Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]([F:9])=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.[CH3:10][N:11]1[CH:15]=[C:14](B2OC(C)(C)C(C)(C)O2)[CH:13]=[N:12]1.C([O-])([O-])=O.[Na+].[Na+].S([O-])([O-])(=O)=O.[Na+].[Na+]>COCCOC>[F:9][C:3]1[C:2]([C:14]2[CH:13]=[N:12][N:11]([CH3:10])[CH:15]=2)=[CH:7][N:6]=[C:5]([NH2:8])[CH:4]=1
Reactant: Nc1cc(F)c(Br)cn1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: Cn1cc(-c2cnc(N)cc2F)cn1
Temperature: 120 °C
Yield: 75.4 %

Procedure:
To the reaction mixture of 5-bromo-4-fluoropyridin-2-amine (369 mg, 1.932 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (603 mg, 2.90 mmol), PdCl2(dppf)DCM (141 mg, 0.193 mmol) and DME (9.660 μL), 2M Na2CO3 (3.220 mL) was added. The reaction mixture was heated at microwave synthesizer (120° C., 12 min). To the reaction mixture, anhydrous sodium sulfate was added, filtered, and concentrated. The crude product was purified by flash chromatography eluting with 0-100% EtOAc (containing 10% of MeOH/heptane to provide 280 mg of desired product in 75% yield. LCMS (m/z): 193.1 (MH+), 0.35 min.
Reaction SMILES: C(=O)(O)O.[NH2:5][NH:6][C:7]([NH2:9])=[NH:8].[C:10]([NH:15][CH:16]([CH3:24])[C:17](=O)[C:18](OCC)=[O:19])(=[O:14])[CH2:11][CH2:12][CH3:13]>C(O)C>[NH2:8][C:7]1[NH:6][N:5]=[C:17]([CH:16]([NH:15][C:10](=[O:14])[CH2:11][CH2:12][CH3:13])[CH3:24])[C:18](=[O:19])[N:9]=1
Reactant: N=C(N)NN
Reactant: CCCC(=O)NC(C)C(=O)C(=O)OCC
Agent: O=C(O)O
Solvent: CCO
Product: CCCC(=O)NC(C)c1n[nH]c(N)nc1=O
Yield: 50.4 %

Procedure:
Aminoguanidine bicarbonate (2.4 g) was suspended in a solution of ethyl 3-butyramido-2-oxo-butyrate (3.8 g) in absolute ethanol (40 ml) and the mixture was heated under reflux for 5 hours. During this period aminoguanidine bicarbonate gradually dissolved and a new product precipitated as a white solid. The mixture was cooled and the solid (2.62 g) collected and taken up in 2 N hydrochloric acid (30 ml). The solution was filtered to remove a small amount of undissolved solid, then adjusted to pH 8 by adding solid sodium carbonate. The triazinone separated as a white solid which was collected, washed with water and dried in vacuo at 100° to give material m.p. 308° (dec.), (2.0 g) (50% approx.).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:28]=[CH:27][C:6]([C:7]([NH:9][C:10]2[S:11][C:12]3[C:13]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)=[N:14][CH:15]=[C:16]([O:19][CH3:20])[C:17]=3[N:18]=2)=[O:8])=[CH:5][CH:4]=1.[CH3:29][O:30][CH2:31][CH2:32][NH:33][CH3:34]>>[CH3:29][O:30][CH2:31][CH2:32][N:33]([CH2:2][C:3]1[CH:28]=[CH:27][C:6]([C:7]([NH:9][C:10]2[S:11][C:12]3[C:13]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)=[N:14][CH:15]=[C:16]([O:19][CH3:20])[C:17]=3[N:18]=2)=[O:8])=[CH:5][CH:4]=1)[CH3:34]
Reactant: CNCCOC
Reactant: COc1cnc(N2CCOCC2)c2sc(NC(=O)c3ccc(CCl)cc3)nc12
Product: COCCN(C)Cc1ccc(C(=O)Nc2nc3c(OC)cnc(N4CCOCC4)c3s2)cc1
Yield: 62.1 %

Procedure:
A solution of 60 mg (0.14 mmol) 4-chloromethyl-N-(7-methoxy-4-morpholin-4-yl-thiazolo[5,4-c]pyridin-2-yl)-benzamide in 0.30 ml (2.70 mmol) N-(2-methoxyethyl)methylamine was ultrasonicated at room temperature for 40 min. The reaction mixture was then concentrated in vacuo. Flash chromatography (methanol/dichloromethane) followed by trituration in ether afforded 41 mg (61%) 4-{[(2-methoxy-ethyl)-methyl-amino]-methyl}-N-(7-methoxy-4-morpholin-4-yl-thiazolo[5,4-c]pyridin-2-yl)-benzamide as a white crystalline solid. ES-MS m/e (%): 472 (M+H+, 100).
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][NH:2]1.C(OC([O:15][C:16]1[CH:25]=[CH:24][C:19]([CH:20]=[CH:21][CH2:22]Cl)=[CH:18][C:17]=1[O:26][CH3:27])=O)C.O>C1C=CC=CC=1.[OH-].[K+].CO>[OH:15][C:16]1[CH:25]=[CH:24][C:19]([CH:20]=[CH:21][CH2:22][N:2]2[CH2:3][C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[CH2:1]2)=[CH:18][C:17]=1[O:26][CH3:27]
Reactant: CCOC(=O)Oc1ccc(C=CCCl)cc1OC
Reactant: c1ccc2c(c1)CNC2
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: c1ccccc1
Solvent: O
Product: COc1cc(C=CCN2Cc3ccccc3C2)ccc1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.7 %

Procedure:
The process for preparing this compound will be described below, along with its physical properties. A solution of 5.6 grams of isoindoline in 50 milliliters of benzene is added dropwise to a solution of 4.7 grams of 4-ethoxycarbonyloxy-3-methoxy-cinnamyl chloride in 30 milliliters of benzene, after which the mixture is stirred for 1 hour at room temperature and then for 2 hours at 60° C. After completion of the reaction, water is added to the reaction mixture and extracted with benzene followed by distilling the solvent off to obtain an oily product, which is dissolved in a solution of 0.95 gram of potassium hydroxide in 50 milliliters of methanol and stirred for 30 minutes at room temperature. The reaction solution is then concentrated to dryness, and a 5% aqueous sodium hydroxide solution is added to the residue to precipitate crystals, which are filtered off. After adding an excess of ammonium chloride to the mother liquor, it is extracted with chloroform. The oily product obtained after distilling off the chloroform is transformed to a maleic acid salt by operating as in Example 15, which then is recrystallized from methanol to obtain 3.5 grams (yield 56.8%) of N-(4-hydroxy-3-methoxycinnamyl)-isoindoline.maleic acid salt as crystals having a melting point of 162°-164° C. (decomposition).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([CH3:17])[CH:15]=3)[NH:10][CH2:9]2)=[CH:4][CH:3]=1.Cl.[N:19]([O-])=[O:20].[Na+]>C(O)C.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([CH3:17])[CH:15]=3)[N:10]([N:19]=[O:20])[CH2:9]2)=[CH:4][CH:3]=1
Reactant: Cc1ccc2c(c1)C(c1ccc(F)cc1)CN2
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cc1ccc2c(c1)C(c1ccc(F)cc1)CN2N=O
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 76 %

Procedure:
3-(4-Fluorophenyl)-5-methylindoline (0.7 g, 0.00308 mol) was dissolved in ethanol (4.2 mL) and concentrated hydrochloric acid (4.2 mL) was added at 0° C. The reaction mixture was stirred for 5 min. at 0° C. A solution of sodium nitrite (0.425 g, 0.00616 mol) in water (4.2 mL) was added at 0° C., and the reaction mixture was stirred for 2 h at RT. After completion of reaction (monitored by TLC), solvent was removed under reduced pressure, the residue basified with 10% aq. sodium hydroxide solution and the mixture extracted with EtOAc (3×100 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give desired compound as a brown colored oil (0.6 g, 76% yield).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([Cl:12])[CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:13])[C:3]=1[CH3:14].[Br:15][C:16]1[CH:17]=[CH:18][C:19]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[C:20]([NH2:22])[CH:21]=1.Cl.O1CCOCC1>CO>[Br:15][C:16]1[CH:17]=[CH:18][C:19]([N:23]2[CH2:24][CH2:25][O:26][CH2:27][CH2:28]2)=[C:20]([NH:22][C:2]2[C:11]3[C:6](=[C:7]([Cl:12])[CH:8]=[CH:9][CH:10]=3)[N:5]=[C:4]([CH3:13])[C:3]=2[CH3:14])[CH:21]=1
Reactant: Nc1cc(Br)ccc1N1CCOCC1
Reactant: Cc1nc2c(Cl)cccc2c(Cl)c1C
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: Cc1nc2c(Cl)cccc2c(Nc2cc(Br)ccc2N2CCOCC2)c1C

Procedure:
Prepared according to Procedure K, Method 1 using 4,8-dichloro-2,3-dimethylquinoline (104 mg, 460 μmol), 5-bromo-2-morpholinobenzenamine (118 mg, 460 μmol) and 4N hydrochloric acid solution in dioxane (0.050 mL, 200 μmol) in MeOH (1.00 mL) to afford a colorless solid upon purification by chromatography on silica gel, eluting with a Et2O gradient in toluene. 1H NMR (400 MHz, chloroform-d) δ ppm 7.69 (1H, dd, J=7.4, 1.2 Hz), 7.55-7.63 (1H, m), 7.23-7.30 (1H, m), 6.92-6.98 (1H, m), 6.85-6.92 (1H, m), 6.83 (1H, s), 6.18 (1H, d, J=2.3 Hz), 3.80-3.91 (4H, m), 2.92-3.08 (4H, m), 2.71-2.78 (3H, m), 2.23 (3H, s).
Reaction SMILES: [C:1]1([CH:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:8]=[CH2:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1C=C(Cl)C=C(C(OO)=[O:24])C=1>C(Cl)Cl>[CH:7]([CH:8]1[CH2:9][O:24]1)([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=CC(c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: c1ccc(C(c2ccccc2)C2CO2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A flask was charged with 3,3-diphenylpropene (5.1 g, 26.3 mmol) in 100 ml CH2Cl2. It was followed by portionwise addition of mCPBA (9.1 g, 70% purity, 52.6 mmol) at 0° C. The mixture was stirred at room temperature for 24 h and the reaction was then quenched with 30 ml 1M Na2SO3. The aqueous layer was extracted with CH2Cl2 (2×100 ml). The combined organic phases were washed in turn with saturated NaHCO3, brine, and then dried over anhydrous Na2SO4. Purification by flash chromatography (Hexane/ether=9:1) gave pure 2-benzhydryl-oxirane, 4.7 g (85%).
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:24][CH2:25][C:26]([F:29])([F:28])[F:27])=[CH:6][C:7]([C:10]([NH:12][C:13]([CH3:23])([C:18]3[N:19]=[N:20][NH:21][N:22]=3)[CH2:14][CH:15]3[CH2:17][CH2:16]3)=[O:11])=[N:8][CH:9]=2)[CH2:3][CH2:2]1.[C:30](=O)([O-])[O-].[K+].[K+].IC>CN(C=O)C.C(OCC)(=O)C>[CH:1]1([C:4]2[C:5]([O:24][CH2:25][C:26]([F:27])([F:28])[F:29])=[CH:6][C:7]([C:10]([NH:12][C:13]([CH3:23])([C:18]3[N:22]=[N:21][N:20]([CH3:30])[N:19]=3)[CH2:14][CH:15]3[CH2:17][CH2:16]3)=[O:11])=[N:8][CH:9]=2)[CH2:2][CH2:3]1
Reactant: O=C([O-])[O-]
Reactant: CC(CC1CC1)(NC(=O)c1cc(OCC(F)(F)F)c(C2CC2)cn1)c1nn[nH]n1
Agent: [K+]
Solvent: CI
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cn1nnc(C(C)(CC2CC2)NC(=O)c2cc(OCC(F)(F)F)c(C3CC3)cn2)n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 38.6 %

Procedure:
To a solution of 5-cyclopropyl-N-[2-cyclopropyl-1-methyl-1-(2H-tetrazol-5-yl)ethyl]-4-(2,2,2-trifluoroethoxy)pyridine-2-carboxamide (example 150b, 100 mg, 0.244 mmol) in dry DMF (1.2 ml) was added potassium carbonate (43.8 mg, 0.317 mmol). The reaction mixture was stirred at room temperature for 10 minutes followed by addition of iodomethane (30.5 μl, 0.487 mmol). The reaction mixture was then stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate and extracted with water and brine. The organic phase was dried over sodium sulfate and evaporated down to dryness. The crude material was purified by preparative HPLC to yield the title compound (40 mg, 39%) and also a second by-product as the regioisomer (11 mg, 10.6%). MS (ESI, m/z): 425.5 (M+H+).
Reaction SMILES: [CH3:1][S:2][C:3](=[NH:5])[NH2:4].C(=O)([O-])[O-].[K+].[K+].[Cl:12][C:13]1[CH:18]=[CH:17][N:16]2[N:19]=[C:20]([C:26]3[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=3)[C:21]([C:22](=O)[C:23]#[CH:24])=[C:15]2[CH:14]=1.C(OCC)(=O)C>C(O)C>[CH3:33][O:32][C:29]1[CH:28]=[CH:27][C:26]([C:20]2[C:21]([C:22]3[CH:23]=[CH:24][N:4]=[C:3]([S:2][CH3:1])[N:5]=3)=[C:15]3[CH:14]=[C:13]([Cl:12])[CH:18]=[CH:17][N:16]3[N:19]=2)=[CH:31][CH:30]=1
Reactant: CSC(=N)N
Reactant: C#CC(=O)c1c(-c2ccc(OC)cc2)nn2ccc(Cl)cc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: COc1ccc(-c2nn3ccc(Cl)cc3c2-c2ccnc(SC)n2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 31.4 %

Procedure:
The suspension of 2-methyl-2-thiopseudourea (358 mg, 1.29 mmol) and potassium carbonate (178 mg, 1.29 mmol) in ethanol was stirred at room temperature for 10 minutes. 1-[5-Chloro-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-propyn-1-one (200 mg, 0.64 mmol) was added. The suspension was stirred at room temperature for 12 hours. Ethyl acetate was added. The ethyl acetate phase was washed with water and brine and dried over magnesium sulfate. Filtration and concentration, followed by chrornatography (3:2 hexanes/ethyl acetate), gave 4-{5-chloro-3-[2-(methylsulfanyl)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-2-yl}phenyl methyl ether (77 mg, 31%) as a white solid. 1H NMR (CDCl3) δ 8.49 (d, 1H), 8.37 (d, 1H), 8.20 (d, 1H), 7.48 (d, 2H), 6.98 (d, 2H), 6.85 (dd, 1H), 6.70 (d, 1H), 3.85 (s, 3H), 2.62 (s, 3H). MS m/z 383 (M+1).
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([NH:13][C:14](SC)=[C:15]([S:18]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)(=[O:20])=[O:19])[C:16]#[N:17])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C(N(CC)CC)C.[NH2:39][C:40]1[N:44]([CH3:45])[N:43]=[C:42]([CH:46]2[CH2:48][CH2:47]2)[CH:41]=1>C(#N)C>[F:10][C:9]([F:11])([F:12])[C:7]1[CH:6]=[C:5]([NH:13][C:14]([NH:39][C:40]2[N:44]([CH3:45])[N:43]=[C:42]([CH:46]3[CH2:48][CH2:47]3)[CH:41]=2)=[C:15]([S:18]([C:21]2[CH:22]=[CH:23][C:24]([Cl:27])=[CH:25][CH:26]=2)(=[O:19])=[O:20])[C:16]#[N:17])[CH:4]=[C:3]([C:2]([F:30])([F:31])[F:1])[CH:8]=1
Reactant: Cn1nc(C2CC2)cc1N
Reactant: CSC(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)=C(C#N)S(=O)(=O)c1ccc(Cl)cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cn1nc(C2CC2)cc1NC(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)=C(C#N)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 80 °C
Reaction time: 41 h
Yield: 25.4 %

Procedure:
To a solution of 3-(3,5-bis(trifluoromethyl)phenylamino)-2-(4-chloro-phenylsulfonyl)-3-methylsulfanyl-2-propenenitrile (0.300 9, 0.6 mmol) in dry acetonitrile (1.0 ml), triethylamine (0.100 ml, 0.7 mmol) and 5-amino-3-cyclopropyl-1-methyl pyrazole (0.100 g, 0.7 mmol) were added. The reaction mixture was stirred for 41 h at 80° C. under nitrogen and then concentrated. The residue was worked up as described in Example 17,2) to give 90 mg (25%) of the title compound. 1H NMR (200 MHz, CDCl3): δ=0.7 (m, 2H), 0.9 (m, 2H), 1.85 (m, 1H), 3.5 (s, 3H), 5.3 (s, 1H), 5.4 (s, 1H), 5.85 (s, 1H), 7.28 (s, 2H), 7.53 (d, 2H), 7.63 (s, 1H), 7.8 (d, 2H); EI SP/MS: 589 (M+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[CH:13]([C:16]([CH3:18])=O)([CH3:15])[CH3:14]>>[CH3:18][C:16]1[C:13]([CH3:15])([CH3:14])[C:7]2[C:2](=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:1]=1
Reactant: CC(=O)C(C)C
Reactant: Nc1ccccc1
Agent: O=S(=O)(O)O
Product: CC1=Nc2ccccc2C1(C)C
Yield: 90 %

Procedure:
This diazonium salt solution was reacted, likewise continuously, with 2.55 mol of sodium sulphite/sodium bisulphite mixture per mole of aniline to form a phenylhydrazodisulphonate solution. A portion of this mixture, corresponding to 1.91 mol of aniline, was added dropwise at 80° C. to 200 ml of a 48% strength sulphuric acid (1.35 mol). After a reaction time of 2 h at 80° C., 225 ml (2.1 mol) of methyl isopropyl ketone were metered in in the course of 30 min. After a reaction time of 3 hours at 95° to 100° C., the mixture was cooled. The batch was neutralised and the organic phase was separated off and distilled. 273.8 g of 98.2% pure 2,3,3-trimethylindolenine were obtained. Yield: 88.4% of the theoretical yield, based on aniline.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:15]([CH3:16])[N:14]=[C:13]([C:17](=[N:19][NH:20][C:21]([C:23]3[CH:32]=[CH:31][C:26]([C:27]([O:29]C)=[O:28])=[C:25]([OH:33])[CH:24]=3)=[O:22])[CH3:18])[C:12]=2[OH:34])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].CO.[OH-].[Na+].Cl>C1COCC1.O>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:15]([CH3:16])[N:14]=[C:13]([C:17](=[N:19][NH:20][C:21]([C:23]3[CH:32]=[CH:31][C:26]([C:27]([OH:29])=[O:28])=[C:25]([OH:33])[CH:24]=3)=[O:22])[CH3:18])[C:12]=2[OH:34])=[CH:7][CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)c1ccc(C(=O)NN=C(C)c2nn(C)c(-c3ccc(C(C)(C)C)cc3)c2O)cc1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC(=NNC(=O)c1ccc(C(=O)O)c(O)c1)c1nn(C)c(-c2ccc(C(C)(C)C)cc2)c1O
Temperature: 50 °C
Reaction time: 14 h
Yield: 76.8 %

Procedure:
To methyl 4-[(2-{1-[5-(4-tert-butylphenyl)-4-hydroxy-1-methyl-1H-pyrazol-3-yl]ethylidene}hydrazino)carbonyl]-2-hydroxybenzoate (0.438 mmol, 203.3 mg), methanol (20 mL) was added, and 1 M aqueous sodium hydroxide (2.2 mmol, 2.2 mL) was added. After 5 hours of stirring at 50° C., 14 hours of stirring at room temperature and 4 hours of stirring at 50° C., 1 M hydrochloric acid (2.2 mmol, 2.2 mL) and water were added. The precipitated solid was recovered by filtration, washed with water and dried by means of a vacuum pump to give the crude desired product as a yellow solid (175.0 mg). It was further dissolved in THF (35 mL) and stirred at room temperature for 2 days. The insolubles were filtered off, and the filtrate was concentrated and dried by means of a vacuum pump. After addition of chloroform, the precipitated solid was recovered by filtration and dried by means of a vacuum pump to give the desired product as a pale yellow solid (151.6 mg, yield 77%).
Reaction SMILES: C([O:8][C:9]1[C:14](=[O:15])[N:13]=[C:12]([CH2:16][C:17]2([C:22]3[CH:31]=[CH:30][C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH:23]=3)[CH2:21][CH2:20][CH2:19][CH2:18]2)[N:11]2[CH2:32][CH2:33][N:34]([CH:37]([CH3:39])[CH3:38])[C:35](=[O:36])[C:10]=12)C1C=CC=CC=1.ClC1C=CC(Cl)=CC=1C1(CC2N3CCN(C(C)C)C(=O)C3=C(O)C(=O)N=2)CCCC1>>[OH:8][C:9]1[C:14](=[O:15])[N:13]=[C:12]([CH2:16][C:17]2([C:22]3[CH:31]=[CH:30][C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH:23]=3)[CH2:21][CH2:20][CH2:19][CH2:18]2)[N:11]2[CH2:32][CH2:33][N:34]([CH:37]([CH3:39])[CH3:38])[C:35](=[O:36])[C:10]=12
Reactant: CC(C)N1CCn2c(CC3(c4ccc5ccccc5c4)CCCC3)nc(=O)c(OCc3ccccc3)c2C1=O
Agent: CC(C)N1CCn2c(CC3(c4cc(Cl)ccc4Cl)CCCC3)nc(=O)c(O)c2C1=O
Product: CC(C)N1CCn2c(CC3(c4ccc5ccccc5c4)CCCC3)nc(=O)c(O)c2C1=O
Yield: 43.1 %

Procedure:
9-Hydroxy-2-isopropyl-6-(1-naphthalen-2-yl-cyclopentylmethyl)-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,8-dione (222) (50.0 mg, 43.12%) was synthesized as a light pink solid from 9-benzyloxy-2-isopropyl-6-(1-naphthalen-2-yl-cyclopentylmethyl)-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,8-dione (221) (140.0 mg, 0.269 mmol) following the procedure described for 6-[1-(2,5-dichlorophenyl)-cyclopentylmethyl]-9-hydroxy-2-isopropyl-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,8-dione (209).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([NH:14][CH:15]3[CH2:17][CH2:16]3)[CH2:10][CH2:9]2)=[N:6][CH:7]=1.[F:18][C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=1[N:28]1[CH:32]=[CH:31][N:30]=[C:29]1[CH3:33])[C:22](O)=[O:23]>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([N:14]([CH:15]3[CH2:17][CH2:16]3)[C:22](=[O:23])[C:21]3[CH:25]=[CH:26][C:27]([N:28]4[CH:32]=[CH:31][N:30]=[C:29]4[CH3:33])=[C:19]([F:18])[CH:20]=3)[CH2:10][CH2:9]2)=[N:6][CH:7]=1
Reactant: Clc1cnc(N2CCC(NC3CC3)CC2)nc1
Reactant: Cc1nccn1-c1ccc(C(=O)O)cc1F
Product: Cc1nccn1-c1ccc(C(=O)N(C2CC2)C2CCN(c3ncc(Cl)cn3)CC2)cc1F

Procedure:
The title compound is prepared from [1-(5-chloro-pyrimidin-2-yl)-piperidin-4-yl]-cyclopropyl-amine and 3-fluoro-4-(2-methyl-imidazol-1-yl)-benzoic acid following a procedure analogous to that described in Example 107. LC (method 19): tR=4.04 min; Mass spectrum (ESI+): m/z=455 [M+H]+.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]2[O:15][C:16]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)=[CH:17][C:18](=[O:20])[CH:19]=2)[CH:9]=1)(C)(C)C>FC(F)(F)C(O)=O.ClCCl>[NH2:7][C:8]1[CH:9]=[C:10]([C:14]2[O:15][C:16]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)=[CH:17][C:18](=[O:20])[CH:19]=2)[CH:11]=[CH:12][CH:13]=1
Reactant: CC(C)(C)OC(=O)Nc1cccc(-c2cc(=O)cc(N3CCOCC3)o2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1cccc(-c2cc(=O)cc(N3CCOCC3)o2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.8 %

Procedure:
[3-(6-Morpholine-4-yl-4-oxo-4H-pyran-2yl)-phenyl]carbamic acid tert-butyl ester (3.4 g, 9.2 mmol) was dissolved in 25% trifluoroacetic acid in dichloromethane mixture (30 ml) and stirred for 1 hour at room temperature. The reaction was concentrated in vacuo, precipitated with saturated NaHCO3, filtered, washed with diethyl ether and dried to yield (3-amino-phenyl)-6-morpholin-4-yl-pyran-4-one as a white solid (2.1 g, 85%). m/z (LC-MS, ESP): 273 (M++1).
Reaction SMILES: [NH:1]1[CH:5]=[N:4][C:3]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=2)=[N:2]1.C(=O)([O-])[O-].[K+].[K+].F[C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[C:22]#[N:23]>CN(C=O)C>[N:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[C:3]1[N:4]=[CH:5][N:1]([C:19]2[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=2)[C:22]#[N:23])[N:2]=1
Reactant: N#Cc1cccc(F)c1
Reactant: c1ccc(-c2nc[nH]n2)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1cccc(-n2cnc(-c3ccccn3)n2)c1
Temperature: 145 °C

Procedure:
2-(1H-1,2,4-Triazol-3-yl)pyridine (0.24 g, 1.6 mmol), potassium carbonate (0.45 g, 3.2 mmol) and 3-fluorobenzonitrile (0.20 g, 1.6 mmol) were stirred in DMF (20 mL) at ambient temperature. The resulting reaction mixture was heated at 145° C. for 16 h, after which time it was quenched with H2O (30 mL) and diluted with EtOAc (200 mL). The EtOAc solution was washed with H2O (3×100 mL), then brine (100 mL) and dried (MgSO4), filtered, and concentrated in vacuo. The resulting residue was chromatographed on silica gel eluting with hexane:EtOAc (40:60) to afford 3-(3-pyridin-2-yl-1H-1,2,4-triazol-1-yl)benzonitrile as a white solid.
Reaction SMILES: C(OC(=O)[NH:10][C:11]1([CH3:25])[CH2:16][CH2:15][N:14]([C:17]([C:19]2[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=2)=[O:18])[CH2:13][CH2:12]1)C1C=CC=CC=1.I[Si](C)(C)C>C(#N)C>[NH2:10][C:11]1([CH3:25])[CH2:16][CH2:15][N:14]([C:17]([C:19]2[CH:20]=[CH:21][N:22]=[CH:23][CH:24]=2)=[O:18])[CH2:13][CH2:12]1
Reactant: CC1(NC(=O)OCc2ccccc2)CCN(C(=O)c2ccncc2)CC1
Agent: C[Si](C)(C)I
Solvent: CC#N
Product: CC1(N)CCN(C(=O)c2ccncc2)CC1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution (4-methyl-1-(pyridine-4-carbonyl)-piperidin-4-yl)-carbamic acid benzyl ester (0.085 g, 0.24 mmol) in acetonitrile (2.0 mL) at room temperature was added iodotrimethysilane (0.06 mL, 0.36 mmol). The reaction mixture was stirred at 50° C. for 30 minutes and concentrated under reduced pressure. The solid residue was washed with acetone and filtered to provide titled compound. MS (CI) m/z 220 (M+1)+; 1H NMR (300 MHz, DMSO-d6) δ ppm 8.89 (d, 2H), 7.74 (d, 2H), 4.04 (m, 2H, NH2), 3.42-3.25 (m, 4H), 1.77-1.45 (m, 4H), 1.42 (s, 3H).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([CH2:14][CH3:15])[C:11]=1[O:12][CH3:13])[C:6]([OH:8])=O)[CH3:2].C(Cl)(=O)C(Cl)=O.[Sn](Cl)(Cl)(Cl)Cl.[CH2:27]([C:34]1[S:35][C:36]([CH3:40])=[C:37]([CH3:39])[CH:38]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[CH2:27]([C:34]1[S:35][C:36]([CH3:40])=[C:37]([CH3:39])[C:38]=1[C:6]([C:5]1[CH:9]=[C:10]([CH2:14][CH3:15])[C:11]([O:12][CH3:13])=[C:3]([CH2:1][CH3:2])[CH:4]=1)=[O:8])[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: Cc1cc(Cc2ccccc2)sc1C
Reactant: CCc1cc(C(=O)O)cc(CC)c1OC
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: O=C(Cl)C(=O)Cl
Product: CCc1cc(C(=O)c2c(Cc3ccccc3)sc(C)c2C)cc(CC)c1OC
Yield: 98.9 %

Procedure:
The title compound was prepared according to the procedure in Example 1, step 4, using 3,5-diethyl-4-methoxybenzoic acid (9.45 g, 45.5 mmol), oxalyl chloride (4.35 mL, 50.0 mmol), N,N-DMF (2 drops), tin(IV) chloride (5.85 mL, 50.0 mmol) and 2-benzyl-4,5-dimethylthiophene (11.0 g, 54.6 mmol) to give 17.67 g (99%) of the title compound. 1H NMR δ 1.13 (t, 6 H), 1.83 (s, 3 H), 2.27 (s, 3 H), 2.64 (q, 4 H), 3.73 (s, 3 H), 3.85 (s, 2 H), 7.04 (d, 2 H), 7.12-7.24 (m, 3 H), 7.43 (s, 2 H).