Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]3[N:13]([N:17]=[C:18]([NH2:20])[N:19]=3)[CH:14]=[CH:15][CH:16]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].Br[C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)=[CH:24][CH:23]=1>>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]3[N:13]([N:17]=[C:18]([NH:20][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[N:19]=3)[CH:14]=[CH:15][CH:16]=2)=[CH:7][CH:6]=1)(=[O:3])=[O:4].[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]3[N:13]([N:17]=[C:18]([NH:20][C:22]4[CH:23]=[CH:24][C:25]([N:28]5[CH2:29][CH2:30][O:31][CH2:32][CH2:33]5)=[CH:26][CH:27]=4)[N:19]=3)[CH:14]=[CH:15][CH:16]=2)=[CH:7][CH:6]=1)(=[O:3])=[O:4]
Reactant: Brc1ccc(N2CCOCC2)cc1
Reactant: CS(=O)(=O)c1ccc(-c2cccn3nc(N)nc23)cc1
Product: CS(=O)(=O)c1ccc(-c2cccn3nc(Nc4ccc(N5CCOCC5)cc4)nc23)cc1
Product: CS(=O)(=O)c1ccc(-c2cccn3nc(Nc4ccccc4)nc23)cc1

Procedure:
[8-(4-Methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-(4-morpholin-4-yl-phenyl)-amine and [8-(4-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-phenyl-amine were prepared from 8-(4-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (100.0 mg, 0.3468 mmol) and 4-(4-bromo-phenyl)-morpholine (100.0 mg, 0.4130 mmol) in a manner analogous to Example 2d. [8-(4-Methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-(4-morpholin-4-yl-phenyl)-amine was isolated as a pale yellow solid (0.063 g, 40%). MP=244-246° C. 1H NMR (400 MHz, CDCl3, δ, ppm): 8.49-8.45 (m, 1H), 8.25-8.20 (m, 2H), 8.11-8.06 (m, 2H), 7.63 (dd, J=7.4, 0.9 Hz, 1H), 7.53-7.48 (m, 2H), 6.99 (t, J=7.0 Hz, 1H), 6.97-6.93 (m, 2H), 6.73 (s, 1H), 3.90-3.86 (m 4H), 3.14-3.09 (m, 7H). MS=450 (MH)+.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].C[O-].[Na+].Cl[C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]([CH2:23][C:24]2[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=2)=[N:15][N:14]=1>O1CCOCC1>[OH:2][C:1]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[O:5][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]([CH2:23][C:24]2[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=2)=[N:15][N:14]=1
Reactant: Clc1nnc(Cc2ccncc2)c2ccccc12
Reactant: Oc1cccc(O)c1
Agent: C[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Oc1cccc(Oc2nnc(Cc3ccncc3)c3ccccc23)c1
Temperature: 120 °C
Reaction time: 18 h

Procedure:
A solution of 0.2 g (1.82 mmol) resorcinol in 5 ml dioxane is spiked with 0.37 ml 5.4M methanolic sodium methylate solution (2 mmol) The crystalline residue is then suspended in 5 ml dioxane, 0.511 g (2 mmol) 1-chloro-4-(4-pyridylmethyl)phthalazine is added, and the reaction mixture stirred under nitrogen atmosphere for 18 h at 120° C. After cooling to RT and filtration, the filtrate is evaporated under vacuum, and the residue purified by means of flash chromatography on silica gel with particle size 0.04-0.06 mm, using acetate and ethyl acetate/methanol mixtures (50:1 and 25:1). The product-containing fractions are evaporated under vacuum, the crystalline residue suspended in about 5 ml dichloromethane, and filtered. Title compound is obtained after drying of the crystallizate under HV (6 h, 100° C.), m.p. 206-207° C.; ESI-MS: (M+H)+=330.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([F:9])[CH:8]=1)[NH2:5].C1COCC1.[CH3:15][S:16](Cl)(=[O:18])=[O:17].Cl>O.N1C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([NH:5][S:16]([CH3:15])(=[O:18])=[O:17])[CH:6]=[C:7]([F:9])[CH:8]=1
Reactant: Nc1cc(F)cc(F)c1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Solvent: O
Product: CS(=O)(=O)Nc1cc(F)cc(F)c1
Temperature: 0 °C

Procedure:
The reactor is charged with 14.0 kg of 3,5-difluoroaniline and 56 liters of THF. 9.6 kg of pyridine are added to the stirred solution. The reaction medium is cooled to 0° C. and 13.10 kg of methanesulfonyl chloride are added, while maintaining the temperature between 0-10° C. for 1 hour 30 minutes. At the end of introduction of the methanesulfonyl chloride, the reaction medium is heated at 25° C. for 2 hours. 29 liters of demineralized water and then 6.6 kg of hydrochloric acid (30% w/w) are added to the reaction medium. 60 liters of solvent are distilled off at atmospheric pressure in the presence of an external bath maintained at 100° C., and the reaction medium is then cooled to 20° C. The resulting suspension is filtered and the solid is washed with a total of 20 liters of demineralized water. The solid is dried under vacuum (20 m bar) at 40° C. until a water content <0.5% is obtained. 19.48 kg (87%) of a slightly yellow crystalline solid are thus obtained (m.p.: 121° C.).
Reaction SMILES: N[C@H:2]([C:10]([OH:12])=[O:11])CC1C=CC=CC=1.[NH2:13][C@H:14]([C:16]([OH:18])=[O:17])[CH3:15].N[C@H](C(O)=O)CC1C=CC(O)=CC=1>>[NH2:13][C@H:14]([C:16]([OH:18])=[O:17])[CH2:15][CH2:2][C:10](=[O:11])[OH:12]
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Reactant: C[C@H](N)C(=O)O
Agent: N[C@@H](Cc1ccc(O)cc1)C(=O)O
Product: N[C@@H](CCC(=O)O)C(=O)O

Procedure:
1.08 His : 1.02 Phe : 1.00 Ala : 1.02 Tyr: 1.00
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([O:10][CH2:11][CH2:12][C:13]1[CH:22]=[CH:21][C:16]([O:17][CH2:18][CH2:19][NH2:20])=[C:15]([CH3:23])[CH:14]=1)[CH3:9].Cl[C:25]1[C:30]([Cl:31])=[C:29]([CH3:32])[N:28]=[C:27]([CH3:33])[N:26]=1>C1(C)C=CC=CC=1>[Cl:31][C:30]1[C:25]([NH:20][CH2:19][CH2:18][O:17][C:16]2[CH:21]=[CH:22][C:13]([CH2:12][CH2:11][O:10][CH2:8][CH3:9])=[CH:14][C:15]=2[CH3:23])=[N:26][C:27]([CH3:33])=[N:28][C:29]=1[CH3:32]
Reactant: CCOCCc1ccc(OCCN)c(C)c1
Reactant: Cc1nc(C)c(Cl)c(Cl)n1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCOCCc1ccc(OCCNc2nc(C)nc(C)c2Cl)c(C)c1
Reaction time: 5 h
Yield: 55.8 %

Procedure:
1.0 g of triethylamine and 2.2 g of 2-[4-(2-ethoxyethyl)-2-methylphenoxy]ethylamine were added to 1.8 g of 4,5-dichloro-2,6-dimethylpyrimidine dissolved in 50 ml of toluene. The mixture was heated under reflux, whilst stirring, for 5 hours. At the end of this time, the reaction product was washed with water and dried over anhydrous sodium sulfate. Toluene was then removed by distillation under reduced pressure, and the oily product obtained was subjected to column chromatography (Wakogel C-200, eluted with a 2:1 by volume mixture of toluene and etyl acetate) to isolate the product. The crystals obtained were recrystallized from hexane, to give 2.0 g of the title compound as colorless granular crystals melting at 61°-63° C.
Reaction SMILES: [CH2:1]1[C@H:5]2[CH2:6][CH2:7][C@H:8]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[C@H:4]2[CH2:3][NH:2]1.Br[C:18]1[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][N:19]=1.C(N(CC)CC)C.O.C(O)C>C(O)C>[F:25][C:24]([F:27])([F:26])[C:21]1[CH:22]=[CH:23][C:18]([N:2]2[CH2:3][C@@H:4]3[C@@H:8]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:13])([CH3:15])[CH3:14])[CH2:7][CH2:6][C@@H:5]3[CH2:1]2)=[N:19][CH:20]=1
Reactant: FC(F)(F)c1ccc(Br)nc1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H]2CNC[C@@H]21
Solvent: CCN(CC)CC
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@@H]2CN(c3ccc(C(F)(F)F)cn3)C[C@@H]21
Temperature: 81 °C

Procedure:
tert-butyl(3aR,4S,6aS)-octahydrocyclopenta[c]pyrrol-4-ylcarbamate from Step B of Example 252 (250 mg, 1.105 mmol), 2-bromo-5-(trifluoromethyl)pyridine (250 mg, 1.105 mmol), and triethylamine (0.462 mL, 3.31 mmol) were combined in ethanol (0.6 mL). The reaction was heated at 81° C. for 16 hours. To the reaction mixture was added 50% water/ethanol (5 mL), and the precipitate was collected by filtration. This crude material was purified using a 12 g silica gel cartridge with a gradient of 0-1.5% methanol (2 N ammonia)/dichloromethane over 20 minutes to give tert-butyl(3aR,4S,6aS)-2-(5-(trifluoromethyl)pyridin-2-yl)octahydrocyclopenta[c]pyrrol-4-ylcarbamate: 1H NMR (500 MHz, pyridine-d5) δ ppm 8.62 (s, 1H), 7.76 (d, J=6.4, 1H), 7.68 (d, J=8.6, 1H), 6.38 (d, J=8.8, 1H), 4.10 (s, 1H), 3.73 (d, J=10.4, 1H), 3.65 (s, 1H), 3.61-3.53 (m, 1H), 3.32 (d, J=10.1, 1H), 2.82-2.71 (m, 2H), 2.15 (td, J=12.6, 6.8, 1H), 1.97 (dt, J=13.1, 6.4, 1H), 1.74 (dq, J=15.6, 7.9, 1H), 1.54 (s, 9H), 1.45-1.34 (m, 1H); MS(DCI+) m/z 372 (M+H)+.
Reaction SMILES: C([O:5][C:6](=[O:18])[C@H:7]([CH2:16]S)[NH:8][C:9](OC(C)(C)C)=O)(C)(C)C.[S:19](OCCNC(OCC1C=CC=CC=1)=O)([C:22]1C=CC(C)=CC=1)(=O)=O.[N:43]12CCC[N:50]=[C:49]1[CH2:48]CCC[CH2:44]2>C1(C)C=CC=CC=1>[NH:50]=[C:49]([NH:43][CH2:44][CH2:9][NH:8][C@H:7]([C:6]([OH:5])=[O:18])[CH2:16][CH2:22][SH:19])[CH3:48]
Reactant: Cc1ccc(S(=O)(=O)OCCNC(=O)OCc2ccccc2)cc1
Reactant: C1CCC2=NCCCN2CC1
Reactant: CC(C)(C)OC(=O)N[C@@H](CS)C(=O)OC(C)(C)C
Solvent: Cc1ccccc1
Product: CC(=N)NCCN[C@@H](CCS)C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of N-t-butoxycarbonyl cysteine t-butyl ester (prepared by reduction of N-t-butoxycarbonyl cystine t-butyl ester with dithiothreitol) (291 mg, 1 mmol) in dry toluene (20 ml) is added N-benzyloxycarbonyl ethanolamine tosylate (349 mg, 1 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (150 μL, 1 mmol) and the mixture stirred vigorously overnight at room temperature under nitrogen. The mixture is partitioned between 50 ml each of ethyl acetate and 1N aqueous HCl. A further organic extract is combined and these extracts washed with aqueous sodium bicarbonate, water and brine, then dried and evaporated. Purification by column chromatography affords the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Cl[S:12]([OH:15])(=O)=[O:13].[NH3:16].Cl>C(Cl)(Cl)Cl.O>[CH3:1][C:2]1[CH:10]=[C:9]([S:12](=[O:15])(=[O:13])[NH2:16])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=S(=O)(O)Cl
Reactant: Cc1ccccc1C(=O)O
Reactant: N
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: O
Product: Cc1cc(S(N)(=O)=O)ccc1C(=O)O
Temperature: 60 °C
Reaction time: 22 h

Procedure:
2-Methyl-benzoic acid (1.36 g, 10 mmol) was dissolved in CHCl3 (8 mL), added ClSO3H (5.83 g, 3.32 mL, 50 mmol) and stirred at 60° C. for 22 h. The reaction mixture was cooled to rt and then added carefully to a stirred solution of 25% NH3 in H2O (75 mL). The obtained solution was acidified to pH=2 using conc. HCl. The precipitate was collected by filtration, washed with H2O affording the title compound as a white powder (1.37 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[C@@H:10]1[N:14]2[CH:15]=[N:16][CH:17]=[C:13]2[C:12](=[O:18])[CH2:11]1)[C:5]#[N:6].[Cl-].[C:20]([O:24][C:25](=[O:28])[CH2:26][Zn+])([CH3:23])([CH3:22])[CH3:21]>C1COCC1.[Cl-].[Zn+2].[Cl-]>[C:5]([C:4]1[CH:7]=[CH:8][C:9]([C@@H:10]2[N:14]3[CH:15]=[N:16][CH:17]=[C:13]3[C@:12]([CH2:26][C:25]([O:24][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:28])([OH:18])[CH2:11]2)=[C:2]([F:1])[CH:3]=1)#[N:6]
Reactant: N#Cc1ccc([C@H]2CC(=O)c3cncn32)c(F)c1
Reactant: CC(C)(C)OC(=O)C[Zn+]
Agent: [Cl-]
Agent: [Zn+2]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C[C@@]1(O)C[C@H](c2ccc(C#N)cc2F)n2cncc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (R)-3-fluoro-4-(7-oxo-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-5-yl)benzonitrile (2.0 g, 8.29 mmol) in THF (40.8 mL) was added a solution of 0.5M (2-tert-butoxy-2-oxoethyl)zinc(II) chloride in THF (39.8 mL, 19.90 mmol). The crude was stirred at room temperature for 2 hrs. To the crude was added and additional 0.5M 2-tert-butoxy-2-oxoethyl)zinc(II) chloride solution in THF (16.6 mL, 8.29 mmol). The crude was stirred at room temperature for 0.5 hr. The crude was quenched with saturated NH4Cl and diluted in EtOAc. The organic layer was washed with brine, dried over MgSO4, filtered, and concentrated. The crude was purified via HPLC 15% to 40% MeCN/H2O, to give 365 mg of the entitled product as the major diastereomer. MS 358.2 (M+H), LCMS condition A, retention time 1.21 min. 1H NMR (400 MHz, CDCl3) δ ppm 1.44 (s, 9H), 2.66-2.74 (m, 1H), 2.76-2.90 (m, 2H), 3.05-3.17 (m, 1H), 5.69 (dd, 1H), 6.96 (s, 1H), 7.12 (t, 1H), 7.31-7.38 (m, 2H), 7.44 (d, 1H).
Reaction SMILES: [NH2:1][C@H:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Br:12])[CH:10]=2)[N:5]([C:13](=[O:15])[CH3:14])[C@@H:4]([CH3:16])[CH2:3]1.Cl[C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][N:19]=1.CN1C(=O)CCC1.CCN(C(C)C)C(C)C>O>[Br:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]([C:13](=[O:15])[CH3:14])[C@@H:4]([CH3:16])[CH2:3][C@H:2]2[NH:1][C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][N:19]=1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: CC(=O)N1c2ccc(Br)cc2[C@H](N)C[C@@H]1C
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CC(=O)N1c2ccc(Br)cc2[C@H](Nc2ccc([N+](=O)[O-])cn2)C[C@@H]1C
Temperature: 200 °C
Reaction time: 2 h
Yield: 161 %

Procedure:
To a flask charged with 1-((2S,4R)-4-amino-6-bromo-2-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone (for a preparation see Intermediate 1)(2 g, 7.06 mmol) and 2-chloro-5-nitropyridine (2.240 g, 14.13 mmol) was added NMP (10 mL) and the resulting mixture treated with DIPEA (3.70 mL, 21.19 mmol). The mixture was divided between 2 flasks, each flask flushed with nitrogen, sealed and the mixture stirred under microwave irradiation at 200° C. for 2 h. The 2 reaction mixtures were combined, diluted with water and extracted with EtOAc (×4). Combined EtOAc layers were washed with water (×3) then brine, dried over MgSO4 and concentrated in vacuo. The residual brown solid was purified by chromatography eluting with an EtOAc/hexanes gradient, which gave 1-((2S,4R)-6-bromo-2-methyl-4-((5-nitropyridin-2-yl)amino)-3,4-dihydroquinolin-1(2H)-yl)ethanone (4.6 g, 11.35 mmol, 161% yield) as a pale brown foam. LCMS (HpH, 2 min), Rt=1.08 min, MH+=405/407 (doublet).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:4])[CH2:2][CH3:3].[CH3:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[Mg]Cl.C1COCC1.[Cl-].[NH4+]>C(OCC)C>[CH3:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)([OH:4])[CH2:2][CH3:3]
Reactant: Cc1ccccc1[Mg]Cl
Reactant: CCC(=O)c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCC(O)(c1ccccc1)c1ccccc1C
Yield: 92 %

Procedure:
Propiophenone (6.7 g, 50 mmol) was added dropwise to a solution of 2-methylphenylmagnesium chloride (30 ml of a 2.0 M solution in diethyl ether) and dry THF (50 ml) under a nitrogen atmosphere. When the addition was complete the reaction mixture was heated at reflux temperature for 5 h. Excess of a saturated ammonium chloride solution was added and the mixture was extracted with diethyl ether (2×100 ml). The combined organic extracts were dried over potassium carbonate and the solvent was evaporated in vacuo to give 10.4 g (92%) of 1-(2-methyl phenyl)-1-phenyl-1-propanol.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][NH2:9])[CH:5]=[CH:4][N:3]=[CH:2]1.[CH3:10][C:11]1[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=1.C([O:21][C:22](=O)[C:23](=[O:32])[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=1)C>C(O)C>[OH:32][C:23]1[C:22](=[O:21])[N:9]([CH2:8][CH2:7][CH2:6][N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)[CH:15]([C:14]2[CH:17]=[CH:18][C:11]([CH3:10])=[CH:12][CH:13]=2)[C:24]=1[C:25]1[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=1
Reactant: CCOC(=O)C(=O)Cc1ccc(O)cc1
Reactant: NCCCn1ccnc1
Reactant: Cc1ccc(C=O)cc1
Solvent: CCO
Product: Cc1ccc(C2C(c3ccc(O)cc3)=C(O)C(=O)N2CCCn2ccnc2)cc1
Temperature: 50 °C
Reaction time: 24 h

Procedure:
3-Imidazol-1-yl-propylamine (1 mmol) and 4-Methyl-benzaldehyde (1 mmol) were added to ethanol (5 ml). After 30 min 2-Oxo-3-(4-hydroxy-phenyl)-propionic acid ethyl ester (1 mmol) was added. The reaction was heated to 50° C. and stirred for 24 h. After evaporation of the solvent the residue was purified with chromatographic methods.
Reaction SMILES: [CH:1]1([CH2:4][O:5][CH2:6][CH2:7][C:8]2[CH:18]=[CH:17][C:11]([O:12][CH2:13][CH:14]3[O:16][CH2:15]3)=[CH:10][CH:9]=2)[CH2:3][CH2:2]1.[NH2:19][CH2:20][CH2:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH2:30][CH2:31][C:32](=[O:35])[NH:33][N:34]=2)=[CH:25][CH:24]=1>>[CH:1]1([CH2:4][O:5][CH2:6][CH2:7][C:8]2[CH:18]=[CH:17][C:11]([O:12][CH2:13][CH:14]([OH:16])[CH2:15][NH:19][CH2:20][CH2:21][O:22][C:23]3[CH:24]=[CH:25][C:26]([C:29]4[CH2:30][CH2:31][C:32](=[O:35])[NH:33][N:34]=4)=[CH:27][CH:28]=3)=[CH:10][CH:9]=2)[CH2:3][CH2:2]1
Reactant: c1cc(OCC2CO2)ccc1CCOCC1CC1
Reactant: NCCOc1ccc(C2=NNC(=O)CC2)cc1
Product: O=C1CCC(c2ccc(OCCNCC(O)COc3ccc(CCOCC4CC4)cc3)cc2)=NN1

Procedure:
Prepared analogously to Example 1 from 1-[4-(2-cyclopropylmethoxy-ethyl)phenoxy]-2,3-epoxypropane and 6-[4-(2-aminoethoxy)-phenyl]-4,5-dihydro-3(2H)-pyridazinone.
Reaction SMILES: [OH:1][C:2]1([CH:8]([C:24]2[CH:29]=[CH:28][C:27]([OH:30])=[C:26]([O:31][C:32]([F:35])([F:34])[F:33])[CH:25]=2)[C:9]([N:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)=[O:10])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.IC.[C:38](=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[OH:1][C:2]1([CH:8]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:38])=[C:26]([O:31][C:32]([F:34])([F:35])[F:33])[CH:25]=2)[C:9]([N:11]2[CH2:12][CH2:13][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:15][CH2:16]2)=[O:10])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)C(c2ccc(O)c(OC(F)(F)F)c2)C2(O)CCCCC2)CC1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: O
Product: COc1ccc(C(C(=O)N2CCN(C(=O)OC(C)(C)C)CC2)C2(O)CCCCC2)cc1OC(F)(F)F
Temperature: 25 °C
Reaction time: 16 h
Yield: 83.4 %

Procedure:
A solution of tert-butyl 4-{(1-hydroxycyclohexyl)[4-hydroxy-3-(trifluoromethoxy)phenyl]acetyl}piperazine-1-carboxylate (0.35 g 0.72 mmol) (See Example 400, step 1) and iodomethane (0.16 g, 1.08 mmol) in N,N′-dimethylformamide (5 mL) was treated with potassium carbonate (0.12 g, 0.86 mmol), and the solution was stirred at room temperature for 16 hours. The reaction was then poured into water and extracted 3 times with ethyl acetate. The combined extracts were washed twice with water, then dried over magnesium sulfate and concentrated to afford 0.31 g of tert-butyl 4-{(1-hydroxycyclohexyl)-[4-methoxy-3-(trifluoromethoxy)phenyl]acetyl}piperazine-1-carboxylate). The product was used in the next step without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:29][C:30]1[CH:35]=[C:34]([F:36])[C:33]([F:37])=[CH:32][C:31]=1[F:38])[CH2:10][C:11]([N:13]1[CH2:18][CH2:17][N:16]2[C:19]([C:25]([F:28])([F:27])[F:26])=[N:20][C:21]([C:22](O)=[O:23])=[C:15]2[CH2:14]1)=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:39][S:40]([N:43]1[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]1)(=[O:42])=[O:41].C(N(CC)CC)C.O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1>ClCCl>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]([CH2:29][C:30]1[CH:35]=[C:34]([F:36])[C:33]([F:37])=[CH:32][C:31]=1[F:38])[CH2:10][C:11]([N:13]1[CH2:18][CH2:17][N:16]2[C:19]([C:25]([F:28])([F:27])[F:26])=[N:20][C:21]([C:22]([N:46]3[CH2:47][CH2:48][N:43]([S:40]([CH3:39])(=[O:42])=[O:41])[CH2:44][CH2:45]3)=[O:23])=[C:15]2[CH2:14]1)=[O:12])([CH3:2])([CH3:4])[CH3:3]
Reactant: CS(=O)(=O)N1CCNCC1
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCn2c(C(F)(F)F)nc(C(=O)O)c2C1)Cc1cc(F)c(F)cc1F
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCn2c(C(F)(F)F)nc(C(=O)N3CCN(S(C)(=O)=O)CC3)c2C1)Cc1cc(F)c(F)cc1F
Yield: 106.3 %

Procedure:
(R)-7-[3-tert-Butoxycarbonylamino-4-(2,4,5-trifluoro-phenyl)-butyryl]-3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-carboxylic acid 2a (0.15 g, 0.27 mmol), 1-methanesulfonyl-piperazine (0.109 g, 0.55 mmol) and triethylamine (0.38 mL, 2.7 mmol) were dissolved in 10 mL of dichloromethane under stirring, and bis(2-oxo-3-oxazolidinyl)phosphinic chloride (0.139 g, 0.55 mmol) was then added to the solution. The reaction mixture was reacted at room temperature overnight and monitored by thin layer chromatography until the disappearance of the starting materials. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (R)-[3-[1-(4-methanesulfonyl-piperazine-1-carbonyl)-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazin-7-yl]-3-oxo-1-(2,4,5-trifluoro-benzyl)-propyl]-carbamic acid tert-butyl ester 22a (0.2 g) as a white solid.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:10]1([NH:16][C:17]2([C:23](=[O:26])[CH2:24][CH3:25])[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(N(CC)CC)C.CN(C)C(=O)C>O>[C:10]1([NH:16][C:17]2([C:23](=[O:26])[CH2:24][CH3:25])[CH2:22][CH2:21][N:20]([CH2:2][CH2:3][C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=3)[CH2:19][CH2:18]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: BrCCc1ccccc1
Reactant: CCC(=O)C1(Nc2ccccc2)CCNCC1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CC(=O)N(C)C
Product: CCC(=O)C1(Nc2ccccc2)CCN(CCc2ccccc2)CC1

Procedure:
A solution of 2.7 parts of (2-bromoethyl)benzene), 3.1 parts of 1-[4-(phenylamino)-4-piperidinyl]-1-propanone and 2.6 parts of N,N-diethylethanamine in 18 parts of N,N-dimethylacetamide is stirred for 4 h. 30 at 80° C. The reaction mixture is poured onto 100 parts of water and the product is extracted with benzene. The extract is washed with water, dried, filtered and evaporated. The oily residue is purified by column-chromatography over silicagel using a mixture of trichloromethane and 5% of methanol as eluent. The pure fractions are collected and the eluent is evaporated. The oily residue is crystallized from 2,2'-oxybispropane, yielding 1-[4-(phenylamino)-1-(2-phenylethyl)-4-piperidinyl]-1-propanone; mp. 105.6° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:9]([C:25](Cl)=[O:26])[CH2:10][CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][O:21][CH2:22][CH3:23])=[CH:15][C:14]=2[CH3:24])=[N:4][CH:5]=[N:6][C:7]=1[CH3:8].[CH3:28][NH2:29]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:3]([N:9]([CH2:10][CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][O:21][CH2:22][CH3:23])=[CH:15][C:14]=2[CH3:24])[C:25](=[O:26])[NH:29][CH3:28])=[N:4][CH:5]=[N:6][C:7]=1[CH3:8]
Reactant: CN
Reactant: CCOCCc1ccc(OCCN(C(=O)Cl)c2ncnc(C)c2Cl)c(C)c1
Solvent: Cc1ccccc1
Product: CCOCCc1ccc(OCCN(C(=O)NC)c2ncnc(C)c2Cl)c(C)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Into a solution of 1.0 g of 5-chloro-N-chlorocarbonyl-N-{2-[4-(2-ethoxyethyl)-2-methylphenoxy]ethyl}-6-methyl-4-pyrimidine amine dissolved in 20 ml of toluene was added under stirring 1 ml of an aqueous 40% monomethylamine solution, and the mixture was stirred at room temperature for one hour.
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]([CH2:12][NH2:13])[CH2:4][CH2:3]1.F[C:15]1[CH:23]=[N:22][CH:21]=[CH:20][C:16]=1[C:17]([OH:19])=[O:18]>>[CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]([CH2:12][NH:13][C:20]2[CH:21]=[N:22][CH:23]=[CH:15][C:16]=2[C:17]([OH:19])=[O:18])[CH2:4][CH2:3]1
Reactant: O=C(O)c1ccncc1F
Reactant: CN1CCC(CN)c2ccccc21
Product: CN1CCC(CNc2cnccc2C(=O)O)c2ccccc21
Yield: 18 %

Procedure:
The title compound was prepared in 18% yield from 1-(1-methyl-1,2,3,4-tetrahydroquinolin-4-yl)methanamine and 3-fluoroisonicotinic acid according to the procedure for the preparation of Example 53. 1H NMR (400 MHz, DMSO-d6): δ 13.36 (br s, 1H), 8.35 (s, 1H), 7.83 (d, 1H, J=5.0 Hz), 7.72 (br s, 1H), 7.56 (d, 1H, J=5.0 Hz), 7.01-7.08 (m, 2H), 6.52-6.62 (m, 2H), 3.45-3.51 (m, 2H), 3.04-3.32 (m, 3H), 2.85 (s, 3H), 1.89-1.95 (m, 2H). [M+H] calc'd for C17H19N3O2, 298. Found 298.