Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:11][N:12]([CH2:23][C:24]2[C:29]([CH3:30])=[CH:28][CH:27]=[CH:26][N:25]=2)[CH:13]2[C:22]3[N:21]=[CH:20][CH:19]=[CH:18][C:17]=3[CH2:16][CH2:15][CH2:14]2)=[C:7]([CH2:9][OH:10])[CH:8]=1.CCN(CC)CC.[CH3:38][C:39](OC(C)=O)=[O:40].C([O-])(O)=O.[Na+]>C(Cl)Cl>[OH:10][CH2:9][C:7]1[CH:8]=[C:3]([CH:4]=[CH:5][C:6]=1[CH2:11][N:12]([CH2:23][C:24]1[C:29]([CH3:30])=[CH:28][CH:27]=[CH:26][N:25]=1)[CH:13]1[C:22]2[N:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH2:16][CH2:15][CH2:14]1)[CH2:2][NH:1][C:39](=[O:40])[CH3:38]
Reactant: Cc1cccnc1CN(Cc1ccc(CN)cc1CO)C1CCCc2cccnc21
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)NCc1ccc(CN(Cc2ncccc2C)C2CCCc3cccnc32)c(CO)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 66.6 %

Procedure:
To a solution of (5-aminomethyl-2-{[(3-methyl-pyridin-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-phenyl)-methanol (0.0980 g, 0.25 mmol) in CH2Cl2 (3 mL) was added Et3N (0.05 mL, 0.38 mmol), KI (0.0042 g, 0.03 mmol), and Ac2O (0.0237 mL, 0.25 mmol). After stirring at room temperature for 18 hours, saturated NaHCO3 (10 mL) was added and extracted with CH2Cl2 (3×30 mL). The combined organic extracts were dried (Na2SO4), filtered, and concentrated. Purification of the crude material by column chromatography on silica gel (100:1:1 CH2Cl2-MeOH—NH4OH) provided 74.0 mg (64%) of COMPOUND 422 as a white solid. 1H NMR (CDCl3) δ 1.56-1.64 (m, 2H), 1.98 (s, 4H), 2.15-2.19 (m, 2H), 2.24 (s, 3H), 2.60-2.80 (m, 2H), 3.66-3.71 (m, 2H), 3.78-3.91 (m, 2H), 4.15 (d, 2H, J=12.3 Hz), 4.33-4.37 (m, 2H), 5.75 (s, 1H), 7.00-7.11 (m, 3H), 7.21 (s, 1H), 7.32 (d, 2H, J=7.5 Hz), 7.42 (d, 2H, J=7.2 Hz), 8.36 (t, 2H, J=5.1 Hz).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[N:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH2:18]Cl.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[N:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH2:18][O:11][C:4]1[CH:5]=[CH:6][C:7]([N+:8]([O-:10])=[O:9])=[C:2]([F:1])[CH:3]=1
Reactant: ClCc1ccccn1
Reactant: O=[N+]([O-])c1ccc(O)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(OCc2ccccn2)cc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 17.3 %

Procedure:
A mixture of 3-fluoro-4-nitrophenol (3.14 g), 2-pyridylmethyl chloride (3.28 g), potassium carbonate (5.52 g) and DMF (20 ml) was stirred at ambient temperature for 16 hours. The mixture was partitioned between ethyl acetate and water. The organic phase was washed with water, dried (MgSO4) and evaporated. The residue was purified by column chromatography using increasingly polar mixtures of hexane and ethyl acetate to give 3-fluoro-4-nitrophenyl 2-pyridylmethyl ether (0.86 g).
Reaction SMILES: Cl[C:2](=[N:9][N:10]=[C:11](Cl)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH3:18])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:20][C:21]1[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[C:22]=1[NH2:23].CN(C)C1C=CC=CC=1.Cl>ClCCl>[CH3:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[C:11]1[N:23]([C:22]2[C:24]([CH3:28])=[CH:25][CH:26]=[CH:27][C:21]=2[CH3:20])[C:2]([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)=[N:9][N:10]=1
Reactant: Cc1ccccc1C(Cl)=NN=C(Cl)c1ccccc1
Reactant: Cc1cccc(C)c1N
Agent: Cl
Solvent: ClCCl
Solvent: CN(C)c1ccccc1
Product: Cc1ccccc1-c1nnc(-c2ccccc2)n1-c1c(C)cccc1C
Temperature: 120 °C
Reaction time: 20 h
Yield: 30.6 %

Procedure:
Then, 12.6 g (43.3 mmol) of [chloro(2-methylphenyl)methanone][chloro(phenyl)methylidene]hydrazone obtained in Step 2, 15.7 g (134.5 mmol) of 2,6-dimethylaniline, and 100 ml of N,N-dimethylaniline were put into a 500-ml recovery flask and heated and stirred at 120° C. for 20 hours. After reaction for the predetermined time, this reacted solution was slowly added to 200 ml of 1N hydrochloric acid. Dichloromethane was added to this solution and an objective substance was extracted to an organic layer. The obtained organic layer was washed with water and an aqueous solution of sodium hydrogen carbonate, and was dried over magnesium sulfate. The magnesium sulfate was removed by gravity filtration, and the obtained filtrate was concentrated to give a black liquid. This liquid was purified by silica gel column chromatography. A mixed solvent of ethyl acetate and hexane in a ratio of 1:5 was used as a developing solvent. The obtained fraction was concentrated to give a white solid. This solid was recrystallized with ethyl acetate to give 4.5 g of a white solid of Hmpptz-dmp in a yield of 31%. Synthesis Scheme (a-3) of Step 3 is shown below.
Reaction SMILES: [CH:1]1([NH:4][C:5](=O)[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[C:19]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)=[N:18][N:17]=[CH:16]4)[CH:7]=2)[CH2:3][CH2:2]1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:39])=CC=1>C1COCC1>[CH:1]1([NH:4][C:5](=[S:39])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[C:19]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)=[N:18][N:17]=[CH:16]4)[CH:7]=2)[CH2:3][CH2:2]1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(N3CCOCC3)nncc2c1
Solvent: C1CCOC1
Product: Cc1ccc(C(=S)NC2CC2)cc1-c1ccc2c(N3CCOCC3)nncc2c1
Temperature: 150 °C

Procedure:
A mixture of N-cyclopropyl-4-methyl-3-(1-morpholinophthalazin-6-yl)benzamide (85 mg, 0.22 mmol) and Lawesson's reagent (97 mg, 0.24 mmol) in 1 mL THF was heated at 150° C. for 10 min in a microwave oven. Volatile solvents were removed under reduced pressure and the brown residue was purified on an ISCO column (12 g, eluted with 1-10% MeOH in ethyl acetate) to provide N-cyclopropyl-4-methyl-3-(l-morpholinophthalazin-6-yl)benzothioamide as a yellow solid. Found MS (ESI+) m/z: 405.3 (M+1).
Reaction SMILES: [CH:1]([C:3]1[C:11]2[C:6](=[N:7][CH:8]=[C:9]([C:12]3[CH:13]=[C:14]([NH:18][C:19](=[O:22])[CH2:20][CH3:21])[CH:15]=[N:16][CH:17]=3)[CH:10]=2)[N:5](C2CCCCO2)[N:4]=1)=O.[S].[N:30]1[CH:35]=[C:34]([NH2:36])[C:33]([NH2:37])=[C:32]([C:38]2[CH:39]=[N:40][CH:41]=[CH:42][CH:43]=2)[CH:31]=1.C([SiH](CC)CC)C.C(O)(C(F)(F)F)=O>CN(C=O)C>[N:40]1[CH:41]=[CH:42][CH:43]=[C:38]([C:32]2[C:33]3[N:37]=[C:1]([C:3]4[C:11]5[C:6](=[N:7][CH:8]=[C:9]([C:12]6[CH:13]=[C:14]([NH:18][C:19](=[O:22])[CH2:20][CH3:21])[CH:15]=[N:16][CH:17]=6)[CH:10]=5)[NH:5][N:4]=4)[NH:36][C:34]=3[CH:35]=[N:30][CH:31]=2)[CH:39]=1
Reactant: Nc1cncc(-c2cccnc2)c1N
Reactant: CCC(=O)Nc1cncc(-c2cnc3c(c2)c(C=O)nn3C2CCCCO2)c1
Agent: CC[SiH](CC)CC
Agent: [S]
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: CCC(=O)Nc1cncc(-c2cnc3[nH]nc(-c4nc5c(-c6cccnc6)cncc5[nH]4)c3c2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 49 %

Procedure:
A solution of N-(5-(3-formyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-5-yl)pyridin-3-yl)propionamide (LX) (1 eq), sulfur (1 eq) and 3,3′-bipyridine-4,5-diamine (XLVIII) (1 eq) in DMF was heated overnight at 140° C. under argon. The solution was cooled and the DMF was distilled under vacuum. The residue was taken in DCM. Triethylsilane (2.5 eq) followed by TFA (30% by volume) was added to the solution and stirred for 2 h at room temperature until TLC showed disappearance of starting material. The solvent was removed under vacuum. Water was added to the residue, sonicated briefly and basified with 5 N NH4OH solution. The solids formed were filtered, washed with cold water and dried at room temperature. The solids were triturated with DCM followed by MeOH to get N-(5-(3-(7-(pyridin-3-yl)-3H-imidazo[4,5-c]pyridin-2-yl)-1H-pyrazolo[3,4-b]pyridin-5-yl)pyridin-3-yl)propionamide (47) as a brown solid (49% yield). 1H NMR (DMSO-d6, 400 MHz,): δ 1.67 (t, J=6 Hz, 3H), 2.45 (q, J=6 Hz, 2H), 7.62 (m, 1H), 8.50 (s, 1H), 8.62 (m, 1H), 8.72 (s, 1H), 8.77 (m, 3H), 8.91 (m, 1H), 8.99 (m, 2H), 9.41 (s, 1H), 10.31 (s, 1H), 13.95 (s, 1H), 14.62 (s, 1H). ESIMS found C25H19N9O m/z 462.50 (M+H).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[CH:7][C:8]([CH3:21])=[C:9]([NH:11][C:12]2[C:17]([O:18][CH3:19])=[CH:16][N:15]=[C:14](Cl)[N:13]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].Cl.Cl.[NH:24]1[CH2:29][CH2:28][CH:27]([CH2:30][C:31]2[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=2)[CH2:26][CH2:25]1.C(N(C(C)C)CC)(C)C>CC(O)C>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([CH3:21])=[C:9]([NH:11][C:12]2[C:17]([O:18][CH3:19])=[CH:16][N:15]=[C:14]([N:34]3[CH2:35][CH2:36][CH:31]([CH2:30][C:27]4[CH:26]=[CH:25][N:24]=[CH:29][CH:28]=4)[CH2:32][CH2:33]3)[N:13]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: c1cc(CC2CCNCC2)ccn1
Reactant: COc1cnc(Cl)nc1Nc1cc(C(C)(C)C)ccc1C
Agent: Cl
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cnc(N2CCC(Cc3ccncc3)CC2)nc1Nc1cc(C(C)(C)C)ccc1C
Yield: 68.2 %

Procedure:
A solution of the product of Step 1 (166 mg, 0.543 mmol), 4-piperidin-4-ylmethylpyridine dihydrochloride (162 mg, 0.651 mmol) and diisopropylethylamine (1.5 mL) was irradiated in 2-propanol (1.5 mL), in a microwave oven, at 180° C. for 2.5 hrs. The mixture was cooled and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (Biotage system, MeOH/dichloromethane, 0%-15%) to give the product (165 mg, 68.2%) as a solid. 1H-NMR (600 MHz, CDCl3) δ=1.21 (2H, m), 1.28 (9H, s), 1.60 (2H, d, J=13.19), 1.74 (1H, m), 2.23 (3H, s), 2.49 (2H, d, J=7.35), 2.72 (2H, td, J=12.76, 1.51), 3.80 (3H, s), 4.64 (2H, d, J=13.35), 6.96 (1H, s), 6.99 (1H, dd, J=7.88, 1.9), 7.03 (2H, d, J=5.43), 7.08 (1H, d, J=8.15), 7.60 (1H, s), 8.27 (1H, d, J=1.9), 8.44 (2H, d, J=5.7), LC-ESMS observed [M+H]+ 446.2 (calcd 446.6).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[N:10][N:11]([CH3:27])[C:12]=1[C:13]1[N:14]=[CH:15][N:16]([C:18]2[CH:26]=[CH:25][C:21]([C:22]([OH:24])=O)=[CH:20][N:19]=2)[CH:17]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:59][CH:60]1[CH2:65][CH2:64][O:63][CH2:62][CH2:61]1>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[N:10][N:11]([CH3:27])[C:12]=1[C:13]1[N:14]=[CH:15][N:16]([C:18]2[CH:26]=[CH:25][C:21]([C:22]([NH:59][CH:60]3[CH2:65][CH2:64][O:63][CH2:62][CH2:61]3)=[O:24])=[CH:20][N:19]=2)[CH:17]=1
Reactant: Cn1nnc(-c2ccccc2F)c1-c1cn(-c2ccc(C(=O)O)cn2)cn1
Reactant: NC1CCOCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1nnc(-c2ccccc2F)c1-c1cn(-c2ccc(C(=O)NC3CCOCC3)cn2)cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81.8 %

Procedure:
To a solution of 6-(4-(4-(2-fluorophenyl)-1-methyl-1H-1,2,3-triazol-5-yl)-1H-imidazol-1-yl)nicotinic acid (75 mg, 0.194 mmol) and TBTU (73 mg, 0.226 mmol) in DMF (2.0 mL) was added DIPEA (180 μL, 1.03 mmol). Then 4-aminotetrahydropyran (24 μL, 0.226 mmol) was added and the mixture was stirred at room temperature under Ar for 30 min. The mixture was then evaporated and purification by chromatography (reverse phase HPLC) afforded the title compound (71 mg, 77%) as a white solid. MS: m/e=448.2 [M+H]+.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:36])=[C:9]([CH2:11][O:12][C:13]2[CH:33]=[CH:32][C:16]([CH2:17][O:18][C:19]3[C:23]([CH:24]=O)=[CH:22][N:21]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[N:20]=3)=[CH:15][C:14]=2[O:34][CH3:35])[N:10]=1.[S:37]1[CH2:41][C:40](=[O:42])[NH:39][C:38]1=[O:43].N1CCCCC1>C(O)C>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:36])=[C:9]([CH2:11][O:12][C:13]2[CH:33]=[CH:32][C:16]([CH2:17][O:18][C:19]3[C:23](/[CH:24]=[C:41]4/[C:40](=[O:42])[NH:39][C:38](=[O:43])[S:37]/4)=[CH:22][N:21]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)[N:20]=3)=[CH:15][C:14]=2[O:34][CH3:35])[N:10]=1
Reactant: COc1cc(COc2nn(-c3ccccc3)cc2C=O)ccc1OCc1nc(-c2ccco2)oc1C
Reactant: O=C1CSC(=O)N1
Solvent: C1CCNCC1
Solvent: CCO
Product: COc1cc(COc2nn(-c3ccccc3)cc2/C=C2\SC(=O)NC2=O)ccc1OCc1nc(-c2ccco2)oc1C
Yield: 85.3 %

Procedure:
A mixture of 3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1-phenyl-1H-pyrazole-4-carbaldehyde (1.10 g), 1,3-thiazolidine-2,4-dione (0.27 g), piperidine (0.04 g) and ethanol (30 mL) was heated under reflux for 3 hrs. The reaction mixture was concentrated, and the obtained crystals were washed with ethanol to give (5Z)-5-({3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1-phenyl-1H-pyrazol-4-yl}methylene)-1,3-thiazolidine-2,4-dione as yellow crystals (1.13 g, yield 84%). Recrystallization from tetrahydrofuran-hexane gave yellow prism crystals. melting point: 252-253° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9]([N:12]([CH3:33])[C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:21]=1[NH:20][C:19]([C:22]1[S:23][CH:24]([CH2:27][C:28](OCC)=[O:29])[CH2:25][N:26]=1)=[CH:18]2)(=[O:11])=[O:10].[BH4-].[Li+].O1CCCC1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CO>[OH:29][CH2:28][CH2:27][CH:24]1[S:23][C:22]([C:19]2[NH:20][C:21]3[C:17]([CH:18]=2)=[CH:16][CH:15]=[CH:14][C:13]=3[N:12]([CH3:33])[S:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])(=[O:11])=[O:10])=[N:26][CH2:25]1
Reactant: CCOC(=O)CC1CN=C(c2cc3cccc(N(C)S(=O)(=O)c4ccccc4OC)c3[nH]2)S1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccccc1S(=O)(=O)N(C)c1cccc2cc(C3=NCC(CCO)S3)[nH]c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 68 %

Procedure:
To a mixture of ethyl (2-{7-[[(2-methoxyphenyl)sulfonyl](methyl)amino]-1H-indol-2-yl}-4,5-dihydro-1,3-thiazol-5-yl)acetate (140 mg), lithium borohydride (40 mg) and tetrahydrofuran (5 mL) was added methanol (1 mL), and the mixture was stirred at room temperature for 2 hr. Aqueous citric acid solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (ethyl acetate:hexane=6:4-10:0), and the obtained pale-yellow oil was crystallized from ethyl acetate-hexane to give the title compound (87 mg, yield: 69%) as colorless needle crystals. MS: 446 (MH+). melting point 154-155° C.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12](=[O:13])[CH2:11][NH:10][C:9]2=[O:14])[CH:5]=[CH:6][CH:7]=1.C(N(CC)C(C)C)(C)C.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>C(Cl)Cl>[I:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12](=[O:13])[CH2:11][N:10]([S:25]([CH3:24])(=[O:27])=[O:26])[C:9]2=[O:14])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CNC(=O)N1c1cccc(I)c1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CS(=O)(=O)N1CC(=O)N(c2cccc(I)c2)C1=O

Procedure:
A solution of 3-(3-iodophenyl)imidazolidine-2,4-dione (950 mg) and N,N-diisopropylethylamine (1.1 ml) in DCM (20 ml) was treated with methanesulfonyl chloride (0.453 ml) at 20° C. After 2 h the reaction mixture was diluted with DCM and washed with aqueous 2M HCl (3×20 ml) and NaHCO3 and dried (MgSO4). The solvent was removed under reduced pressure to give the title compound (1.15 g). LCMS RT=2.91 min.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([CH:14]2[CH2:16][CH2:15]2)=[O:13])=[C:7]2[C:3]=1[CH2:4][N:5]([CH:18]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH:30]([F:32])[F:31])=[C:25]([O:33][CH2:34][CH3:35])[CH:24]=1)[CH2:19][C:20]([OH:22])=O)[C:6]2=[O:17].C1N=C[N:38](C(N2C=NC=C2)=O)C=1.[NH4+].[OH-]>C1COCC1>[C:20]([CH2:19][CH:18]([N:5]1[C:6](=[O:17])[C:7]2[C:3](=[C:2]([Cl:1])[CH:10]=[CH:9][C:8]=2[NH:11][C:12]([CH:14]2[CH2:15][CH2:16]2)=[O:13])[CH2:4]1)[C:23]1[CH:28]=[CH:27][C:26]([O:29][CH:30]([F:31])[F:32])=[C:25]([O:33][CH2:34][CH3:35])[CH:24]=1)(=[O:22])[NH2:38]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CCOc1cc(C(CC(=O)O)N2Cc3c(Cl)ccc(NC(=O)C4CC4)c3C2=O)ccc1OC(F)F
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCOc1cc(C(CC(N)=O)N2Cc3c(Cl)ccc(NC(=O)C4CC4)c3C2=O)ccc1OC(F)F
Yield: 17.9 %

Procedure:
Cyclopropanecarboxylic acid {2-[2-carbamoyl-1-(4-difluoromethoxy-3-ethoxy-phenyl)-ethyl]-7-chloro-3-oxo-2,3-dihydro-1H-isoindol-4-yl }-amide was prepared by the procedure of Example 6 from 3-[4-chloro-7-(cyclopropanecarbonylamino)-1-oxo-1,3-dihydro-isoindol-2-yl]-3-(4-difluoromethoxy-3-ethoxy-phenyl)-propionic acid (0.55 g, 1.1 mmol), CDI (0.26 g, 1.6 mmol) and NH4OH (0.35 ml, 3.3 mmol) in THF (15 ml) to give cyclopropanecarboxylic acid {2-[2-carbamoyl-1-(4-difluoromethoxy-3-ethoxy-phenyl)-ethyl]-7-chloro-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide as white solid (0.10 g, 20%): mp 198–200° C.; 1HNMR (CDCl3): δ 0.89–0.93 (m, 2H, c-CH2), 1.10–1.20 (m, 2H, c-CH2), 1.44 (t, J=7.5 Hz, 3H, OCH2CH3), 1.66–1.68 (m, 1H, c-CH), 2.98 (dd, J=5, 15 Hz, 1H, CH2), 3.43 (dd, J=10, 15 Hz, 1H, CH2), 4.09 (q, J=7.5 Hz, 2H, OCH2CH3), 4.18 (d, J=17.5 Hz, 1H, CHHN), 4.37 (d, J=17.5 Hz, 1H, CHHN), 5.48 (br, 1H, NHH), 5.57–5.53 (m, 1H, CHN), 5.92 (br, 1H, NHH), 6.86 (t, JH-F=75 Hz, 1H, CF2H), 6.94–7.02 (m, 3H, Ar), 7.16(d, J=10 Hz, 1H, Ar), 7.38 (t, J=8 Hz, 1H, Ar), 8.45 (d, J=8 Hz, 1H, Ar), 10.40 (s, 1H, NHCO). 13CNMR (CDCl3): δ 8.5, 14.6, 16.2, 38.6, 47.9, 54.1, 64.9, 101.57, 102.3, 113.2, 116.0, 119.2, 119.8, 121.8, 123.0, 133.2, 136.8, 137.1, 139.1, 150.9, 169.4, 171.1, 172.6; Anal Calcd for C24H26ClF2N3O5: C, 56.75; H, 4.76; N, 8.27. Found: C, 56.68; H, 4.63; N, 8.04.
Reaction SMILES: [CH:1](O)=[O:2].C(OC(=O)C)(=O)C.Cl.[NH2:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[C:17]([O:22][CH3:23])[CH:16]=1>O1CCCC1>[OH:21][C:18]1[CH:19]=[CH:20][C:15]([CH2:14][CH2:13][NH:12][CH:1]=[O:2])=[CH:16][C:17]=1[O:22][CH3:23]
Reactant: O=CO
Reactant: COc1cc(CCN)ccc1O
Agent: Cl
Solvent: CC(=O)OC(C)=O
Solvent: C1CCOC1
Product: COc1cc(CCNC=O)ccc1O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Formic acid (230 g, 5.0 mol) is added dropwise to acetic anhydride (383 g, 3.75 mol) at 0° C. This mixture is stirred for 2 hours at +55° C. and subsequently cooled again to 0° C. Tetrahydrofuran (500 ml) is added at this temperature followed by 4-(2-amino-ethyl)-2-methoxyphenol hydrochloride (50 g, 0.25 mol). The resulting white suspension is stirred for 18 hours at +75° C., changing into a yellow solution. The reaction mixture is evaporated and the residue is submitted to flash-chromatography to yield N-[2-(4-hydroxy-3-methoxy-phenyl)-ethyl]-formamide.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.Br.Br.[CH3:23][N:24]1[CH2:31][C:30]2[CH2:29][NH:28][CH2:27][C:26]=2[CH2:25]1.N12CCCN=C1CCCCC2>C(#N)C>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11]([N:28]4[CH2:29][C:30]5[CH2:31][N:24]([CH3:23])[CH2:25][C:26]=5[CH2:27]4)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: CN1CC2=C(CNC2)C1
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Agent: Br
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CN1CC2=C(C1)CN(c1c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c1F)C2
Reaction time: 8 h
Yield: 62.7 %

Procedure:
1-Cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (0.42 g), 3-methyl-3,7-diazabicyclo[3.3.0]oct-1(5)-ene dihydrobromide (0.47 g) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 0.63 g) were dissolved in acetonitrile (20 ml) and refluxed for 7 hours. The reaction mixture was kept at room temperature overnight and then the produced precipitate was filtered, washed with acetonitrile and methanol to give the title compound 0.36 g (yield 62%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([O:9][CH:10]([F:12])[F:11])[C:5]([OH:8])=[N:6][CH:7]=1.[CH3:13]I>C(Cl)(Cl)Cl.C(=O)([O-])[O-].[Ag+2]>[Br:1][C:2]1[CH:3]=[C:4]([O:9][CH:10]([F:12])[F:11])[C:5]([O:8][CH3:13])=[N:6][CH:7]=1
Reactant: CI
Reactant: Oc1ncc(Br)cc1OC(F)F
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: ClC(Cl)Cl
Product: COc1ncc(Br)cc1OC(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
As shown in step 3-v of Scheme 3, 5-bromo-3-(difluoromethoxy)pyridin-2-ol (300 mg; 1.25 mmol) was dissolved in 5 mL of chloroform. Silver carbonate (690 mg; 2.5 mmol) and methyl iodide (780 μL; 1.77 g; 12.5 mmol) were added and the mixture stirred at RT overnight. The reaction mixture was filtered through diatomaceous earth, which was washed with additional CHCl3. The filtrates were concentrated under reduced pressure to yield an oil which was purified by silica gel chromatography to yield 5-bromo-3-(difluoromethoxy)-2-methoxypyridine as a white solid (Compound 1010, 250 mg, 78% yield): ESMS (M+H) 254/256; 1H NMR (CDCl3) δ 8.08 (d, 1H, J=2.1 Hz), 7.56 (d, 1H, J=2.1 Hz), 6.60 (t, 1H, J=75 Hz), 3.98 (s, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:5]=1[CH2:14][C:15]([O:17]C(C)(C)C)=[O:16])([O-:3])=[O:2].FC(F)(F)C(O)=O>C(Cl)Cl>[N+:1]([C:4]1[CH:9]=[C:8]([C:10]([F:11])([F:12])[F:13])[CH:7]=[CH:6][C:5]=1[CH2:14][C:15]([OH:17])=[O:16])([O-:3])=[O:2]
Reactant: CC(C)(C)OC(=O)Cc1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)Cc1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3 h

Procedure:
16.7 g of tert.butyl 2-nitro-4-trifluoromethyl-phenylacetate and 50 ml of trifluoroacetic acid are dissolved in 50 ml of methylene chloride and stirred for 3 hours at ambient temperature. After elimination of the solvent the residue is taken up in petroleum ether/ether (10:1), suction filtered and dried in vacuo at 80° C.
Reaction SMILES: F[C:2]1[N:23]=[CH:22][CH:21]=[CH:20][C:3]=1[C:4]([NH:6][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][CH:8]=1)=[O:5].[NH2:24][C:25]1[CH:34]=[C:33]2[C:28]([CH:29]=[CH:30][N:31]=[CH:32]2)=[CH:27][CH:26]=1.C(O)(C(F)(F)F)=O>CC(O)(C)C>[CH:32]1[C:33]2[C:28](=[CH:27][CH:26]=[C:25]([NH:24][C:2]3[N:23]=[CH:22][CH:21]=[CH:20][C:3]=3[C:4]([NH:6][C:7]3[CH:12]=[CH:11][C:10]([C:13]([F:19])([F:18])[C:14]([F:17])([F:16])[F:15])=[CH:9][CH:8]=3)=[O:5])[CH:34]=2)[CH:29]=[CH:30][N:31]=1
Reactant: O=C(Nc1ccc(C(F)(F)C(F)(F)F)cc1)c1cccnc1F
Reactant: Nc1ccc2ccncc2c1
Solvent: O=C(O)C(F)(F)F
Solvent: CC(C)(C)O
Product: O=C(Nc1ccc(C(F)(F)C(F)(F)F)cc1)c1cccnc1Nc1ccc2ccncc2c1
Temperature: 90 °C
Reaction time: 24 h

Procedure:
To a mixture of 2-fluoro-N-(4-pentafluoroethyl-phenyl)-nicotinamide (112 mg) and 7-aminoisoquinoline (40 mg) in t-BuOH (0.5 mL) was added TFA (94 μL). The resulting mixture was stirred for 24 h at 90° C., cooled to RT and purified by flash chromatography (4:1:0.1; MeOH/CH2Cl2/MeOH) to give the title compound as a yellow solid. MS (ES+): 459 (M+H)+. Calc'd for C23H15F5N4O—458.12.
Reaction SMILES: [O:1]=[C:2]1[NH:8][CH:7]([CH2:9][CH:10]=[CH:11][C:12]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][C:13]=2[C:14]([O:16][CH3:17])=[O:15])[CH2:6][CH2:5][CH2:4][CH2:3]1.F[B-](F)(F)F.[CH3:30][O+](C)C>C(Cl)Cl>[N+:22]([C:19]1[CH:20]=[CH:21][C:12]([CH:11]=[CH:10][CH2:9][CH:7]2[CH2:6][CH2:5][CH2:4][CH2:3][C:2]([O:1][CH3:30])=[N:8]2)=[C:13]([CH:18]=1)[C:14]([O:16][CH3:17])=[O:15])([O-:24])=[O:23]
Reactant: COC(=O)c1cc([N+](=O)[O-])ccc1C=CCC1CCCCC(=O)N1
Reactant: C[O+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: COC(=O)c1cc([N+](=O)[O-])ccc1C=CCC1CCCCC(OC)=N1

Procedure:
The product of Example 159 is reacted with trimethyloxonium tetrafluoroborate in CH2Cl2 by the method of Example 3 to produce the title material.
Reaction SMILES: C(C1C=C(B(O)O)C=CC=1)(=O)C.Br[C:14]1[CH:15]=[CH:16][C:17]([C:20]([OH:23])([CH3:22])[CH3:21])=[N:18][CH:19]=1.C(NC(C1C(=O)C2C(=NC=CC=2)[N:32]([C:41]2[CH:46]=[CH:45][CH:44]=[C:43](Br)[CH:42]=2)C=1)=O)(C)C>>[NH2:32][C:41]1[CH:42]=[C:43]([C:14]2[CH:15]=[CH:16][C:17]([C:20]([OH:23])([CH3:22])[CH3:21])=[N:18][CH:19]=2)[CH:44]=[CH:45][CH:46]=1
Reactant: CC(C)NC(=O)c1cn(-c2cccc(Br)c2)c2ncccc2c1=O
Reactant: CC(C)(O)c1ccc(Br)cn1
Agent: CC(=O)c1cccc(B(O)O)c1
Product: CC(C)(O)c1ccc(-c2cccc(N)c2)cn1

Procedure:
Following the procedure of Step 5 of Example 1, but substituting 3-aminophenylboronic acid for 3-acetyl phenylboronic acid and 5-bromo-2-(1-hydroxy-1-methylethyl)pyridine from Step 1 of Example 30 for N-isopropyl-1-(3-bromophenyl)-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide, the 5-(3-Aminophenyl)-2-(1-hydroxy-1-methylethyl) pyridine compound was obtained as a solid.