Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[C:9]3[C:15]([C:16]4[N:21]=[C:20]([N:22]5[CH2:28][CH2:27][CH2:26][C@H:25]([NH:29]C(=O)OCC6C=CC=CC=6)[CH2:24][CH2:23]5)[CH:19]=[CH:18][CH:17]=4)=[N:14][N:13](C4CCCCO4)[C:10]3=[CH:11][N:12]=2)[CH:4]=[N:3]1.B(Br)(Br)Br.C(OCC)(=O)C.O>C(Cl)Cl>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[C:9]3[C:15]([C:16]4[N:21]=[C:20]([N:22]5[CH2:28][CH2:27][CH2:26][C@H:25]([NH2:29])[CH2:24][CH2:23]5)[CH:19]=[CH:18][CH:17]=4)=[N:14][NH:13][C:10]3=[CH:11][N:12]=2)[CH:4]=[N:3]1
Reactant: Cn1cc(-c2cc3c(-c4cccc(N5CCC[C@H](NC(=O)OCc6ccccc6)CC5)n4)nn(C4CCCCO4)c3cn2)cn1
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cn1cc(-c2cc3c(-c4cccc(N5CCC[C@H](N)CC5)n4)n[nH]c3cn2)cn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 8.5 %

Procedure:
To a solution of benzyl (4S)-1-(6-(5-(1-methyl-1H-pyrazol-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)pyridin-2-yl)azepan-4-ylcarbamate (70.0 mg, 0.13 mmol) in DCM (5.0 mL) at −10° C. was added dropwise 1 M of boron tribromide in DCM (0.33 mL, 0.33 mmol), and the reaction mixture was slowly warmed to room temperature (RT) and stirred at RT under N2 for 16 h. The reaction mixture was diluted into ethyl acetate and water. The organic layer was washed with aqueous saturated sodium bicarbonate solution, water and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude was redissolved in DMSO (1 mL) and was purified by reverse phase HPLC to give 227 as a white solid (4.3 mg, 8.3%). 1H NMR (400 MHz, DMSO) δ 9.03 (s, 1H), 8.55 (s, 1H), 8.11 (s, 1H), 7.83 (s, 1H), 7.60 (t. J=7.8 Hz, 1H), 7.37 (d, J=7.1 Hz, 1H), 6.61 (d, J=8.4 Hz, 1H), 3.91 (s, 3H), 3.85-3.75 (m, 1H), 3.74-3.58 (m, 2H), 3.33-3.40 (m, 1H), 2.95-2.85 (m, 1H), 2.12-1.93 (m, 2H), 1.86-1.58 (m, 3H), 1.56-1.33 (m, 2H); 2 protons not seen. LC/MS: m/z 389.4 [M+1]
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[OH:11].CC[O:14][CH2:15][CH3:16].[C:17](O)(=O)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28].CS(O)(=O)=O>>[C:15]([O:11][C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]=1)(=[O:14])[CH2:16][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:9][CH2:10][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCOCC
Reactant: Oc1ccc2ccccc2c1
Reactant: CCCCCCCCCCCC(=O)O
Agent: CS(=O)(=O)O
Product: CCCCCCCCCCCCCCCCCCCCCC(=O)Oc1ccc2ccccc2c1
Temperature: 220 °C

Procedure:
To a four neck round bottom flask fitted with nitrogen inlet, mechanical stirrer, temperature probe and condenser is charged 1017.59 g (1.80 moles) of the Alkoxylate from example 18 and 582.41 g (1.71 moles) of Lauric Acid. A catalytic amount of Methanesulfonic Acid (1.6 g) is charged and the reaction mixture is heated to 220° C. under nitrogen sparge. The reaction is monitored by measuring the acid value to an AV of preferably less than 5. Once the AV is reached, the temperature is cooled to 85° C. and the catalyst is neutralized with an equivalent molar amount of 45% KOH and washed once with water. The reaction is dried under vacuum yielding the desired product.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C@@H:3]([OH:26])[CH2:4][C@@H:5]([NH:13][C:14]([C@@H:16]([NH:21][C:22](=[O:25])[O:23][CH3:24])[C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.FC(F)(F)C(O)=O.[CH3:41][C@@H:42]([CH2:64][CH3:65])[C@H:43]([N:47]1[CH2:51][CH2:50][N:49]([CH2:52][C:53]2[C:62]3[C:57](=[CH:58][CH:59]=[CH:60][CH:61]=3)[N:56]=[CH:55][CH:54]=2)[C:48]1=[O:63])[C:44](O)=[O:45].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1>CN(C=O)C>[CH2:6]([C@H:5]([NH:13][C:14]([C@@H:16]([NH:21][C:22](=[O:25])[O:23][CH3:24])[C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:4][C@H:3]([OH:26])[C@@H:2]([NH:1][C:44](=[O:45])[C@@H:43]([N:47]1[CH2:51][CH2:50][N:49]([CH2:52][C:53]2[C:62]3[C:57](=[CH:58][CH:59]=[CH:60][CH:61]=3)[N:56]=[CH:55][CH:54]=2)[C:48]1=[O:63])[CH:42]([CH3:41])[CH2:64][CH3:65])[CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccccc1)C[C@H](O)[C@@H](N)Cc1ccccc1)C(C)(C)C
Reactant: CC[C@H](C)[C@@H](C(=O)O)N1CCN(Cc2ccnc3ccccc23)C1=O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CCC(C)[C@@H](C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)C[C@H](Cc1ccccc1)NC(=O)[C@@H](NC(=O)OC)C(C)(C)C)N1CCN(Cc2ccnc3ccccc23)C1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 22.5 %

Procedure:
A solution containing the product from Example 3D (0.078 g, 0.171 mmol) in DMF (0.5 mL) was treated with the product from Example 4A (0.070 g, 0.205 mmol), EDAC (0.050 g, 0.261 mmol), HOBT (0.035 g, 0.259 mmol), and NMM (0.060 mL, 0.546 mmol) at 0° C., stirred at 25° C. for 16 hours and partitioned between ethyl acetate and water. The organic phase was washed with 10% citric acid, diluted sodium bicarbonate, and brine, dried over MgSO4, filtered and concentrated. The residue was purified by reversed phase chromatography on a C18 column, eluting with 5-100% acetonitrile in water (0.1% TFA) to give the title compound (0.030 g, 23% yield). 1H NMR (300 MHz, DMSO-d6), δ ppm 0.79 (m, 15 H), 1.00 (m, 1 H), 1.25 (m, 1 H), 1.51 (m, 2 H), 1.82 (m, 1 H), 2.64 (m, 5 H), 3.02 (m, 3 H), 3.55 (s, 3 H), 3.63 (m, 1 H), 3.82 (d, J=9.93 Hz, 1 H), 3.99 (d, J=11.03 Hz, 1 H), 4.13 (m, 2 H), 4.64 (d, J=7.72 Hz, 1 H), 4.80 (m, 2 H), 6.62 (d, J=9.93 Hz, 1 H), 6.98 (m, 5 H), 7.14 (m, 5 H), 7.32 (d, J=9.56 Hz, 1 H), 7.41 (d, J=4.41 Hz, 1 H), 7.62 (t, J=7.54 Hz, 1 H), 7.76 (m, 2 H), 8.06 (d, J=7.72 Hz, 1 H), 8.30 (d, J=8.46 Hz, 1 H), 8.88 (d, J=4.41 Hz, 1 H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH3:14])([CH3:13])[CH2:8][C:9]2=[O:12])=[CH:5][CH:4]=1.[CH3:15][CH:16](O)[CH:17]=[CH2:18].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>COC(OC)(C)C>[CH2:15]([CH:8]1[C:7]([CH3:14])([CH3:13])[C:6]2[C:10](=[CH:11][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[C:9]1=[O:12])[CH:16]=[CH:17][CH3:18]
Reactant: C=CC(C)O
Reactant: COc1ccc2c(c1)C(=O)CC2(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: COC(C)(C)OC
Solvent: O
Product: CC=CCC1C(=O)c2cc(OC)ccc2C1(C)C
Yield: 38 %

Procedure:
A solution of 12.1 g of 6-methoxy-3.3-dimethyl-1-indanone, 11.1 ml of 3-buten-2-ol and 110 mg of p-toluenesulfonic acid in 110 ml of 2,2-dimethoxy-propane was boiled under reflux for 67 hours on a water separator filled with molecular sieve (0.4 nm, 2 mm pearl shaped). The reaction mixture was subsequently concentrated in a vacuum and purified by column chromatography on silica gel (hexane/diethyl ether 4:1). In addition to 4.64 g of educt, there were obtained 5.86 g (38%) of (RS)-2-(2-buten-1-yl)-6-methoxy-3,3-dimethyl-1-indanone as a yellow oil.
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[H-].[Na+].Cl.[CH:13]1([CH:18]([NH:20][C:21]2[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][CH:22]=2)[CH3:19])[CH2:17][CH2:16][CH2:15][CH2:14]1>COCCOC>[CH:13]1([CH:18]([NH:20][C:21]2[CH:29]=[CH:28][C:24]([C:25]([CH:2]([C:3]([CH3:5])=[O:4])[C:1]([O:7][CH2:8][CH3:9])=[O:6])=[O:26])=[CH:23][CH:22]=2)[CH3:19])[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: CCOC(=O)CC(C)=O
Reactant: CC(Nc1ccc(C(=O)Cl)cc1)C1CCCC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CCOC(=O)C(C(C)=O)C(=O)c1ccc(NC(C)C2CCCC2)cc1

Procedure:
A solution of 21.6 g. of ethyl acetoacetate and 10 ml. of 1,2-dimethoxyethane is added to a suspension of 4.0 g. of sodium hydride in 1,2-dimethoxyethane under argon. A solution of 17.3 g. of 4-(1-cyclopentylethylamino)benzoyl chloride hydrochloride in 1,2-dimethoxyethane is then added. The reaction mixture is refluxed for 5 hours, cooled, poured on ice and extracted with ether. The ether solution is washed with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated to dryness. Recrystallization from ether affords ethyl 2-[4-(1-cyclopentylethylamino)benzoyl]acetoacetate as a white solid.
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].[CH3:9][O:10][C:11](=[O:20])[C:12]([CH3:19])([CH3:18])[C:13](=O)[CH2:14][O:15][CH3:16].C([BH3-])#N.[Na+].C(O)(=O)C>CO.CCOC(C)=O>[CH3:9][O:10][C:11](=[O:20])[C:12]([CH3:18])([CH3:19])[CH:13]([NH:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[NH2:8])[CH2:14][O:15][CH3:16]
Reactant: COCC(=O)C(C)(C)C(=O)OC
Reactant: Nc1ccccc1N
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: CC(=O)O
Product: COCC(Nc1ccccc1N)C(C)(C)C(=O)OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 24.9 %

Procedure:
To a mixture of 1,2-phenylenediamine (900 mg, 8.3 mmol) and 4-methoxy-2,2-dimethyl-3-oxo-butyric acid methyl ester (1.7 g, 9.8 mmol) in MeOH (5 mL) was added sodium cyanoborohydride (700 mg, 11.1 mmol) and acetic acid (1.0 mL). The mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with EtOAc (100 mL) and washed with H2O (75 mL×3). The organic layer was dried over sodium sulfate and concentrated. The resulting residue was purified by CombiFlash with 40% EtOAc in Hexane as the eluent to afford the desired 3-(2-amino-phenylamino)-4-methoxy-2,2-dimethyl-butyric acid methyl ester (550 mg, 25%).
Reaction SMILES: [CH3:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[C:7]([CH3:14])[C:3]=1[C:4](O)=[O:5].B.O>O1CCCC1>[CH3:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[C:7]([CH3:14])[C:3]=1[CH2:4][OH:5]
Reactant: Cc1ccc([N+](=O)[O-])c(C)c1C(=O)O
Agent: B
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc([N+](=O)[O-])c(C)c1CO
Temperature: 75 °C
Yield: 93.8 %

Procedure:
2,6-Dimethyl-3-nitrobenzoic acid (10 g) was dissolved in 100 ml of dry tetrahydrofuran and 165 ml of 1M borane in tetrahydrofuran added. The mixture was heated to 75° C. for 4 hr. The mixture was cooled to room temperature and the excess reagent slowly decomposed with water and the solvent evaporated. The residue was treated with ethyl acetate, washed with 1M hydrochloric acid, then with water, dried, and evaporated to give 8.71 g of (2,6-dimethyl-3-nitro-phenyl)-methanol, mp 94.5-96.1° C. ##STR124##
Reaction SMILES: [CH2:1]([N:4]([CH2:10][CH:11]=O)[C:5](=[O:9])[O:6][CH2:7][CH3:8])[CH:2]=[CH2:3].[CH2:13]([NH:20][CH:21]([CH2:25][CH2:26][CH:27]1[O:32][CH2:31][CH2:30][CH2:29][O:28]1)C(O)=O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C1(C)C=CC=CC=1>[CH2:13]([N:20]1[CH:21]([CH2:25][CH2:26][CH:27]2[O:28][CH2:29][CH2:30][CH2:31][O:32]2)[CH2:3][CH:2]2[CH:11]1[CH2:10][N:4]([C:5]([O:6][CH2:7][CH3:8])=[O:9])[CH2:1]2)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=C(O)C(CCC1OCCCO1)NCc1ccccc1
Reactant: C=CCN(CC=O)C(=O)OCC
Solvent: Cc1ccccc1
Product: CCOC(=O)N1CC2CC(CCC3OCCCO3)N(Cc3ccccc3)C2C1
Yield: 70.5 %

Procedure:
A mixture of N-allyl-N-(2-oxoethyl)carbamic acid, ethyl ester (Schenke, T.; Peterson, U. Eur. patent EPO393424A2, 1992) (0.203 g, 1.19 mmol) and 2-benzylamino-4-(1,3-dioxan-2-yl)butyric acid (0.330 g, 1.18 mmol) in anhydrous toluene (5 mL) was heated at reflux under argon for 24 h. After cooling, the solvents were removed in vacuo and the residue was purified by flash chromatography (silica gel, 50% EtOAc/petroleum ether) to give 0.3234 g (71%) of the title compound as a yellow oil. δH (360 MHz, CDCl3) 1.26 (3H, m), 1.28-1.40 (2H, m), 1.48-1.89 (5H, m), 2.05 (1H, m), 2.69 (1H, m), 2.94 (1H, m), 3.10 (1H, m), 3.30-3.47 (4H, m), 3.58 (1H, m), 3.74 (2H, td), 3.92 (1H, d, J=13.6 Hz), 4.07-4.14 (4H, m), 4.48 (1H, t, J=5.0 Hz), 7.22-7.34 (5H, m). m/e (ES+) 389 (M+H)+.
Reaction SMILES: Cl[C:2](=[N:13][OH:14])[C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6]([O:8][CH3:9])=[O:7].[C:15]([C:17]1[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=1)#[CH:16].C(N(CC)CC)C.O>O1CCCC1>[F:24][C:23]([F:25])([F:26])[C:20]1[CH:19]=[CH:18][C:17]([C:15]2[O:14][N:13]=[C:2]([C:3]3[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=3)[C:6]([O:8][CH3:9])=[O:7])[CH:16]=2)=[CH:22][CH:21]=1
Reactant: C#Cc1ccc(C(F)(F)F)cc1
Reactant: COC(=O)c1cccc(C(Cl)=NO)c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: COC(=O)c1cccc(-c2cc(-c3ccc(C(F)(F)F)cc3)on2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.1 %

Procedure:
To a solution (60 ml) of methyl 3-[chloro(hydroxyimino)methyl]benzoate (2.14 g) and 1-ethynyl-4-trifluoromethylbenzene (1.73 g) in tetrahydrofuran was added dropwise a solution (40 ml) of triethylamine(2.79 ml) in tetrahydrofuran under an argon atmosphere at 0° C. This mixture was stirred overnight at room temperature and poured into water. The mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was recrystallized from hexane-ethyl acetate to give methyl 3-[5-(4-trifluoromethylphenyl)-3-isoxazolyl]benzoate (1.64 g, yield 47%) as a colorless crystalline powder. melting point: 139–140° C.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:36])=[C:9]([CH2:11][O:12][C:13]2[CH:33]=[CH:32][C:16]([CH2:17][O:18][C:19]3[CH:23]=[C:22]([CH:24]=O)[N:21]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[N:20]=3)=[CH:15][C:14]=2[O:34][CH3:35])[N:10]=1.[Cl-].[S:38]1[CH:42]=[C:41]([CH2:43][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[N:40]=[CH:39]1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:36])=[C:9]([CH2:11][O:12][C:13]2[CH:33]=[CH:32][C:16]([CH2:17][O:18][C:19]3[CH:23]=[C:22](/[CH:24]=[CH:43]/[C:41]4[N:40]=[CH:39][S:38][CH:42]=4)[N:21]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[N:20]=3)=[CH:15][C:14]=2[O:34][CH3:35])[N:10]=1
Reactant: COc1cc(COc2cc(C=O)n(-c3ccccc3)n2)ccc1OCc1nc(-c2ccco2)oc1C
Reactant: c1ccc([P+](Cc2cscn2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(COc2cc(/C=C/c3cscn3)n(-c3ccccc3)n2)ccc1OCc1nc(-c2ccco2)oc1C
Temperature: 25 °C
Reaction time: 15 h
Yield: 66 %

Procedure:
A mixture of 3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1-phenyl-1H-pyrazole-5-carbaldehyde (1.00 g), [(1,3-thiazol-4-yl)methyl]triphenylphosphonium chloride (1.27 g), potassium carbonate (0.44 g) and N,N-dimethylformamide (50 mL) was stirred at room temperature for 15 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (1:1, v/v) to give 2-(2-furyl)-4-({2-methoxy-4-[({1-phenyl-5-[(E)-2-(1,3-thiazol-4-yl)ethenyl]-1H-pyrazol-3-yl}oxy)methyl]phenoxy}methyl)-5-methyl-1,3-oxazole as colorless crystals (0.77 g, yield 78%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 154-155° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[N:6][C:5]([CH3:8])=[CH:4][N:3]=1.Cl.[CH3:10][NH:11][CH3:12].[CH2:13]=O.[OH-].[Na+]>O>[CH3:10][N:11]([CH3:13])[CH2:12][CH2:1][C:2]1[CH:7]=[N:6][C:5]([CH3:8])=[CH:4][N:3]=1
Reactant: CNC
Reactant: C=O
Reactant: Cc1cnc(C)cn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1cnc(CCN(C)C)cn1
Temperature: 140 °C
Yield: 34.6 %

Procedure:
A mixture of 75.0 g (0.7 mole) of 2,5-dimethylpyrazine and 41.0 g (0.5 mole) of dimethylamine hydrochloride was heated at 140° C. 60.0 g (38% aqueous solution) (0.75 mole) of formaldehyde was added over a period of two hours. After two hours additional heating the mixture was cooled. It was diluted with 110 ml of water, made basic with 10% sodium hydroxide and extracted with chloroform. The solvent was removed and the residue distilled to give 28.6 g of 2-(β-dimethylaminoethyl)-5-methylpyrazine, b.p. 106°-110° C. at 10 mm Hg.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:14]=[CH:13][N:12]([CH2:15][C@@H:16]([NH:18][C:19]([C:21]3[N:22]=[C:23]([CH3:26])[NH:24][CH:25]=3)=[O:20])[CH3:17])[N:11]=2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].C(=O)([O-])[O-].[K+].[K+].[CH3:33][C@H:34]1[CH2:36][O:35]1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:14]=[CH:13][N:12]([CH2:15][C@@H:16]([NH:18][C:19]([C:21]3[N:22]=[C:23]([CH3:26])[N:24]([CH2:33][C@@H:34]([OH:35])[CH3:36])[CH:25]=3)=[O:20])[CH3:17])[N:11]=2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: C[C@H]1CO1
Reactant: Cc1nc(C(=O)N[C@@H](C)Cn2ccc(-c3ccc(C#N)c(Cl)c3)n2)c[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1nc(C(=O)N[C@@H](C)Cn2ccc(-c3ccc(C#N)c(Cl)c3)n2)cn1C[C@H](C)O
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 54.5 %

Procedure:
(S)—N-(1-(3-(3-Chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-2-methyl-1H-imidazole-4-carboxamide (0.271 mmol, 100 mg) and potassium carbonate (2.71 mmol, 375 mg) were dissolved in dry DMF (3 ml) under nitrogen atmosphere. (S)-2-methyl-oxirane (0.298 mmol, 0.021 ml) was added and the resulting mixture was stirred for 2.5 h at RT. The mixture was heated to 60° C. for two days during which more (S)-2-methyloxirane (0.252 ml) was added. The solvent was evaporated and the residue was purified by flash chromatography. 63 mg of the title compound was obtained. 1H-NMR (400 MHz, DMSO-d6): δ 1.05 (d, 3H), 1.07 (d, 3H), 2.34 (s, 3H), 3.67-3.93 (m, 3H), 4.20-4.50 (m, 3H), 4.92 (bs, 1H), 6.95 (d, 1H), 7.47 (s, 1H), 7.83 (d, 1H), 7.98-8.00 (m, 2H), 8.04 (d, 1H), 8.11-8.12 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10]3[CH:12]=[CH:13][C:14]([O:16][CH3:17])=[CH:15][C:9]=3[C:8](=O)[NH:7][C:6]=2[CH:19]=1.[NH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10]3[CH:12]=[CH:13][C:14]([O:16][CH3:17])=[CH:15][C:9]=3[C:8]([N:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)=[N:7][C:6]=2[CH:19]=1
Reactant: C1CNCCN1
Reactant: COc1ccc2c(c1)C(=O)Nc1cc(Cl)ccc1N2
Product: COc1ccc2c(c1)C(N1CCNCC1)=Nc1cc(Cl)ccc1N2
Yield: 55.4 %

Procedure:
8-Chloro-2-methoxy-5,10-dihydro-dibenzo[b,e][1,4]diazepine-11-one (28 mg, 0.1 mmol) and piperazine (86 mg, 1.0 mmol) were reacted according to GP4 to give 19 mg of the title compound (160FE20A). MS (ESI) 342 (MH+). Purity for MH+ (UV/MS) 99/100.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8](Br)[CH:7]=[CH:6]2.[H-].[Ca+2].[H-].[C:17]([O:24][CH3:25])(=[O:23])[CH2:18][CH2:19][CH2:20][C:21]#[CH:22]>C(NCC)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C:22]#[C:21][CH2:20][CH2:19][CH2:18][C:17]([O:24][CH3:25])=[O:23])[CH:7]=[CH:6]2
Reactant: C#CCCCC(=O)OC
Reactant: COc1ccc2cc(Br)ccc2c1
Agent: [Ca+2]
Agent: [H-]
Solvent: CCNCC
Product: COC(=O)CCCC#Cc1ccc2cc(OC)ccc2c1

Procedure:
Into a solution of 2.51 g (9.2 mmol) of 6-methoxy-2-naphthyl bromide in 31 ml of diethylamine distilled with calcium hydride were charged 324 mg (0.46 mmol) of bistriphenylphosphine palladium dichloride and 192 mg of cupric iodide (1.01 mmol), followed by stirring. To the mixture was gradually added 1.06 g (9.4 mmol) of methyl 5-hexynoate, and the mixture was stirred at room temperature overnight (about 15 hours). Diethylamine was evaporated under a reduced pressure, to the residue were added ethyl acetate and water, and the mixture was extracted with ethyl acetate. Anhydrous magnesium sulfate was introduced into the organic layer for drying.
Reaction SMILES: Cl.[C@@H:2]1([NH2:6])[CH2:4][C@@H:3]1[NH2:5].[Cl:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12]([C:17](O)=[O:18])=[CH:11]2.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(C(C)C)CC)(C)C>CN(C)C=O>[NH2:5][C@H:3]1[CH2:4][C@H:2]1[NH:6][C:17]([C:12]1[NH:13][C:14]2[C:10]([CH:11]=1)=[CH:9][C:8]([Cl:7])=[CH:16][CH:15]=2)=[O:18]
Reactant: O=C(O)c1cc2cc(Cl)ccc2[nH]1
Reactant: N[C@@H]1C[C@@H]1N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: N[C@H]1C[C@H]1NC(=O)c1cc2cc(Cl)ccc2[nH]1
Reaction time: 50 h

Procedure:
To a solution of cis-1,2-cyclopropanediamine hydrochloride (J. Med. Chem., vol. 41, pp. 4723-4732 (1998)) (405 mg) and 5-chloroindole-2-carboxylic acid (546 mg) in N,N-dimethylformamide (10 mL) were added 1-hydroxybenzotriazole monohydrate (377 mg), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (642 mg), and diisopropylethylamine (1.95 mL) at room temperature, followed by stirring for 50 hours. The reaction mixture was concentrated under reduced pressure, and thereto were added methylene chloride (50 mL) and saturated aqueous sodium hydrogencarbonate (200 mL). The precipitated colorless solid was filtered off. The filtrate was partitioned, and aqueous layer was extracted with methylene chloride. The organic layers were combined, and the combined organic layer was dried over sodium sulfate anhydrate. The solvent was distilled away under reduced pressure, and the resultant residue was purified by silica gel flash column chromatography (methylene chloride:methanol=100:7→10:1), to thereby give the title compound (110 mg).
Reaction SMILES: [CH2:1]([N:3]([CH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)[CH2:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([C:11]2[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH3:20])=[C:13]([O:21][CH3:22])[CH:12]=2)[CH:6]=1)[CH3:2].[Cl:29][CH2:30][C:31]1[CH:36]=[CH:35][N:34]=[C:33]([C:37]2[CH:42]=[C:41]([O:43][CH3:44])[C:40]([O:45][CH3:46])=[C:39]([O:47][CH3:48])[CH:38]=2)[CH:32]=1>>[ClH:29].[ClH:29].[ClH:29].[ClH:29].[CH2:1]([N:3]([CH:23]1[CH2:24][CH2:25][N:26]([CH2:30][C:31]2[CH:36]=[CH:35][N:34]=[C:33]([C:37]3[CH:42]=[C:41]([O:43][CH3:44])[C:40]([O:45][CH3:46])=[C:39]([O:47][CH3:48])[CH:38]=3)[CH:32]=2)[CH2:27][CH2:28]1)[CH2:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([C:11]2[CH:12]=[C:13]([O:21][CH3:22])[C:14]([O:19][CH3:20])=[C:15]([O:17][CH3:18])[CH:16]=2)[CH:6]=1)[CH3:2]
Reactant: COc1cc(-c2cc(CCl)ccn2)cc(OC)c1OC
Reactant: CCN(Cc1ccnc(-c2cc(OC)c(OC)c(OC)c2)c1)C1CCNCC1
Product: CCN(Cc1ccnc(-c2cc(OC)c(OC)c(OC)c2)c1)C1CCN(Cc2ccnc(-c3cc(OC)c(OC)c(OC)c3)c2)CC1
Product: Cl

Procedure:
4-[N-ethyl-N-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]amino]piperidine (65 mg) and 4-chloromethyl-2-(3,4,5-trimethoxyphenyl)pyridine (50 mg) were condensed in the same manner as described in Example 2. The title compound was obtained after converting a free base to a tetrahydrochloride.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.CN(C)C=O.[O:11]=[C:12]1[CH2:17][C:16](=O)[CH2:15][CH:14]([C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=2)[CH:13]1[C:26]([O:28][CH2:29][CH3:30])=[O:27].C([O-])([O-])=O.[Na+].[Na+]>ClCCl>[Cl:3][C:16]1[CH2:15][CH:14]([C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=2)[CH:13]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[C:12](=[O:11])[CH:17]=1
Reactant: CCOC(=O)C1C(=O)CC(=O)CC1c1ccc(C)cc1
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOC(=O)C1C(=O)C=C(Cl)CC1c1ccc(C)cc1
Reaction time: 0.5 h

Procedure:
To a mixture of phosphoryl chloride (3.53 g.) and dimethylformamide (1.68 g.) at 0° C was added a cooled solution of ethyl 2,4-dioxo-6-p-tolylcyclohexanecarboxylate (6.2 g.) a dione of formula II prepared as in Example 1, in dichloromethane (60 ml.). After keeping at 0° C for 30 minutes the mixture was poured into excess 2N-Na2CO3 solution and extracted with ether. After washing the ether extracts with water and drying over magnesium sulphate, evaporation of the solvents gave crude ethyl 4-chloro-2-oxo-6-p-tolyl-3-cyclohexenecarboxylate (a halide of formula IV) as a pale yellow oil.