Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH:11]=O)=[CH:8][C:6]=2[N:7]=1.[NH:19]1[CH2:22][CH:21]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[CH2:20]1.C(OC)(OC)OC.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH2:11][N:19]3[CH2:22][CH:21]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)[CH2:20]3)=[CH:8][C:6]=2[N:7]=1
Reactant: C1CN(C2CNC2)CCO1
Reactant: O=Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Solvent: COC(OC)OC
Product: Clc1nc(N2CCOCC2)c2sc(CN3CC(N4CCOCC4)C3)cc2n1
Reaction time: 2 h
Yield: 62.1 %

Procedure:
To a solution of 2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-carbaldehyde (953 mg, 3.36 mmol) in DCE (50 mL) was added 4-azetidin-3-ylmorpholine (525 mg, 3.69 mmol), trimethyl orthoformate (3.67 mL, 33.58 mmol) and acetic acid (0.19 mL, 3.36 mmol). After stirring at room temperature for 2 h sodium triacetoxyborohydride (1.10 g, 5.03 mmol) was added and the resulting mixture stirred for a further 2 h. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge, washed with H2O/MeOH then eluted with 2 M NH3 in MeOH/DCM. The resulting residue was purified by column chromatography (Si—PCC, MeOH:EtOAc, gradient 0:100 to 20:80) to give 2-chloro-4-morpholin-4-yl-6-(3-morpholin-4-yl-azetidin-1-ylmethyl)thieno[3,2-d]pyrimidine as a pale yellow solid (856 mg, 62%). LCMS (Method C): RT=2.77 min, [M+H]+ 410
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][OH:8].[H-].[Na+].O1CCCC1.Br[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]>ClCCl.O>[CH2:17]([O:8][CH2:7][CH2:6][C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: OCCc1cccs1
Reactant: CCCCCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: C1CCOC1
Product: CCCCCCCCCOCCc1cccs1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 60.3 %

Procedure:
17 g of 2-thiopheneethanol was cooled to 0° C., and to this, a suspension formed by adding 7.1 g of sodium hydride (60% in oil) to 110 ml of tetrahydrofuran was added dropwise. The solution was stirred at 0° C. for 20 minutes under a nitrogen atmosphere, and to this, 27 g of 1-bromononane was added dropwise. The resulting solution was heated to 90° C. and stirred for 8 hours. 100 ml of water and 100 ml of dichloromethane were added to the reaction solution to separate the organic layer. The organic layer was washed with 300 ml of saturated salt water and then dried over anhydrous magnesium sulfate. The resulting solution was concentrated by a rotary evaporator and purified by a column chromatography (filler: silica gel, eluent: hexane/dichloromethane) to obtain 20 g of 2-(2-nonyloxyethyl)thiophene.
Reaction SMILES: [CH2:1]([CH:3]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[CH:4](O)[CH2:5][CH3:6])[CH3:2].C#CC([OH:20])CCC.C(O)CCCCCCC/C=C\CCCCCCCC>>[CH2:1]([CH:3]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[CH2:4][CH:5]([OH:20])[CH3:6])[CH3:2]
Reactant: C#CC(O)CCC
Reactant: CCCCCCC(CC)C(O)CC
Agent: CCCCCCCC/C=C\CCCCCCCCO
Product: CCCCCCC(CC)CC(C)O

Procedure:
4-ethyl-3-decanol; 1-hexyn-3-ol and oleyl alcohol.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([CH2:14][OH:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:16][S:17](Cl)(=[O:19])=[O:18]>C(Cl)(Cl)Cl.C(N(CC)CC)C>[CH3:16][S:17]([O:15][CH2:14][C@H:10]1[CH2:11][CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9]1)(=[O:19])=[O:18]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](CO)C1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC[C@H](COS(C)(=O)=O)C1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 7.96 g of {(3S)-1-(tert-butoxycarbonyl)-3-piperidyl}methanol in 150 ml of chloroform, 3.4 ml of methanesulfonyl chloride and 6.7 ml of triethylamine were added under cooling with ice, followed by an hour's stirring at room temperature. The reaction liquid was distilled off under reduced pressure, diluted with ethyl acetate and saturated aqueous sodium bicarbonate solution was added, followed by 1.5 hours' stirring. Thereafter the reaction liquid was successively washed with water and saturated brine and dried over anhydrous magnesium sulfate. Distilling the solvent off, 10.50 g of the title compound was obtained.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][C:5]([N:8]2[C@@H:15]3[C@@H:10]([CH2:11][CH2:12][NH:13][CH2:14]3)[CH2:9]2)=[N:6][CH:7]=1.CC1C=C(C)N=C(N2[C@@H]3[C@@H](CCNC3)C2)N=1.[N:32]1[N:33]([C:37]2[CH:45]=[CH:44][CH:43]=[CH:42][C:38]=2[C:39](O)=[O:40])[N:34]=[CH:35][CH:36]=1.S1C=CC=C1C1C=CC=CC=1C(O)=O>C(Cl)Cl>[CH3:1][C:2]1[N:3]=[CH:4][C:5]([N:8]2[C@@H:15]3[C@@H:10]([CH2:11][CH2:12][N:13]([C:39]([C:38]4[CH:42]=[CH:43][CH:44]=[CH:45][C:37]=4[N:33]4[N:34]=[CH:35][CH:36]=[N:32]4)=[O:40])[CH2:14]3)[CH2:9]2)=[N:6][CH:7]=1
Reactant: O=C(O)c1ccccc1-n1nccn1
Reactant: Cc1cnc(N2C[C@@H]3CCNC[C@@H]32)cn1
Agent: Cc1cc(C)nc(N2C[C@@H]3CCNC[C@@H]32)n1
Agent: O=C(O)c1ccccc1-c1cccs1
Solvent: ClCCl
Product: Cc1cnc(N2C[C@@H]3CCN(C(=O)c4ccccc4-n4nccn4)C[C@@H]32)cn1

Procedure:
The title compound was prepared in a manner analogous to Example 1, substituting (1R,6S)-8-(5-methylpyrazin-2-yl)-3,8-diazabicyclo[4.2.0]octane (Intermediate 29) for (1R,6S)8-(4,6-dimethyl-pyrimidin-2-yl)-3,8-diaza-bicyclo[4.2.0]octane and 2-[1,2,3]triazol-2-yl-benzoic acid (Intermediate 14) for 2-thiophen-2-yl-benzoic acid. DCM was used in place of DMF. MS (ESI) mass calcd. For C20H21N7O, 375.44; m/z found 376.0 [M+H]+. 1H NMR (CDCl3): 8.06-7.78 (m, 3H), 7.72-7.44 (m, 3H), 7.39-7.28 (m, 1H), 7.16-6.96 (m, 1H), 4.56-3.98 (m, 4H), 3.80-2.96 (m, 4H), 2.46-2.03 (m, 5H).
Reaction SMILES: Cl[CH2:2][C:3](=O)[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:15])[CH3:14])=[CH:8][CH:7]=1.C[O:18][C:19]([NH:21][NH2:22])=[S:20]>C1(C)C=CC=CC=1>[C:13]([NH:12][C:9]1[CH:10]=[CH:11][C:6]([CH2:5][CH2:4][CH:3]2[CH2:2][S:20][C:19](=[O:18])[NH:21][NH:22]2)=[CH:7][CH:8]=1)(=[O:15])[CH3:14]
Reactant: CC(=O)Nc1ccc(C=CC(=O)CCl)cc1
Reactant: COC(=S)NN
Solvent: Cc1ccccc1
Product: CC(=O)Nc1ccc(CCC2CSC(=O)NN2)cc1

Procedure:
A mixture containing 4.0 g of 1-chloro-4-(4-acetamidophenyl)-2-oxo-3-butene (J. Org. Chem., 28, 2446, 1963) and 2.3 g of hydrazinecarbothioic acid O-methylester in 150 ml of toluene was refluxed for 3 h. The crystals were filtered and washed with toluene. Yield 3.0 g (65%), mp. 235°-240° C.
Reaction SMILES: [CH3:1][Si:2]([CH3:11])([CH3:10])[C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)[NH2:6].N1C=CC=CC=1.Cl[C:19]([C:21]1[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][CH:22]=1)=[O:20].O>C1C=CC=CC=1>[CH3:1][Si:2]([CH3:11])([CH3:10])[C:3]1[CH:4]=[C:5]([NH:6][C:19]([C:21]2[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][CH:22]=2)=[O:20])[CH:7]=[CH:8][CH:9]=1
Reactant: C[Si](C)(C)c1cccc(N)c1
Reactant: COC(=O)c1ccc(C(=O)Cl)cc1
Solvent: c1ccccc1
Solvent: O
Solvent: c1ccncc1
Product: COC(=O)c1ccc(C(=O)Nc2cccc([Si](C)(C)C)c2)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 101.7 %

Procedure:
To a solution of 135 mg (0.817 mmol) of m-trimethylsilylaniline in 8 ml of dry benzene were added 1.0 ml of dry pyridine and 179 mg (0.900 mmol) of methyl p-chloroformylbenzoate, successively. The mixture was stirred at room temperature for 20 hours. To the reaction mixture was added water and the aqueous solution was extracted with AcOEt. The extract was washed successively with water, sat.eq.NaHCO3 and sat.ag.NaCl, dried and evaporated to give 272 mg of white powder, which was purified by column chlomatography on silica gel (eluent: methylene chloride) to give 266 mg of white powder (yield: 99%). Recrystallization of the powder from a mixture of methylene chloride, n-hexane and chloroform gave 120 mg of white needles, m.p. 125°-126° C. (yield 45%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=1.CN(C)C=O.S(Cl)([Cl:21])=O.[CH:23]([N:26]([CH2:30][CH3:31])[CH:27]([CH3:29])[CH3:28])([CH3:25])[CH3:24]>COCCOC>[Cl-:21].[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=1.[CH:23]([N:26]([CH2:30][CH3:31])[CH:27]([CH3:29])[CH3:28])([CH3:25])[CH3:24]
Reactant: O=S(Cl)Cl
Agent: COC(=O)c1ccc(C(=O)O)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: COCCOC
Solvent: CN(C)C=O
Product: [Cl-]
Temperature: 10 °C
Reaction time: 0.63 h

Procedure:
A suspension of 1.997 kg (11.08 mol) of terephthalic acid monomethyl ester in 15.60 kg of 1,2-dimethoxyethane was stirred in a nitrogen atmosphere while being cooled at 10° C. To the suspension was added 400 mL (5.17 mol) of N,N-dimethylformamide and 1.323 kg (10.56 mol) of thionyl chloride in this order, and then the container was washed with 1.00 L of 1,2-dimethoxyethane. The suspension was stirred under heating at 60 to 73° C. for 1 hour and 2 minutes and then stirred while being cooled. 1.36 kg (10.52 mol) of N,N-diisopropylethylamine was added dropwise to the solution while cooling at 0° C., and the container was washed with 1.00 L of 1,2-dimethoxyethane. Then the reaction solution was stirred at 25° C., and the stirring was stopped 38 minutes after the internal temperature had reached 20° C. The reaction mixture was transferred into a plastic container, and 22.00 kg of “monomethyl terephthalate chloride/N,N-diisopropylethylamine” solution (terephthalic acid monomethyl ester chloride content: 1.84 kg) was obtained as a slightly tannish solution.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)[C:9](=[O:22])[CH2:8][CH2:7]2)([O-])=O.N>CO.[Ni].CO.C(Cl)Cl>[NH2:1][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH2:14][CH2:15][N:16]1[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]1)[C:9](=[O:22])[CH2:8][CH2:7]2
Reactant: O=C1CCc2cc([N+](=O)[O-])ccc2N1CCN1CCCCC1
Agent: [Ni]
Agent: N
Solvent: CO
Solvent: ClCCl
Product: Nc1ccc2c(c1)CCC(=O)N2CCN1CCCCC1
Yield: 77.6 %

Procedure:
A solution of 6-nitro-1-(2-(piperidin-1-yl)ethyl)-3,4-dihydroquinolin-2(1H)-one (500 mg, 1.65 mmol) in 10 mL methanol was added to Raney Nickel (slurry in H2O, 50 mg) in a round bottom flask. The suspension was heated at reflux for 10 minutes then filtered through a pad of celite. The celite pad was washed with 10 mL methanol. The filtrate was concentrated to give a dark brown residue was subjected to flash silica gel chromatography using 5% 2M NH3 in MeOH/CH2Cl2 to give an off-white solid (350 mg, 77.7%). 1H-NMR (DMSO-d6) δ: 6.81 (d, J=8.2 Hz, 1H), 6.46-6.41 (m, 2H), 4.84 (br s, 2H), 3.87 (t, J=7.1 Hz, 2H), 2.66 (t, J=6.5 Hz, 2H), 2.40-2.32 (m, 8H), 1.46-1.35 (m, 6H); MS (ESI): 274.2 (M+1, 100%).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:4][CH2:3]1.Cl[C:17]1[N:22]=[CH:21][CH:20]=[CH:19][N:18]=1>CN(C=O)C.CCOC(C)=O>[N:18]1[CH:19]=[CH:20][CH:21]=[N:22][C:17]=1[NH:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:14])[CH3:13])[CH2:4][CH2:3]1
Reactant: Clc1ncccn1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](N)CC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](Nc2ncccn2)CC1

Procedure:
As shown in step 5-i of Scheme 5, a mixture of tert-butyl ((cis)-4-aminocyclohexyl)carbamate (compound 1009, 490 mg, 2.3 mmol), 2-chloropyrimidine (262 mg, 2.3 mmol) and TEA (463 mg, 6374, 4.6 mmol) in DMF (10 mL) was subjected to microwave irradiation for 20 minutes at 150° C. The reaction mixture was diluted with EtOAc, washed with H2O, dried over Na2SO4, concentrated under reduced pressure, and purified by medium pressure silica gel chromatography (0 to 50% EtOAc/hexanes gradient) to provide tert-butyl ((cis)-4-(pyrimidin-2-ylamino)cyclohexyl)carbamate (compound 1010) as a white solid: 1H-NMR (300 MHz, CDCl3) δ 8.28 (d, J=4.8 Hz, 2H), 6.53 (t, J=4.8 Hz, 1H), 5.12 (s, 1H), 4.56 (s, 1H), 3.99 (dq, J=7.0, 3.5 Hz, 1H), 3.65 (s, 1H), 1.83 (tq, J=10.2, 3.6 Hz, 5H), 1.66 (s, 8H), 8.13-7.91 (m, 3H), 1.47 (s, 9H).
Reaction SMILES: C(N(CC)CC)C.Cl.Cl.[C:10](=[NH:20])(OCC)[CH2:11][C:12](=[NH:16])OCC.[C:21]1([NH:27][NH2:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(O)C>[NH2:16][C:12]1[CH:11]=[C:10]([NH2:20])[N:27]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:28]=1
Reactant: CCOC(=N)CC(=N)OCC
Reactant: NNc1ccccc1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: Nc1cc(N)n(-c2ccccc2)n1
Temperature: 95 °C
Reaction time: 0.5 h

Procedure:
Triethylamine (6 ml) was added over 5 minutes to a stirred suspension of diethyl malonimidate dihydrochloride (5 g) in ethanol (50 ml). Phenylhydrazine (2.1 ml) was added, then the mixture was stirred at ambient temperature for 4 hours and at 95° C. for 30 minutes. The solvent was removed in vacuo, and the residue was partitioned between ethyl acetate (100 ml) and water (50 ml). The organic layer was separated, washed with water (50 ml), dried (MgSO4), and the solvent was removed in vacuo. The residue was purified by flash chromatography over silica using a 19:1 mixture of dichloromethane and methanol as eluant, appropriate fractions were combined, and the solvents were removed in vacuo to give 3,5-diamino-1-phenylpyrazole as a red-brown oil (0.76 g).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][NH:3][C:2]1=[O:6].[H-].[Na+].Br[CH2:10][C:11]1[S:19][C:18]2[C:17]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[N:16][C:15](Cl)=[N:14][C:13]=2[CH:12]=1.C[N:28]([CH:30]=O)C>>[NH:28]1[C:30]2[C:18](=[C:13]([C:15]3[N:16]=[C:17]([N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)[C:18]4[S:19][C:11]([CH2:10][N:3]5[CH2:4][CH2:5][O:1][C:2]5=[O:6])=[CH:12][C:13]=4[N:14]=3)[CH:12]=[CH:11][CH:10]=2)[CH:17]=[N:16]1
Reactant: O=C1NCCO1
Reactant: CN(C)C=O
Reactant: Clc1nc(N2CCOCC2)c2sc(CBr)cc2n1
Agent: [H-]
Agent: [Na+]
Product: O=C1OCCN1Cc1cc2nc(-c3cccc4[nH]ncc34)nc(N3CCOCC3)c2s1
Reaction time: 0.25 h

Procedure:
To a solution of 2-oxazolidinone (50 mg, 0.6 mmol) in DMF (2 mL) at 0° C. NaH (60% in mineral oil; 0.7 mmol) was added. After 15 minutes, 6-(bromomethyl)-2-chloro-4-morpholinothieno[3,2-d]pyrimidine 30 from Example 9 (200 mg, 0.6 mmol) in DMF (0.5 mL) was added and the reaction stirred 15 min. The reaction was quenched by the addition of saturated aqueous ammonium chloride. The aqueous layer was extracted with EtOAc. The combined organics were dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was utilized in a Suzuki coupling using General Procedure A with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole 7 to provide 311 after reverse phase HPLC purification (6 mg). MS (Q1) 437 (M)+
Reaction SMILES: [CH3:1][C:2]1(C)[O:9]C(=O)CC(=O)[O:3]1.[C:11]([O:20][CH2:21][CH3:22])(=[O:19])[C:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=O.C(O)=O.Cl>O.C(N(CC)CC)C>[CH2:17]([O:16][C:14]([CH:12]([C:11]([O:20][CH2:21][CH3:22])=[O:19])[CH2:1][C:2]([OH:9])=[O:3])=[O:15])[CH3:18]
Reactant: CCOC(=O)C(=O)C(=O)OCC
Reactant: CC1(C)OC(=O)CC(=O)O1
Agent: Cl
Solvent: O=CO
Solvent: CCN(CC)CC
Solvent: O
Product: CCOC(=O)C(CC(=O)O)C(=O)OCC
Temperature: 95 °C
Reaction time: 0.5 h

Procedure:
After weighing in 14.4 g (0.1 mol) of Meldrum's acid and 17.4 g (0.1 mol, 15.5 ml) of diethyl mesoxalate to 100 ml of the mixture of formic acid and triethylamine prepared as described in Example 1, the reaction mixture was heated to 95° C. during 1 hour and reacted at the same temperature for 2 hours. After cooling the reaction mixture to room temperature, adding 350 ml of water and adjusting the pH value to 2 with concentrated hydrochloric acid, the aqueous solution was extracted with 200 ml and then with 100 ml of chloroform. The combined chloroform extract was stirred with 5 g of sodium sulfate and 1 g of activated charcoal at room temperature for 30 minutes, then filtered and the chloroform was distilled off under reduced pressure. After adding 25 ml of diethyl ether to the evaporation residue the mixture was let stand at 0°-5° C. for 16 hours. After filtering the white solid precipitate, ether was evaporated from the filtrate to give the aimed product as a liquid residue.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:12][CH2:13][C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)=[N:4][N:3]=1.[C:20]([CH:24]1[CH2:29][CH2:28][CH:27]([NH2:30])[CH2:26][CH2:25]1)([CH3:23])([CH3:22])[CH3:21]>C(OCC)(=O)C.O.N>[C:20]([C@@H:24]1[CH2:25][CH2:26][C@H:27]([NH:30][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([CH2:12][CH2:13][C:14]3[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=3)=[N:4][N:3]=2)[CH2:28][CH2:29]1)([CH3:23])([CH3:21])[CH3:22]
Reactant: CC(C)(C)C1CCC(N)CC1
Reactant: Clc1nnc(CCc2cccnc2)c2ccccc12
Agent: N
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)[C@H]1CC[C@@H](Nc2nnc(CCc3cccnc3)c3ccccc23)CC1

Procedure:
Under N2-atmosphere, 500 mg (1.85 mmol) 1-chloro-4-[2-(pyridin-3-yl)ethyl]phthalazine and 1.25 g (8 mmol) of 4-tert.-butylcyclohexylamine (trans/cis mixture) are heated at 150° C. for 2.5 h. The reaction mixture is diluted with ethyl acetate, water and conc. NH3-solution (=1 ml), then the aqueous layer is separated off and extracted 2× with ethyl acetate. The organic phases are washed twice with water and brine, dried (Na2SO4) and concentrated. Chromatography (SiO2; ethyl acetate to ethyl acetate/ethanol 10:1) yields the trans isomer followed by the cis isomer of the title compound. trans 1-(4-tert.-Butylcyclohexylamino)-4-[(2-(pyridin-3-yl)ethyl]phthalazine: m.p. 155-157° C.; 1H-NMR (DMSO-d6) 8.50 (s, 1H), 8.38 (d, 1H), 8.35 (d, 1H), 8.06 (d, 1H), 7.83 (m, 2H), 7.74 (d, 1H), 7.30 (m, 1H), 6.89 (d, HN), 4.08 (m, 1H), 3.38 (t, 2H), 3.10 (t, 2H), 2.12 (m, 2H), 1.81 (m, 2H), 1.35 (q, 2H), 1.14 (q, 2H), 1.07 (m, 1H), 0.88 (s, 9H); FAB-MS (M+H)+=389. cis 1-(4-tert.-Butylcyclohexylamino)-4-[(2-(pyridin-3-yl)ethyl]phthalazine: 1H-NMR (DMSO-d6) 8.48 (m, 2H), 8.38 (d, 1H), 8.08 (m, 1H), 7.84 (m, 2H), 7.73 (m, 1H), 7.29 (m, 1H), 6.49 (d, HN), 4.33 (sb, 1H), 3.39 (m, 2H), 3.10 (m, 2H), 2.18 (d, 2H), 1.6-1.4 (m, 6H), 1.06 (m, 1H), 0.87 (s, 9H); FAB-MS (M+H)+-=389.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.CN(C)[CH:8]=[O:9].[CH3:11][C:12]1[CH:13]=[C:14]([C:23]([O:25][CH3:26])=[O:24])[N:15]([CH2:18][C@H:19]2[CH2:21][C@@H:20]2[CH3:22])[C:16]=1[CH3:17].C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1.O>[CH:8]([C:13]1[C:12]([CH3:11])=[C:16]([CH3:17])[N:15]([CH2:18][C@H:19]2[CH2:21][C@@H:20]2[CH3:22])[C:14]=1[C:23]([O:25][CH3:26])=[O:24])=[O:9]
Reactant: COC(=O)c1cc(C)c(C)n1C[C@H]1C[C@@H]1C
Reactant: CN(C)C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: COC(=O)c1c(C=O)c(C)c(C)n1C[C@H]1C[C@@H]1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78.2 %

Procedure:
Phosphorous oxychloride (2.15 g, 14 mmol) was added to a solution of dimethylformamide (1.10 g, 15 mmol) in toluene (2 ml) and the mixture was stirred at room temperature for 30 minutes. To this mixture was added a solution of methyl 4,5-dimethyl-1-[(1S,2S)-2-methylcyclopropylmethyl]pyrrole-2-carboxylate (2.21 g, 10 mmol) in toluene (6 ml) and the mixture was then heated at 80° C. for 10 hours. After this time, the reaction mixture was poured into water and neutralized with saturated aqueous sodium hydrogencarbonate solution. The organic layer was separated and was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and then concentrated in vacuo. The residue was chromatographed on a column using ethyl acetate/hexane=10/1 as the eluant to afford the title compound (1.95 g, 78.2%) as a pale yellow oil.
Reaction SMILES: Cl[C:2]1[C:3]([CH2:10][N:11]2[CH:15]=[CH:14][N:13]=[C:12]2[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[N:17]=2)=[N:4][CH:5]=[C:6]([O:8][CH3:9])[N:7]=1.C([Sn](CCCC)(CCCC)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1)CCC>C1(C)C=CC=CC=1.C(Cl)Cl.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:22][C:18]1[N:17]=[C:16]([C:12]2[N:11]([CH2:10][C:3]3[C:2]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=4)=[N:7][C:6]([O:8][CH3:9])=[CH:5][N:4]=3)[CH:15]=[CH:14][N:13]=2)[CH:21]=[CH:20][CH:19]=1
Reactant: COc1cnc(Cn2ccnc2-c2cccc(F)n2)c(Cl)n1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COc1cnc(Cn2ccnc2-c2cccc(F)n2)c(-c2ccccn2)n1
Temperature: 110 °C
Yield: 86.1 %

Procedure:
A mixture of 3-chloro-2-[2-(6-fluoro-pyridin-2-yl)-imidazol-1-ylmethyl]-5-methoxy-pyrazine (80 mg, 0.25 mmol), 2-tributylstannylpyridine (138 mg, 0.37 mmol), and PdCl2(PPh3)2 (18 mg, 0.026 mmol) in toluene (10 mL) is heated at 110° C. in a sealed tube for 16 hours. On cooling, the mixture is diluted with DCM (20 mL) and filtered. After the solvent is removed, the residue is purified by PTLC (silica gel; 5% MeOH in DCM) to give 78 mg of 2-[2-(6-fluoro-pyridin-2-yl)-imidazol-1-ylmethyl]-5-methoxy-3-pyridin-2-yl-pyrazine. 1H NMR (CDCl3) 8.59 (d, 1H), 8.15 (d, 1H), 8.08 (s, 1H), 8.02 (d, 1H), 7.85(t, 1H), 7.72 (dd, 1H), 7.32 (dd, 1H), 7.10 (s, 1H), 7.15 (s, 1H), 6.65 (dd, 1H), 6.31 (s, 2H), 4.01 (s, 3H). G. 2-[1-(3-Chloro-5-methoxy-pyrazin-2-ylmethyl)-1H-imidazol-2-yl]-pyrimidine (Compound 8) 1. Synthesis of 2-(1H-imidazol-2-yl)-pyrimidine hydrochloride
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][CH:18]=[CH:17][C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([Cl:14])=[CH:11][CH:12]=2)[C:7](=[O:15])[C:6]1=[O:16].[N+:21]([CH3:24])([O-:23])=[O:22]>O>[Cl:14][C:10]1[CH:9]=[C:8]2[C:13](=[CH:12][CH:11]=1)[N:5]([CH2:4][C:3]1[CH:17]=[CH:18][CH:19]=[CH:20][C:2]=1[Cl:1])[C:6](=[O:16])[C:7]2([OH:15])[CH2:24][N+:21]([O-:23])=[O:22]
Reactant: O=C1C(=O)N(Cc2ccccc2Cl)c2ccc(Cl)cc21
Reactant: C[N+](=O)[O-]
Solvent: O
Product: O=C1N(Cc2ccccc2Cl)c2ccc(Cl)cc2C1(O)C[N+](=O)[O-]
Temperature: 30 °C
Reaction time: 18 h

Procedure:
1-(2-chlorobenzyl)-5-chloroindoline-2,3-dione (0.153 g) and nitromethane (0.15 ml) were added to water and the reaction mixture was vigorously stirred at a temperature of 30° C. for 18 hours. The formed solid product was filtered and recrystallized with MeOH to afford pure product.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[C:17]([O:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[CH:22][CH:21]=2)=[O:18])=[CH:11][CH:10]=1.[NH2:32][C:33]1[CH:34]=[C:35]([CH:39]=[C:40]([NH2:42])[CH:41]=1)[C:36]([OH:38])=[O:37]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O>[NH2:32][C:33]1[CH:34]=[C:35]([CH:39]=[C:40]([NH2:42])[CH:41]=1)[C:36]([O:38][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[C:17]([O:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[CH:22][CH:21]=2)=[O:18])=[CH:11][CH:10]=1)=[O:37]
Reactant: CCCCCOc1ccc(OC(=O)/C=C/c2ccc(OCCCCCCCl)cc2)cc1
Reactant: Nc1cc(N)cc(C(=O)O)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CN(C)C=O
Product: CCCCCOc1ccc(OC(=O)/C=C/c2ccc(OCCCCCCOC(=O)c3cc(N)cc(N)c3)cc2)cc1
Temperature: 80 °C
Yield: 69.9 %

Procedure:
7.50 g (16.85 mmol) 4-pentoxyphenyl (2E)-3-{4-(6-chlorohexyloxy)phenyl}acrylate, 2.82 g (18.54 mmol) 3,5-diaminobenzoic acid and 0.62 g (1.69 mmol) tetrabutylammonium iodide were dissolved in 80 ml dimethylformamide. 3.00 ml (20.22 mmol) 1,8-diazabicyclo[5.4.0]undec-7-ene(1,5-5) (DBU) were added dropwise in the course of 10 minutes. The reaction temperature rose to 30° C. The mixture was then heated at 80° C. for 22 h. The reaction mixture was cooled and then partitioned between ethyl acetate and a saturated sodium bicarbonate solution; the organic phase was washed repeatedly with water, dried over sodium sulphate, filtered and concentrated by rotary evaporation. Chromatography of the residue on 1 kg silica gel using cyclohexane:ethyl acetate 1:1 as eluent yielded 6.6 g of 6-{4-[(1E)-3-(4-pentyloxyphenoxy)-3-oxoprop-1-enyl]phenoxy}hexyl 3,5 diamino-benzoate.