Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([C:11]([OH:13])=O)[CH:2]=1.C(Cl)(=O)C(Cl)=O.[NH2:20][CH:21]1[C:25](=[O:26])[N:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[F:33])[CH2:23][CH:22]1[C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35].C(N(CC)CC)C>C(Cl)Cl>[F:33][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[N:24]1[C:25](=[O:26])[C@H:21]([NH:20][C:11]([C:3]2[CH:2]=[N:1][C:10]3[C:5]([CH:4]=2)=[CH:6][CH:7]=[CH:8][CH:9]=3)=[O:13])[C@H:22]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:23]1
Reactant: CC(C)(C)OC(=O)C1CN(c2ccccc2F)C(=O)C1N
Reactant: O=C(O)c1cnc2ccccc2c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)[C@@H]1CN(c2ccccc2F)C(=O)[C@@H]1NC(=O)c1cnc2ccccc2c1
Reaction time: 2.5 h
Yield: 73 %

Procedure:
To a solution of 3-quinolinecarboxylic acid (118 mg, 0.68 mmol) in CH2Cl2 (3 ml) was added oxalyl chloride (0.12 ml, 1.36 mmol) and the solution was stirred for 2.5 h. Removal of the solvent in vacuo gave a colorless solid which was redissolved in CH2Cl2 (3 ml). To this solution was added a solution of aminopyrrolidinone of Example W (200 mg, 0.68 mmol) and triethylamine (344 mg, 3.4 mmol) in CH2Cl2 (3 ml) and the resulting solution was stirred for 18 h. Removal of the solvent in vacuo and purification of the resulting solid via radial chromatography (4 mm plate) eluting with 2% EtOH/CH2Cl2 gave the title compound (223 mg, 73%) as a solid. 1H NMR (300 MHz, CDCl3) δ9.35 (1H, d), 8.68 (1H, d), 8.19 (1H, d), 7.94 (1H, d), 7.84 (1H t), 7.64 (1H, t), 7.54 (1H, t), 7.32 (1H, m), 7.19 (2H, m), 5.28 (1H, t), 4.21 (1H, m), 3.91 (1H, d), 3.78 (1H, q), 3.49 (1H, s), 1.41 (9H, s).
Reaction SMILES: [N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][C:17]([OH:19])=O)=[CH:12][CH:11]=2)[CH:2]=1.[CH3:20][O:21][C:22]1[CH:38]=[CH:37][C:25]([C:26]2[CH:27]=[C:28]([C:33]([F:36])([F:35])[F:34])[CH:29]=[C:30]([NH2:32])[CH:31]=2)=[CH:24][CH:23]=1>CCCCCC.CCOC(C)=O>[N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]([C:10]2[CH:11]=[CH:12][C:13]([CH2:16][C:17]([NH:32][C:30]3[CH:31]=[C:26]([C:25]4[CH:37]=[CH:38][C:22]([O:21][CH3:20])=[CH:23][CH:24]=4)[CH:27]=[C:28]([C:33]([F:34])([F:35])[F:36])[CH:29]=3)=[O:19])=[CH:14][CH:15]=2)[CH:2]=1
Reactant: O=C(O)Cc1ccc(-n2cnc3cccnc32)cc1
Reactant: COc1ccc(-c2cc(N)cc(C(F)(F)F)c2)cc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COc1ccc(-c2cc(NC(=O)Cc3ccc(-n4cnc5cccnc54)cc3)cc(C(F)(F)F)c2)cc1

Procedure:
The title compound is prepared as described in Example 1 but using (4-imidazo[4,5-b]pyridin-3-yl-phenyl)acetic acid (Step 7.1) and 4′-methoxy-5-trifluoromethyl-biphen-3-ylamine. Title compound: ES-MS: 502.9 [M+H]+; tR=5.00 min (System 1); Rf=0.21 (Hexane/EtOAc, 1:4).
Reaction SMILES: C(O[C:4]([C:6]1[N:7]=[N:8][N:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:10]=1[NH2:11])=[O:5])C.[Br:18][C:19]1[CH:34]=[CH:33][C:22]([C:23](Cl)=[N:24][C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=2)=[CH:21][CH:20]=1>ClC(Cl)C.Cl[Ti](Cl)(Cl)Cl>[Br:18][C:19]1[CH:20]=[CH:21][C:22]([C:23]2[N:24]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)[C:4](=[O:5])[C:6]3[N:7]=[N:8][N:9]([C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=4)[C:10]=3[N:11]=2)=[CH:33][CH:34]=1
Reactant: ClC(=Nc1ccc(Cl)cc1)c1ccc(Br)cc1
Reactant: CCOC(=O)c1nnn(-c2ccccc2)c1N
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: CC(Cl)Cl
Product: O=c1c2nnn(-c3ccccc3)c2nc(-c2ccc(Br)cc2)n1-c1ccc(Cl)cc1
Temperature: 170 °C
Reaction time: 48 h

Procedure:
A mixture of 5-amino-1-phenyl-1H-[1,2,3]triazole-4-carboxylic acid ethyl ester (30 mg, 0.33 mmol), 4-bromo-N-(4-chloro-phenyl)-benzimidoyl chloride (51 mg, 0.16 mmol) and TiCl4 (20 μL) in anhydrous dichloroethane (1 mL) is heated in microwave reactor at 170° C. for 1 h and then at 115° C. for 48 h in an oil bath. After cooling down to room temperature, the mixture is worked up as in example 2 and purified by flash column chromatography (silica gel, 0˜30% EtOAc/hexane) to provide the title compound 5-(4-Bromo-phenyl)-6-(4-chloro-phenyl)-3-phenyl-3,6-dihydro-[1,2,3]triazolo[4,5-d]pyrimidin-7-one as white solid. (45 mg, 73%). 1H NMR (CDCl3) δ (ppm) 8.15(d, 2H), 7.59(t, 2H), 7.49(t, 1H), 7.43 (d, 2H), 7.37(d, 2H), 7.21(d, 2H), 7.10(d, 2H), 2.87(m, 1H). HPLC-MS calculated C22H13BrClN5O (M+1+): 478.0. Found: 478.0.
Reaction SMILES: C(OC([N:8]1CCN(CCCN)[CH2:10][CH2:9]1)=O)(C)(C)C.[C:18]([O:22][C:23]([N:25]1[CH2:32][CH:31]2[CH:27]([CH2:28][NH:29][CH2:30]2)[CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19]>>[C:18]([O:22][C:23]([N:25]1[CH2:26][CH:27]2[CH:31]([CH2:30][N:29]([CH2:10][CH2:9][NH2:8])[CH2:28]2)[CH2:32]1)=[O:24])([CH3:21])([CH3:19])[CH3:20]
Reactant: CC(C)(C)OC(=O)N1CCN(CCCN)CC1
Reactant: CC(C)(C)OC(=O)N1CC2CNCC2C1
Product: CC(C)(C)OC(=O)N1CC2CN(CCN)CC2C1

Procedure:
Using the method of 4-(3-aminopropyl)-piperazine-1-carboxylic acid tert-butyl ester, the title compound is synthesized from hexahydropyrrolo[3,4-c]pyrrole-2-carboxylic acid tert-butyl ester.
Reaction SMILES: [CH2:1]([O:3][C@@H:4]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:20]=[C:19]([CH2:21][NH:22][CH3:23])[S:18][CH:17]=2)=[CH:12][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6])[CH3:2].[CH:24]1([CH2:29][C:30](Cl)=[O:31])[CH2:28][CH2:27][CH2:26][CH2:25]1>>[CH:24]1([CH2:29][C:30]([CH2:23][NH:22][CH2:21][C:19]2[S:18][CH:17]=[C:16]([C:13]3[CH:14]=[CH:15][C:10]([CH2:9][C@H:4]([O:3][CH2:1][CH3:2])[C:5]([O:7][CH3:8])=[O:6])=[CH:11][CH:12]=3)[CH:20]=2)=[O:31])[CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: O=C(Cl)CC1CCCC1
Reactant: CCO[C@@H](Cc1ccc(-c2csc(CNC)c2)cc1)C(=O)OC
Product: CCO[C@@H](Cc1ccc(-c2csc(CNCC(=O)CC3CCCC3)c2)cc1)C(=O)OC
Yield: 87.9 %

Procedure:
In a manner similar to that of Example 16(e), starting with 0.35 g (1 mmol) of methyl 2(S)-ethoxy-3-[4-(5-methylaminomethylthiophen-3-yl)phenyl]propanoate and 170 μl (1.15 mmol) of 2-cyclopentylacetyl chloride, 0.39 g (85%) of methyl 3-[4-(5-{[(2-cyclopentylacetyl)methylamino]methyl}thiophen-3-yl)phenyl]-2(S)-ethoxypropanoate is obtained.
Reaction SMILES: [NH2:1][CH2:2][C:3]([N:5]([C:7]1[C:8]([Cl:27])=[C:9]([C:23]([Cl:26])=[CH:24][CH:25]=1)[CH2:10][O:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[N:20]=[C:19]([CH3:22])[CH:18]=[CH:17]2)[CH3:6])=[O:4].[C:28]([NH:31][C:32]1[N:37]=[CH:36][C:35](/[CH:38]=[CH:39]/[C:40](O)=[O:41])=[CH:34][CH:33]=1)(=[O:30])[CH3:29].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>O.CN(C)C=O>[C:28]([NH:31][C:32]1[N:37]=[CH:36][C:35](/[CH:38]=[CH:39]/[C:40]([NH:1][CH2:2][C:3]([N:5]([C:7]2[C:8]([Cl:27])=[C:9]([C:23]([Cl:26])=[CH:24][CH:25]=2)[CH2:10][O:11][C:12]2[CH:13]=[CH:14][CH:15]=[C:16]3[C:21]=2[N:20]=[C:19]([CH3:22])[CH:18]=[CH:17]3)[CH3:6])=[O:4])=[O:41])=[CH:34][CH:33]=1)(=[O:30])[CH3:29]
Reactant: Cc1ccc2cccc(OCc3c(Cl)ccc(N(C)C(=O)CN)c3Cl)c2n1
Reactant: CC(=O)Nc1ccc(/C=C/C(=O)O)cn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)Nc1ccc(/C=C/C(=O)NCC(=O)N(C)c2ccc(Cl)c(COc3cccc4ccc(C)nc34)c2Cl)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 53.8 %

Procedure:
To a mixture of 8-[3-(N-glycyl-N-methylamino)-2,6-dichlorobenzyloxy]-2-methylquinoline (100 mg), (E)-3-(6-acetamidopyridin-3-yl)acrylic acid (56.1 mg) and N,N-dimethylformamide (2 ml) were added 1-hydroxybenzotriazole (43.4 mg) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (56.9 mg) in a nitrogen stream at 0° C., and the resulting mixture was stirred at ambient temperature for 2 hours. The reaction mixture was poured into water, and extracted with chloroform. The organic layer was washed with an aqueous solution of saturated sodium hydrogencarbonate, water and brine successively, and dried over magnesium sulfate, and thereafter the solvent was removed under reduced pressure. The residue was purified by preparative thin-layer chromatography (methanol:dichloromethane=1:10, v/v), and solidified with diethyl ether and ethyl acetate to give 8-[3-[N-[(E)-3-(6-acetamidopyridin-3-yl)acryloylglycyl]-N-methylamino]-2,6-dichlorobenzyloxy]-2methylquinoline (FR173657) (78.8 mg) as a grayish white solid.
Reaction SMILES: [CH3:1][N:2]([CH2:14][C:15]1[CH:16]=[C:17]([C:21]2[CH:26]=[CH:25][C:24]([N:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)=[CH:23][CH:22]=2)[CH:18]=[CH:19][CH:20]=1)[C:3](=[O:13])[CH2:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9].[CH2:33](I)[CH3:34].O>ClCCl>[CH2:33]([N:30]1[CH2:31][CH2:32][N:27]([C:24]2[CH:23]=[CH:22][C:21]([C:17]3[CH:18]=[CH:19][CH:20]=[C:15]([CH2:14][N:2]([CH3:1])[C:3](=[O:13])[CH2:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:9])[CH3:10])[CH:16]=3)=[CH:26][CH:25]=2)[CH2:28][CH2:29]1)[CH3:34]
Reactant: CCI
Reactant: CN(Cc1cccc(-c2ccc(N3CCNCC3)cc2)c1)C(=O)CNC(=O)OC(C)(C)C
Solvent: O
Solvent: ClCCl
Product: CCN1CCN(c2ccc(-c3cccc(CN(C)C(=O)CNC(=O)OC(C)(C)C)c3)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.5 %

Procedure:
tert-Butyl (2-{methyl[(4′-piperazin-1-ylbiphenyl-3-yl)methyl]amino}-2-oxoethyl)carbamate (180 mg) was dissolved in dichloromethane (3.6 ml), and TEA (125 mg) was added thereto under ice-cooling. Subsequently, ethyl iodide (128 mg) was added thereto, followed by stirring at room temperature overnight. To the reaction mixture was added water, followed by extraction with CHCl3. The organic layer was dried over MgSO4, and then the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (2% MeOH/CHCl3) to obtain tert-butyl {2-[{[4′-(4-ethylpiperazin-1-yl)biphenyl-3-yl]methyl}(methyl)amino]-2-oxoethyl}carbamate (137 mg).
Reaction SMILES: O1CCC[CH2:2]1.CO[C:8]([C:10]1[CH:23]=[CH:22][C:13]2[N:14]([CH:18]3[CH2:21][CH2:20][CH2:19]3)[C:15](=[O:17])[NH:16][C:12]=2[CH:11]=1)=[O:9].[BH4-].[Li+]>CO>[CH:18]1([N:14]2[C:13]3[CH:22]=[CH:23][C:10]([CH2:8][OH:9])=[CH:11][C:12]=3[N:16]([CH3:2])[C:15]2=[O:17])[CH2:19][CH2:20][CH2:21]1
Reactant: COC(=O)c1ccc2c(c1)[nH]c(=O)n2C1CCC1
Reactant: C1CCOC1
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Product: Cn1c(=O)n(C2CCC2)c2ccc(CO)cc21
Temperature: 65 °C
Reaction time: 0.5 h

Procedure:
To a tetrahydrofuran (150 mL) solution of 1-Cyclobutyl-2-oxo-2,3-dihydro-1H-benzoimidazole-5-carboxylic acid methyl ester 16.35 g, 62.8 mmol) was added lithium borohydride (63 mL, 2.0 M in tetrahydrofuran). The mixture was heated to 65° C. then methanol (2.5 mL) was added. The reaction was complete after 0.5 hours and was cooled and extracted into ethyl acetate from saturated ammonium chloride. The organic layer was washed with water and brine, dried over sodium sulfate and concentrated to give 13.79 g of 1-Cyclobutyl-5-hydroxymethyl-3-methyl-1,3-dihydro-benzoimidazol-2-one.
Reaction SMILES: [CH3:1][N:2]([CH3:11])[C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.[CH3:12][C:13]1[CH:14]=[C:15]([CH:17]=[CH:18][C:19]=1[CH3:20])[NH2:16]>>[CH3:1][N:2]([CH3:11])[C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH:16][C:15]2[CH:17]=[CH:18][C:19]([CH3:20])=[C:13]([CH3:12])[CH:14]=2)=[CH:5][CH:4]=1
Reactant: Cc1ccc(N)cc1C
Reactant: CN(C)c1ccc(C=O)cc1
Product: Cc1ccc(NCc2ccc(N(C)C)cc2)cc1C
Yield: 55.6 %

Procedure:
By the reaction and treatment in the same manner as in Preparation Example 1 using 4-dimethylaminobenzaldehyde (1.5 g) and 3,4-dimethylaniline (1.2 g) as starting materials, [(4-dimethylaminophenyl)methyl](3,4-dimethylphenyl)amine (1.4 g) was obtained. melting point: 73–75° C.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.C[Si](C)(C)[N:15]1[CH2:19][CH2:18][CH2:17][C:16]1=[O:20].[CH:23]1[N:24]=[CH:25][N:26]2[CH2:31][CH2:30][CH2:29][C:28](=[O:32])[C:27]=12>O1CCCC1>[OH:32][C:28]1([CH:17]2[CH2:18][CH2:19][NH:15][C:16]2=[O:20])[CH2:29][CH2:30][CH2:31][N:26]2[CH:25]=[N:24][CH:23]=[C:27]12
Reactant: O=C1CCCn2cncc21
Reactant: C[Si](C)(C)N1CCCC1=O
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: O=C1NCCC1C1(O)CCCn2cncc21
Reaction time: 0.5 h

Procedure:
1.25 ml of n-butyllithium (1.6M in hexane) are added dropwise to a solution to 0.29 ml of diisopropylamine and 2 ml of tetrahydrofuran at −78° C. After 30 minutes, a solution, cooled to −78° C., of 0.31 g of 1-trimethylsilanylpyrrolidin-2-one and 5 ml of tetrahydrofuran is added dropwise. The mixture is stirred for a further 30 minutes and then a solution of 0.27 g of 6,7-dihydro-5H-imidazo[1,5-a]pyridin-8-one [426219-51-4] and 5 ml tetrahydrofuran is added dropwise. The reaction mixture is stirred at −78° C. for 1 hour and then at 0° C. for 2 hours. The mixture is quenched with saturated aqueous ammonium chloride solution/water (1:1), the tetrahydrofuran is evaporated, and the residue is extracted with dichloromethane (3×). The combined organic phases are dried with sodium sulphate and evaporated. The title compound is identified from the residue by flash chromatography (SiO2 60F) on the basis of the Rf.
Reaction SMILES: [CH2:1]([SH:3])[CH3:2].[OH-].[Na+].Cl[C:7]1[N:12]=[C:11]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=3[C:19](=[O:20])[C:10]2=[N:9][C:8]=1[C:21]#[N:22]>C1COCC1>[CH2:1]([S:3][C:7]1[N:12]=[C:11]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=3[C:19](=[O:20])[C:10]2=[N:9][C:8]=1[C:21]#[N:22])[CH3:2]
Reactant: CCS
Reactant: N#Cc1nc2c(nc1Cl)-c1ccccc1C2=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCSc1nc2c(nc1C#N)C(=O)c1ccccc1-2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87.3 %

Procedure:
To a mixture of ethanethiol (62 μl, 0.84 mmol) and 1N NaOH (0.5 ml, 0.5 mmol) in THF (2.1 ml) 9 (101 mg, 0.42 mmol) was added. The mixture was stirred at room temperature for 30 min then the solvent was evaporated under reduced pressure. The residue was dissolved in H2O (4 ml) and extracted with CH2Cl2 (2×4 ml). The collected organic phases were dried over Na2SO4, filtered and evaporated. The crude was purified by flash chromatography (CH2Cl2) affording 23 (98 mg, 87%) as orange solid.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[C:7]([NH2:10])[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[F:11][C:12]([F:19])([F:18])[C:13](=[CH2:17])[C:14]([OH:16])=[O:15].C1(O)C=CC(O)=CC=1>C1(C)C=CC=CC=1>[S:1]1[C:5]2[CH:6]=[C:7]([NH:10][CH2:17][CH:13]([C:12]([F:19])([F:18])[F:11])[C:14]([OH:16])=[O:15])[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: C=C(C(=O)O)C(F)(F)F
Reactant: Nc1ccc2ncsc2c1
Agent: Oc1ccc(O)cc1
Solvent: Cc1ccccc1
Product: O=C(O)C(CNc1ccc2ncsc2c1)C(F)(F)F
Yield: 19.7 %

Procedure:
Benzothiazol-6-ylamine (1 g, 6.66 mmol) was reacted with 2-trifluoromethyl-acrylic acid (1.39 g, 9.99 mmol), benzene-1,4-diol (51.3 mg, 0.46 mmol) and toluene (10 mL) to afford the crude product. Purification by column chromatography on silica gel (30% ethyl acetate in hexane) afforded 380 mg of the product (19.67% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH:8]2[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:10][CH2:9]2)[CH:5]=[CH:4][C:3]=1[C:19]1[CH2:24][CH2:23][CH:22]([CH:25]2[CH2:34][CH2:33][C:28]3([O:32][CH2:31][CH2:30][O:29]3)[CH2:27][CH2:26]2)[CH2:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+].[H][H]>C1(C)C=CC=CC=1.C(O)(C)C.[Pd]>[F:1][C:2]1[CH:7]=[C:6]([CH:8]2[CH2:9][CH2:10][CH:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:12][CH2:13]2)[CH:5]=[CH:4][C:3]=1[CH:19]1[CH2:24][CH2:23][CH:22]([CH:25]2[CH2:34][CH2:33][C:28]3([O:29][CH2:30][CH2:31][O:32]3)[CH2:27][CH2:26]2)[CH2:21][CH2:20]1
Reactant: CCCCCC1CCC(c2ccc(C3=CCC(C4CCC5(CC4)OCCO5)CC3)c(F)c2)CC1
Reactant: [H][H]
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Solvent: Cc1ccccc1
Product: CCCCCC1CCC(c2ccc(C3CCC(C4CCC5(CC4)OCCO5)CC3)c(F)c2)CC1

Procedure:
The compound (4) was dissolved in a mixed solvent of toluene (150 ml) and isopropyl alcohol (100 ml), and palladium on carbon catalyst (NX type of 5% Pd/C; 50% wet; made by N. E. Chemcat; hereinafter referred to as Pd/C) (3.06 g) and potassium carbonate (0.52 g) were added thereto. The mixture was stirred at room temperature under a hydrogen atmosphere until hydrogen absorption had ceased. After the reaction had been completed, Pd/C was removed and then the solvent was distilled off, and the residue was purified with a fractional operation by means of column chromatography using a mixed solvent of toluene and ethyl acetate (toluene:ethyl acetate=9:1 by volume) as an eluent and silica gel as a stationary phase powder, and further purified by means of recrystallization from heptane and dried, giving 26.35 g of 8-{4-[2-fluoro-4-(4-pentyl-cyclohexyl)-phenyl]-cyclohexyl}-1,4-dioxa-spiro[4,5]decane (5). The yield based on the compound (4) was 44.6%.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[N:12]=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[CH3:18][C@@H:19]1[CH2:24][CH2:23][CH2:22][NH:21][C@@H:20]1[CH2:25][NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30].CCN(C(C)C)C(C)C.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>C(Cl)Cl>[CH3:18][C@@H:19]1[CH2:24][CH2:23][CH2:22][N:21]([C:7](=[O:9])[C:6]2[CH:10]=[C:2]([CH3:1])[CH:3]=[CH:4][C:5]=2[C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[N:12]=2)[C@@H:20]1[CH2:25][NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30]
Reactant: C[C@@H]1CCCN[C@@H]1CNC(=O)OC(C)(C)C
Reactant: Cc1ccc(-c2cccc(C)n2)c(C(=O)O)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ccc(-c2cccc(C)n2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNC(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To the mixture of 5-methyl-2-(6-methylpyridin-2-yl)benzoic acid (0.229 g, 0.868 mmol), tert-butyl (((2S,3R)-3-methylpiperidin-2-yl)methyl)carbamate (0.24 g, 1.04 mmol) and DIPEA (0.3 mL, 1.738 mmol) in DCM (20 mL) was slowly added O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (TBTU; 0.278 g, 0.869 mmol). The mixture was stirred at rt for 1 h. The mixture was diluted with DCM and was washed with satd. aq. NaHCO3 and brine and dried over Na2SO4. The solvent was removed in vacuo to obtain the title compound which was used without further purification. ESI-MS (m/z): 438 [M+1]+.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]3[C:13](=[CH:14][CH:15]=2)[C:12]([C@@H:16]2[CH2:21][O:20][C@@H:19]([CH2:22][CH2:23][CH2:24][NH2:25])[O:18][CH2:17]2)=[CH:11][CH:10]=[CH:9]3)[CH2:3][CH2:2]1.Cl[C:27]([O:29][C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=1)=[O:28].C(N(CC)C(C)C)(C)C>ClCCl>[CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]3[C:13](=[CH:14][CH:15]=2)[C:12]([C@@H:16]2[CH2:21][O:20][C@@H:19]([CH2:22][CH2:23][CH2:24][NH:25][C:27](=[O:28])[O:29][C:30]4[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=4)[O:18][CH2:17]2)=[CH:11][CH:10]=[CH:9]3)[CH2:2][CH2:3]1
Reactant: NCCC[C@H]1OC[C@H](c2cccc3cc(OCC4CC4)ccc32)CO1
Reactant: O=C(Cl)Oc1ccc(Cl)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCCC[C@H]1OC[C@H](c2cccc3cc(OCC4CC4)ccc32)CO1)Oc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
0.205 g (0.60 mmol) of trans-3-[5-(6-cyclopropylmethoxynaphthalen-1-yl)-1,3-dioxan-2-yl]propylamine is added, in small portions and at ambient temperature, to a solution of 0.110 ml (0.78 mmol) of 4-chlorophenyl chloroformate and 0.205 ml (1.2 mmol) of N,N-diisopropylethylamine in 6 ml of dichloromethane. The mixture is stirred at ambient temperature for 16 hours, then washing is carried out with 5 ml of a saturated sodium bicarbonate solution. The phases are separated and the organic phase is filtered through a hydrophobic sintered glass funnel. The filtrate is concentrated under reduced pressure and the residue is purified by chromatography on silica gel, eluting with an 80/20 mixture of cyclohexane and ethyl acetate. After washing in 5 ml of diisopropyl ether, 0.176 g of a white solid is obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([F:10])[C:7](Cl)=[CH:6][C:5]=1[NH:12]C(=O)C)([O-:3])=[O:2].[NH:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.[OH-].[K+].[K+].[Br-]>CS(C)=O>[N+:1]([C:4]1[CH:9]=[C:8]([F:10])[C:7]([N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)=[CH:6][C:5]=1[NH2:12])([O-:3])=[O:2]
Reactant: C1CNCCN1
Reactant: CC(=O)Nc1cc(Cl)c(F)cc1[N+](=O)[O-]
Agent: [Br-]
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: Nc1cc(N2CCNCC2)c(F)cc1[N+](=O)[O-]
Yield: 77.7 %

Procedure:
2-Nitro-4-fluoro-5-(piperazin-1-yl)aniline (5.6 g, 77%) was prepared by a procedure analogous to that described in preparation 1 (step 3) using N-(2-nitro-4-fluoro-5-chlorophenyl)acetamide (7.4 g, 0.03 mol) (obtained in preparation 1, step 2), piperazine (27.2 g, 0.3 mol), potassium hydroxide (2.5 g, 0.045 mol) and dimethyl sulfoxide (30 mL). mp 120-121° C.; IR (KBr) 3334, 1504, 1251 cm-1 ; 1H NMR (CDCl3 +CD3OD) δ 3.00 (t, J=5.4 Hz, 4H, N(CH2)2); 3.20 (t, J=5.6 Hz, 4H, N(CH2)2), 3.82 (brs, 3H, NH), 6.18 (d, J=8.2 Hz, 1H), 7.74 (d, J=13.8 Hz, 1H); Mass (m/z) 240 (M+.).
Reaction SMILES: [CH2:1]([CH:8]1[NH:13][CH2:12][CH2:11][N:10]([C:14]2[CH:22]=[C:21]3[C:17]([C:18]([CH2:27][CH3:28])=[N:19][N:20]3[CH:23]3[CH2:26][CH2:25][CH2:24]3)=[CH:16][CH:15]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O:30][C:31](=O)[CH2:32][C:33]1[CH:34]=[N:35][NH:36][CH:37]=1>>[CH2:1]([C@H:8]1[CH2:9][N:10]([C:14]2[CH:22]=[C:21]3[C:17]([C:18]([CH2:27][CH3:28])=[N:19][N:20]3[CH:23]3[CH2:24][CH2:25][CH2:26]3)=[CH:16][CH:15]=2)[CH2:11][CH2:12][N:13]1[C:31](=[O:30])[CH2:32][C:33]1[CH:34]=[N:35][NH:36][CH:37]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)Cc1cn[nH]c1
Reactant: CCc1nn(C2CCC2)c2cc(N3CCNC(Cc4ccccc4)C3)ccc12
Product: CCc1nn(C2CCC2)c2cc(N3CCN(C(=O)Cc4cn[nH]c4)[C@@H](Cc4ccccc4)C3)ccc12
Yield: 13 %

Procedure:
Prepared by the method outlined for Example 275 using 6-(3-benzyl-piperazin-1-yl)-1-cyclobutyl-3-ethyl-1H-indazole (185 mg, 0.494 mmol) and (1H-pyrazol-4-yl)-acetic acid methyl ester (148 mg, 1.06 mmol) with heating for 5 days to afford product as a colorless solid (31 mg, 13%). LC/MS (Method B) 3.70 min, [M+1]+ 483.
Reaction SMILES: [N:1]1([C:7]2[C:11]([C:12]#[N:13])=[C:10]([N:14]=[CH:15][N:16](C)C)[NH:9][N:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Cl.[Cl:20][C:21]1[CH:22]=[C:23]([CH:25]=[CH:26][CH:27]=1)N>CO>[Cl:20][C:21]1[CH:27]=[C:26]([NH:13][C:12]2[N:16]=[CH:15][N:14]=[C:10]3[NH:9][N:8]=[C:7]([N:1]4[CH2:2][CH2:3][O:4][CH2:5][CH2:6]4)[C:11]=23)[CH:25]=[CH:23][CH:22]=1
Reactant: CN(C)C=Nc1[nH]nc(N2CCOCC2)c1C#N
Reactant: Nc1cccc(Cl)c1
Agent: Cl
Solvent: CO
Product: Clc1cccc(Nc2ncnc3[nH]nc(N4CCOCC4)c23)c1
Reaction time: 0.5 h

Procedure:
With the exclusion of air, 1.86 g (7.49 mmol) of N′-[3-(morpholin-4-yl)-4-cyano-1 H-pyrazol-5-yl]-N,N-dimethyl-formamidine in 45 ml of methanol are heated to boiling with 1.84 g (11.2 mmol) of 3-chloro-aniline hydrochloride, during which the solid temporarily dissolves. After about 30 min, a precipitate separates out again. After 8 hours the reaction mixture is cooled, filtered and washed with methanol and DIPE. Stirring the crude product in a boiling mixture of 40 ml of ethanol, 20 ml of chloroform and 20 ml of dioxane yields 4-(3-chloro-phenylamino)-3-(morpholin-4-yl)-1H-pyrazolo[3,4-d]pyrimidine; m.p. 275-276° C.; HPLC:tRet(grad20-100/20)=11.6.
Reaction SMILES: [CH2:1]([C:3]1[N:11]=[C:10]([O:12][CH3:13])[C:9]([NH:14][C:15]([N:17]2[CH2:22][CH2:21][N:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:19][CH2:18]2)=[O:16])=[CH:8][C:4]=1[C:5](O)=[O:6])C.C1CCC(N=C=NC2CCCCC2)CC1.[CH:44]1[C:57]2[C:48](=[N:49][C:50]3[C:55]([C:56]=2[NH:58][C:59]2[CH:60]=[C:61]([NH:67][C:68](=[O:72])[CH:69]([NH2:71])[CH3:70])[CH:62]=[C:63]([CH2:65][OH:66])[CH:64]=2)=[CH:54][CH:53]=[CH:52][CH:51]=3)[CH:47]=[CH:46][CH:45]=1>N1C=CC=CC=1.CN(C1C=CN=CC=1)C>[CH:54]1[C:55]2[C:50](=[N:49][C:48]3[C:57]([C:56]=2[NH:58][C:59]2[CH:60]=[C:61]([NH:67][C:68]([CH:69]([NH:71][C:5]([C:4]4[CH:8]=[C:9]([NH:14][C:15]([N:17]5[CH2:22][CH2:21][N:20]([C:23]6[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=6)[CH2:19][CH2:18]5)=[O:16])[C:10]([O:12][CH3:13])=[N:11][C:3]=4[CH3:1])=[O:6])[CH3:70])=[O:72])[CH:62]=[C:63]([CH2:65][OH:66])[CH:64]=2)=[CH:44][CH:45]=[CH:46][CH:47]=3)[CH:51]=[CH:52][CH:53]=1
Reactant: CCc1nc(OC)c(NC(=O)N2CCN(c3ccccc3)CC2)cc1C(=O)O
Reactant: CC(N)C(=O)Nc1cc(CO)cc(Nc2c3ccccc3nc3ccccc23)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: COc1nc(C)c(C(=O)NC(C)C(=O)Nc2cc(CO)cc(Nc3c4ccccc4nc4ccccc34)c2)cc1NC(=O)N1CCN(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 68.2 %

Procedure:
2-ethyl-6-methoxy-5-[(4-phenylpiperazine-1-carbonyl)amino]nicotinic acid(0.5 g, 1.24 mmole) was dissolved in pyridine(30 mL) and thereto DCC(0.26 g, 1.24 nmole), DMAP(0.15 g, 1.24 mmole) and N-[3-(acridine-9-yl-amino)-5-hydroxymethyl-phenyl]-2-aminopropaneamide were added. After stirring the resulting mixture for 24 hours at the room temperature. The resulting product was purified by column chromatography to give the titled compound.