Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1C2C(=CC(C(OC)=O)=CC=2)C=CC=1C(OC)=O.[C:19]([O:29]C)(=[O:28])[CH2:20][CH2:21][CH2:22][CH2:23][C:24]([O:26]C)=[O:25].[OH:31][C:32]1[CH:37]=[CH:36][C:35]([C:38]([C:41]2[CH:46]=[CH:45][C:44]([OH:47])=[CH:43][CH:42]=2)([CH3:40])[CH3:39])=[CH:34][CH:33]=1.O=[Sb]O[Sb]=O.P(OC)(OC)(OC)=O>C(O)CO.O.O.O.O.C([O-])(=O)C.[Mn+2].C([O-])(=O)C.CO>[C:19]([OH:29])(=[O:28])[CH2:20][CH2:21][CH2:22][CH2:23][C:24]([OH:26])=[O:25].[OH:31][C:32]1[CH:33]=[CH:34][C:35]([C:38]([C:41]2[CH:42]=[CH:43][C:44]([OH:47])=[CH:45][CH:46]=2)([CH3:40])[CH3:39])=[CH:36][CH:37]=1
Reactant: COC(=O)CCCCC(=O)OC
Agent: [Mn+2]
Agent: CC(=O)[O-]
Agent: CC(C)(c1ccc(O)cc1)c1ccc(O)cc1
Solvent: CO
Solvent: COP(=O)(OC)OC
Solvent: O
Product: O=C(O)CCCCC(=O)O

Procedure:
Dimethyl 2,6-naphthalenedicarboxylate and dimethyl adipate were dispersed in ethylene glycol and an addition product of two ethylene oxides to bisphenol A (BPA•2EO). Then, 0.029 part of manganese acetate tetrahydrate, 0.028 parts of antimony trioxide and 0.1% of spherical silica particles having a mean particle size of 0.3 μm were added to 100 parts of the total of dimethyl 2,6-naphthalenedicarboxylate and dimethyl adipate, and heated with stirring to conduct the reaction. The temperature was elevated to 235° C. while removing methanol produced as a by-product. After the by-production of methanol was completed, 0.03 part of trimethyl phosphate was added thereto. Then, the pressure was reduced to 0.3 Torr while elevating the temperature to 285° C. to conduct the polymerization by changing the reaction time. Dyes described in JP-A-7-168309, compounds I-6 and I-24, were each further added to the solid matter in an amount of 54 ppm. The copolymerization composition ratios of adipic acid (AA) and BPA•2EO and the intrinsic viscosities of polyesters thus obtained are shown in Table I-1.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]([OH:16])[CH:10]([N+:13]([O-])=O)[CH2:11][CH3:12].C([O-])=O.[NH4+]>C1COCC1.CO.[Pd].CCOCC>[F:1][C:2]([F:17])([F:18])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]([OH:16])[CH:10]([NH2:13])[CH2:11][CH3:12]
Reactant: CCC(C(O)c1ccccc1C(F)(F)F)[N+](=O)[O-]
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCC(N)C(O)c1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of etythro 1-(2-trifluoromethylphenyl)-2-nitro-butan-1-ol (0.18 g, 0.00068 mole) in THF (5 mL) and methanol (5 mL) was added 10% palladium on carbon (50 mg) followed by ammonium formate (0.21 g, 5 equivalents). The resulting mixture was stirred at room temperature for 1.5 hour then diluted with Et2O, filtered and evaporated in vacuo. Flash column chromatography (SiO2, 2% MeOH in CHCl3) gave erythro 1-(2-trifluoromethylphenyl)-2-amino-butan-1-ol. (0.074 g, 47%), and some starting material (0.035 g).
Reaction SMILES: [H-].[Na+].[CH3:3][S:4][C:5]1[CH:6]=[C:7]([NH:11][C:12](=[O:16])[CH2:13][CH2:14]Cl)[CH:8]=[CH:9][CH:10]=1.C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[CH3:3][S:4][C:5]1[CH:6]=[C:7]([N:11]2[CH2:14][CH2:13][C:12]2=[O:16])[CH:8]=[CH:9][CH:10]=1
Reactant: CSc1cccc(NC(=O)CCCl)c1
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CSc1cccc(N2CCC2=O)c1
Reaction time: 8 h

Procedure:
Sodium hydride (0.1 mole; 57% dispersion in mineral oil) is charged into a glass reaction flask. The mineral oil is removed by washing the sodium hydride with benzene, and dimethyl sulfoxide (50 ml) is thereafter slowly added with stirring. The mixture is stirred until no more hydrogen gas evolves. A solution of N-(3-methylthiophenyl)-β-chloropropionamide (0.08 mole) in carbon tetrachloride (50 ml) is added dropwise to the reaction flask with stirring while maintaining the temperature of the reaction mixture below about 30°C. After the addition is completed the reaction mixture is allowed to stand at room temperature for a period of about 8 hours. After this time benzene is added and the reaction mixture is washed with water and aqueous sodium bicarbonate. The washed mixture is then dried over anhydrous magnesium sulfate, is filtered, and is stripped of solvents under reduced pressure to yield the desired product N-(3-methylthiophenyl)-2-azetidinone as the residue.
Reaction SMILES: C(O[C:4]([C:6]1[C:11](=[O:12])[N:10]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[N:9]2[CH:22]=[CH:23][CH:24]=[C:8]2[C:7]=1[OH:25])=[O:5])C.[NH2:26][CH2:27][C:28]([O-:30])=[O:29].[Na+]>>[CH3:21][O:20][C:17]1[CH:16]=[CH:15][C:14]([CH2:13][N:10]2[C:11](=[O:12])[C:6]([C:4]([NH:26][CH2:27][C:28]([OH:30])=[O:29])=[O:5])=[C:7]([OH:25])[C:8]3=[CH:24][CH:23]=[CH:22][N:9]23)=[CH:19][CH:18]=1
Reactant: CCOC(=O)c1c(O)c2cccn2n(Cc2ccc(OC)cc2)c1=O
Reactant: NCC(=O)[O-]
Agent: [Na+]
Product: COc1ccc(Cn2c(=O)c(C(=O)NCC(=O)O)c(O)c3cccn32)cc1

Procedure:
Prepared according to the glycinolysis condition used in Example 1 step d) from 1-(4-methoxy-benzyl)-4-hydroxy-2-oxo-1,2-dihydro-pyrrolo[1,2-b]pyridazine-3-carboxylic acid ethyl ester (1.0 eq.) and sodium glycinate (15 eq.). ESI (m/z): 372 (M+H)+.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]2[CH:13]=[C:12](B(O)O)[CH:11]=[CH:10][C:8]=2[N:9]=1)(=[O:3])[CH3:2].Br[C:18]1[CH:19]=[C:20]([O:24][CH2:25][CH2:26][N:27]2[CH2:31][CH2:30][CH2:29][C:28]2=[O:32])[CH:21]=[N:22][CH:23]=1.C(=O)([O-])[O-].[Na+].[Na+]>[Pd].O1CCOCC1>[O:32]=[C:28]1[CH2:29][CH2:30][CH2:31][N:27]1[CH2:26][CH2:25][O:24][C:20]1[CH:19]=[C:18]([C:12]2[CH:11]=[CH:10][C:8]3[N:9]=[C:5]([NH:4][C:1](=[O:3])[CH3:2])[S:6][C:7]=3[CH:13]=2)[CH:23]=[N:22][CH:21]=1
Reactant: O=C1CCCN1CCOc1cncc(Br)c1
Reactant: CC(=O)Nc1nc2ccc(B(O)O)cc2s1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(=O)Nc1nc2ccc(-c3cncc(OCCN4CCCC4=O)c3)cc2s1
Reaction time: 0.33 h

Procedure:
To a 5 ml CEM microwave tube was added 2-acetamidobenzo[d]thiazol-6-ylboronic acid (0.1 g, 0.4 mmol), 1-(2-(5-bromopyridin-3-yloxy)ethyl)pyrrolidin-2-one (0.2 g, 0.6 mmol), sodium carbonate (0.6 ml, 1 mmol), Pd FibreCat® (Anchored homogeneous catalyst, Johnson Matthey, West Deptford, N.J. (30% wt, 45 mg), and dioxane (3 mL). The vial was sealed and placed into CEM microwave for 20 min. at 100° C., with 100 watts of power via Powermax®. The reaction mixture was partitioned between EtOAc/water. The aqueous layer was extracted with EtOAc (2×10 mL). The combined organic layers were washed with water, brine, dried over MgSO4 and removed solvent. The crude product was purified using SiO2 chromatography with DCM:MeOH (95%:5%) solvent system to afford the product as white solid. Wt: 45.0 mg. MS (ESI pos. ion) m/z: 397.3. Calc'd exact mass for C20H20N4O3S: 396.46. 1H NMR (300 MHz, chloroform-d) δ ppm 1.99-2.14 (m, 2H) 2.33 (s, 3H) 2.42 (t, J=8.11 Hz, 2H) 3.62 (t, J=7.09 Hz, 2H) 3.74 (t, J=5.19 Hz, 2H) 4.25 (t, J=5.19 Hz, 2H) 7.43 (d, J=2.48 Hz, 1H) 7.62 (dd, J=8.48, 1.90 Hz, 1H) 7.81 (d, J=8.33 Hz, 1H) 7.99 (d, J=1.46 Hz, 1H) 8.27 (d, J=2.63 Hz, 1H) 8.50 (s, 1H).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[C:3]1[CH2:11][O:12][C:13]1[CH:14]=[C:15]([N+:19]([O-])=O)[CH:16]=[CH:17][CH:18]=1>Cl.[Fe]>[CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[C:3]1[CH2:11][O:12][C:13]1[CH:14]=[C:15]([NH2:19])[CH:16]=[CH:17][CH:18]=1
Reactant: Cn1c(COc2cccc([N+](=O)[O-])c2)nc2ccccc21
Agent: [Fe]
Agent: Cl
Product: Cn1c(COc2cccc(N)c2)nc2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.7 %

Procedure:
To a suspension of 3-[(1-methyl-2-benzimidazolyl)methoxy]nitrobenzene (8 g) in ethanolic hydrochloric acid is added powdered iron. The reaction is stirred overnight at room temperature. After neutralization with saturated aqueous sodium bicarbonate, the mixture is extracted three times with methylene chloride. The extract is dried over magnesium sulfate and concentrated to give 7.2 g (100% yield) of product, m.p. 149°-153° C.
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:23]=[CH:22][C:14]3[N:15]([CH2:18][CH:19]4[CH2:21][CH2:20]4)[N:16]=[N:17][C:13]=3[C:12]=2[C:24]([F:27])([F:26])[F:25])=[CH:7][CH:6]=1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)(O)[O-].[Na+].O>O1CCCC1>[CH:19]1([CH2:18][N:15]2[C:14]3[CH:22]=[CH:23][C:11]([C:8]4[CH:7]=[CH:6][C:5]([CH2:4][NH2:1])=[CH:10][CH:9]=4)=[C:12]([C:24]([F:27])([F:26])[F:25])[C:13]=3[N:17]=[N:16]2)[CH2:21][CH2:20]1
Reactant: [N-]=[N+]=NCc1ccc(-c2ccc3c(nnn3CC3CC3)c2C(F)(F)F)cc1
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: NCc1ccc(-c2ccc3c(nnn3CC3CC3)c2C(F)(F)F)cc1
Temperature: 50 °C
Reaction time: 0.08 h

Procedure:
5-[4-(Azidomethyl)phenyl]-1-(cyclopropylmethyl)-4-(trifluoromethyl)-1H-benzotriazole (162 mg, 0.435 mmol) and triphenylphosphine (342 mg, 1.30 mmol, 3 equiv) were combined in tetrahydrofuran (10 mL) at ambient temperature. After stirring for 5 minutes, the mixture was placed into a preheated oil bath at 50° C. for 2 hours. The mixture was treated with sodium bicarbonate (1.5 mL, aqueous saturated) and heated for an additional 1 hour at 50° C. The mixture was cooled to ambient temperature, poured into water (25 mL) and extracted with ethyl acetate (2×50 mL). The combined organic extracts were washed with brine (25 mL), dried with sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel gradient chromatography (100:0 to 80:20; dichloromethane:methanol containing 10% ammonium hydroxide), providing the titled compound as a light green gum.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)=[O:15])[CH:11]=[C:10]([C:21]([O:23]CC)=[O:22])[CH:9]=2)=[CH:4][CH:3]=1.CO.[OH-].[Li+]>O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([N:16]3[CH2:17][CH2:18][CH2:19][CH2:20]3)=[O:15])[CH:11]=[C:10]([C:21]([OH:23])=[O:22])[CH:9]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cc(C(=O)N2CCCC2)cc(-c2ccc(Br)cc2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1cc(C(=O)N2CCCC2)cc(-c2ccc(Br)cc2)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of ethyl 4′-bromo-5-(pyrrolidine-1-carbonyl)biphenyl-3-carboxylate (3.3 g, 8.2 mmol), MeOH (100 mL), water (20 mL), and lithium hydroxide (0.90 g, 38 mmol) was stirred at room temperature for 3 h. The mixture was concentrated in vacuo and the residue was acidified with 1N aq. HCl to pH 2-3 and extracted with EtOAc (2×100 mL). The combined organic layers were dried (Na2SO4) and concentrated to afford a white foam. LC-MS: 376.1 [M+1]+.
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([CH2:12][N:13]3[C:22]4[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=4[C:16]4=[N:23][NH:24][C:25](=[O:26])[C:15]4=[CH:14]3)=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.[H-].[Na+].Br[CH2:30][C:31]1[CH:36]=[CH:35][C:34]([N:37]2[CH:41]=[CH:40][CH:39]=[N:38]2)=[CH:33][CH:32]=1.C(=O)(O)[O-].[Na+]>CN(C)C=O>[N:37]1([C:34]2[CH:35]=[CH:36][C:31]([CH2:30][N:24]3[C:25](=[O:26])[C:15]4=[CH:14][N:13]([CH2:12][C:9]5[CH:10]=[CH:11][C:6]([N:1]6[CH:5]=[CH:4][CH:3]=[N:2]6)=[CH:7][CH:8]=5)[C:22]5[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=5[C:16]4=[N:23]3)=[CH:32][CH:33]=2)[CH:41]=[CH:40][CH:39]=[N:38]1
Reactant: O=c1[nH]nc2c3ccccc3n(Cc3ccc(-n4cccn4)cc3)cc1-2
Reactant: BrCc1ccc(-n2cccn2)cc1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=c1c2cn(Cc3ccc(-n4cccn4)cc3)c3ccccc3c-2nn1Cc1ccc(-n2cccn2)cc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
5-{[4-(1H-Pyrazol-1-yl)phenyl]methyl}-2,5-dihydro-3H-pyrazolo[4,3-c]quinolin-3-one (Example 406, 71 mg, 0.21 mmol) was suspended in degassed N,N-dimethylformamide (3 mL), cooled to 0° C. and sodium hydride (17 mg, 0.42 mmol, 2 equiv, 60% dispersion in mineral oil) was added. After stirring for 10 minutes at 0° C., the mixture was warmed to ambient temperature and stirred for 45 minutes. 1-[4-(Bromomethyl)phenyl]-1H-pyrazole (74 mg, 0.31 mmol, 1.5 equiv) was added, the mixture as stirred for 2 hours and then poured into sodium bicarbonate (30 mL, aqueous saturated) and extracted with ethyl acetate (3×50 mL). The combined organic extracts were dried with sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel gradient chromatography (100:0 to 88:12; dichloromethane:methanol), providing the titled compound: 1H-NMR (400 MHz, d6-DMSO) δ 9.09 (1H, s), 8.45-8.44 (2H, m), 8.15 (1H, d, J=7.8 Hz), 7.82-7.78 (4H, m), 7.75-7.72 (2H, m), 7.57 (1H, t, J=7.8 Hz), 7.48 (1H, t, J=7.7 Hz), 7.45-7.40 (4H, m), 6.52 (2H, s), 5.75 (2H, s), 5.14 (2H, s) ppm; high resolution mass spectrometry (ES+) m/z 498.2063 [(M+H)+; calculated for C30H24N7O: 498.2037].
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[N:8][CH:7]=[CH:6]2)=C.C[OH:14]>C(Cl)Cl>[CH:9]1[C:10]2[C:5](=[CH:4][C:3]([CH:1]=[O:14])=[CH:12][CH:11]=2)[CH:6]=[CH:7][N:8]=1
Reactant: CO
Reactant: C=Cc1ccc2cnccc2c1
Solvent: ClCCl
Product: O=Cc1ccc2cnccc2c1
Temperature: -78 °C
Reaction time: 8 h
Yield: 94 %

Procedure:
To a 150 mL round-bottomed flask was added 6-vinylisoquinoline (2.47 g, 16 mmol) and MeOH (35 mL)/DCM (35 mL). The resulting solution was cooled to −78° C. The reaction was ozonized until a blue color persisted, then nitrogen gas was bubbled through the solution for 15 minutes to purge the ozone. The reaction was then treated with solid sodium bicarbarbonate. (1.5 g) and dimethyl sulfide (3.2 mL, 0.2 mL/mmol of SM) and the mixture was warmed to room temperature and stirred overnight. The reaction mixture was diluted with water (100 mL) and extracted with DCM (3×75 mL). The combined organic layers were dried over Na2SO4, filtered, and the residue product isoquinoline-6-carbaldehyde (2.35 g, 94% yield) was used without further manipulation. LCMS (API-ES) m/z (%): 158.1 (100%, M++H).
Reaction SMILES: [Si]([O:8][C@@H:9]1[CH2:13][C:12](=[O:14])[N:11]([C:15]2[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[C:17]([Cl:23])[CH:16]=2)[C@H:10]1[CH2:24][CH3:25])(C(C)(C)C)(C)C.CO.Cl.C(=O)([O-])O.[Na+]>O1CCCC1>[Cl:23][C:17]1[CH:16]=[C:15]([N:11]2[C:12](=[O:14])[CH2:13][C@@H:9]([OH:8])[C@@H:10]2[CH2:24][CH3:25])[CH:22]=[CH:21][C:18]=1[C:19]#[N:20]
Reactant: CC[C@H]1[C@H](O[Si](C)(C)C(C)(C)C)CC(=O)N1c1ccc(C#N)c(Cl)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CC[C@H]1[C@H](O)CC(=O)N1c1ccc(C#N)c(Cl)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 86.5 %

Procedure:
To a solution of 4-[(2S,3R)-3-(tert-butyldimethylsilyloxy)-2-ethyl-5-oxopyrrolidin-1-yl]-2-chlorobenzonitrile (366 mg) in tetrahydrofuran (5 mL)-methanol (5 mL) was added 6 mol/L hydrochloric acid (5 mL), and the mixture was stirred at room temperature for 18 hr. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent:hexane/ethyl acetate=10/1→1/3) to give the title compound as a colorless solid (yield: 221.2 mg, 87%).
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)=[C:12]([CH3:20])[CH:11]=2)[CH:2]=1.[F:21][C:22]([F:31])([F:30])[C:23]1[CH:24]=[C:25]([CH:27]=[CH:28][CH:29]=1)[NH2:26]>C(Cl)Cl.CO>[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]([NH:26][C:25]3[CH:27]=[CH:28][CH:29]=[C:23]([C:22]([F:21])([F:30])[F:31])[CH:24]=3)=[O:19])=[C:12]([CH3:20])[CH:11]=2)[CH:2]=1
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: Cc1cc(-n2cnc3cccnc32)ccc1CC(=O)O
Solvent: ClCCl
Solvent: CO
Product: Cc1cc(-n2cnc3cccnc32)ccc1CC(=O)Nc1cccc(C(F)(F)F)c1

Procedure:
The title compound is prepared as described in Example 7 but using (4-imidazo[4,5-b]pyridin-3-yl-2-methyl-phenyl)-acetic acid (Step 60.1) and 3-(trifluoromethyl)aniline. Title compound: ES-MS: 411.1 [M+H]+; tR=4.19 min (System 1); Rf=0.28 (CH2Cl2/MeOH, 95:5+0.1% NH3aq).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[N:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:12]([O:14]CC)=O.Cl.[NH:18]([C:20]1[N:25]=[CH:24][CH:23]=[CH:22][N:21]=1)[NH2:19]>C(O)CCC>[ClH:1].[N:21]1[CH:22]=[CH:23][CH:24]=[N:25][C:20]=1[N:18]1[C:12](=[O:14])[C:3]2=[CH:4][NH:5][C:6]3[CH:7]=[CH:8][N:9]=[CH:10][C:11]=3[C:2]2=[N:19]1
Reactant: CCOC(=O)c1cnc2ccncc2c1Cl
Reactant: NNc1ncccn1
Agent: Cl
Solvent: CCCCO
Product: O=c1c2c[nH]c3ccncc3c-2nn1-c1ncccn1
Temperature: 25 °C

Procedure:
A solution of 1.75 g of ethyl 4-chloro-1,6-naphthyridine-3-carboxylate and 1.17 g of 2-hydrazinopyrimidine hydrochloride (prepared according to Yakugakuzasshi, 1953, 73, 598) in 60 ml of n-butanol is refluxed for 3 hours. The resultant slurry is cooled to room temperature and filtered. Collected solid is washed with ethanol, then with ether to yield 2-(2-pyrimidyl)pyrazolo[4,3-c][1,6]naphthyridin-3(5H)-one hydrochloride, m.p. above 350°; IR (KBr) 782, 791, 820, 830, 871 cm-1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8](=O)[CH2:9][CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]3[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=3)[CH2:15][CH2:14]2)[CH:5]=[CH:6][CH:7]=1.[C:32]1([NH:38]N)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[NH:38][C:32]3[C:37]([C:9]=2[CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]4[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=4)[CH2:15][CH2:14]2)=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3cccc(Cl)c3)CC2)c1
Reactant: NNc1ccccc1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCc3c(-c4cccc(Cl)c4)[nH]c4ccccc34)CC2)c1

Procedure:
Prepared by Procedure E and Scheme M using N-(3-{1-[5-(3-chlorophenyl)-5-oxopentyl]-4-piperidinyl}phenyl)-2-methylpropanamide and phenylhydrazine: ESMS m/e: 514.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:17]=[C:16](Cl)[C:15]3[C:10](=[C:11]([O:23][CH3:24])[C:12]([O:21][CH3:22])=[C:13]([O:19][CH3:20])[CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1.[CH2:25]([N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:17]=[C:16]([N:35]3[CH2:36][CH2:37][N:32]([CH2:25][C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH2:33][CH2:34]3)[C:15]3[C:10](=[C:11]([O:23][CH3:24])[C:12]([O:21][CH3:22])=[C:13]([O:19][CH3:20])[CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1
Reactant: COc1cc2c(Cl)nc(-c3ccc(Cl)cc3)nc2c(OC)c1OC
Reactant: c1ccc(CN2CCNCC2)cc1
Product: COc1cc2c(N3CCN(Cc4ccccc4)CC3)nc(-c3ccc(Cl)cc3)nc2c(OC)c1OC
Temperature: 150 °C

Procedure:
A mixture of 2.0 g of 2-(4-chlorophenyl)-4-chloro-6,7,8-trimethoxyquinazoline and 5.0 g of N-benzylpiperazine was heated at 150° C. for 1 h. After cooling, 20 ml of ice water were added and the mixture was extracted with ethyl acetate. The organic phase was dried over sodium sulfate and concentrated. The oily crude product thus obtained was recrystallized from isopropanol. Yield: 1 g. M.p.: 150° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1([C:11]2[O:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH3:17][N:18](C=O)C>CC#N.C([O-])(O)=O.[Na+]>[C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1([C:11]2[O:12][C:13]([C:17]#[N:18])=[CH:14][CH:15]=2)[CH2:9][CH2:10]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C)C=O
Reactant: CC(C)(C)OC(=O)NC1(c2ccco2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)NC1(c2ccc(C#N)o2)CC1
Temperature: -40 °C
Reaction time: 0.75 h

Procedure:
(1-Furan-2-yl-cyclopropyl)-carbamic acid tert-butyl ester (765 mg, 3.43 mmol) was dissolved in MeCN (7.7 mL) and cooled to −40° C. in an acetone/dry ice bath. Chloroulfonyl isocyante (0.45 mL, 5.1 mmol) was added in one portion via syringe and the reaction was allowed to stir at a temperature between −40 and −30° C. for 45 min. Anhydrous DMF (1.2 mL) was then added and stirring continued at room temperature for 30 min. The reaction was diluted with saturated aqueous NaHCO3 (100 ml) and extracted with EtOAc (3×50 mL). The combined organic layers were concentrated to a red liquid and chromatographed (silica, 5→25% EtOAc/hexanes) to give 400 mg of the title compound as a white solid, m/z 234.35 [M-t-Bu+MeCN]+.
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[C:7]([C:23]#[N:24])[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:9]=2)=[O:4].Cl.[NH2:26][CH2:27][C:28]([CH3:34])([CH3:33])[CH2:29][C:30]([OH:32])=[O:31]>C[O-].[Na+].CO>[C:23]([C:7]1[C:8]2[C:13](=[CH:12][CH:11]=[C:10]([O:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:9]=2)[C:14]([OH:15])=[C:5]([C:3]([NH:26][CH2:27][C:28]([CH3:34])([CH3:33])[CH2:29][C:30]([OH:32])=[O:31])=[O:4])[N:6]=1)#[N:24]
Reactant: CC(C)(CN)CC(=O)O
Reactant: COC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CC(C)(CNC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O)CC(=O)O
Yield: 7.7 %

Procedure:
A mixture of 1-cyano-4-hydroxy-7-phenoxy-isoquinoline-3-carboxylic acid methyl ester (70 mg, 0.22 mmol) and 4-amino-3,3-dimethyl-butyric acid HCl salt (110 mg, 0.66 mmol) (Oakwood Products) in 0.5 M NaOMe/MeOH (2.62 mL, 1.3 μmol) was microwaved at 120° C. for 1 h. Reaction mixture was concentrated and residue was dissolved in water (50 mL), It was acidified by 1 N HCl to pH=3-4 and extracted with EtOAc. Organic layer was washed with brine, dried over MgSO4, filtered and concentrated. Crude product was purified by chromatography, eluting with 50-100% EtOAc/hexanes to provide the title compound 7.2 mg (0.017 mmol) in 7.8% yield. LC-MS ESI−: 417.95 (M-1)−.
Reaction SMILES: O.[NH2:2][NH2:3].Cl[C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][N:6]=1>C(O)C>[NH:2]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][N:6]=1)[NH2:3]
Reactant: NN
Reactant: O=C(O)c1ccc(Cl)nc1
Solvent: CCO
Solvent: O
Product: NNc1ccc(C(=O)O)cn1
Yield: 71 %

Procedure:
Hydrazine monohydrate (101 g) was added to a solution of 6-chloronicotinic acid (20 g) in ethanol (20 ml) at room temperature and stirred under reflux. After completion of the reaction, the solvent was evaporated, ethanol was added and the solid was collected by filtration to give 6-hydrazinonicotinic acid (13.8 g).
Reaction SMILES: CO[C:3](=[O:13])[C:4]1[CH:9]=[C:8]([Br:10])[C:7]([O:11][CH3:12])=[N:6][CH:5]=1.Cl.[CH3:15][O:16][C:17]([C:19]1([NH2:28])[CH2:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20]1)=[O:18]>>[CH3:15][O:16][C:17]([C:19]1([NH:28][C:3]([C:4]2[CH:5]=[N:6][C:7]([O:11][CH3:12])=[C:8]([Br:10])[CH:9]=2)=[O:13])[CH2:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20]1)=[O:18]
Reactant: COC(=O)C1(N)Cc2ccccc2C1
Reactant: COC(=O)c1cnc(OC)c(Br)c1
Agent: Cl
Product: COC(=O)C1(NC(=O)c2cnc(OC)c(Br)c2)Cc2ccccc2C1

Procedure:
5-Bromo-6-methoxy-nicotinic acid methyl ester (W. J. Thompson and J. Gaudino, J. Org. Chem. 49 (1984), 5237-5243) (2.00 g, 8.13 mmol) was hydrolyzed in analogy to example 2. The obtained acid was reacted with 2-amino-indane-2-carboxylic acid methyl ester hydrochloride in analogy to step 2 of example 13.
Reaction SMILES: Cl[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[CH2:12]([O:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[OH-].[K+].C(OCC)(=O)C>CN(C)C=O>[CH2:12]([O:19][C:20]1[CH:21]=[CH:22][C:23]([O:26][C:2]2[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=2[N+:9]([O-:11])=[O:10])=[CH:24][CH:25]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: Oc1ccc(OCc2ccccc2)cc1
Reactant: Nc1ccc(Cl)c([N+](=O)[O-])c1
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Nc1ccc(Oc2ccc(OCc3ccccc3)cc2)c([N+](=O)[O-])c1
Temperature: 0 °C
Yield: 55.1 %

Procedure:
A solution of 4-chloro-3-nitro aniline (2.0 g, 11.16 mmol), 4-benzyloxyphenol (2.55 g, 12.76 mmol), powdered potassium hydroxide (0.94 g, 16.80 mmol) in dimethylformamide (15 ml) was heated at 120° C. for 20 hours. Afterwards ice water (50 mL) was added to the solution and the resultant slurry was treated with ethyl acetate (100 ml). The layers were separated and the organic layer was washed with 10% sodium bicarbonate and 10% sodium chloride, then dried over anhydrous sodium sulfate. The drying agent was filtered and solvent was removed under vacuum leaving a dark red solid as the title compound, (2.07 g, 53%).