Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC1C=CC([CH2:7][N:8](C)[C:9]2[C:14]3=[C:15]([C:19]4[CH:20]=[N:21][N:22]([CH3:34])[C:23]=4[C:24]4[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][N:25]=4)[N:16]=[C:17]([CH3:18])[N:13]3[N:12]=[CH:11][N:10]=2)=CC=1.FC(F)(F)C(O)=O.COC1C=CC=CC=1.C>ClCCl.CO>[CH3:7][NH:8][C:9]1[C:14]2=[C:15]([C:19]3[CH:20]=[N:21][N:22]([CH3:34])[C:23]=3[C:24]3[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][N:25]=3)[N:16]=[C:17]([CH3:18])[N:13]2[N:12]=[CH:11][N:10]=1
Reactant: COc1ccc(CN(C)c2ncnn3c(C)nc(-c4cnn(C)c4-c4ccc(C(F)(F)F)cn4)c23)cc1
Agent: C
Solvent: ClCCl
Solvent: COc1ccccc1
Solvent: CO
Product: CNc1ncnn2c(C)nc(-c3cnn(C)c3-c3ccc(C(F)(F)F)cn3)c12
Temperature: 40 °C

Procedure:
N-(4-Methoxybenzyl)-N,7-dimethyl-5-{1-methyl-5-[5-(trifluoromethyl)pyridin-2-yl]-1H-pyrazol-4-yl}imidazo[5,1-f][1,2,4]triazin-4-amine (7.00 g, 13.8 mmol) was dissolved in dichloromethane (46 mL) and treated with trifluoroacetic acid (40 mL, 520 mmol) and methoxybenzene (99.7%, 7.0 mL, 64 mmol). The reaction mixture was heated at 40° C. for 4 hours, then concentrated in vacuo. Aqueous 1 N sodium hydroxide solution was added, and the mixture was extracted with ethyl acetate. The organic layer was concentrated under reduced pressure to provide crude product (12 g), which was combined with the crude product from two additional runs of this reaction (total starting material: 18.09 g, 35.57 mmol). The combined material was dissolved in hot methanol, allowed to cool slightly, and treated with Darco® activated carbon (8 g); this mixture was heated for 1 hour at 50° C. and filtered through Celite. The volume of the filtrate was reduced, and the solution was left to crystallize for 18 hours. The resulting beige crystals were determined by 1H NMR to contain residual methoxybenzene. Trituration with diethyl ether provided the product as a white solid. Combined yield: 8.73 g, 22.5 mmol, 63%. LCMS m/z 389.2 (M+1). 1H NMR (400 MHz, CD3OD) δ 2.58 (s, 3H), 2.85 (s, 3H), 4.15 (s, 3H), 7.38 (br d, J=8.3 Hz, 1H), 7.73 (s, 1H), 7.85 (s, 1H), 7.98-8.01 (m, 1H), 9.02-9.04 (m, 1H).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:12][C:11](=[O:13])[NH:10][C:9]2=[O:14])[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.Cl>CN(C=O)C>[CH2:17]([N:10]1[C:11](=[O:13])[CH2:12][N:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([I:1])[CH:3]=2)[C:9]1=[O:14])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: BrCc1ccccc1
Reactant: O=C1CN(c2cccc(I)c2)C(=O)N1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1CN(c2cccc(I)c2)C(=O)N1Cc1ccccc1
Reaction time: 0.33 h

Procedure:
1-(3-Iodophenyl)imidazolidine-2,4-dione (0.5 g) was taken up in dry DMF (10 ml) and treated with sodium hydride (60% oil dispersion, 73 mg) and stirred for 20 min under nitrogen. Benzyl bromide (0.295 ml) was added and stirring continued for 3 h. 2M HCl (100 ml) was added and the mixture extracted with EtOAc. The combined extracts were washed with saturated aqueous sodium hydrogen carbonate (50 ml), brine (50 ml) and dried (MgSO4). This was recrystallised from MeOH to give the title compound (0.255 g). LCMS RT 3.53 min.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH3:12].[CH3:13][O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1B(O)O.C([O-])([O-])=O.[K+].[K+].O>C1(C)C=CC=CC=1.CCOC(C)=O.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>[CH3:13][O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH3:12]
Reactant: COC(=O)c1ccc(Br)c(C)c1
Reactant: COCc1ccccc1B(O)O
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: O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COCc1ccccc1-c1ccc(C(=O)OC)cc1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Methyl 4-bromo-3-methylbenzoate (Aldrich 532878, 2 g; 8.73 mmol; 1 eq.), (2-methoxymethylphenyl)boronic acid (1.59 g; 9.60 mmol; 1.10 eq.), K2CO3 (6.03 g; 43.65 mmol; 5 eq.), tetrakis(triphenylphosphine)palladium (0) (1.01 g; 0.87 mmol; 0.10 eq.) were taken up in Toluene (10 mL) and water (10 mL) under N2 atmosphere. The reaction mixture was purged with vacuum, then degassed with N2 and then for 2 hours. The reaction mixture was cooled to RT, filtered over a pad of celite and washed with EtOAc (500 mL). The filtrate was concentrated to afford a yellow oil which was taken in EtOAc (100 mL). The organic layer was washed with a saturated aqueous solution of NaHCO3 solution (30 mL), water (30 mL) and brine (30 mL), dried over MgSO4 and concentrated affording the title compound as a brown oil used without further purification (3 g, quantitative). HPLC (Method A) Rt 5.20 min (Purity: 64.5%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]SNC1C=CC=CC=1.[C:17]([O:21][CH2:22][CH3:23])(=[O:20])[C:18]#[CH:19]>C(OCC)(=O)C.CCCCCC>[S:8]1[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[NH:1][CH:19]=[C:18]1[C:17]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: Nc1ccccc1SSNc1ccccc1
Reactant: C#CC(=O)OCC
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCOC(=O)C1=CNc2ccccc2S1
Temperature: 150 °C
Yield: 22.6 %

Procedure:
2-(2-Aminophenyl)disulfanylaniline (1.0 g, 4.0 mmol) and ethyl prop-2-ynoate (790 mg, 816 μL, 8.05 mmol) were combined in a microwave tube and heated at 150° C. for 30 min. The reaction was concentrated in vacuo. Silica gel chromatography (10-35% ethyl acetate/hexane) provided ethyl 4H-1,4-benzothiazine-2-carboxylate as an orange solid (200 mg, 23% yield). LC/MS m/z 222.0 [M+H]+. 1H NMR (400.0 MHz, CDCl3) δ 7.11 (d, J=6.6 Hz, 1H), 6.86-6.82 (m, 1H), 6.79-6.74 (m, 2H), 6.27 (d, J=7.9 Hz, 1H), 5.68 (br d, J=4.2 Hz, 1H), 4.19 (q, J=7.2 Hz, 2H), 1.28 (t, J=7.1 Hz, 3H)
Reaction SMILES: [CH2:1]([C@H:3]1[CH2:8][C@H:7]2[C@H:9]3[C@H:18]([CH2:19][CH2:20][C@:5]2([CH3:6])[C@H:4]1[OH:22])[C@@H:17]1[C:12](=[CH:13][C:14](=[O:21])[CH2:15][CH2:16]1)[CH2:11][CH2:10]3)[CH3:2].CN(C)C1C=CC=CC=1.[Br:32][CH:33]([CH3:37])[C:34](Br)=[O:35].C(OCC)(=O)C>ClCCl>[CH2:1]([C@H:3]1[CH2:8][C@H:7]2[C@H:9]3[C@H:18]([CH2:19][CH2:20][C@:5]2([CH3:6])[C@H:4]1[O:22][C:34](=[O:35])[CH:33]([Br:32])[CH3:37])[C@@H:17]1[C:12](=[CH:13][C:14](=[O:21])[CH2:15][CH2:16]1)[CH2:11][CH2:10]3)[CH3:2]
Reactant: CC[C@H]1C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@@H]4[C@H]3CC[C@]2(C)[C@H]1O
Reactant: CC(Br)C(=O)Br
Solvent: CCOC(C)=O
Solvent: CN(C)c1ccccc1
Solvent: ClCCl
Product: CC[C@H]1C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@@H]4[C@H]3CC[C@]2(C)[C@H]1OC(=O)C(C)Br

Procedure:
In 70 ml of dichloromethane are dissolved 3.0 g of 16β-ethyl-17β-hydroxy-4-estren-3-one and 1.6 ml of N,N-dimethylaniline and, with stirring, 1.2 ml of α-bromopropionyl bromide is added to the above solution. The mixture is stirred at room temperature (15°-25° C.) for 30 hours followed by addition of 300 ml of ethyl acetate. The mixture is washed with 10% sulfuric acid and saturated aqueous sodium chloride solution in that order and dried over anhydrous magnesium sulfate. The solvent is then distilled off under reduced pressure and the residue is subjected to column chromatography. Following passage of 300 ml of diisopropyl ether-n-hexane (1:1), elution is carried out with 600 ml of diisopropyl ether. The eluate is evaporated under reduced pressure to remove the solvent, giving 2.7 g of the above-identified compound as a light-yellow viscous oil.
Reaction SMILES: [C:1](OCC)(=[O:6])[CH2:2][C:3]([CH3:5])=O.[Cl:10][C:11]1[CH:12]=[C:13]([NH:17][C:18]2[CH2:22][C:21](=[O:23])[N:20]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[N:19]=2)[CH:14]=[CH:15][CH:16]=1>C(O)(=O)C>[Cl:10][C:11]1[CH:12]=[C:13]([N:17]2[C:1](=[O:6])[CH:2]=[C:3]([CH3:5])[C:22]3[C:21](=[O:23])[N:20]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)[NH:19][C:18]2=3)[CH:14]=[CH:15][CH:16]=1
Reactant: O=C1CC(Nc2cccc(Cl)c2)=NN1c1ccccc1
Reactant: CCOC(=O)CC(C)=O
Solvent: CC(=O)O
Product: Cc1cc(=O)n(-c2cccc(Cl)c2)c2[nH]n(-c3ccccc3)c(=O)c12
Temperature: 150 °C
Reaction time: 0.33 h
Yield: 32.8 %

Procedure:
30 ml of acetic acid and 4 g of ethyl acetoacetate were added to 5.7 g of 3-(3-chlorophenylamino)-1-phenyl-2-pyrazolin-5-one, and they were heated and stirred over a bath of 150° C. for 10 hours and 20 minutes. Insoluble matter was filtrated from the reaction solution in a hot state, and washed with isopropanol, followed by drying with air, to obtain 2.3 g of 7-(3-chlorophenyl)-2-phenyl-4-methylpyrazolo(3,4-b)pyridin-3,6-dione. It had a melting point of from 278 to 282° C.
Reaction SMILES: [C:1]([C:3]1([F:15])[CH2:7][CH2:6][N:5]([C:8]([O:10]C(C)(C)C)=O)[CH2:4]1)#[N:2].C(O)(C(F)(F)F)=O.[C:23]([O:27][C:28]([NH:30][C@H:31]([C:35]([CH3:38])([CH3:37])[CH3:36])C(O)=O)=[O:29])([CH3:26])([CH3:25])[CH3:24].C1C=CC2N(O)N=NC=2C=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>C(Cl)Cl.CN(C=O)C>[C:1]([C:3]1([F:15])[CH2:7][CH2:6][N:5]([C:8](=[O:10])[C@H:31]([NH:30][C:28](=[O:29])[O:27][C:23]([CH3:26])([CH3:25])[CH3:24])[C:35]([CH3:38])([CH3:37])[CH3:36])[CH2:4]1)#[N:2]
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)O)C(C)(C)C
Reactant: CC(C)(C)OC(=O)N1CCC(F)(C#N)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)OC(=O)N[C@@H](C(=O)N1CCC(F)(C#N)C1)C(C)(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 82.2 %

Procedure:
To a solution of tert-butyl 3-cyano-3-fluoropyrrolidine-1-carboxylate (240 mg, 1.12 mmol) in CH2Cl2 (5 mL) was added TFA (2.0 mL, 26.0 mmol). The pale yellow reaction mixture was stirred at room temperature for 4 h then concentrated to a yellow oil and dried under high vacuum. In a 50 mL flask were combined the above oil (237 mg, 1.04 mmol), (R)-2-(tert-butoxycarbonylamino)-3,3-dimethylbutanoic acid (200 mg, 0.87 mmol), and HOBT (146 mg, 0.95 mmol). Then added DMF (4 mL) followed by HATU (362 mg, 0.95 mmol) and N,N-diisopropylethylamine (0.45 mL, 2.59 mmol). The yellow reaction mixture was stirred at room temperature overnight then quenched with H2O and extracted with EtOAc (3×). The combined organics were washed with H2O (3×) then dried over MgSO4 and concentrated. The crude residue was purified by SiO2 chromatography (20% to 50% EtOAc/hexanes) to isolate 234 mg (83%) of tert-butyl (2R)-1-(3-cyano-3-fluoropyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-ylcarbamate as a viscous colorless oil.
Reaction SMILES: [CH:1]([C:4]1[CH:15]=[CH:14][C:7]([O:8][CH2:9][C:10]([O:12]C)=[O:11])=[CH:6][C:5]=1[CH3:16])([CH3:3])[CH3:2].[OH-].[Na+].Cl>C(O)C>[CH:1]([C:4]1[CH:15]=[CH:14][C:7]([O:8][CH2:9][C:10]([OH:12])=[O:11])=[CH:6][C:5]=1[CH3:16])([CH3:3])[CH3:2]
Reactant: COC(=O)COc1ccc(C(C)C)c(C)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(OCC(=O)O)ccc1C(C)C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of methyl 2-(4-isopropyl-3-methylphenoxy)acetate (13.0 g, 58.5 mmol) in abs. ethanol (240 mL) was treated with aq. sodium hydroxide solution (13 ml, 5 M). The resulting solution was stirred for 4 h at ambient temperature, then poured into aq. HCl (800 mL, 1 N). This was extracted with ether (2×200 mL), and the extracts were washed with brine, combined, dried over anhydrous magnesium sulfate, filtered and evaporated to afford the solid product, 2-(4-isopropyl-3-methylphenoxy)acetic acid, which was dried under vacuum (12.0 g, 58.5 mmol 100%). 1H NMR (d6-DMSO, 300 MHz): δ 12.91 (1H, s), 7.12 (1H, d, J=8 Hz), 6.70–6.65 (2H, m), 4.58 (2H, s), 3.02 (1H, m, J=6.7 Hz), 2.24 (3H, s), 1.12 (6H, d, J=6.7 Hz).
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH2:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C:5]2[CH:15]=[CH:16][CH:17]=[CH:18][C:4]=2[NH:3]1.Br[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1.CC([O-])=O.[K+]>N1C=CC=CC=1.[Cu].Cl[Cu]>[O:1]=[C:2]1[N:6]([CH2:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C:5]2[CH:15]=[CH:16][CH:17]=[CH:18][C:4]=2[N:3]1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1
Reactant: Brc1ccccn1
Reactant: CC(C)(C)OC(=O)Cn1c(=O)[nH]c2ccccc21
Agent: Cl[Cu]
Agent: [Cu]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)Cn1c(=O)n(-c2ccccn2)c2ccccc21
Temperature: 100 °C

Procedure:
A mixture of tert-butyl (2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)acetate from Step A (1.75 g, 7.05 mmol), 2-bromopyridine (3.36 mL, 35.2 mmol), copper powder (1.57 g, 24.7 mmol), CuCl (140 mg, 1.41 mmol), and KOAc (2.08 g, 21.1 mmol) in pyridine (30 mL) was heated at 100° C. for 3 h. The cooled mixture was partitioned between EtOAc (150 mL) and 10% aqueous citric acid (100 mL) and the organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography, eluting with a gradient of hexane:EtOAc—100:0 to 0:100, to give the title compound. MS: m/z=326 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][NH:9][C:10]1[C:11]2[C:18]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)=[C:17](Br)[O:16][C:12]=2[N:13]=[CH:14][N:15]=1.[F:29][C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][CH:35]=1.C(=O)([O-])[O-].[Cs+].[Cs+].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.CC(O)=O.CC(O)=O.C1CCC([N-]C2CCCCC2)CC1.C1CCC([N-]C2CCCCC2)CC1.[Pd+2]>[CH3:1][O:2][C:3](=[O:28])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][NH:9][C:10]1[C:11]2[C:18]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)=[C:17]([C:34]3[CH:33]=[CH:32][CH:31]=[C:30]([F:29])[CH:35]=3)[O:16][C:12]=2[N:13]=[CH:14][N:15]=1
Reactant: COC(=O)CCCCCNc1ncnc2oc(Br)c(-c3ccc(OC)cc3)c12
Reactant: OB(O)c1cccc(F)c1
Agent: [Pd+2]
Agent: C1CCC([N-]C2CCCCC2)CC1
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: COC(=O)CCCCCNc1ncnc2oc(-c3cccc(F)c3)c(-c3ccc(OC)cc3)c12
Temperature: 80 °C
Reaction time: 16 h

Procedure:
Add 3 mg (0.01 mmol) trans-bis(dicyclohexylamine)palladium(II) acetate [T. Bin, J. Org. Chem. 2004, 69, 4330-4335] to a mixture of 100 mg (0.22 mmol) 6-{[6-bromo-5-(4-methoxyphenyl)furo[2,3-d]pyrimidin-4-yl]amino}hexanoic acid methyl ester, 47 mg (0.34 mmol) 3-fluorophenylboronic acid and 145 mg (0.45 mmol) caesium carbonate in 5 ml dioxan, and stir for 16 h at 80° C. After adding 95 mg (0.45 mmol) potassium phosphate, a further 47 mg (0.34 mmol) 3-fluorophenylboronic acid and a spatula tip of trans-bis(dicyclohexylamin)palladium(II) acetate, stir the reaction mixture for a further 4 h at 80° C. Then filter the reaction mixture and purify directly by preparative RP-HPLC (gradient: water/acetonitrile). 57 mg (53% of theor.) of the desired product is obtained.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:9].Br[CH2:11][CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15].C(=O)([O-])[O-].[K+].[K+]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C1COCC1>[CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[O:9][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: Cc1cccc(O)c1C
Reactant: CCOC(=O)CCCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: C1CCOC1
Product: CCOC(=O)CCCOc1cccc(C)c1C
Temperature: 60 °C
Yield: 95.2 %

Procedure:
A mixture of 2,3-dimethylphenol (12.2 g, 100 mmol), tetrabutylammonium iodide (0.738 g, 1.997 mmol), ethyl 4-bromobutanoate (14.29 mL, 100 mmol), and potassium carbonate (27.6 g, 200 mmol) in THF (100 mL) was heated at 60° C. for 20 h. After this time, the reaction mixture was cooled to room temperature. Once at the prescribed temperature, the reaction mixture was quenched with water (50 mL), and extracted with EtOAc (2×50 mL). The combined organic phases were concentrated, and purified by flash chromatography (0 to 30% EtOAc:hexanes) to afford the title compound (22.5 g, 90% yield) as colorless oil. LCMS, [M+Na]+=259.1. 1H NMR (400 MHz, CDCl3) δ 7.01 (dd, J=8.2, 7.5 Hz, 1H), 6.75 (d, J=7.5 Hz, 1H), 6.67 (d, J=8.2 Hz, 1H), 4.13 (q, J=7.1 Hz, 2H), 3.97 (t, J=6.0 Hz, 2H), 2.52 (t, J=7.4 Hz, 2H), 2.25 (s, 3H), 2.15-2.07 (m, 2H), 2.12 (s, 3H), 1.24 (t, J=7.1 Hz, 3H).
Reaction SMILES: [CH2:1]([C:3]1[CH:7]=[C:6]([C:8]([OH:10])=O)[N:5]([CH3:11])[N:4]=1)[CH3:2].CN(C)C=O.C(Cl)(=O)C(Cl)=O.[NH2:23][C:24]1[CH:25]=[C:26]([CH:44]=[CH:45][C:46]=1[Cl:47])[O:27][C:28]1[CH:29]=[CH:30][C:31]2[N:32]([CH:34]=[C:35]([NH:37][C:38]([CH:40]3[CH2:42][CH:41]3[CH3:43])=[O:39])[N:36]=2)[N:33]=1>CN(C)C(=O)C.O1CCCC1>[Cl:47][C:46]1[CH:45]=[CH:44][C:26]([O:27][C:28]2[CH:29]=[CH:30][C:31]3[N:32]([CH:34]=[C:35]([NH:37][C:38]([CH:40]4[CH2:42][CH:41]4[CH3:43])=[O:39])[N:36]=3)[N:33]=2)=[CH:25][C:24]=1[NH:23][C:8]([C:6]1[N:5]([CH3:11])[N:4]=[C:3]([CH2:1][CH3:2])[CH:7]=1)=[O:10]
Reactant: CC1CC1C(=O)Nc1cn2nc(Oc3ccc(Cl)c(N)c3)ccc2n1
Reactant: CCc1cc(C(=O)O)n(C)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CC(=O)N(C)C
Solvent: CN(C)C=O
Product: CCc1cc(C(=O)Nc2cc(Oc3ccc4nc(NC(=O)C5CC5C)cn4n3)ccc2Cl)n(C)n1
Yield: 49.9 %

Procedure:
Using 3-ethyl-1-methyl-1H-pyrazole-5-carboxylic acid (181 mg, 1.17 mmol), tetrahydrofuran (4.5 mL), N,N-dimethylformamide (30 μL, 0.39 mmol), oxalyl chloride (102 μL, 1.17 mmol), N-[6-(3-amino-4-chlorophenoxy)imidazo[1,2-b]pyridazin-2-yl]-2-methylcyclopropanecarboxamide (300 mg, 0.84 mmol) and N,N-dimethylacetamide (6.0 mL), and in the same manner as in Example 249, the title compound (207 mg, 50%) was obtained as a white powder.
Reaction SMILES: C([O:3][C:4](=[O:43])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13]([C@@H:15]2[NH:19][C@@H:18]([CH2:20][C:21]([CH3:24])([CH3:23])[CH3:22])[C@:17]3([C:32]4[C:27](=[CH:28][C:29]([Cl:33])=[CH:30][CH:31]=4)[NH:26][C:25]3=[O:34])[C@H:16]2[C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([Cl:41])[C:36]=2[F:42])=[O:14])=[CH:8][CH:7]=1)C.Cl>C1COCC1.O.C(OCC)(=O)C>[Cl:33][C:29]1[CH:28]=[C:27]2[NH:26][C:25](=[O:34])[C@:17]3([C@@H:16]([C:35]4[CH:40]=[CH:39][CH:38]=[C:37]([Cl:41])[C:36]=4[F:42])[C@H:15]([C:13]([NH:12][C:9]4[CH:10]=[CH:11][C:6]([CH2:5][C:4]([OH:43])=[O:3])=[CH:7][CH:8]=4)=[O:14])[NH:19][C@H:18]3[CH2:20][C:21]([CH3:23])([CH3:22])[CH3:24])[C:32]2=[CH:31][CH:30]=1
Reactant: CCOC(=O)Cc1ccc(NC(=O)[C@@H]2N[C@@H](CC(C)(C)C)[C@@]3(C(=O)Nc4cc(Cl)ccc43)[C@H]2c2cccc(Cl)c2F)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)C[C@@H]1N[C@@H](C(=O)Nc2ccc(CC(=O)O)cc2)[C@H](c2cccc(Cl)c2F)[C@]12C(=O)Nc1cc(Cl)ccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.6 %

Procedure:
To a solution of rac-(4-{[(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carbonyl]amino}-phenyl)-acetic acid ethyl ester (52 mg, 0.083 mmol) in THF (3 mL) was added LiOH monohydrate (15 mg, 0.35 mmol) in water (1.5 mL) and the reaction mixture was allowed to stir at rt overnight. The mixture was then treated with 1N HCl to slightly acidic, diluted with ethyl acetate (80 mL), washed with water (2×15 mL), dried with Na2SO4 and concentrated to give rac-(4-{[(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carbonyl]amino}-phenyl)-acetic acid as a white solid (47 mg, 95%). MS (ES+) m/z [(M+H)+]: 598.
Reaction SMILES: [NH2:1][C:2]1[C:11]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][C:7]2=O.C[Si]([C:25]#[N:26])(C)C.[H-].[Al+3].[Li+].[H-].[H-].[H-].[ClH:33]>>[ClH:33].[NH2:26][CH2:25][C:7]1[C:8]2[C:3](=[C:2]([NH2:1])[C:11]([O:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:10][CH:9]=2)[CH2:4][CH2:5][CH:6]=1
Reactant: C[Si](C)(C)C#N
Reactant: Nc1c(OCc2ccccc2)ccc2c1CCCC2=O
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Product: NCC1=CCCc2c1ccc(OCc1ccccc1)c2N

Procedure:
5-amino-6-benzyloxy-1,2,3,4-tetrahydro-1-naphthalenone (such as that disclosed in U.S. Pat. No. 4,035,512) is reacted with trimethylsilylcyanide followed by lithium aluminum hydride. The resultant 1-hydroxy-1- aminomethyl compound is dehydrated with HCl to give 1-aminomethyl-5-amino-6-benzyloxy-3,4-dihydronaphthalene HCl. This latter compound is reacted with trifluoro acetic anhydride to give 1-trifluoroacetylaminomethyl-5-amino-6-benzyloxy-3,4-dihydronaphthalene. This latter compound is formylated with formic acid and acetic anhydride and the trifluoroacetyl group is removed with Na2CO3 to yield 1-aminomethyl-5-formamido 6-benzyloxy-3,4-dihydronaphthalene HCl.
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[CH:6][N:7]=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12].Cl.[NH2:17][C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1.[F-].[K+].C>O1CCOCC1.O.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.C(N(CC)CC)C>[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:2]2[C:10]3[C:5](=[CH:6][N:7]=[CH:8][CH:9]=3)[NH:4][C:3]=2[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:20][CH:19]=1
Reactant: Nc1ccc(B(O)O)cc1
Reactant: CCOC(=O)c1[nH]c2cnccc2c1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: [F-]
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)c1[nH]c2cnccc2c1-c1ccc(N)cc1
Reaction time: 0.25 h
Yield: 57.4 %

Procedure:
To a solution of 1 g of ethyl 3-bromo-1H-pyrrolo[2,3-c]pyridine-2-carboxylate in 100 mL of dioxane are added 773 mg of 4-aminophenylboronic acid hydrochloride and 1.1 g of potassium fluoride in 9 mL of water. The reaction mixture is stirred under an argon atmosphere for 15 minutes. 425 mg of tetrakis(triphenylphosphine)palladium(0) and 630 μL of triethylamine are added. The reaction mixture is stirred for 17 hours at reflux. After treating with carbon black and then filtering through Celite®, the filtrate is concentrated under reduced pressure. The residue is purified by flash chromatography on a column of silica (60; 35-70 μM), eluting with a mixture of dichloromethane, methanol and acetonitrile (90/5/5 by volume). 600 mg of ethyl 3-(4-aminophenyl)-1H-pyrrolo[2,3-c]pyridine-2-carboxylate are obtained, the characteristics of which are as follows:
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:28][C:29](=[CH:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:30](Cl)=[O:31].O>C(OC(C)C)(C)C>[CH3:28][C:29](=[CH:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:30]([N:14]([CH:11]1[CH2:10][CH2:9][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:13][CH2:12]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:31]
Reactant: CC(=Cc1ccccc1)C(=O)Cl
Reactant: c1ccc(CN2CCC(Nc3ccccc3)CC2)cc1
Solvent: O
Solvent: CC(C)OC(C)C
Solvent: CCN(CC)CC
Product: CC(=Cc1ccccc1)C(=O)N(c1ccccc1)C1CCN(Cc2ccccc2)CC1
Reaction time: 0.5 h
Yield: 90.2 %

Procedure:
To a mixture of N-(1-benzyl-4-piperidinyl)aniline (6.4 g), diisopropyl ether (70 ml) and triethylamine (4.8 ml) is added at 70° C. a solution of α-methylcinnamoyl chloride (4.9 g) in diisopropyl ether (10 ml). After stirring at the same temperature for 30 minutes, water is added to the reaction solution and the mixture is extracted with ethyl acetate. The extract is concentrated by distilling off the solvent and to the resulting residue is added diethyl ether and the formed crystals are separated by filtration to give N-(α-methylcinnamoyl)-N-(1-benzyl-4-piperidinyl)aniline (8.9 g), m.p. 150°-152° C.