Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[C:8]([Cl:11])[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[Cl:12][C:13]1[CH:18]=[C:17](B(O)O)[CH:16]=[CH:15][N:14]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:11][C:8]1[CH:9]=[CH:10][C:5]2[N:6]([C:2]([C:17]3[CH:16]=[CH:15][N:14]=[C:13]([Cl:12])[CH:18]=3)=[CH:3][N:4]=2)[CH:7]=1
Reactant: Clc1ccc2ncc(Br)n2c1
Reactant: OB(O)c1ccnc(Cl)c1
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Clc1ccc2ncc(-c3ccnc(Cl)c3)n2c1
Temperature: 100 °C

Procedure:
To a solution of 3-bromo-6-chloro-imidazo[1,2-a]pyridine (1 eq, 18.1 mmol, 4.2 g), 2-chloropyridin-4-yl boronic acid (1.05 eq, 19 mmol, 3 g), Na2CO3 (2 eq, 36.2 mmol, 3.84 g) in dioxane (30 ml) and water (10 ml), under an inert atmosphere of argon is added bis(triphenylphosphine)palladium II chloride (1.23 g). The reaction mixture is heated at 100° C. for 16 hours. The mixture is diluted with H2O (50 ml) and extracted with EtOAc. The combined organic portions are washed with brine, dried (MgSO4) and concentrated in vacuo. The residue is purified by flash chromatography on silica eluting with 0-50% EtOAc in iso-hexane to afford the title compound; [M+H]+=264 (266).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:17](=[O:19])[CH3:18])[CH:13]=2)[NH:8][CH:7]=1)=[O:5])[CH3:2].[F:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27]Cl)=[CH:23][CH:22]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:17](=[O:19])[CH3:18])[CH:13]=2)[N:8]([CH2:27][C:24]2[CH:25]=[CH:26][C:21]([F:20])=[CH:22][CH:23]=2)[CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c[nH]c2ccc(C(C)=O)cc2c1=O
Reactant: Fc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cn(Cc2ccc(F)cc2)c2ccc(C(C)=O)cc2c1=O
Temperature: 100 °C
Reaction time: 18 h
Yield: 88.8 %

Procedure:
A suspension of ester compound 8 (0.6 g, 2.3 mmol) 4-fluorophenylmethyl chloride (0.97 g, 6.8 mmol) and anhydrous K2CO3 (0.44 g, 6.8 mmol) in dry DMF (20 mL) was stirred for 18 hours at 100° C. After this time the mixture was poured into water (100 mL) and the solid that precipitated was filtered, washed with water, ethanol and light petroleum ether, in turn, and finally dried under IR lamp to give compound 9 (0.75 g, 95%); mp 207-209° C. (washed with dry ethanol).
Reaction SMILES: C(S)C.[H-].[Na+].C[O:7][C:8]1[CH:17]=[C:16]2[C:11]([C:12]([C:18]3[C:19]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=4)=[N:20][N:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=34)=[CH:13][CH:14]=[N:15]2)=[CH:10][CH:9]=1>CN(C=O)C>[N:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[C:19]1[C:18]([C:12]2[C:11]3[C:16](=[CH:17][C:8]([OH:7])=[CH:9][CH:10]=3)[N:15]=[CH:14][CH:13]=2)=[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][N:21]2[N:20]=1
Reactant: COc1ccc2c(-c3c(-c4ccccn4)nn4ccccc34)ccnc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CCS
Solvent: CN(C)C=O
Product: Oc1ccc2c(-c3c(-c4ccccn4)nn4ccccc34)ccnc2c1
Yield: 51.4 %

Procedure:
Add ethanethiol (6.8 mL, 92.5 mmol), followed by a sodium hydride (60% dispersion in mineral oil, 3.7 g, 92.5 mmol) to a solution of 7-methoxy-4-(2-pyridin-2-yl-pyrazolo[1,5-a]pyridin-3-yl)-quinoline (1.63 g, 4.6 mmol) in DMF (50 mL) at room temperature. Following the same procedure described above affords the title compound 0.8 g (52%) as a yellow solid.
Reaction SMILES: [O:1]=[C:2]1[C:15]2[CH:14]=[C:13]([C:16]([OH:18])=[O:17])[CH:12]=[CH:11][C:10]=2[O:9][C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2.[CH2:19](O)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30].S(=O)(=O)(O)O.[Na]>S(=O)(=O)(O)O>[O:1]=[C:2]1[C:15]2[CH:14]=[C:13]([C:16]([O:18][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH3:19])=[O:17])[CH:12]=[CH:11][C:10]=2[O:9][C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2
Reactant: CCCCCCCCCCCCO
Reactant: O=C(O)c1ccc2oc3ccccc3c(=O)c2c1
Agent: O=S(=O)(O)O
Agent: [Na]
Product: CCCCCCCCCCCCOC(=O)c1ccc2oc3ccccc3c(=O)c2c1
Reaction time: 6 h
Yield: 81.8 %

Procedure:
A mixture of 12.01 g (50 mmol) of the above 9-oxo-9H-xanthene-2-carboxylic acid, 77.4 g (420 mmol) of n-dodecanol and 0.2 g (2 mmol) of concentrated sulfuric acid is kept at 140° C. for 6 hours. The sulfuric acid is neutralized with 0.33 g (4 mmol) of sodium acetam and the excess n-dodecanol is removed by distillation (98° C./0.1 mbar). The brown residue is taken up in isopropanol and the product which has precipitated is filtered off and dried uider a high vacuum. 16.7 g (82%) of n-dodecyl 9-oxo-9H-xanthene-2-carboxylate, melting point 79°-81° C., result as a beige powder.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH2:16][S:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)/[CH:10]=[CH:11]/[C:12]([O:14][CH3:15])=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].CO>C(OCC)(=O)C.[Pd]>[C:1]([O:5][C:6]([NH:8][CH:9]([CH2:16][S:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)/C=C/C(CSc1ccccc1)NC(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)CCC(CSc1ccccc1)NC(=O)OC(C)(C)C

Procedure:
A mixture of Example 384A (650 mg, 1.92 mmol) and 10% Pd/C (2.3 g, 2.2 mmol) in ethyl acetate (15 mL0 and methanol (5 mL) was stirred at room temperature under a hydrogen balloon for 6 hours and filtered through diatomaceous earth (Celite®). The pad was rinsed with hot ethyl acetate, and the combined organic phases were concentrated to provide the desired product.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[F:9].[CH3:10][O:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][C:19]=1[OH:20])[CH:15]=[O:16].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[F:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[CH2:2][O:20][C:19]1[CH:18]=[CH:17][C:14]([CH:15]=[O:16])=[CH:13][C:12]=1[O:11][CH3:10]
Reactant: Fc1ccccc1CBr
Reactant: COc1cc(C=O)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(C=O)ccc1OCc1ccccc1F
Yield: 99.5 %

Procedure:
0.5M solution of 1-bromomethyl-2-fluoro-benzene (1.5 mg, 8 mmol) in DMF was added dropwise to a suspension of 3-methoxy-4-hydroxy-benzaldehyde (1.1 g, 7.3 mmol), K2CO3 (1.51 g, 11 mmol) and KI (120 mg, 7.3 mmol) in DMF (100 ml). The reaction mixture was treated as described in Example 4. The residue was purified on silica gel, obtaining 1.89 g (quantitative yield) of the title compound, yield 100%.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:9][CH2:10][O:11][C:12]([CH2:14][C:15]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=O)=[O:13]>C1(C)C=CC=CC=1>[CH2:10]([O:11][C:12](=[O:13])[CH:14]=[C:15]([NH:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH3:9]
Reactant: NCc1ccccc1
Reactant: CCOC(=O)CC(=O)CC(=O)OCC
Solvent: Cc1ccccc1
Product: CCOC(=O)C=C(CC(=O)OCC)NCc1ccccc1
Temperature: 25 °C
Reaction time: 15.5 h

Procedure:
Benzylamine (89.1 g, 0.83 moles) is added over 10 minutes to a suspension of 5 A powdered molecular sieves (270 g) and diethyl 1,3-acetonedicarboxylate 160 g) (0.79 moles) in 350 ml toluene (external cooling applied to control exotherm). The suspension is stirred at room temperature for 14-17 hours and then filtered to provide 2. The filter cake is washed with three portions of toluene. The combined filtrates may be used as is in the subsequent ketene reaction.
Reaction SMILES: [CH3:1][N:2]([CH3:24])[CH2:3][CH2:4][CH2:5][N:6]([CH3:23])[C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:19])([F:18])[C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=1[N+:20]([O-])=O.[H][H]>CO.[Pd]>[CH3:24][N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][N:6]([CH3:23])[C:7]1[C:8]([NH2:20])=[CH:9][C:10]([C:13]([F:19])([F:18])[C:14]([F:15])([F:16])[F:17])=[CH:11][CH:12]=1
Reactant: CN(C)CCCN(C)c1ccc(C(F)(F)C(F)(F)F)cc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CN(C)CCCN(C)c1ccc(C(F)(F)C(F)(F)F)cc1N
Temperature: 25 °C
Reaction time: 18 h

Procedure:
N,N, N′-Trimethyl-N′-(2-nitro-4-pentafluoroethyl-phenyl)-propane-1,3-diamine (Step 2, 800 mg, 2.25 mmol) was dissolved in 15 mL MeOH. Palladium (120 mg, 0.307 mmol, 10% w/w on carbon) was added, a balloon containing hydrogen was inserted, and the reaction was stirred at RT for 18 h. The solution was then filtered through a pad of Celite and concentrated, yielding viscous brown oil. The crude mixture was purified using reverse phase chromatography to give the title compound as reddish-brown oil. MS (M+H)+=326; Calc'd 325.32 for C14H20F5N3.
Reaction SMILES: C(Cl)(=O)C([Cl:4])=O.[CH3:7][NH:8][C:9]([C:11]12[CH2:18][CH2:17][C:14]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])([CH2:15][CH2:16]1)[CH2:13][CH2:12]2)=O>C(Cl)Cl>[CH3:7][N:8]=[C:9]([Cl:4])[C:11]12[CH2:18][CH2:17][C:14]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])([CH2:15][CH2:16]1)[CH2:13][CH2:12]2
Reactant: CCCCCC12CCC(C(=O)NC)(CC1)CC2
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: CCCCCC12CCC(C(Cl)=NC)(CC1)CC2
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Oxalyl chloride (846 μL, 9.7 mmol) was added dropwise to a solution of N-methyl-4-pentylbicyclo[2.2.2]octane-1-carboxamide (3-C) (230 mg, 0.97 mmol) in methylene chloride (2.0 mL) and the mixture stirred at room temperature for 4 h. The solvent and excess reagent were removed in vacuo to provide N-methyl-4-pentylbicyclo[2.2.2]octane-1-carboximidoyl chloride (3-D). Toluene (1.5 mL) was added followed by 5-(2-chloro-4-methoxyphenyl)-1H-tetrazole (3-E) (204 mg, 0.97 mmol) and the mixture refluxed for 18 h. The reaction was cooled to room temperature and the precipitate was filtered, washed with cold toluene, hexane, dissolved in methylene chloride, dried (MgSO4) and concentrated in vacuo to provide 3-(2-chloro-4-methoxyphenyl)-4-methyl-5-(4-pentylbicyclo[2.2.2]oct-1-yl)-4H-1,2,4-triazole (3-F). Mass spectrum: 402 (M+1); 1H NMR (500 MHz, CDCl3): δ 0.94 (t, 3H); 1.27 (m, 8H); 1.56 (m, 6H); 2.13 (m, 6H); 3.56 (s, 3H); 3.89 (s, 3H); 6.95 (dd, 1H); 7.07 (d, 1H); 7.43 (d, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH:18][C:19](=[O:30])[C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=2)[CH:7]=[CH:8][C:9]=1[S:10][C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=1)([O-])=O.[NH4+].[Cl-]>[Fe]>[NH2:1][C:4]1[CH:5]=[C:6]([NH:18][C:19](=[O:30])[C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:27])[F:28])[CH:21]=2)[CH:7]=[CH:8][C:9]=1[S:10][C:11]1[CH:12]=[CH:13][C:14]([CH3:17])=[CH:15][CH:16]=1
Reactant: Cc1ccc(Sc2ccc(NC(=O)c3cccc(C(F)(F)F)c3)cc2[N+](=O)[O-])cc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Product: Cc1ccc(Sc2ccc(NC(=O)c3cccc(C(F)(F)F)c3)cc2N)cc1
Yield: 73 %

Procedure:
The product from Example 243a was reduced with Fe and NH4Cl following the procedure from Example 9E to give the title compound (420 mg, 73%).
Reaction SMILES: [C:1]1(=[O:9])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:10](OC)(OC)OC>C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:10][O:9][C:1]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: O=C1CCCCCCC1
Reactant: COC(OC)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: COC1=CCCCCCC1
Yield: 75.2 %

Procedure:
In the presence of 0.2 g of para-toluenesulfonic acid, 16.5 g (0.13 mol) of cyclooctanone and 16.5 g (0.15 mol) of trimethyl orthoformate were stirred at room temperature for four hours. The resultant mixture was heated at 100° C. for 14 hours. The vacuum distillation of the mixture gave 13.7 g (75% in yield) of 1-methoxycyclooctene having a boiling point of 83° to 88° C./27 mmHg.
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]1(=[O:13])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.Br[CH2:15][CH2:16][CH2:17][CH2:18]Br.Cl>C1(C)C=CC=CC=1>[CH2:15]1[C:8]2([CH2:9][CH2:10][CH2:11][CH2:12][C:7]2=[O:13])[CH2:18][CH2:17][CH2:16]1
Reactant: O=C1CCCCC1
Reactant: BrCCCCBr
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: Cc1ccccc1
Product: O=C1CCCCC12CCCC2
Temperature: 25 °C
Yield: 51.5 %

Procedure:
To a suspension of potassium tert-butoxide (22.4 g) in toluene (120 mL) was added a solution of cyclohexanone (9.82 g) and 1,4-dibromobutane (21.6 g) in toluene (30 mL) while stirring, followed by stirring the reaction mixture at 95° C. for 3.5 hours. After cooling down to room temperature and adding ice-cold water (100 mL) and 2N aqueous hydrochloric acid solution (50 mL) to the reaction mixture, the organic layer was separated. Then, after the aqueous layer was extracted with ethyl acetate, the organic layers were combined, washed with saturated brine, dried and concentrated. The residue was distilled in vacuo (90 to 100° C./3 to 4 mmHg) to give spiro[4.5]decan-6-one (7.85 g).
Reaction SMILES: CO[CH:3]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[C:13](=[O:28])[CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][N:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:18][CH2:17]2)[NH:5][C:4]1=[O:29].Br.[OH2:31]>>[OH:31][C:7]1[CH:8]=[CH:9][C:10]([C:13](=[O:28])[CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][N:19]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH2:18][CH2:17]2)=[C:11]2[C:6]=1[NH:5][C:4](=[O:29])[CH2:3][CH2:12]2
Reactant: COC1Cc2c(cccc2C(=O)CCN2CCN(c3ccccc3)CC2)NC1=O
Reactant: O
Agent: Br
Product: O=C1CCc2c(C(=O)CCN3CCN(c4ccccc4)CC3)ccc(O)c2N1

Procedure:
To 19.7 g of methoxy-5-[1-oxo-3-(4-phenyl-1-piperazinyl)propyl]-3,4-dihydrocarbostyril was added 300 ml of 47%-hydrobromic acid and the mixture was refluxed for 18 hours. The reaction mixture was concentrated under a reduced pressure to dryness. Then to the residue thus obtained was added water and again concentrated under a reduced pressure to dryness. Acetone was added to the crystalline residue and collected by filtration and were recrystallize from methanol. The crystals were suspended in 500 ml of water and the suspension was neutralized with 5%-sodium hydroxide aqueous solution and crystalline precipitates thus formed were collected by filtration and were washed with water. 17.1 Grams of 8-hydroxy-5-[1-oxo-3-(4-phenyl-1-piperazinyl)propyl]-3,4-dihydrocarbostyril was obtained in amorphous-like crystals. Melting point: 287°-291° C.
Reaction SMILES: [CH3:1][N:2]1[C:11]([OH:12])=[C:5]2[N:6]=[CH:7][N:8]=[C:9]([SH:10])[C:4]2=[N:3]1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:20][C:21]([O:23][CH3:24])=[O:22]>CO>[CH3:1][N:2]1[C:11]([OH:12])=[C:5]2[N:6]=[CH:7][N:8]=[C:9]([S:10][CH2:20][C:21]([O:23][CH3:24])=[O:22])[C:4]2=[N:3]1
Reactant: Cn1nc2c(S)ncnc2c1O
Reactant: COC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: COC(=O)CSc1ncnc2c(O)n(C)nc12
Temperature: 60 °C

Procedure:
1.5 g of 2-methyl-3-hydroxy-7-mercapto-pyrazolo [4,3-d]pyrimidine was suspended in 35 ml of methanol, and 1.25 g of anhydrous potassium carbonate and 1.07 g of methyl chloroacetate were sequentially added. The mixture was heated at 60° C. for 18 hours. Then, the solvent was distilled off. Water was added to the residue, and the residue was dissolved. Chloroform-soluble substances were extracted with chloroform and removed. Then, the aqueous layer was acidified with 1:1 hydrochloric acid, and the precipitated solid was extracted with chloroform. This chloroform layer was washed with water, and dried over anhydrous magnesium sulfate. Then, the solvent was distilled off. The remaining solid was recrystallized from acetone-chloroform.
Reaction SMILES: [C:1]([C:3]1[C:8]([CH:9]([CH3:11])[CH3:10])=[CH:7][C:6]([S:12]([NH2:15])(=[O:14])=[O:13])=[C:5]([CH:16]([CH3:18])[CH3:17])[CH:4]=1)#[N:2].[CH:19](OC)(OC)[O:20][CH3:21].C1(C)C=CC(S(O)(=O)=O)=CC=1>>[C:1]([C:3]1[C:8]([CH:9]([CH3:11])[CH3:10])=[CH:7][C:6]([S:12]([N:15]=[CH:19][O:20][CH3:21])(=[O:14])=[O:13])=[C:5]([CH:16]([CH3:18])[CH3:17])[CH:4]=1)#[N:2]
Reactant: CC(C)c1cc(S(N)(=O)=O)c(C(C)C)cc1C#N
Reactant: COC(OC)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: COC=NS(=O)(=O)c1cc(C(C)C)c(C#N)cc1C(C)C

Procedure:
To a mechanically stirred mixture of 27 parts of 4-cyano-2,5-diisopropylbenzenesulfonamide and 22 parts trimethyl orthoformate was added a trace of p-toluenesulfonic acid. The reaction was heated at reflux for 4 hours. It was filtered, the filtrate stripped to dryness in vacuo, and the resulting solid recrystallized from methanol to give the title product, m.p. 130°-132°.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:10])/[CH:5]=[CH:6]\[C:7]([OH:9])=[O:8])[CH3:2].[CH:11]1([NH:17][CH2:18][CH2:19][CH2:20][NH2:21])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.N[C@H](C(O)=O)CC(O)=O>C(N(CC)CC)C>[CH2:1]([O:3][C:4](=[O:10])[CH2:5][C@@H:6]([C:7]([OH:9])=[O:8])[NH:21][CH2:20][CH2:19][CH2:18][NH:17][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)[CH3:2]
Reactant: CCOC(=O)/C=C\C(=O)O
Reactant: NCCCNC1CCCCC1
Agent: N[C@@H](CC(=O)O)C(=O)O
Solvent: CCN(CC)CC
Product: CCOC(=O)C[C@H](NCCCNC1CCCCC1)C(=O)O

Procedure:
In a manner analogous to that of Example 1, 394.3 g (2.4 mols+14% excess) of maleic acid-monoethyl ester are placed into the glass flask, and 480 ml of triethylamine are added dropwise with cooling. There are subsequently added 372.6 g (2.4 mols) of 3-cyclohexylaminopropylamine, and the reaction mixture is reacted for 25 minutes at 84°-86° C. It is further processed according to Example 1 and the yield is 546.8 g (75.7% of theory) of a white crystalline aspartic acid derivative, which decomposes at 152° C.
Reaction SMILES: Cl[C:2]1[C:7]2[C:8]([CH3:12])=[C:9]([CH3:11])[NH:10][C:6]=2[CH:5]=[CH:4][N:3]=1.[F:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18][NH2:19])=[CH:16][CH:15]=1>>[CH3:11][C:9]1[NH:10][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:19][CH2:18][C:17]3[CH:20]=[CH:21][C:14]([F:13])=[CH:15][CH:16]=3)[C:7]=2[C:8]=1[CH3:12]
Reactant: Cc1[nH]c2ccnc(Cl)c2c1C
Reactant: NCc1ccc(F)cc1
Product: Cc1[nH]c2ccnc(NCc3ccc(F)cc3)c2c1C
Temperature: 160 °C
Reaction time: 12 h
Yield: 83.2 %

Procedure:
A mixture of 4-chloro-2,3-dimethyl-1H-pyrrolo[3,2-c]pyridine (1.16 g, 6.43 mmol) prepared in Preparation 1 and 4-fluorobenzylamine (3 ml, 26.2 mmol) was stirred for 12 hours at 160° C. The reaction mixture was cooled to room temperature and purified with silica gel column chromatography (ethyl acetate: 100%) to give the titled compound as a white solid. (Yield: 83.2%)
Reaction SMILES: [H-].[Na+].[C:3]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:8]=1[OH:17])([CH3:6])([CH3:5])[CH3:4].[C:18]1([N:24]2[C:28](=[O:29])[CH:27]=[CH:26][C:25]2=[O:30])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>O1CCCC1>[C:13]([C:9]1[CH:10]=[C:11]([CH:27]2[CH2:26][C:25](=[O:30])[N:24]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:28]2=[O:29])[CH:12]=[C:7]([C:3]([CH3:6])([CH3:5])[CH3:4])[C:8]=1[OH:17])([CH3:16])([CH3:15])[CH3:14]
Reactant: O=C1C=CC(=O)N1c1ccccc1
Reactant: CC(C)(C)c1cccc(C(C)(C)C)c1O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(C2CC(=O)N(c3ccccc3)C2=O)cc(C(C)(C)C)c1O
Yield: 2.1 %

Procedure:
This compound is prepared by the procedure of Example 1 from 2.40 g (0.1 mol) of sodium hydride, 20.63 g (0.1 mol) of 2,6-di-tert-butylphenol, and 17.32 g (0.1 mol) of N-phenylmaleimide in tetrahydrofuran. The reaction mixture is concentrated in vacuo and the residue is dissolved in 150 ml of toluene. The toluene solution is extracted sequentially with 1M sodium hydroxide (2×100 ml) and water (2×50 ml). The organic phase is dried over anhydrous sodium sulfate and then the solvent is removed in vacuo. The residue is triturated with petroleum ether to give 0.78 g (2%) of white crystals: mp 204° C.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([Cl:12])[C:9]([Cl:13])=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].O.[Li+].[OH-]>C1COCC1>[NH2:1][C:2]1[CH:11]=[C:10]([Cl:12])[C:9]([Cl:13])=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COC(=O)c1cc(Cl)c(Cl)cc1N
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Nc1cc(Cl)c(Cl)cc1C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methyl 2-amino-4,5-dichlorobenzoate (2.1 g, 9.41 mmol) was dissolved in THF (15 mL) and water (30 mL) was added. LiOH (0.79 g, 18.8 mmol) was added the mixture was stirred overnight at rt. The product was precipitated by addition of 10% aq. HCl (30 mL) and isolated by suction filtration. The white solid was dried under vacuum (1.6 g, 81%). 1H NMR (400 MHz, DMSO-d6): 7.78 (s, 1H), 7.01 (s, 1H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:10]=[CH:11][CH:12]=[C:13]3[C:18]=2[C:17](=[O:19])[N:16]([CH3:20])[CH2:15][CH2:14]3)[C:5]([Cl:21])=[CH:4][N:3]=1.[CH3:22][N:23]1[C:27]([NH2:28])=[CH:26][CH:25]=[N:24]1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:21][C:5]1[C:6]([NH:8][C:9]2[CH:10]=[CH:11][CH:12]=[C:13]3[C:18]=2[C:17](=[O:19])[N:16]([CH3:20])[CH2:15][CH2:14]3)=[CH:7][C:2]([NH:28][C:27]2[N:23]([CH3:22])[N:24]=[CH:25][CH:26]=2)=[N:3][CH:4]=1
Reactant: CN1CCc2cccc(Nc3cc(Cl)ncc3Cl)c2C1=O
Reactant: Cn1nccc1N
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Product: CN1CCc2cccc(Nc3cc(Nc4ccnn4C)ncc3Cl)c2C1=O
Temperature: 100 °C
Yield: 69.9 %

Procedure:
8-[(2,5-Dichloropyridin-4-yl)amino]-2-methyl-3,4-dihydroisoquinolin-1-one (100 mg, 0.31 mmol, example 3.23), 1-Methylpyrazol-5-amine (60.3 mg, 0.62 mmol), cesium carbonate (121 mg, 0.37 mmol), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (28.7 mg, 0.05 mmol) and palladium(II) acetate (5.57 mg, 0.02 mmol) were suspended in dioxane (2 mL) and sealed in a tube. The reaction was degased, purged with nitrogen and heated to 100° C. for 12 hours. The reaction mixture was filtered, washed with DCM and concentrated to dryness. The reaction mixture was purified by preparative HPLC using a Waters X-Bridge reverse-phase column (5 microns silica, 30 mm diameter, 150 mm length) and decreasingly polar mixtures of water (containing 0.2% ammonium carbonate) and acetonitrile as eluent. The fractions were evaporated to dryness to afford 8-(5-chloro-2-(1-methyl-1H-pyrazol-5-ylamino)pyridin-4-ylamino)-2-methyl-3,4-dihydroisoquinolin-1(2H)-one (83 mg, 69.8%) as a grey solid. 1H NMR spectrum (500 MHz, DMSO): 2.95 (t, 2H), 3.05 (s, 3H), 3.56 (t, 2H), 3.63 (s, 3H), 6.19 (d, 1H), 6.86 (s, 1H), 6.91 (dd, 1H), 7.29 (d, 1H), 7.42 (s, 1H), 7.43 (d, 1H), 8.02 (s, 1H), 8.68 (s, 1H), 11.26 (s, 1H); Mass spectrum: ESI+ MH+ 383.
Reaction SMILES: [Li+].[BH4-].CO.[H][H].C([O:9][C:10](=O)[C:11]([CH3:19])([CH3:18])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][Br:17])C.Cl.[Cl-].[NH4+]>ClCCl>[Br:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][C:11]([CH3:19])([CH3:18])[CH2:10][OH:9]
Reactant: [H][H]
Reactant: CCOC(=O)C(C)(C)CCCCCBr
Agent: Cl
Agent: [BH4-]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CO
Product: CC(C)(CO)CCCCCBr
Temperature: 45 °C
Reaction time: 0.5 h
Yield: 108.1 %

Procedure:
Under Ar atmosphere, to a stirred suspension solution of LiBH4 (5.55 g, 95%, 0.24 mol) in dichloromethane (80 mL) was added dropwise methanol (9.8 mL, 0.24 mol), keeping a gentle reflux while hydrogen gas was formed. The mixture was stirred for 30 min at 45° C. To this solution was added dropwise a solution of 7-bromo-2,2-dimethylheptanoic acid ethyl ester (43 g, 0.15 mol) in dichloromethane (120 mL) at such a rate as to maintain a gentle reflux. The reaction mixture was heated at reflux for 20 h, cooled to room temperature and carefully hydrolyzed with 6 N hydrochloric acid (30 mL) and saturated ammonium chloride solution (360 mL). The aqueous layer was extracted with dichloromethane (3×50 mL). The combined organic layers were washed with water (2□100 mL) and dried over anhydrous MgSO4. The reaction mixture was evaporated to yield crude 7-bromo-2,2-dimethylheptan-1-ol (36.2 g, 88%) as a colorless, viscous oil. 1H NMR (300 MHz, CDCl3/TMS): δ (ppm): 3.41 (t, 2H, J=6.9 Hz), 3.30 (br. s, 2H), 1.90-1.84 (m, 3H), 1.42-1.22 (m, 6), 0.86 (s, 6H). 13C NMR (75 MHz, CDCl3/TMS): δ (ppm): 71.9, 38.6, 35.1, 34.1, 32.9, 29.2, 24.0, 23.2. HRMS (LSIMS, nba): Calcd. for C9H18Br (MH+−H2O): 205.0592, found: 205.0563.