl)aminomethyl-3-(3-hydroxypropyl)indole (0.48 g, 0.0016 mol) in 45 mL of dichloromethane-THF (4:1) , cooled at -20° C. under Ar, was added triethylamine (0.28 mL, 0.002 mol) followed by methanesulfonyl chloride (0.16 mL, 0.002 mol) . The resulting solution was stirred at -20° C. for 1.5 h and then it was washed (brine), dried (Na2SO4) and evaporated to give a brown gum. This material was chromatographed (SiO2 /ethyl acetate) to give the title compound (0.50 g, 83%) as a beige foam: IR (neat) 3320 (br), 1785, 1727, 1600 (br), 1350 (br) cm-1 ; 1H NMR (DMSO-d6, 200 MHz) δ10.86 (s, 1H), 9.45 (m, 0.5H), 9.21 (m, 0.5H), 7.48 (s, 1H), 7.33 (d, J=8.3 Hz, 1H), 7.17 (s, 1H), 7.03 (d, J=8.3 Hz, 1H), 4.78 (d, J=5.9 Hz, 1.2H), 4.62 (d, J=6.0 Hz, 0.8H), 4.23 (m, 2H), 3.80 (s, 3H), 3.06 (m, 2H), 2.76 (m, 2H), 2.14 (s, 1.2H), 2.05 (s, 1.8H).
Reaction SMILES: C([O-])C.[Na+].[C:5]([O:11][CH2:12][CH3:13])(=[O:10])[CH2:6][C:7]([CH3:9])=O.[F:14][C:15]([F:41])([F:40])[C:16]1[CH:17]=[C:18]([NH:22][N:23]=[C:24](OS(C2C=CC(C)=CC=2)(=O)=O)[C:25]([F:28])([F:27])[F:26])[CH:19]=[CH:20][CH:21]=1>C(O)C.CCOC(C)=O>[CH2:12]([O:11][C:5]([C:6]1[C:24]([C:25]([F:26])([F:27])[F:28])=[N:23][N:22]([C:18]2[CH:19]=[CH:20][CH:21]=[C:16]([C:15]([F:40])([F:41])[F:14])[CH:17]=2)[C:7]=1[CH3:9])=[O:10])[CH3:13]
Reactant: Cc1ccc(S(=O)(=O)OC(=NNc2cccc(C(F)(F)F)c2)C(F)(F)F)cc1
Reactant: CCOC(=O)CC(C)=O
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(=O)c1c(C(F)(F)F)nn(-c2cccc(C(F)(F)F)c2)c1C
Reaction time: 1 h

Procedure:
A solution of sodium ethanolate 21% (in ethanol, 0.75 ml, 2 mmol) was added to ethyl acetoacetate (0.25 ml, 1.97 mmol) in 3 ml ethanol at 0° C. After 1 h at 0° C., a solution of (2Z or E)-1-[3-(trifluoromethyl)phenyl]-2-(2,2,2-trifluoro-1-{[(4-methylphenyl)sulfonyl]-oxy}ethylidene)hydrazine (254 mg, 0.60 mmol) in 5 ml ethanol was added. Stirring was continued for 18 h at room temperature and then the yellow solution was diluted with EtOAc washed with water and brine. The combined organic layers were dried over magnesium sulfate and evaporated. Column chromatography (EtOAc:n-heptane 1:3) delivered the title compound as light yellow solid (107 mg, 48%). MS: 367.3 (MH+).
Reaction SMILES: I[C:2]1[N:6]2[N:7]=[CH:8][C:9]([C:11]3[CH:16]=[CH:15][C:14]([CH:17]([CH3:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:13][CH:12]=3)=[CH:10][C:5]2=[N:4][CH:3]=1.CC1(C)C(C)(C)OB([C:32]2[CH:33]=[C:34]([NH:38][C:39]([NH:41][CH2:42][C:43]([F:46])([F:45])[F:44])=[O:40])[CH:35]=[CH:36][CH:37]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.C(OCC)(=O)C.Cl[Pd](Cl)(P(C(C)(C)C)(C(C)(C)C)C1C=CC(N(C)C)=CC=1)P(C1C=CC(N(C)C)=CC=1)(C(C)(C)C)C(C)(C)C>[F:44][C:43]([F:45])([F:46])[CH2:42][NH:41][C:39]([NH:38][C:34]1[CH:35]=[C:36]([C:2]2[N:6]3[N:7]=[CH:8][C:9]([C:11]4[CH:16]=[CH:15][C:14]([CH:17]([CH3:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:13][CH:12]=4)=[CH:10][C:5]3=[N:4][CH:3]=2)[CH:37]=[CH:32][CH:33]=1)=[O:40]
Reactant: CC1(C)OB(c2cccc(NC(=O)NCC(F)(F)F)c2)OC1(C)C
Reactant: CCOC(=O)C(C)c1ccc(-c2cnn3c(I)cnc3c2)cc1
Agent: CN(C)c1ccc([PH](C(C)(C)C)(C(C)(C)C)[Pd](Cl)(Cl)[PH](c2ccc(N(C)C)cc2)(C(C)(C)C)C(C)(C)C)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C)c1ccc(-c2cnn3c(-c4cccc(NC(=O)NCC(F)(F)F)c4)cnc3c2)cc1
Temperature: 95 °C
Reaction time: 8 h

Procedure:
Dichloro(bis{di-tert-butyl[4-(dimethylamino)phenyl]phosphoranyl})palladium (12 mg, 0.017 mmol) was added to a mixture of ethyl 2-[4-(3-iodoimidazo[1,2-b]pyridazin-7-yl)phenyl]propanoate (0.24 g, 0.58 mmol), N-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-N′-(2,2,2-trifluoroethyl)urea (240 mg, 0.70 mmol), sodium carbonate (130 mg, 1.2 mmol) in 1,4-dioxane (5 mL) and water (0.5 mL) and then the reaction was vacuumed and refilled with nitrogen for 3 times. The reaction was stirred at 95° C. overnight. The mixture was diluted with ethyl acetate, washed with water and brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column with methanol in methylene chloride (0-10%) to afford the desired product. LCMS (M+H)+: m/z=512.1
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]([F:12])([F:11])[F:10])=[CH:4][C:3]=1[NH2:13].C(N(CC)CC)C.C1C=[CH:23][C:24](=[O:37])[C:25]2C=1C(C(Cl)=O)=C1C=2C=CC=C1>ClCCl>[CH:2]([O:37][CH:24]([CH3:23])[CH3:25])([CH3:7])[CH3:3].[NH2:13][C:3]1[CH:4]=[C:5]([O:8][C:9]([F:10])([F:11])[F:12])[CH:6]=[CH:7][C:2]=1[NH-:1]
Reactant: O=C(Cl)C1=c2ccccc2=C2C(=O)C=CC=C12
Reactant: Nc1ccc(OC(F)(F)F)cc1N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)OC(C)C
Product: [NH-]c1ccc(OC(F)(F)F)cc1N
Temperature: 25 °C
Reaction time: 20 h
Yield: 97.5 %

Procedure:
The procedure used in stage 1 of Example 1 is followed, but starting from 1 g of 1,2-diamino-4-(trifluoromethoxy)benzene, 1.3 ml of triethylamine and 1.15 g of fluoren-4-one-9-carboxylic acid chloride in 30 ml of dichloromethane. After stirring for 20 hours at room temperature, the precipitate that formed is filtered off, and washed with dichloromethane, with water, and then with a 10% saturated aqueous solution of sodium hydrogen carbonate and, finally, with water. After drying and formation of a paste with diisopropyl ether, in this way we obtain 485 mg of (2-amino-4-trifluoromethoxyphenyl)amide of 9-oxo-9H-fluorene-4-carboxylic acid, in the form of a yellow powder, which is used as it is in the following stage, with the following characteristics:
Reaction SMILES: [CH2:1]([NH:5][CH2:6][CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][CH:9]=1)[CH:2]([CH3:4])[CH3:3].[CH3:17][O:18][C:19]([CH2:21][CH2:22][CH2:23][C:24](Cl)=O)=[O:20]>>[CH2:1]([N:5]([CH2:24][CH2:23][CH2:22][CH2:21][C:19]([O:18][CH3:17])=[O:20])[CH2:6][CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][CH:9]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)CNCCc1c[nH]c2ccccc12
Reactant: COC(=O)CCCC(=O)Cl
Product: COC(=O)CCCCN(CCc1c[nH]c2ccccc12)CC(C)C
Yield: 73.5 %

Procedure:
10 g of N-isobutyl-tryptamine (i.e., 3-(2-isobutylaminoethyl)-indole) and 9.1 g of 4-methoxycarbonylbutyryl chloride were treated in the same manner as described in Example 1. 11.23 g of N-isobutyl-N-(4-methoxycarbonylbutyl)-tryptamine (i.e., 3-[2-(N-isobutyl-4-methoxycarbonylbutanamido)ethyl]-indole) were thereby obtained. Yield: 70.5%
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH3:11])[CH:5]=[C:6]([N+:8]([O-])=O)[CH:7]=1.C(O)(=O)C.O>C(O)C.[Fe]>[Br:1][C:2]1[CH:7]=[C:6]([CH:5]=[C:4]([CH3:11])[CH:3]=1)[NH2:8]
Reactant: Cc1cc(Br)cc([N+](=O)[O-])c1
Agent: [Fe]
Solvent: O
Solvent: CC(=O)O
Solvent: CCO
Product: Cc1cc(N)cc(Br)c1
Reaction time: 3 h

Procedure:
A solution of 3-bromo-5-nitrotoluene (21 g, prepared by the method of R. B. Carlin and G. E. Foltz, J. Amer. Chem. Soc., 1956, 78, 1992) in ethanol (250 ml) containing acetic acid (40.8 g) and iron powder (19.0 g) was refluxed with stirring for 3 h. Additional iron powder (9.5 g) was added, and the reaction mixture refluxed a further 3 h, cooled, and added to excess water. The mixture was filtered and the aqueous filtrate extracted with diethyl ether. The organic layer was extracted with 1N hydrochloric acid, the acid extracts basified with sodium hydroxide and the mixture extracted with diethyl ether. The organic extract was dried and evaporated to give 3-bromo-5-methylaniline (15.6 g) which without further purification was dissolved in methanol (200 ml) containing dimethyl acetylene dicarboxylate (11.37 g). The solution was refluxed for 16 hr, evaporated to dryness, and the residue taken up in ether and washed with dilute hydrochloric acid. Evaporation of the ether gave the intermediate enamine (26.1 g) which was added dropwise to stirring diphenyl ether (250 ml) at 250° C. After 15 minutes, the mixture was allowed to cool to room temperature, the crystalline product collected and recrystallised from acetic acid to give a mixture of the 5,7-regioisomers (23 g). This mixture (5 g) was separated by chromatography on silica gel, eluting with dichloromethane/methanol (94:6) to give methyl 7-bromo-5-methyl-4-oxo-1,4-dihydroquinoline-2-carboxylate (0.50 g), mp 270°-271° C., a (360 MHz, DMSO-d6) 2.75 (3H, s, CH3), 3.95 (3H, s, OCH3), 6.51 (1H, s, 3-H), 7.24 (1H, d, 6-H) and 7.99 (1H, d, 8-H) (NOE to 6-H only on irradiation of 5-CH3 confirms regiochemistry); and methyl 5-bromo-7-methyl-4-oxo-1,4-dihydroquinoline-2-carboxylate (0.18 g), mp 258°-9° C., δ (360 MHz, DMSO-d6) 2.37 (3H, s, CH3), 3.95 (3H, s, OCH3) 6.58 (1H, s, 2-H), 7.41 (1H, d, 6-H) and 7.72 (1H, d, 8-H) (NOE to both 6-H and 8-H on irradiation of 7-CH3 confirms regiochemistry).
Reaction SMILES: [C:1]([N:5]1[C:10](=[O:11])[CH:9]=[CH:8][C:7]([C:12]([OH:14])=O)=[CH:6]1)([CH3:4])([CH3:3])[CH3:2].[NH2:15][C:16]1[CH:17]=[C:18]([CH:25]=[CH:26][C:27]=1[CH3:28])[C:19]([NH:21][CH:22]1[CH2:24][CH2:23]1)=[O:20].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[CH:22]1([NH:21][C:19]([C:18]2[CH:25]=[CH:26][C:27]([CH3:28])=[C:16]([NH:15][C:12]([C:7]3[CH:8]=[CH:9][C:10](=[O:11])[N:5]([C:1]([CH3:2])([CH3:3])[CH3:4])[CH:6]=3)=[O:14])[CH:17]=2)=[O:20])[CH2:24][CH2:23]1
Reactant: CC(C)(C)n1cc(C(=O)O)ccc1=O
Reactant: Cc1ccc(C(=O)NC2CC2)cc1N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1ccc(=O)n(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 47.8 %

Procedure:
To a solution of 1-tert-butyl-6-oxo-1,6-dihydro-3-pyridinecarboxylic acid (30 mg) in DMF (0.6 mL) were added 3-amino-N-cyclopropyl-4-methylbenzamide (44 mg), HATU (88 mg) and iPr2NEt (89 mg), and the mixture was stirred under a nitrogen atmosphere at room temperature for 3 hr. The reaction mixture was diluted with EtOAc (3 mL) and the resulting mixture was washed with 1 M HCl (3 mL×2), water (3 mL), saturated aqueous NaHCO3 (3 mL) and brine successively, dried over MgSO4, filtered and evaporated in vacuo. The residue was purified by preparative thin layer chromatography eluting with 10% MeOH in CH2Cl2 to give N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-1-tert-butyl-6-oxo-1,6-dihydro-3-pyridinecarboxamide (27 mg).