Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[O:5][C:6]1[CH:18]=[CH:17][C:9]2[N:10]=[C:11]([NH:13][C:14](=[O:16])[CH3:15])[S:12][C:8]=2[CH:7]=1.[Cl:22][C:23]1[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][C:24]=1[C:32]([C:35]#[N:36])([CH3:34])[CH3:33].O1CCCC1.C(Cl)(=O)C(Cl)=O>CN(C)C=O>[C:14]([NH:13][C:11]1[S:12][C:8]2[CH:7]=[C:6]([O:5][C:4]3[CH:3]=[C:2]([NH:1][C:27](=[O:28])[C:26]4[CH:30]=[CH:31][C:23]([Cl:22])=[C:24]([C:32]([C:35]#[N:36])([CH3:33])[CH3:34])[CH:25]=4)[CH:21]=[CH:20][CH:19]=3)[CH:18]=[CH:17][C:9]=2[N:10]=1)(=[O:16])[CH3:15]
Reactant: CC(C)(C#N)c1cc(C(=O)O)ccc1Cl
Reactant: CC(=O)Nc1nc2ccc(Oc3cccc(N)c3)cc2s1
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(=O)Nc1nc2ccc(Oc3cccc(NC(=O)c4ccc(Cl)c(C(C)(C)C#N)c4)c3)cc2s1
Yield: 41.5 %

Procedure:
Using N-[6-(3-aminophenoxy)-1,3-benzothiazol-2-yl]acetamide (160 mg, 0.534 mmol) produced in Example A40(x), 4-chloro-3-(1-cyano-1-methylethyl)benzoic acid (240 mg, 1.07 mmol), tetrahydrofuran (4 mL), N,N-dimethylformamide (10 μL), oxalyl chloride (170 mg, 1.34 mmol) and N,N-dimethylformamide (4 mL), and in the same manner as in Example A40(xi), the title compound (112 mg, 42%) was obtained as a colorless solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH2:13][CH:12]3[C:14](=O)[CH:9]([CH2:10][CH2:11]3)[CH2:8][C:7]=2[CH:16]=1.Cl.[NH2:18][OH:19]>C(O)C.N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH2:13][CH:12]3[C:14](=[N:18][OH:19])[CH:9]([CH2:10][CH2:11]3)[CH2:8][C:7]=2[CH:16]=1
Reactant: COc1ccc2c(c1)CC1CCC(C2)C1=O
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: COc1ccc2c(c1)CC1CCC(C2)C1=NO
Yield: 86.9 %

Procedure:
2-Methoxy-11-oxo-5,6,7,8,9,10-hexahydro-6,9-methanobenzocyclooctene (20.0 g; 0.1 mole) is reacted with hydroxylamine hydrochloride (20.0 g; 0.29 mole) in ethanol (100 ml) and pyridine (100 ml) to yield 20.1 g of the title compound.
Reaction SMILES: [CH:1]1([C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C:9]2[N:13]=[CH:12][NH:11][N:10]=2)[OH:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:20]([O:24][C:25]([N:27]1[CH2:32][CH2:31][CH:30]([CH2:33]Br)[CH2:29][CH2:28]1)=[O:26])([CH3:23])([CH3:22])[CH3:21]>>[C:20]([O:24][C:25]([N:27]1[CH2:32][CH2:31][CH:30]([CH2:33][N:11]2[CH:12]=[N:13][C:9]([C:7]([CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)([OH:8])[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[N:10]2)[CH2:29][CH2:28]1)=[O:26])([CH3:23])([CH3:21])[CH3:22]
Reactant: OC(c1ccccc1)(c1nc[nH]n1)C1CCCCC1
Reactant: CC(C)(C)OC(=O)N1CCC(CBr)CC1
Product: CC(C)(C)OC(=O)N1CCC(Cn2cnc(C(O)(c3ccccc3)C3CCCCC3)n2)CC1
Yield: 47 %

Procedure:
The title compound was prepared from cyclohexyl(phenyl)1H-1,2,4-triazol-3-ylmethanol (Preparation 18, 500 mg, 1.94 mmol) and tert-butyl4-(bromomethyl)piperidine-1-carboxylate (649 mg, 2.33 mmol) using the same method as described in preparation 3, to give a clear oil, in 47% yield, 415 mg.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[O:19][CH3:20])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([F:14])=[C:10]([F:15])[CH:9]=1)=[O:6].[Cl:21][C:22]1[CH:23]=[C:24]([N:29]=[C:30]=[S:31])[CH:25]=[C:26]([Cl:28])[CH:27]=1>>[Cl:21][C:22]1[CH:23]=[C:24]([NH:29][C:30](=[S:31])[NH:1][C:2]2[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=2[O:19][CH3:20])[C:5]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([F:14])=[C:10]([F:15])[CH:9]=2)=[O:6])[CH:25]=[C:26]([Cl:28])[CH:27]=1
Reactant: COc1ccc(C(=O)Nc2ccc(F)c(F)c2)cc1N
Reactant: S=C=Nc1cc(Cl)cc(Cl)c1
Product: COc1ccc(C(=O)Nc2ccc(F)c(F)c2)cc1NC(=S)Nc1cc(Cl)cc(Cl)c1
Yield: 83.3 %

Procedure:
Prepared according to the procedure described for Example 60 using 3-amino-N-(3,4-difluorophenyl)-4-methoxy-benzamide from Example 15 (0.834 g, 3.00 mmol) and 3,5-dichlorophenyl isothiocyanate (0.6124 g, 3.00 mmol) to afford the product (1.206 g) in 3 crops; m.p. 180-183° C.
Reaction SMILES: [ClH:1].[C:2]([O:6][C:7](=[O:10])[CH2:8][NH2:9])([CH3:5])([CH3:4])[CH3:3].Cl.[C:12]([CH2:15][CH2:16][C:17]([NH:19][CH2:20][C:21]1[O:25][C:24]([C:26]([O:28][C:29]2[CH:38]=[CH:37][C:36]3[C:31](=[CH:32][CH:33]=[C:34]([C:39](=[NH:41])[NH2:40])[CH:35]=3)[CH:30]=2)=[O:27])=[CH:23][CH:22]=1)=[O:18])(O)=[O:13].CN(C=O)C.C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[ClH:1].[C:2]([O:6][C:7]([CH2:8][NH:9][C:12]([CH2:15][CH2:16][C:17]([NH:19][CH2:20][C:21]1[O:25][C:24]([C:26]([O:28][C:29]2[CH:38]=[CH:37][C:36]3[C:31](=[CH:32][CH:33]=[C:34]([C:39](=[NH:40])[NH2:41])[CH:35]=3)[CH:30]=2)=[O:27])=[CH:23][CH:22]=1)=[O:18])=[O:13])=[O:10])([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(C)(C)OC(=O)CN
Reactant: N=C(N)c1ccc2cc(OC(=O)c3ccc(CNC(=O)CCC(=O)O)o3)ccc2c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)CNC(=O)CCC(=O)NCc1ccc(C(=O)Oc2ccc3cc(C(=N)N)ccc3c2)o1
Reaction time: 0.17 h
Yield: 74.4 %

Procedure:
To 0.75 g of glycine t-butyl ester hydrochloride, 0.15 g of DMAP and 1.5 g of 6-amidino-2-naphthyl 5-(3-carboxypropionylaminomethyl)furan-2-carboxylate hydrochloride were added 20 ml of DMF and 1 ml of pyridine, and the mixture was stirred while cooling with ice. After 10 minutes, 0.9 g of DCC was added thereto, and the mixture was stirred for 3 hours while cooling with ice and then for 24 hours at room temperature. The precipitate was filtered off, the filtrate was added in small portions to 300 ml of ether, and the mixture was stirred at room temperature for 3 hours. The supernatant was decanted, then 200 ml of ether was added to the residue and stirred at room temperature for 19 hours. The precipitate was collected by filtration, then dissolved in 15 ml of methanol, 0.4 g of active carbon was added thereto and the mixture was stirred for 15 minutes while cooling with ice. The insoluble was filtered off, the filtrate was added to 200 ml of ether and the mixture was stirred for 5 hours while cooling with ice. The precipitate was collected by filtration to obtain 1.4 g of the intended product.
Reaction SMILES: C[N:2]([CH2:10][C:11]1[CH:15]=[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[NH:13][CH:12]=1)[C:3](=O)OC(C)(C)C.[H-].[Na+].[CH:24]([O:27][C:28]1[CH:33]=[CH:32][C:31]([S:34](Cl)(=[O:36])=[O:35])=[CH:30][CH:29]=1)([CH3:26])[CH3:25]>>[CH:24]([O:27][C:28]1[CH:33]=[CH:32][C:31]([S:34]([N:13]2[C:14]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:15][C:11]([CH2:10][NH:2][CH3:3])=[CH:12]2)(=[O:36])=[O:35])=[CH:30][CH:29]=1)([CH3:26])[CH3:25]
Reactant: CC(C)Oc1ccc(S(=O)(=O)Cl)cc1
Reactant: CN(Cc1c[nH]c(-c2ccccc2)c1)C(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Product: CNCc1cc(-c2ccccc2)n(S(=O)(=O)c2ccc(OC(C)C)cc2)c1
Yield: 50 %

Procedure:
Using tert-butyl methyl[(5-phenyl-1H-pyrrol-3-yl)methyl]carbamate (70 mg), sodium hydride (60% in oil, 98 mg) and 4-isopropoxybenzenesulfonyl chloride (201 mg), a procedure as in Example 38 was performed to give the title compound as pale-red crystals (yield 47 mg, 45%).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5]Cl.[N:11]1([C:17]([S:19][CH3:20])=[S:18])[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[CH3:1][S:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5][N:14]1[CH2:15][CH2:16][N:11]([C:17]([S:19][CH3:20])=[S:18])[CH2:12][CH2:13]1
Reactant: CSc1ccccc1CCl
Reactant: CSC(=S)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CSC(=S)N1CCN(Cc2ccccc2SC)CC1
Yield: 30.9 %

Procedure:
In 20 ml of ethanol, 2.1 g (12.2 mmol.) of 2-methylthiobenzyl chloride, 2.17 g (12.3 mmol.) of methyl 1-piperazinecarbodithioate and 1.30 g (12.3 mmol.) of sodium carbonate were refluxed under heating for 2 hours. Ethanol was distilled off under reduced pressure. The residue was extracted with ether, after addition of water. The ether portion was washed with water and a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and placed under reduced pressure to distill off the solvent. The residue was purified over silica gel column, to give 1.18 g of the desired compound as a yellow oil, yield 31%.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[CH3:10].[NH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.O>CS(C)=O>[CH3:10][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:2]=1[N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)[C:6]#[N:7]
Reactant: C1CNCCN1
Reactant: Cc1cc(C#N)ccc1F
Solvent: CS(C)=O
Solvent: O
Product: Cc1cc(C#N)ccc1N1CCNCC1
Temperature: 140 °C
Reaction time: 16 h
Yield: 69.6 %

Procedure:
To a solution of 4-fluoro-3-methylbenzonitrile (2.5 g, 18.50 mmol) in DMSO (Volume: 10.0 mL) was added piperazine (7.97 g, 92 mmol) at 23° C. The reaction was stirred at 140° C. for 16 hr. The reaction mixture was poured into H2O (100 mL) and the reaction vessel was rinsed with H2O (˜50 mL). The resulting suspension was filtered, rinsed with H20 (3×10 mL) and the resulting solid was dried in vacuo to provide 3-methyl-4-(piperazin-1-yl)benzonitrile (2.593 g, 12.88 mmol, 69.6% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.21-2.30 (m, 3 H) 2.57-2.70 (m, 1 H) 2.83 (s, 8 H) 7.03-7.09 (m, 1 H) 7.55-7.62 (m, 2 H). ESI-MS: m/z 202.1 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][N:7]=1.[CH3:14][O:15][C:16](=[O:29])[CH:17]([N:19]1[C:27]2[C:22](=[CH:23][C:24](O)=[CH:25][CH:26]=2)[CH:21]=[CH:20]1)[CH3:18].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C(Cl)Cl>[C:10]([C:9]1[CH:12]=[CH:13][C:6]([O:5][CH2:4][CH2:3][CH2:2][O:1][C:24]2[CH:23]=[C:22]3[C:27](=[CH:26][CH:25]=2)[N:19]([CH:17]([CH3:18])[C:16]([O:15][CH3:14])=[O:29])[CH:20]=[CH:21]3)=[N:7][CH:8]=1)#[N:11]
Reactant: N#Cc1ccc(OCCCO)nc1
Reactant: COC(=O)C(C)n1ccc2cc(O)ccc21
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)C(C)n1ccc2cc(OCCCOc3ccc(C#N)cn3)ccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 85 %

Procedure:
To a solution of 6-(3-hydroxypropoxy)nicotinonitrile (Example 66, 0.55 g, 3.09 mmol) and methyl 2-(5-hydroxy-1H-indol-1-yl)propanoate (Example 7, 0.34 g, 1.55 mmol) in CH2Cl2 (7.73 mL) were added triphenylphosphine (0.61 g, 2.32 mmol) and 1,1′-(azodicarbonyl)-dipiperidine (0.59 g, 2.32 mmol). The yellow reaction mixture was stirred at rt for 18 h and then concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (eluting with 67% hexanes/EtOAc) to give the title compound (0.5 g, 85%). 1H NMR (400 MHz, CD2Cl2) δ 8.49 (dd, 1H), 7.79 (dd, 1H), 7.25-7.09 (m, 3H), 6.85-6.83 (m, 2H), 6.47 (d, 1H), 5.11 (qt, 1H), 4.60 (t, 2H), 4.17 (t, 2H), 3.71 (s, 3H), 2.35-2.25 (m, 2H), 1.82 (d, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH:13][C:14](=[O:26])[C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:17][CH:16]=2)[CH:7]=[CH:8][C:9]=1[N+:10]([O-])=O)([O-])=O.[CH3:27][C:28]1[C:32]([NH:33][C:34]([C:36]2[CH:43]=[CH:42][C:39]([CH:40]=O)=[CH:38][CH:37]=2)=[O:35])=[CH:31][NH:30][N:29]=1>>[CH3:27][C:28]1[C:32]([NH:33][C:34](=[O:35])[C:36]2[CH:43]=[CH:42][C:39]([C:40]3[NH:10][C:9]4[CH:8]=[CH:7][C:6]([NH:13][C:14](=[O:26])[C:15]5[CH:20]=[CH:19][C:18]([N:21]6[CH2:25][CH2:24][CH2:23][CH2:22]6)=[CH:17][CH:16]=5)=[CH:5][C:4]=4[N:1]=3)=[CH:38][CH:37]=2)=[CH:31][NH:30][N:29]=1
Reactant: Cc1n[nH]cc1NC(=O)c1ccc(C=O)cc1
Reactant: O=C(Nc1ccc([N+](=O)[O-])c([N+](=O)[O-])c1)c1ccc(N2CCCC2)cc1
Product: Cc1n[nH]cc1NC(=O)c1ccc(-c2nc3cc(NC(=O)c4ccc(N5CCCC5)cc4)ccc3[nH]2)cc1

Procedure:
Compound 232 was prepared according to the procedure similar to that described in Scheme III from N-(3,4-dinitrophenyl)-4-pyrrolidinylbenzamide and 4-(3-methyl-4-pyrazolyl)aminocarbonylbenzaldehyde. [M+H]+ calcd for C29H27N7O2: 506.23; found: 506.25.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[OH:13][C:14]1[C:19]([C:20]([OH:22])=O)=[CH:18][N:17]=[C:16]2[S:23][C:24]([I:26])=[CH:25][C:15]=12.[Cl:27][C:28]1[CH:35]=[CH:34][C:31]([CH2:32][NH2:33])=[CH:30][CH:29]=1.CC(O)=O>CN(C=O)C>[Cl:27][C:28]1[CH:35]=[CH:34][C:31]([CH2:32][NH:33][C:20]([C:19]2[C:14]([OH:13])=[C:15]3[CH:25]=[C:24]([I:26])[S:23][C:16]3=[N:17][CH:18]=2)=[O:22])=[CH:30][CH:29]=1
Reactant: NCc1ccc(Cl)cc1
Reactant: O=C(O)c1cnc2sc(I)cc2c1O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: O=C(NCc1ccc(Cl)cc1)c1cnc2sc(I)cc2c1O
Temperature: 60 °C
Reaction time: 18 h
Yield: 74 %

Procedure:
Mercuric oxide (7.10 g) and iodine (8.32 g) are added portion-wise to a solution of ethyl 4-hydroxythieno[2,3-b]pyridine-5-carboxylate (J. Heterocyclic Chem. 1977, 14, 807) (5.22 g) in CHCl3 (90 mL). The reaction is stirred at rt for 18 h. The reaction mixture is filtered, and the solid is washed with CHCl3 (400 mL). The organic layer is washed with H2O (200 mL), dried with MgSO4, filtered, and concentrated in vacuo. The resulting orange solid is purified by column chromatography (CH2Cl2:heptane, 1:1). Fractions homogeneous by TLC are combined and concentrated in vacuo to yield 2.95 g (36%) of ethyl 4-hydroxy-2-iodothieno[2,3-b]pyridine-5-carboxylate as a pale yellow solid. Ethyl 4-hydroxy-2-iodothieno[2,3-b]pyridine-5-carboxylate (2.64 g) is suspended in 10% NaOH (21 mL) and heated to reflux. The reaction is stirred at reflux for 1 h and then cooled to rt. The reaction mixture is poured into H2O (80 mL). Conc. HCl is added until a precipitate forms, and 2.272 g (94%) of 4-hydroxy-2-iodothieno[2,3-b]pyridine-5-carboxylic acid is isolated as a white solid. Carbonyldiimidazole (1.34 g) is added to a solution of 4-hydroxy-2-iodothieno[2,3-b]pyridine-5-carboxylic acid (2.041 g) in DMF (58 mL). The reaction is heated to 60° C. and stirred for 18 h. The reaction mixture is cooled to rt, and 4-chlorobenzylamine (1.01 mL, 8.27) is added. The reaction is stirred at rt for 7 h. The reaction mixture is poured into 20% aqueous HOAc (180 mL), and the resulting white solid is filtered off. This material is recrystallized from methanol then toluene to yield 2.095 g (74%) of the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][CH3:13])[C:6]([NH:14][C:15](=[O:19])OCC)=[N:5]2.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([N:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[CH:25]=[C:26]([O:30][CH3:31])[C:27]=1[O:28][CH3:29]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][CH3:13])[C:6]([NH:14][C:15]([N:35]1[CH2:34][CH2:33][N:32]([C:24]3[CH:23]=[C:22]([O:21][CH3:20])[C:27]([O:28][CH3:29])=[C:26]([O:30][CH3:31])[CH:25]=3)[CH2:37][CH2:36]1)=[O:19])=[N:5]2
Reactant: CCOC(=O)Nc1nc2cc(Cl)ccc2nc1OC
Reactant: COc1cc(N2CCNCC2)cc(OC)c1OC
Product: COc1cc(N2CCN(C(=O)Nc3nc4cc(Cl)ccc4nc3OC)CC2)cc(OC)c1OC
Yield: 84 %

Procedure:
Ethyl N-(6-chloro-2-methoxyquinoxalin-3-yl)carbamate and 1-(3,4,5-trimethoxyphenyl)piperazine were reacted by the same way with the example 22 to obtain the titled compound (yield, 84%). 1H NMR (300 MHz, CDCl3): 3.17-3.25 (m, 4H), 3.81-3.86 (m, 12H), 4.09-4.16 (m, 4H), 6.21 (s, 2H), 7.21-7.30 (m, 1H), 7.33-7.54 (m, 1H), 7.58-7.69 (m, 1H), 7.81 (s, 1H).
Reaction SMILES: [F:1][CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([C:11]2[CH:12]=[C:13]([CH:17]([NH:23][C:24]([C@@H:26]3[CH2:31][CH2:30][CH2:29][N:28]([C:32](=[O:48])[CH2:33][CH2:34][CH:35]4[CH2:40][CH2:39][N:38]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:37][CH2:36]4)[CH2:27]3)=[O:25])[CH2:18][C:19]([O:21]C)=[O:20])[CH:14]=[N:15][CH:16]=2)[CH:8]=[CH:9][CH:10]=1.O.O.O.O.O.O.O.O.[OH-].[Ba+2].[OH-]>CO>[C:44]([O:43][C:41]([N:38]1[CH2:37][CH2:36][CH:35]([CH2:34][CH2:33][C:32]([N:28]2[CH2:29][CH2:30][CH2:31][C@@H:26]([C:24]([NH:23][CH:17]([C:13]3[CH:14]=[N:15][CH:16]=[C:11]([C:7]4[CH:8]=[CH:9][CH:10]=[C:5]([O:4][CH2:3][CH2:2][F:1])[CH:6]=4)[CH:12]=3)[CH2:18][C:19]([OH:21])=[O:20])=[O:25])[CH2:27]2)=[O:48])[CH2:40][CH2:39]1)=[O:42])([CH3:47])([CH3:46])[CH3:45]
Reactant: COC(=O)CC(NC(=O)[C@@H]1CCCN(C(=O)CCC2CCN(C(=O)OC(C)(C)C)CC2)C1)c1cncc(-c2cccc(OCCF)c2)c1
Agent: [Ba+2]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(CCC(=O)N2CCC[C@@H](C(=O)NC(CC(=O)O)c3cncc(-c4cccc(OCCF)c4)c3)C2)CC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
95 mg (0.14 mmol) Tert-butyl 4-{3-[(3R)-3-{[1-{5-[3-(2-fluoroethoxy)phenyl]pyridin-3-yl}-3-methoxy-3-oxopropyl]carbamoyl}piperidin-1-yl]-3-oxopropyl}piperidine-1-carboxylate were dissolved in 17 ml methanol. 448 mg (1.42 mmol) barium hydroxide octahydrate were added. The mixture was stirred at room temperature for 20 hours and then concentrated to give 3-({[(3R)-1-{3-[1-(tert-butoxycarbonyl)piperidin-4-yl]propanoyl}piperidin-3-yl]carbonyl}amino)-3-{5-[3-(2-fluoroethoxy)phenyl]pyridin-3-yl}propanoic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:33])=[C:6]([C:8]2[CH:17]=[C:16]([C:18]3[CH:19]=[N:20][CH:21]=[C:22]([C:24]#[C:25][Si](CC)(CC)CC)[CH:23]=3)[C:15]3[C:10](=[N:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)[CH:7]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(N(CC)CC)C.[N:59]([CH2:62][CH2:63][N:64]1[CH2:69][CH2:68][O:67][CH2:66][CH2:65]1)=[N+:60]=[N-:61]>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:33])=[C:6]([C:8]2[CH:17]=[C:16]([C:18]3[CH:19]=[N:20][CH:21]=[C:22]([C:24]4[N:61]=[N:60][N:59]([CH2:62][CH2:63][N:64]5[CH2:65][CH2:66][O:67][CH2:68][CH2:69]5)[CH:25]=4)[CH:23]=3)[C:15]3[C:10](=[N:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)[CH:7]=1
Reactant: [N-]=[N+]=NCCN1CCOCC1
Reactant: CC[Si](C#Cc1cncc(-c2cc(-c3cc(Cl)ccc3F)nc3ncccc23)c1)(CC)CC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Fc1ccc(Cl)cc1-c1cc(-c2cncc(-c3cn(CCN4CCOCC4)nn3)c2)c2cccnc2n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 471 mg (0.994 mmol) 2-(5-chloro-2-fluoro-phenyl)-4-(5-triethylsilanylethynyl-pyridin-3-yl)-[1,8]naphthyridine in 6 ml THF was treated with 1.19 ml of a 1 M solution of tetra-n-butylammonium fluoride in THF and stirred for 1 hour at room temperature. Then 276 μl (1.99 mmol) triethylamine, 190 mg (1.21 mmol) 4-(2-azido-ethyl)-morpholine and 9.5 mg (0.05 mmol) cuprous iodide were added. The reaction mixture was stirred for 66 hours at 70° C. The reaction mixture was cooled to room temperature and partitioned between ethylacetate and brine. The organic phase was dried over sodium sulfate and evaporated. The residue was chromatographed on a silica gel column with dichloromethane/methanol as eluent yielding 2-(5-chloro-2-fluoro-phenyl)-4-{5-[1-(2-morpholin-4-yl-ethyl)-1H-[1,2,3]triazol-4-yl]-pyridin-3-yl}-[1,8]naphthyridine as colourless solid; HPLC-MS: 1.50 min, [M+H] 516.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[CH:3]([OH:7])[CH2:4][CH2:5]I.[N-:10]=[N+:11]=[N-:12].[Na+]>CS(C)=O.O>[N:10]([CH2:5][CH2:4][CH:3]([OH:7])[C:2]([F:9])([F:8])[F:1])=[N+:11]=[N-:12]
Reactant: [N-]=[N+]=[N-]
Reactant: OC(CCI)C(F)(F)F
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: [N-]=[N+]=NCCC(O)C(F)(F)F
Temperature: 50 °C
Yield: 92.4 %

Procedure:
A solution of 1,1,1-trifluoro-4-iodo-2-butanol (0.604 g, 2.38 mmol) in DMSO (4 mL) was treated with sodium azide (0.178 g, 2.74 mmol) at ambient temperature, followed by heating at 50° C. for 21 h. The mixture was diluted with cold water and extracted with ethyl acetate. The combined organic extracts were washed (brine), dried, and evaporated to give the product as a pale yellow oil (0.372 g, 92%).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(C[C:25]([C:33]([OH:35])=O)([N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)O)(C)(C)C.CCOC(/N=N/C(OCC)=O)=O.O1CCCCC1[N:54]1[C:62]2[C:57](=[CH:58][C:59]([C:63]3[N:67]=[CH:66][N:65](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:64]=3)=[CH:60][CH:61]=2)[C:56]([C:87]2[CH:88]=[C:89](O)[CH:90]=[CH:91][CH:92]=2)=[N:55]1.Cl>O1CCCC1>[NH:65]1[CH:66]=[N:67][C:63]([C:59]2[CH:58]=[C:57]3[C:62](=[CH:61][CH:60]=2)[NH:54][N:55]=[C:56]3[C:87]2[CH:88]=[CH:89][CH:90]=[C:91]([O:35][CH2:33][CH2:25][N:27]3[CH2:28][CH2:29][NH:30][CH2:31][CH2:32]3)[CH:92]=2)=[N:64]1
Reactant: Oc1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1
Reactant: CC(C)(C)CC(O)(C(=O)O)N1CCNCC1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: c1cc(OCCN2CCNCC2)cc(-c2n[nH]c3ccc(-c4nc[nH]n4)cc23)c1
Temperature: 25 °C
Reaction time: 1.17 h
Yield: 27.1 %

Procedure:
Triphenylphosphine (0.694 g, 2.65 mmol), tetrahydrofuran (2.12 mL), tert-butylcarboxypiperazinylethanol (0.610 g, 2.65 mmol) and diethylazodicarboxylate (0.418 mL) were added to 3-{1-perhydro-2H-pyran-2-yl-5-[1-(triphenylmethyl)(1,2,4-triazol-3-yl)]-1H-indazol-3-yl}phenol (0.400 g, 1.25 mmol). The mixture was stirred at ambient temperature for 21h and poured into aqueous 6N hydrochloric acid (30 mL). After stirring at ambient temperature for 4h, the mixture was extracted with ethyl acetate (3×). The aqueous fraction was added to aqueous 6N sodium hydroxide (30 mL) and the pH adjusted to 11. The solution was extracted with ethyl acetate (3×) and the organic fractions were combined and dried over anhydrous sodium sulfate, filtered and evaporated. The residue was stirred with trifluoracetic acid (3.0 mL) at ambient temperature for 70 min. Purification by preparative HPLC (5-70% acetonitrile/water) gave the title compound (0.132 g, 27% yield). ES-MS (m/z) 390 [M+1]+.
Reaction SMILES: [CH2:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[NH:6][CH3:7])[CH:2]=[CH2:3].C(=O)([O-])[O-].[Na+].[Na+].[CH2:18](Br)[CH:19]=[CH2:20]>O>[CH2:18]([N:6]([CH3:7])[C:5]1[CH:8]=[CH:9][CH:10]=[CH:11][C:4]=1[CH2:1][CH:2]=[CH2:3])[CH:19]=[CH2:20]
Reactant: C=CCc1ccccc1NC
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: C=CCc1ccccc1N(C)CC=C

Procedure:
2-Allyl-N-methylaniline (14.7 g, 0.10 mol) is heated to 80° C. in the presence of 2M sodium carbonate solution (75 ml) and allyl bromide (14.1 g, 0.116 mol) for 6 hours. The mixture is diluted with water and extracted with ether twice (150 and 75 ml portions). The extracts are washed with water and brine, dried over potassium carbonate, and concentrated to an oil. The oil is distilled on a Kugelrohr apparatus to provide pure N,2-diallyl-N-methylaniline.
Reaction SMILES: [O:1]=[C:2]1[N:6]([C:7]2[CH:17]=[CH:16][C:10]([C:11]([O:13]CC)=O)=[CH:9][CH:8]=2)[CH2:5][CH2:4][O:3]1.[CH3:18][C:19]1[C:24]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[CH:23][CH:22]=[C:21]([CH3:31])[N:20]=1>>[CH3:18][C:19]1[C:24]([N:25]2[CH2:30][CH2:29][N:28]([C:11]([C:10]3[CH:9]=[CH:8][C:7]([N:6]4[CH2:5][CH2:4][O:3][C:2]4=[O:1])=[CH:17][CH:16]=3)=[O:13])[CH2:27][CH2:26]2)=[CH:23][CH:22]=[C:21]([CH3:31])[N:20]=1
Reactant: Cc1ccc(N2CCNCC2)c(C)n1
Reactant: CCOC(=O)c1ccc(N2CCOC2=O)cc1
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N4CCOC4=O)cc3)CC2)c(C)n1
Yield: 15.8 %

Procedure:
By reaction and treatment in the same manner as in Example 34 and using ethyl 4-(2-oxooxazolidin-3-yl)benzoate (353 mg) described in Preparation Example 12 and 1-(2,6-dimethylpyridin-3-yl)piperazine (287 mg) described in Preparation Example 153, the title compound (90.2 mg) was obtained.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([Cl:14])=[CH:9][C:8]=2[Cl:15])[N:5]=[C:4]([CH:16]([CH3:18])[CH3:17])[C:3]=1[C:19]([NH2:21])=[O:20].[OH:22][CH2:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][C:31](OCC)=O)=[CH:26][CH:25]=1.[O-]CC.[Na+]>C(O)C>[Cl:13][C:12]1[CH:11]=[C:10]([Cl:14])[CH:9]=[C:8]([Cl:15])[C:7]=1[N:6]1[C:2]2=[N:1][C:31]([CH2:30][C:27]3[CH:28]=[CH:29][C:24]([CH2:23][OH:22])=[CH:25][CH:26]=3)=[N:21][C:19](=[O:20])[C:3]2=[C:4]([CH:16]([CH3:18])[CH3:17])[NH:5]1
Reactant: CC(C)c1nn(-c2c(Cl)cc(Cl)cc2Cl)c(N)c1C(N)=O
Reactant: CCOC(=O)Cc1ccc(CO)cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)c1[nH]n(-c2c(Cl)cc(Cl)cc2Cl)c2nc(Cc3ccc(CO)cc3)nc(=O)c1-2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of 347 mg (1.0 mmol) of 5-amino-3-isopropyl-1-(2,4,6-trichlorophenyl)pyrazole-4-carboxamide in 6 mL of absolute ethanol was added 777 mg (4.0 mmol) of ethyl 4-(hydroxymethyl)phenylacetate followed by 2.0 mL (5.33 mmol) of 2.66 M sodium ethoxide in ethanol. The solution was stirred 18 h at reflux, and the heating mantle was then removed. The reaction was treated with 25 mL of 5% aq. HOAc, cooled to ambient temperature, and extracted with EtOAc. The organic extract was washed twice with water and once with brine, dried (MgSO4), and chromatographed on silica gel (elution with 1:1 EtOAc-hexanes) to give, after removal of solvent, 320 mg (67%) of 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-(hydroxymethyl)benzyl)pyrazolo[3,4-d]pyrimidin-4-one as a white, amorphous solid. 1H NMR (300 MHz, CDCl3) d 11.46(br. s, 1H); 7.54(s, 2H); 7.42(d, 2H, J=8.1 Hz); 7.31(d, 2H, J=8.5 Hz); 4.66(s, 2H); 4.00(s, 2H); 3.47(septet, 1H, J=7.0 Hz); 1.48(d, 6H, J=7.0 Hz).