Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([O:35][CH3:36])[N:6]2[CH2:16][CH2:17][CH2:18][CH:19]1[CH2:24][CH2:23][CH2:22]CN1C(OCC1C=CC=CC=1)=O.FC(F)(F)C(O)=O.C(OC1N=C2C(N=C(OC)N2)=C(N)N=1)CCC.BrCCCC1CCC[N:67]([C:71]([O:73][CH2:74][C:75]2[CH:80]=[CH:79][CH:78]=[CH:77][CH:76]=2)=[O:72])[CH2:66]1>>[NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([O:35][CH3:36])[N:6]2[CH2:16][CH2:17][CH2:18][CH:19]1[CH2:24][CH2:23][CH2:22][N:67]([C:71]([O:73][CH2:74][C:75]2[CH:80]=[CH:79][CH:78]=[CH:77][CH:76]=2)=[O:72])[CH2:66]1
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCCC3CCCCN3C(=O)OCc3ccccc3)c2n1
Reactant: O=C(OCc1ccccc1)N1CCCC(CCCBr)C1
Agent: CCCCOc1nc(N)c2nc(OC)[nH]c2n1
Solvent: O=C(O)C(F)(F)F
Product: CCCCOc1nc(N)c2nc(OC)n(CCCC3CCCN(C(=O)OCc4ccccc4)C3)c2n1

Procedure:
Prepared similarly to Intermediate 31 from 2-(butyloxy)-8-(methyloxy)-9H-purin-6-amine trifluoroacetate and phenylmethyl 3-(3-bromopropyl)-1-piperidinecarboxylate.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5](Cl)=[CH:6][CH:7]=1.CCN(C(C)C)C(C)C.[CH3:18][O:19][C:20]1[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:21]=1[CH2:22][NH2:23]>C(O)CCC>[Cl:1][C:2]1[N:3]=[N:4][C:5]([NH:23][CH2:22][C:21]2[CH:24]=[CH:25][C:26]([O:28][CH3:29])=[CH:27][C:20]=2[O:19][CH3:18])=[CH:6][CH:7]=1
Reactant: Clc1ccc(Cl)nn1
Reactant: COc1ccc(CN)c(OC)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: COc1ccc(CNc2ccc(Cl)nn2)c(OC)c1
Temperature: 100 °C

Procedure:
To a solution of 3,6-dichloropyridazine (1 g, 6.71 mmol) in nBuOH (25 mL) was added DIPEA (3.31 mL, 18.6 mmol) and 2,4-dimethoxybenzylamine (1.12 g, 6.71 mmol) and the reaction mixture was heated to 100° C. for 18 hours. The reaction mixture was concentrated in vacuo to afford 6-chloro-N-(2,4-dimethoxybenzyl)pyridazin-3-amine.
Reaction SMILES: [CH2:1]([CH:8]([C:11]#[N:12])[C:9]#[N:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].FC(F)(F)S(O[CH2:25][C:26]([F:29])([F:28])[F:27])(=O)=O>CN(C)C=O>[CH2:1]([C:8]([CH2:25][C:26]([F:29])([F:28])[F:27])([C:9]#[N:10])[C:11]#[N:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#CC(C#N)Cc1ccccc1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: N#CC(C#N)(Cc1ccccc1)CC(F)(F)F
Yield: 55.5 %

Procedure:
Using 0.1 g of benzylmalononitrile, 5 ml of N,N-dimethylformamide, 0.073 g of cesium carbonate, and 0.1 g of 2,2,2-trifluoroethyl trifluoromethanesulfonate, and according to the process described in the Production Example 1, there was obtained 0.057 g of 2-benzyl-2-(2,2,2-trifluoroethyl)malononitrile (the present compound (3)).
Reaction SMILES: [CH:1]1[C:11]2[CH2:10][C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=3[CH2:7][NH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[F:23][C:24]1[CH:25]=[CH:26][C:27]([CH3:42])=[C:28]([CH:41]=1)[C:29]([NH:31][C:32]1[N:37]=[CH:36][C:35]([C:38](Cl)=[O:39])=[CH:34][CH:33]=1)=[O:30]>ClCCl>[CH:1]1[C:11]2[CH2:10][C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=3[CH2:7][N:6]([C:38]([C:35]3[CH:34]=[CH:33][C:32]([NH:31][C:29](=[O:30])[C:28]4[CH:41]=[C:24]([F:23])[CH:25]=[CH:26][C:27]=4[CH3:42])=[N:37][CH:36]=3)=[O:39])[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc2c(c1)CNc1ccccc1C2
Reactant: Cc1ccc(F)cc1C(=O)Nc1ccc(C(=O)Cl)cn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(F)cc1C(=O)Nc1ccc(C(=O)N2Cc3ccccc3Cc3ccccc32)cn1

Procedure:
As described for Example 1, 6,11-dihydro-5H-dibenz[b,e]azepine is reacted in dichloromethane in the presence of triethylamine, with 6-[(5-fluoro-2-methylbenzoyl)amino]pyridine-3-carbonyl chloride to give the product as a solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)Cl)=[CH:4][CH:3]=1.[K].[OH:18][N:19]1[CH:23]=[N:22][CH:21]=[N:20]1>CN(C)C=O.[I-].[K+]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[O:18][N:19]2[CH:23]=[N:22][CH:21]=[N:20]2)=[CH:4][CH:3]=1
Reactant: Fc1ccc(C(Cl)c2ccc(F)cc2)cc1
Reactant: On1cncn1
Agent: [I-]
Agent: [K+]
Agent: [K]
Solvent: CN(C)C=O
Product: Fc1ccc(C(On2cncn2)c2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
100 mg of potassium iodide and 2.9 g of di-(4-fluorophenyl)-chloromethane were added to 1.5 g of the potassium salt of 1-hydroxy-1,2,4-triazole in 100 ml of dimethylformamide and the mixture was stirred for 2 hours at room temperature. The solvent was evaporated off under reduced pressure, after which the residue was taken up with 50 ml of methyl tert-butyl ether and the solution was extracted twice by shaking with water. The organic phase was evaporated down to give 3.3 g of a pale yellow oil, which was chromatographed over a short silica gel column using dichloromethane. The yield was 2.0 g of a pale oil.
Reaction SMILES: [N:1]1[C:6]2[NH:7][C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[NH:10][CH2:11][C:5]=2[CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].[F:22][C:23]([F:35])([F:34])[C:24]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:25]=1[C:26](Cl)=[O:27]>CN(C)C=O.O>[N:1]1[C:6]2[NH:7][C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[N:10]([C:26]([C:25]3[CH:29]=[CH:30][C:31]([F:33])=[CH:32][C:24]=3[C:23]([F:35])([F:22])[F:34])=[O:27])[CH2:11][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: c1cnc2c(c1)CNc1ccccc1N2
Reactant: O=C(Cl)c1ccc(F)cc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(c1ccc(F)cc1C(F)(F)F)N1Cc2cccnc2Nc2ccccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 33.1 %

Procedure:
To a solution of 6,11-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepine of Example 1, Step B (10.6 g, 53.8 mmol) in dimethylformamide (125 mL) under nitrogen was added potassium carbonate (22.4 g, 162 mmol). The mixture was cooled and treated dropwise with a solution of crude 2-trifluoromethyl-4-fluorobenzoyl chloride of Step A (81 mmol) in dimethylformamide (25 mL). After stirring at room temperature for 2 hours, the mixture was diluted with water and extracted with dichloromethane. The organic extracts were dried over magnesium sulfate and evaporated to dryness. The crude material was dissolved in dichloromethane and purified by flash chromatography (on silica Merck-60, hexane-ethyl acetate 80:20) to provide the pure title compound (6.9 g) which was crystallized by sonication from ethanol-hexane, m.p. 183-185° C.
Reaction SMILES: CS([O:5][CH:6]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH3:7])(=O)=O.[I:21][C:22]1[CH:27]=[CH:26][C:25](O)=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+].IC1C=CC(OC(CCCCCCCC)C)=CC=1>CN(C=O)C>[I:21][C:22]1[CH:27]=[CH:26][C:25]([O:5][CH:6]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH3:7])=[CH:24][CH:23]=1
Reactant: Oc1ccc(I)cc1
Reactant: CCCCCCCCCCCCCC(C)OS(C)(=O)=O
Agent: CCCCCCCCC(C)Oc1ccc(I)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCC(C)Oc1ccc(I)cc1
Temperature: 80 °C
Reaction time: 24 h
Yield: 43.1 %

Procedure:
The 2-methanesulfonyloxypentadecane (34.4 g, 102 mmol) was reacted with 4-iodophenol (22.7 g, 103 mmol) and potassium carbonate (14.3 g, 103 mmol) in DMF (200 ml) as per 2-(4-iodophenoxy)decane except that the temperature of the oil bath was maintained at 80° C. for 15 hrs and increased to 86° C. with stirring for an additional 24 hrs. At the end of this period, NMR spectral analysis indicated that the reaction was complete. The reaction mixture was processed as for 2-(4-iodophenoxy)decane except with four times the volumes to provide a light yellow oil. Flash column chromatography (silica, hexanes) yielded 2-(4-iodophenoxy)pentadecane (18.9 g, 43.0%) as a clear oil.
Reaction SMILES: C1([N:7]2[C:12](=[O:13])[C:11]3[S:14][CH:15]=[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:10]=3[N:9]=[CH:8]2)C=CC=CC=1.NC1[C:28]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=CSC=1C(OC)=O.C(OCC)(OCC)OCC.C1(CN)CCCCC1>C(O)(=O)C>[CH:29]1([CH2:28][N:7]2[C:12](=[O:13])[C:11]3[S:14][CH:15]=[C:16]([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:10]=3[N:9]=[CH:8]2)[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: O=c1c2scc(-c3ccccc3)c2ncn1-c1ccccc1
Reactant: COC(=O)c1scc(-c2ccccc2)c1N
Agent: NCC1CCCCC1
Solvent: CCOC(OCC)OCC
Solvent: CC(=O)O
Product: O=c1c2scc(-c3ccccc3)c2ncn1CC1CCCCC1
Yield: 73.3 %

Procedure:
In the same manner as the synthesis of Compound 1, methyl 3-amino-4-phenylthiophene-2-carboxylate (100 mg, 0.43 mmol), triethyl orthoformate (1.0 ml), cyclohexanemethylamine (0.129 ml, 0.99 mmol), and acetic acid (0.1 ml) were used to give 102.3 mg (0.32 mmol, 73.3% yield) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[NH:4][C@H:5]([C:10]([NH:12][NH:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17](Br)[CH:16]=1)=[O:11])[C:6]([CH3:9])([CH3:8])C.CCO[CH2:26][CH3:27].C([O-])(O)=O.[Na+]>C1COCC1.CC(O[Ti](OC(C)C)(OC(C)C)OC(C)C)C>[CH2:1]([O:2][C:3](=[O:22])[NH:4][C@H:5]([C:10]([NH:12][NH:13][CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:11])[CH:6]([CH3:8])[CH3:9])[C:27]1[CH:26]=[CH:8][CH:6]=[CH:5][CH:10]=1
Reactant: COC(=O)N[C@H](C(=O)NNCc1cccc(Br)c1)C(C)(C)C
Reactant: CCOCC
Agent: CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)NNCc1ccccc1
Temperature: 40 °C
Reaction time: 2 h
Yield: 46 %

Procedure:
(2S)-2-Benzyl-oxirane-N-[(1S,2R)-2-hydroxy-indan-1-yl]-2-carboxylic acid amide (0.930 g, 3.01 mmol) and compound 25 (1.23 g, 3.31 mmol) were dissolved in dry THF (40 mL), Ti(OiPr)4 (1.79 mL, 6.02 mmol) was added and the mixture was stirred at 40° C. for 2 h. Et2O (100 mL) and saturated NaHCO3 (aq., 100 mL) was added to the reaction mixture and the phases were separated. The organic phase was then washed with H2O (2×200 mL). All water phases were reextracted with CHCl3 (100 mL), and the combined organic phases were dried (Na2SO4), filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography (RP-silica, CH3CN/H2O, 50:50-70:30) affording 3 (0.95 g, 46%) as a light yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:8][N:9]([C:13]([N:15]([CH3:17])[CH3:16])=[O:14])[C:10](Cl)=[O:11]>O1CCCC1>[CH3:16][N:15]([CH3:17])[C:13]([N:9]([CH3:8])[C:10]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:11])=[O:14]
Reactant: Nc1ccccc1
Reactant: CN(C)C(=O)N(C)C(=O)Cl
Solvent: C1CCOC1
Product: CN(C)C(=O)N(C)C(=O)Nc1ccccc1
Reaction time: 1 h
Yield: 146.9 %

Procedure:
In 50 ml of anhydrous tetrahydrofuran, 7.4 g (0.08 mole) of aniline was dissolved. The mixture was cooled below 0° C., and a solution prepared by dissolving 6.4 g (0.04 mole) of 2,4,4-trimethylallophanoyl chloride in 10 ml of anhydrous tetrahydrofuran was added dropwise under stirring. The reaction was continued at a room temperature for 1 hour, then the solvent was removed by distillation under a reduced pressure, and water was added to form an insoluble matter. The insoluble matter was obtained by filtration and was recrystallized from ethanol to obtain 13.0 g (yield 73%) of 1,1,3-trimethyl-5-phenylbiuret having a melting point 89.5°-90.5° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14][CH:13]=1)[C:6]1[C:22](=[O:27])[O:23][C:24](=[O:26])[CH2:25][C:5]2=1.[NH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1>>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14][CH:13]=1)[C:6]([C:22]([OH:23])=[O:27])=[C:5]2[CH2:25][C:24](=[O:26])[N:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: O=C1Cc2c(n(Cc3cccc4ccccc34)c3ccc(F)cc23)C(=O)O1
Reactant: C1CCNCC1
Product: O=C(O)c1c(CC(=O)N2CCCCC2)c2cc(F)ccc2n1Cc1cccc2ccccc12

Procedure:
6-Fluoro-9-naphthalen-1-ylmethyl-4,9-dihydro-pyrano[3,4-b]indole-1,3-dione (from example 34.1.) was ring opened with piperidine at 22° C. to give the title compound as a white solid. MS: 445.4 ([M+H]+).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[CH2:10][N:9](CC1C=CC(OC)=CC=1OC)[CH2:8]2)=[O:4].[C:25]1(OC)C=CC=CC=1.[C:33]([OH:39])([C:35]([F:38])([F:37])[F:36])=[O:34]>>[F:36][C:35]([F:38])([F:37])[C:33]([OH:39])=[O:34].[CH2:1]([O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[CH2:10][NH:9][CH2:8]2)=[O:4])[CH3:25]
Reactant: COc1ccccc1
Reactant: COC(=O)c1ccc2c(c1)CN(Cc1ccc(OC)cc1OC)C2
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1ccc2c(c1)CNC2

Procedure:
A solution of 2-(2,4-dimethoxy-benzyl)-2,3-dihydro-1H-isoindole-5-carboxylic acid methyl ester (215 mg) and anisole (200 μl) in 1 ml of TFA was heated at 140° C. for 30 minutes in a CEM discover microwave synthesiser. The reaction was partitioned between water and DCM, the water layer was separated, washed with DCM then evaporated and re-evaporated with toluene/MeOH (×2) to give 105 mg of the title compound. 1H NMR (DMSO-d6) 9.70 (2H, br s), 8.02 (1H, s), 8.98 (1H, d), 7.57 (1H, d), 4.60 (2H, s), 4.56 (2H, s), 3.89 (3H, s).
Reaction SMILES: [O:1]=[C:2]1[C:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:5][CH2:4][N:3]1[CH2:19][C:20]([OH:22])=O.FC1C=CC(C2(C3C=CC(F)=CC=3)CCN(CC(O)=O)C2=O)=CC=1.O[NH:48]/[C:49](=[N:60]\[H])/[C:50]1[C:55]([C:56]([F:59])([F:58])[F:57])=[CH:54][CH:53]=[N:52][CH:51]=1.ON/C(=N\[H])/C1C=CC(C(F)(F)F)=CC=1>>[C:13]1([C:6]2([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH2:5][CH2:4][N:3]([CH2:19][C:20]3[O:22][N:60]=[C:49]([C:50]4[CH:51]=[N:52][CH:53]=[CH:54][C:55]=4[C:56]([F:59])([F:57])[F:58])[N:48]=3)[C:2]2=[O:1])[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: [H]/N=C(\NO)c1cnccc1C(F)(F)F
Reactant: O=C(O)CN1CCC(c2ccccc2)(c2ccccc2)C1=O
Agent: O=C(O)CN1CCC(c2ccc(F)cc2)(c2ccc(F)cc2)C1=O
Agent: [H]/N=C(\NO)c1ccc(C(F)(F)F)cc1
Product: O=C1N(Cc2nc(-c3cnccc3C(F)(F)F)no2)CCC1(c1ccccc1)c1ccccc1

Procedure:
The title compound was prepared using the procedure described in Example 190 substituting 2-(2-oxo-3,3-diphenylpyrrolidin-1-yl)acetic acid from Example 1C for 2-(3,3-bis(4-fluorophenyl)-2-oxopyrrolidin-1-yl)acetic acid and (Z)—N-hydroxy-4-(trifluoromethyl)nicotinimidamide for (Z)—N-hydroxy-4-(trifluoromethyl)benzimidamide. 1H NMR (300 MHz, CDCl3) δ ppm 9.09 (s, 1H), 8.97 (d, J=5.1, 1H), 7.73 (d, J=5.2, 1H), 7.42-7.18 (m, 10H), 4.95 (s, 2H), 3.59 (t, J=6.5, 2H), 2.89 (t, J=6.5, 2H); MS (DCI) m/z 465.1 (M+H)+.
Reaction SMILES: [CH3:1][NH:2][CH3:3].[CH2:4]([O:6][C:7]([C:9]1[S:10][C:11](S(C)(=O)=O)=[C:12]([C:21]#[N:22])[C:13]=1[C:14]1[CH:19]=[CH:18][C:17]([I:20])=[CH:16][CH:15]=1)=[O:8])[CH3:5]>C1COCC1>[CH2:4]([O:6][C:7]([C:9]1[S:10][C:11]([N:2]([CH3:3])[CH3:1])=[C:12]([C:21]#[N:22])[C:13]=1[C:14]1[CH:19]=[CH:18][C:17]([I:20])=[CH:16][CH:15]=1)=[O:8])[CH3:5]
Reactant: CNC
Reactant: CCOC(=O)c1sc(S(C)(=O)=O)c(C#N)c1-c1ccc(I)cc1
Solvent: C1CCOC1
Product: CCOC(=O)c1sc(N(C)C)c(C#N)c1-c1ccc(I)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
Add 3 mL of 2N dimethylamine in THF to 3-(4-iodophenyl)-4-cyano-5-methanesulfonyl-thiophene-2-carboxylic acid ethyl ester (0.23 mmol) and stir under nitrogen at room temperature for 2 h. Evaporate to dryness to provide the title compound which is used without further purification. Yield 95%. MS (ES+, m/e)=427 (M++1).
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([N:12]([CH3:14])[CH3:13])[C:9]2[C:4](=[N:5][C:6]([NH:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[C:7]([Cl:15])[N:8]=2)[N:3]=1.[NH:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1>>[Cl:15][C:7]1[N:8]=[C:9]2[C:4](=[N:5][C:6]=1[NH:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[N:3]=[C:2]([N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)[N:11]=[C:10]2[N:12]([CH3:14])[CH3:13]
Reactant: C1CNCCN1
Reactant: CN(C)c1nc(Cl)nc2nc(NCc3ccccc3)c(Cl)nc12
Product: CN(C)c1nc(N2CCNCC2)nc2nc(NCc3ccccc3)c(Cl)nc12

Procedure:
This compound was prepared analogous to Example 1 from 2,6-dichloro-4-dimethylamino-7-benzylamino-pteridine and piperazine.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3](O)=[O:4].ClCCl.[NH2:11][C:12]1[CH:37]=[CH:36][C:15]([O:16][CH2:17][CH2:18][CH2:19][N:20]2[CH2:25][CH2:24][N:23]([C:26]3[N:31]([CH3:32])[C:30](=[O:33])[N:29]([CH3:34])[C:28](=[O:35])[CH:27]=3)[CH2:22][CH2:21]2)=[CH:14][CH:13]=1>C(Cl)(Cl)Cl.[OH-].[Na+]>[CH3:32][N:31]1[C:26]([N:23]2[CH2:24][CH2:25][N:20]([CH2:19][CH2:18][CH2:17][O:16][C:15]3[CH:36]=[CH:37][C:12]([NH:11][C:3](=[O:4])[C:2]([F:7])([F:6])[F:1])=[CH:13][CH:14]=3)[CH2:21][CH2:22]2)=[CH:27][C:28](=[O:35])[N:29]([CH3:34])[C:30]1=[O:33]
Reactant: O=C(O)C(F)(F)F
Reactant: Cn1c(N2CCN(CCCOc3ccc(N)cc3)CC2)cc(=O)n(C)c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: Cn1c(N2CCN(CCCOc3ccc(NC(=O)C(F)(F)F)cc3)CC2)cc(=O)n(C)c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 38 %

Procedure:
0.5 ml of anhydrous trifluoroacetic acid was added dropwise at 0° C. to 20 ml of a dichloromethane solution containing 1.1 g of 6-[4-(3-[4-aminophenoxy]propyl)piperazin-1-yl]-1,3-dimethyl-2,4(1H,3H)-pyrimidinedione obtained in Example 6, and the solution was then stirred at the same temperature for 10 minutes and further at room temperature for 1 hour. Next, the reaction mixture was diluted with 100 ml of chloroform and 50 ml of a 0.5N aqueous sodium hydroxide solution so as to dissolve insolubles therein, and the resultant organic layer was then separated. The aqueous layer was neutralized and then extracted with 50 ml of chloroform, and the extract layer was mixed with the organic layer previously separated and the mixture was dried and then concentrated to obtain 0.52 g (yield: 38% ) of 1,3-dimethyl-6-[4-(3-[4-trifluoroacetylaminophenoxy]propyl)piperazin-1-yl]-2,4(1H,3H)-pyrimidinedione.
Reaction SMILES: [CH2:1]([O:11][C:12]1[CH:20]=[CH:19][C:18]([O:21][CH2:22]/[CH:23]=[C:24](/[CH2:26][CH2:27][CH:28]=[C:29]([CH3:31])[CH3:30])\[CH3:25])=[CH:17][C:13]=1[C:14](O)=[O:15])/[CH:2]=[C:3](/[CH2:5][CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9])\[CH3:4].[NH2:32][CH2:33][CH:34]1[CH2:38][CH2:37][CH2:36][N:35]1[CH2:39][CH3:40]>>[CH2:39]([N:35]1[CH2:36][CH2:37][CH2:38][CH:34]1[CH2:33][NH:32][C:14](=[O:15])[C:13]1[CH:17]=[C:18]([O:21][CH2:22]/[CH:23]=[C:24](/[CH2:26][CH2:27][CH:28]=[C:29]([CH3:30])[CH3:31])\[CH3:25])[CH:19]=[CH:20][C:12]=1[O:11][CH2:1]/[CH:2]=[C:3](/[CH2:5][CH2:6][CH:7]=[C:8]([CH3:9])[CH3:10])\[CH3:4])[CH3:40]
Reactant: CCN1CCCC1CN
Reactant: CC(C)=CCC/C(C)=C/COc1ccc(OC/C=C(\C)CCC=C(C)C)c(C(=O)O)c1
Product: CCN1CCCC1CNC(=O)c1cc(OC/C=C(\C)CCC=C(C)C)ccc1OC/C=C(\C)CCC=C(C)C
Yield: 55 %

Procedure:
In a manner identical to Example 15, 2,5-digeranyloxybenzoic acid(2.13 g) was subjected to a condensation reaction with 2-aminomethyl-1-ethylpyrrolidine (0.7 ml), thereby yielding 1.47 g(55%) of the aimed compound.
Reaction SMILES: [C:1]1([CH3:16])[CH:6]=[CH:5][C:4]([S:7]([NH:10][C@H:11]([C:13](O)=[O:14])[CH3:12])(=[O:9])=[O:8])=[CH:3][CH:2]=1.C(Cl)(=O)C([Cl:20])=O>CN(C)C=O.ClCCl>[S:7]([NH:10][C@H:11]([C:13]([Cl:20])=[O:14])[CH3:12])([C:4]1[CH:5]=[CH:6][C:1]([CH3:16])=[CH:2][CH:3]=1)(=[O:9])=[O:8]
Reactant: Cc1ccc(S(=O)(=O)N[C@@H](C)C(=O)O)cc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)N[C@@H](C)C(=O)Cl)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
30.0 g of N-(p-toluenesulfonyl)-alanine and 6 to 7 drops of DMF (dimethylformamide) were dissolved in 100 ml of dichloromethane and 5 ml of oxalyl chloride was added dropwise. After stirring for 3 hours at room temperature the reaction mixture was evaporated down to an oily residue which was dissolved in 100 ml of dichloromethane. The dichloromethane was again evaporated and the resulting residue dissolved in 50 ml of dichloromethane followed by the addition of 100 ml hexane. After standing in the refrigerator overnight the crystals, so formed, were filtered and dried.
Reaction SMILES: C[O:2][C:3](=[O:34])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([CH:16]2[CH2:21][CH2:20][N:19]([C:22](=[O:32])[NH:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[O:30][CH3:31])[CH2:18][CH2:17]2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:33])[CH:11]=2)[CH:6]=1.O.[OH-].[Li+]>C1COCC1.O>[F:33][C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][CH:9]=1)[CH:6]=[C:5]([CH2:4][C:3]([OH:34])=[O:2])[C:14]([CH3:15])=[C:13]2[CH:16]1[CH2:21][CH2:20][N:19]([C:22](=[O:32])[NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[O:30][CH3:31])[CH2:18][CH2:17]1
Reactant: COC(=O)Cc1cc2ccc(F)cc2c(C2CCN(C(=O)Nc3ccccc3OC)CC2)c1C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccccc1NC(=O)N1CCC(c2c(C)c(CC(=O)O)cc3ccc(F)cc23)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.7 %

Procedure:
To a solution of {6-fluoro-4-[1-(2-methoxy-phenylcarbamoyl)-piperidin-4-yl]-3-methyl-naphthalen-2-yl}-acetic acid methyl ester (107.6 mg, 0.232 mmol) in THF (8.0 mL) was added a solution of lithium hydroxide monohydrate (111.1 mg, 2.6 mmol) in water (2.0 mL) at room temperature. The resulting solution was stirred overnight at room temperature under a nitrogen atmosphere. The solvent was evaporated. Water (˜25 mL) was added and the mixture was acidified with 1.0 N aqueous HCl (4.6 mL). The resulting white precipitate was collected by filtration and dried under high vacuum to provide {6-fluoro-4-[1-(2-methoxy-phenylcarbamoyl)-piperidin-4-yl]-3-methyl-naphthalen-2-yl}-acetic acid (86.4 mg, 83%) as a white powder. 1H NMR (300 MHz, DMSO-d6) δ ppm 12.45 (b. s, 1H), 7.90 (dd, J=9.23, 6.59 Hz, 1H), 7.78 (br. s., 1H), 7.65-7.72 (m, 2H), 7.35 (t, J=8.01 Hz, 1H), 6.99-7.06 (m, 2H), 6.86-6.95 (m, 1H), 4.23 (m, 2H), 3.82 (s, 3H), 3.78 (br. s., 2H), 3.32 (br. s., 3H), 3.09 (br. s., 2H), 2.43 (s, 3H), 1.66 (m, 2H). MS cald. for C26H28FN2O4 [(M+H)+]: 451, obsd. 451.2.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:12]2[O:13][C:14]3[CH:20]=[CH:19][C:18](Br)=[CH:17][C:15]=3[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])([O-:3])=[O:2].[F:22][C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[CH:27][C:28]=1[F:29]>>[N+:1]([C:4]1[CH:5]=[C:6]([C:12]2[O:13][C:14]3[CH:20]=[CH:19][C:18]([C:26]4[CH:25]=[CH:24][C:23]([F:22])=[C:28]([F:29])[CH:27]=4)=[CH:17][C:15]=3[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])([O-:3])=[O:2]
Reactant: OB(O)c1ccc(F)c(F)c1
Reactant: COc1ccc(-c2nc3cc(Br)ccc3o2)cc1[N+](=O)[O-]
Product: COc1ccc(-c2nc3cc(-c4ccc(F)c(F)c4)ccc3o2)cc1[N+](=O)[O-]

Procedure:
Prepared by the method of Example 15d), from 2-(3-nitro-4-methoxyphenyl)-5-bromobenzoxazole (200 mg, 0.57 mmol) and 3,4-difluorophenylboronic acid (134 mg, 0.85 mmol) the subtitle compound was obtained (68 mg, 21%). MS 383 m/z (M+H)+.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:5][N:6]([C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:12][CH:11]=1)[CH:7]([CH3:9])C)[CH2:3][OH:4].[N:23]#[C:24]Br>>[CH2:16]([C:13]1[CH:14]=[CH:15][C:10]([N:6]([CH2:5][CH:2]2[CH2:3][O:4][C:24]([NH2:23])=[N:1]2)[CH2:7][CH3:9])=[CH:11][CH:12]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: N#CBr
Reactant: CC(C)N(C[C@H](N)CO)c1ccc(Cc2ccccc2)cc1
Product: CCN(CC1COC(N)=N1)c1ccc(Cc2ccccc2)cc1

Procedure:
In analogy to example 1.d (S)-2-amino-3-[(4-benzyl-phenyl)-isopropyl-amino]-propan-1-ol was reacted with cyanogen bromide to give S)-4-{[(4-benzyl-phenyl)-ethyl-amino]-methyl}-4,5-dihydro-oxazol-2-ylamine. Colorless gum. MS (ISP): 310.4 ([M+H]+)
Reaction SMILES: N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.[F:19][C:20]([F:36])([F:35])[C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[NH:26][C:25]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:24]2.[N:37]1[CH:42]=[CH:41][C:40]([CH2:43]O)=[CH:39][CH:38]=1.C(P(CCCC)CCCC)CCC>C1(C)C=CC=CC=1>[F:36][C:20]([F:35])([F:19])[C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[N:26]([CH2:43][C:40]1[CH:41]=[CH:42][N:37]=[CH:38][CH:39]=1)[C:25]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:24]2
Reactant: OCc1ccncc1
Reactant: CCOC(=O)c1cc2cc(C(F)(F)F)ccc2[nH]1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cc2cc(C(F)(F)F)ccc2n1Cc1ccncc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.5 %

Procedure:
A solution of 1.47 g (5.83 mmol) of 1,1′-(azodicarbonyl)dipiperidine in 50 ml of toluene is added dropwise to a solution of 1 g (3.89 mmol) of ethyl 5-trifluoromethyl-1H-indole-2-carboxylate, 0.63 g (5.83 mmol) of 4-pyridylcarbinol and 1.46 ml (5.83 mmol) of tributylphosphine in 50 ml of toluene. The reaction mixture is stirred overnight at room temperature and then concentrated under reduced pressure and chromatographed on a column of silica (eluent: dichloromethane/methanol). 1.05 g of expected product are obtained.