Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[CH3:8][C:9]1[N:14]=[C:13]([N:15]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:12]([NH2:30])=[C:11]([NH:31][CH2:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:10]=1.[C:40](Cl)(=[O:42])[CH3:41].C(OCC)(=O)C.CCCCCC>C(Cl)Cl.O>[C:40]([C:10]1[C:11]([NH:31][CH2:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[C:12]([NH2:30])[C:13]([N:15]([CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[N:14][C:9]=1[CH3:8])(=[O:42])[CH3:41]
Reactant: CC(=O)Cl
Reactant: Cc1cc(NCCc2ccccc2)c(N)c(N(Cc2ccccc2)Cc2ccccc2)n1
Solvent: O
Solvent: ClCCl
Solvent: CCCCCC
Product: CC(=O)c1c(C)nc(N(Cc2ccccc2)Cc2ccccc2)c(N)c1NCCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.1 %

Procedure:
Triethylamine (2 mL) was added to a solution of 6-methyl-N4 -(2-phenylethyl)-N2,N2 -bis(phenylmethyl)-pyridine-2,3,4-triamine (6 g, 14.2 mmole) in methylene chloride (50 mL). Acetyl chloride (1.1 mL, 15.5 mmole) was slowly added to the reaction mixture which was then heated on a steam bath for about 1 hour. The reaction mixture was stirred at ambient temperature overnight then diluted with water and methylene chloride. The organic phase was separated, washed with water, dried over magnesium sulfate and then concentrated under vacuum to provide a light green solid. This solid was slurried with ethyl acetate/hexane then recrystallized from ethyl acetate/hexane to provide 4.1 g of a white solid. A small portion (0.8 g) was purified by silica gel column chromatography to provide the desired compound as a white solid, m.p. 152°-153° C. Analysis: Calculated for C30H32N4O: % C, 77.56; % H, 6.94; % N, 12.06; Found: % C, 77.61; % H, 6.89: % N, 12.05.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[O:9][C@H:8]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C@H:7]([NH:22]C(=O)OC(C)(C)C)[C:6]2=[O:30])[CH2:3][CH2:2]1.FC(F)(F)C(O)=O>ClCCl>[NH2:22][C@@H:7]1[C:6](=[O:30])[N:5]([CH2:4][CH:1]2[CH2:3][CH2:2]2)[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[O:9][C@@H:8]1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1C(=O)N(CC2CC2)c2ccccc2O[C@@H]1c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@@H]1C(=O)N(CC2CC2)c2ccccc2O[C@@H]1c1ccccc1

Procedure:
tert-Butyl [(2R,3S)-5-(cyclopropylmethyl)-4-oxo-2-phenyl-2,3,4,5-tetrahydro-1,5-benzoxazepin-3-yl]carbamate (72a) (201 mg, 0.492 mmol) was dissolved in 5:1 (v/v) dichloromethane:trifluoroacetic acid (5 mL) and kept at ambient temperature for 1 h. The solution was evaporated and the residue was dissolved in ethyl acetate and extracted with saturated aqueous sodium bicarbonate. The organic solution was dried and evaporated and the residue used immediately in the next step. MS APCI, m/z=309 (M+1). LC/MS: 1.82 min.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:8](O)=[O:9]>>[CH:8]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:9]
Reactant: O=CO
Reactant: Nc1ccccc1
Product: O=CNc1ccccc1

Procedure:
There are gradually added 58.8 parts by weight of formic acid (97%) to 113.0 parts by weight of aniline while maintaining a temperature of 90°±5° C. After completion of the addition, the mixture is heated at refluxing temperatures for about 25±5 minutes and finally heated to a pot temperature of 170°±5° C. The distillate collected consists of 27.0 parts by weight of water and a very small amount of formic acid (maximum 0.3 parts by weight). To the product in the pot, comprising 142.7 parts by weight of formanilide and 2.2±0.3 parts by weight of aniline, 75.0 parts by weight of xylene is added.
Reaction SMILES: Cl.Cl.[C:3]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.Cl[C:22]1[N:23]([CH3:35])[C:24](=[O:34])[CH:25]=[C:26]([C:28]2[CH:33]=[CH:32][N:31]=[CH:30][N:29]=2)[N:27]=1.C(N(CC)CC)C>O1CCCC1>[C:3]1([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:10][CH2:11][N:12]([C:22]2[N:23]([CH3:35])[C:24](=[O:34])[CH:25]=[C:26]([C:28]3[CH:33]=[CH:32][N:31]=[CH:30][N:29]=3)[N:27]=2)[CH2:13][CH2:14]1
Reactant: Cn1c(Cl)nc(-c2ccncn2)cc1=O
Reactant: c1ccc(-c2ccccc2N2CCNCC2)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cn1c(N2CCN(c3ccccc3-c3ccccc3)CC2)nc(-c2ccncn2)cc1=O
Temperature: 90 °C
Reaction time: 4 h
Yield: 64.7 %

Procedure:
To a solution of 1-biphenyl-2-yl-piperazine dihydrochloride (311 mg, 1.0 mmol) and 2-chloro-1-methyl-1H-[4,4′]bipyrimidinyl-6-one (202 mg, 0.91 mmol) in tetrahydrofuran (20 mL) was added triethylamine (404 mg, 4.0 mmol). The mixture was stirred at 90° C. for 4 h. The solvent was evaporated off in vacuo and the residue treated with water and chloroform. The organic layer was dried over sodium sulfate and the solvent was evaporated under reduced pressure. Recrystallization from ethyl acetate gave 2-[4-(biphenyl-2-yl)piperazin-1-yl]-1-methyl-1H-[4,4′]bipyrimidinyl-6-one (250 mg, 65%) as colorless crystals.
Reaction SMILES: Cl[C:2]1[N:6]([CH:7]2[CH2:9][CH2:8]2)[N:5]=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[F:13][C:14]([F:26])([F:25])[C:15]([NH:17][C@@H:18]1[CH2:24][CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)=[O:16]>>[CH:7]1([N:6]2[C:2]([N:21]3[CH2:22][CH2:23][CH2:24][C@@H:18]([NH:17][C:15](=[O:16])[C:14]([F:25])([F:13])[F:26])[CH2:19][CH2:20]3)=[C:3]([N+:10]([O-:12])=[O:11])[CH:4]=[N:5]2)[CH2:9][CH2:8]1
Reactant: O=C(N[C@@H]1CCCNCC1)C(F)(F)F
Reactant: O=[N+]([O-])c1cnn(C2CC2)c1Cl
Product: O=C(N[C@@H]1CCCN(c2c([N+](=O)[O-])cnn2C2CC2)CC1)C(F)(F)F
Yield: 61 %

Procedure:
Following the procedure for Intermediate 28 starting with 5-chloro-1-cyclopropyl-4-nitro-1H-pyrazole and (R)-2,2,2-trifluoro-N-(hexahydro-1H-azepin-4-yl)-acetamide gave (R)—N-(1-(1-cyclopropyl-4-nitro-1H-pyrazol-5-yl)azepan-4-yl)-2,2,2-trifluoroacetamide as a pale yellow gum (105 mg, 61%). 1H-NMR (400 MHz, CDCl3) δ 7.96 (s, 1H), 6.55-6.38 (m, 1H), 4.30-4.15 (m, 1H), 3.65-3.53 (m, 1H), 3.55-3.25 (m, 4H), 2.25-2.05 (m, 6H), 1.35-1.05 (m, 4H).
Reaction SMILES: C(OC([NH:8][CH:9]1[CH2:14][CH2:13][C:12]([C:15]2[CH:16]=[C:17]([CH:23]=[CH:24][CH:25]=2)[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:11][CH2:10]1)=O)(C)(C)C>Cl.O1CCOCC1>[NH2:8][CH:9]1[CH2:14][CH2:13][C:12]([C:15]2[CH:16]=[C:17]([CH:23]=[CH:24][CH:25]=2)[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:11][CH2:10]1
Reactant: CCOC(=O)c1cccc(C2=CCC(NC(=O)OC(C)(C)C)CC2)c1
Agent: Cl
Solvent: C1COCCO1
Product: CCOC(=O)c1cccc(C2=CCC(N)CC2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 57.8 %

Procedure:
A 4 N hydrochloric acid/1,4-dioxane solution (20 mL) was added to ethyl 3-(4-tert-butoxycarbonylaminocyclohex-1-enyl)benzoate obtained in Example (195b) (510 mg, 1.48 mmol). The mixture was stirred at room temperature for one hour, and the solvent was evaporated under reduced pressure. The resulting residue was dissolved in methanol. Amberlite IRA-400(Cl) ion exchange resin (20 g) was added, and the mixture was stirred at room temperature for one hour. Amberlite was filtered off, and then the solution was concentrated under reduced pressure to obtain 210 mg of the title compound as a colorless oily substance.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][NH:10][C:11](=[O:13])[CH3:12])=[CH:5][CH:4]=1.[CH3:14][O:15][C:16]1[CH:21]=[C:20]([O:22][CH3:23])[N:19]=[C:18]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[N:17]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:14][O:15][C:16]1[CH:21]=[C:20]([O:22][CH3:23])[N:19]=[C:18]([N:24]2[CH2:25][CH2:26][N:27]([CH2:2][C:3]3[CH:8]=[CH:7][C:6]([CH2:9][NH:10][C:11](=[O:13])[CH3:12])=[CH:5][CH:4]=3)[CH2:28][CH2:29]2)[N:17]=1
Reactant: COc1cc(OC)nc(N2CCNCC2)n1
Reactant: CC(=O)NCc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(OC)nc(N2CCN(Cc3ccc(CNC(C)=O)cc3)CC2)n1
Yield: 123.8 %

Procedure:
A solution of N-(4-chloromethylphenylmethyl) acetamide (0.93 g), 1-(4,6-dimethoxypyrimidin-2-yl)piperazine (0.94 g) and potassium carbonate (0.97 g) in dimethylformamide (10 ml) was stirred at 80° C. for 1.5 hr. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated to give a brown oil (2.0 g). The obtained brown oil was crystallized from ethyl acetate:diisopropyl ether(1:3, 40 ml) to give the title compound (1.3 g) as pale-yellow crystals, m.p.=130-131° C.
Reaction SMILES: [C:1]([NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=1)([O:3]CC1C=CC=CC=1)=[O:2].C([Li])CCC.[Cl-].[NH4+].[O:26]1[CH2:30][CH2:29][CH2:28]C1>>[F:18][C:14]1[CH:13]=[C:12]([N:11]2[CH2:28][C@H:29]([CH2:30][OH:26])[O:3][C:1]2=[O:2])[CH:17]=[CH:16][CH:15]=1
Reactant: O=C(Nc1cccc(F)c1)OCc1ccccc1
Reactant: C1CCOC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Product: O=C1O[C@@H](CO)CN1c1cccc(F)c1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 70 %

Procedure:
123 g of N-carbobenzyloxy-3-fluoroaniline 132 g prepared in the Preparation example 1 was dissolved in 1.3 L of tetrahydrofuran and the solution was cooled to −78° C. 370 ml of n-butyllithium (n-BuLi, 1.6M/n-hexane) was slowly added to the solution in a nitrogen atmosphere, followed by stirring for 10 min. And 84 ml of (R)-(−)-glycidylbutylate was slowly added to the reaction mixture, stirred at the same temperature for 2 hours and allowed to react for 24 hours at room temperature. After completion of the reaction, the solution was added with ammonium chloride (NH4Cl) solution and extracted with 0.5 L of ethyl acetate at room temperature. The organic layer, thus separated, was washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was dissolved in 100 ml of ethyl acetate and washed with n-hexane to give white crystals, which were purified to the title compound. 80 g. Yield 70%.
Reaction SMILES: O=[C:2]([NH:9][C:10](=[O:15])[C:11]([O:13]C)=[O:12])[CH2:3][C:4]([F:8])=[C:5]([F:7])[F:6].[OH-].[Na+]>CO.O>[F:8][C:4](=[C:5]([F:6])[F:7])[CH2:3][CH2:2][NH:9][C:10](=[O:15])[C:11]([OH:13])=[O:12]
Reactant: COC(=O)C(=O)NC(=O)CC(F)=C(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)C(=O)NCCC(F)=C(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 25.4 %

Procedure:
A solution of Compound 142 (3.16 g, 0.015 mole) in methanol (25 mL) is treated with a solution of NaOH (0.8 g, 0.02 mole) in water (5 mL). The solution is stirred at room temperature for 30 min and concentrated. The residue is dissolved in water (20 mL) and extracted with dichloromethane (2×30 mL). The aqueous layer is acidified with conc. HCl and extracted with ethyl acetate. The organic layer is dried and evaporated to give 0.75 g of the title compound as a white solid, a 25% yield. m.p. 95°-100° C.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.C([O:13][C:14]([C:16]1[N:17]=[C:18]2[N:22]([C:23]=1[CH2:24][CH3:25])[CH:21]=[CH:20][S:19]2)=O)C.Cl.[OH-].[Na+]>C1COCC1>[CH2:24]([C:23]1[N:22]2[C:18]([S:19][CH:20]=[CH:21]2)=[N:17][C:16]=1[CH2:14][OH:13])[CH3:25]
Reactant: CCOC(=O)c1nc2sccn2c1CC
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: C1CCOC1
Product: CCc1c(CO)nc2sccn12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Diisobutylaluminum hydride (1M in THF, 11 mL, 11 mmol) is added to a solution of 5-ethyl-imidazo[2,1-b]thiazole-6-carboxylic acid ethyl ester (800 mg, 3.6 mmol) in THF (20 mL). The mixture is stirred at room temperature for 0.5 h. HCl (10%, 2 mL) is added, and the mixture is stirred for an additional 5 min. The mixture is neutralized by the addition of sodium hydroxide (2 N) until pH is above 10 and then extracted with ethyl acetate (3×20 mL). The combined organic layers are dried and solvent removed to give 5-ethyl-6-hydroxymethyl-imidazo[2,1-b]thiazole as a solid. Step 3. Preparation of 6-chloromethyl-5-ethyl-imidazo[2,1-b]thiazole
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][NH:14][C:15]1[C:16]([O:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)=[N:17][C:18](Cl)=[N:19][CH:20]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:31][S:32][C:33]1[N:38]=[C:37]([Sn](CCCC)(CCCC)CCCC)[CH:36]=[CH:35][N:34]=1>O1CCOCC1.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][NH:14][C:15]1[C:16]([O:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)=[N:17][C:18]([C:35]2[CH:36]=[CH:37][N:38]=[C:33]([S:32][CH3:31])[N:34]=2)=[N:19][CH:20]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(Oc2nc(Cl)ncc2NC[C@@H]2CCCN2C(=O)OC(C)(C)C)cc1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccnc(SC)n1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COc1ccc(Oc2nc(-c3ccnc(SC)n3)ncc2NC[C@@H]2CCCN2C(=O)OC(C)(C)C)cc1
Yield: 50.2 %

Procedure:
To a teflon-lined septum-sealed Schlenk tube, a mixture of Compound 1e (213 mg; 0.49 mmol), 2-methylsulfanyl-4-tributylstannanyl-pyrimidine (Compound 7a) (305 mg; 0.735 mmol) and tetrakis-(triphenylphosphine)palladium(0) (57 mg; 0.049 mmol) in dioxane (1.0 mL) was irradiated in a Microwave reactor at 150° C. for 30 min. The resultant mixture was diluted with EtOAc, and washed with saturated NH4Cl(aq) and H2O. The organic phase was washed with H2O, and then dried over Na2SO4. The mixture was filtered and the filtrate was evaporated under reduced pressure to give the crude material. The crude material was purified by flash column chromatography (SiO2), eluting with a heptane-EtOAc gradient to afford Compound 7b (129 mg; 50% yield). 1H-NMR (400 MHz, CDCl3): δ 8.48-8.50 (m, 1H), 8.08-8.12 (m, 1H), 7.54-7.57 (m, 1H), 7.16-7.23 (m, 2H), 6.96-7.01 (m, 2H), 6.27 (br. s, 0.7H), 5.18 (br, 0.3H), 4.25-4.36 (m, 1H), 3.88 (s, 3H), 3.24-3.59 (m, 4H), 2.68 (s, 3H), 1.79-2.16 (m, 4H), 1.44-1.54 (m, 9H); MS: m/z 525.2 (M+H)+.
Reaction SMILES: [OH-].[Li+].C[O:4][C:5]([C:7]1[NH:8][C:9](=[O:25])[N:10]([CH:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]2)[CH:11]=1)=[O:6]>CO>[C:21]([O:20][C:18]([N:15]1[CH2:16][CH2:17][CH:12]([N:10]2[CH:11]=[C:7]([C:5]([OH:6])=[O:4])[NH:8][C:9]2=[O:25])[CH2:13][CH2:14]1)=[O:19])([CH3:24])([CH3:22])[CH3:23]
Reactant: COC(=O)c1cn(C2CCN(C(=O)OC(C)(C)C)CC2)c(=O)[nH]1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(n2cc(C(=O)O)[nH]c2=O)CC1
Reaction time: 2 h
Yield: 35.5 %

Procedure:
Lithium hydroxide (64 mg, 1.54 mmol) was added to a solution of tert-butyl 4-[4-(methoxycarbonyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl]piperidine-1-carboxylate (50 mg, 0.154 mmol) in methanol (10 mL). After 2 h, the reaction was quenched with saturated sodium bicarbonate solution and dichloromethane was added. The mixture was filtered and the filtrate was concentrated. Purification by silica gel chromatography (100% dichloromethane→25% methanol {1% ammonium hydroxide}/dichloromethane) gave the title compound (17 mg). MS 312.2 (M+1)
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3([CH2:22][NH2:23])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:31][N:32]([CH3:36])[C:33](Cl)=[O:34]>ClCCl>[CH3:31][N:32]([CH3:36])[C:33]([NH:23][CH2:22][C:16]1([C:13]2[CH:14]=[CH:15][C:10]([O:9][CH2:8][CH2:7][CH2:6][N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[CH:11][CH:12]=2)[CH2:17][CH2:18][O:19][CH2:20][CH2:21]1)=[O:34]
Reactant: NCC1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Reactant: CN(C)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)C(=O)NCC1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Temperature: 0 °C
Reaction time: 3 h
Yield: 32.6 %

Procedure:
To a stirred solution of {4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydropyran-4-yl}methylamine (200 mg, 0.63 mmol) and triethylamine (106 μL, 0.754 mmol) in anhydrous dichloromethane (9 mL) under nitrogen atmosphere was added dropwise a solution of dimethylcarbamoylchloride (69 μL, 0.754 mmol) in anhydrous dichloromethane (1 mL). After stirring for 3 h at 0° C., the reaction mixture was quenched with a saturated aqueous solution of NaHCO3. The organic layer was separated and washed with water then dried over magnesium sulfate, filtered, concentrated under reduced pressure and purified by column chromatography on silica gel eluting with DCM:MeOH (95:5 to 90:10) to give the title compound (80 mg, 32%). 1H NMR (400 MHz, CDCl3) δ7.13 (d, 2H), 6.86 (d, 2H), 3.98 (t, 2H), 3.84 (t, 1H), 3.74 (m, 2H), 3.52 (m, 2H), 3.36 (d, 2H), 2.69 (s, 6H), 2.65 (m, 2H), 2.57 (m, 4H), 2.02-1.95 (m, 4H), 1.84-1.78 (m, 6H).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:15]([CH3:34])=[C:16]([CH3:33])[C:17]3[O:21][C:20]([CH3:23])([CH3:22])[CH:19]([C:24]4[CH:25]=[N:26][C:27]([F:30])=[CH:28][CH:29]=4)[C:18]=3[C:31]=2[CH3:32])[CH2:10][CH2:9]1)C1C=CC=CC=1.C([O-])=O.[NH4+]>CO.[C].[Pd]>[F:30][C:27]1[N:26]=[CH:25][C:24]([CH:19]2[C:18]3[C:31]([CH3:32])=[C:14]([N:11]4[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]4)[C:15]([CH3:34])=[C:16]([CH3:33])[C:17]=3[O:21][C:20]2([CH3:23])[CH3:22])=[CH:29][CH:28]=1
Reactant: Cc1c(C)c(N2CCN(Cc3ccccc3)CC2)c(C)c2c1OC(C)(C)C2c1ccc(F)nc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: Cc1c(C)c(N2CCNCC2)c(C)c2c1OC(C)(C)C2c1ccc(F)nc1
Temperature: 25 °C
Yield: 88 %

Procedure:
A mixture of 10% palladium carbon (50% water, 183 mg), 4-benzyl-1-(3-(6-fluoropyridine-3-yl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl)piperazine (1.83 g, 4 mmol) obtained in Example 126 and ammonium formate (505 mg, 8 mmol) in methanol (50 ml) was refluxed for 2 hours under nitrogen atmosphere. The resulting mixture was cooled to room temperature and the catalyst was removed by filtration. The filtrate was concentrated under reduced pressure. The residue was diluted with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate, and dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure. The residue was purified with basic silica gel column chromatography (ethyl acetate) to obtain 1.3 g (yield 88%) of the title compound as an amorphous powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=O)[CH:5]=[CH:6][C:7]=1[Cl:8].C1(N=C=NC2CCCCC2)CCCCC1.[OH:28][CH2:29][CH2:30][CH2:31][C:32]1[CH:37]=[CH:36][C:35]([C@H:38]2[CH2:43][CH2:42][C@H:41]([NH:44][CH3:45])[CH2:40][CH2:39]2)=[C:34]([CH2:46][NH:47][CH3:48])[CH:33]=1.C(OCC)(=O)C>C1(C)C(C)=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([N:44]([C@H:41]2[CH2:40][CH2:39][C@H:38]([C:35]3[CH:36]=[CH:37][C:32]([CH2:31][CH2:30][CH2:29][OH:28])=[CH:33][C:34]=3[CH2:46][NH:47][CH3:48])[CH2:43][CH2:42]2)[CH3:45])=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CNCc1cc(CCCO)ccc1[C@H]1CC[C@H](NC)CC1
Reactant: O=C(O)Cc1ccc(Cl)c(Cl)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1C
Product: CNCc1cc(CCCO)ccc1[C@H]1CC[C@H](N(C)C(=O)Cc2ccc(Cl)c(Cl)c2)CC1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
141 mg (0.68 mMol) of 3,4-dichlorophenylacetic acid in 5 ml of xylene are mixed with 112 mg (0.54 mMol) of N,N'-dicyclohexylcarbodiimide and heated to 50° C. for 1 hour. After the addition of 200 mg (0.68 mMol) of trans-4-[4-(3-hydroxypropyl)methylaminomethylphenyl]-N-methylcyclohexylamine the mixture is stirred overnight at 140° C. After cooling to ambient temperature and adding ethyl acetate, the mixture is washed with water and saturated saline solution, then dried and evaporated down. After purification by column chromatography (alumina, ethyl acetate/methanol=100:1 to 10:1, v:v), 110 mg (34% of theory) of the title compound are obtained, melting point 82°-84° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[C:18]=1[CH3:19])=[C:15]([CH2:20][OH:21])[CH:14]=[CH:13][CH:12]=3)=[O:5])[CH3:2].C(OC(=O)C([N+]([O-])=O)C(O)C)C>>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[C:18]=1[CH3:19])=[C:15]([CH:20]=[O:21])[CH:14]=[CH:13][CH:12]=3)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ncc2[nH]c3cccc(CO)c3c2c1C
Agent: CCOC(=O)C(C(C)O)[N+](=O)[O-]
Product: CCOC(=O)c1ncc2[nH]c3cccc(C=O)c3c2c1C

Procedure:
The synthesis takes place according to the method described in example 1 from 5-hydroxymethyl-4-methyl-beta-carboline-3-carboxylic acid ethyl ester, which in turn is prepared according to example 2 from 2-nitro-3-hydroxybutyric acid ethyl ester in 5 stages.
Reaction SMILES: [OH:1][C:2]1[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][N:4]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[N:3]=1.[CH3:19][O:20][CH2:21]Cl.C(N(CC)C(C)C)(C)C.C(=O)([O-])O.[Na+]>O1CCCC1>[CH3:19][O:20][CH2:21][O:1][C:2]1[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][N:4]([C:12]([O:14][C:15]([CH3:17])([CH3:16])[CH3:18])=[O:13])[N:3]=1
Reactant: COCCl
Reactant: CCOC(=O)c1cn(C(=O)OC(C)(C)C)nc1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCOC(=O)c1cn(C(=O)OC(C)(C)C)nc1OCOC
Temperature: 25 °C
Reaction time: 2 h
Yield: 20 %

Procedure:
A mixture of 4-ethyl 1-tert-butyl 3-hydroxy-1H-pyrazole-1,4-dicarboxylate (30.75 g), chloromethyl methyl ether (4.56 mL), N,N-diisopropylethylamine (11.9 mL) and tetrahydrofuran (150 mL) was stirred at room temperature for 2 hrs. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate, 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 (1:9-1:2, v/v) to give 4-ethyl 1-tert-butyl 3-(methoxymethoxy)-1H-pyrazole-1,4-dicarboxylate as a pale-yellow oil (3.52 g, yield 20%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C@H:9]([NH:11][C:12]1[CH:19]=[C:18]([N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[CH:17]=[CH:16][C:13]=1[C:14]#[N:15])[CH3:10].C(OC([N:33]1[CH2:38][CH2:37][CH2:36][CH2:35][C@@H:34]1[C:39](O)=[O:40])=O)(C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C@H:9]([NH:11][C:12]1[CH:19]=[C:18]([N:20]2[CH2:25][CH2:24][N:23]([C:39]([C@H:34]3[CH2:35][CH2:36][CH2:37][CH2:38][NH:33]3)=[O:40])[CH2:22][CH2:21]2)[CH:17]=[CH:16][C:13]=1[C:14]#[N:15])[CH3:10]
Reactant: CC(C)(C)OC(=O)N1CCCC[C@@H]1C(=O)O
Reactant: C[C@@H](Nc1cc(N2CCNCC2)ccc1C#N)c1ccc(Cl)cc1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: C[C@@H](Nc1cc(N2CCN(C(=O)[C@H]3CCCCN3)CC2)ccc1C#N)c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.2 %

Procedure:
To a stirred solution of the (R)-2-(1-(2,4-dichlorophenyl)ethylamino)-4-(piperazin-1-yl)benzonitrile (0.080 g, 0.21 mmol) and (R)-1-(t-butoxycarbonyl)piperidine-2-carboxylic acid (0.049 g, 0.21 mmol) in 1-methyl pyyrolidinone (NMP) (1.0 mL) was added HATU (0.085 g, 0.22 mmol) and iPr2NEt (0.055 g, 0.43 mmol). The reaction mixture was stirred at room temperature for 2 h, and quenched with deionzied water. The aqueous layer was extracted with diethyl ether (2×10 mL). The organic layer was dried (Na2SO4), filtered, and concentrated in vacuo. The crude product was purified by flash chromatography (SiO2, 0-25% ethyl acetate in hexanes) to afford the desired product (0.095 g, 0.16 mmol, 77%).