Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Cl[C:16]1[CH:21]=[CH:20][N:19]=[CH:18][C:17]=1[N+:22]([O-:24])=[O:23].O>CN(C=O)C>[CH3:8][C:5]1[N:4]=[CH:3][C:2]([O:1][C:16]2[CH:21]=[CH:20][N:19]=[CH:18][C:17]=2[N+:22]([O-:24])=[O:23])=[CH:7][CH:6]=1
Reactant: O=[N+]([O-])c1cnccc1Cl
Reactant: Cc1ccc(O)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(Oc2ccncc2[N+](=O)[O-])cn1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 99.2 %

Procedure:
To a solution of 3-hydroxy-6-methylpyridine (1.0 g, 9.16 mmol) in DMF (5 ml) at room temperature was added potassium carbonate (2.53 g, 18.32 mmol) in DMF (10 mL) and the mixture was stirred at room temperature for 15 min. Then, 4-chloro-3-nitropyridine (1.45 g, 9.16 mmol) was added and the resulting solution was stirred at room temperature for 2 h. The mixture was poured into water and extracted with EtOAc. The organic layer was washed with water and brine, dried (MgSO4), filtered and evaporated. 4-(6-Methylpyridin-3-yloxy)-3-nitropyridine (2.1 g, 100%) was obtained as an orange oil, which precipitated on standing, mp 87-90° C., and was used in the next step without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:16][S:17](Cl)(=[O:19])=[O:18]>C(Cl)Cl>[CH3:16][S:17]([O:15][C:12]1[CH:11]=[CH:10][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:14][CH:13]=1)(=[O:19])=[O:18]
Reactant: Oc1ccc(OCc2ccccc2)cc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Product: CS(=O)(=O)Oc1ccc(OCc2ccccc2)cc1
Yield: 95.7 %

Procedure:
4-(Benzyloxy)phenol (4.00 g, 19.98 mmol) was dissolved in dry DCM (80 mL) under nitrogen atmosphere and cooled in an ice-water bath. Methanesulfonyl chloride (2.75 g, 23.97 mmol) was added during stirring followed by TEA (3.03 g, 29.96 mmol). The reaction mixture was stirred at rt for 2 h and then washed with saturated aqueous NaHCO3, dried (MgSO4), filtered and evaporated affording the title compound (5.32 g, 95.6%). 1H NMR (500 MHz, CDCl3): δ 3.13 (s, 3H), 5.08 (s, 2H), 7.01 (m, 2H), 7.23 (m, 2H), 7.35-7.45 (m, 5H).
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([C:10]([OH:12])=O)[C:4]=2[CH:3]=[CH:2]1.[NH2:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[NH:1]1[C:9]2[C:4](=[C:5]([C:10](=[O:12])[NH:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: O=C(O)c1cccc2[nH]ccc12
Reactant: CC(C)(C)OC(=O)CCOCCOCCOCCN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CCOCCOCCOCCNC(=O)c1cccc2[nH]ccc12
Reaction time: 16 h

Procedure:
To a mixture of 1H-indole-4-carboxylic acid (322 mg, 2.00 mmol), tert-butyl 3-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)propanoate (554 mg, 2.00 mmol), and diisporopylethylamine (700 μL, 4.00 mmol) in DMF (3 mL) was added HATU (950 mg, 2.50 mmol) and the solutions stirred for 16 h. The solvent was removed and the resulting residue was purified by silica gel chromatography, using a gradient of 70% to 100% EtOAc in hexanes as eluent and the solvent removed. This gave 557 mg (66%) of the product.
Reaction SMILES: C(=O)(O)O.[NH2:5][C:6]([NH2:8])=[NH:7].C[O-].[Na+].[Cl:12][C:13]1[CH:35]=[CH:34][C:16]2[C:17](=O)[C:18](=[CH:29]N(C)C)[CH2:19][N:20]=[C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[Cl:28])[C:15]=2[CH:14]=1>CO.O>[NH2:7][C:6]1[N:8]=[CH:29][C:18]2[CH2:19][N:20]=[C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[Cl:28])[C:15]3[CH:14]=[C:13]([Cl:12])[CH:35]=[CH:34][C:16]=3[C:17]=2[N:5]=1
Reactant: N=C(N)N
Reactant: CN(C)C=C1CN=C(c2ccccc2Cl)c2cc(Cl)ccc2C1=O
Agent: C[O-]
Agent: O=C(O)O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Nc1ncc2c(n1)-c1ccc(Cl)cc1C(c1ccccc1Cl)=NC2

Procedure:
In two equal portions 14.4 g (80 mmole) of guanidine carbonate and 20 ml (82 mmole) of 4.12 M methanol solution of sodium methoxide was added over 90 min to a solution of 3.6 g (10 mmole) of 8-chloro-1-(2-chlorophenyl)-3,4-dihydro-4-[(dimethylamino)methylene]-5H-2-benzazepine-5-one in 100 ml of methanol. The mixture was diluted with water and extracted with methylene chloride. The methylene chloride solution was dried over anhydrous sodium sulfate and concentrated at reduced pressure to give a yellow oil. Crystallization of the oil with methylene chloride gave a white solid, mp 240°-241° C. Recrystallization from a mixture of ether and methylene chloride gave colorless needles, mp 240°-241° C.
Reaction SMILES: [CH:1]1([N:4]([CH3:27])[C:5]2[C:6](OS(C(F)(F)F)(=O)=O)=[N:7][C:8]3[C:13]([N:14]=2)=[CH:12][C:11]([C:15]([O:17][CH3:18])=[O:16])=[CH:10][CH:9]=3)[CH2:3][CH2:2]1.[O:28]1[C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=2[CH:30]=[C:29]1B(O)O.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.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>[O:28]1[C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=2[CH:30]=[C:29]1[C:6]1[C:5]([N:4]([CH:1]2[CH2:3][CH2:2]2)[CH3:27])=[N:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:15]([O:17][CH3:18])=[O:16])[CH:12]=2)[N:7]=1
Reactant: OB(O)c1cc2ccccc2o1
Reactant: COC(=O)c1ccc2nc(OS(=O)(=O)C(F)(F)F)c(N(C)C3CC3)nc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1ccc2nc(-c3cc4ccccc4o3)c(N(C)C3CC3)nc2c1
Temperature: 90 °C
Reaction time: 1 h

Procedure:
To a solution of methyl 3-(cyclopropyl(methyl)amino)-2-(trifluoromethylsulfonyloxy)quinoxaline-6-carboxylate (180.0 mg, crude) in dioxane (6 mL) was added benzofuran-2-ylboronic acid (149.0 mg, 0.92 mmol), K3PO4 (195.0 mg, 0.92 mmol), Pd(PPh3)4 (30.0 mg, 0.03 mmol) and water (3 drops). The resulting solution was stirred for 1 h at 90° C. and then concentrated under vacuum to give a residue, which was purified by a silica gel column (5%-20% ethyl acetate in petroleum ether) to afford methyl 2-(benzofuran-2-yl)-3-(cyclopropyl(methyl)amino)quinoxaline-6-carboxylate as a yellow solid (95.0 mg, 39% 2 steps).
Reaction SMILES: C1(SC)C=CC=CC=1.C([O:16][C:17]1[CH:26]=[C:25]2[C:20]([C:21]([O:27][C:28]3[CH:33]=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[CH:30][CH:29]=3)=[CH:22][CH:23]=[N:24]2)=[CH:19][C:18]=1[O:37][CH3:38])C1C=CC=CC=1>FC(F)(F)C(O)=O>[CH3:38][O:37][C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][C:17]=1[OH:16])[N:24]=[CH:23][CH:22]=[C:21]2[O:27][C:28]1[CH:29]=[CH:30][C:31]([N+:34]([O-:36])=[O:35])=[CH:32][CH:33]=1
Reactant: COc1cc2c(Oc3ccc([N+](=O)[O-])cc3)ccnc2cc1OCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: CSc1ccccc1
Product: COc1cc2c(Oc3ccc([N+](=O)[O-])cc3)ccnc2cc1O
Temperature: 70 °C
Reaction time: 2 h
Yield: 128.9 %

Procedure:
After adding trifluoroacetic acid (30 ml) and thioanisole (3 ml) to 7-benzyloxy-6-methoxy-4-(4-nitrophenoxy)quinoline (4.0 g), the mixture was heated and stirred at 70° C. for 2 hours. After cooling the reaction solution, it was concentrated under reduced pressure, sodium bicarbonate water and methanol were added and the precipitated crystals were filtered out. They were then washed with diethyl ether to obtain 4.0 g of the title compound.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].C(O[CH2:14][C:15]([C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1)=O)CCC.P(Cl)(OCC)([O:29][CH2:30][CH3:31])=O>O1CCCC1>[C:15]([C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][C:18]=1[O:29][CH2:30][CH3:31])#[CH:14]
Reactant: CCCCOCC(=O)c1cccc2ccccc12
Reactant: CCOP(=O)(Cl)OCC
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C#Cc1c(OCC)ccc2ccccc12
Reaction time: 2 h
Yield: 71.1 %

Procedure:
Under a nitrogen atmosphere, 9.19 ml of 2 mol/l tetrahydrofuran solution of lithium diisopropyl amide was added dropwise to 3.3 g of 2-butoxyacetonaphthone at −78° C., and the mixture was stirred for 2 hours. After addition of 3.17 g of diethyl chlorophosphate, the mixture was stirred at room temperature for 1 hour. 2.65 ml of 2 mol/l tetrahydrofuran solution of lithium diisopropyl amide was added dropwise thereto at −78° C., and the mixture was stirred for 18 hours. The compounds obtained were extracted with added ethyl ether. The ethyl ether layer was washed twice with 300 ml of distilled water, dried over anhydrous magnesium sulfate for 24 hours and filtered, and the solvent was evaporated. The residue was subjected to column purification by using chloroform/hexane (1/4) as the developing solvent, to give 1.9 g of 1-ethynyl-2-ethoxynaphthalene.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[N:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[CH:20][N:19]=2)[CH:5]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:7]=1.Br[C:29]1[CH:30]=[C:31]([CH:34]=[CH:35][CH:36]=1)[C:32]#[N:33].O1CCOCC1.C(=O)([O-])[O-].[Na+].[Na+]>C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>[CH3:1][C:2]1[CH:7]=[C:6]([C:29]2[CH:36]=[CH:35][CH:34]=[C:31]([C:32]#[N:33])[CH:30]=2)[CH:5]=[C:4]([NH:17][C:18]2[N:23]=[C:22]([C:24]([F:27])([F:25])[F:26])[CH:21]=[CH:20][N:19]=2)[CH:3]=1
Reactant: N#Cc1cccc(Br)c1
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(B2OC(C)(C)C(C)(C)O2)c1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cccc(C#N)c2)c1
Temperature: 160 °C

Procedure:
A suspension of N-[3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-4-(trifluoromethyl)pyrimidin-2-amine (1.00 g, 2.64 mmol), 3-bromobenzonitrile (0.492 g, 2.70 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (0.054 g, 0.066 mmol), 1,4-dioxane (10 mL), and aqueous sodium carbonate (2 M, 2.64 mL, 5.27 mmol) was placed under an argon atmosphere by performing 6 vacuum/argon cycles. The reaction mixture was then heated to 160° C. for 10 minutes using a microwave reactor. The resulting suspension was diluted with ethyl acetate (75 mL) and saturated aqueous sodium bicarbonate (25 mL). The layers were separated, and the organic layer was washed with water (10 mL) and then brine (25 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (ethyl acetate/hexanes) to afford 3′-methyl-5′-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}biphenyl-3-carbonitrile. MS ESI calc'd. for C19H14F3N4 [M+H]+ 355, found 355.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]2[C:3]=1[CH2:4][O:5][C:6]2=[O:12].[F:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=1.[O-]S([O-])(=O)=O.[Mg+2]>C(Cl)Cl>[F:11][C:9]1[CH:8]=[C:7]2[C:3]([CH2:4][O:5][C:6]2=[O:12])=[C:2](/[N:1]=[CH:18]/[C:17]2[CH:20]=[CH:21][C:14]([F:13])=[CH:15][CH:16]=2)[CH:10]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: Nc1cc(F)cc2c1COC2=O
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: ClCCl
Product: O=C1OCc2c(/N=C/c3ccc(F)cc3)cc(F)cc21
Yield: 34.6 %

Procedure:
4-amino-6-fluoroisobenzofuran-1(3H)-one (1.5 g, 8.98 mmol), 4-fluorobenzaldehyde (1.67 g, 13.47 mmol) and 12.75 g of MgSO4 were added into 40 ml of DCM and stirred under reflux overnight, then the mixture was evaporated under reduced pressure and the residues was dried in vacuum. 850 mg of (E)-6-fluoro-4-(4-fluorobenzylideneamino)isobenzofuran-1(3H)-one was obtained. 1H-NMR (400 MHz, CDCl3) δ (ppm): 5.37 (s, 2); 7.09-7.12 (dd, 1H), 7.19-7.23 (t, 2H), 7.43-7.45 (dd, 1H), 7.92-7.95 (m, 2H), 8.49 (s, 1H); LC-MS (ESI) m/z: 274 (M+1)+.
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].[C:4]([NH:6][C:7](=[N:10][CH2:11][CH2:12][S:13][CH2:14][C:15]1[NH:19][CH:18]=[N:17][C:16]=1[CH3:20])SC)#[N:5]>C(O)C>[C:4]([NH:6][C:7]([NH:3][CH2:1][CH3:2])=[N:10][CH2:11][CH2:12][S:13][CH2:14][C:15]1[NH:19][CH:18]=[N:17][C:16]=1[CH3:20])#[N:5]
Reactant: CCN
Reactant: CSC(=NCCSCc1[nH]cnc1C)NC#N
Solvent: CCO
Product: CCNC(=NCCSCc1[nH]cnc1C)NC#N

Procedure:
Anhydrous ethylamine (9.0 g.) was added to a solution of N-cyano-N-'-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]-S-methylisothiourea (Example 3(c). 5.0 g.) in ethanol. The solution was heated under reflux for 8 hours and concentrated under reduced pressure. The residue was dissolved in isopropyl alcohol, filtered, and diluted with water. The white solid obtained was recrystallised from isopropyl alcohol-ether to yield N-cyano-N'-ethyl-N"-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]guanidine. m.p. 118°-120°. (Found: C, 49.6; H, 6.8; N, 31.2 S. 11.7. C11H18N6S requires: C, 49.6; H, 6.8; N, 31.6; S, 12.0).
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.C(O)CO.COC.O.[CH3:28][O:29][C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[C:34]([O:38][CH3:39])[C:35]=1[O:36][CH3:37].C(=O)(O)[O-].[Na+]>>[C:16]1([CH3:19])[CH:17]=[CH:18][C:13]([NH:12][C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=[C:2]([C:32]3[CH:33]=[C:34]([O:38][CH3:39])[C:35]([O:36][CH3:37])=[C:30]([O:29][CH3:28])[CH:31]=3)[N:11]=2)=[CH:14][CH:15]=1
Reactant: Cc1ccc(Nc2nc(Cl)nc3ccccc23)cc1
Reactant: COc1cc(B(O)O)cc(OC)c1OC
Agent: COC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: OCCO
Solvent: O
Product: COc1cc(-c2nc(Nc3ccc(C)cc3)c3ccccc3n2)cc(OC)c1OC
Temperature: 25 °C

Procedure:
A mixture of (2-chloro-quinazolin-4-yl)-p-tolyl-amine, 3.76 g, 0.014 mol), ethylene-glycol-dimethyl-ether/water (1 l/120 ml), 3,4,5-trimethoxyphenylboronic acid (2.714 g, 0.014 mol) and sodium bicarbonate (3.6 g) was degassed with argon for 15 minutes. Pd(dppf)Cl2 (0.84 g) was added, and the mixture was heated to reflux overnight. After cooling to room temperature CH2Cl2 (1 l) and H2O (500 ml) were added. The organic and aqueous layers were separated, the aqueous layer was extracted with CH2Cl2 (2×500 ml), and the combined organic layers were dried over anhydrous sodium sulfate. The organic solvent was removed under reduced pressure. The crude product was purified by methanol. Filtration in a Büchner apparatus afforded p-tolyl-[2-(3,4,5-trimethoxy-phenyl)-quinazolin-4-yl]-amine, 2 (3.15 g, 0.0078 mol 56%). m.p.: >250° C.; 1H NMR (300 MHz, DMSO-d6) δ 2.33 (s, 3H), 3.74 (s, 3H), 3.91 (s, 6H), 6.81 (s, 2H), 7.24 (d, J=8.4 Hz, 2H), 7.33 (d, J=7.3 Hz, 2H), 7.58 (t, J=8.2 Hz, 1H), 7.83 (t, J=7.2 Hz, 2H), 8.54 (d, J=7.5 Hz, 1H). Anal. (C24H23N3O3) C, H, N.
Reaction SMILES: [C:1](#[N:4])[CH:2]=[CH2:3].[CH2:5]([N:12]1[CH2:17][CH:16]2[CH2:18][CH:13]1[CH2:14][NH:15]2)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C1(C)C=CC=CC=1>[CH2:5]([N:12]1[CH2:17][CH:16]2[CH2:18][CH:13]1[CH2:14][N:15]2[CH2:3][CH2:2][C:1]#[N:4])[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: C=CC#N
Reactant: c1ccc(CN2CC3CC2CN3)cc1
Solvent: Cc1ccccc1
Product: N#CCCN1CC2CC1CN2Cc1ccccc1
Yield: 89.2 %

Procedure:
Freshly distilled acrylonitrile (2.5 g) is added to a solution of 3 g of 2-benzyl-2,5-diazabicyclo[2.2.1]heptane in 40 mL of anhydrous toluene and refluxed with vigorous stirring. The solution was cooled, filtered and evaporated. Bulb tube distillation (boiling point: 120°–130° C. at 0.01 mbar) resulted in 3.43 g of 142 as a colorless oil (88% of the theoretical yield).
Reaction SMILES: [O:1]([CH2:8][CH:9]1[CH2:25][N:13]2[CH2:14][CH2:15][N:16]([C:18]3[CH:23]=[CH:22][N:21]=[C:20](Cl)[N:19]=3)[CH2:17][CH:12]2[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>Cl.C(O)C.[Pd]>[O:1]([CH2:8][CH:9]1[CH2:25][N:13]2[CH2:14][CH2:15][N:16]([C:18]3[CH:23]=[CH:22][N:21]=[CH:20][N:19]=3)[CH2:17][CH:12]2[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [H][H]
Reactant: Clc1nccc(N2CCN3CC(COc4ccccc4)CCC3C2)n1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: c1ccc(OCC2CCC3CN(c4ccncn4)CCN3C2)cc1
Yield: 20.1 %

Procedure:
A mixture of 0.110 g (0.307 mmol) of (7RS,9aSR)-7-phenoxymethyl-2-(2-chloropyrimidin4-yl)-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine (Example 29), 20 mg of 10% Pd/C, and several drops of conc. hydrochloric acid in 30 mL of ethanol were shaken under 50 psi of hydrogen gas at room temperature for 6 h. The mixture was filtered through Celite and the filtrate was evaportated. The residue was basified with conc. ammonium hydroxide, extracted with chloroform, dried (magnesium sulfate), filtered and evaporated. Purification by flash silica gel chromatography with a solvent gradient from 100% chloroform to 95:5 chloroform:methanol gave 0.020 g (20%) of the title compound. mp (.HCl) >265° C. (dec). HRMS calc for C19H24N4O: 324.1945, found: 324.1970.
Reaction SMILES: [NH2:1][C@H:2]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:3][C:4]([O:6][CH3:7])=[O:5].[CH:14]1([C:18](O)=[O:19])[CH2:17][CH2:16][CH2:15]1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[CH:14]1([C:18]([NH:1][C@H:2]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:3][C:4]([O:6][CH3:7])=[O:5])=[O:19])[CH2:17][CH2:16][CH2:15]1
Reactant: O=C(O)C1CCC1
Reactant: COC(=O)C[C@H](N)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)C[C@H](NC(=O)C1CCC1)c1ccccc1

Procedure:
To a solution of the amino ester from Example 6, Step A (4.2 mmol, 896 mg) and cyclobutanecarboxylic acid (5.0 mmol, 476 μL) in 10 mL of DCM containing N,N-diisopropylethylamine (12.5 mmol, 2.17 mL) was added 1-(3-dimethylamino)propyl-3-ethylcarbodiimide hydrochloride (5.0 mmol, 958 mg). After 16 h the reaction mixture was washed with H2O (10 mL), 1 M citric acid (10 mL) and saturated NaHCO3 (10 mL). The organic phase was dried with MgSO4 and the solvent removed under reduced pressure to afford the product as a white solid. MS (ESI): m/z 485 (M+H). HPLC B: 1.58 min.
Reaction SMILES: [CH3:1][C:2]([CH:5]1[CH2:10][CH2:9][C:8](=O)[CH2:7][CH2:6]1)([CH3:4])[CH3:3].[C:12]([NH:14][C:15]([NH2:17])=[NH:16])#[N:13]>C(OCCOCCO)C>[NH2:17][C:15]1[N:14]=[C:12]([NH2:13])[C:9]2[CH2:10][CH:5]([C:2]([CH3:4])([CH3:3])[CH3:1])[CH2:6][CH2:7][C:8]=2[N:16]=1
Reactant: CC(C)(C)C1CCC(=O)CC1
Reactant: N#CNC(=N)N
Solvent: CCOCCOCCO
Product: CC(C)(C)C1CCc2nc(N)nc(N)c2C1
Temperature: 160 °C
Reaction time: 18 h

Procedure:
A reaction vessel equipped with a Dean Stark trap was charged with 11.8 grams (0.075 mole) of 4-(1,1-dimethylethyl)cyclohexanone and 4.2 grams (0.050 mole) of cyanoguanidine in 20 mL of 2-(2-ethoxyethoxy)ethanol. The mixture was heated incrementally at 80° C., 100° C., 140° C. and 160° C., the latter where it was stirred for about 18 hours. The reaction mixture was then cooled to ambient temperature, where it solidified. The reaction mixture was triturated with 30 mL of diethyl ether, and the resultant solid was collected by filtration. The solid was washed several times with diethyl ether, yielding, when dried, 4.5 grams of 2,4-diamino-6-(1,1-dimethylethyl)-5,6,7,8-tetrahydroquinazoline, mp>250° C. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: N1C[CH2:4][CH2:3][CH2:2]1.CC(C)=O.[C:10]([C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][C:21]=1[OH:22])[C:16]([OH:18])=[O:17])(=[O:12])[CH3:11]>C(#N)C>[C:16]([C:15]1[CH:14]=[C:13]2[C:21](=[CH:20][CH:19]=1)[O:22][C:3]([CH3:4])([CH3:2])[CH2:11][C:10]2=[O:12])([OH:18])=[O:17]
Reactant: CC(=O)c1cc(C(=O)O)ccc1O
Reactant: C1CCNC1
Solvent: CC(C)=O
Solvent: CC#N
Product: CC1(C)CC(=O)c2cc(C(=O)O)ccc2O1
Reaction time: 48 h

Procedure:
13.8 g of pyrrolidine and 40 ml of acetone are added to a suspension of 14.7 g (0.0815 mol) of 3-acetyl-4-hydroxybenzoic acid in 200 ml of acetonitrile. The slowly discoloring solution is allowed to stand at room temperature for 2 days, the solvent is distilled off on a rotary evaporator, the residue is treated with water and adjusted to acidic pH<1 using conc. hydrochloric acid and the crystalline substance is filtered off.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.Cl[CH:8]([CH3:11])[C:9]#[N:10].C(=O)([O-])[O-].[Cs+].[Cs+].O1CCCC1>CCOCC>[Cl:1][C:2]1[CH:3]=[N:4][N:5]([CH:8]([CH3:11])[C:9]#[N:10])[CH:6]=1
Reactant: CC(Cl)C#N
Reactant: Clc1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C#N)n1cc(Cl)cn1
Temperature: 100 °C
Yield: 116.3 %

Procedure:
4-Chloro-1H-pyrazole (4.05 g, 39.5 mmol), 2-chloropropanenitrile (3.71 g, 41.5 mmol), cesium carbonate (15.6 g, 44.3 mmol) and anhydrous tetrahydrofuran (20 mL) were added into a sealed tube and the reaction mixture was heated to 100° C. for 2 h. The mixture was diluted with ether (100 mL) and filtered. The solids were rinsed with ether (30 mL×3) and the filtrate was diluted with dichloromethane (10 mL). The solution was concentrated under reduced pressure to afford the title compound as oil (7.15 g). The material was taken to the next step without further purification. 1H NMR (500 MHz, CDCl3) δ 1.90 (d, 3H), 5.21-5.30 (m, 1H), 7.51 (s, 1H), 7.58 (s, 1H); MS (EI+) (M+) 155; GCMS retention time: 1.23 minutes (Method O).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2[OH:12].[CH2:13]=[O:14]>[OH-].[Na+]>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([CH2:13][OH:14])=[C:5]2[OH:12]
Reactant: C=O
Reactant: Oc1ccnc2ccc(Cl)cc12
Agent: [Na+]
Agent: [OH-]
Product: OCc1cnc2ccc(Cl)cc2c1O

Procedure:
6-Chloro-4-hydroxyquinoline was reacted with formaldehyde in aqueous sodium hydroxide at 55° for 24 hours to give the novel compound 6-chloro-4-hydroxy-3-hydroxymethylquinoline, m.p. >300°.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:12]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:19]3[C:27]([CH2:28][CH2:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[CH:26][CH:25]=[CH:24][C:20]=3[C:21](O)=[O:22])[CH:9]=2)[N:4]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[F:59][C@@H:60]1[CH2:64][CH2:63][NH:62][CH2:61]1.CCN(C(C)C)C(C)C>CN(C=O)C>[NH2:2][C:3]1[C:12]([N:13]2[CH2:14][CH2:15][O:16][CH2:17][CH2:18]2)=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:19]3[C:27]([CH2:28][CH2:29][C:30]([CH3:31])([CH3:32])[CH3:33])=[CH:26][CH:25]=[CH:24][C:20]=3[C:21]([N:62]3[CH2:63][CH2:64][C@@H:60]([F:59])[CH2:61]3)=[O:22])[CH:9]=2)[N:4]=1
Reactant: CC(C)(C)CCc1cccc(C(=O)O)c1-c1ccc2nc(N)c(N3CCOCC3)cc2c1
Reactant: F[C@@H]1CCNC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)CCc1cccc(C(=O)N2CC[C@@H](F)C2)c1-c1ccc2nc(N)c(N3CCOCC3)cc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 2-(2-amino-3-morpholinoquinolin-6-yl)-3-(3,3-dimethylbutyl)benzoic acid hydrochloride (168 mg, 0.357 mmol) and HATU (204 mg, 0.536 mmol) in DMF (5 mL) was stirred for 10 min at RT. (R)-(−)-3-fluoropyrrolidine hydrochloride (224 mg, 1.787 mmol) and 1,1′-dimethyltriethylamine (0.622 mL, 3.57 mmol) were added and the reaction mixture was allowed to stir overnight at RT. The reaction mixture was partitioned between water and ethyl acetate. The organic phase was separated, dried over MgSO4 and the solvent was removed under reduced pressure. The residue was purified by preparative HPLC (10-100% water with 0.1% TFA/CH3CN, 11 min). The obtained product was eluted on an SCX cartridge with MeOH followed by 2M NH3/MeOH. The basic fraction was concentrated to afford the titled compound as a white solid. MS (ESI, pos. ion) m/z: 505 (M+1).