Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[N+:2]([O-:11])([O:4][CH:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1)=[O:3].C(N(CC)CC)C.[C:19](=O)([O:30]C1C=CC([N+]([O-])=O)=CC=1)[O:20][C@@H:21]1[CH2:25][O:24][C@@H:23]2[C@H:26]([OH:29])[CH2:27][O:28][C@H:22]12>CN(C)C1C=CN=CC=1.C(Cl)Cl>[N+:2]([O:4][CH:5]1[CH2:10][CH2:9][N:8]([C:19]([O:20][C@@H:21]2[CH2:25][O:24][C@@H:23]3[C@H:26]([OH:29])[CH2:27][O:28][C@H:22]23)=[O:30])[CH2:7][CH2:6]1)([O-:11])=[O:3]
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)O[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2O
Reactant: O=[N+]([O-])OC1CCNCC1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(O[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2O)N1CCC(O[N+](=O)[O-])CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of piperidin-4-yl nitrate hydrochloride (0.620 g, 3.40 mmol), triethylamine (0.567 mL, 4.07 mmol) and 4-dimethylaminopyridine (0.083 g, 0.680 mmol) in DCM (23 mL), (3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl 4-nitrophenyl carbonate (1.06 g, 3.40 mmol) was added; the mixture was stirred at room temperature for 18 hrs. Then the mixture was diluted with DCM and washed with a 5% solution of sodium dihydrogen phosphate (2×30 mL) and brine (1×30 mL). The organic layer was dried over sodium sulfate, filtered, concentrated and purified by flash chromatography (Biotage SP1, EtOAc/n-hexane from 30 to 100%), affording the title compound as a yellow oil.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[N+:13]([O-:15])=[O:14])[C:7]([OH:9])=O)([O-:3])=[O:2].O=S(Cl)Cl.[CH3:20][N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.CCN(CC)CC>C(Cl)Cl>[N+:1]([C:4]1[CH:5]=[C:6]([C:7]([N:24]2[CH2:25][CH2:26][N:21]([CH3:20])[CH2:22][CH2:23]2)=[O:9])[CH:10]=[CH:11][C:12]=1[N+:13]([O-:15])=[O:14])([O-:3])=[O:2]
Reactant: O=C(O)c1ccc([N+](=O)[O-])c([N+](=O)[O-])c1
Reactant: CN1CCNCC1
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN1CCN(C(=O)c2ccc([N+](=O)[O-])c([N+](=O)[O-])c2)CC1
Temperature: 5 °C
Reaction time: 8 h
Yield: 95.2 %

Procedure:
A mixture of 3,4-dinitrobenzoic acid (10.6 g, 50 mmol) and SOCl2 (50 mL) was heated at reflux for 6 hrs. Then the mixture was evaporated to dryness in vacuo. The residue was dissolved in CH2Cl2 (50 mL) and cooled to 5° C. To this solution, N-methylpiperazine (5.5 g, 55 mmol) and Et3N (5.5 g, 55 mmol) were added dropwise as a solution in CH2Cl2 (50 mL). After stirring overnight at rt, the combined organic phase was washed with water (100 mL), dried over Na2SO4, filtered and concentrated, the resulting residue was purified by silica gel chromatography (eluent: 5% MeOH in CH2Cl2) to give a yellow solid (14.0 g, 95.2%). 1H NMR (300 MHz, DMSO-d6) δ: 8.29 (1 H, s), 8.25-8.27 (1 H, d, J=9.0 Hz), 7.95-7.98 (1 H, d, J=9.0 Hz), 3.62 (2 H, m), 3.28 (2 H, m), 2.38 (2 H, m), 2.26 (2 H, m), 2.19 (3 H, s).
Reaction SMILES: [CH2:1]([N:8]([CH2:30][C@@H:31]1[CH2:35][O:34]C(C)(C)[O:32]1)[CH2:9][C:10]1[C:14]2[N:15]=[CH:16][N:17]=[C:18]([O:19]C)[C:13]=2[N:12](COCC2C=CC=CC=2)[CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)Cl>Cl.CO>[CH2:1]([N:8]([CH2:9][C:10]1[C:14]2[N:15]=[CH:16][N:17]=[C:18]([OH:19])[C:13]=2[NH:12][CH:11]=1)[CH2:30][C@@H:31]([OH:32])[CH2:35][OH:34])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ncnc2c(CN(Cc3ccccc3)C[C@@H]3COC(C)(C)O3)cn(COCc3ccccc3)c12
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: OC[C@H](O)CN(Cc1ccccc1)Cc1c[nH]c2c(O)ncnc12
Yield: 91.8 %

Procedure:
(R)—N-benzyl-1-(5-(benzyloxymethyl)-4-methoxy-5H-pyrrolo[3,2-d]pyrimidin-7-yl)-N-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)methanamine (0.6 g, 1.194 mmol) was heated to 100° C. in HCl (15 ml, 37%) for 3 h. Tlc (CH2Cl2-6M NH3 in MeOH, 9:1) showed reaction over. The solvent was evaporated and the residue dissolved in MeOH, neutralized with Amberlyst A21 resin, filtered and the solvent evaporated. The residue was chromatographed (CH2Cl2-6M NH3 in MeOH, 9:1 then 85:15) to give (R)-3-(benzyl((4-hydroxy-5H-pyrrolo[3,2-d]pyrimidin-7-yl)methyl)amino)propane-1,2-diol (0.36 g, 1.096 mmol, 92% yield) as a colourless solid. [α]D22 +13.0 (c 0.715, MeOH). 1H NMR (CD3OD, 300 MHz), δ ppm, 7.90 (s, 1H), 7.37 (s, 1H), 7.31-7.16 (m, 5H), 3.97-3.78 (m, 3H), 3.69 (d, 1H, J 13.8 Hz), 3.63 (d, 1H, J 13.8 Hz), 3.50 (dd, 1H, J 11.2, 4.8 Hz), 3.42 (dd, 1H, J 11.2, 5.7 Hz), 2.60 (d, 2H, J 6.4 Hz). 13C NMR (CD3OD, 75.5 MHz), δ ppm, 156.1 (C), 145.5 (C), 142.5 (CH), 140.2 (C), 130.2 (CH), 129.4 (CH), 129.2 (CH), 128.1 (CH), 119.3 (C), 115.0 (C), 70.6 (CH), 66.3 (CH2), 60.0 (CH2), 57.6 (CH2), 49.0 (CH2). +ESMS Found 329.1600 C17H21N4O3 (M+H)+ requires 329.1614.
Reaction SMILES: OC1C2N=NNC=2C=CC=1.C(N=C=NC(C)C)(C)C.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=1)[C:25]([OH:27])=O.[CH3:31][C:32]1[C:36]([NH2:37])=[C:35]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[NH:34][N:33]=1>CN(C)C=O.O>[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=1)[C:25]([NH:37][C:36]1[C:32]([CH3:31])=[N:33][NH:34][C:35]=1[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:27]
Reactant: Cc1n[nH]c(-c2ccccc2)c1N
Reactant: COc1cccc(C(=O)O)c1
Agent: CC(C)N=C=NC(C)C
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Solvent: O
Product: COc1cccc(C(=O)Nc2c(C)n[nH]c2-c2ccccc2)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
311 mg of hydroxybenzotriazole and 445 μl of diisopropylcarbodiimide were added to a solution of 160 mg of 3-methoxybenzoic acid in 10 ml of dimethylformamide, after which 200 mg of 3-methyl-5-phenyl-1H-pyrazol-4-ylamine were added; the mixture was then stirred at RT for 12 h, after which water was added and the whole was extracted with methylene chloride. The organic phase was dried over magnesium sulfate, concentrated under reduced pressure and purified by means of HPLC (Merk-Hibar-Lichrospher 100-RP-18, water (0.1% trifluoroacetic acid)/acetonitrile (0.1% trifluoroacetic acid)=80/20→10/90). The following was obtained: 4 C17H15N3O2 (293.33); MS (ESI) 294 (M+H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:5]=1[NH2:6])[CH3:2].[C:14]1(=O)[O:19][C:17](=[O:18])[C:16]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:15]12.O>C(O)(=O)C>[CH2:1]([O:3][C:4]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:5]=1[N:6]1[C:17](=[O:18])[C:16]2[C:15](=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:14]1=[O:19])[CH3:2]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: CCOc1cc([N+](=O)[O-])ccc1N
Solvent: O
Solvent: CC(=O)O
Product: CCOc1cc([N+](=O)[O-])ccc1N1C(=O)c2ccccc2C1=O
Yield: 83.6 %

Procedure:
A stirred mixture of 15.0 g (10.1 mole) of 2-ethoxy-4-nitroaniline and 13.4 g (0.09 mole) of phthalic anhydride in 100 ml of glacial acetic acid was heated at reflux for approximately 18 hours. The reaction mixture was cooled then poured into 700 ml of water to produce a solid which was collected by filtration. The solid was dissolved in methylene chloride, and the resultant solution washed first with an aqueous 10% potassium carbonate solution followed by an aqueous sodium chloride solution. The washed organic solution was dried over anhydrous sodium sulfate, filtered, and the filtrate evaporated under reduced pressure to yield 23.5 g of 2-(2-ethoxy-4-nitrophenyl)-1H-isoindol-1,3-(2H)-dione as a solid (mp 204°-206° C.).
Reaction SMILES: C(OCC1C(N2CCC3C4CCCCC=4SC=3C2=O)=CC(F)=CC=1[B:27]1[O:31][C:30]([CH3:33])([CH3:32])[C:29]([CH3:35])([CH3:34])[O:28]1)(=O)C.[C:36]([O:39][CH2:40][C:41]1[C:46]([N:47]2[CH2:58][CH2:57][N:56]3[C:49](=[CH:50][C:51]4[CH2:52][C:53]([CH3:60])([CH3:59])[CH2:54][C:55]=43)[C:48]2=[O:61])=[CH:45][C:44]([F:62])=[CH:43][C:42]=1Br)(=[O:38])[CH3:37].CC1(C)C(C)(C)OB(B2OC(C)(C)C(C)(C)O2)O1.C([O-])(=O)C.[K+].C(Cl)Cl>C1(P([C-]2C=CC=C2)C2C=CC=CC=2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].O1CCOCC1>[C:36]([O:39][CH2:40][C:41]1[C:46]([N:47]2[CH2:58][CH2:57][N:56]3[C:49](=[CH:50][C:51]4[CH2:52][C:53]([CH3:60])([CH3:59])[CH2:54][C:55]=43)[C:48]2=[O:61])=[CH:45][C:44]([F:62])=[CH:43][C:42]=1[B:27]1[O:31][C:30]([CH3:33])([CH3:32])[C:29]([CH3:35])([CH3:34])[O:28]1)(=[O:38])[CH3:37]
Reactant: CC(=O)OCc1c(Br)cc(F)cc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cc(F)cc1N1CCc2c(sc3c2CCCC3)C1=O
Agent: [Fe+2]
Agent: CC(=O)[O-]
Agent: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cc(F)cc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Temperature: 100 °C

Procedure:
Compound 110g was synthesized using the same procedure as 103g, except using 110f (450 mg, 1.0 mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (635 mg, 2.5 mmol), potassium acetate (393 mg, 4.0 mmol), bis(diphenylphosphino)-ferrocene]dichloropalladium(II) complex with CH2Cl2 (Pd Cl2dppf:CH2Cl2 (1:1), 66 mg, 0.08 mmol) and 1,4-dioxane (20 mL). The reaction mixture was heated at 100° C. for 5 h. The reaction mixture was cooled to room temperature and filtered through a pad of Celite 521. The filter cake was washed with Ethyl Acetate (2×25 mL), and the combined filtrates were concentrated to dryness under reduced pressure to afford 110g (quantitative yield) as black oil, which was used directly for the next step. MS (ESI+) m/z 497.3 (M+H).
Reaction SMILES: [C:1]1(=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Br.[NH2:9][CH:10]1[CH2:19][CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([OH:21])[C:16]=2[OH:20])[C:11]1=[O:22]>C(O)C>[C:1]1(=[N:9][CH:10]2[CH2:19][CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([OH:21])[C:16]=3[OH:20])[C:11]2=[O:22])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC1CCc2c(ccc(O)c2O)C1=O
Reactant: O=C1CCCCC1
Agent: Br
Solvent: CCO
Product: O=C1c2ccc(O)c(O)c2CCC1N=C1CCCCC1

Procedure:
In a mixture of 50 volume parts of cyclohexanone and 200 volume parts of ethanol is dissolved 0.151 part of 2-amino-5,6-dihydroxy-3,4-dihydro-1(2H)-naphthalenone hydrobromide to produce 2-cyclohexylideneamino-5,6-dihydroxy-3,4-dihydro-1(2H)-naphthalenone.
Reaction SMILES: [CH:1]1([N:6]2[C:14]3[CH:13]=[CH:12][N:11]=[C:10]([O:15]C)[C:9]=3[C:8]([C:17]3[CH:18]=[C:19]([C:22]([O:24][CH3:25])=[O:23])[S:20][CH:21]=3)=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[I-].[Na+].Cl[Si](C)(C)C.O>C(#N)C>[CH:1]1([N:6]2[C:14]3[CH:13]=[CH:12][NH:11][C:10](=[O:15])[C:9]=3[C:8]([C:17]3[CH:18]=[C:19]([C:22]([O:24][CH3:25])=[O:23])[S:20][CH:21]=3)=[N:7]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COC(=O)c1cc(-c2nn(C3CCCC3)c3ccnc(OC)c23)cs1
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: COC(=O)c1cc(-c2nn(C3CCCC3)c3cc[nH]c(=O)c23)cs1
Temperature: 60 °C
Reaction time: 0.33 h
Yield: 91.3 %

Procedure:
To a solution of methyl 4-(1-cyclopentyl-4-methoxy-1H-pyrazolo[4,3-c]pyridin-3-yl)thiophene-2-carboxylate (122 mg) in acetonitrile (20 mL) were added sodium iodide (102 mg) and chloro(trimethyl)silane (297 mg), and the mixture was stirred at 60° C. for 20 min. To the reaction mixture was added water, and the mixture was concentrated under reduced pressure to evaporate the acetonitrile. The precipitate in the remaining aqueous solution was collected by filtration to give the title compound (107 mg).
Reaction SMILES: [BH4-].[Na+].[CH3:3][C:4]([N+:21]([O-])=O)([CH3:20])[CH2:5][C:6]1[CH:19]=[CH:18][C:9]([O:10][C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)=[CH:8][CH:7]=1.[BH4-].[Na+]>CO>[CH3:20][C:4]([NH2:21])([CH3:3])[CH2:5][C:6]1[CH:7]=[CH:8][C:9]([O:10][C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)=[CH:18][CH:19]=1
Reactant: CC(C)(Cc1ccc(Oc2ccc(O)cc2)cc1)[N+](=O)[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(N)Cc1ccc(Oc2ccc(O)cc2)cc1
Temperature: 25 °C

Procedure:
A mixture of NiCl2.6H2O (1.40 g, 5.9 mmol) in MeOH (100 mL) was stirred at RT under a nitrogen atmosphere. Sodium borohydride (0.675 g, 17.9 mmol) was carefully added to the mixture in small portions. Twenty minutes after complete addition of the initial sodium borohydride 4-(4-(2-methyl-2-nitropropyl)phenoxy)phenol (3.20 g, 11 ntnol) was added followed by the careful portionwise addition of Inore NaBH4 (1.58 g, 42 mmol) which caused a frothing exothermic reaction. All starting nitro compound had been consumed within 15 minutes of the last hydride addition as judged by TLC analysis. The mixture was then filtered through Celite and the filtrate concentrated in vacuo. The resulting residue was chromatographed over silica gel (MeOH/CHCl3) which allowed for isolation of both the incompletely reduced hydroxylamine product (0.675 g, 22%) and the desired amine product (0.94 g, 34%). MS (FD+): 258 (amine)
Reaction SMILES: [C:1]([C:4]1[C:5]([F:19])=[C:6]2[O:10][C:9]([CH:11]3[CH2:13][CH2:12]3)=[N:8][C:7]2=[C:14]([C:17]#[N:18])[C:15]=1[CH3:16])(=O)[CH3:2].[C:20](OCC)(=O)C>O1CCCC1.[Zn].[Ti](Cl)(Cl)(Cl)Cl>[CH:11]1([C:9]2[O:10][C:6]3[C:7](=[C:14]([C:17]#[N:18])[C:15]([CH3:16])=[C:4]([C:1]([CH3:20])=[CH2:2])[C:5]=3[F:19])[N:8]=2)[CH2:13][CH2:12]1
Reactant: CCOC(C)=O
Reactant: CC(=O)c1c(C)c(C#N)c2nc(C3CC3)oc2c1F
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [Zn]
Solvent: C1CCOC1
Product: C=C(C)c1c(C)c(C#N)c2nc(C3CC3)oc2c1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 17 %

Procedure:
Under nitrogen atmosphere, zinc (520 mg, 0.79 mmol) was suspended in tetrahydrofuran (8 ml), then diiodomethyl (320 μl, 3.97 mmol) was added to the suspension, followed by stirring at room temperature for 30 minutes. The reaction liquid was cooled to 0° C. then titanium tetrachloride (794 μl 0794 mmol) was dropwise added, followed by stirring at room temperature for 30 minutes. After 30 minutes, 6-acetyl-2-cyclopropyl-7-fluoro-5-methyl-1,3-benzoxazole-4-carbonitrile (I-82) (205 mg, 0-794 mmol) dissolved in tetrahydrofuran (2 ml) was dropwise added to the reaction liquid, followed by stirring at room temperature for 30 minutes. Ethyl acetate was added to the reaction liquid, followed by washing with 1 N hydrochloric acid and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, then the solvent was evaporated away under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent, ethyl acetate:n-hexane=4:1, v/v) to obtain the entitled compound (35 mg, 17%) as a white crystal.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([S:12](Cl)(=[O:14])=[O:13])[CH:7]=1.[C:17]1([CH2:27][NH2:28])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1.C([O-])(O)=O.[Na+]>O1CCOCC1.O>[CH3:1][O:2][C:3](=[O:16])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([S:12](=[O:14])(=[O:13])[NH:28][CH2:27][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=[CH:19][CH:18]=2)[CH:7]=1
Reactant: NCc1cccc2ccccc12
Reactant: COC(=O)C=Cc1cccc(S(=O)(=O)Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)C=Cc1cccc(S(=O)(=O)NCc2cccc3ccccc23)c1
Yield: 75.4 %

Procedure:
A solution of 3-(3-chlorosulfonylphenyl)acrylic acid methyl ester (3) (0.4 g, 1.53 mmol) in dioxane (5 ml) was added to a mixture of 1-naphthalenemethylamine (0.24 g, 1.53 mmol) in dioxane (1 ml) and NaHCO3 (0.25 g, 3.06 mmol) in water (3 ml), and the resultant solution was stirred at room temperature until the completion of the reaction (control by TLC). The reaction mixture was evaporated and the residue was partitioned between ethyl acetate and 2N HCl. The organic layer was washed successively with water, saturated NaCl, and dried (Na2SO4). The solvent was removed and the residue was chromatographed on silica gel with petroleum ether-ethyl acetate (2:1, v/v) as eluent. The obtained product was washed with diethyl ether to give the title compound (0.44 g, 76%) as a white solid. 1H NMR (DMSO-d6, HMDSO), δ: 3.74 (3H, s); 4.47 (2H, d, J=6.0 Hz); 6.69 (1H, d, J=16.0 Hz); 7.32-8.32 (13H, m).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1.Br[CH2:21][C:22]1[CH:35]=[CH:34][C:25]2[N:26]=[C:27]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[O:28][C:24]=2[CH:23]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([O:19][CH2:21][C:22]2[CH:35]=[CH:34][C:25]3[N:26]=[C:27]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[O:28][C:24]=3[CH:23]=2)=[CH:17][CH:18]=1
Reactant: CCOC(=O)c1nc2ccc(CBr)cc2o1
Reactant: Oc1ccc(OCc2ccc3ccccc3n2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1nc2ccc(COc3ccc(OCc4ccc5ccccc5n4)cc3)cc2o1
Temperature: 70 °C

Procedure:
0.8 g of 4-(2-quinolinylmethyloxy)phenol, 0.89 g of ethyl 6-bromomethylbenzoxazole-2-carboxylate and 0.44 g of potassium carbonate are combined in 15 ml of dimethylformamide and heated at 70° C. for 18 hours. The mixture is poured into water and the aqueous mixture extracted with ethyl acetate. The organic solution is dried and evaporated and the resulting crude product is purified by column chromatography on silica gel to give ethyl 6-(4-(quinolin-2-ylmethyloxy)phenoxymethyl)-benzoxazole-2carboxylate.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][N:7]=[C:6]([N:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][CH2:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:17])[CH2:12][CH2:11]2)[CH:5]=1)([O-])=O.[H][H]>CO.[OH-].[Pd+2].[OH-].[C]>[NH2:1][C:4]1[CH:9]=[CH:8][N:7]=[C:6]([N:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][CH2:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:17])[CH2:12][CH2:11]2)[CH:5]=1
Reactant: CC(C)(C)COC(=O)N1CCN(c2cc([N+](=O)[O-])ccn2)CC1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)COC(=O)N1CCN(c2cc(N)ccn2)CC1
Yield: 11 %

Procedure:
2,2-Dimethylpropyl 4-(4-nitropyridin-2-yl)-1-piperazinecarboxylate (482 mg) obtained in Example 8 was dissolved in methanol (10 mL), and a catalytic amount of palladium hydroxide-carbon was added thereto, stirred in a hydrogen atmosphere at room temperature for 2 hours, and the reaction liquid was filtered. The filtrate was evaporated, and the resulting residue was isolated and purified through thin-layer silica gel chromatography (chloroform/methanol=19/1) to obtain 48 mg of the entitled compound as an oil.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][N:6]1[C:10]2[CH2:11][N:12]=[C:13]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:14]3[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=3[C:9]=2[CH:8]=[N:7]1)C.[NH3:28]>>[Cl:20][C:18]1[CH:17]=[CH:16][C:15]2[C:9]3[CH:8]=[N:7][N:6]([CH2:5][C:4]([NH2:28])=[O:3])[C:10]=3[CH2:11][N:12]=[C:13]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:14]=2[CH:19]=1
Reactant: CCOC(=O)Cn1ncc2c1CN=C(c1ccccc1)c1cc(Cl)ccc1-2
Reactant: N
Product: NC(=O)Cn1ncc2c1CN=C(c1ccccc1)c1cc(Cl)ccc1-2

Procedure:
A mixture of 0.4 g (1.05 mmol) of 8-chloro-6-phenyl-3H,4H-pyrazolo[3,4-d][2]benzazepine-3-acetic acid ethyl ester and 20 ml of methanolic ammonia (ca 20% v/v) was heated in an autoclave on the steam bath overnight. The solvent was evaporated and the residue was purified by chromatography over 15 g of silica gel using 5% (v/v) of ethanol in methylene chloride. Crystallization from ethyl acetate/ether gave colorless crystals with mp 218°-219°.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([CH2:9]O)=[CH:5][CH:4]=1.S(Cl)([Cl:13])=O.C1(C)C=CC=CC=1.[OH-].[Na+]>CN(C)C=O>[Cl:13][CH2:9][C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[N:8][CH:7]=1
Reactant: COc1ccc(CO)cn1
Reactant: O=S(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: COc1ccc(CCl)cn1
Reaction time: 1 h
Yield: 101.7 %

Procedure:
To a solution of (6-methoxypyridin-3-yl)methanol (2) (537.8 g, 3.86 mol) obtained in Preparation Example 1 in dimethylformamide (1.6 L) was added dropwise thionyl chloride (310 mL, 4.25 mol) over a period of 1.3 hours while cooling in an ice bath under a nitrogen atmosphere. After stirring for 1 hour while cooling in an ice bath, toluene (5.4 L) and a 2N aqueous solution of sodium hydroxide (5.4 L) were added successively to the reaction mixture at 23° C. or below. The reaction mixture was stirred for about 10 minutes and then the aqueous layer was separated, the organic layer was washed with water (2.7 L). The organic layer was concentrated under reduced pressure to dryness, and then toluene (1.0 L) was added to the residue and azeotropic distillation was carried out to give 618.8 g of the title compound as a pale yellow oil (content 556.3 g, yield 91.4%).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9](Cl)=[O:10])[CH:4]=1.[NH3:12]>>[Cl:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]([NH2:12])=[O:10])[CH:4]=1
Reactant: N
Reactant: O=C(Cl)c1cc(Cl)ccn1
Agent: Cl
Product: NC(=O)c1cc(Cl)ccn1

Procedure:
Entry 43: 4-Chloropyridine-2-carbonyl chloride HCl salt was reacted with ammonia according to Method A2, Step 3b to form 4-chloro-2-pyridinecarboxamide. 4-Chloro-2-pyridinecarboxamide was reacted with 4-aminophenol according to Method A2, Step 4 to form 4-(2-carbamoyl-4-pyridyloxy)aniline. According to Method C1a, 4-chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(2-carbamoyl-4-pyridyloxy)aniline to afford the urea.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:16]([O:18][C@@H:19]([CH:25]([CH3:27])[CH3:26])[C:20]([O:22][CH2:23]Cl)=[O:21])=[O:17])[CH:13]([CH3:15])[CH3:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I-:28]>>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:16]([O:18][C@@H:19]([CH:25]([CH3:27])[CH3:26])[C:20]([O:22][CH2:23][I:28])=[O:21])=[O:17])[CH:13]([CH3:15])[CH3:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O[C@H](C(=O)OCCl)C(C)C
Reactant: [I-]
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O[C@H](C(=O)OCI)C(C)C

Procedure:
Chloromethyl 2-(N-benzyloxycarbonyl-L-valyloxy)-3-methyl-(S)-(+)-butyrate was converted to iodide by the method described in Example A-I-1, step e to give the title compound (3.64 g) practically pure. Rf (2%MeOH/CHCl3) 0.85.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:37])[CH2:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:36])[CH2:21][CH2:22][NH:23][C:24]([C:26]3[NH:27][C:28]4[C:33]([CH:34]=3)=[CH:32][C:31]([Cl:35])=[CH:30][CH:29]=4)=[O:25])=[CH:15][CH:14]=2)[CH2:9][CH2:8]1>C1COCC1.CO.O>[Cl:35][C:31]1[CH:32]=[C:33]2[C:28](=[CH:29][CH:30]=1)[NH:27][C:26]([C:24]([NH:23][CH2:22][CH2:21][C:20]([NH:19][C:16]1[CH:17]=[CH:18][C:13]([C@H:10]3[CH2:11][CH2:12][C@H:7]([CH2:6][C:5]([OH:37])=[O:4])[CH2:8][CH2:9]3)=[CH:14][CH:15]=1)=[O:36])=[O:25])=[CH:34]2
Reactant: COC(=O)C[C@H]1CC[C@H](c2ccc(NC(=O)CCNC(=O)c3cc4cc(Cl)ccc4[nH]3)cc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C(O)C[C@H]1CC[C@H](c2ccc(NC(=O)CCNC(=O)c3cc4cc(Cl)ccc4[nH]3)cc2)CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
NaOH (56.5 mg, 1.4 mmol) was added to trans-[4-(4-{3-[(5-chloro-1H-indole-2-carbonyl)amino]propionylamino}phenyl)cyclohexyl]acetic acid methyl ester (70 mg, 0.14 mmol) dissolved in THF/MeOH/water (20 mL, 3:2:1). The reaction mixture was stirred at 25° C. for 5 hours, concentrated under vacuum, and the residue was acidified with 1M HCl up to pH 2 and extracted with ethyl acetate. The extract was washed with brine and dried with anhydrous sodium sulfate and concentrated under vacuum. The residue was stirred with acetonitrile and filtered. The filtrate was eluted with a gradient of methanol/DCM (5-10%) on a silica gel by a column chromatography and purified to obtain the desired compound (64 mg, 94%) as a white solid.
Reaction SMILES: C[N:2](C)[CH:3]=[CH:4][C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)[N:8]=1)=O.[C:21]1([NH:27]N)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CO>[C:21]1([N:27]2[C:5]([C:7]3[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]4[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=4)[N:8]=3)=[CH:4][CH:3]=[N:2]2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CN(C)C=CC(=O)c1nn(-c2ccncc2)ccc1=O
Reactant: NNc1ccccc1
Solvent: CO
Product: O=c1ccn(-c2ccncc2)nc1-c1ccnn1-c1ccccc1
Yield: 16 %

Procedure:
To a solution of 3-[3-(dimethylamino)prop-2-enoyl]-1-pyridin-4-ylpyridazin-4(1H)-one (crude 158 mg, 0.58 mmol) in 20 mL of methanol was added phenylhydrazine (253 mg, 2.34 mmol). The mixture was refluxed for 4 h and concentrated. The residue was dissolved in dichloromethane (20 mL), washed with 1N HCl aqueous solution and brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by prep-HPLC to give 3-(1-phenyl-1H-pyrazol-5-yl)-1-pyridin-4-ylpyridazin-4(1H)-one (30 mg, 16% for two steps) as a yellow solid.