Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][NH:3]1.C(N(CC)CC)C.CN(C)C=O.[Cl:24][C:25]1[N:34]=[C:33](Cl)[C:32]2[CH2:31][CH2:30][CH2:29][CH2:28][C:27]=2[N:26]=1>C(OCC)(=O)C>[CH3:1][CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][N:3]1[C:33]1[C:32]2[CH2:31][CH2:30][CH2:29][CH2:28][C:27]=2[N:26]=[C:25]([Cl:24])[N:34]=1
Reactant: Clc1nc(Cl)c2c(n1)CCCC2
Reactant: CC1NCCc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC1c2ccccc2CCN1c1nc(Cl)nc2c1CCCC2
Temperature: 80 °C
Reaction time: 3 h
Yield: 62.5 %

Procedure:
A mixture solution of 1-methyl-1,2,3,4-tetrahydroisoquinoline(2.6 g, 17.4 mmol), triethylamine(2.8 mL), N,N-dimethylformamide (20 ml) and 2,4-dichloro-5,6,7,8-tetrahydroquinazoline(3.2 g, 15.8 mmol) prepared in the above Step 2 were stirred at 80° C. for 3 hours and cooled. The reaction mixture was diluted with ethyl acetate and washed with water. The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated. The residue was purified with silica gel column chromatography to give 3.1 g of the titled compound. (Yield: 62.5%)
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:10]([O:12][CH3:13])=[O:11])[C@@H:3]([CH3:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6]>C(O)(=O)C.[Pd]>[NH2:1][C@H:2]([C:10]([O:12][CH3:13])=[O:11])[C@@H:3]([CH3:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6]
Reactant: COC(=O)[C@@H](NC(=O)OCc1ccccc1)[C@@H](C)OC(C)(C)C
Agent: [Pd]
Solvent: CC(=O)O
Product: COC(=O)[C@@H](N)[C@@H](C)OC(C)(C)C
Reaction time: 1 h
Yield: 96.4 %

Procedure:
12.92 g (40 mmols) of Z-Thr(tBu)-OMe are hydrogenated in 200 ml of glacial acetic acid and 3 g of Pd on charcoal (10 %) at room temperature. The absorption of hydrogen is complete after 1 hour. The solution is freed of the catalyst by filtration and is evaporated under a waterpump vacuum at 35°C. After drying in a high vacuum at 35°C, 7.3 g of an oil result which according to a thin layer chromatogram is homogeneous and is directly used further.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]2[C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.C([O-])([O-])=O.[K+].[K+].[C:21]([O:27][CH2:28]Cl)(=[O:26])[C:22]([CH3:25])([CH3:24])[CH3:23].O>CN(C=O)C>[Br:1][C:2]1[N:3]=[C:4]2[C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:9][N:8]([CH2:28][O:27][C:21](=[O:26])[C:22]([CH3:25])([CH3:24])[CH3:23])[C:5]2=[N:6][CH:7]=1
Reactant: COC(=O)c1c[nH]c2ncc(Br)nc12
Reactant: CC(C)(C)C(=O)OCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cn(COC(=O)C(C)(C)C)c2ncc(Br)nc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 79.3 %

Procedure:
To a stirred mixture of methyl 2-bromo-5H-pyrrolo[2,3-b]pyrazine-7-carboxylate (0.24 g, 0.94 mmol) and K2CO3 (0.156 g, 1.13 mmol) in 10 mL of DMF was added chloromethyl pivalate (0.17 g, 1.13 mmol) drop-wise at room temperature. Then the mixture was stirred at room temperature for 16 hours. The mixture was then poured into 30 mL of water, extracted with ethyl acetate (90 mL). The organic phase was washed with brine (10 mL) and dried over Na2SO4 to give a crude product, which was purified by column chromatography (silica gel, 200-300 mesh, eluting with a mixture of ethyl acetate and petroleum ether (1:1, v/v) to give methyl 2-bromo-5-(pivaloyloxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylate (0.276 g, 79.5%) as a pale yellow solid. LCMS: (M+H)+=370; 1H NMR (300 MHz, CDCl3): δ 8.42 (s, 1H), 8.38 (s, 1H), 6.21 (s, 2H), 3.96 (s, 3H), 1.15 (s, 9H).
Reaction SMILES: [CH3:1][CH2:2][NH:3][CH2:4][CH2:5][NH:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]([CH3:18])=[O:17])=[CH:11][CH:10]=1)=[O:8].[CH:19]1C=CC2N(O)N=NC=2[CH:24]=1.CCN=C=NCCCN(C)C>CN(C=O)C>[CH3:1][CH2:2][N:3]([CH2:4][CH2:5][NH:6][C:7]([C:9]1[CH:10]=[CH:11][C:12]([NH:15][C:16]([CH3:18])=[O:17])=[CH:13][CH:14]=1)=[O:8])[CH2:19][CH3:24]
Reactant: On1nnc2ccccc21
Reactant: CCNCCNC(=O)c1ccc(NC(C)=O)cc1
Agent: CCN=C=NCCCN(C)C
Solvent: CN(C)C=O
Product: CCN(CC)CCNC(=O)c1ccc(NC(C)=O)cc1
Reaction time: 8 h

Procedure:
The N-Acetylprocainamide probe was prepared as follows: 1.0 mg desethyl-N-Acetylprocainamide was placed in a 3.0 ml reaction vial and dissolved with 100 μl DMF. In a separate vial, caged dicarboxy silicon phthalocyanine (1.0 mg) was dissolved in 400 μl DMF and then transferred to the reaction vial along with 200 μl of wash DMF for a total of 600 μl. To the reaction vial was added 4.2 mg HOBT, dissolved and mixed well. To make the final reaction mixture, 10.5 mg EDAC was added and mixed thoroughly. The reaction mixture was stirred overnight at about 4° to 8° C.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6](Cl)[CH:5]=1.[Cl:12][C:13]1[N:14]=[N:15][C:16](Cl)=[CH:17][CH:18]=1.Cl>CS(C)=O>[Cl:12][C:13]1[N:14]=[N:15][C:16]([O:10][C:7]2[CH:8]=[CH:9][C:4]([NH2:3])=[CH:5][CH:6]=2)=[CH:17][CH:18]=1
Reactant: Nc1ccc(O)c(Cl)c1
Reactant: Clc1ccc(Cl)nn1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: Nc1ccc(Oc2ccc(Cl)nn2)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
12 g of sodium hydride was added in portions to a stirred solution of 71.8 g of 1A and 25 g of 3,6-dichloropyridazine in 300 ml of dimethyl sulfoxide, the temperature of the mixture being held at 50° C. The mixture then was stirred for one hour and poured into ice water. The mixture was slightly acidified with dilute hydrochloric acid, and was extracted with methylene chloride. The extract was washed with water, dried (magnesium sulfate) and the solvent was evaporated to give 4-(6-chloro-3-pyridazinyloxy)benzeneamine (1B), as a tan solid, mp: 126°-129° C.
Reaction SMILES: [CH3:1][CH:2]1[C:7]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[N:14]([CH3:18])[C:13](=[O:19])[CH2:12][C:11]3([CH3:21])[CH3:20])=[N:6][NH:5][C:4](=[O:22])[CH2:3]1.[Na].[CH2:24](Br)[CH2:25][CH2:26][CH3:27]>CN(C)C=O>[CH2:24]([N:5]1[C:4](=[O:22])[CH2:3][CH:2]([CH3:1])[C:7]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[N:14]([CH3:18])[C:13](=[O:19])[CH2:12][C:11]3([CH3:21])[CH3:20])=[N:6]1)[CH2:25][CH2:26][CH3:27]
Reactant: CCCCBr
Reactant: CC1CC(=O)NN=C1c1ccc2c(c1)C(C)(C)CC(=O)N2C
Agent: [Na]
Solvent: CN(C)C=O
Product: CCCCN1N=C(c2ccc3c(c2)C(C)(C)CC(=O)N3C)C(C)CC1=O
Reaction time: 0.5 h
Yield: 73 %

Procedure:
To a mixture of 6 g of 6-(5-methyl-3-oxo-2,3,4,5-tetrahydropyridazin-6-yl)-1,4,4-trimethyl-1,2,3,4-tetrahydroquinolin-2-one and 60 ml of dimethylformamide was added 1.8 g of sodium hdyride. After 30 minutes, 4.6 g of butyl bromide was added to the mixture and the whole mixture was stirred for one hour. After completion of the reaction, the mixture was poured into ice-cold water and the precipitated crystals were filtered off and recrystallized from a mixture of ethanol and water to give 5.2 g of 6-(2-butyl-5-methyl-3-oxo-2,3,4,5-tetrahydropyridazin-6-yl)-1,4,4-trimethyl-1,2,3,4-tetrahydroquinolin-2-one, melting at 137°-139° C.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH:5]([C:8]([OH:10])=[O:9])[CH2:4][CH2:3]1.[N+:11]([C:14]1[CH:21]=[CH:20][CH:19]=[C:18]([N+]([O-])=O)[C:15]=1[C:16]#[N:17])([O-:13])=[O:12]>>[C:16]([C:15]1[C:14]([N+:11]([O-:13])=[O:12])=[CH:21][CH:20]=[CH:19][C:18]=1[O:1][CH:2]1[CH2:7][CH2:6][CH:5]([C:8]([OH:10])=[O:9])[CH2:4][CH2:3]1)#[N:17]
Reactant: O=C(O)C1CCC(O)CC1
Reactant: N#Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Product: N#Cc1c(OC2CCC(C(=O)O)CC2)cccc1[N+](=O)[O-]

Procedure:
Prepared as in Example 47d from 4-hydroxycyclohexanecarboxylic acid and 2,6-dinitrobenzonitrile as a brown solid (50%). MS 291 (MH+).
Reaction SMILES: [NH:1]=[C:2]1[N:6]([CH2:7][CH2:8]O)[C:5]2[CH:10]=[CH:11][CH:12]=[CH:13][C:4]=2[N:3]1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[BrH:20].S(Cl)(Cl)=O>C(Cl)(Cl)Cl.C(O)(C)C>[C:14]1([N:3]2[C:4]3[CH:13]=[CH:12][CH:11]=[CH:10][C:5]=3[N:6]3[CH2:7][CH2:8][N:1]=[C:2]23)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[BrH:20]
Reactant: N=c1n(CCO)c2ccccc2n1-c1ccccc1
Agent: Br
Solvent: ClC(Cl)Cl
Solvent: CC(C)O
Solvent: O=S(Cl)Cl
Product: c1ccc(N2C3=NCCN3c3ccccc32)cc1

Procedure:
A solution of 2,3-dihydro-2-imino-3-phenyl-1H-benzimidazole-1-ethanol [prepared by basification of the hydrobromide (2.23 g.)]and thionyl chloride (1.5 ml.) in chloroform (20 ml.) was heated under reflux for 2 hours. After removal of the solvent the oily residue was dissolved in ethanol (50 ml.), 10N aqueous sodium hydroxide solution (2ml.) added and the solution heated under reflux for 5 hours. After removal of the ethanol the residue was taken up in chloroform, washed twice with water and dried over magnesium sulphate. Removal of the chloroform gave an oil which was taken up in isopropanol and acidified with conc. hydrobromic acid. The isopropanol was evaporated and the residue crystallised from acetone. The product (0.862 g., m.p. 223°-225°C.) was recrystallised from ethanol/ether to give the title compound as its hydrobromide (0.765 g., m.p. 225°-228° C).
Reaction SMILES: [NH2:1][C:2]1[C:3](=[S:17])[NH:4][C:5]([C:8]2([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH2:10][CH2:9]2)=[CH:6][CH:7]=1.[F:18][C:19]1[CH:26]=[CH:25][C:22]([CH:23]=O)=[CH:21][CH:20]=1.NC1C(=S)NC=CC=1>>[F:18][C:19]1[CH:26]=[CH:25][C:22]([C:23]2[S:17][C:3]3[C:2]([N:1]=2)=[CH:7][CH:6]=[C:5]([C:8]2([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[CH2:10][CH2:9]2)[N:4]=3)=[CH:21][CH:20]=1
Reactant: Nc1ccc(C2(c3ccccc3)CC2)[nH]c1=S
Reactant: O=Cc1ccc(F)cc1
Agent: Nc1ccc[nH]c1=S
Product: Fc1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)cc1

Procedure:
Reaction of 3-amino-6-(1-phenylcyclopropyl)pyridine-2(1H)-thione (52.6 mg, 0.217 mmol) and 4-fluorobenzaldehyde (22 μl, 0.206 mmol) according to Reference V and the general procedure for the condensation of 3-aminopyridine-2-thione with aryl acid chlorides gave 2-(4-fluorophenyl)-5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine as a white solid. MS (ESI) m/z: Calculated: 346.1; Observed: 347.1 (M++1).
Reaction SMILES: CS(C)=O.[C:5]([C:9]1[C:10](=[O:28])[CH2:11][CH:12]([C:16]2[CH:17]=[CH:18][C:19]3[O:24][CH2:23][C:22](=[O:25])[N:21]([CH3:26])[C:20]=3[CH:27]=2)[CH2:13][C:14]=1[OH:15])(=O)[CH2:6][CH3:7].Cl.[CH2:30]([O:32][NH2:33])[CH3:31].C([O-])(=O)C.[Na+]>O>[CH2:30]([O:32][N:33]=[C:5]([C:9]1[C:10](=[O:28])[CH2:11][CH:12]([C:16]2[CH:17]=[CH:18][C:19]3[O:24][CH2:23][C:22](=[O:25])[N:21]([CH3:26])[C:20]=3[CH:27]=2)[CH2:13][C:14]=1[OH:15])[CH2:6][CH3:7])[CH3:31]
Reactant: CCON
Reactant: CCC(=O)C1=C(O)CC(c2ccc3c(c2)N(C)C(=O)CO3)CC1=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CCON=C(CC)C1=C(O)CC(c2ccc3c(c2)N(C)C(=O)CO3)CC1=O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To 20 mL of methyl sulfoxide were added in sequence, 1.0 g (3.0 mmol) of 2-propionyl-3-hydroxy-5-(N-methyl-3-oxo-(2H)-1,4-benzoxazin-6-yl)cyclohex-2-en-1-one, 0.37 g (3.9 mmol) of ethoxyamine hydrochloride and 0.32 g (3.9 mmol) of anhydrous sodium acetate. The resulting mixture was stirred at ambient temperature for 5 hours, becoming a clear amber solution. The reaction mixture was diluted with 100 mL of water and extracted twice with 30 mL portions of ether. The extracts were combined, washed with water, then aqueous sodium chloride and dried over MgSO4 and filtered. Evaporation off of the solvent gave the crude product as an oily residue which solidified upon standing. The crude solid was crushed and triturated in ether. The purified above-named product, as a tan solid, was recovered in a yield of 0.9 g (80 percent of theoretical). The title compound melted at 90°-92° C.; 1H NMR(CDCl3): d1.05-1.48 (m, 6H, both --CCH2CH3 's), 2.55-3.62 (m including s at 3.31 for --N--CH3, 1 OH) 4.18 (q, J=7 Hz, 2H,--OCH2CH3), 4.60 (s, 2H, --OCH2C=O), 6.82-7.13 (m, 3H, aromatic H's), 15.10 (broad s, 1H, enol H); (Compound 3).
Reaction SMILES: [NH:1]([C:8]1[N:9]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:10]2[C:15]([C:16](=[O:18])[CH:17]=1)=[C:14](Cl)[N:13]=[C:12]([CH3:20])[CH:11]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CCOC(C)=O.CCO.[Pd]>[NH:1]([C:8]1[N:9]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:10]2[C:15]([C:16](=[O:18])[CH:17]=1)=[CH:14][N:13]=[C:12]([CH3:20])[CH:11]=2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc2c(c(Cl)n1)c(=O)cc(Nc1ccccc1)n2-c1ccccc1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cc1cc2c(cn1)c(=O)cc(Nc1ccccc1)n2-c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.5 %

Procedure:
To a flask containing 2-anilino-5-chloro-7-methyl-1-phenyl-1,6-naphthyridin-4(1H)-one (10 mg, 0.03 mmol) in EtOAc (2 mL) and EtOH (2 mL) at room temperature was added a drop of TEA, and Pd/C (10 weight % on activated carbon Degussa type E101, 2 mg). The system was purged with H2 and left stirring at room temperature overnight. The reaction mixture was filtered and concentrated in vacuo to provide 2-anilino-7-methyl-1-phenyl-1,6-naphthyridin-4(1H)-one (8 mg, 91%): LCMS RT: 1.22 min, MH+: 328.3.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1.[H-].[Na+].[CH3:16]I>O1CCCC1.O>[CH3:16][O:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1
Reactant: CI
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](O)C1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CO[C@@H]1CCN(C(=O)OC(C)(C)C)C1
Temperature: 0 °C

Procedure:
tert-Butyl (3R)-3-hydroxypyrrolidine-1-carboxylate (12.5 g, 66.70 mmol) was dissolved in tetrahydrofuran (334 mL) and the reaction mixture cooled to 0° C. in an ice bath. The reaction mixture was treated with 80% sodium hydride in mineral oil (2.20 g, 73.3 mmol) and stirred until back at room temperature. The reaction mixture was then treated with methyl iodide (14.5 g, 100.0 mmol) and stirred at room temperature for 18 hours. The reaction mixture was diluted with water (100 mL) and concentrated in vacuo until just the aqueous remained. The aqueous solution was treated with ethyl acetate (750 mL), the organic layer separated, dried over magnesium sulphate and concentrated in vacuo to yield the title product as a brown oil, 12.48 g. 1H NMR (CDCl3, 400 MHz) δ: 1.41 (s, 9H), 1.95 (m, 2H), 3.30 (s, 3H), 3.40 (m, 4H), 3.86 (m, 1H)
Reaction SMILES: [O:1]=[C:2]1[O:6][C@@H:5]([C@@H:7]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:4][CH:3]1[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=2)=[CH:26][CH:25]=1.[OH-:36].[Na+].N1C=CN=C1.[Si:43](Cl)([C:46]([CH3:49])([CH3:48])[CH3:47])([CH3:45])[CH3:44]>O1CCOCC1.O>[C:18]([O:17][C:16]([NH:15][C@@H:7]([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C@H:5]([O:6][Si:43]([C:46]([CH3:49])([CH3:48])[CH3:47])([CH3:45])[CH3:44])[CH2:4][CH:3]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=2)=[CH:26][CH:25]=1)[C:2]([OH:36])=[O:1])=[O:22])([CH3:20])([CH3:21])[CH3:19]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@H]1CC(Cc2ccc(-c3ccccn3)cc2)C(=O)O1
Reactant: [OH-]
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@@H](CC(Cc1ccc(-c2ccccn2)cc1)C(=O)O)O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution containing the product from Example 107B (10.55 g, 22.35 mmol) in a mixture of dioxane (130 mL) and water (65 mL) was treated with sodium hydroxide solution (33.5 mL, 1N), stirred for 30 minutes at 25° C., concentrated, cooled to 0° C., acidified to pH 5 using 10% citric acid, and partitioned between dichloromethane and water. The organic phase layer was washed with brine, dried over Na2SO4, filtered and concentrated. A solution of the concentrate in dimethylformamide (130 mL) was treated with imidazole (18.3 g, 268.80 mmol) and t-butyldimethylsilyl chloride (20.2 g, 134.01 mmol), stirred at 25° C. for 16 hours, and concentrated. The concentrate was combined with ice and extracted with ethyl acetate. The organic phase was washed with 10% citric acid and brine, dried over MgSO4, filtered, and concentrated. A solution of the residue in a mixture of THF (100 mL), acetic acid (100 mL) and water (33 mL) was stirred at 25° C. for 2 hours, and concentrated under reduced pressure. The residue was dissolved in toluene and concentrated several times, followed by drying under high vacuum to give the title compound, which was used without further purification.
Reaction SMILES: [C:1]1([CH:7]2[C:11]3([CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)[C:10](=[O:17])[NH:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:18]1(=O)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1.[Si]([C:29]#[N:30])(C)(C)C>CC(O)=O>[O:17]=[C:10]1[C:11]2([CH2:12][CH2:13][N:14]([C:18]3([C:29]#[N:30])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[CH2:15][CH2:16]2)[CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:8][NH:9]1
Reactant: O=C1CCCCC1
Reactant: O=C1NCC(c2ccccc2)C12CCNCC2
Reactant: C[Si](C)(C)C#N
Solvent: CC(=O)O
Product: N#CC1(N2CCC3(CC2)C(=O)NCC3c2ccccc2)CCCCC1
Temperature: 25 °C
Reaction time: 120 h
Yield: 61.9 %

Procedure:
To a mixture of rac-4-phenyl-2,8-diaza-spiro[4.5]decan-1-one (8.0 g, 34.7 mmol) in AcOH (80 mL) was added cyclohexanone (3-4 g, 34.7 mmol) followed by the dropwise addition of TMSCN (10.4 g, 104.2 mmol) and the resulting mixture stirred at room temperature for 5 days. The resulting mixture was poured onto ice—sodium hydroxide (25%, 200 mL) and the resulting white solid filtered off. The solid was dissolved in DCM (50 mL) and washed with water (40 mL) and dried over sodium sulfate. Filtration and evaporation afforded the title compound (7.25 g, 62%) as a white solid after purification by silica gel chromatography eluting with DCM: MeOH (9: 1). MS: m/e=338.3 (M+H).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1)[C:6](Cl)=[O:7].[CH3:18][O:19][C:20]1[CH:21]=[C:22]([C:26]2([OH:32])[CH2:31][CH2:30][CH2:29][NH:28][CH2:27]2)[CH:23]=[CH:24][CH:25]=1>>[F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([C:6]([N:28]2[CH2:29][CH2:30][CH2:31][C:26]([OH:32])([C:22]3[CH:23]=[CH:24][CH:25]=[C:20]([O:19][CH3:18])[CH:21]=3)[CH2:27]2)=[O:7])[CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1
Reactant: COc1cccc(C2(O)CCCNC2)c1
Reactant: O=C(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Product: COc1cccc(C2(O)CCCN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)C2)c1

Procedure:
The compound of Example 25 was prepared according to the general preparation protocol A from 3,5-bis(trifluoromethyl)benzoyl chloride and 3-(3-methoxy-phenyl)-piperidine-3-ol.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[CH2:11][CH:12]([NH:14][C:15](=[O:24])[O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH3:13])=[CH:4][CH:3]=1.[Br:25]N1C(=O)CCC1=O.[Cl-].[NH4+]>ClCCl.O1CCCC1>[Br:25][C:10]1[C:2]([OH:1])=[CH:3][CH:4]=[C:5]2[C:9]=1[N:8]([CH2:11][CH:12]([NH:14][C:15](=[O:24])[O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH3:13])[N:7]=[CH:6]2
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(Cn1ncc2ccc(O)cc21)NC(=O)OCc1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(Cn1ncc2ccc(O)c(Br)c21)NC(=O)OCc1ccccc1
Reaction time: 16 h

Procedure:
To a stirred solution of benzyl 2-(6-hydroxy-1H-indazol-1-yl)-1-methylethylcarbamate (0.90 g, 2.98 mmol) in dichloromethane (10 mL) and tetrahydrofuran (5 mL) was added N-bromosuccinimide (0.59 g, 3.38 mmol) at room temperature. After 16 h, a saturated aqueous solution of ammonium chloride (25 mL) was added and this mixture was extracted with ethyl acetate (3×60 mL). The combined extracts were washed with brine (10 mL), dried (magnesium sulfate), and evaporated. The residue was purified by chromatography (silica, 30% to 50% ethyl acetate in hexane) to give (1.1 g, 91%): 1H NMR (CDCl3) δ 7.86 (1H, d, J=8.8 z), 7.80 (1H, s), 7.37 (6H, m), 6.18 (1H, brs), 5.24 (1H, brs), 4.95 (2H, s), 4.80 (2H, m), 4.34 (1H, m), 1.26 (3H, d, J=6.8 Hz); MS (ES) m/z 404, 406 (M+).
Reaction SMILES: CO[C:3](=[O:20])[C:4]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][N:13]=[N:12][CH:11]=2)[C:7]([CH:16]([CH3:18])[CH3:17])=[CH:6][C:5]=1[NH2:19].ClC([O:24][C:25]1C=CC(Cl)=CC=1)=O.[CH3:32][S:33]([NH:36][NH2:37])(=[O:35])=[O:34].CCN(C(C)C)C(C)C>O1CCOCC1>[CH:16]([C:7]1[CH:6]=[C:5]2[C:4]([C:3](=[O:20])[N:37]([NH:36][S:33]([CH3:32])(=[O:35])=[O:34])[C:25](=[O:24])[NH:19]2)=[CH:9][C:8]=1[C:10]1[CH:15]=[CH:14][N:13]=[N:12][CH:11]=1)([CH3:17])[CH3:18]
Reactant: O=C(Cl)Oc1ccc(Cl)cc1
Reactant: COC(=O)c1cc(-c2ccnnc2)c(C(C)C)cc1N
Reactant: CS(=O)(=O)NN
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)c1cc2[nH]c(=O)n(NS(C)(=O)=O)c(=O)c2cc1-c1ccnnc1
Temperature: 25 °C
Yield: 51.3 %

Procedure:
A solution of 2-amino-4-isopropyl-5-pyridazin-4-yl-benzoic acid methyl ester (220 mg, 0.81 mmol) and 4-chlorophenyl chloroformate (170 μL, 1.22 mmol) in dioxane (10 mL) was stirred at r.t. for 10 min and at 80° C. for 30 min. After cooling to r.t., CH3SO2NHNH2 (178.6 mg, 1.6 mmol) and i-Pr2NEt (425 μL, 2.43 mmol) were added. The mixture was heated at 80° C. for 1.5 h, cooled to r.t., and the solvent was removed in vacuo. The residue was purified by flash chromatography (100 g silica gel, DCM→MeOH in DCM (2.5% to 5%)). The fractions containing the product were combined and concentrated in vacuo and the residue was further purified by trituration in MeOH-Et2O. After filtration and drying, the title compound (156 mg, 51%) was isolated as a white powder. API-ES: m/z 376 [M+H]+, rt 2.12 min.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][NH:8][C:9]([C:11]1[CH:20]=[C:19]2[C:14]([CH2:15][CH2:16][NH:17][CH2:18]2)=[CH:13][CH:12]=1)=[O:10].[CH3:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][CH:23]=1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C.C(N(CC)CC)C>[CH3:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([N:17]2[CH2:16][CH2:15][C:14]3[C:19](=[CH:20][C:11]([C:9]([NH:8][O:7][CH:2]4[CH2:3][CH2:4][CH2:5][CH2:6][O:1]4)=[O:10])=[CH:12][CH:13]=3)[CH2:18]2)=[O:27])=[CH:24][CH:23]=1
Reactant: O=C(NOC1CCCCO1)c1ccc2c(c1)CNCC2
Reactant: Cc1ccc(C(=O)O)cc1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1ccc(C(=O)N2CCc3ccc(C(=O)NOC4CCCCO4)cc3C2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 27 %

Procedure:
A mixture of 200 mg N-(tetrahydro-2H-pyran-2-yloxy)-1,2,3,4-tetrahydroisoquinoline-7-carboxamide, 108 mg 4-methylbenzoic acid, 98 mg HOBt, 278 mg EDC, 0.6 ml triethylamine and 8 ml DMF is stirred overnight at ambient temperature. The mixture is evaporated. The residue is purified by silica gel flash chromatography. 77 mg of the title compound are obtained after drying as colorless foam.
Reaction SMILES: [F-].[CH2:2]([N+](CCCC)(CCCC)CCCC)[CH2:3][CH2:4]C.[F:19][C:20]([Si](C)(C)C)([F:22])[F:21].[O:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1>>[CH:30]1([CH:31]([OH:27])[C:20]([F:22])([F:21])[F:19])[CH2:4][CH2:3][CH2:2][CH2:28][CH2:29]1
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Reactant: C1CCOC1
Reactant: C[Si](C)(C)C(F)(F)F
Agent: [F-]
Product: OC(C1CCCCC1)C(F)(F)F
Yield: 37 %

Procedure:
According to Reference Example 8-12, by use of cyclohexylcarbaldehyde (300 mg, 2.67 mmol) dissolved in tetrahydrofuran (6 mL), a 1 mol/L solution of tetrabutylammonium fluoride in tetrahydrofuran (0.534 mL, 0.534 mmol) and (trifluoromethyl)trimethylsilane (0.474 mL, 3.20 mmol), the mixture was stirred and reacted at room temperature for 1.5 hours. Then, purification by preparative thin-layer chromatography (hexane/ethyl acetate=10/1) was performed to give 1-cyclohexyl-2,2,2-trifluoroethanol (Compound DP) (181 mg, yield: 37%).