Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]([C:5]1[S:9][C:8]([NH:10][S:11]([C:14]2[CH:19]=[CH:18][C:17]([NH:20]C(=O)C)=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[N:7][N:6]=1)(=[O:4])(=[O:3])[NH2:2]>Cl>[NH2:20][C:17]1[CH:18]=[CH:19][C:14]([S:11]([NH:10][C:8]2[S:9][C:5]([S:1]([NH2:2])(=[O:3])=[O:4])=[N:6][N:7]=2)(=[O:13])=[O:12])=[CH:15][CH:16]=1
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Nc2nnc(S(N)(=O)=O)s2)cc1
Agent: Cl
Product: Nc1ccc(S(=O)(=O)Nc2nnc(S(N)(=O)=O)s2)cc1
Yield: 57.7 %

Procedure:
Compound 138 (1.0 g, 2.6 mmol) was heated at reflux with aqueous HCl (6 M, 10 mL) for 50 min. The homogeneous solution was evaporated to dryness and the residue was taken up in distilled water (10 mL). The pH was adjusted to 9 with 25% aqueous ammonia, the resulting solution was filtered to remove insoluble matter, and the solution acidified to pH 4 with glacial acetic acid. Cooling the solution overnight gave a solid, which was collected by filtration, washed with cold water, and air-dried. Recrystallization from 20% ethanol/H2O gave the pure product (500 mg, 1.5 mmol, 57%), mp 241-242° C. (lit17 mp 247-248° C.); 1H NMR (300 MHz, DMSO-d6) δ 6.58 (d, 2H, J=7.8 Hz), 7.43 (d, 2H, J=8.1 Hz), 8.43 (s, 2H); 13C NMR (75 MHz, DMSO-d6) δ 112.8, 125.9, 128.0, 153.1, 157.6, 166.0; LRMS (LCQ, ESI+) calcd for C8H10N5O4S3 336.0. found 335.8 (M+H)+. HRMS (ESI+, m/z) calcd for C8H10N5O4S3 335.9889. found 335.9883 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[CH:10]=[C:9]2[C:4]([CH:5]=[CH:6][C:7]3[CH2:13][CH2:12][C:11](=[CH:14][C:15]#[N:16])[C:8]=32)=[N:3]1.N.C(O)C>C(O)C.[Co]>[CH3:1][N:2]1[CH:10]=[C:9]2[C:4]([CH:5]=[CH:6][C:7]3[CH2:13][CH2:12][C:11](=[CH:14][CH2:15][NH2:16])[C:8]=32)=[N:3]1
Reactant: Cn1cc2c3c(ccc2n1)CCC3=CC#N
Agent: [Co]
Agent: N
Solvent: CCO
Product: Cn1cc2c3c(ccc2n1)CCC3=CCN
Temperature: 25 °C
Reaction time: 3 h
Yield: 100.3 %

Procedure:
To a solution of (2-methyl-6,7-dihydrocyclopenta[e]indazol-8(2H)-ylidene)acetonitrile (600 mg, 2.87 mmol) in ethanol (14 mL) were added Raney cobalt (6 g) and 2M ammonia/ethanol solution (14 mL), and the mixture was stirred under a hydrogen atmosphere at room temperature for 3 hr. The catalyst was filtered off through celite, and the filtrate was concentrated under reduced pressure to give the title compound (614 mg, yield 99%).
Reaction SMILES: CS([N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[C:6]1[CH2:14][O:15][CH:16]1[CH:21]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH2:30][CH2:31][O:32][CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[O:40][CH3:41])=[CH:24][CH:23]=2)[CH2:20][CH2:19][N:18]([C:42]([O:44][CH2:45][C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)=[O:43])[CH2:17]1)(=O)=O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[NH:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[C:6]1[CH2:14][O:15][CH:16]1[CH:21]([C:22]2[CH:23]=[CH:24][C:25]([O:28][CH2:29][CH2:30][CH2:31][O:32][CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[O:40][CH3:41])=[CH:26][CH:27]=2)[CH2:20][CH2:19][N:18]([C:42]([O:44][CH2:45][C:46]2[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=2)=[O:43])[CH2:17]1
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OCc3ccccc3)CC2OCc2cc3ccccc3n2S(C)(=O)=O)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OCc3ccccc3)CC2OCc2cc3ccccc3[nH]2)cc1

Procedure:
The solution of 0.160 g of benzyl 3-(1-methanesulphonyl-1H-indol-2-ylmethoxy)-4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}piperidine-1-carboxylate in 11 ml of tetrahydrofuran is admixed with 0.44 ml of tetrabutylammonium fluoride solution (1M in tetrahydrofuran) and stirred at reflux over 20 hours. The reaction mixture is cooled, poured onto brine (40 ml) and extracted with ethyl acetate (2×40 ml). The organic phases are washed with brine (1×40 ml), dried over sodium sulphate, filtered and concentrated by evaporation. The title compound is obtained as an orange oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.18 (1:2 EtOAc-heptane); Rt=26.90 (II).
Reaction SMILES: Br[CH2:2][CH:3]1[O:8][C:7]2[CH:9]=[C:10]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:11]=[C:12]([F:13])[C:6]=2[CH2:5][O:4]1.[CH3:18][NH:19][CH2:20][CH3:21]>CCO>[F:13][C:12]1[C:6]2[CH2:5][O:4][CH:3]([CH2:2][N:19]([CH3:18])[CH2:20][CH3:21])[O:8][C:7]=2[CH:9]=[C:10]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:11]=1
Reactant: CCNC
Reactant: CS(=O)(=O)c1cc(F)c2c(c1)OC(CBr)OC2
Solvent: CCO
Product: CCN(C)CC1OCc2c(F)cc(S(C)(=O)=O)cc2O1

Procedure:
Preparation according to Example 34 using 2-(bromomethyl)-5-fluoro-7-(methylsulfonyl)-4H-1,3-benzodioxine (8.5 mg, 0.026 mmol), N-methylethanamine (0.5 ml) and EtOH (3 ml). MS m/z (rel. intensity, 70 eV) 303 (M+, 0.2), 95 (5), 75 (5), 73 (5), 72 (bp), 58 (3).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:17])[CH2:15]Cl)[CH:10]([CH2:18][OH:19])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+]>C1COCC1>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]2[CH:10]([CH2:18][O:19][CH2:15][C:14]2=[O:17])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(CCl)N1CCN(Cc2ccccc2)CC1CO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1COCC2CN(Cc3ccccc3)CCN12
Reaction time: 6 h
Yield: 71.7 %

Procedure:
To a stirred mixture of 1-(4-Benzyl-2-hydroxymethyl-piperazin-1-yl)-2-chloro-ethanone (425 mg, 1.50 mmol) in anhydrous THF (10 mL) under N2 was added 60% sodium hydride (240.5 mg, 6.0 mmol, 4.0 eq). The mixture was stirred at rtT for 6 h and quenched with aqueous, saturated NH4Cl solution. The mixture was poured into EtOAc, and the organic layer was washed with 50% aqueous brine (3×), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by MPLC (Biotage®, gradient elution 75 to 100% EtOAc/hexane) to give the product (265 mg, 72%) as clear oil. 1H-NMR (300 MHz, DMSO-d6) 7.34 to 7.24 (m, 5H), 4.34 to 4.29 (m, 1H), 3.99 (s, 2H), 2.92 (dd, 1H), 3.57 to 3.52 (m, 1H), 3.49 (d, 2H), 3.47 to 3.42 (dd, 1H), 2.82 to 2.74 (m, 2H), 2.69 (dt, 1H), 1.89 (dt, 1H), 1.77 (t, 1H); ES-MS m/z 247.2 [M+H]+, RT (min) 1.07.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([CH3:11])[N:10]=2)[N:7]=1.[I:12]Cl.S([O-])([O-])(=O)=S.[Na+].[Na+].C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl.CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([I:12])=[C:9]([CH3:11])[N:10]=2)[N:7]=1
Reactant: Cc1cn2nc(Cl)ccc2n1
Reactant: ClI
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: Cc1nc2ccc(Cl)nn2c1I
Temperature: 0 °C
Reaction time: 16 h

Procedure:
Added to a solution of 7.00 g (41.8 mmol) of 6-chloro-2-methylimidazo[1,2-b]pyridazine (CAS 14793-00-1) in 300 ml of chloroform, cooled to 0° C., are 10.2 g (62.7 mmol) of iodine monochloride in solution in 20 ml of methanol. The reaction is then left at ambient temperature for 16 hours then poured over a mixture of a 5% sodium thiosulphate solution and of sodium hydrogen carbonate. The product is extracted with dichloromethane, the organic phase is dried over sodium sulphate and the solvent is evaporated under reduced pressure.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4](Cl)[CH:3]=1.[O:9]1[C:14]2[CH:15]=[CH:16][C:17]([NH2:19])=[CH:18][C:13]=2[O:12][CH2:11][CH2:10]1>[Cu]I>[O:9]1[C:14]2[CH:15]=[CH:16][C:17]([NH:19][C:4]3[CH:3]=[C:2]([NH2:1])[CH:7]=[CH:6][N:5]=3)=[CH:18][C:13]=2[O:12][CH2:11][CH2:10]1
Reactant: Nc1ccc2c(c1)OCCO2
Reactant: Nc1ccnc(Cl)c1
Agent: [Cu]I
Product: Nc1ccnc(Nc2ccc3c(c2)OCCO3)c1
Temperature: 200 °C

Procedure:
In a 5-mL vial was added 4-amino-2-chloropyridine (Aldrich Chemical Company) (1.1 g, 8.7 mmol), 1,4-benzodioxane-6-amine (Aldrich Chemical Company) (5.3 g, 35 mmol) and copper (I) iodide (Aldrich Chemical Company) (0.17 g, 0.87 mmol). The content was sonicated at room temperature for 5 min and then heated in the Smith Microwave Synthesizer at 200° C. for 10 min. The residue was purified by flash chromatography (95:5 dichloromethane:2N NH3 in MeOH) to give the title compound as a dark solid. MS (ESI, pos. ion) m/z: 244 (M+1).
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH:12]2[O:24][CH2:25][C:26]2[CH:35]=[CH:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=2)=[CH:7][CH:6]=1.Cl[C:37]1[N:42]=[CH:41][CH:40]=[CH:39][N:38]=1>>[CH:27]1[C:28]2[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:34]=[CH:35][C:26]=1[CH2:25][O:24][CH:12]1[CH:11]([C:8]2[CH:9]=[CH:10][C:5]([O:4][CH2:3][CH2:2][O:1][C:37]3[N:42]=[CH:41][CH:40]=[CH:39][N:38]=3)=[CH:6][CH:7]=2)[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:21])[CH3:22])=[O:18])[CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCO)cc2)C(OCc2ccc3ccccc3c2)C1
Reactant: Clc1ncccn1
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCOc3ncccn3)cc2)C(OCc2ccc3ccccc3c2)C1

Procedure:
In an analogous manner to that described in Example 1 (9), by alkylating tert-butyl (3RS,4RS)-4-[4-(2-hydroxy-ethoxy)-phenyl]-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate [Example 53 (c)] with 2-chloro-pyrimidine there was obtained tert-butyl (3RS,4RS)-3-(naphthalen-2-ylmethoxy)-4-[4-[2-(pyrimidin-2-yloxy)-ethoxy]-phenyl]-piperidine-1-carboxylate as a colourless solid; MS: 556 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][C:10]=1[OH:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].O[NH3+:20].C([O-])(=O)C.[Na+]>O.C(O)C>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([C:13]#[N:20])=[CH:11][C:10]=1[OH:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [NH3+]O
Reactant: O=Cc1ccc(OCc2ccccc2)c(O)c1
Agent: CC(=O)[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: N#Cc1ccc(OCc2ccccc2)c(O)c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 5.3 %

Procedure:
A mixture of 4-benzyloxy-3-hydroxybenzaldehyde (19.0 g), hydroxylammonium chloride (8.6 g), sodium acetate (13.7 g), water (30 mL) and ethanol (150 mL) was stirred at 80° C. for 8 hours. Water (100 mL) was added to the reaction mixture and the whole was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in dichloromethane (100 mL), and then pyridine (20 mL) was added. Trifluoroacetic anhydride (35.3 mL) was added dropwise under ice-cooling, and the resulting mixture was stirred at room temperature for 6 hours. Two mol/L hydrochloric acid was added to the reaction mixture and the whole was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate and brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: ethyl acetate/hexane=1/10) to give the title compound (1.0 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([C:9]([N:11]2[C:19]3[CH:18]=[CH:17][N:16]=[CH:15][C:14]=3[CH:13]=[CH:12]2)=[O:10])=[C:4]([Cl:20])[CH:3]=1.[C:21]([CH2:23][C:24](O)=[O:25])#[N:22].OC1C2N=NNC=2C=CC=1.C(N=C=NCCCN(C)C)C.C(N(CC)C(C)C)(C)C>CN(C)C=O>[C:21]([CH2:23][C:24]([NH:1][C:2]1[CH:3]=[C:4]([Cl:20])[C:5]([C:9]([N:11]2[C:19]3[CH:18]=[CH:17][N:16]=[CH:15][C:14]=3[CH:13]=[CH:12]2)=[O:10])=[C:6]([Cl:8])[CH:7]=1)=[O:25])#[N:22]
Reactant: Nc1cc(Cl)c(C(=O)n2ccc3cnccc32)c(Cl)c1
Reactant: N#CCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: N#CCC(=O)Nc1cc(Cl)c(C(=O)n2ccc3cnccc32)c(Cl)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 12.3 %

Procedure:
To a solution of (4-amino-2,6-dichlorophenyl)(1H-pyrrolo[3,2-c]pyridin-1-yl)methanone (60 mg, 0.19 mmol) in dimethylformamide (1 mL) was added cyanoacetic acid (25 mg, 0.29 mmol), hydroxybenzotriazole (39.73 mg, 0.29 mmol), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (56.17 mg, 0.29 mmol) and N,N-diisopropylethyl amine (0.06 mL, 0.31 mmol) in the same order. The reaction mixture was stirred at room temperature for 20 hours. The reaction mixture was poured onto water (10 mL) and extracted with ethyl acetate (2×50 mL). The combined organic layer was washed with saturated aqueous solution of sodium bicarbonate, dried over anhydrous sodium sulphate, filtered and the solvent was removed under rotary evaporator. The product was purified by silica gel column chromatography using dichloromethane and methanol (1.5-2%) as eluant to yield 2-cyano-N-[3,5-dichloro-4-(1H-pyrrolo[3,2-c]pyridin-1-ylcarbonyl)phenyl]acetamide (8.7 mg, 12%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][CH2:12][CH2:13][CH3:14])[CH:6]=[CH:5]2.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1>>[CH2:11]([N:7]1[C:8]2[C:4](=[CH:3][C:2]([C:20]3[CH:21]=[CH:22][C:17]([O:16][CH3:15])=[CH:18][CH:19]=3)=[CH:10][CH:9]=2)[CH:5]=[CH:6]1)[CH2:12][CH2:13][CH3:14]
Reactant: COc1ccc(B(O)O)cc1
Reactant: CCCCn1ccc2cc(Br)ccc21
Product: CCCCn1ccc2cc(-c3ccc(OC)cc3)ccc21

Procedure:
The title compound was prepared from 5-bromo-1-butyl-1H-indole (Step 1 of Example 29) and 4-methoxyphenylboronic acid in substantially the same manner, as described in Step 2 of Example 25. The product was obtained as an oil. Mass spectrum (ESI, [M+H]+) m/z 280.1 HNMR (400 MHz, DMSO-d6): δ 7.72 (s, 1H), 7.58 (dd, 2H, J=8.86 and 1.99 Hz), 7.54-7.49 (m, 2H), 7.37-7.35 (m, 2H), 6.98 (dd, 1H, J=7.33 and 7.34 Hz), 6.44 (d, 1H, J=3.05 Hz), 4.17 (t, 2H, J=7.01 Hz), 3.78 (s, 3H), 1.73 (p, 2H, J=7.16 Hz), 1.25 (h, 2H, J=7.46 Hz), and 0.88 ppm (t, 3H, J=7.3, 1 Hz).
Reaction SMILES: C[N:2](/[CH:4]=[CH:5]/[C:6]([C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)=O)C.O.[NH2:18]N>C(O)C>[N+:14]([C:11]1[CH:12]=[CH:13][C:8]([C:6]2[CH:5]=[CH:4][NH:2][N:18]=2)=[CH:9][CH:10]=1)([O-:16])=[O:15]
Reactant: CN(C)/C=C/C(=O)c1ccc([N+](=O)[O-])cc1
Reactant: NN
Solvent: CCO
Solvent: O
Product: O=[N+]([O-])c1ccc(-c2cc[nH]n2)cc1
Yield: 78.9 %

Procedure:
A solution of 1-(4-nitrophenyl)-3-N,N-dimethylamino-2-propen-1-one (27.3 g) and 85% hydrazine hydrate (23.6 g) in ethanol was heated at 60° C. for one hour. The crystallized solid was filtered to give 18.5 g of 3-(4-nitrophenyl)-pyrazole; M.p. 196°-197° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH2:13][C:14]1([OH:20])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)=[N:9][CH:8]=[CH:7][CH:6]=2.[C:21](OC)(OC)(OC)[CH2:22][CH2:23][CH3:24].Cl.N1C=CC=CC=1>C1(C)C=CC=CC=1>[CH2:22]([C:21]1[N:12]([CH2:13][C:14]2([OH:20])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[C:11]2[C:10]3[N:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:4]=[CH:3][C:2]=2[N:1]=1)[CH2:23][CH3:24]
Reactant: Nc1cnc2cccnc2c1NCC1(O)CCCCC1
Reactant: CCCC(OC)(OC)OC
Agent: Cl
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CCCc1nc2cnc3cccnc3c2n1CC1(O)CCCCC1
Temperature: 25 °C
Yield: 69.4 %

Procedure:
A solution of 1-{[(3-amino[1,5]naphthyridin-4-yl)amino]methyl}cyclohexanol (prepared as described in Part B, 15.1 mmol), trimethyl orthobutyrate (2.63 mL, 16.6 mmol), and pyridine hydrochloride (0.650 g, 5.64 mmol) in toluene (100 mL) was heated at reflux overnight. The solution was allowed to cool to rt, then was concentrated under reduced pressure. The residue was partitioned between chloroform (200 mL) and saturated aqueous sodium bicarbonate (75 mL). The aqueous layer was extracted with chloroform (2×50 mL). The combined organic layers were washed with brine (50 mL), dried over MgSO4, filtered, and concentrated under reduced pressure. The resulting solid was triturated with ethyl acetate and isolated by filtration. The filtrate was concentrated and the solid was again triturated with ethyl acetate; this procedure was repeated two more times. The white solids were combined and dried under vacuum to yield 1-[(2-propyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)methyl]cyclohexanol (3.40 g, 70% over two steps).
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:26])=[CH:4][C:5]([F:25])=[C:6]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([F:20])=[C:15](F)[C:16]=3[Cl:18])[C:11](=[O:21])[C:10]([C:22]([OH:24])=[O:23])=[CH:9]2)[CH:7]=1.[NH2:27][CH2:28][C@@H:29]([OH:31])[CH3:30]>N1C=CC=CC=1>[NH2:1][C:2]1[C:3]([F:26])=[CH:4][C:5]([F:25])=[C:6]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([F:20])=[C:15]([NH:27][CH2:28][C@@H:29]([OH:31])[CH3:30])[C:16]=3[Cl:18])[C:11](=[O:21])[C:10]([C:22]([OH:24])=[O:23])=[CH:9]2)[CH:7]=1
Reactant: C[C@H](O)CN
Reactant: Nc1cc(-n2cc(C(=O)O)c(=O)c3cc(F)c(F)c(Cl)c32)c(F)cc1F
Solvent: c1ccncc1
Product: C[C@H](O)CNc1c(F)cc2c(=O)c(C(=O)O)cn(-c3cc(N)c(F)cc3F)c2c1Cl
Temperature: 55 °C
Reaction time: 2.5 h
Yield: 85.8 %

Procedure:
1-(5-Amino-2,4-difluorophenyl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (150 mg) and (S)-1-amino-2-propanol (150 mg) were added to pyridine (450 mg), and the mixture was stirred at 55° C. for 2.5 hours. The reaction mixture was concentrated under reduced pressure. A process of adding ethanol (2 ml) to the residue and then concentrating the mixture under reduced pressure was conducted twice repeatedly. Concentrated hydrochloric acid (150 mg) was added to the resultant residue, and the mixture was concentrated under reduced pressure. Ethanol (1 ml) was added to the resultant residue, and deposits were collected by filtration and washed with ethanol and diisopropyl ether in that order to obtain the title compound (147 mg) as a colorless powder.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([N:19]([CH2:31][C:32]([OH:34])=[O:33])[CH2:20][CH2:21][N:22]([CH2:27][C:28]([OH:30])=[O:29])[CH2:23][C:24]([OH:26])=[O:25])[CH2:9][N:10]([CH2:15][C:16]([OH:18])=[O:17])[CH2:11][C:12]([OH:14])=[O:13].C(OC([NH:42][CH2:43][CH:44]1[CH2:49][CH2:48][CH:47]([CH2:50][NH-:51])[CH2:46][CH2:45]1)=O)(C)(C)C>C(OCC)C>[CH2:20]([N:19]([CH2:31][C:32]([OH:34])=[O:33])[CH2:8][CH2:9][N:10]([CH2:11][C:12]([OH:14])=[O:13])[CH2:15][C:16]([OH:18])=[O:17])[CH2:21][N:22]([CH2:27][C:28]([OH:30])=[O:29])[CH2:23][C:24]([OH:26])=[O:25].[NH2:42][CH2:43][CH:44]1[CH2:49][CH2:48][CH:47]([CH2:50][NH-:51])[CH2:46][CH2:45]1
Reactant: CC(C)(C)OC(=O)NCC1CCC(C[NH-])CC1
Agent: O=C(O)CN(CCN(CC(=O)O)CC(=O)O)CCN(CC(=O)O)CC(=O)O
Solvent: O=C(O)C(F)(F)F
Solvent: CCOCC
Product: [NH-]CC1CCC(CN)CC1
Reaction time: 3 h

Procedure:
Subsequently, 95 ml of trifluoroacetic acid (produced by Wako Pure Chemical Industries, Ltd.) was added to 9.22 g of the DTPA-mono-(4-(N-tert-butoxycarbonylaminomethyl)cyclohexyl)methylamide obtained above, and, after stirring the mixture for 3 hours, the reaction mixture was added dropwise to diethyl ether to precipitate the reaction product. The reaction product precipitated was collected by suction filtration, and was dried under a reduced pressure, to obtain 11.0 g of DTPA-mono-(4-(aminomethyl)cyclohexyl)methylamide as the objective compound.
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([CH2:8][N:9]([C:23]2[CH:28]=[CH:27][C:26]([CH:29]([CH3:31])[CH3:30])=[CH:25][CH:24]=2)[C:10]([CH:12]2[C:21]3[C:16](=[CH:17][C:18]([OH:22])=[CH:19][CH:20]=3)[CH2:15][CH2:14][CH2:13]2)=[O:11])[CH:5]=[N:4]1)[CH3:2].Cl.Cl[CH2:34][CH2:35][N:36]([CH3:38])[CH3:37]>>[CH3:37][N:36]([CH3:38])[CH2:35][CH2:34][O:22][C:18]1[CH:17]=[C:16]2[C:21](=[CH:20][CH:19]=1)[CH:12]([C:10]([N:9]([CH2:8][C:6]1[CH:5]=[N:4][N:3]([CH2:1][CH3:2])[CH:7]=1)[C:23]1[CH:24]=[CH:25][C:26]([CH:29]([CH3:30])[CH3:31])=[CH:27][CH:28]=1)=[O:11])[CH2:13][CH2:14][CH2:15]2
Reactant: CCn1cc(CN(C(=O)C2CCCc3cc(O)ccc32)c2ccc(C(C)C)cc2)cn1
Reactant: CN(C)CCCl
Agent: Cl
Product: CCn1cc(CN(C(=O)C2CCCc3cc(OCCN(C)C)ccc32)c2ccc(C(C)C)cc2)cn1
Yield: 38.7 %

Procedure:
By the reaction and treatment in the same manner as in Example 106 using N-[(1-ethylpyrazol-4-yl)methyl]-6-hydroxy-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.42 g) and 2-chloro-N,N-dimethylethylamine hydrochloride (0.22 g) as starting materials, 6-[2-(dimethylamino)ethoxy]-N-[(1-ethylpyrazol-4-yl)methyl]-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.19 g) was obtained.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]23[N:30]([C:31]([C:33]4[C:34]([CH3:38])=[N:35][O:36][CH:37]=4)=[O:32])[CH2:29][CH2:28][N:19]2[C:20](=[O:27])[C:21]2[N:22]([CH:24]=[CH:25][CH:26]=2)[CH2:23]3)=[CH:14][CH:13]=1)(C(C)(C)C)(C)C.C(O)(=O)C.C1COCC1.O>C(Cl)Cl>[OH:8][CH2:9][CH2:10][O:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]23[N:30]([C:31]([C:33]4[C:34]([CH3:38])=[N:35][O:36][CH:37]=4)=[O:32])[CH2:29][CH2:28][N:19]2[C:20](=[O:27])[C:21]2[N:22]([CH:24]=[CH:25][CH:26]=2)[CH2:23]3)=[CH:16][CH:17]=1
Reactant: Cc1nocc1C(=O)N1CCN2C(=O)c3cccn3CC12c1ccc(OCCO[Si](C)(C)C(C)(C)C)cc1
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cc1nocc1C(=O)N1CCN2C(=O)c3cccn3CC12c1ccc(OCCO)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.3 %

Procedure:
10a-[4-(2-{[tert-butyl(dimethyl)silyl]oxy}ethoxy)phenyl]-1-[(3-methyl-1,2-oxazol-4-yl)carbonyl]-2,3,10,10a-tetrahydro-1H,5H-imidazo[1,2-a]pyrrolo[1,2-d]pyrazin-5-one (80 mg, 0.14 mmol) was treated with a 3:1:1 mixture of acetic acid/THF/water (2 mL). The solution was stirred at room temperature overnight. The mixture was then diluted with CH2Cl2 (20 mL) and washed with a saturated aqueous solution of NaHCO3 (3×6 mL). The organic layer was dried (MgSO4), filtered and concentrated in vacuo to give a gummy solid that was purified by flash chromatography (Biotage SP4, 12 g silica column gradient 0-10% MeOH in CH2Cl2) to give 10a-[4-(2-hydroxyethoxy)phenyl]-1-[(3-methyl-1,2-oxazol-4-yl)carbonyl]-2,3,10,10a-tetrahydro-1H,5H-imidazo[1,2-a]pyrrolo[1,2-d]pyrazin-5-one (109) (38 mg, yield 64%).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)=[N:6][CH:7]=1.C([O-])(=O)C.[K+].Br[C:27]1[N:32]=[CH:31][CH:30]=[CH:29][N:28]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:14][C:11]1[CH:12]=[CH:13][C:8]([C:5]2[N:6]=[CH:7][C:2]([C:27]3[N:32]=[CH:31][CH:30]=[CH:29][N:28]=3)=[CH:3][C:4]=2[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:9][CH:10]=1
Reactant: Cc1ccc(-c2ncc(Cl)cc2-c2ccccc2)cc1
Reactant: Brc1ncccn1
Agent: [Pd]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(=O)[O-]
Solvent: C1COCCO1
Product: Cc1ccc(-c2ncc(-c3ncccn3)cc2-c2ccccc2)cc1
Temperature: 160 °C

Procedure:
A mixture of 5-Chloro-2-(4-methylphenyl)-3-phenylpyridine (10-2; 0.050 g, 0.179 mmol), bis(pinacoloto)diboron (0.054 g, 0.214 mmol), potassium acetate (0.026 g, 0.268 mmol), Pd2(dba)3 (5 mg, 0.005 mmol) tricyclohexylphosphine (4 mg, 0.013 mmol) in anhydrous dioxane (2 mL) was degassed (3× pump/N2) and heated at 160° C. in the microwave for 1 hr. forms the boronic acid. In the same pot, 2-bromopyrimidine (0.042 g, 0.26mmol), tetrakis(triphenylphosphine)palladium (0.010 g, 0.00895 mmol), and 2M aq Na2CO3 (1 mL) were added and the resulting mixture was degassed (3× pump/N2) and heated in the microwave at 150° C. for 3 hr. Reaction partitioned between CH2Cl2 and water, extracted 3× with CH2Cl2, and the combined organics were dried (anhd. Na2SO4), filtered, and concentrated. The residue was purified by silica gel chromatography (10-20% EtOAc in Hexanes) to give the title compound. 1H-NMR (500 MHz, CDCl3) δ 9.69 (d, 1H, J=2.0 Hz), 8.86 (d, 2H, J=4.9 Hz), 8.73 (d, 1H, J=2.0 Hz), 7.37-7.23 (m, 8H), 7.08 (d, 2H J=7.82 Hz), 2.33 (s, 3H). LRMS m/z (M+H) Calcd: 324.0, found: 324.0.