Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[I:6][C:7]1[C:8]([CH3:18])=[CH:9][CH:10]=[C:11]2[C:16]=1[N:15]=[CH:14][NH:13][C:12]2=O>>[Cl:3][C:12]1[C:11]2[C:16](=[C:7]([I:6])[C:8]([CH3:18])=[CH:9][CH:10]=2)[N:15]=[CH:14][N:13]=1
Reactant: Cc1ccc2c(=O)[nH]cnc2c1I
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1ccc2c(Cl)ncnc2c1I
Yield: 92.1 %

Procedure:
Phosphorous oxychloride (19.5 mL, 210 mmol) and 8-iodo-7-methylquinazolin-4(3H)-one (2.00 g, 6.99 mmol) were added to a round bottomed flask. The reaction mixture was heated at reflux for 2 h. Upon cooling, excess POCl3 was removed under reduced pressure and the remaining crude product dissolved in DCM (100 mL) and washed with ice-cold water (300 mL) to remove excess acid. The crude residue dissolved in DCM was then dried over anhydrous sodium sulfate and concentrated in vacuo to give 4-chloro-8-iodo-7-methylquinazoline (1.96 g, 92%) as an amorphous brown solid. MS (M+H)+ 305.
Reaction SMILES: [Br:1][C:2]1[C:15]2[C:16]3=[C:17]4[C:12](=[CH:13][CH:14]=2)[CH:11]=[CH:10][C:9](Br)=[C:8]4[CH:7]=[CH:6][C:5]3=[CH:4][CH:3]=1.[C:19]1(B(O)O)[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][CH:20]=1.C([O-])([O-])=O.[Na+].[Na+].CCO>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.C1(C)C=CC=CC=1>[Br:1][C:2]1[C:15]2[C:16]3=[C:17]4[C:12](=[CH:13][CH:14]=2)[CH:11]=[CH:10][C:9]([C:27]2[C:28]5[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=5)[CH:24]=[CH:25][CH:26]=2)=[C:8]4[CH:7]=[CH:6][C:5]3=[CH:4][CH:3]=1
Reactant: OB(O)c1cccc2ccccc12
Reactant: Brc1ccc2ccc3c(Br)ccc4ccc1c2c43
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: Brc1ccc2ccc3c(-c4cccc5ccccc45)ccc4ccc1c2c43
Temperature: 90 °C
Yield: 45.5 %

Procedure:
A mixture of 27.2 g (75.6 mmol) of 1,6-dibromopyrene, 13 g (75.6 mmol) of naphthalen-1-ylboronic acid, 0.87 g(0.756 mmol) of Tetrakis(triphenylphosphine)Palladium, 57 ml of 2M Na2CO3, 120 ml of EtOH and 300 ml toluene was degassed and placed under nitrogen, and then heated at 90° C. for 24 h. After the reaction finish, the mixture was allowed to cool to room temperature. Than 500 ml MeOH was added, while stirring and the precipitated product was filtered off with suction. To give 14 g (yield 45.5%) of beige product which was recrystallized from 1,4-Dioxane.
Reaction SMILES: [CH:1]1([CH:4]([O:6][C:7]2[CH:12]=[C:11]([CH3:13])[C:10]([N+:14]([O-])=O)=[CH:9][C:8]=2[CH3:17])[CH3:5])[CH2:3][CH2:2]1.C(O)(=O)C>[Fe].O>[CH:1]1([CH:4]([O:6][C:7]2[C:8]([CH3:17])=[CH:9][C:10]([NH2:14])=[C:11]([CH3:13])[CH:12]=2)[CH3:5])[CH2:3][CH2:2]1
Reactant: Cc1cc([N+](=O)[O-])c(C)cc1OC(C)C1CC1
Agent: [Fe]
Solvent: CC(=O)O
Solvent: O
Product: Cc1cc(OC(C)C2CC2)c(C)cc1N
Temperature: 80 °C
Reaction time: 1 h
Yield: 66.2 %

Procedure:
A mixture of 0.97 g of 1-(1-cyclopropylethoxy)-2,5-dimethyl-4-nitrobenzene, 1.15 g of iron powder, 15 mL of acetic acid and 15 mL of water was stirred at 80° C. for 1 hour. The reaction mixture was cooled to around room temperature, and then concentrated under reduced pressure. The resulting residue was converted into basic with an aqueous 1 N sodium hydroxide solution, then ethyl acetate was added, and the mixture was filtered. The filtrate was extracted with ethyl acetate, and then the organic layer was washed with water and saturated salt water, and dried over anhydrous magnesium sulfate. The resulting residue was subjected to silica gel column chromatography to obtain 0.56 g of 4-(1-cyclopropylethoxy)-2,5-dimethylphenylamine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][CH2:12][C:13]2[CH:21]=[CH:20][C:16]([C:17]([OH:19])=O)=[CH:15][CH:14]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].Cl.Cl.[NH2:24][C:25]1[C:29]([NH2:30])=[CH:28][S:27][CH:26]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>CC#N>[NH2:30][C:29]1[C:25]([NH:24][C:17](=[O:19])[C:16]2[CH:15]=[CH:14][C:13]([CH2:12][NH:11][C:5]3[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=3)=[CH:21][CH:20]=2)=[CH:26][S:27][CH:28]=1
Reactant: COc1ccc(NCc2ccc(C(=O)O)cc2)cc1OC
Reactant: Nc1cscc1N
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COc1ccc(NCc2ccc(C(=O)Nc3cscc3N)cc2)cc1OC
Temperature: 25 °C
Reaction time: 18 h
Yield: 38 %

Procedure:
Acid 424a (1040 mg; 3.62 mmol); 3,4-diaminothiophene dihydrochloride (1017 mg; 5.44 mmol; 1.50 eq.) and BOP (1770 mg; 4.0 mmol; 1.1 eq.) were suspended in MeCN, treated with triethylamine (4 mL; 29 mmol) and stirred for 18 h at room temperature; concentrated and purified by chromatographic column on silica gel (elution 50% EtOAc in DCM) to render 527 mg (1.37 mmol; 38% yield) of compound 424c which was 90% pure. 1H-NMR (300.07 MHz; DMSO-d6) δ (ppm): 8.56 (s, 1H), 7.78 (d, J=7.9 Hz, 2H), 7.43 (d, J=3.5 Hz, 1H), 7.38 (d, J=7.9 Hz, 2H), 6.73 (d, J=8.8 Hz, 1H), 6.33 (d, J=3.5 Hz, 1H), 6.58 (d, J=2.6 Hz, 1H), 6.13 (dd, J=2.6, 8.3 Hz, 1H), 4.33 (s, 2H), 3.80 (s, 3H), 3.78 (s, 3H). LRMS: calc: 383.4642. found: 384.2 (M+H); 406.2 (M+Na) and 192.6 (M+2H)/2.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][C:14]2[N:17]=[C:18](Br)[S:19][C:13]=2[CH:12]1[C:21]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=1[O:28][CH2:29][C:30]([OH:32])=[O:31])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:33][NH:34][CH3:35]>C1COCC1>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][C:14]2[N:17]=[C:18]([N:34]([CH3:35])[CH3:33])[S:19][C:13]=2[CH:12]1[C:21]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=1[O:28][CH2:29][C:30]([OH:32])=[O:31])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)COc1ccc(Cl)cc1C1c2sc(Br)nc2CCN1C(=O)OCc1ccccc1
Reactant: CNC
Solvent: C1CCOC1
Product: CN(C)c1nc2c(s1)C(c1cc(Cl)ccc1OCC(=O)O)N(C(=O)OCc1ccccc1)CC2
Temperature: 25 °C

Procedure:
A solution of (±)-2-bromo-4-(2-carboxymethoxy-5-chloro-phenyl)-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylic acid benzyl ester (21 mg, 0.04 mmol, 1.0 eq.) in 2M dimethylamine in THF (0.5 mL) was heated at 80° C. for 18 hours. The reaction mixture was allowed to cool to r.t. and concentrated in vacuo. The residue was taken up in DMF, filtered, and purified by prep. HPLC (column: Atlantis, 30×75 mm, 10 um, UV/MS, acidic conditions) and concentrated in vacuo to give the title compound as a white solid.
Reaction SMILES: [N+:1]([CH2:4][CH:5]([CH2:12][CH2:13][CH3:14])[CH2:6][C:7]([O:9]CC)=O)([O-])=O.C([O-])=O.[NH4+].[CH3:19][O:20][C:21]1[CH:44]=[CH:43][C:24]([CH2:25][N:26]2[C:30]3=[N:31][CH:32]=[CH:33][C:34]([CH:35]=O)=[C:29]3[N:28]=[C:27]2[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[CH:23][CH:22]=1>CO.CCOCC.[Pd]>[CH3:19][O:20][C:21]1[CH:44]=[CH:43][C:24]([CH2:25][N:26]2[C:30]3=[N:31][CH:32]=[CH:33][C:34]([CH2:35][N:1]4[CH2:4][CH:5]([CH2:12][CH2:13][CH3:14])[CH2:6][C:7]4=[O:9])=[C:29]3[N:28]=[C:27]2[C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)=[CH:23][CH:22]=1
Reactant: COc1ccc(Cn2c(-c3ccccc3)nc3c(C=O)ccnc32)cc1
Reactant: CCCC(CC(=O)OCC)C[N+](=O)[O-]
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: CO
Product: CCCC1CC(=O)N(Cc2ccnc3c2nc(-c2ccccc2)n3Cc2ccc(OC)cc2)C1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 68.2 %

Procedure:
Ethyl 3-(nitromethyl)hexanoate (0.52 g, 1.1 eq, 2.55 mmol) is dissolved in absolute methanol (8 ml). Then 10% Pd/C (0.2 g) and ammonium formate (1 g) are added under vigorous stirring. After 15 min, the mixture is diluted with ether (100 ml) and filtered. The solid on the filter is washed with ether (2×50 ml). A solution of 3-(4-methoxybenzyl)-2-phenyl-3H-imidazo[4,5-b]pyridine-7-carbaldehyde x225 (1 g, 1 eq, 2.9 mmol) in methanol (5 ml) is added immediately. The combined solution is evaporated in the vacuum of a rotary evaporator. The residue is dissolved in methanol (10 ml), CH(OMe)3 (0.5 ml) is added and the obtained solution is stirred at room temperature for 16 h. An excess of NaBH4 (1 g in several small portions) is then added under vigorous stirring for 20 min. The reaction mixture is evaporated in the vacuum of a rotary evaporator. The residue is partitioned between ethyl acetate and water. The organic phase is separated, dried with anhydrous sodium sulfate, and evaporated. The residue is dissolved in acetonitrile (10 ml), and the solution is refluxed for 24 h to complete the cyclization. The solvent is distilled off. The residue is purified by chromatography on silicagel (CCl4/MeCN) to yield 0.79 g of 1-{[3-(4-methoxybenzyl)-2-phenyl-3H-imidazo[4,5-b]pyridin-7-yl]methyl}-4-propylpyrrolidin-2-one x226.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2=[C:6]([CH:29]=1)[N:7]=[C:8]([NH:21]C(=O)OC(C)(C)C)[CH2:9][C:10]([C:12](=[O:20])[N:13]([CH2:17][CH2:18][CH3:19])[CH2:14][CH2:15][CH3:16])=[CH:11]2.[CH2:30]([O:32][C:33]([C:35]1[CH:40]=[CH:39][C:38](B(O)O)=[CH:37][CH:36]=1)=[O:34])[CH3:31]>>[NH2:21][C:8]1[CH2:9][C:10]([C:12](=[O:20])[N:13]([CH2:14][CH2:15][CH3:16])[CH2:17][CH2:18][CH3:19])=[CH:11][C:5]2[CH:4]=[CH:3][C:2]([C:38]3[CH:39]=[CH:40][C:35]([C:33]([O:32][CH2:30][CH3:31])=[O:34])=[CH:36][CH:37]=3)=[CH:29][C:6]=2[N:7]=1
Reactant: CCOC(=O)c1ccc(B(O)O)cc1
Reactant: CCCN(CCC)C(=O)C1=Cc2ccc(Br)cc2N=C(NC(=O)OC(C)(C)C)C1
Product: CCCN(CCC)C(=O)C1=Cc2ccc(-c3ccc(C(=O)OCC)cc3)cc2N=C(N)C1

Procedure:
The title compound was prepared by the procedures as described in Example 124 (Step F) and Example 101 (Step I) using tert-butyl (1E,4E)-8-bromo-4-(dipropylcarbamoyl)-3H-benzo[b]azepin-2-ylcarbamate and 4-(ethoxycarbonyl)phenylboronic acid. MS APCI (+) m/z 434 (M+1) detected; 1H-NMR (400 MHz, CDCl3) δ 8.11 (d, 2H), 7.72 (d, 2H), 7.54 (d, 1H), 7.38 (d, 1H), 7.34 (dd, 1H), 6.84 (s, 1H), 4.40 (q, 2H), 3.47 (br s, 4H), 2.83 (s, 2H), 1.62-1.72 (m, 4H), 1.42 (t, 3H), 0.94 (t, 6H).
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[F:11][C:12]1[CH:17]=[CH:16][C:15]([C:18](=[O:22])[CH2:19][NH:20][CH3:21])=[CH:14][CH:13]=1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[F:11][C:12]1[CH:13]=[CH:14][C:15]([C:18](=[O:22])[CH2:19][N:20]([CH3:21])[C:8]([NH:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[O:9])=[CH:16][CH:17]=1
Reactant: CNCC(=O)c1ccc(F)cc1
Reactant: O=C=Nc1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CN(CC(=O)c1ccc(F)cc1)C(=O)Nc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.26 g (12.5 mmol) of phenyl isocyanate are used to a suspension of 3 g (12.5 mmol) of the compound from Example 2 in 30 ml of toluene and 1.5 g (12.5 mmol) of triethylamine are slowly added dropwise at 0° C. The mixture is stirred overnight at 25° C. The toluene phase is washed with water, the product precipitating out. After drying 3.54 g are obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12]O)=[CH:6][C:5]=1[OH:14].C(Br)(Br)(Br)[Br:17].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][Br:17])=[CH:6][C:5]=1[OH:14]
Reactant: COC(=O)c1ccc(OCCO)cc1O
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)c1ccc(OCCBr)cc1O
Temperature: 25 °C
Reaction time: 3 h
Yield: 78.3 %

Procedure:
To a solution of 2-hydroxy-4-(2-hydroxy-ethoxy)-benzoic acid methyl ester (3.025 g, 14.25 mmol) in methylene chloride (80 mL) was added carbon tetrabromide (6.216 g, 18.74 mmol) and triphenylphosphine (5.012 g, 19.10 mmol). The reaction was stirred 3 hours at room temperature then additional carbon tetrabromide (1.967 g, 5.931 mmol) and triphenylphosphine (1.568 g, 5.97 mmol) was added and stirring continued overnight. The reaction mixture was concentrated in vacuo and the residue was purified by flash chromatography using ethyl acetate/hexanes (10/90 to 20/80) to afford 4-(2-bromo-ethoxy)-2-hydroxy-benzoic acid methyl ester (3.070 g, 78%) as a white solid. 1H NMR (300 MHz, CDCl3); δ 11.00 (s, 1H), 7.76 (d, 2H), 6.46 (m, 2H), 4.32 (t, 2H), 3.93 (s, 3H), 3.65 (t, 2H).
Reaction SMILES: [OH:1][N:2]=[C:3]([NH2:15])[C:4]1[O:8][C:7]2[CH:9]=[CH:10][CH:11]=[C:12]([O:13][CH3:14])[C:6]=2[CH:5]=1.[C:16](OC(=O)C)(=O)[CH3:17]>>[CH3:14][O:13][C:12]1[C:6]2[CH:5]=[C:4]([C:3]3[N:15]=[C:16]([CH3:17])[O:1][N:2]=3)[O:8][C:7]=2[CH:9]=[CH:10][CH:11]=1
Reactant: CC(=O)OC(C)=O
Reactant: COc1cccc2oc(C(N)=NO)cc12
Product: COc1cccc2oc(-c3noc(C)n3)cc12

Procedure:
1-(Hydroxyimino)-1-(4-methoxybenzo(b)furan-2-yl)methylamine (3.4 g) was dissolved in acetic anhydride (40 ml) and the mixture was refluxed under heating for 14 hr. The reaction mixture was concentrated under reduced pressure and the obtained residue was recrystallized from acetonitrile to give the title compound (1.1 g) as pale-as brown crystals.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1.Cl[C:11]1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][N:12]=1.[OH-].[K+].O>CS(C)=O>[CH3:9][O:8][C:5]1[CH:4]=[CH:3][C:2]([O:1][C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][N:12]=2)=[CH:7][N:6]=1
Reactant: FC(F)(F)c1ccc(Cl)nc1
Reactant: COc1ccc(O)cn1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: COc1ccc(Oc2ccc(C(F)(F)F)cn2)cn1
Temperature: 25 °C
Yield: 94.7 %

Procedure:
A solution of 5-hydroxy-2-methoxypyridine (1.25 g, 10.0 mmol), 2-chloro-5-trifluoromethylpyridine (1.82 g, 10.0 mmol) and potassium hydroxide (85% pure, 1.08 g, 10.0 mmol) in dimethyl sulfoxide (25 mL) was heated at 90° C. for 2.5 hours. The solution was cooled to room temperature and poured slowly into water (200 mL). After cooling with an external ice-bath, the precipitate was collected by suction, washed thoroughly with water and dried in a vacuum oven at 45° C., yielding the title compound (2.56 g, 95% yield).
Reaction SMILES: C(OC([NH:11][C:12]12[CH2:18][C:15]([C:19]([OH:21])=[O:20])([CH2:16][CH2:17]1)[CH2:14][CH2:13]2)=O)C1C=CC=CC=1.CO.Cl.[H][H]>[Pd].CO.C(OCC)(=O)C>[NH2:11][C:12]12[CH2:18][C:15]([C:19]([OH:21])=[O:20])([CH2:14][CH2:13]1)[CH2:16][CH2:17]2
Reactant: [H][H]
Reactant: O=C(NC12CCC(C(=O)O)(CC1)C2)OCc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: NC12CCC(C(=O)O)(CC1)C2
Yield: 99.9 %

Procedure:
A 2-L Parr bottle was charged with 4-(benzyloxycarbonylamino)bicyclo[2.2.1]heptane-1-carboxylic acid (105 g, 363 mmol), methanol (500 mL), 0.8 N hydrochloric acid (500 mL), and 10% palladium on carbon (38.6 g, 18.15 mmol, 50% wet with water). The reaction mixture was reacted on a Parr shaker under 30 gpsi hydrogen for 10 h when TLC analysis (10% methanol/ethyl acetate) indicated a complete reaction. The catalyst was removed by filtration through a short plug of celite and the plug was washed thoroughly with water (4×100 mL). The filtrate was concentrated to provide 4-aminobicyclo[2.2.1]heptane-1-carboxylic acid (56.3 g, 100%) as a wet white solid which was used in the next step without any further purification; MS (ESI) m/z 156.2 [M+1]+
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]1[NH:15][C:16]1[N:21]=[C:20](Cl)[C:19]2[C:23](=[O:33])[N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][C:18]=2[C:17]=1[F:34])=[O:7])([CH3:4])([CH3:3])[CH3:2].CC1(C)C(C)(C)OB([C:43]#[C:44][C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]1[NH:15][C:16]1[N:21]=[C:20]([C:43]#[C:44][C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[C:19]2[C:23](=[O:33])[N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][C:18]=2[C:17]=1[F:34])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1Nc1nc(Cl)c2c(c1F)CN(C(=O)OC(C)(C)C)C2=O
Reactant: CC1(C)OB(C#Cc2ccccc2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1Nc1nc(C#Cc2ccccc2)c2c(c1F)CN(C(=O)OC(C)(C)C)C2=O
Temperature: 90 °C

Procedure:
In a 30 mL glass vial, tert-butyl 6-((1R,2S)-2-(tert-butoxycarbonylamino)cyclohexylamino)-4-chloro-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate (150 mg, 0.301 mmol), 4,4,5,5-tetramethyl-2-(phenylethynyl)-1,3,2-dioxaborolane (103 mg, 0.451 mmol) and PdCl2(PPh3)2 (105 mg, 0.150 mmol) were dissolved in dioxane (5 mL). To the reaction mixture was added 2N aqueous sodium carbonate solution (2 mL). The vessel was sealed with a cap and the reaction mixture was heated at 90° C. for 2 hours. The reaction mixture was subsequently diluted with water (10 mL) and was extracted with EtOAc (2×50 mL). The combined organic phase was dried over sodium sulfate and evaporated to give the intermediate, tert-butyl 6-(((1R,2S)-2-((tert-butoxycarbonyl)amino)cyclohexyl)amino)-7-fluoro-3-oxo-4-(phenylethynyl)-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate. The intermediate was dissolved in dichloromethane (3 mL), TFA (3 mL) was added, and the mixture was stirred for 1 hour. The volatiles were subsequently evaporated and the residual material was dissolved in DMSO (5 mL) and purified by preparative HPLC, eluting with a gradient of 15-50% ACN (0.035% TFA) and water (0.05% TFA). The pure product fractions were combined, evaporated to a minimal volume, and lyophilized to give a TFA salt of the title compound as a pale yellow solid (32 mg, 29%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.43 (br s, 3H), 1.66-1.91 (m, 5H), 3.63 (br s, 1H), 4.34-4.52 (m, 3H), 6.87 (d, J=7.07 Hz, 1H), 7.41-7.52 (m, 3H), 7.56-7.65 (m, 2H), 7.74 (br s, 3H), 8.48 (s, 1H). ESI-MS m/z [M+H]+ calc'd for C21H21FN4O, 365. found, 365.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)=[N:3]1.[Cl:21]Cl>C(O)(=O)C>[CH3:1][N:2]1[C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([Cl:21])[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:19])([F:18])[F:20])[CH:12]=2)=[N:3]1
Reactant: ClCl
Reactant: COC(=O)c1cc(-c2cccc(C(F)(F)F)c2)nn1C
Solvent: CC(=O)O
Product: COC(=O)c1c(Cl)c(-c2cccc(C(F)(F)F)c2)nn1C
Reaction time: 4 h

Procedure:
A solution was prepared by dissolving 5.2 g. of methyl 1-methyl-3-(3-trifluoromethylphenyl)pyrazole-5-carboxylate in 200 ml. of glacial acetic acid. The solution was heated to refluxing temperature while gaseous chlorine was passed into the mixture. After about four hours, the addition of chlorine was stopped and the reaction mixture poured over ice. The consequent aqueous mixture was extracted with two 150 ml. portions of chloroform and the chloroform extracts separated, combined and dried. Removal of the chloroform in vacuo yielded as a residue methyl 1-methyl-3-(3-trifluoromethylphenyl)-4-chloropyrazole-5-carboxylate formed in the above reaction. The residue was dissolved in ethyl acetate and the ethyl acetate solution washed with saturated aqueous sodium bicarbonate. The ethyl acetate solution was then dried with phase separation paper. Removal of the solvent in vacuo left a residue which was dissolved in hexane and chromatographed over grade 62 silica. The chromatogram was developed with chloroform/hexane mixtures as the eluant. Use of 100% chloroform as the eluant yielded a small amount of a rapidly moving material which was not the desired product. The desired product, methyl 1-methyl-3-(3-trifluoromethylphenyl)-4-chloropyrazole carboxylate, was next eluted. Fractions containing this material were combined and the chloroform removed in vacuo. Recrystallization of the residue (weight 1.5 g.) from hexane yielded methyl 1-methyl-3-(3-trifluoromethylphenyl)-4-chloropyrazole-5-carboxylate; melting point=97° -8° C. The compound has the following elemental analysis.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[CH2:5][N:6]1[CH2:11][CH2:10][N:9]([C:12]2([CH3:25])[CH2:17][CH2:16][N:15](CC3C=CC=CC=3)[CH2:14][CH2:13]2)[CH2:8][CH2:7]1)[CH3:2].[H][H]>CCO.[Pd]>[CH2:1]([O:3][C:4](=[O:26])[CH2:5][N:6]1[CH2:11][CH2:10][N:9]([C:12]2([CH3:25])[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[CH2:8][CH2:7]1)[CH3:2]
Reactant: CCOC(=O)CN1CCN(C2(C)CCN(Cc3ccccc3)CC2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CN1CCN(C2(C)CCNCC2)CC1
Reaction time: 12 h

Procedure:
A suspension of 0.44 g (1.10 mmol) ethyl[4-(1-benzyl-4-methyl-piperidin-4-yl)-piperazin-1-yl]-acetate and 100 mg 10% Pd/C in 20 mL EtOH was hydrogenated for 12 h at 50° C. and 3447 hPa hydrogen pressure. The catalyst was filtered off and the filtrate was evaporated to dryness. The product was reacted further without purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:8][CH:9]([C:15]([CH3:17])=O)[C:10]([O:12]CC)=[O:11]>>[NH:1](/[C:15](/[CH3:17])=[C:9](/[CH3:8])\[C:10]([OH:12])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(C)C(C)=O
Reactant: Nc1ccccc1
Product: C/C(Nc1ccccc1)=C(\C)C(=O)O

Procedure:
In the process of the invention, the 3-methyl substituted compound among the starting 2-formyl-3-substituted-4-(hydroxy or acyloxy) quinoline derivatives represented by the general formula (II) can be prepared by subjecting aniline to dehydration condensation with ethyl 2-methylacetoacetate to form a 3-anilino-2-methylcrotonic acid derivative, followed by intramolecular cyclization by heating to high temperature of, preferably, 200° to 250° C. to obtain 2, 3-dimethyl-4-quinoline. Moreover, this compound may further reacted with an anhydrous alkanoic acid such as, for example, acetic anhydride, to obtain 2, 3-dimethyl-4-acyloxyquinoline, e.g. 2, 3-dimethyl-4-acetoxyquinoline, followed by oxidation with selenium dioxide in an aqueous organic solvent to obtain the derivative.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]=O.C(N(CC)CC)C.Cl.[NH2:21][OH:22]>C(Cl)Cl>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]=[N:21][OH:22]
Reactant: NO
Reactant: O=Cc1ccc2ccccc2c1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: ON=Cc1ccc2ccccc2c1
Temperature: 35 °C
Yield: 98.2 %

Procedure:
To a mixture of 7.8 g of 2-naphthalaldehyde and 7.1 ml of triethylamine in 100 ml of methylene chloride was added 3.54 g of hydroxylamine hydrochloride and the mixture heated at 35° C. for three hours. The organic reaction solvent was washed with water, dried and concentrated to give 8.4 g of product.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[CH:4][C:3]=1[C:10]1[N:14]([CH3:15])[N:13]=[CH:12][C:11]=1[CH:16]([CH3:18])[CH3:17].[NH2:19][C@@H:20]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[C:40]([F:43])([F:42])[F:41])[CH2:21][N:22]1[C:30](=[O:31])[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]1=[O:32].C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1>C(Cl)Cl>[O:31]=[C:30]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23](=[O:32])[N:22]1[CH2:21][C@@H:20]([NH:19][C:7]([C:5]1[S:6][C:2]([CH3:1])=[C:3]([C:10]2[N:14]([CH3:15])[N:13]=[CH:12][C:11]=2[CH:16]([CH3:18])[CH3:17])[CH:4]=1)=[O:9])[CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[C:40]([F:42])([F:41])[F:43]
Reactant: Cc1sc(C(=O)O)cc1-c1c(C(C)C)cnn1C
Reactant: N[C@@H](Cc1ccccc1C(F)(F)F)CN1C(=O)c2ccccc2C1=O
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1sc(C(=O)N[C@@H](Cc2ccccc2C(F)(F)F)CN2C(=O)c3ccccc3C2=O)cc1-c1c(C(C)C)cnn1C
Temperature: 25 °C
Reaction time: 12 h
Yield: 64.2 %

Procedure:
To a solution of 5-methyl-4-[1-methyl-4-(1-methylethyl)-1H-pyrazol-5-yl]-2-thiophenecarboxylic acid (137 mg, 0.52 mmol), 2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione (200 mg, 0.52 mmol) [Prepared in Preparation 6] and diisopropylethylamine (0.45 ml, 2.60 mmol) in DCM at 25° C. was added bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (267 mg, 0.572 mmol) in one portion. The solution stirred at 25° C. for 12 h and was then dry loaded onto silica and purified via column chromatography (silica, 30-70% EtOAc in hexanes) yielding N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-methyl-4-[1-methyl-4-(1-methylethyl)-1H-pyrazol-5-yl]-2-thiophenecarboxamide (211 mg, 0.334 mmol, 64.2% yield) as a yellow oil: LCMS (ES) m/e 595 (M+H)+.