Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]3[O:15][CH2:16][CH2:17][O:18][C:11]=3[CH:10]=2)[C:5]([F:19])=[CH:4][N:3]=1.[CH3:20][O:21][C:22]1[CH:23]=[CH:24][C:25]([CH3:29])=[C:26]([CH:28]=1)[NH2:27]>>[CH2:17]1[CH2:16][O:15][C:12]2[CH:13]=[CH:14][C:9]([NH:8][C:6]3[C:5]([F:19])=[CH:4][N:3]=[C:2]([NH:27][C:26]4[CH:28]=[C:22]([O:21][CH3:20])[CH:23]=[CH:24][C:25]=4[CH3:29])[N:7]=3)=[CH:10][C:11]=2[O:18]1
Reactant: COc1ccc(C)c(N)c1
Reactant: Fc1cnc(Cl)nc1Nc1ccc2c(c1)OCCO2
Product: COc1ccc(C)c(Nc2ncc(F)c(Nc3ccc4c(c3)OCCO4)n2)c1

Procedure:
In like manner to the preparation of 5-fluoro-N4-(3-hydroxyphenyl)-N2-[4-(3-phenyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine, 2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine and 5-methoxy-2-methylaniline were reacted to provide N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(5-methoxy-2-methylphenyl)-2,4-pyrimidinediamine. 1H NMR (CDCl3): δ 7.91 (bs, 1H), 7.61 (d, 1H, J=2.1 Hz), 7.17 (d, 1H, J=3.0 Hz), 7.05 (d, 1H, J=9.3 Hz), 7.03 (dd, 1H, J=3.0 and 8.7 Hz), 6.82 (d, 1H, J=8.1 Hz), 6.68–6.60 (m, 2H), 6.55 (dd, 1H, J=2.1 and 8.1 Hz), 4.26 (s, 4H), 3.70 (s, 3H), 2.22 (s, 3H); 19F NMR (282 MHz, CDCl3): −47450; LCMS: purity: 99%; MS (m/e): 383(MH+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[N:10]=[C:9]([NH2:11])[S:8][C:5]2=[N:6][CH:7]=1.[CH2:12]([N:14]=[C:15]=[O:16])[CH3:13]>O1CCOCC1>[Br:1][C:2]1[CH:3]=[C:4]2[N:10]=[C:9]([NH:11][C:15]([NH:14][CH2:12][CH3:13])=[O:16])[S:8][C:5]2=[N:6][CH:7]=1
Reactant: CCN=C=O
Reactant: Nc1nc2cc(Br)cnc2s1
Solvent: C1COCCO1
Product: CCNC(=O)Nc1nc2cc(Br)cnc2s1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To a solution of 6-bromothiazolo[5,4-b]pyridin-2-amine IV (1.30 g, 5.55 mmol) in 1,4-dioxane (20.0 mL) was added ethylisocyanate (2.19 mL, 27.07 mmol) and the resulting reaction mixture was heated to 80° C. for 8 h. After the completion of the reaction (TLC monitoring), 1,4-dioxane was distilled off followed by co-distillation with n-hexane (2 times). The residue was then stirred with water at 90° C. for 2 h followed by filtration to obtain the desired product that was further washed with hot water and then dried. The residue was finally washed with ether to obtain the desired product (1.40 g, 83%). 1H NMR (400 MHz, DMSO-d6): δ 1.10 (t, J=7.20 Hz, 3H), 3.20 (quintet, J=7.20 Hz, 2H), 6.76 (br s, 1H), 8.24 (d, J=2.0 Hz, 1H), 8.45 (d, J=2.0 Hz, 1H) and 11.05 (br s, 1H).
Reaction SMILES: [C:1]([CH2:3][NH:4][C:5]([C@@H:7]([NH:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][C:23]([N:26]3[CH2:31][CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28][CH2:27]3)=[CH:22][CH:21]=2)=[CH:16][CH:15]=1)[CH2:8][CH:9]([CH3:11])[CH3:10])=[O:6])#[N:2].CS(O)(=O)=O.C([O-])(O)=O.[Na+]>C1COCC1>[C:1]([CH2:3][NH:4][C:5](=[O:6])[C@@H:7]([NH:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][C:23]([N:26]3[CH2:27][CH2:28][NH:29][CH2:30][CH2:31]3)=[CH:22][CH:21]=2)=[CH:16][CH:15]=1)[CH2:8][CH:9]([CH3:11])[CH3:10])#[N:2]
Reactant: CC(C)C[C@H](NCc1ccc(-c2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)cc2)cc1)C(=O)NCC#N
Agent: CS(=O)(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)C[C@H](NCc1ccc(-c2ccc(N3CCNCC3)cc2)cc1)C(=O)NCC#N

Procedure:
To tert-butyl 4-(4′-{[((1S)-1-{[(cyanomethyl)amino]carbonyl}-3-methylbutyl)amino]-methyl}[1,1′-biphenyl]-4-yl)-1-piperazinecarboxylate (85 mg, 0.164 mmol) in dry THF (5 mL) under dry nitrogen was gradually added a total of 8 equivalents of MeSO3H (total of 85 μL, 1.31 mmol) over a period of 2 days in portions of 1–2 equivalents at a time. Aqueous sat. NaHCO3 was added carefully and the product extracted with EtOAc (3×), dried over Na2SO4, concentrated in vacuo, and purified by flash chromatography over silica gel (NH4OH/MeOH/CH2Cl2, 1/9/90) to afford (2S)-N-(cyanomethyl)-4-methyl-2-({[4′-(1-piperazinyl)[1,1′-biphenyl]-4-yl]methyl}amino)pentanamide. MS (+APCI): 420.3 [M+1]+.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:25]([N:28]1[C:37]2[C:32](=[CH:33][C:34]([NH2:38])=[CH:35][CH:36]=2)[C:31]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)([CH3:39])[CH2:30][C:29]1([CH3:47])[CH3:46])(=[O:27])[CH3:26].[Cl:48][C:49]1[C:50]([O:61][CH3:62])=[C:51]([C:55]([O:59][CH3:60])=[C:56]([Cl:58])[CH:57]=1)[C:52](O)=[O:53].C(N(CC)C(C)C)(C)C>O1CCCC1>[C:25]([N:28]1[C:37]2[C:32](=[CH:33][C:34]([NH:38][C:52](=[O:53])[C:51]3[C:55]([O:59][CH3:60])=[C:56]([Cl:58])[CH:57]=[C:49]([Cl:48])[C:50]=3[O:61][CH3:62])=[CH:35][CH:36]=2)[C:31]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)([CH3:39])[CH2:30][C:29]1([CH3:47])[CH3:46])(=[O:27])[CH3:26]
Reactant: CC(=O)N1c2ccc(N)cc2C(C)(c2ccccc2)CC1(C)C
Reactant: COc1c(Cl)cc(Cl)c(OC)c1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1c(Cl)cc(Cl)c(OC)c1C(=O)Nc1ccc2c(c1)C(C)(c1ccccc1)CC(C)(C)N2C(C)=O

Procedure:
HATU condensation of 1-acetyl-6-amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline (10 mg) with 3,5-dichloro-2,6-dimethoxybenzoic acid (9.0 mg) and N,N-diisopropylethylamine (22 μl) in tetrahydrofuran (1 ml) was performed according to the method described in example 11.
Reaction SMILES: C(O[C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][CH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)=[CH:13][CH:12]=[CH:11][C:10]=2[O:22][CH3:23])=[O:5])C.[CH3:24][N:25]=[C:26]=[O:27]>>[CH:17]1([N:16]2[C:15]3[C:14]4[CH:13]=[CH:12][CH:11]=[C:10]([O:22][CH3:23])[C:9]=4[N:8]=[CH:7][C:6]=3[C:4](=[O:5])[N:25]([CH3:24])[C:26]2=[O:27])[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: CN=C=O
Reactant: CCOC(=O)c1cnc2c(OC)cccc2c1NC1CCCC1
Product: COc1cccc2c1ncc1c(=O)n(C)c(=O)n(C3CCCC3)c12
Yield: 55.3 %

Procedure:
1-Cyclopentyl-7-methoxy-3-methyl-1H-pyrimido[5,4-c]quinoline-2,4-dione (18 mg) was prepared from 4-cyclopentylamino-8-methoxy-quinoline-3-carboxylic acid ethyl ester (0.1 mmol) and methyl isocyanate (0.5 mmol) following general procedure C. LCMS: m/z 326 [M+1]+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=O)([O-:3])=[O:2].[C:12]([NH:15][CH2:16][C:17]([OH:19])=[O:18])(=O)[CH3:13].C([O-])(=O)C.[Na+].C(OC(=O)C)(=O)C>>[CH3:13][C:12]1[O:19][C:17](=[O:18])[C:16](=[CH:7][C:6]2[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[N:15]=1
Reactant: CC(=O)NCC(=O)O
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: CC1=NC(=Cc2cccc([N+](=O)[O-])c2)C(=O)O1
Temperature: 120 °C
Reaction time: 6 h
Yield: 70.3 %

Procedure:
3-Nitrobenzaldehyde (45.3 g, 0.3 mol), N-acetylglycine (42.1 g, 0.36 mol) and sodium acetate (32 g, 0.39 mol) were mixed with acetic anhydride (142 ml, 1.5 mol) and the resulting mixture heated with stirring to 120° C. for 6 hrs, giving a dark solution. The mixture was then cooled to RT overnight, resulting in the formation of a precipitated solid. The reaction mixture was poured into ice-water (130 g) and the resulting suspended solid was collected by filtration. The crude solid product (72 g) was washed with acetone (80 ml) then recrystallized from hot acetone (320 ml) to give a crystalline solid that was washed with 50% aqueous ethanol, then dried at 40° C./40 mmHg to give 2-methyl-4-(3-nitrobenzylidene)oxazol-5(4H)-one (49.0 g, 78%) as pale yellow needles.
Reaction SMILES: [CH2:1]([O:3][Si:4]([CH2:11][Si:12]([O:19][CH2:20][CH3:21])([O:16][CH2:17][CH3:18])[O:13][CH2:14][CH3:15])([O:8][CH2:9][CH3:10])[O:5][CH2:6][CH3:7])[CH3:2].C([Li:26])(C)(C)C>>[CH2:17]([O:16][Si:12]([CH:11]([Li:26])[Si:4]([O:8][CH2:9][CH3:10])([O:5][CH2:6][CH3:7])[O:3][CH2:1][CH3:2])([O:19][CH2:20][CH3:21])[O:13][CH2:14][CH3:15])[CH3:18]
Reactant: [Li]C(C)(C)C
Reactant: CCO[Si](C[Si](OCC)(OCC)OCC)(OCC)OCC
Product: [Li]C([Si](OCC)(OCC)OCC)[Si](OCC)(OCC)OCC
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A commercially available bis(triethoxysilyl)methane (BTM) was lithiated by the following procedure. To 300 mL of freshly distilled dry tetrahydrofuran (THF) in a 3-neck flask attached to a bubbler was added 3.07 g (9.00 mmol) BTM and the solution was flushed for 5 minutes with nitrogen that had been passed through a drying column packed with CaCl2 and Drierite. The solution was cooled down to −78° C. and then 5.2 mL, 1.7 M (9 mmol) of t-butyllithium was added dropwise over 10 minutes. The solution was stirred for 30 minutes at −78° C. after which a very, faint yellowish solution resulted. Then the temperature of the solution was raised to room temperature (RT) and stirring continued for 30 minutes at RT after which the solution turned colorless.
Reaction SMILES: [C:1]([Si:5]([CH3:51])([CH3:50])[O:6][CH:7]([C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[CH2:8][CH2:9][CH:10]([CH:25]([C:36]1[CH:41]=[CH:40][C:39](OC)=[CH:38][CH:37]=1)[NH:26][C:27]1[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=1)[C:11](N1C(C2C=CC=CC=2)COC1=O)=[O:12])([CH3:4])([CH3:3])[CH3:2].C[Si](C([Si](C)(C)C)[C:57](N)=[O:58])(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OC)(C)(C)C>C(O)(=O)C>[C:1]([Si:5]([CH3:51])([CH3:50])[O:6][CH:7]([C:44]1[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=1)[CH2:8][CH2:9][CH:10]1[CH:25]([C:36]2[CH:37]=[CH:38][CH:39]=[C:40]([O:58][CH3:57])[CH:41]=2)[N:26]([C:27]2[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=2)[C:11]1=[O:12])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[Si](C)(C)C(C(N)=O)[Si](C)(C)C
Reactant: COc1ccc(C(Nc2ccc([N+](=O)[O-])cc2)C(CCC(O[Si](C)(C)C(C)(C)C)c2ccccc2)C(=O)N2C(=O)OCC2c2ccccc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: COC(C)(C)C
Solvent: CC(=O)O
Product: COc1cccc(C2C(CCC(O[Si](C)(C)C(C)(C)C)c3ccccc3)C(=O)N2c2ccc([N+](=O)[O-])cc2)c1
Yield: 70 %

Procedure:
A mixture comprising 6.1 g (8.6 mmol) of product 3, 7.3 ml of bistrimethylsilylacetamid, 0.5 g of Tetrabutylammoniumfluorid and 100 ml of tert -butylmethylether is stirred under a argon atmosphere for 10 h at room temperature. After finishing of the reaction 5 ml of acetic acid are added slowly by cooling with ice and evaporated. The residue is separated by chromatography on silica gel (ethylacetate/heptane=1/2). 3.3 g (70%) of product 4 is obtained in form of a light yellow compound in solid form: C31H38N2O5Si (546.74) MS (ESI+) 547.3 (M+H+).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[NH:6][C:7]([NH2:9])=S.CI.[CH3:12][O:13][C:14]1[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=1[CH2:16][NH2:17]>CO.C(O)C>[CH3:12][O:13][C:14]1[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=1[CH2:16][NH:17][C:7]([NH:6][C:2]1[S:1][CH:5]=[CH:4][N:3]=1)=[NH:9]
Reactant: COc1ccccc1CN
Reactant: NC(=S)Nc1nccs1
Solvent: CI
Solvent: CO
Solvent: CCO
Product: COc1ccccc1CNC(=N)Nc1nccs1
Reaction time: 4 h
Yield: 57.7 %

Procedure:
400 mg (2.51 mmol) N-1,3-thiazole-2-yl-thiourea were suspended in 20 ml of methanol and 392 mg (2.76 mmol) methyl iodide were added. The reaction mixture was stirred for 4 hours at reflux. Following removal of the solvent by vacuum distillation, the residue obtained was dissolved in 20 ml ethanol, 1.72 g (12.6 mmol) 2-methoxybenzylamine were added and the mixture was stirred for 20 hours at reflux. The solvent was removed on the rotovap. The residue was separated by preparative HPLC (RP-18 column, eluent water/acetonitrile/0.1% acetic acid) and 380 mg N-(2-methoxybenzyl)-N′-1,3-thiazole-2-ylguanidine were obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N+:4]([O-])[CH:5]=[C:6]([CH3:17])[C:7]=1[O:8][CH2:9][C:10]([F:16])([F:15])[C:11]([F:14])([F:13])[F:12].S(OC)([O:22][CH3:23])(=O)=O.S(OOS([O-])(=O)=O)([O-])(=O)=O.[NH4+].[NH4+]>O.CO>[CH3:1][C:2]1[C:3]([CH2:23][OH:22])=[N:4][CH:5]=[C:6]([CH3:17])[C:7]=1[O:8][CH2:9][C:10]([F:16])([F:15])[C:11]([F:14])([F:13])[F:12]
Reactant: Cc1c[n+]([O-])cc(C)c1OCC(F)(F)C(F)(F)F
Reactant: COS(=O)(=O)OC
Agent: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: [NH4+]
Solvent: O
Solvent: CO
Product: Cc1cnc(CO)c(C)c1OCC(F)(F)C(F)(F)F
Temperature: 120 °C
Reaction time: 0.5 h

Procedure:
A mixture of 3,5-dimethyl-4-(2,2,3,3,3-pentafluoropropoxy)pyridine-1-oxide (2.5 g) and dimethyl sulfate (1 ml) was heated at 120° C. for 30 minutes, to which was then added methanol (12.5 ml). To the mixture was added dropwise at 80° C. ammonium persulfate (4.3 g) dissolved in water (20 ml)-methanol (10 ml) over 30 minutes, which was stirred for further 30 minutes. The resultant solution was concentrated. To the residue was added ice, which was neutralized with sodium carbonate, followed by extraction with chloroform. The extract was dried on sodium sulfate, followed by removing the solvent by evaporation to give 2.2 g of 3,5-dimethyl-2-hydroxymethyl-4-(2,2,3,3,3-pentafluoropropoxy)pyridine as an oily substance.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:17])=[C:4]([C:13](O)([CH3:15])[CH3:14])[C:5]2[O:9][CH2:8][C:7]([CH3:11])([CH3:10])[C:6]=2[CH:12]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>ClCCl.O.CO>[Br:1][C:2]1[C:3]([CH3:17])=[C:4]([CH:13]([CH3:14])[CH3:15])[C:5]2[O:9][CH2:8][C:7]([CH3:10])([CH3:11])[C:6]=2[CH:12]=1
Reactant: Cc1c(Br)cc2c(c1C(C)(C)O)OCC2(C)C
Agent: CC[SiH](CC)CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: Cc1c(Br)cc2c(c1C(C)C)OCC2(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.5 %

Procedure:
A stirred, cooled (ice bath)solution of 2-(5-bromo-3,3,6-trimethyl-2,3-dihydro-benzofuran-7-yl)-propan-2-ol (Compound 49, 1.51 g, 5.03 mmol) in 15 mL of dichloromethane was treated with triethyl silane (1.4 mL, 8.76 mmol) followed by trifluoroacetic acid (0.65 mL, 8.43 mmol) and the resulting clear, colorless solution was stirred at ambient temperature overnight. The reaction mixture was cooled, treated with 6 mL each of methanol and water, neutralized cautiously with saturated sodium bicarbonate solution and extracted with diethylether. The organic extract was dried over anhydrous sodium sulfate, filtered and evaporated to an oil. Flash column chromatography using 0.5% ethyl acetate in hexanes as the eluent afforded the title compound (1.36 g, 95%) as an oil. 1H NMR (300 MHz, CDCl3): δ 7.11 (s, 1H), 4.18 (s, 2H), 3.25 (heptet, 1H, J=7.1 Hz), 2.40 (s, 3H), 1.30 (s, 6H), 1.31 (d, 6H, J=7.1 Hz).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][N:13]3[C:16]4[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=4[N:18]=[C:12]3[N:11]=2)=[CH:6][CH:5]=1)([O-])=O.O.O.Cl[Sn]Cl>C(O)C>[N:11]1[C:12]2[N:13]([C:16]3[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=3[N:18]=2)[CH:14]=[CH:15][C:10]=1[C:7]1[CH:6]=[CH:5][C:4]([NH2:1])=[CH:9][CH:8]=1
Reactant: O=[N+]([O-])c1ccc(-c2ccn3c(n2)nc2ccccc23)cc1
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCO
Product: Nc1ccc(-c2ccn3c(n2)nc2ccccc23)cc1
Yield: 67.2 %

Procedure:
To a suspension of 2-(4-nitrophenyl)benzo[4,5]imidazo[1,2-a]pyrimidine (58 mg, 0.20 mmol) in ethanol (3 mL) was added SnCl2.2H2O (361 mg, 1.6 mmol). The solution was refluxed for 1.5 hours and then the volatiles were removed under vacuum. The residue was dissolved in DCM, washed with 1 N NaOH, and then H2O. The DCM layer was dried with MgSO4. The crude product was purified on flash chromatography (silica gel, 5% MeOH/DCM) to provide T518 as a yellow solid (35 mg, 67%). 1H NMR (400 MHz, DMSO-d6) δ 5.94 (s, 2H), 6.70 (m, 2H), 7.34 (m, 1H), 7.47 (m, 1H), 7.61 (d, J=7.6 Hz, 1H), 7.75 (m, 1H), 8.08 (m, 2H), 8.21 (m, 1H), 9.34 (d, J=7.6 Hz, 1H). MS (ESI): 261.1 (M+H+).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:23]=[CH:22][CH:21]=[CH:20][C:15]=2[C:16]([O:18][CH3:19])=[O:17])[CH2:10][CH2:9]1)C1C=CC=CC=1>[Pd]>[N:11]1([C:14]2[CH:23]=[CH:22][CH:21]=[CH:20][C:15]=2[C:16]([O:18][CH3:19])=[O:17])[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1
Reactant: COC(=O)c1ccccc1N1CCN(Cc2ccccc2)CC1
Agent: [Pd]
Product: COC(=O)c1ccccc1N1CCNCC1

Procedure:
The title compound was prepared according to the procedure described in Preparation IV by using methyl 2-[4-benzylpiperazinyl]benzoate (2.8 g, 8.9 mmol), 10% Pd/C (Aldrich) (940 mg), and HCO2NH4 (2.8, 44 mmol). The title compound was isolated as a colorless oil (1.75 g). (MS (ESI, pos. ion) m/z: 221 (M+H). Calc'd for C12H16N2O2: 220.12.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:25])[C:7]([C:16]3[S:20][C:19]([C:21]([O:23]C)=[O:22])=[CH:18][CH:17]=3)=[C:8]([C:12]([F:15])([F:14])[F:13])[O:9]2)=[CH:4][CH:3]=1.Cl>O1CCOCC1>[OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:25])[C:7]([C:16]3[S:20][C:19]([C:21]([OH:23])=[O:22])=[CH:18][CH:17]=3)=[C:8]([C:12]([F:15])([F:13])[F:14])[O:9]2)=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(-c2c(C(F)(F)F)oc3cc(O)ccc3c2=O)s1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(O)c1ccc(-c2c(C(F)(F)F)oc3cc(O)ccc3c2=O)s1
Temperature: 70 °C
Reaction time: 24 h

Procedure:
To a solution of methyl 5-(7-hydroxy-4-oxo-2-(trifluoromethyl)-4H-chromen-3-yl)thiophene-2-carboxylate (295 mg, 0.80 mmol) in dioxane (1.5 ml) was added concentrated HCl (1.5 ml). The reaction mixture was stirred at 70° C. for 24 hours, cooled to room temperature and centrifuged. The precipitate was rinsed with water (2 ml×2), DCM (2 ml×2) and dried in vacuo to afford the desired product in Example 2 as a gray powder (216.1 mg, 76.3%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][CH:9]=2)[C:5]([CH3:17])=[CH:4][N:3]=1.[CH3:18][O:19][C:20]1[CH:21]=[C:22]([N:29]2[CH2:34][CH2:33][CH:32]([N:35](C)[C:36](=O)OC(C)(C)C)[CH2:31][CH2:30]2)[CH:23]=[CH:24][C:25]=1[N+:26]([O-])=O>>[NH:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([C:6]2[C:5]([CH3:17])=[CH:4][N:3]=[C:2]([NH:26][C:25]3[CH:24]=[CH:23][C:22]([N:29]4[CH2:34][CH2:33][CH:32]([NH:35][CH3:36])[CH2:31][CH2:30]4)=[CH:21][C:20]=3[O:19][CH3:18])[N:7]=2)=[CH:9]1
Reactant: COc1cc(N2CCC(N(C)C(=O)OC(C)(C)C)CC2)ccc1[N+](=O)[O-]
Reactant: Cc1cnc(Cl)nc1-c1c[nH]c2ccccc12
Product: CNC1CCN(c2ccc(Nc3ncc(C)c(-c4c[nH]c5ccccc45)n3)c(OC)c2)CC1

Procedure:
Starting materials: 3-(2-chloro-5-methylpyrimidin-4-yl)-1H-indole (INTERMEDIATE 1) and tert-butyl 1-(3-methoxy-4-nitrophenyl)piperidin-4-yl(methyl)carbamate (INTERMEDIATE 10).
Reaction SMILES: [ClH:1].C([N:9]1[CH2:13][C:12](=[O:14])[NH:11][CH:10]1[CH2:15][CH2:16][C:17]([O:19][CH2:20][CH:21]([CH3:23])[CH3:22])=[O:18])C1C=CC=CC=1.[H][H]>[Pd].O.CO>[ClH:1].[O:14]=[C:12]1[NH:11][CH:10]([CH2:15][CH2:16][C:17]([O:19][CH2:20][CH:21]([CH3:23])[CH3:22])=[O:18])[NH:9][CH2:13]1
Reactant: [H][H]
Reactant: CC(C)COC(=O)CCC1NC(=O)CN1Cc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: O
Solvent: CO
Product: CC(C)COC(=O)CCC1NCC(=O)N1
Yield: 872.5 %

Procedure:
To a mixture of 10% palladium on charcoal (1 g) and 99% formic acid (1 ml) in methanol (25 ml), under nitrogen, was added a solution of isobutyl 3-benzyl-5-oxo-2-imidazolidinepropanoate hydrochloride (1 g, 2.93 mmol) and 99% formic acid (1.25 ml) in methanol (25 ml). The mixture was stirred under nitrogen for 6 hours. After addition of water (15 ml) and removal of the catalyst, the solvent was evaporated and the residue was triturated with ethanol to give 0.3 g (41%) of the title compound, m.p. 136°-140° C. The same compound was obtained also by the following procedure: into a mixture of isobutyl 3-benzyl-5-oxo-2-imidazolidinepropanoate hydrochloride (2.2 g, 6.4 mmol), and 10% palladium on charcoal (1.1 g) in water-methanol 2:1 (150 ml) hydrogen was bubbled at room temperature and at atmosphere pressure for 2 hours. Removal of the catalyst and evaporation of the solvent under reduced pressure gave a residue which was triturated with ethanol to afford 14 g (90%) of the title compound, m.p.136°-40° C. NMR (DMSO-d6): deltaH =11.1-9.50 (b.s., 2H, NH2+); 9.20 (b.s., 1H, CONH); 4.95 (t, J=6.2 Hz, 1H, NHCHNH); 3.84 (d, J=6.7 Hz, 2H, COOCH2); 3.65 (s, 2H, NCH2CO); 2.70-2.30 (c.a., 2H, CH2CH2COO); 2.25-1.60 (c.a., 3H, CH2CH2COO, CH(CH3)2); 0.87 (d, J=6.7 Hz, 6H, CH(CH3)2. MS (E.I., 70 eV, 1.5 mA) m/z=214 (M+), 141(M--OC4H9)+, 85 (C3H5N2O)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10](I)=[CH:9][CH:8]=1.[CH3:17][Si:18]([C:21]#[CH:22])([CH3:20])[CH3:19].[Cl-].[NH4+]>C1COCC1.C(N(CC)CC)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[F:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:22]#[C:21][Si:18]([CH3:20])([CH3:19])[CH3:17])=[CH:9][CH:8]=1
Reactant: Fc1cccc(COc2ccc(I)cc2)c1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1ccc(OCc2cccc(F)c2)cc1

Procedure:
A well stirred suspension of 4.0 g (12.2 mmol) of 1-(3-fluorobenzyloxy)-4-iodo-benzene, 0.23 g (1.22 mmol) of cuprous iodide and 0.856 mg (1.22 mmol) of dichloro bis(triphenylphosphine) palladium(II) in a mixture of 20 ml THF and 10 ml triethylamine is treated dropwise with 1.44 g (14.6 mmol) of trimethylsilyl acetylene. The reaction is exothermic. The mixture is stirred overnight at RT, treated with saturated aqueous ammonium chloride and extracted three times with ethyl acetate. The organic phase is dried, concentrated and subjected to flash-chromatography (silica gel, cyclohexane) to yield 3.48 g (95%) of a slightly orange oil. NMR (CDCl3; 300 MHz): 0.24 ppm (s, 9H); 5.06 ppm (s, 2H); 6.85-7.45 ppm (m, 8H).
Reaction SMILES: ClCC1C=CN=CN=1.Cl[CH2:10][C:11]1[N:12]=[N:13][CH:14]=[CH:15][CH:16]=1.[C:17]1(=[O:27])[NH:21][C:20](=[O:22])[C:19]2=[CH:23][CH:24]=[CH:25][CH:26]=[C:18]12.[K]>>[N:13]1[CH:14]=[CH:15][CH:16]=[C:11]([CH2:10][N:21]2[C:17](=[O:27])[C:18]3[C:19](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:20]2=[O:22])[N:12]=1
Reactant: ClCc1cccnn1
Reactant: O=C1NC(=O)c2ccccc21
Agent: ClCc1ccncn1
Agent: [K]
Product: O=C1c2ccccc2C(=O)N1Cc1cccnn1
Yield: 17 %

Procedure:
Following the procedure as described in step A of Preparation 14, making variations as required to replace 4-(chloromethyl)pyrimidine with 3-(chloromethyl)pyridazine (prepared according to R. W. Carling, et al., J. Med. Chem., (2004), Vol. 47, pp. 1807-1822) to react with potassium phthalimide, 2-(pyridazin-3-ylmethyl)isoindoline-1,3-dione was obtained as a colorless solid in 17% yield: 1H NMR (300 MHz, CDCl3) δ 9.12 (d, J=3.0 Hz, 1H), 7.90-7.85 (m, 2H), 7.78-7.72 (m, 2H), 7.51-7.43 (m, 2H), 5.21 (s, 2H):MS (ES+) m/z 240.1 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([OH:12])[CH:9]=[C:8]2[C:3]=1[C:4](=[S:14])[CH:5]=[C:6]([CH3:13])[O:7]2.C(=O)([O-])[O-].[K+].[K+].[CH:21](I)([CH3:23])[CH3:22]>CN(C=O)C>[OH:1][C:2]1[CH:11]=[C:10]([O:12][CH:21]([CH3:23])[CH3:22])[CH:9]=[C:8]2[C:3]=1[C:4](=[S:14])[CH:5]=[C:6]([CH3:13])[O:7]2
Reactant: CC(C)I
Reactant: Cc1cc(=S)c2c(O)cc(O)cc2o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(=S)c2c(O)cc(OC(C)C)cc2o1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 88.3 %

Procedure:
A mixture consisting of 6.88 g (30.35 mmol) 5,7-dihydroxy-2-methylthiochromone, 12.56 g (91.05 mmol) potassium carbonate, 6.07 ml (60.70 mmol) isopropyl iodide, and 150 ml DMF was stirred at 60° C. for 30 min. Subsequently, 5 added to the solution thus reacted. The product was extracted twice with ethyl acetate. organic layer was washed with saturated salt water and dried over sodium sulfate anhydride. The solvent was distilled out under reduced pressure. The resulting crude product was purified by flash column cliromatography (hexane ethyl acetate =4:1), whereby 6.71 g of 5-hydroxy-7-isopropoxy-2-methylthiochromone was obtained (yield: 83%).