Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:14][CH2:13][N:12]3[C:7](=[C:8]([CH2:22][NH:23][CH2:24][C:25]#[N:26])[CH:9]=[C:10]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[C:11]3=[O:15])[C:6]=2[CH:27]=1.[CH:28](O)=[O:29].C(OC(=O)C)(=O)C>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:14][CH2:13][N:12]3[C:7](=[C:8]([CH2:22][N:23]([CH2:24][C:25]#[N:26])[CH:28]=[O:29])[CH:9]=[C:10]([C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=4)[C:11]3=[O:15])[C:6]=2[CH:27]=1
Reactant: O=CO
Reactant: N#CCNCc1cc(-c2ccccc2)c(=O)n2c1-c1cc(Cl)ccc1CC2
Solvent: CC(=O)OC(C)=O
Solvent: C1CCOC1
Product: N#CCN(C=O)Cc1cc(-c2ccccc2)c(=O)n2c1-c1cc(Cl)ccc1CC2
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A suspension of 0.376 g of [[(10-chloro-6,7-dihydro-4-oxo-3-phenyl-4H-benzo[a]quinolizine-1-yl)methyl]amino]-acetonitrile in 10 ml of tetrahydrofuran was treated with 0.1 ml of formic acid-acetic acid anhydride and the clear yellow solution which formed after a short time was stirred at room temperature for 45 minutes. After evaporation the residue was taken up in chloroform, washed with 10 percent potassium bicarbonate solution and saturated sodium chloride solution, dried over magnesium sulfate, concentrated and purified by chromatography on silica gel with toluene/dioxane (9:1). N-[(10-Chloro-6,7-dihydro-4-oxo-3-phenyl-4H- benzo[a]quinolizine-1-yl)methyl]-N-(cyanomethyl)formamide formed a yellow resin.
Reaction SMILES: O.[OH-].[Li+].[CH2:4]([N:7]([CH2:22][CH2:23][CH3:24])[C:8]([C:10]1[CH:11]=[C:12]([CH:17]=[C:18]([CH2:20][CH3:21])[CH:19]=1)[C:13]([O:15]C)=[O:14])=[O:9])[CH2:5][CH3:6]>C1COCC1.O.Cl>[CH2:22]([N:7]([CH2:4][CH2:5][CH3:6])[C:8]([C:10]1[CH:11]=[C:12]([CH:17]=[C:18]([CH2:20][CH3:21])[CH:19]=1)[C:13]([OH:15])=[O:14])=[O:9])[CH2:23][CH3:24]
Reactant: CCCN(CCC)C(=O)c1cc(CC)cc(C(=O)OC)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCCN(CCC)C(=O)c1cc(CC)cc(C(=O)O)c1
Temperature: 22.5 °C
Reaction time: 3 h

Procedure:
Lithium hydroxide monohydrate (0.0680 g, 1.6 mmol) is added to a mixture of methyl 3-[(dipropylamino)carbonyl]-5-ethylbenzoate (PREPARATION 20, 0.450 g, 1.6 mmol) in a mixture of THF/methanolwater (2/1/1, 8 mL). The mixture is stirred at 20-25 degrees C. for 3 hours. The mixture is then diluted with water (20 mL) and hydrochloric acid (1 N) is added to bring the pH to less than 3. The aqueous mixture is extracted with ethyl acetate. The organic phase is separated and washed with saline, dried over anhydrous magnesium sulfate, filtered and concentrated to give the title compound, MS (ESI+) for C16H23NO3 m/z (M+H)+=278.2.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH:11]1[CH:15]2[O:16][C:17]([CH3:20])([CH3:19])[O:18][CH:14]2[CH:13]([CH2:21][OH:22])[O:12]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:42][O:43][C:44]([C:46]1[O:50][N:49]=[C:48](O)[CH:47]=1)=[O:45].CCOC(/N=N/C(OCC)=O)=O>ClCCl>[CH3:42][O:43][C:44]([C:46]1[O:50][N:49]=[C:48]([O:22][CH2:21][CH:13]2[CH:14]3[CH:15]([O:16][C:17]([CH3:19])([CH3:20])[O:18]3)[CH:11]([N:6]3[CH:5]=[N:4][C:3]4[C:7]3=[N:8][CH:9]=[N:10][C:2]=4[Cl:1])[O:12]2)[CH:47]=1)=[O:45]
Reactant: CC1(C)OC2C(CO)OC(n3cnc4c(Cl)ncnc43)C2O1
Reactant: COC(=O)c1cc(O)no1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)c1cc(OCC2OC(n3cnc4c(Cl)ncnc43)C3OC(C)(C)OC23)no1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.5 %

Procedure:
To a solution of [6-(6—Chloro-purin-9-yl)-2,2-dimethyl-tetrahydro-furo[3,4-d][1,3]dioxol-4-yl]-methanol (0.570 g, 1.74 mmol) in 16 mL of dry dichloromethane was added polymer-bound triphenylphosphine (PS-TPP; Argonaut Tech., 2.14 mmol/g, 0.91 g, 1.2 eq), followed by methyl-3-hydroxy-5-isoxazolecarboxylate (0.248 g, 1 eq). The mixture was sonicated for 15 minutes then stirred at room temperature for 1 h under argon. The reaction mixture was cooled to 0° C. and under argon flow diethylazodicarboxylate (0.33 g, 1.1 eq), dissolved in 1 ml of dichloromethane, was added dropwise via syringe. The mixture was protected from light and stirred at 0° C. for 30 min. then at room temperature for 20 h. The resin was washed liberally with dichloromethane and methanol. The organic solution obtained from the washes was concentrated to give, after flash chromatography purification, 0.740 g of the product as a white solid (95% yield). 1H NMR (300 MHz, CDCl3) δ 8.76 (s, 1H), 8.23 (s, 1H), 6.42 (s, 1H), 6.23 (d, J=2.1 Hz, 1H), 5.43 (dd, J=2.1 Hz, 1H), 5.14 (dd, J=3.6 Hz, 1H), 4.7 (m, 1H), 4.61 (dd, J=3.9 Hz, 1H), 4.49 (dd, J=5.7 Hz, 1H), 3.93 (s, 3H), 1.65 (s, 3H), 1.42 (s, 3H). MW calculated for C18H18ClN5O7 (MH+) 452, found 452 by LCMS.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([N+:20]([O-:22])=[O:21])=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](O[Si](C)(C)C)([C:13]#[N:14])[CH2:8][CH2:7][CH2:6]2.C(Cl)(C)=O>CC(O)=O>[CH3:1][O:2][C:3]1[C:4]([N+:20]([O-:22])=[O:21])=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([C:13]#[N:14])=[CH:8][CH2:7][CH2:6]2
Reactant: COc1ccc2c(c1[N+](=O)[O-])CCCC2(C#N)O[Si](C)(C)C
Solvent: CC(=O)Cl
Solvent: CC(=O)O
Product: COc1ccc2c(c1[N+](=O)[O-])CCC=C2C#N
Yield: 100 %

Procedure:
A solution of 6-methoxy-5-nitro-1-trimethylsilyloxy-l,2,3,4-tetrahydronaphthalene-1-carbonitrile (1.3 g, 4.0 mmol) and AcCl (1.0 ml) in 20 ml AcOH was stirred for 2 h at 80°-100° C. The resulting reaction mixture was concentrated in vacuo to yield the desired product as a colorless oil (0.86 g, 4.0 mmol, 96% for two steps), which was subjected to the following step without any further purification. 1H NMR (300 MHz, CDCl3):δ 2.48 (dt, 2H, J=2.3, 6.7 Hz), 2.78 (t, 2H, J=8.9 Hz ), 3.89 (s, 3H), 6.82 (t, 1H, J=2.3 Hz), 6.92 (d, 1H, J=8.9 Hz), 7.53 (d, 1H, J=8.9 Hz).
Reaction SMILES: [CH:1]1([NH:7][CH2:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=2)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:21](O)C>O>[CH:1]1([N:7]2[CH2:8][C:9](=[O:10])[N:11]([C:12]3[CH:13]=[CH:14][C:15]([N+:18]([O-:20])=[O:19])=[CH:16][CH:17]=3)[CH2:21]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(CNC1CCCCC1)Nc1ccc([N+](=O)[O-])cc1
Reactant: CCO
Solvent: O
Product: O=C1CN(C2CCCCC2)CN1c1ccc([N+](=O)[O-])cc1

Procedure:
2-Cyclohexylamino-N-(4-nitrophenyl)-acetamide (3.5g) were added to ethanol (85 ml). p-Formaldehyde (0.8g) in water (110 ml) was added and the mixture was refluxed 4 hours, cooled and filtered to yield 3.1 g, m.p. 132°-133°C
Reaction SMILES: [CH3:1][C:2]1([C:18](O)=[O:19])[CH2:7][CH2:6][N:5]([C:8]2[C:9]3[C:16]([CH3:17])=[CH:15][NH:14][C:10]=3[N:11]=[CH:12][N:13]=2)[CH2:4][CH2:3]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[NH2:52][C:53]1[CH:54]=[C:55]([CH:62]=[CH:63][CH:64]=1)[C:56]([NH:58][CH:59]([CH3:61])[CH3:60])=[O:57]>CN(C=O)C>[CH:59]([NH:58][C:56]([C:55]1[CH:54]=[C:53]([NH:52][C:18]([C:2]2([CH3:1])[CH2:3][CH2:4][N:5]([C:8]3[C:9]4[C:16]([CH3:17])=[CH:15][NH:14][C:10]=4[N:11]=[CH:12][N:13]=3)[CH2:6][CH2:7]2)=[O:19])[CH:64]=[CH:63][CH:62]=1)=[O:57])([CH3:61])[CH3:60]
Reactant: CC(C)NC(=O)c1cccc(N)c1
Reactant: Cc1c[nH]c2ncnc(N3CCC(C)(C(=O)O)CC3)c12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1c[nH]c2ncnc(N3CCC(C)(C(=O)Nc4cccc(C(=O)NC(C)C)c4)CC3)c12
Temperature: 50 °C
Reaction time: 48 h
Yield: 48.1 %

Procedure:
To a solution of 4-methyl-1-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4yl)-piperidine-4-carboxylic acid from example 6, step B, (0.030 g, 0.11 mmol) in DMF (1 mL) were added HATU (0.042 g, 0.11 mmol), triethylamine (0.028 mL, 0.22 mmol) and 3-amino-N-isopropyl-benzamide (0.029 mg, 0.17 mmol). The reaction was stirred at 50° C. for 48 hours and concentrated under vacuum. The residue was purified by prep HPLC to give the title compound (0.023 g, 48%).
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].Br[C:8]1[CH:9]=[C:10]([N+:15]([O-:17])=[O:16])[CH:11]=[CH:12][C:13]=1[F:14].[C:18]([O:22][C:23]([N:25]1[CH:29]=[CH:28][CH:27]=[C:26]1B(O)O)=[O:24])([CH3:21])([CH3:20])[CH3:19].C(=O)(O)[O-].[Na+]>C(COC)OC.O>[F:14][C:13]1[CH:12]=[CH:11][C:10]([N+:15]([O-:17])=[O:16])=[CH:9][C:8]=1[C:26]1[N:25]([C:23]([O:22][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:24])[CH:29]=[CH:28][CH:27]=1
Reactant: O=[N+]([O-])c1ccc(F)c(Br)c1
Reactant: CC(C)(C)OC(=O)n1cccc1B(O)O
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CC(C)(C)OC(=O)n1cccc1-c1cc([N+](=O)[O-])ccc1F

Procedure:
1.1 g of tetrakis-triphenylphosphine palladium and 4.2 g of sodium carbonate were added to a solution of 4.3 g of 3-bromo-4-fluoro-nitrobenzene and 5.0 g of 1-(t-butoxycarbonyl)pyrrole-2-boronic acid in a mixture of 130 ml of dimethoxyethane and 22 ml of water, and the reaction liquid was heated overnight under reflux. Aqueous saturated sodium bicarbonate was added to the reaction liquid, and this was extracted with ethyl acetate. The organic layer was washed with water and saturated saline in order, and dried with anhydrous sodium sulfate. The solvent was evaporated away under reduced pressure, and the resulting residue was purified through silica gel column chromatography (developing solvent: hexane/ethyl acetate=20/1) to obtain the entitled compound as a yellow oily substance.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2.[CH3:11][O:12][C:13](=[O:24])[C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][CH:22]=O)=[CH:16][CH:15]=1.C(O)(C(F)(F)F)=O.C([SiH](CC)CC)C>C(Cl)Cl>[CH3:11][O:12][C:13](=[O:24])[C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][CH2:22][C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[NH:3][C:2]=2[CH3:1])=[CH:16][CH:15]=1
Reactant: Cc1cc2ccccc2[nH]1
Reactant: COC(=O)c1ccc(CCC=O)cc1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ccc(CCCc2c(C)[nH]c3ccccc23)cc1
Reaction time: 8 h

Procedure:
To a solution of 2-Methyl-1H-indole (0.86 g, 5.2 mmol) and 4-(3-Oxo-propyl)-benzoic acid methyl ester (1.0 g, 5.2 mmol) in methylene chloride (50 mL), was added TFA (1.78 g, 15.6 mmol), followed by triethylsilane (1.81 g, 15.6 mmol). The reaction mixture was stirred overnight, quenched with sat. NaHCO3 solution (50 mL), and the organic layer was washed with sat. NaHCO3 solution, water, brine, and dried (Na2SO4). Solvent was removed under reduced pressure, and the residue was purified by flash column chromatography with 10-20% EtOAc/hexanes to yield the desired 4-[3-(2-Methyl-1H-indol-3-yl)-propyl]-benzoic acid methyl ester in 88% (1.67 g) yield.
Reaction SMILES: [S-:1][C:2]#[N:3].[K+].[NH2:5][C:6]1[CH:7]=[CH:8][C:9]([O:12][C:13]2[CH:14]=[CH:15][C:16]([CH3:33])=[C:17]([NH:19][C:20](=[O:32])[C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([C:30]#[N:31])([CH3:29])[CH3:28])[CH:22]=3)[CH:18]=2)=[N:10][CH:11]=1.BrBr>C(O)(=O)C>[NH2:3][C:2]1[S:1][C:11]2[C:6]([N:5]=1)=[CH:7][CH:8]=[C:9]([O:12][C:13]1[CH:14]=[CH:15][C:16]([CH3:33])=[C:17]([NH:19][C:20](=[O:32])[C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([C:30]#[N:31])([CH3:28])[CH3:29])[CH:22]=3)[CH:18]=1)[N:10]=2
Reactant: Cc1ccc(Oc2ccc(N)cn2)cc1NC(=O)c1cccc(C(C)(C)C#N)c1
Reactant: N#C[S-]
Agent: BrBr
Agent: [K+]
Solvent: CC(=O)O
Product: Cc1ccc(Oc2ccc3nc(N)sc3n2)cc1NC(=O)c1cccc(C(C)(C)C#N)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 95.4 %

Procedure:
Potassium thiocyanate (2.02 g, 20.8 mmol) was suspended in acetic acid (40 mL), and the mixture was stirred at room temperature for 10 min. A solution of N-{5-[(5-aminopyridin-2-yl)oxy]-2-methylphenyl}-3-(1-cyano-1-methylethyl)benzamide (2.0 g, 5.20 mmol) in acetic acid (40 mL) was added to the obtained solution, and the mixture was further stirred at room temperature for 10 min. A solution of bromine (914 mg, 5.72 mmol) in acetic acid (28 mL) was slowly added dropwise to the obtained solution. After the completion of the dropwise addition, the mixture was stirred at room temperature for 4 hr. The yielded yellow insoluble material was filtered off, and washed with acetic acid. The filtrate and washing solution were combined, and concentrated under reduced pressure. The obtained residue was suspended in ethyl acetate (300 mL), and the suspension was washed with 5% aqueous sodium hydrogen carbonate solution (300 mL), water (300 mL) and saturated brine (300 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (hexane/ethyl acetate=20/80→0/100), and the obtained solution was concentrated under reduced pressure to give the title compound (2.20 g, 95%) as a colorless amorphous substance.
Reaction SMILES: [C:1]1([C@H:7]2[C:12]3[NH:13][C:14]4[C:19]([C:11]=3[CH2:10][C@@H:9]([C:20](OC)=[O:21])[NH:8]2)=[CH:18][CH:17]=[CH:16][CH:15]=4)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:24]1([N:30]=[C:31]=[O:32])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>>[CH:24]1([N:30]2[C:20](=[O:21])[C@@H:9]3[N:8]([C@@H:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[C:12]4[NH:13][C:14]5[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=5[C:11]=4[CH2:10]3)[C:31]2=[O:32])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: O=C=NC1CCCCC1
Reactant: COC(=O)[C@@H]1Cc2c([nH]c3ccccc23)[C@H](c2ccccc2)N1
Product: O=C1[C@H]2Cc3c([nH]c4ccccc34)[C@H](c3ccccc3)N2C(=O)N1C1CCCCC1

Procedure:
The same method as employed in the preparation of Example 1 but starting from cis methyl 1,2,3,4-tetrahydro-1-phenyl-9H-pyrido[3,4-b]indole-3-carboxylate and cyclohexyl isocyanate gave after recrystallisation from methanol, the title compound as white crystals m.p.:267-270° C.
Reaction SMILES: C(O[CH:4]=[C:5]([C:8]#[N:9])[C:6]#[N:7])C.Cl.[CH:11]([NH:14][NH2:15])([CH3:13])[CH3:12].C(N(C(C)C)CC)(C)C>CCO>[NH2:9][C:8]1[N:14]([CH:11]([CH3:13])[CH3:12])[N:15]=[CH:4][C:5]=1[C:6]#[N:7]
Reactant: CCOC=C(C#N)C#N
Reactant: CC(C)NN
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CC(C)n1ncc(C#N)c1N
Temperature: 25 °C
Reaction time: 18 h

Procedure:
(Ethoxymethylene)malononitrile (12.83 g, 105 mmol) and isopropylhydrazine hydrochloride (11.06 g, 100 mmol) were combined in EtOH (250 mL). Diisopropylethylamine (36.6 mL, 210 mmol) was added drop-wise, resulting in some warming of the reaction mixture. The reaction was allowed to stir for about 18 h at room temp. Volatiles were then removed in vacuo, and the resulting viscous yellow oil was dissolved in dichloromethane and loaded onto a short column of silica gel. The column was eluted with dichloromethane (about 300 mL), followed by a 1:1 mixture of EtOAc and hexanes (about 750 mL), and the EtOAc:hexanes eluant was concentrated under reduced pressure to provide C20 as a pale yellow solid. Yield: 12.1 g, 80.6 mmol, 81%. LCMS m/z 151.1 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 1.26 (d, J=6.6 Hz, 6H), 4.41 (septet, J=6.5 Hz, 1H), 6.52 (br s, 2H), 7.53 (s, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([CH3:10])[CH:3]=1.Br[CH2:12][CH2:13][CH3:14]>>[CH3:10][C:4]1[CH:3]=[C:2]([O:1][CH2:12][CH2:13][CH3:14])[CH:9]=[CH:8][C:5]=1[CH:6]=[O:7]
Reactant: Cc1cc(O)ccc1C=O
Reactant: CCCBr
Product: CCCOc1ccc(C=O)c(C)c1
Yield: 70.1 %

Procedure:
The compound was synthesized as in Example 87.1, using 4-hydroxy-2-methylbenzaldehyde (54.4 mg, 0.40 mmol) in place of 4-hydroxybenzaldehyde and 1-bromopropane (98 mg, 0.80 mmol) in place of 1-iodo-(3,3,3-trifluoro)propane to give 2-methyl-4-propoxybenzaldehyde (50 mg, 71%). Used without further characterization.
Reaction SMILES: [CH2:1]([NH:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]([OH:19])=[O:18])=[N:15][CH:16]=1)[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[H][H]>[OH-].[Na+].C(O)C.[Pd]>[C:4]1([CH2:3][CH2:2][CH2:1][NH:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]([OH:19])=[O:18])=[N:15][CH:16]=2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: [H][H]
Reactant: O=C(O)c1ccc(NCC=Cc2ccccc2)cn1
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1ccc(NCCCc2ccccc2)cn1

Procedure:
3 g of 5-cinnamylamino pyridine-2-carboxylic acid are dissolved in 50 ml of 0.5 N aqueous sodium hydroxide containing 1 ml of ethanol and the solution is hydrogenated over 0.5 g of 10% palladium on charcoal at atmospheric pressure and room temperature. After the hydrogen uptake has ceased, the mixture is filtered and the filtrate acidified with hydrochloric acid. The solution is extracted with ethyl acetate, the extract washed with water, dried, evaporated and the residue crystallized from methanol, to yield the 5-(3-phenylpropylamino)-pyridine-2-carboxylic acid melting at 167°-169°.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[N:6][C:7]([C:12]3[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=3)=[N:8][C:9]=2[NH2:11])[NH:4][N:3]=1.[H-].[Na+].[CH:20]1([CH2:25]Br)[CH2:24][CH2:23][CH2:22][CH2:21]1>CN(C=O)C>[CH:20]1([CH2:25][N:4]2[C:5]3=[N:6][C:7]([C:12]4[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=4)=[N:8][C:9]([NH2:11])=[C:10]3[C:2]([CH3:1])=[N:3]2)[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: Cc1n[nH]c2nc(-c3ccncc3)nc(N)c12
Reactant: BrCC1CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1nn(CC2CCCC2)c2nc(-c3ccncc3)nc(N)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 26.4 %

Procedure:
To a solution of 3-methyl-6-(4-pyridyl)-pyrazolo[3,4-d]pyrimidin-4-amine (6.0 g, 0.027 mol) in DMF (50 ml) at 0° C. was added 60% NaH/mineral oil dispersion (1.06 g, 0.027 mol) in one portion. The reaction mixture was warmed to room temperature and stirred for 1 hour. The reaction mixture was cooled to 0° C. and cyclopentylmethyl bromide (4.3 g, 0.027 mol) was added dropwise over 5 minutes. The reaction mixture was warmed to room temperature and stirred for 50 hours. The solvent was removed in vacuo, the yellow slurry was added to water (100 ml) and acidified with acetic acid. The resulting paste was stripped to dryness and the residue was slurried with ethanol. A tan solid was collected by filtration and purified by column chromatography on silica eluting with ether/ethanol/water (97.5/2/0.5) followed by recrystallization from cyclohexane to afford 2.2 g (26%) of 1-cyclopentylmethyl-3-methyl-6-(4-pyridyl)-pyrazolo[3,4-d]-pyrimidin-4-amine, m.p. 177°-178° C.
Reaction SMILES: [Cl:1][CH2:2][C:3]([N:5]([CH3:9])[C:6](Cl)=[O:7])=[O:4].[CH3:10][C:11]1([CH3:21])[CH2:15][C:14]2[CH:16]=[CH:17][CH:18]=[C:19]([OH:20])[C:13]=2[O:12]1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[Cl:1][CH2:2][C:3]([N:5]([CH3:9])[C:6](=[O:7])[O:20][C:19]1[C:13]2[O:12][C:11]([CH3:21])([CH3:10])[CH2:15][C:14]=2[CH:16]=[CH:17][CH:18]=1)=[O:4]
Reactant: CC1(C)Cc2cccc(O)c2O1
Reactant: CN(C(=O)Cl)C(=O)CCl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CN(C(=O)CCl)C(=O)Oc1cccc2c1OC(C)(C)C2
Yield: 79.4 %

Procedure:
A mixture of 1.0 g (0.006 m) of N-chloroacetyl-N-methylcarbamoyl chloride and 1.0 g (0.006 m) of 2,3-dihydro-2,2-dimethyl-7-benzofuranol in 15 cc dry toluene was stirred under nitrogen and 0.61 g (0.006 m) of triethylamine was added dropwise over a period of 10 mts. The mixture was stirred for an additional period of 2 hrs., filtered through a bed of celite and then the solvent was stripped off under reduced pressure to yield 1.39 g (yield 77%) of 2,3-dihydro-2,2-dimethyl-7-benzofuranyl N-chloroacetyl-N-methylcarbamate, a light yellow oil. NMR (CDCl3): δ 7.3-6.6 (mn,3H); 4.75(s,2H); 3.40 (s,3H); 3.05 (s,2H) and 1.45 (s,6H). IR (CHCl3): ν1760 and 1725 cm-1
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][CH2:8][CH2:9][O:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:20]=1[N:19]=[C:18]([CH3:21])[CH:17]=[C:16]2Cl)([CH3:4])([CH3:3])[CH3:2].[Cl:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][C:32]=1[Cl:33])[CH2:28][NH2:29]>CS(C)=O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Cu+2]>[C:1]([O:5][C:6](=[O:23])[NH:7][CH2:8][CH2:9][O:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:20]=1[N:19]=[C:18]([CH3:21])[CH:17]=[C:16]2[NH:29][CH2:28][C:27]1[CH:30]=[CH:31][C:32]([Cl:33])=[C:25]([Cl:24])[CH:26]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(Cl)c2cccc(OCCNC(=O)OC(C)(C)C)c2n1
Reactant: NCc1ccc(Cl)c(Cl)c1
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: O
Solvent: CS(C)=O
Product: Cc1cc(NCc2ccc(Cl)c(Cl)c2)c2cccc(OCCNC(=O)OC(C)(C)C)c2n1
Yield: 12.5 %

Procedure:
[2-(4-Chloro-2-methylquinolin-8-yloxy)-ethyl]-carbamate tert-butyl ester (1.30 g, 3.86 mmole), 3,4-dichlorobenzylamine (1.36 g, 7.72 mmole) and a catalytic effective amount of copper(II)sulphate pentahydrate in dimethylsulfoxide (0.2 mL) were stirred at 155° C. for 30 min in a microwave oven. The organic phases were washed with water and saturated NaCl solution, dried and the solvent was removed. The residue thus obtained was purified using silica gel chromatography, eluting with dichloromethane:water 90:10. Precipitation in ethyl acetate gave a brownish solid (230 mg, 13%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[C@@H:4]([NH:10][CH2:11][C:12]([O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[Cl:27])=[CH:13][C:14](OCCC)=[O:15])[CH2:5][C:6]([F:9])([F:8])[CH3:7]>C(#N)C.ClCCl>[CH3:1][O:2][C:3](=[O:28])[C@@H:4]([N:10]1[CH2:11][C:12]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[Cl:27])=[CH:13][C:14]1=[O:15])[CH2:5][C:6]([F:9])([F:8])[CH3:7]
Reactant: CCCOC(=O)C=C(CN[C@@H](CC(C)(F)F)C(=O)OC)Oc1ccccc1Cl
Solvent: CC#N
Solvent: ClCCl
Product: COC(=O)[C@H](CC(C)(F)F)N1CC(Oc2ccccc2Cl)=CC1=O
Temperature: 140 °C
Yield: 44.1 %

Procedure:
A solution of (S)-2-[2-(2-chloro-phenoxy)-3-propoxycarbonyl-allylamino]-4,4-difluoro-pentanoic acid methyl ester (255 mg, 0.63 mmol) in acetonitrile (2 mL) was placed in a sealed microwave reaction tube and heated in a microwave reactor at 140° C. for 3.5 h. The mixture was diluted with dichloromethane and concentrated in vacuo with silica gel (2 g). Purification by Biotage flash chromatography (Aspire 40 g column, 16% ethyl acetate/hexanes to 50% ethyl acetate/hexanes) afforded (S)-2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4,4-difluoro-pentanoic acid methyl ester (100 mg, 32% over two steps) as a colorless gum: HR-ES-MS m/z calculated for C16H16NO4ClF2 [M+Na]+ 382.0628, observed 382.0629.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][NH2:9])=[CH:4][CH:3]=1.[C:10]([C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)(=O)[CH3:11]>>[I:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][N:9]=[C:10]([C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)[CH3:11])=[CH:4][CH:3]=1
Reactant: CC(=O)c1cccnc1
Reactant: NNc1ccc(I)cc1
Product: CC(=NNc1ccc(I)cc1)c1cccnc1

Procedure:
Analogously to the process described in Example 1A, 5.0 g (21.36 mmol) of 4-iodophenylhydrazine and 3-acetylpyridine give 5.15 g (71% of theory) of the title compound.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:20])[N:9]2[C:12]2[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:19])=[C:4]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[Cl:27])[N:3]=1.N[CH:29]1[CH2:34][C:33](C)(C)[NH:32][C:31](C)(C)[CH2:30]1>CS(C)=O>[C:5]([N:32]1[CH2:31][CH2:30][CH:29]([C:2]2[CH:11]=[C:10]3[C:5]([CH:6]=[CH:7][C:8](=[O:20])[N:9]3[C:12]3[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:19])=[C:4]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[Cl:27])[N:3]=2)[CH2:34][CH2:33]1)([CH3:10])([CH3:6])[CH3:4]
Reactant: O=c1ccc2c(-c3ccccc3Cl)nc(Br)cc2n1-c1c(Cl)cccc1Cl
Reactant: CC1(C)CC(N)CC(C)(C)N1
Solvent: CS(C)=O
Product: CC(C)(C)N1CCC(c2cc3c(ccc(=O)n3-c3c(Cl)cccc3Cl)c(-c3ccccc3Cl)n2)CC1
Temperature: 130 °C
Reaction time: 3 h

Procedure:
A mixture of 200 mg of 7-bromo-5-(2-chlorophenyl)-1-(2,6-dichlorophenyl)-1,6-naphthyridin-2(1H)-one (COMPOUND HHH2) and 1 mL of 4-amino-2,2,6,6-tetramethylpiperidine in 0.5 mL of DMSO was stirred at 130° C. for 3 h. The mixture was cooled, filtered, and purified by reverse-phase preparative HPLC (YMC C18 100×50 mm column; 10:90 to 90:10 v/v acetonitrile/water+0.1% TFA over 15 min; 20 mL/min) to yield the title compound. Mass spectrum (ESI) 557 (M+1). 1H NMR (500 MHz, CD3OD): selected peaks δ 1.32-1.58 (m, 14H), 2.05-2.24 (m, 2H), 4.40 (br s, 1H).