Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]2)[N:5]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:4][NH:3]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:32][C:33]1[CH:34]=[C:35]([CH:40]=[CH:41][CH:42]=1)[C:36]([O:38][CH3:39])=[O:37]>CN(C)C=O.C(OCC)(=O)C>[CH3:39][O:38][C:36]([C:35]1[CH:34]=[C:33]([CH:42]=[CH:41][CH:40]=1)[CH2:32][N:3]1[C:2](=[O:1])[C:6]2([CH2:7][CH2:8][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:10][CH2:11]2)[N:5]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:4]1)=[O:37]
Reactant: COC(=O)c1cccc(CBr)c1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)C(=O)NCN2c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(CN2CN(c3ccccc3)C3(CCN(C(=O)OC(C)(C)C)CC3)C2=O)c1
Temperature: 60 °C
Reaction time: 60 h

Procedure:
To a solution of tert-butyl 4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate (0.15 g, 0.45 mmol) and potassium carbonate (0.124 g, 0.9 mmol) in N,N-dimethylformamide (4 mL), was added methyl 3-(bromomethyl)benzoate (0.114 g, 0.5 mmol). After stirring at 60° C. for 60 hours, the reaction mixture was diluted with ethyl acetate (25 mL), washed with dilute citric acid, water and brine. The organic phase was dried over MgSO4, filtered and concentrated to a yellowish brown solid (0.2 g, 93%); 1H NMR (DMSO-d6): δ 1.45 (s, 9H), 1.64 (d, 2H, J=13.6 Hz), 2.41-2.49 (m, 2H), 3.48 (br, 2H), 3.85 (s, 3H), 3.86-3.90 (m, 2H), 4.59-4.64 (m, 4H), 6.68 (d, 2H, J=8.4 Hz), 6.77 (t, 1H, J=7.4 Hz), 7.17 (t, 2H, J=8 Hz), 7.54-7.60 (m, 2H), 7.89-7.92 (m, 2H); MS for C27H33N3O5 m/z 480.08 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]([CH2:13][C:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=O)[C:8](=O)[CH2:7][CH2:6]2.[NH2:23][C:24]1[CH:32]=[C:28]([C:29]([OH:31])=[O:30])[C:27]([OH:33])=[CH:26][CH:25]=1>C(O)(=O)C>[C:29]([C:28]1[CH:32]=[C:24]([N:23]2[C:8]3[CH2:7][CH2:6][C:5]4[CH:4]=[C:3]([O:2][CH3:1])[CH:12]=[CH:11][C:10]=4[C:9]=3[CH:13]=[C:14]2[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:25]=[CH:26][C:27]=1[OH:33])([OH:31])=[O:30]
Reactant: COc1ccc2c(c1)CCC(=O)C2CC(=O)c1ccccc1
Reactant: Nc1ccc(O)c(C(=O)O)c1
Solvent: CC(=O)O
Product: COc1ccc2c(c1)CCc1c-2cc(-c2ccccc2)n1-c1ccc(O)c(C(=O)O)c1
Yield: 64.4 %

Procedure:
A mixture of 5.8 g. (0.02 mole) of 6-methoxy-1-phenacyl-2-tetralone, 3.02 g. (0.02 mole) of 5-aminosalicylic acid, and 20 ml. of glacial acetic acid was heated under reflux for 1 hour, cooled, and filtered. The collected solid was washed with acetic acid and petroleum ether and recrystallized from acetonitrile to provide 5.3 g (67%) of pale yellow crystals, m.p. 233°-234°.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][SH:5].C(N(CC)CC)C.O=[C:14]([CH2:18][CH3:19])[C:15]([OH:17])=[O:16]>C(O)C>[CH2:18]([C:14]1([C:15]([OH:17])=[O:16])[NH:2][CH2:3][CH2:4][S:5]1)[CH3:19]
Reactant: CCC(=O)C(=O)O
Reactant: NCCS
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCC1(C(=O)O)NCCS1
Yield: 65.8 %

Procedure:
11.4 g of cysteamine hydrochloride and 10.1 g of triethylamine were dissolved in 100 ml of ethanol, to which was added 10.2 g of 2-keto-butyric acid. The mixture was refluxed for 30 minutes, cooled and filtered thereby giving 10.6 g (yield 65.7%) of 2-ethyl-thiazolidine-2-carboxylic acid with a melting point of 235°-238° C. (decomposed).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[C:6](C)(C)[NH:5]2.C(N(CC)CC)C.[C:22](Cl)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C1COCC1>[C:22]([N:5]1[C:4]2[C:9](=[CH:10][CH:11]=[CH:2][CH:3]=2)[NH:8][C:7](=[O:12])[CH2:6]1)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CC1(C)Nc2cc(F)ccc2NC1=O
Reactant: O=C(Cl)c1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C1CN(C(=O)c2ccccc2)c2ccccc2N1
Reaction time: 0.5 h

Procedure:
A mixture of 1,2,3,4-tetrahydroquinoxalin-2-one (IV, EXAMPLE 1, 0.593 g) and triethylamine (0.725 ml) in THF (5 ml) is cooled at 0°. To this is added benzoyl chloride (0.56 ml). After the addition is complete, the ice bath is removed and additional THF (5 ml) is added. The reaction is stirred for 30 min and then partitioned between ethyl acetate, aq. sodium bicarbonate, and saline. The organic phases are separated and the organic phase is dried over magnesium sulfate and concentrated. The crude product is recrystallized from methanol/dichloromethane/hexane to give the title compound, mp 208.0°-208.5°; MS (m/z) at 252; IR (mineral oil) 1684, 1666, 1502, 757 and 1362 cm-1 ; NMR (CDCl3) 4.58, 6.7, 6.79, 6.98, 7.10, 7.34 and 7.40 δ.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:11]#[N:12])=[N:4][C:5]([CH2:9]Cl)=[C:6]([Cl:8])[N:7]=1.Cl.[CH3:14][NH:15][C:16]1[CH:26]=[CH:25][C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1>[NH2:1][C:2]1[C:3]([C:11]#[N:12])=[N:4][C:5]([CH2:9][N:15]([C:16]2[CH:26]=[CH:25][C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:18][CH:17]=2)[CH3:14])=[C:6]([Cl:8])[N:7]=1
Reactant: N#Cc1nc(CCl)c(Cl)nc1N
Reactant: CCOC(=O)c1ccc(NC)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(N(C)Cc2nc(C#N)c(N)nc2Cl)cc1
Yield: 34.7 %

Procedure:
Compound 4 (4.04 g, 0.02 mole) and ethyl 4-methylaminobenzoate hydrochloride (3) (4.10 g, 0.02 mole) were dissolved in 200 ml of tetrahydrofuran. The solution was chilled in an ice bath, and to the solution was added slowly a potassium carbonate solution (3.0 g, 0.022 mole in 200 ml water) with stirring. After 24 hours of continuous stirring at room temperature, a yellow precipitate was collected and washed with water. Recrystallization of the product from methanol gave 2.4 g (70% yield) of yellow solid 5. This solid had a melting point of 206°-207° C. The IR spectrum (KBr) showed absorptions corresponding to --NH2 at 3389.9, 3194, and 3264 cm-1, --C≡N at 2240 cm-1, and --C(=O)O-- at 1713 cm-1. The nmr spectrum (DMSO-d6) revealed signals at 7.75 δ (2H,b,NH2), 7.70 δ (2H,d,arom), 6.67 δ (2H,d,arom), 4.35 δ (2H, s,CH2N--), 4.21 δ (2H,q,OCH2CH3), 3.20 δ (3H,s,NCH3), and 1.32 δ (3H,t,CH2CH3). The FAB mass spectrum showed a molecular ion peak at m/z 345. This peak confirmed that the molecular weight of this compound was 345. Elemental analysis confirmed the presence of C, H, N and Cl in the compound.
Reaction SMILES: [Sn](Cl)Cl.[N+](=[CH:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=[N-].[O:12]=[CH:13][CH2:14][CH2:15][O:16][C:17](=[O:19])[CH3:18]>C(Cl)Cl>[CH2:10]([O:9][C:7](=[O:8])[CH2:6][C:13](=[O:12])[CH2:14][CH2:15][O:16][C:17](=[O:19])[CH3:18])[CH3:11]
Reactant: CCOC(=O)C=[N+]=[N-]
Reactant: CC(=O)OCCC=O
Agent: Cl[Sn]Cl
Solvent: ClCCl
Product: CCOC(=O)CC(=O)CCOC(C)=O
Yield: 31.2 %

Procedure:
Charge a round-bottom flask with tin(II) chloride (16.6 g, 0.088 mol), purge with nitrogen, and add dichloroethane (300 mL) by cannula. Add ethyl diazoacetate (92 mL, 0.88 mol) by cannula and stir 10 min. Add a solution of acetic acid 3-oxo-propyl ester (0.44 mol) in CH2Cl2 (600 mL) slowly by cannula over 1 h, then stir the reaction in a 50° C. oil bath for 3 h. Concentrate under vacuum, add saturated aqueous NaHCO3 and remove the organic phase. Extract the aqueous portion with EtOAc (2×). Wash the combined organic portions with brine, dry over MgSO4, filter through Celite®, and concentrate under vacuum. Purify by flash chromatography on silica gel, eluting with a gradient of EtOAc/hexane 8%-25% to give the title compound (27.8 g, 31%), exact mass 202.08, mass spectrum (ES) 225.1 (M+Na). 1H NMR (CDCl3): δ 4.34 (t, J=6.1 Hz, 2H), 4.20 (q, J=7.1 Hz, 2H), 3.46 (s, 2H), 2.89 (t, J=6.1 Hz, 2H), 2.03 (s, 3H), 1.28 (t, J=7.1 Hz, 3H).
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[C:12]([O:16][C:17]([N:19]1[CH2:24][CH:23]=[CH:22][CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13]>ClCCl>[C:12]([O:16][C:17]([N:19]1[CH2:20][CH2:21][C@@H:22]2[C@@H:23]([O:6]2)[CH2:24]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CC=CCC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC[C@H]2O[C@H]2C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 87.8 %

Procedure:
Add a solution of m-chloroperoxybenzoic acid (0.77 mol, 133.1 g) in dichloromethane (200 mL) drop wise to a solution of 3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (0.64 mol, 117.8 g) in dichloromethane (1 L) at 0° C. Upon complete addition, warm the reaction mixture to room temperature and stir for 16 h. Dilute the reaction mixture with dichloromethane and wash with 4 N sodium hydroxide solution, water, and brine. Dry the organic layer over anhydrous sodium sulfate, filter, and concentrate to obtain the title compound (112 g, 87%) as a light yellow oil. 1H NMR (400 MHz, CDCl3) δ 1.44 (s, 9H), 1.87-1.93 (m s, 1H), 2.04 (br s, 1H), 3.11 (br s, 1H), 3.20 (br s, 1H), 3.28 (s, 1H), 3.44 (br s, 1H), 3.68 (br s 1H). 3.81-3.92 (m, 1H). ES-MS m/z 204 [M+H]+.
Reaction SMILES: [F:1]/[C:2](=[C:14](/[F:22])\[C:15]1[CH:20]=[CH:19][C:18](Br)=[CH:17][CH:16]=1)/[C:3]#[C:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][CH3:13])=[CH:7][CH:6]=1.C(N)CCC.[C:28]1([CH3:36])[CH:33]=[CH:32][C:31]([C:34]#[CH:35])=[CH:30][CH:29]=1.C([O-])(O)=O.[Na+]>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.C1COCC1>[F:1]/[C:2](=[C:14](/[F:22])\[C:15]1[CH:20]=[CH:19][C:18]([C:35]#[C:34][C:31]2[CH:32]=[CH:33][C:28]([CH3:36])=[CH:29][CH:30]=2)=[CH:17][CH:16]=1)/[C:3]#[C:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][CH3:13])=[CH:7][CH:6]=1
Reactant: C#Cc1ccc(C)cc1
Reactant: CCCc1ccc(C#C/C(F)=C(\F)c2ccc(Br)cc2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCCN
Solvent: C1CCOC1
Product: CCCc1ccc(C#C/C(F)=C(\F)c2ccc(C#Cc3ccc(C)cc3)cc2)cc1
Temperature: 25 °C
Yield: 64.9 %

Procedure:
Into a 100 ml three-necked flask, 2.86 g of cuprous iodide, 4.33 g (0.012 mol) of (E)-3,4-difluoro-1-(4-propylphenyl)-4-(4-bromophenyl)-3-buten-1-yne obtained in Example 4 and 30 ml of dry THF were charged under an argon atmosphere, followed by stirring at room temperature. Then, 1.42 g of n-butylamine and 1.53 g of p-toluylacetylene were added thereto. Then, 10 ml of a dry THF solution containing 0.69 g of (Ph3P)4Pd was added thereto, and the mixture was stirred at room temperature for 2 hours. After an addition of 30 ml of a saturated NaHCO3 aqueous solution, the mixture was subjected to liquid separation, and then extracted with methylene chloride. The solvent was distilled off, and the residue was purified by silica gel column chromatography to obtain 3.09 g (yield: 65%) of (E)-3,4-difluoro-1-(4-propylphenyl)-4-[4-(2-p-toluylethynyl)phenyl]-3-buten-1-yne.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[CH2:13][N:14]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:6]([O:8]C)=[O:7])#[N:2].CO.[Li+].[OH-]>C1COCC1>[C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[CH2:13][N:14]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:22]([O:24][C:25]([CH3:26])([CH3:27])[CH3:28])=[O:23])[C:6]([OH:8])=[O:7])#[N:2]
Reactant: COC(=O)c1ccc(CN(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c(C#N)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)N(Cc1ccc(C(=O)O)cc1C#N)C(=O)OC(C)(C)C
Reaction time: 1.25 h
Yield: 43.9 %

Procedure:
To a −25° C. solution of methyl 3-cyano-4-(N,N-bis-(t-butoxycarbonyl)aminomethyl)benzoate (1.81 g, 4.64 mmol) in THF (14 mL) was added a 1:1 mixture of MeOH (4.6 mL) and 1 M LiOH (4.6 mL). After 1.25 h, the reaction was quenched with 1 N HCl (4.6 mL), diluted with Et2O (150 mL) and washed with H2O (2×30 mL). The combined aqueous layers was extracted with EtOAc (150 mL). The combined organic layers was MgSO4 dried, filtered, and concentrated. The crude material was chromatographed (0.5% HOAc in 30% EtOAc/hexanes to 0.5% HOAc in 40% EtOAc/hexanes) to give the title compound (767 mg, 44%); IR(CHCl3): 1146, 1370, 1704, 2984, 3020 cm−1; NMR(300 MHz, DMSO-d6): 1.36 (s, 18H); 4.93 (s, 2H); 7.41 (d, 1H, J=8.4 Hz); 8.21 (d, 1H, J=8.4 Hz); 8.25 (s, 1H); MS(FD): 377.0.
Reaction SMILES: Br[C:2]1[CH:22]=[CH:21][C:5]([O:6][C:7]2[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:8]=2[NH:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:4]([Cl:23])[CH:3]=1.[N:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[Sn](CCCC)(CCCC)CCCC>O1CCOCC1.O>[Cl:13][C:11]1[CH:10]=[CH:9][C:8]([NH:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:7]([O:6][C:5]2[CH:21]=[CH:22][C:2]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][N:24]=3)=[CH:3][C:4]=2[Cl:23])[CH:12]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Reactant: CCOC(=O)CNc1ccc(Cl)cc1Oc1ccc(Br)cc1Cl
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)CNc1ccc(Cl)cc1Oc1ccc(-c2ccccn2)cc1Cl

Procedure:
The subtitle compound was prepared by using the product from example 30 step ii) (0.20 g) which was dissolved in dry dioxane (10 ml). 2-pyridyl tributyl tin (0.181 g) and palladium (0) tetrakistriphenylphosphine (0.028 g) were added and the mixture was heated at 80 C for 16 hours. The mixture was diluted with water, extracted with ethyl acetate, dried and concentrated under reduced pressure to give an oil. Yield 0.20 g.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:4](C2CCCCO2)[C:5]2[C:10]([N:11]=1)=[C:9]([NH2:12])[N:8]=[C:7]([NH:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[N:6]=2.[C:25]([OH:31])([C:27]([F:30])([F:29])[F:28])=[O:26]>CO>[F:28][C:27]([F:30])([F:29])[C:25]([OH:31])=[O:26].[CH3:1][O:2][C:3]1[NH:4][C:5]2[C:10]([N:11]=1)=[C:9]([NH2:12])[N:8]=[C:7]([NH:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[N:6]=2
Reactant: CCCCCNc1nc(N)c2nc(OC)n(C3CCCCO3)c2n1
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: CCCCCNc1nc(N)c2nc(OC)[nH]c2n1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 8-methoxy-N2-pentyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purine-2,6-diamine (520 mg) in dry MeOH (5.2 mL) was added TFA (0.52 mL) and the mixture was stirred at room temperature for 48 h. The reaction was concentrated in vacuo to give an orange residue which was triturated with Et2O and filtered to give the title compound as an off-white solid (223 mg).
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][CH:14]=[CH:13]2)=[O:9])([CH3:6])([CH3:5])[CH3:4].[CH2:19]([C:27]1[CH:37]=[CH:36][C:30]([O:31][CH2:32][CH:33]2[CH2:35][O:34]2)=[CH:29][CH:28]=1)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].[Na+].[Cl-]>CN(C=O)C>[C:3]([O:7][C:8]([C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[N:15]([CH2:35][CH:33]([OH:34])[CH2:32][O:31][C:30]1[CH:36]=[CH:37][C:27]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[CH:28][CH:29]=1)[CH:14]=[CH:13]2)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)OC(=O)c1ccc2[nH]ccc2c1
Reactant: CCCCCCCCc1ccc(OCC2CO2)cc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCCCc1ccc(OCC(O)Cn2ccc3cc(C(=O)OC(C)(C)C)ccc32)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
0.077 g (1.93 mmol) sodium hydride as a 60% dispersion in mineral oil is suspended in 15 ml absolute DMF, stirred at room temperature for 10 min, mixed with a solution of 0.400 g (1.84 mmol) tert-butylindole-5-carboxylate in 15 ml absolute DMF and stirred at room temperature for one hour. A solution of 0.483 g (1.84 mmol) 2-(4-octyl-phenoxymethyl)oxirane in 15 ml absolute DMF is added drop-wise. Following four hours of heating at 60° C. and subsequent cooling, hydrolysis is carried out in a semi-saturated NaCl solution. Four extractions with diethyl ether, combination of the organic phases, concentration to half the volume on the rotary evaporator, three wash steps with saturated NaCl solution, drying on sodium sulfate, filtration and reconcentration on the rotary evaporator leave as a crude product a yellow oil which is purified on silica gel by means of flash column chromatography (flow agent: petroleum ether/ethyl acetate 90:10) and yields the product as a colorless oil.
Reaction SMILES: [CH2:1]([N:3]1[CH:25]=[CH:24][C:6]2[NH:7][C:8]([N:11]3[CH2:16][CH2:15][N:14](CC4C=CC=CC=4)[CH2:13][CH2:12]3)=[N:9][CH2:10][C:5]=2[C:4]1=[O:26])[CH3:2].[H][H]>C(O)C.[Pd]>[CH2:1]([N:3]1[CH:25]=[CH:24][C:6]2[NH:7][C:8]([N:11]3[CH2:12][CH2:13][NH:14][CH2:15][CH2:16]3)=[N:9][CH2:10][C:5]=2[C:4]1=[O:26])[CH3:2]
Reactant: [H][H]
Reactant: CCn1ccc2c(c1=O)CN=C(N1CCN(Cc3ccccc3)CC1)N2
Agent: [Pd]
Solvent: CCO
Product: CCn1ccc2c(c1=O)CN=C(N1CCNCC1)N2
Yield: 94.1 %

Procedure:
Dissolved in 20 ml of ethanol was 1.0 g of the 1,4,5,6-tetrahydro-6-ethyl-5-oxo-2-(4-benzylpiperazino)pyrido[4,3-d]pyrimidine obtained in Referential Example 31, followed by an addition of 10% Pd-C. The resultant mixture was stirred at 70° C. for 2.5 hours in a hydrogen atmosphere. After removal of the catalyst by filtration, the filtrate was concentrated to obtain 0.7 g of 1,4,5,6-Tetrahydro-6-ethyl-5-oxo-2-piperazinopyrido[4,3-d]pyrimidine as crystals (yield: 95%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[NH:22][C:21]3[C:20](=[O:23])[N:19]([CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:18](=[O:30])[N:17]([CH3:31])[C:16]=3[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:32][O:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1B(O)O.N1C=CC=CC=1>O1CCCC1.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:22]([C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=3[O:33][CH3:32])[C:21]3[C:20](=[O:23])[N:19]([CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:18](=[O:30])[N:17]([CH3:31])[C:16]=3[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: COc1ccccc1B(O)O
Reactant: CCOC(=O)Cn1c(=O)c2[nH]c(N3CCN(C(=O)OC(C)(C)C)CC3)nc2n(C)c1=O
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CCOC(=O)Cn1c(=O)c2c(nc(N3CCN(C(=O)OC(C)(C)C)CC3)n2-c2ccccc2OC)n(C)c1=O
Temperature: 25 °C
Reaction time: 72 h

Procedure:
4-[1-(Ethoxycarbonylmethyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]piperazine-1-carboxylic acid tert-butyl ester, 2-methoxyphenyl boronic acid (60 mg), and copper (II) acetate (200 mg) were dissolved in anhydrous tetrahydrofuran (5 ml), and pyridine (0.2 ml) was added thereto. The reaction mixture was stirred at room temperature for 3 days, filtered through a short column packed with NH-silica gel, and the filtrate was concentrated. The residue was purified by silica gel column chromatography to obtain 18 mg of the title compound from a fraction eluted with hexane-ethyl acetate (1:1).
Reaction SMILES: CC(C)([O-])C.[K+].[Cl-].[NH2:8][C:9]([NH2:11])=[NH2+:10].[CH2:12]([N:16]1[C:24](=[O:25])[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]1[CH2:26][C:27](OCC)=[O:28])[CH:13]([CH3:15])[CH3:14]>>[CH2:12]([N:16]1[C:24](=[O:25])[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]1[CH2:26][C:27]([NH:10][C:9]([NH2:11])=[NH:8])=[O:28])[CH:13]([CH3:15])[CH3:14]
Reactant: NC(N)=[NH2+]
Reactant: CCOC(=O)CC1c2ccccc2C(=O)N1CC(C)C
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Product: CC(C)CN1C(=O)c2ccccc2C1CC(=O)NC(=N)N
Temperature: 20 °C
Reaction time: 40 h
Yield: 57.3 %

Procedure:
(−)-N-[(2-Isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-y)acetyl]guanidine is prepared as described in Example 1, starting with 2.6 g of potassium tert-butoxide, 2.6 g of guanidinium chloride and 1.25 g of ethyl (−)-(2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol1-y)acetate. The reaction mixture is stirred at a temperature in the region of 20° C. for 40 hours and is then filtered. The filtrate is taken up in 80 cm3 of water and 120 cm3 of ethyl acetate. After separation of the phases by settling, the organic phase is separated out and the aqueous phase is extracted with twice 120 cm3 of ethyl acetate. The organic extracts are combined, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (0.6 kPa) at a temperature in the region of 40° C. The evaporation residue is taken up in 30 cm3 of diethyl ether and the precipitate formed is filtered off and then washed three times with 5 cm3 of diethyl ether. The solid is dried under reduced pressure (10 Pa) at a temperature in the region of 45° C. 0.75 g of (−)-N-[(2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)acetyl]guanidine is thus obtained in the form of an off-white solid melting at 264° C. (αD20=−10.2°±0.6 in methanol at 0.5%). Mass spectrum EI: m/e 288 (M+), m/e 245, m/e 201, m/e 132.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14]#[N:15])[CH:12]=2)[C:7]([CH3:17])([CH3:16])[CH2:6]1)=[O:4].[CH3:18][C@@H:19]1[CH2:24][NH:23][CH2:22][CH2:21][N:20]1[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26].C(N(CC)CC)C>C(#N)C>[C:28]([O:27][C:25]([N:20]1[CH2:21][CH2:22][N:23]([CH2:2][C:3]([N:5]2[C:13]3[C:8](=[CH:9][CH:10]=[C:11]([C:14]#[N:15])[CH:12]=3)[C:7]([CH3:17])([CH3:16])[CH2:6]2)=[O:4])[CH2:24][C@H:19]1[CH3:18])=[O:26])([CH3:31])([CH3:29])[CH3:30]
Reactant: C[C@@H]1CNCCN1C(=O)OC(C)(C)C
Reactant: CC1(C)CN(C(=O)CCl)c2cc(C#N)ccc21
Solvent: CC#N
Solvent: CCN(CC)CC
Product: C[C@@H]1CN(CC(=O)N2CC(C)(C)c3ccc(C#N)cc32)CCN1C(=O)OC(C)(C)C
Temperature: 50 °C
Yield: 175.7 %

Procedure:
To a solution of 1-(2-chloroacetyl)-3,3-dimethylindoline-6-carbonitrile (0.10 g, 0.40 mmol) and (R)-tert-butyl 2-methylpiperazine-1-carboxylate (0.088 g, 0.41 mmol) in acetonitrile (1.5 mL) was added triethylamine (0.083 mL, 0.6 mmol). The reaction mixture was heated at 50° C. for 3 h. The reaction mixture was then cooled and concentrated. The reaction was repeated on a 0.6 mmol scale and the combined crude material was purified by flash column chromatography, eluting with 20% EtOAc in heptane, to give the title compound (0.29 g) [M+H]+=413.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:10][C@@H:9]2[CH:11]=[CH2:12])=[CH:4][CH:3]=1.CCCCCC.C(OCC)(=[O:21])C>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:10][C@@H:9]2[CH2:11][CH2:12][OH:21])=[CH:4][CH:3]=1
Reactant: CCOC(C)=O
Reactant: C=C[C@H]1C[C@@H]1c1ccc(Br)cc1
Solvent: CCCCCC
Product: OCC[C@H]1C[C@@H]1c1ccc(Br)cc1

Procedure:
The product from Example 30B was subjected to the conditions outlined in Example 26F, followed by chromatography (7:3 hexane/ethyl acetate) to provide the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][NH:5][CH:6]=1.Cl[C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][C:9]=1[O:17][CH3:18].[OH-].[K+].O>CS(C)=O>[Cl:1][C:2]1[N:3]=[CH:4][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][C:9]=2[O:17][CH3:18])[CH:6]=1
Reactant: COc1cc([N+](=O)[O-])ccc1Cl
Reactant: Clc1c[nH]cn1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: COc1cc([N+](=O)[O-])ccc1-n1cnc(Cl)c1
Temperature: 80 °C
Reaction time: 2 h
Yield: 42 %

Procedure:
A mixture of 4-chloro-1H-imidazole (5.0 g, 48.8 mmol), 1-chloro-2-methoxy-4-nitrobenzene (9.15 g, 48.8 mmol), and potassium hydroxide flakes (2.74 g, 48.8 mmol) in anhydrous DMSO (50 mL) was heated at 80° C. for 20 h. The reaction mixture was allowed to cool to rt and was poured into 800 mL of water with vigorous stirring. The resulting yellow-orange precipitate was collected by vacuum filtration using a coarse sintered glass funnel. The crude wet solid was transferred to a 1 L Erlenmeyer flask. Absolute ethanol (250 mL) was added to the flask and the resulting suspension was heated until all of the solids dissolved. The clear solution was cooled to rt and the desired product slowly crystallized. After 2 h, the crystalline solid was collected by vacuum filtration and rinsed with 100 mL of fresh ethanol. The solid was dried under high vacuum to afford 4-chloro-1-(2-methoxy-4-nitrophenyl)-1H-imidazole (5.2 g, 42% yield) as an off-white crystalline solid. LC-MS (M+H)+=254.0. 1H NMR (500 MHz, CDCl3) δ ppm 7.94-8.01 (m, 2H) 7.76 (d, J=1.53 Hz, 1H) 7.45 (d, J=8.55 Hz, 1H) 7.21 (d, J=1.53 Hz, 1H) 4.02 (s, 3H).