Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.C1C=CC2N(O)N=NC=2C=1.O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:55][C:56]1[CH:57]=[N:58][C:59]2[N:60]([N:62]=[CH:63][C:64]=2[C:65](O)=[O:66])[CH:61]=1.CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)Cl>[CH3:55][C:56]1[CH:57]=[N:58][C:59]2[N:60]([N:62]=[CH:63][C:64]=2[C:65]([N:15]2[CH2:16][CH2:17][N:12]([S:9]([C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:18])[F:19])=[CH:8][CH:7]=3)(=[O:10])=[O:11])[CH2:13][CH2:14]2)=[O:66])[CH:61]=1
Reactant: Cc1cnc2c(C(=O)O)cnn2c1
Reactant: O=S(=O)(c1ccc(C(F)(F)F)cc1)N1CCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cnc2c(C(=O)N3CCN(S(=O)(=O)c4ccc(C(F)(F)F)cc4)CC3)cnn2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 51.2 %

Procedure:
To a solution of 1-{[4-(trifluoromethyl)phenyl]sulfonyl}piperazine (may be prepared as described in Description 1) (100 mg, 0.340 mmol) in DMF (5 ml) was added HOBT.H2O (52.0 mg, 0.340 mmol), HBTU (129 mg, 0.340 mmol), 6-methylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid (60.2 mg, 0.340 mmol) and DIPEA (0.178 ml, 1.019 mmol), in a 2.0-5.0 ml microwave vial. The reaction mixture was stirred for 3 hours at rt. The reaction mixture was transferred to a 100 ml round bottom flask and was reduced to dryness in vacuo. The residue was dissolved in DCM (50 ml) and was transferred to a separating funnel then washed with saturated aq. NaHCO3 solution (5 ml), twice. The organic layer was collected and dried with dried magnesium sulfate. The solid was removed by filtration and the filtrate collected in a 250 ml round bottom flask and reduced to dryness in vacuo. The residue was then dissolved in 1.8 ml (1:1) MeCN/DMSO and purified by MDAP in 2 batches. The fractions containing desired product were combined in a 250 ml round bottom flask and reduced in vacuo to yield the title compound (79 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]([CH3:10])([CH3:9])[CH3:8])[NH:4][N:3]=1.C(N(CC)CC)C.[CH:18]1([C:22](Cl)=[O:23])[CH2:21][CH2:20][CH2:19]1.O>C(Cl)Cl.C(Cl)(Cl)(Cl)Cl>[C:7]([C:5]1[NH:4][N:3]=[C:2]([NH:1][C:22]([CH:18]2[CH2:21][CH2:20][CH2:19]2)=[O:23])[CH:6]=1)([CH3:10])([CH3:9])[CH3:8]
Reactant: O=C(Cl)C1CCC1
Reactant: CC(C)(C)c1cc(N)n[nH]1
Solvent: O
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)c1cc(NC(=O)C2CCC2)n[nH]1

Procedure:
4.3 g (0.03 mole) of 3-amino-5-t-butylpyrazole as prepared in Example 1 and 3 g of triethylamine were dissolved in 30 ml of methylene chloride. To this solution was added dropwise 3.6 g of cyclobutanecarboxylic acid chloride dissolved in 30 ml of carbon tetrachloride. The resulting mixture was allowed to stand at room temperature over night. Thereafter, water was added thereto followed by shaking it. Crystals thus formed were collected by filtration and washed with water and carbon tetrachloride to obtain 5-t-butyl-3-cyclobutanecarbonylaminopyrazole.
Reaction SMILES: [H][H].[O:3]1[C:9]2([CH3:10])[CH:4]1[C:5]([O:7][C:8]2([CH3:12])[CH3:11])=[O:6]>[Pd].O1CCCC1>[OH:3][C:9]1([CH3:10])[C:8]([CH3:12])([CH3:11])[O:7][C:5](=[O:6])[CH2:4]1
Reactant: CC1(C)OC(=O)C2OC21C
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: CC1(O)CC(=O)OC1(C)C
Yield: 82 %

Procedure:
By using ethyl crotonate instead of ethyl acrylate, 2 hydroxy-3,4,4-trimethyl-γ-butyrolactone was prepared in a yield of 15% in the same manner as in Production Example 10. The prepared 2-hydroxy-3,4,4-trimethyl-γ-butyrolactone was subjected to a reaction (dehydration reaction) with equivalent P2O5 at room temperature to yield a corresponding α,β-unsaturated-γ-butyrolactone in a yield of 34%. This compound was then allowed to react with m-chloroperbenzoic acid (MCPBA) in methylene chloride at room temperature to yield 2,3epoxy-3,4,4-trimethyl-γ-butyrolactone in a yield of 75%. Hydrogen was bubbled in a mixture of 10 mmole of the above-prepared 2,3-epoxy-3,4,4-trimethyl-γ-butyrolactone, 1 g of a 5% by weight Pd-C, and 20 ml of tetrahydrofuran at room temperature for 11 hours. The reaction mixture was filtrated and was concentrated, and the concentrate was subjected to column chromatography on a silica gel to yield 3-hydroxy-3,4,4-trimethyl-γ-butyrolactone in a yield of 82%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:34])[NH:20][CH2:21][CH2:22][C:23]3[C:24]([O:32][CH3:33])=[N:25][C:26]([CH:29]4[CH2:31][CH2:30]4)=[CH:27][CH:28]=3)=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:35]([OH:37])=[O:36].C[O-].[Na+:40]>CO>[Na+:40].[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:14]=[CH:15][C:16]([C:19](=[O:34])[NH:20][CH2:21][CH2:22][C:23]3[C:24]([O:32][CH3:33])=[N:25][C:26]([CH:29]4[CH2:31][CH2:30]4)=[CH:27][CH:28]=3)=[CH:17][CH:18]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:35]([O-:37])=[O:36]
Reactant: COc1nc(C2CC2)ccc1CCNC(=O)c1ccc(Oc2cc3c(cc2Cl)C(C(=O)O)CCO3)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1nc(C2CC2)ccc1CCNC(=O)c1ccc(Oc2cc3c(cc2Cl)C(C(=O)[O-])CCO3)cc1
Reaction time: 2 h
Yield: 58.5 %

Procedure:
6-Chloro-7-(4-(2-(6-cyclopropyl-2-methoxypyridin-3-yl)ethylcarbamoyl)phenoxy)chroman-4-carboxylic acid (70 mg, 0.13 mmol) was diluted with methanol (1 mL) followed by the addition of NaOMe (268 μL, 0.13 mmol). After stirring for 2 hours, the reaction was concentrated and dried under high vacuum pressure for 2 hours. The material was diluted with hexanes, sonicated and concentrated to afford 6-chloro-7-(4-(2-(6-cyclopropyl-2-methoxypyridin-3-yl)ethylcarbamoyl)phenoxy)chroman-4-carboxylic acid sodium salt (40 mg, 0.076 mmol, 57% yield). MS (es+apci, positive) m/z=523.2.]
Reaction SMILES: [CH3:1][O-:2].[Na+].[O:4]1[C:6]2([CH2:15][CH2:14][C:9]3([O:13][CH2:12][CH2:11][O:10]3)[CH2:8][CH2:7]2)[CH2:5]1>CO>[CH3:1][O:2][CH2:5][C:6]1([OH:4])[CH2:15][CH2:14][C:9]2([O:13][CH2:12][CH2:11][O:10]2)[CH2:8][CH2:7]1
Reactant: C[O-]
Reactant: C1COC2(CCC3(CC2)CO3)O1
Agent: [Na+]
Solvent: CO
Product: COCC1(O)CCC2(CC1)OCCO2
Temperature: 60 °C
Reaction time: 8 h

Procedure:
75 ml of a 25% strength methanolic sodium methoxide solution were added to 4.56 g (26.8 mmol) of the compound from Example 6A in 150 ml of methanol, and the mixture was stirred at 60° C. overnight. After cooling, the reaction mixture was concentrated and the residue was taken up in saturated aqueous ammonium chloride solution and extracted repeatedly with ethyl acetate. The combined organic phases were dried over sodium sulphate, filtered and concentrated. This gave 3.23 g (60% of theory) of the title compound.
Reaction SMILES: [OH-].[Na+].CC1(C)C(C)(C)OB([C:11]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:12]=2[CH:13]=[CH:14][NH:15]3)O1.Br[C:22]1[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=1>[Pd].C1COCC1>[N:24]1[CH:25]=[CH:26][CH:27]=[C:22]([C:11]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:12]=2[CH:13]=[CH:14][NH:15]3)[CH:23]=1
Reactant: CC1(C)OB(c2cccc3[nH]ccc23)OC1(C)C
Reactant: Brc1cccnc1
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: c1cncc(-c2cccc3[nH]ccc23)c1
Temperature: 70 °C
Reaction time: 6 h
Yield: 62.8 %

Procedure:
Palladium catalyst Pd(PPh3)4 (284 mg, 0.25 mmol) and freshly prepared aqueous sodium hydroxide (984 mg in 9 mL of water) were added to a mixture of 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indole (2 g, 8.2 mmol) and 3-bromopyridine (0.8 mL, 8.3 mmol) in THF (28 mL). The system was degassed and then purged three times with nitrogen. The mixture was stirred under nitrogen at 70° C. in an oil bath for 6 hours. It was then cooled to room temperature and 400 ml ethyl acetate was added. The organic layer was isolated, washed with brine, dried over anhydrous Na2SO4 and concentrated. The residue was column chromatographed to give 1 g (62%) of 4-pyridin-3-yl-1H-indole as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH2:9][CH3:10])=[CH:6][C:5]([CH2:11][OH:12])=[CH:4][C:3]=1[O:13][CH2:14][CH3:15]>C1COCC1.O=[Mn]=O>[Cl:1][C:2]1[C:7]([O:8][CH2:9][CH3:10])=[CH:6][C:5]([CH:11]=[O:12])=[CH:4][C:3]=1[O:13][CH2:14][CH3:15]
Reactant: CCOc1cc(CO)cc(OCC)c1Cl
Agent: O=[Mn]=O
Solvent: C1CCOC1
Product: CCOc1cc(C=O)cc(OCC)c1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 93.3 %

Procedure:
To a solution of (4-chloro-3,5-diethoxy-phenyl)-methanol (4.0 g, 17.34 mmol, 1.0 equiv) in THF (40 mL) was added activated MnO2 (15.08 g, 173.4 mmol, 10.0 equiv) and the reaction mixture stirred for 18 h at rt. Filtration through Hyflo Super Cel and purification of the crude material by silica column chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of heptane/ethyl acetate provided 3.7 g (92%) of the title compound. 1H NMR (300 MHz, CDCl3): δ1.50 (t, J=7.0 Hz, 6H), 4.19 (q, J=7.0 Hz, 4H), 7.07 (s, 2H), 9.89 (s, 1H). 13C NMR (75 MHz, CDCl3): δ14.61, 65.22, 106.26, 118.64, 135.08, 156.22, 191.01. MS (EI): 229.4 [M]+.
Reaction SMILES: [Br:1][C:2]1[C:3]([N:18]2[CH2:23][CH2:22][C:21](=[C:24]([CH3:26])[CH3:25])[CH2:20][CH2:19]2)=[C:4]([C@H:10]([OH:17])[C:11]([O:13][CH:14]([CH3:16])[CH3:15])=[O:12])[C:5]([CH3:9])=[N:6][C:7]=1[CH3:8]>C(Cl)Cl>[Br:1][C:2]1[C:3]([N:18]2[CH2:23][CH2:22][C:21](=[C:24]([CH3:26])[CH3:25])[CH2:20][CH2:19]2)=[C:4]([C@H:10]([O:17][C:4]([CH3:10])([CH3:5])[CH3:3])[C:11]([O:13][CH:14]([CH3:16])[CH3:15])=[O:12])[C:5]([CH3:9])=[N:6][C:7]=1[CH3:8]
Reactant: CC(C)=C1CCN(c2c(Br)c(C)nc(C)c2[C@H](O)C(=O)OC(C)C)CC1
Solvent: ClCCl
Product: CC(C)=C1CCN(c2c(Br)c(C)nc(C)c2[C@H](OC(C)(C)C)C(=O)OC(C)C)CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 180.6 %

Procedure:
The isobutylene gas was bubbled into a nitrogen purged, cooled (0° C.) solution of (S)-isopropyl 2-(5-bromo-2,6-dimethyl-4-(4-(propan-2-ylidene)piperidin-1-yl)pyridin-3-yl)-2-hydroxyacetate (1.0 g, 2.3 mmol) and 0.30 mL of 70% HClO4 in DCM (30 mL) for 20 min. The reaction mixture was allowed to warm to rt and stirred for 48 h in a pressure sealed vessel. The reaction was then diluted with DCM, washed with 1M Na2CO3 solution, and dried over MgSO4. The crude product was charged (DCM) to a 80 g ISCO silica gel cartridge and gradient elution (0-50% EtOAc/hexanes) using an Isolera chromatography station gave (S)-isopropyl 2-(5-bromo-2,6-dimethyl-4-(4-(propan-2-ylidene)piperidin-1-yl)pyridin-3-yl)-2-(tert-butoxy)acetate 1.0 g (67%). 1H NMR (500 MHz, DMSO-d6) δ 6.24 (br. s, 1H), 4.95-4.90 (m, 1H), 3.68 (br. s, 1H), 3.18-3.12 (m, 1H), 3.06 (br. s, 1H), 2.83 (br. s, 1H), 2.72 (br. s, 1H), 2.59 (br. s, 1H), 2.51 (s, 3H), 2.43 (s, 3H), 2.13-2.01 (m, 2H), 1.68 (s, 6H), 1.17-1.15 (m, 12H), 1.08 (d, J=6.2 Hz, 3H). UPLC (M+H)=483.2.
Reaction SMILES: C[O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[NH:12][C:13]1[N:14]([CH3:23])[N:15]=[C:16]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:17]=1Br.[CH3:25][O:26][C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1.C(Cl)Cl.C(=O)([O-])[O-].[Na+].[Na+].[OH-].[Li+]>C1(C)C=CC=CC=1.O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:19]([C:16]1[C:17]([C:30]2[CH:31]=[CH:32][C:27]([O:26][CH3:25])=[CH:28][CH:29]=2)=[C:13]([NH:12][C:5]2[CH:6]=[CH:7][C:8]([O:10][CH3:11])=[CH:9][C:4]=2[C:3]([OH:2])=[O:24])[N:14]([CH3:23])[N:15]=1)([CH3:21])([CH3:22])[CH3:20]
Reactant: COC(=O)c1cc(OC)ccc1Nc1c(Br)c(C(C)(C)C)nn1C
Reactant: COc1ccc(B(O)O)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Product: COc1ccc(-c2c(C(C)(C)C)nn(C)c2Nc2ccc(OC)cc2C(=O)O)cc1
Temperature: 75 °C
Reaction time: 0.25 h
Yield: 27.3 %

Procedure:
To a solution 2-(4-bromo-5-tert-butyl-2-methyl-2H-pyrazol-3-ylamino)-5-methoxybenzoic acid methyl ester (Example 96, 100 mg, 0.25 mmol), 4-methoxyphenylboronic acid (153.4 mg, 1.01 mmol), PdCl2(dppf).CH2Cl2 (18.46 mg, 0.03 mmol) in a mixture of toluene (6.1 mL) and dioxane (1.22 mL) was added a 2M aqueous solution of sodium carbonate (1.22 mL, 2.44 mmol). A flow of Ar was passed through the reaction mixture for 15 min, and then the reaction was stirred at 75° C. for 18 h. The reaction mixture was then cooled to rt, and filtered through a plug of silica gel. The filtrate was concentrated under reduced pressure, and then the residue was dissolved in a mixture of THF (4 mL), MeOH (2 mL) and water (4 mL). Lithium hydroxide (60 mg, 2.52 mmol) was added, and the mixture was stirred at rt for 18 h. The reaction mixture was then concentrated and the residue purified by preparative HPLC to give the title compound (27.9 mg, 27%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 1.21 (s, 9H), 3.61 (s, 3H), 3.74 (s, 6H), 6.41 (d, 1H), 6.70 (d, 2H), 7.04 (dd, 1H), 7.09 (d, 2H), 7.39 (d, 1H). ES-MS m/z 410.2 (MH+); HPLC RT (min) 3.66.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]3[CH:14]=[CH:15][C:16]([OH:18])=[CH:17][C:12]=3[CH2:11][O:10][N:9]=2)=[CH:4][CH:3]=1.[Br:19][CH2:20]/[CH:21]=[CH:22]/[CH2:23]Br.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Br:19][CH2:20][CH:21]=[CH:22][CH2:23][O:18][C:16]1[CH:15]=[CH:14][C:13]2[C:8]([C:5]3[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=3)=[N:9][O:10][CH2:11][C:12]=2[CH:17]=1
Reactant: BrC/C=C/CBr
Reactant: Oc1ccc2c(c1)CON=C2c1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: BrCC=CCOc1ccc2c(c1)CON=C2c1ccc(Br)cc1
Temperature: 65 °C
Yield: 78.3 %

Procedure:
A mixture of 1.28 g of 4-(4-bromo-phenyl)-1H-benzo[d][1,2]oxazin-7-ol, 2.71 g of (E)-1,4-dibromo-2-butene and 1.74 g of potassium carbonate in 80 ml of acetone is stirred at 65° C. After cooling the reaction mixture is filtered and the filtrate is concentrated and purified by chromatography (silica gel, toluene/acetone 98:2). There are obtained 1.44 g of 7-(4-bromo-but-2-enyloxy)-4-(4-bromo-phenyl)-1H-benzo[d][1,2]oxazine, MS: m/e 437 (64%, M+, 2 Br).
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([C:10]2[N:15]=[C:14]([NH2:16])[C:13]([C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)=[CH:12][N:11]=2)=[N:2]1.C(=O)([O-])[O-].[Na+].[Na+].[C:29]([C:31]1[CH:38]=[CH:37][CH:36]=[CH:35][C:32]=1[CH2:33]Br)#[N:30]>CN(C)C=O>[NH2:16][C:14]1[C:13]([C:17]2[CH:18]=[CH:19][N:20]=[CH:21][CH:22]=2)=[CH:12][N:11]=[C:10]([C:3]2[C:4]3[C:5](=[N:6][CH:7]=[CH:8][CH:9]=3)[N:1]([CH2:33][C:32]3[CH:35]=[CH:36][CH:37]=[CH:38][C:31]=3[C:29]#[N:30])[N:2]=2)[N:15]=1
Reactant: Nc1nc(-c2n[nH]c3ncccc23)ncc1-c1ccncc1
Reactant: N#Cc1ccccc1CBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1ccccc1Cn1nc(-c2ncc(-c3ccncc3)c(N)n2)c2cccnc21
Temperature: 50 °C
Reaction time: 1 h

Procedure:
60 mg (0.21 mmol) of 2-(1H-pyrazolo[3,4-b]pyridin-3-yl)-5-(4-pyridinyl)-4-pyrimidinylamine from Example 35 A are suspended in 6 ml of dimethylformamide under argon. Addition of 26.38 mg (0.25 mmol) of sodium carbonate is followed by stirring at 50° C. for one hour. Then 40.66 mg (0.21 mmol) of 2-cyanobenzyl bromide are added thereto, and the mixture is stirred at 50° C. overnight. For work up, the mixture is filtered and the filtrate is adjusted to pH 4–5 with 1 normal hydrochloric acid and purified by preparative RP-HPLC.
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][C@@H:8]1[CH2:13][CH2:12][CH2:11][N:10]([C:14]2[CH:19]=[C:18]([CH3:20])[N:17]=[C:16](Cl)[C:15]=2[N+:22]([O-:24])=[O:23])[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:33][O:34][C:35]1[CH:42]=[C:41]([O:43][CH3:44])[CH:40]=[CH:39][C:36]=1[CH2:37][NH2:38].C(OCC)(=O)C>CN1CCCC1=O>[C:1]([O:5][C:6](=[O:25])[NH:7][C@@H:8]1[CH2:13][CH2:12][CH2:11][N:10]([C:14]2[CH:19]=[C:18]([CH3:20])[N:17]=[C:16]([NH:38][CH2:37][C:36]3[CH:39]=[CH:40][C:41]([O:43][CH3:44])=[CH:42][C:35]=3[O:34][CH3:33])[C:15]=2[N+:22]([O-:24])=[O:23])[CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(CN)c(OC)c1
Reactant: Cc1cc(N2CCC[C@@H](NC(=O)OC(C)(C)C)C2)c([N+](=O)[O-])c(Cl)n1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: COc1ccc(CNc2nc(C)cc(N3CCC[C@@H](NC(=O)OC(C)(C)C)C3)c2[N+](=O)[O-])c(OC)c1
Reaction time: 24 h
Yield: 73 %

Procedure:
1.85 g (R)-1-(2-chloro-6-methyl-3-nitropyridin-4-yl)piperidine-3-carbamic acid tert-butyl ester (5 mmol) was dissolved in 10 mL N-methylpyrrolidone, to which 1.4 mL triethylamine (10 mmol) was added, and 1.25 g 2,4-dimethoxybenzylamine (7.5 mmoL) was added. The reaction was continued for 24 h at 80° C. The reaction solution was exacted three times with ethyl acetate. The ethyl acetate phase was combined, washed three times with water, dried, and evaporated to dryness. The resultant crude product was purified through a column chromatography (ethyl acetate:petroleum ether=1:8) to afford 1.83 g titled product with a yield of 73.1%.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]2[CH:24]([O:25][CH2:26][C:27]3[CH:36]=[CH:35][C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[CH:28]=3)[CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH:20]2[CH2:44][O:45][CH3:46])=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>CO>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([CH:19]2[CH:24]([O:25][CH2:26][C:27]3[CH:36]=[CH:35][C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[CH:28]=3)[CH2:23][NH:22][CH2:21][CH:20]2[CH2:44][O:45][CH3:46])=[CH:17][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COCC1CN(C(=O)OC(C)(C)C)CC(OCc2ccc3ccccc3c2)C1c1ccc(OCCCOCc2ccccc2)cc1
Agent: Cl
Solvent: CO
Product: COCC1CNCC(OCc2ccc3ccccc3c2)C1c1ccc(OCCCOCc2ccccc2)cc1

Procedure:
In an analogous manner to that described in Example 22 (l), from tert-butyl (3SR,4RS,5RS)-4-[4-(3-benzyloxy-propoxy)-phenyl]-3-methoxymethyl-5-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate by cleavage of the BOC group by means of hydrogen chloride in methanol there was obtained (3SR,4RS,5RS)-4-[4-(3-benzyloxy-propoxy)-phenyl]-3-methoxymethyl-5-(naphthalen-2-ylmethoxy)-piperidine as an amorphous, colourless solid; MS: 526 (M+H)+.
Reaction SMILES: [CH2:1]([C:3]1[N:4]([CH2:9][CH2:10][NH2:11])[CH:5]=[C:6]([I:8])[N:7]=1)[CH3:2].[F:12][C:13]([F:25])([F:24])[C:14]1[CH:15]=[C:16]([CH:21]=[CH:22][CH:23]=1)[O:17][CH2:18][CH:19]=O>>[CH2:1]([C:3]1[N:4]2[CH2:9][CH2:10][NH:11][CH:19]([CH2:18][O:17][C:16]3[CH:21]=[CH:22][CH:23]=[C:14]([C:13]([F:12])([F:24])[F:25])[CH:15]=3)[C:5]2=[C:6]([I:8])[N:7]=1)[CH3:2]
Reactant: CCc1nc(I)cn1CCN
Reactant: O=CCOc1cccc(C(F)(F)F)c1
Product: CCc1nc(I)c2n1CCNC2COc1cccc(C(F)(F)F)c1

Procedure:
According to the general procedure (GP10), microwave-assisted Pictet-Spengler reaction (60 W; 140° C.; 6.5 bars; 10 min.) between 2-(2-ethyl-4-iodo-imidazol-1-yl)-ethylamine (3.880 mmol) and (3-trifluoromethyl-phenoxy)-acetaldehyde (0.792 g; 3.880 mmol) afforded 3-ethyl-1-iodo-8-(3-trifluoromethyl-phenoxymethyl)-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine.
Reaction SMILES: O[CH2:2][C:3]1[CH:12]=[N:11][C:10]2[N:9]3[CH2:13][CH2:14][CH2:15][C@H:8]3[C:7](=[O:16])[NH:6][C:5]=2[CH:4]=1.Cl.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[CH:21][CH:20]=1.C(N(CC)C(C)C)(C)C.[I-].C(C[P+](C)(C)C)#N>C(#N)CC.CO>[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([N:25]2[CH2:30][CH2:29][N:28]([CH2:2][C:3]3[CH:12]=[N:11][C:10]4[N:9]5[CH2:13][CH2:14][CH2:15][C@H:8]5[C:7](=[O:16])[NH:6][C:5]=4[CH:4]=3)[CH2:27][CH2:26]2)=[CH:23][CH:24]=1
Reactant: O=C1Nc2cc(CO)cnc2N2CCC[C@@H]12
Reactant: Clc1ccc(N2CCNCC2)cc1
Agent: C[P+](C)(C)CC#N
Agent: Cl
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Solvent: CCC#N
Product: O=C1Nc2cc(CN3CCN(c4ccc(Cl)cc4)CC3)cnc2N2CCC[C@@H]12
Temperature: 90 °C
Yield: 39.5 %

Procedure:
(S)-3-(hydroxymethyl)-6a,7,8,9-tetrahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-6(5H)-one (200 mg, 0.912 mmol), 1-(4-chlorophenyl)piperazine hydrochloride (200 mg, 0.858 mmol), N,N-diisopropylethylamine (DIPEA; 0.50 mL), and (cyanomethyl)trimethylphosphonium iodide (220 mg, 1.08 mmol) were suspended in propionitrile (2 mL) and heated in a closed vial at 90° C. for 4 h. The reaction mixture was diluted with MeOH (2 mL) and purified using preparative scale HPLC (45-95% acetonitrile in water, buffered with NH4HCO3). The fractions containing product were concentrated in vacuo and diluted with water (5 mL). The resulting precipitate was filtered and dried in vacuum to afford the title compound as an off-white solid (135 mg, 40%). 1H NMR (DMSO-d6) δ (ppm): 10.43 (s, 1H), 7.61 (d, J=1.8 Hz, 1H), 7.21 (d, J=8.8 Hz, 2H), 6.98 (d, J=1.8 Hz, 1H), 6.92 (d, J=9.1 Hz, 2H), 3.91-4.06 (m, 1H), 3.51-3.66 (m, 1H), 3.37-3.47 (m, 1H), 3.10 (br. s., 4H), 2.46 (d, J=4.3 Hz, 4H), 2.09-2.26 (m, 1H), 1.80-2.03 (m, 3H); [M+H] calc'd for C21H24ClN5O, 398; found, 398. melting point 265-268° C.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([NH:12][C:13](=[O:15])[CH3:14])=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].[Cl:22][C:23]1[CH:28]=[N:27][CH:26]=[C:25](Cl)[N:24]=1>CN(C=O)C>[Cl:22][C:23]1[N:24]=[C:25]([O:1][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([NH:12][C:13](=[O:15])[CH3:14])=[CH:4][CH:3]=2)[CH:26]=[N:27][CH:28]=1
Reactant: CC(=O)Nc1ccc(O)c2ccccc12
Reactant: Clc1cncc(Cl)n1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)Nc1ccc(Oc2cncc(Cl)n2)c2ccccc12
Temperature: 90 °C
Reaction time: 1 h
Yield: 68.2 %

Procedure:
Method KK. A mixture of N-(4-hydroxynaphthalen-1-yl)acetamide (1.22 g, 6.08 mmol) and potassium tert-butoxide (0.68 g, 6.08 mmol) in dry DMF (19 mL) was stirred for 1 hour under argon. To this mixture, 2,6-dichloropyrazine (1.09 g, 7.30 mmol) was added and the temperature was raised to 90° C. and maintained for 20 hours. The DMF was evaporated in vacuo. The resulting crude was dissolved in a (hot) mixture of AcOEt (25 mL) and acetone (175 mL) and filtered. The volume of the filtrate was reduced to 100 mL and this filtrate crystallised upon storage at low temperature to yield the title compound (1.30 g). Yield: 68%. 1H NMR (500 MHz, DMSO-d6) δ 2.21 (s, 3H), 7.42 (d, 1H, J=8.2 Hz), 7.57 (t, 1H, J=7.5 Hz), 7.64 (t, 1H, J=7.6 Hz), 7.72 (d, 1H, J=8.1 Hz), 7.90 (d, 1H, J=8.3 Hz), 8.16 (d, 1H, J=8.5 Hz), 8.52 (s, 1H), 8.72 (s, 1H), 10.02 (s, 1H). 13C NMR (125.8 MHz, DMSO-d6) δ 23.42, 117.59, 121.40, 121.65, 123.42, 126.53, 126.71, 126.85, 128.90, 131.85, 133.59, 137.50, 144.40, 145.04, 158.92, 169.04. m/z 314.0 [(M+H)+ calcd for C16H12ClN3O2 313.1].
Reaction SMILES: [CH3:1][N:2]([C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][N:13]=1)[C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=1.[CH2:21]([N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(N(CC)CC)C.C(P(=O)(OCC)OCC)#N>CN(C=O)C.O>[CH2:21]([N:28]1[CH2:33][CH2:32][N:31]([C:7]([C:6]2[CH:5]=[CH:4][C:3]([N:2]([CH3:1])[C:12]3[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][N:13]=3)=[CH:11][CH:10]=2)=[O:9])[CH2:30][CH2:29]1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: CN(c1ccc(C(=O)O)cc1)c1ccc([N+](=O)[O-])cn1
Agent: CCOP(=O)(C#N)OCC
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CN(c1ccc(C(=O)N2CCN(Cc3ccccc3)CC2)cc1)c1ccc([N+](=O)[O-])cn1
Reaction time: 3 h

Procedure:
To a solution of 4-[methyl-(5-nitropyridin-2-yl)amino]benzoic acid (0.800 g, 2.93 mmol) and 1-benzylpiperazine (0.542 g, 3.08 mmol) in DMF (15 mL) were added triethylamine (1.02 mL, 7.32 mmol) and diethyl cyanophosphonate (0.593 mL, 3.52 mmol), and the resulting solution was stirred for 3 hours. To the resulting reaction solution was added water and extracted with ethyl-acetate. The ethyl acetate layer was washed with brine, dried over anhydrous sodium sulfate, evaporated, and the residue was purified by silica gel column chromatography (ethyl acetate), to thereby yield 1.25 g of the title compound.