Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1/[C:11](=[CH:19]/[C:20]1[NH:24][CH:23]=[C:22]([C:25](O)=[O:26])[C:21]=1[CH3:28])/[C:12](=[O:18])[NH:13]2.[N:29]1([CH2:34][C@@H:35]2[CH2:40][CH2:39][CH2:38][NH:37][CH2:36]2)[CH2:33][CH2:32][CH2:31][CH2:30]1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1/[C:11](=[CH:19]/[C:20]1[NH:24][CH:23]=[C:22]([C:25]([N:37]3[CH2:38][CH2:39][CH2:40][C@@H:35]([CH2:34][N:29]4[CH2:30][CH2:31][CH2:32][CH2:33]4)[CH2:36]3)=[O:26])[C:21]=1[CH3:28])/[C:12](=[O:18])[NH:13]2
Reactant: Cc1c(C(=O)O)c[nH]c1/C=C1\C(=O)Nc2cccc(-c3c(F)cccc3F)c21
Reactant: C1CNC[C@H](CN2CCCC2)C1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: ClCCCl
Product: Cc1c(C(=O)N2CCC[C@@H](CN3CCCC3)C2)c[nH]c1/C=C1\C(=O)Nc2cccc(-c3c(F)cccc3F)c21
Yield: 69.9 %

Procedure:
5-[4-(2,6-Difluoro-phenyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-4-methyl-1H-pyrrole-3-carboxylic acid (114 mg, 0.3 mmol) was coupled with (R)-3-pyrrolidin-1-ylmethyl-piperidine (99 mg, 2 eq.), HOBt (1 eq.), EDC (1.5 eq.) and TEA (3 drops) in THF (1 mL) and aceonitrile (1 mL) at rt for overnight to give 111.3 mg (70%) of the titled compound as a yellow solid.
Reaction SMILES: C[O:2][C:3](=[O:31])[CH2:4][N:5]([CH2:17][C@@H:18]([NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C@@H:19]([CH3:22])[CH2:20][CH3:21])[CH2:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][CH:8]=1.[OH-].[Na+]>CO>[C:27]([O:26][C:24]([NH:23][C@@H:18]([C@@H:19]([CH3:22])[CH2:20][CH3:21])[CH2:17][N:5]([CH2:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][CH:8]=1)[CH2:4][C:3]([OH:31])=[O:2])=[O:25])([CH3:30])([CH3:29])[CH3:28]
Reactant: CC[C@H](C)[C@@H](CN(CC(=O)OC)Cc1cccc2ccccc12)NC(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC[C@H](C)[C@@H](CN(CC(=O)O)Cc1cccc2ccccc12)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
N-[2(S)-(t-Butoxycarbonylamino)-3(S)-methylpentyl]-N-(1-naphthylmethyl)glycine methyl ester (2.61 g, 6.10 mmol) was dissolved in MeOH (50 ml) and 1N NaOH (24.4 ml, 24.4 mmol) was added. The mixture was stirred at ambient temperature for 4 h and concentrated. The resulting residue was dissolved in water (25 ml) and neutralized with 1N HCl (24.4 ml). The aqueous layer was washed with EtOAc (3×50 ml). The organic layers were combined, dried with Na2SO4, filtered, and concentrated to give the product. 1H NMR (CD3OD) δ8.43 (1H, d, J=6Hz), 7.97 (2H, t, J=6 Hz) 7.75-7.48 (4H, m), 4.96 (1H, d, J=12Hz), 4.72 (1H, d, J=12 Hz), 3.80-3.58 (3H, m), 3.49-3.40 (1H, dd,, J=3 and 12 Hz), 3.03 (1H, dd, J=3 and 12 Hz), 1.42 (9H, s,), 1.37-1.28 (2H, m), 1.80-1.00 (1H, m), 0.94-0.78 (6H, m,) ppm.
Reaction SMILES: Br[C:2]1[S:3][C:4]([Br:7])=[CH:5][N:6]=1.[CH3:8][N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1>CCN(C(C)C)C(C)C>[Br:7][C:4]1[S:3][C:2]([N:12]2[CH2:13][CH2:14][N:9]([CH3:8])[CH2:10][CH2:11]2)=[N:6][CH:5]=1
Reactant: Brc1cnc(Br)s1
Reactant: CN1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCN(c2ncc(Br)s2)CC1
Temperature: 110 °C

Procedure:
A solution of 2,5-dibromothiazole (1.000 g, 4.116 mmol) in DIPEA (3.00 mL) was charged with 1-methylpiperazine (0.457 mL, 4.12 mmol) and heated to 110° C. for 3 h then an additional 48 h at rt. The reaction mixture was partitioned between CHCl3 and H2O, and the layers were separated. The aqueous layer was re-extracted with CHCl3 (3×) and the combined organic fractions were dried over Na2SO4, filtered and concentrated in vacuo. The crude material was purified by chromatography on silica gel [eluting with 5% EtOAc in CHCl3→20% EtOAc in CHCl3] resulting in the title compound as an off-white solid. 1H NMR (400 MHz, CDCl3): δ=2.34 (s, 3H), 2.48-2.56 (m, 4H), 3.42-3.51 (m, 4H), 7.07 (s, 1H). MS (ES+): m/z=262.09/264.06 (51/49) [MH+]. HPLC: tR=1.57 & 0.53 min (peak splitting; ZQ2, polar—5 min).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[CH:10]=[C:9]([C:12]([NH:14][NH:15][C:16](=[O:18])[CH3:17])=O)[O:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>ClCCCl>[CH3:1][O:2][C:3]1[C:11]2[CH:10]=[C:9]([C:12]3[O:18][C:16]([CH3:17])=[N:15][N:14]=3)[O:8][C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: COc1cccc2oc(C(=O)NNC(C)=O)cc12
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: COc1cccc2oc(-c3nnc(C)o3)cc12
Reaction time: 1.5 h
Yield: 31.8 %

Procedure:
To a solution (400 ml) of N′-(4-methoxybenzo(b)furan-2-ylcarbonyl)acetohydrazide (15.6 g) in 1,2-dichloroethane were added triethylamine (21 ml) and triphenylphosphine (19.8 g) and the reaction temperature was set to 5° C. To this reaction mixture was added dropwise diethyl azodicarboxylate (40% toluene solution) (33 ml) over 15 min. The reaction temperature was set to room temperature and the mixture was stirred for 1.5 hr and washed with saturated aqueous solution of ammonium chloride. After partitioning, the obtained organic layer was dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. The obtained residue was concentrated under reduced pressure and purified by silica gel column chromatography (chloroform/ethyl acetate) to give the title compound (4.6 g) as pale-yellow crystals.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:35])[CH2:11][N:12]1[CH:16]=[C:15]([NH:17][C:18]2[C:27]3[C:22](=[CH:23][C:24]([O:28][CH2:29][CH:30](OC)[O:31]C)=[CH:25][CH:26]=3)[N:21]=[CH:20][N:19]=2)[CH:14]=[N:13]1.Cl>O1CCCC1>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:35])[CH2:11][N:12]1[CH:16]=[C:15]([NH:17][C:18]2[C:27]3[C:22](=[CH:23][C:24]([O:28][CH2:29][CH:30]=[O:31])=[CH:25][CH:26]=3)[N:21]=[CH:20][N:19]=2)[CH:14]=[N:13]1
Reactant: COC(COc1ccc2c(Nc3cnn(CC(=O)Nc4cccc(F)c4F)c3)ncnc2c1)OC
Agent: Cl
Solvent: C1CCOC1
Product: O=CCOc1ccc2c(Nc3cnn(CC(=O)Nc4cccc(F)c4F)c3)ncnc2c1
Temperature: 25 °C

Procedure:
A solution of N-(2,3-difluorophenyl)-2-(4-{[7-(2,2-dimethoxyethoxy)quinazolin-4-yl]amino}-1H-pyrazol-1-yl)acetamide (0.104 g, 0.21 mmol) in a dilute solution of hydrochloric acid (1M, 1 ml) and tetrahydrofuran (5 ml) was heated at reflux for 10 hours. The mixture was allowed to cool to room temperature and was then filtered. The filtered solid was triturated with tetrahydrofuran and then dried under vaccum to give N-(2,3-difluorophenyl)-2-(4-{[7-(2-oxoethoxy)quinazolin-4-yl]amino}-1H-pyrazol-1-yl)acetamide as an approximate 1:1 mixture of aldehyde:hemiacetal (0.080 g, 87% yield) which was used in the next step without further purification:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([N:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][N:18]=3)[CH:13]=[C:12]([CH2:20][CH2:21][CH:22]([OH:29])[C:23]3[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=3)[C:11]2=[O:30])[CH:7]=[CH:8][CH:9]=1)([O-])=O.[Sn](Cl)(Cl)(Cl)Cl>>[NH2:1][C:4]1[CH:5]=[C:6]([N:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][N:18]=3)[CH:13]=[C:12]([CH2:20][CH2:21][CH:22]([OH:29])[C:23]3[CH:24]=[CH:25][N:26]=[CH:27][CH:28]=3)[C:11]2=[O:30])[CH:7]=[CH:8][CH:9]=1
Reactant: O=c1c(CCC(O)c2ccncc2)cc2cccnc2n1-c1cccc([N+](=O)[O-])c1
Agent: Cl[Sn](Cl)(Cl)Cl
Product: Nc1cccc(-n2c(=O)c(CCC(O)c3ccncc3)cc3cccnc32)c1
Yield: 65.1 %

Procedure:
The procedure of Example 19 was repeated using 1-(3-nitrophenyl)-3-[3-hydroxy-3-(pyridin-4-yl)propyl]-1,8-naphthyridin-2(1H)-one (400 mg, 0.99 mmol; prepared in Example 20) and tin chloride.2H2O (2 g, 5-fold weights) while ice-cooling to obtain 1-(3-aminophenyl)-3-[3-hydroxy-3-(pyridin-4-yl)propyl]-1,8-naphthyridin-2(1H)-one (240 mg, 65%; mp 209–211° C.).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:14][CH:15]1[CH2:20][CH2:19][CH:18]([O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])[CH2:17][CH2:16]1)[C:10](OC)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+]>CO>[Si:22]([O:21][CH:18]1[CH2:17][CH2:16][CH:15]([CH2:14][C@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:10][OH:11])[CH2:20][CH2:19]1)([C:25]([CH3:27])([CH3:28])[CH3:26])([CH3:24])[CH3:23]
Reactant: COC(=O)[C@H](CC1CCC(O[Si](C)(C)C(C)(C)C)CC1)NC(=O)OC(C)(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@H](CO)CC1CCC(O[Si](C)(C)C(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 82.2 %

Procedure:
To a solution of (S)-methyl 2-(tert-butoxycarbonylamino)-3-(4-(tert-butyldimethylsilyloxy)cyclohexyl)propanoate (133 g, 0.32 mol) in 1500 mL methanol was added NaBH4 (73 g, 1.92 mol) at rt. After stirring at rt for 4 h, the solution was evaporated to remove methanol. The remaining solution was treated with water (800 mL), extracted with EtOAc (500 mL×3). The combined organic layers were washed with water (300 mL), dried, filtered, and evaporated to give the desired (S)-tert-butyl 1-(4-(tert-butyldimethylsilyloxy)cyclohexyl)-3-hydroxypropan-2-ylcarbamate (102 g, yield 82%). 1H NMR (CDCl3, 400 MHz) δ 0.08 (d, 6H), 0.89 (d, 9H), 1.30 (m, 4H), 1.40 (t, 2H), 1.45 (s, 9H), 1.61 (m, 1H), 1.58 (m, 1H), 1.68 (t, 4H), 1.85 (d, 1H), 3.50 (m, 1H), 3.65 (m, 1H), 3.73 (m, 1H), 3.91 (s, 1H), 4.53 (s, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:15]([O:20][CH3:21])=[N:16][NH:17][C:18]=2[CH3:19])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].N1CCC[CH2:24][CH2:23]1>>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]2[C:15]([O:20][CH3:21])=[N:16][N:17]([CH2:23][CH3:24])[C:18]=2[CH3:19])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C1CCNCC1
Reactant: COc1n[nH]c(C)c1C1CCN(C(=O)OC(C)(C)C)CC1
Product: CCn1nc(OC)c(C2CCN(C(=O)OC(C)(C)C)CC2)c1C

Procedure:
The title compound was prepared from 1-tert-butoxycarbonyl-4-(3-methoxy-5-methyl-(1H)-pyrazol-4-yl)piperidine (Step D) using a procedure analogous to that described for Piperidine 15, Step E. RF: 0.29 (9:1 v/v hexanes/acetone); 1H-NMR (500 MHz) δ 1.31 (t, J=7.3, 3H), 1.47 (s, 9H), 1.54–1.56 (m, 2H), 1.79–1.87 (m, 2H), 2.13 (s, 3H), 2.38–2.45 (m, 1H), 2.70 (m, 2H), 3.84 (s, 3H), 3.91 (q, J=7.3, 2H), 4.25 (m, 2H).
Reaction SMILES: [OH-].[Na+].S(O)(O)(=O)=O.[CH3:8][S:9][C:10](=[NH:12])[NH2:11].[NH2:13][C:14]1[C:15]([C:26](OC(C)=CC(=O)NC(C)(C)C)=[O:27])=[N:16][C:17]([Cl:25])=[C:18]([NH:20][CH2:21][CH:22]2[CH2:24][CH2:23]2)[N:19]=1>C1COCC1>[NH2:13][C:14]1[C:15]([C:26]([NH:12][C:10]([S:9][CH3:8])=[NH:11])=[O:27])=[N:16][C:17]([Cl:25])=[C:18]([NH:20][CH2:21][CH:22]2[CH2:23][CH2:24]2)[N:19]=1
Reactant: CC(=CC(=O)NC(C)(C)C)OC(=O)c1nc(Cl)c(NCC2CC2)nc1N
Reactant: CSC(=N)N
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CSC(=N)NC(=O)c1nc(Cl)c(NCC2CC2)nc1N

Procedure:
To NaOH (2 mol/l in water; 9.07 ml; 18.1 mmol) is added S-methylisothiourea sulphate (5.05 g; 18.1 mmol). The mixture is stirred until complete solution is achieved. The resulting solution is added to 1-(tert-butylcarbamoyl)prop-1-en-2-yl 3-amino-6-chloro-5-[(cyclopropylmethyl)amino]pyrazine-2-carboxylate (example 5) (2.31 g; 6.05 mmol) in THF (50 ml). The mixture is stirred at r.t. for 3 d, then volatiles are evaporated. The residue is purified by RP-HPLC (modifier: trifluoro acetic acid (TFA) (C11H15ClN6OS).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[CH2:11]([N:18]1[C:23](=[O:24])[C:22]2[CH:25]=[CH:26][S:27][C:21]=2[N:20]=[C:19]1[CH:28]([NH:31][CH2:32][CH2:33][N:34]([CH3:36])[CH3:35])[CH2:29][CH3:30])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)C(C)C)(C)C>ClCCl>[CH2:11]([N:18]1[C:23](=[O:24])[C:22]2[CH:25]=[CH:26][S:27][C:21]=2[N:20]=[C:19]1[CH:28]([N:31]([CH2:32][CH2:33][N:34]([CH3:36])[CH3:35])[C:6](=[O:7])[C:5]1[CH:9]=[CH:10][C:2]([Br:1])=[CH:3][CH:4]=1)[CH2:29][CH3:30])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CCC(NCCN(C)C)c1nc2sccc2c(=O)n1Cc1ccccc1
Reactant: O=C(Cl)c1ccc(Br)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCC(c1nc2sccc2c(=O)n1Cc1ccccc1)N(CCN(C)C)C(=O)c1ccc(Br)cc1
Reaction time: 1 h

Procedure:
A solution of 4-bromobenzoyl chloride (8 mg, 0.035 mmol, 1 equiv) in dichloromethane (1 mL) was added to a solution of 3-benzyl-2-(1-{[2-(dimethylamino)ethyl]amino}propyl)thieno[2,3-d]pyrimidin-4(3H)-one (3-1, 13 mg, 0.035 mmol, 1 equiv) and N,N-diisopropylethylamine (5 mg, 0.035 mmol, 1 equiv) in dichloromethane (1 mL), and the resulting mixture was stirred under ambient conditions for 1 h. The reaction mixture was washed with saturated aqueous NaHCO3 solution, and brine, then dried (MgSO4) and concentrated. The residue was purified by flash chromatography. Elution with CH2Cl2 to 5% NH3-EtOH/CH2Cl2 gave N-[1-(3-benzyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidin-2-yl)propyl]-4-bromo-N-[2-(dimethylamino)ethyl]benzamide (3-2) as an off-white foam. 1H NMR (500 MHz, CDCl3) δ 7.53 (m, 3H), 7.31 (m, 5H), 7.14 (m, 2H), 6.09 (d, J=15.6 Hz, 1H), 5.94 (m, 1H), 5.10 (d, J=15.6 Hz, 1H), 3.40 (m, 2H), 2.11 (m, 1H), 2.03 (m, 2H), 1.87 (m, 1H), 1.79 (s, 6H), 0.66 (t, J=6.6 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[C:7]#[N:8].[C:9]([N:17]=[C:18]=[O:19])(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[C:7]([C:6]1[CH:5]=[CH:4][S:3][C:2]=1[NH:1][C:18]([NH:17][C:9](=[O:16])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)=[O:19])#[N:8]
Reactant: O=C=NC(=O)c1ccccc1
Reactant: N#Cc1ccsc1N
Product: N#Cc1ccsc1NC(=O)NC(=O)c1ccccc1

Procedure:
Prepared as in Example 1a from 2-aminothiophene-3-carbonitrile and benzoyl isocyanate as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 7.23-7.19 (m, 2H), 7.55 (t, J=8.0 Hz, 2H), 7.70-7.66 (m, 1H), 8.04-8.02 (m, 2H), 11.62 (bs, 1H), 12.18 (bs, 1H). MS 272 (MH+).
Reaction SMILES: I[C:2]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[N:4]([CH3:11])[N:3]=1.C([Mg]Cl)(C)C.[CH2:17]([Sn:21]([CH2:27][CH2:28][CH2:29][CH3:30])([CH2:23][CH2:24][CH2:25][CH3:26])Cl)[CH2:18][CH2:19][CH3:20]>C1COCC1>[CH3:11][N:4]1[C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10]=2[C:2]([Sn:21]([CH2:23][CH2:24][CH2:25][CH3:26])([CH2:27][CH2:28][CH2:29][CH3:30])[CH2:17][CH2:18][CH2:19][CH3:20])=[N:3]1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: Cn1nc(I)c2c1CCCC2
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1nn(C)c2c1CCCC2
Temperature: -16 °C
Reaction time: 0.33 h

Procedure:
In a 25 mL round-bottomed flask, 3-iodo-1-methyl-4,5,6,7-tetrahydro-1H-indazole (62 mg, 237 μmol) was dissolved in THF (3 mL). The colorless solution was cooled to −16° C. (NaCl/ice bath) and isopropylmagnesium chloride 2 M in THF (132 μL, 265 μmol) was added dropwise at −16° C. The reaction mixture was stirred at −16° C. for 20 min. Then, tributylchlorostannane (88.6 mg, 73.8 μL, 272 μmol) was added slowly. The reaction mixture was warmed to 25° C. and stirred for 1.5 h. The reaction mixture was quenched with saturated ammonium chloride solution, extracted with dichloromethane (3×30 mL), organics dried over MgSO4 and concentrated to an off-white waxy solid. The residue was dried under high vacuum yielding 1-methyl-3-(tributylstannyl)-4,5,6,7-tetrahydro-1H-indazole assumed quantitative and taken into next step without further treatment.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:10][C:11]2[N:16]=[C:15]([C:17]3[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=3)[C:20]#[N:21])[CH:14]=[C:13]([NH:25][C:26]3[CH:31]=[N:30][CH:29]=[CH:28][N:27]=3)[N:12]=2)[CH3:9])=[CH:4][CH:3]=1.[F-].[K+].C([OH:38])(C)(C)C>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:10][C:11]2[N:16]=[C:15]([C:17]3[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=3)[C:20]([NH2:21])=[O:38])[CH:14]=[C:13]([NH:25][C:26]3[CH:31]=[N:30][CH:29]=[CH:28][N:27]=3)[N:12]=2)[CH3:9])=[CH:4][CH:3]=1
Reactant: C[C@H](Nc1nc(Nc2cnccn2)cc(-c2cccc(C#N)c2)n1)c1ccc(F)cc1
Reactant: CC(C)(C)O
Agent: [F-]
Agent: [K+]
Product: C[C@H](Nc1nc(Nc2cnccn2)cc(-c2cccc(C(N)=O)c2)n1)c1ccc(F)cc1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
192 mg of (S)-3-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}benzonitrile (Example 81) was added to 5 ml of t-butanol, and 384 mg of potassium fluoride supported on activated alumina was added thereto, and the mixture was stirred at 80° C. for 2 hours. 384 mg of potassium fluoride supported on activated alumina was added thereto, and the mixture was further stirred for 15 hours. The reaction solution was filtrated to remove precipitates, and then the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography to obtain 158 mg of the objective compound as white powder.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:7]3[CH:12]=[N:11][NH:10][C:8]=3[N:9]=2)[CH2:3][CH2:2]1.CC(C)([O-])C.[K+].C[N:25]1CCCC1=O>CCOC(C)=O>[NH2:25][N:10]1[C:8]2[N:9]=[C:4]([CH:1]3[CH2:2][CH2:3]3)[CH:5]=[C:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:7]=2[CH:12]=[N:11]1
Reactant: CN1CCCC1=O
Reactant: CCOC(=O)c1cc(C2CC2)nc2[nH]ncc12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc(C2CC2)nc2c1cnn2N
Reaction time: 0.33 h

Procedure:
Ethyl 6-cyclopropyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylate (200 mg, 0.865 mmol) was dissolved in N-Methyl-2-pyrrolidone (NMP) (8 mL), followed by addition of potassium tert-butoxide (116 mg, 1.038 mmol). After 20 minutes stirring, 0-{[4-(methyloxy)phenyl]carbonyl}hydroxylamine 1-[(aminooxy)carbonyl]-4-(methyloxy)benzene (289 mg, 1.730 mmol) was added and the mixture stirred at room temperature for 16 h. The contents were diluted with EtOAc, and then washed with brine, and saturated NaHCO3. The organic phase was dried over MgSO4, filtered, and concentrated in vacuo. The crude product was purified via silica gel chromatography (eluent: 0 to 50% EtOAc). The final product as collected as 106 mg (50%). LCMS E-S (M+H)=274.4. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.00-1.14 (m, 4H), 1.41 (t, J=7.07 Hz, 3H), 2.34-2.47 (m, 1H), 4.44 (q, J=7.07 Hz, 2H), 6.39 (s, 2H), 7.64 (s, 1H), 8.09 (s, 1H).
Reaction SMILES: [CH2:1]([C:8]1[N:9]=[N:10][C:11]([N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)=[C:12]([CH3:15])[C:13]=1[CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:22]([N:29]=[C:30]=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(Cl)Cl>[CH2:22]([NH:29][C:30]([N:19]1[CH2:18][CH2:17][N:16]([C:11]2[N:10]=[N:9][C:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[C:13]([CH3:14])[C:12]=2[CH3:15])[CH2:21][CH2:20]1)=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: Cc1c(Cc2ccccc2)nnc(N2CCNCC2)c1C
Reactant: O=C=NCc1ccccc1
Solvent: ClCCl
Product: Cc1c(Cc2ccccc2)nnc(N2CCN(C(=O)NCc3ccccc3)CC2)c1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 52.7 %

Procedure:
To a solution of 3-benzyl-4,5-dimethyl-6-piperazin-1-yl-pyridazine (60 mg, 0.21 mmol)) in CH2Cl2 (5 mL) at 25° C. is added benzyl isocyanate (37 mg, 0.28 mmol). After being stirred at 25° C. for 2 h, the reaction mixture is concentrated and purified by HPLC (CH3CN/H2O: 22%˜45% with 0.1% TFA) to give 4-(6-benzyl-4,5-dimethyl-pyridazin-3-yl)-piperazine-1-carboxylic acid benzylamide (46 mg, 60%).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][C:11]2[CH:12]=[N:13][C:14]3[C:19]([CH:20]=2)=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:3]=1[C:4]#[N:5].[OH-:21].[Na+]>S(=O)(=O)(O)O>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][C:11]2[CH:12]=[N:13][C:14]3[C:19]([CH:20]=2)=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:3]=1[C:4]([NH2:5])=[O:21]
Reactant: [OH-]
Reactant: N#Cc1c(Cl)cccc1Oc1cnc2ccccc2c1
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: NC(=O)c1c(Cl)cccc1Oc1cnc2ccccc2c1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
1.18 g of 2-chloro-6-(quinolin-3-yloxy)-benzonitrile was dissolved in 5 ml of 80% sulfuric acid and the mixture was stirred for 3 hours at 100° C. After being neutralized with an aqueous solution of sodium hydroxide, the liquid was separated with ethyl acetate, the organic layer was concentrated and 1.03 g of 2-chloro-6-(quinolin-3-yloxy)-benzamide (Compound Number 20) was obtained.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][CH2:8][CH2:9][NH:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:27]/[CH:28]=[CH:29]/[C:30]([O:32][CH3:33])=[O:31]>CC(C)=O>[CH3:33][O:32][C:30](=[O:31])[CH:29]=[CH:28][CH2:27][N:10]([CH2:9][CH2:8][NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:19])[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1
Reactant: CC(C)(C)OC(=O)NCCNCc1ccc(F)cc1
Reactant: COC(=O)/C=C/CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)C=CCN(CCNC(=O)OC(C)(C)C)Cc1ccc(F)cc1
Yield: 89.2 %

Procedure:
[2-(4-Fluoro-benzylamino)-ethyl]-carbamic acid tert-butyl ester (7.0 g, 26.1 mmol) and potassium carbonate (7.2 g, 52.2 mmol) were stirred in acetone (150 mL). A mixture of methyl 4-bromocrotonate (4.7 g, 26.1 mmol, 3.1 mL) in acetone (50 mL) was added to this solution dropwise using an addition funnel. After 18 h the solution was filtered, concentrated and chromatographed on silica gel to yield the title compound as a yellow oil (8.53 g).
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[CH:11]=[C:12]([CH:29]=[CH:30][C:31]=1[CH2:32][O:33][Si:34]([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:36])[CH3:35])[O:13][CH2:14][C:15]1[S:19][C:18](/[C:20](/[CH2:27][CH3:28])=[CH:21]/[CH2:22][CH2:23][C:24]([OH:26])=[O:25])=[CH:17][CH:16]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:41](=O)([O-])[O-].[K+].[K+].IC>CC(=O)CC>[Si:1]([O:8][CH2:9][C:10]1[CH:11]=[C:12]([CH:29]=[CH:30][C:31]=1[CH2:32][O:33][Si:34]([C:37]([CH3:39])([CH3:38])[CH3:40])([CH3:35])[CH3:36])[O:13][CH2:14][C:15]1[S:19][C:18](/[C:20](/[CH2:27][CH3:28])=[CH:21]/[CH2:22][CH2:23][C:24]([O:26][CH3:41])=[O:25])=[CH:17][CH:16]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC/C(=C\CCC(=O)O)c1ccc(COc2ccc(CO[Si](C)(C)C(C)(C)C)c(CO[Si](C)(C)C(C)(C)C)c2)s1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CCC(C)=O
Product: CC/C(=C\CCC(=O)OC)c1ccc(COc2ccc(CO[Si](C)(C)C(C)(C)C)c(CO[Si](C)(C)C(C)(C)C)c2)s1

Procedure:
4.3 g (7.1 mmol) of (E)-5-{5-[3,4-bis(tert-butyldimethylsilanyloxymethyl)phenoxymethyl]-2-thienyl}-4-heptenoic acid are dissolved in 70 mL of 2-butanone, and 1.1 g of potassium carbonate (7.8 mmol) and 2.2 mL of iodomethane (35 mmol) are added. The medium is refluxed for 12 hours, cooled and filtered. The filtrate is concentrated under reduced pressure and then purified by chromatography on a column of silica. A yellow oil is obtained (m=4.34 g; Y=98%).
Reaction SMILES: Cl[C:2]1[N:14]([CH3:15])[C:5]2=[N:6][CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=[C:4]2[N:3]=1.[CH2:16]([S:18][C:19]1[NH:20][CH:21]=[CH:22][CH:23]=1)[CH3:17].[H-].[Na+].O>CN(C=O)C>[CH2:16]([S:18][C:19]1[N:20]([C:2]2[N:14]([CH3:15])[C:5]3=[N:6][CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=[C:4]3[N:3]=2)[CH:21]=[CH:22][CH:23]=1)[CH3:17]
Reactant: CCSc1ccc[nH]1
Reactant: Cn1c(Cl)nc2cc(C(F)(F)F)cnc21
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCSc1cccn1-c1nc2cc(C(F)(F)F)cnc2n1C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 86.1 %

Procedure:
A solution of 0.49 g of 2-chloro-3-methyl-6-trifluoromethyl-3H-imidazo[4,5-b]pyridine in DMF (2 ml) was added to a mixture of 0.24 g of 2-ethylthio-1H-pyrrole, 0.11 g of sodium hydride (60% oil-based) and 3 ml of DMF, and the mixture was stirred at room temperature for 1.5 hours. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, then dried over anhydrous magnesiums sulfate and concentrated under reduced pressure. The resulting residue was applied to a silica gel column chromatography to obtain 0.53 g of 2-(2-ethylthiopyrrol-1-yl)-3-methyl-6-trifluoromethyl-3H-imidazo[4,5-b]pyridine (Compound of Present Invention (23)).