Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[N:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]2=[N:5][CH:4]=1)#[CH:2].N1C=C(C#C[C:23]2[CH:24]=[C:25]([CH:47]=[CH:48][C:49]=2[CH3:50])[C:26]([NH:28][C:29]2[CH:34]=[CH:33][C:32]([CH2:35][N:36]3[CH2:41][CH2:40][N:39]([CH3:42])[CH2:38][CH2:37]3)=[C:31]([C:43]([F:46])([F:45])[F:44])[CH:30]=2)=[O:27])N2C=CN=CC=12.N#N.C(N(CC)C(C)C)(C)C>[Cu]I.CN(C=O)C>[N:5]1[CH:4]=[C:3]([C:1]#[C:2][C:48]2[CH:47]=[C:25]([CH:24]=[CH:23][C:49]=2[CH3:50])[C:26]([NH:28][C:29]2[CH:34]=[CH:33][C:32]([CH2:35][N:36]3[CH2:41][CH2:40][N:39]([CH3:42])[CH2:38][CH2:37]3)=[C:31]([C:43]([F:46])([F:45])[F:44])[CH:30]=2)=[O:27])[N:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=12
Reactant: Cc1ccc(C(=O)Nc2ccc(CN3CCN(C)CC3)c(C(F)(F)F)c2)cc1C#Cc1cnc2cnccn12
Reactant: C#Cc1cnc2ccccn12
Agent: [Cu]I
Agent: N#N
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(C(=O)Nc2ccc(CN3CCN(C)CC3)c(C(F)(F)F)c2)cc1C#Cc1cnc2ccccn12
Temperature: 25 °C
Reaction time: 16 h
Yield: 52.7 %

Procedure:
3-Ethynylimidazo[1,2-a]pyridine (37 mg, 0.26 mmol), 3-iodo-4-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide (103.4 mg, 0.2 mmol), (prepared as in Example 2), Pd[(PPh3)4](11.6 mg, 5 mol %), and CuI (2.9 mg, 7.5 mmol %) was placed in a vial with rubber septum. The mixture underwent 3 cycles of vacuum/filling with N2, and DMF (1.5 ml) and N,N-diisopropylethylamine (53 mL, 0.3 mmol) was added. The mixture was stirred at rt for 16 h, and the reaction was quenched with H2O. EtOAc and more water were added for extraction. The combined organic layer was dried (Na2SO4), filtered, concentrated, and the resulting residue was purified by silica gel chromatography (eluent: 5% MeOH in methylene chloride, MeOH was pre-saturated with ammonia gas), giving the titled compound as an off-white solid (53%, 56 mg): MS (M+H)+ 532.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]([O:9][CH3:10])=[O:8].[Cl-].[Al+3].[Cl-].[Cl-].Cl[CH:16]([O:18]C)Cl>ClCCCl.[N+](C)([O-])=O>[CH:16]([C:5]1[CH:4]=[C:3]([C:7]([O:9][CH3:10])=[O:8])[N:2]([CH3:1])[CH:6]=1)=[O:18]
Reactant: COC(=O)c1cccn1C
Reactant: COC(Cl)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: C[N+](=O)[O-]
Solvent: ClCCCl
Product: COC(=O)c1cc(C=O)cn1C

Procedure:
To a mixture of methyl 1-methylpyrrole-2-carboxylate (5.0 g, 0.036 m) and 11.4 g anhydrous aluminum chloride in 150 ml of 1:1 1,2-dichloroethane and nitromethane at -20° C. was added over two minutes a solution of dichloromethyl methylether (3.9 ml, 0.043 m) in 1,2-dichloroethane (20 ml). The resultant mixture was stirred at -10° to -30° C. for 3 hours, quenched with excess ice-water, the resultant mixture extracted well with ether, and the combined ether extracts washed two times with water, passed through a small layer of sodium sulfate-silica gel, and concentrated in vacuo to 5.4 g (90%) of methyl 4-formyl-1-methylpyrrole-2-carboxylate, m.p. 95°-97° C.
Reaction SMILES: [CH2:1]([C:3]1[CH2:26][CH:25]([C:27]2[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=2)[O:24][C:5]2([CH2:10][CH2:9][N:8]([C:11]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH:20]([CH3:22])[CH3:21])=[C:15]([CH3:23])[CH:14]=3)=[O:12])[CH2:7][CH2:6]2)[CH:4]=1)[CH3:2]>CCO.[Pd]>[CH2:1]([C@H:3]1[CH2:4][C:5]2([CH2:10][CH2:9][N:8]([C:11]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH:20]([CH3:22])[CH3:21])=[C:15]([CH3:23])[CH:14]=3)=[O:12])[CH2:7][CH2:6]2)[O:24][C@@H:25]([C:27]2[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=2)[CH2:26]1)[CH3:2]
Reactant: CCC1=CC2(CCN(C(=O)c3ccc(OC(C)C)c(C)c3)CC2)OC(c2cccnc2)C1
Agent: [Pd]
Solvent: CCO
Product: CC[C@@H]1C[C@H](c2cccnc2)OC2(CCN(C(=O)c3ccc(OC(C)C)c(C)c3)CC2)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 18.5 %

Procedure:
A solution of [8-ethyl-10-(3-pyridyl)-11-oxa-3-azaspiro[5.5]undec-7-en-3-yl]-(4-isopropoxy-3-methyl-phenyl)methanone (90 mg, 0.21 mmol) in EtOH (14 mL) was purged with nitrogen for 5 min and then treated with 10% palladium on carbon (220 mg, 0.21 mmol). The mixture was evacuated and put under a hydrogen atmosphere (balloon). The reaction mixture was stirred for 4 h at 25° C. The reaction mixture was evacuated and put under an inert atmosphere. The Pd-catalyst was removed via filtration and was washed with ethyl acetate. The filtrate was concentrated to dryness. The crude mixture was purified on silica gel utilizing a gradient of 50-100% ethyl acetate and hexanes to yield (cis-4-ethyl-2-(pyridin-3-yl)-1-oxa-9-azaspiro[5.5]undecan-9-yl)(4-isopropoxy-3-methylphenyl)methanone (17 mg) ESI-MS m/z calc. 436.27, found 437.5 (M+1)+; Retention time: 1.68 minutes (3 min run).
Reaction SMILES: [CH2:1]([N:8]([C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[C:30]([O:36][CH3:37])[CH:29]=1)[S:9]([C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH2:27][CH2:26][C:21]3(OCC[O:22]3)[CH2:20][CH2:19]2)=[CH:14][CH:13]=1)(=[O:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)=O>Cl>[CH2:1]([N:8]([C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[C:30]([O:36][CH3:37])[CH:29]=1)[S:9]([C:12]1[CH:13]=[CH:14][C:15]([N:18]2[CH2:27][CH2:26][C:21](=[O:22])[CH2:20][CH2:19]2)=[CH:16][CH:17]=1)(=[O:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(N(Cc2ccccc2)S(=O)(=O)c2ccc(N3CCC4(CC3)OCCO4)cc2)cc1OC
Agent: Cl
Solvent: CC(C)=O
Product: COc1ccc(N(Cc2ccccc2)S(=O)(=O)c2ccc(N3CCC(=O)CC3)cc2)cc1OC
Yield: 709.6 %

Procedure:
N-Benzyl-N-(3,4-dimethoxy-phenyl)-4-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-benzenesulfonamide(0.10 g, 0.19 mM) was stirred in 6M HCl (2 ml) and acetone(5 ml) at 60° C. overnight. The reaction mixture was basified with 5N NaOHaq. (until pH>7) and washed with ethyl acetate (3×10 ml). The organic extracts were dried with sodium sulfate, passed through a plug of magnesol, concentrated and triturated with hexanes to afford 0.65 g of the desired product as a white solid. H1 NMR(CDCl3) δ 2.58(t, 4H, J=6.06 Hz), 3.67(s, 3H), 3.74(t, 4H, J=6.12 Hz), 3.81(s, 3H), 4.71 (s, 2H), 6.48(m, 3H), 6.67(d, 1H, J=8.46 Hz), 6.93(d, 2H, J=9.9 Hz), 7.20(m, 4H), 7.59(d, 2H, J=4.71 Hz). MS(ES) m/z 481.0; (MH+); HRMS for C26H28SN2O5: 481.1778.
Reaction SMILES: N[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[NH4+].[F-:16].N([O-])=O.[Na+]>>[F:16][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Cc1ccc(-c2ccccc2)c(N)c1
Reactant: [F-]
Agent: O=N[O-]
Agent: [NH4+]
Agent: [Na+]
Product: Cc1ccc(-c2ccccc2)c(F)c1
Reaction time: 0.67 h

Procedure:
To a cold (ice-salt bath) solution of 21.3 g (0.115 mol) of 2-amino-4-methylbiphenyl (prepared in Example 2) and 6.5 g (0.11 mol) of NH4F.HF and 75 g of 70% HF (2.6 mol) was portion-wise added 8.9 g (0.13 mol) of NaNO2 so that the temperature of the reaction mixture did not rise above 5°. This addition took approximately 40 minutes. The reaction mixture was allowed to stir at 0° for 15 minutes thereafter, and then the cooling bath was removed and stirring continued. The temperature rose to 15° after 20 minutes and then to 60° over a subsequent 25 minute period during which time nitrogen was evolved. The reaction mixture was cooled in an ice bath and extracted three times with petroleum ether. This organic extract was washed successively with water, aqueous NaHCO3, and H2O and then dried over MgSO4 which, after concentration left 18.8 g of dark red liquid. Subsequent analysis of this material by gas chromatography showed the fluoride compound present at about 90% by weight and about 6% by weight of the corresponding hydroxy compound. A solution of the crude product in petroleum ether was passed through a short column of silica gel. Removal of the solvent at reduced pressure left 16.6 g of pure 2-fluoro-4-methylbiphenyl (78%) as a colorless liquid.
Reaction SMILES: [C:1]([Si:5]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)Cl)([CH3:4])([CH3:3])[CH3:2].N1C=CN=C1.[Br:24][CH2:25][C@H:26]([CH3:29])[CH2:27][OH:28].O>C1COCC1>[Br:24][CH2:25][C@H:26]([CH3:29])[CH2:27][O:28][Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: C[C@H](CO)CBr
Agent: c1c[nH]cn1
Solvent: C1CCOC1
Solvent: O
Product: C[C@@H](CBr)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
tert-Butyldiphenylchlorosilane (83 mL) and imidazole (30 g) were added to a solution of (R)-3-bromo-2-methyl-1-propanol (45 g) in THF (150 mL) under ice-cooling, and the reaction mixture was stirred at room temperature overnight. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (carrier: Chromatorex NH; elution solvent: heptane-ethyl acetate system) to obtain 117 g of the title compound. The property values of the compound are as follows.
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]1[CH:11]=[C:12]([NH:16]/[C:17](=[C:24]2\[C:25](=[O:33])[NH:26][C:27]3[C:32]\2=[CH:31][CH:30]=[CH:29][CH:28]=3)/[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:13]=[CH:14][CH:15]=1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:8][CH2:9][C:10]1[CH:11]=[C:12]([NH:16]/[C:17](=[C:24]2\[C:25](=[O:33])[NH:26][C:27]3[C:32]\2=[CH:31][CH:30]=[CH:29][CH:28]=3)/[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:13]=[CH:14][CH:15]=1
Reactant: CC(C)(C)OC(=O)NCc1cccc(N/C(=C2\C(=O)Nc3ccccc32)c2ccccc2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCc1cccc(N/C(=C2\C(=O)Nc3ccccc32)c2ccccc2)c1

Procedure:
Prepared analogously to Example 57 from (Z)-3-[1-(3-tert.butoxycarbonylaminomethyl-phenylamino)-1-phenyl-methylidene]-2-indolinone and trifluoroacetic acid in dichloromethane.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([N:14]([CH2:22][C:23]2[CH:24]=[C:25]([CH:30]=[CH:31][CH:32]=2)[C:26](OC)=[O:27])[CH2:15][CH:16]([OH:21])[C:17]([F:20])([F:19])[F:18])[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:34][NH:35][O:36][CH3:37].C([Mg]Cl)(C)C>O1CCCC1>[CH3:37][O:36][N:35]([CH3:34])[C:26](=[O:27])[C:25]1[CH:30]=[CH:31][CH:32]=[C:23]([CH2:22][N:14]([C:10]2[CH:11]=[CH:12][CH:13]=[C:8]([O:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:9]=2)[CH2:15][CH:16]([OH:21])[C:17]([F:20])([F:18])[F:19])[CH:24]=1
Reactant: COC(=O)c1cccc(CN(CC(O)C(F)(F)F)c2cccc(Oc3ccccc3)c2)c1
Reactant: CNOC
Agent: CC(C)[Mg]Cl
Agent: Cl
Solvent: C1CCOC1
Product: CON(C)C(=O)c1cccc(CN(CC(O)C(F)(F)F)c2cccc(Oc3ccccc3)c2)c1
Temperature: -15 °C
Reaction time: 1 h
Yield: 66 %

Procedure:
EX-620A) To a slurry of methyl 3-[[(3-phenoxyphenyl)(3,3,3-trifluoro-2-hydroxypropyl)amino]methyl]benzoate (1.03 g, 0.0023 mol) and N,O-dimethylhydroxylamine hydrochloride (386 mg, 0.0040 mol) in 4.6 mL of tetrahydrofuran at −15° C. was added a 2.0 M solution of isopropylmagnesium chloride in THF (4.6 mL, 0.0092 mol) over 15 min. The reaction was stirred for 1 h at −15° C. then quenched with 20% aqueous ammonium chloride and extracted with ethyl acetate. The organic layers were dried over Na2SO4 and concentrated in vacuo. The crude product was purified by column chromatography on silica gel eluting with 1:1 ethyl acetate:hexane to afford 0.72 g (66%) of the desired N-methoxy-N-methyl-3-[[(3-phenoxyphenyl)-(3,3,3-trifluoro-2-hydroxypropyl)amino]methyl]benzamide product as an off-white solid. HRMS calcd. for C25H25N2O4F3: 475.1845 [M+H]+, found: 475.1840.
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[CH2:8][C@@H:7]([NH:12][S:13]([CH:16]([CH3:18])[CH3:17])(=[O:15])=[O:14])[CH2:6]2.S(Cl)(Cl)=O.[F:23][C:24]([F:35])([F:34])[C:25]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[NH:27][N:26]=1.C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl>[F:33][C:30]([F:31])([F:32])[C:28]1[CH:29]=[C:25]([C:24]([F:23])([F:34])[F:35])[N:26]([CH2:2][C:3]2[CH:4]=[C:5]3[C:9](=[CH:10][CH:11]=2)[CH2:8][C@@H:7]([NH:12][S:13]([CH:16]([CH3:18])[CH3:17])(=[O:15])=[O:14])[CH2:6]3)[N:27]=1
Reactant: FC(F)(F)c1cc(C(F)(F)F)[nH]n1
Reactant: CC(C)S(=O)(=O)N[C@@H]1Cc2ccc(CO)cc2C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: CC(C)S(=O)(=O)N[C@@H]1Cc2ccc(Cn3nc(C(F)(F)F)cc3C(F)(F)F)cc2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 1.9 %

Procedure:
(R)—N-(5-(hydroxymethyl)-2,3-dihydro-1H-inden-2-yl)propane-2-sulfonamide (50 mg, 0.19 mmol) was dissolved in DCM (5 mL) and cooled to 0° C. before thionyl chloride (110 mg, 0.93 mmol) was added. The reaction mixture was stirred at room temperature for 1 h before being concentrated to dryness. The whole was dissolved in DMF (3 mL) to this was added 3,5-bis(trifluoromethyl)-1H-pyrazole (38 mg 0.19 mmol) followed by potassium carbonate (51 mg, 0.37 mmol). The reaction mixture was heated to 60° C. for 2 h before being quenched with water (2 mL) and the organics extracted with EtOAc (3×5 mL). The combined organics were washed with brine, dried (MgSO4) and concentrated under reduced pressure. Purification by preparative acidic HPLC gave (R)—N-(5-((3,5-bis(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-2,3-dihydro-1H-inden-2-yl)propane-2-sulfonamide (1.7 mg, 3.7 μmol, 2.0%). MS (ESI): m/z [M+H]+ 456.1
Reaction SMILES: [OH:1][C:2]1([CH2:12][NH:13][CH3:14])[CH2:7][CH2:6][CH2:5][N:4](C(OC)=O)[CH2:3]1>O>[OH:1][C:2]1([CH2:12][NH:13][CH3:14])[CH2:7][CH2:6][CH2:5][NH:4][CH2:3]1
Reactant: CNCC1(O)CCCN(C(=O)OC)C1
Solvent: O
Product: CNCC1(O)CCCNC1

Procedure:
8.7 g (43 mmol) of methyl 3-hydroxy-3-methylaminomethylpiperidine-1-carboxylate are heated overnight under reflux with 24 g of Ba(OH)2. 8H2O in 240 ml of water. The product is filtered off from BaCO3 with suction and concentrated. The residue is boiled five times using 100 ml of dioxane each time, and the dioxane solution is concentrated and distilled.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:59])[C@H:10]([CH2:49][C:50]1[C:58]2[C:53](=[CH:54][CH:55]=[CH:56][CH:57]=2)[NH:52][CH:51]=1)[NH:11][C:12](=[O:48])[CH:13]([C:39]1[CH:44]=[CH:43][C:42]2[O:45][CH2:46][O:47][C:41]=2[CH:40]=1)[CH2:14][C:15]1[N:16]=[CH:17][N:18](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)(=O)C.O.O>[CH2:1]([O:8][C:9](=[O:59])[C@H:10]([CH2:49][C:50]1[C:58]2[C:53](=[CH:54][CH:55]=[CH:56][CH:57]=2)[NH:52][CH:51]=1)[NH:11][C:12](=[O:48])[CH:13]([C:39]1[CH:44]=[CH:43][C:42]2[O:45][CH2:46][O:47][C:41]=2[CH:40]=1)[CH2:14][C:15]1[N:16]=[CH:17][NH:18][CH:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(N[C@@H](Cc1c[nH]c2ccccc12)C(=O)OCc1ccccc1)C(Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)c1ccc2c(c1)OCO2
Solvent: O
Solvent: CC(=O)O
Product: O=C(N[C@@H](Cc1c[nH]c2ccccc12)C(=O)OCc1ccccc1)C(Cc1c[nH]cn1)c1ccc2c(c1)OCO2
Temperature: 50 °C
Reaction time: 5 h
Yield: 90.1 %

Procedure:
A mixture of Nα-[3-(1-triphenylmethylimidazol-4-yl)-2-(3,4-methylenedioxyphenyl)propionyl]-L-tryptophan benzyl ester (290 mg) in 80% acetic acid-water (5 ml) was stirred at 50° C. for 5 hours. The resulting mixture was cooled to ambient temperature and the solution was diluted with water. Carbinol was removed by filtration and the filtrate was neutralized with saturated sodium hydroxide aqueous solution, and then the aqueous layer was extracted with ethyl acetate. Drying, filtering and removal of the solvents afforded Nα-[3-(imidazol-4-yl)-2-(3,4-methylenedioxyphenyl)propionyl]-L-tryptophan benzyl ester (180 mg) as a yellow powder.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[CH:10]([C:12]1[CH:13]=[C:14]([Mg]Br)[CH:15]=[CH:16][CH:17]=1)=[CH2:11]>>[CH:10]([C:12]1[CH:13]=[C:14]([C:1]([OH:3])([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH3:2])[CH:15]=[CH:16][CH:17]=1)=[CH2:11]
Reactant: CC(=O)c1ccccc1
Reactant: C=Cc1cccc([Mg]Br)c1
Product: C=Cc1cccc(C(C)(O)c2ccccc2)c1

Procedure:
A method to use acetophenone (formula VIII) as a starting material is described. Acetophenone is reacted with a Grignard reagent of 3-vinylphenylmagnesium bromide (formula VII) to obtain 1-(3-vinylphenyl)-1-phenylethyl alcohol (formula V) (hereinafter referred to as "VPA"). The reaction product is then dehydrated in the presence of potassium hydrogensulfate to form 1-(3-vinylphenyl)-1-phenylethylene (formula I). This Grignard addition reaction is carried out at a temperature in the range of 0° to 100° C., preferably 20° to 80° C. The dehydration is carried out at 170° to 250° C., preferably 190° to 230° C., under a reduced pressure. The quantity of Grignard reagent is 1.0 to 1.2 equivalents relative to the acetophenone. ##STR7##
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@H:6]([C:11](O)=[O:12])[C@H:7]([CH2:9][CH3:10])[CH3:8])=[O:4].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[S:28]1[C:32]([C:33]2[CH:38]=[CH:37][C:36]([CH2:39][N:40]([NH2:65])[CH2:41][C@H:42]([OH:64])[C@@H:43]([NH:51][C:52](=[O:63])[C@H:53]([C@H:59]([CH2:61][CH3:62])[CH3:60])[NH:54][C:55]([O:57][CH3:58])=[O:56])[CH2:44][C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)=[CH:35][CH:34]=2)=[CH:31][N:30]=[CH:29]1>CN(C=O)C>[CH3:62][CH2:61][C@@H:59]([C@H:53]([NH:54][C:55]([O:57][CH3:58])=[O:56])[C:52]([NH:51][C@H:43]([C@@H:42]([OH:64])[CH2:41][N:40]([NH:65][C:11]([C@@H:6]([NH:5][C:3]([O:2][CH3:1])=[O:4])[C@H:7]([CH2:9][CH3:10])[CH3:8])=[O:12])[CH2:39][C:36]1[CH:35]=[CH:34][C:33]([C:32]2[S:28][CH:29]=[N:30][CH:31]=2)=[CH:38][CH:37]=1)[CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)=[O:63])[CH3:60]
Reactant: CC[C@H](C)[C@H](NC(=O)OC)C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)CN(N)Cc1ccc(-c2cncs2)cc1
Reactant: CC[C@H](C)[C@H](NC(=O)OC)C(=O)O
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC[C@H](C)[C@H](NC(=O)OC)C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)CN(Cc1ccc(-c2cncs2)cc1)NC(=O)[C@@H](NC(=O)OC)[C@@H](C)CC

Procedure:
Analogously to Example 7, 175 mg (0.92 mmol) of N-methoxycarbonyl-(L)-iso-leucine, 332 mg (1.7 mmol) of EDC and 156 mg (1.15 mmol) of HOBT in 2.5 ml of DMF and 483 μl (3.47 mmol) of TEA are reacted with 0.578 mmol of 1-[4-(thiazol-5-yl)-phenyl]-4(S)-hydroxy-2-amino-5 (S)-N-(N-methoxycarbonyl-(L)-iso-leucyl)amino-6-phenyl-2-azahexane (Example 11b) in 5.2 ml of DMF to form the title compound: m.p: 213°-216° C.; HPLC20-100 : tret =14.7; FAB MS (M+H)+ =711.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([N:24]4[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]4)=[CH:20][N:19]=3)=[O:16])=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1.CCN(C(C)C)C(C)C.Cl[C:40]([O:42][CH3:43])=[O:41]>C1COCC1>[CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15]([NH:17][C:18]3[N:19]=[CH:20][C:21]([N:24]4[CH2:29][CH2:28][N:27]([C:40]([O:42][CH3:43])=[O:41])[CH2:26][CH2:25]4)=[CH:22][CH:23]=3)=[O:16])=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1
Reactant: COC(=O)Cl
Reactant: Cc1cc(-c2ccc(CC(=O)Nc3ccc(N4CCNCC4)cn3)cc2)ccn1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)N1CCN(c2ccc(NC(=O)Cc3ccc(-c4ccnc(C)c4)cc3)nc2)CC1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To the solution of 2-(4-(2-methylpyridin-4-yl)phenyl)-N-(5-(piperazin-1-yl)pyridin-2-yl)acetamide 131-1 (20 mg, 0.05 mmol) in THF (1 mL) was added DIEA (19 mg, 0.15 mmol) and methyl chloroformate (5.2 mg, 0.055 mmol). The reaction was stirred at room temperature for 40 min. The solvent was removed by rotary evaporation and the residue was purified by reverse phase HPLC to give N-(5-(4-acetylpiperazin-1-yl)pyridin-2-yl)-2-(4-(2-methylpyridin-4-yl)phenyl)acetamide 132 as off-white solid. MS m/z 446.2 (M+1); 1H NMR 400 MHz (DMSO-d6) δ10.55 (s, 1H), 8.72 (d, 1H), 8.18 (s, 1H), 8.08 (m, 1H), 7.96 (d, 1H), 7.90 (d, 2H), 7.84 (d, 1H), 7.50 (d, 2H), 7.35 (dd, 1H), 3.72 (s, 2H), 3.54 (s, 3H), 3.43 (t, 4H), 3.03 (t, 3H), 2.65 (s, 3H).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[C:7]3[CH2:11][CH:10]([CH2:12][NH2:13])[C:8]3=[CH:9][C:4]=2[O:3][CH2:2]1.O.[OH-].[Na+].Cl[C:18]([O:20][CH2:21][CH3:22])=[O:19]>ClCCl>[CH2:21]([O:20][C:18](=[O:19])[NH:13][CH2:12][CH:10]1[C:8]2=[CH:9][C:4]3[O:3][CH2:2][O:1][C:5]=3[CH:6]=[C:7]2[CH2:11]1)[CH3:22]
Reactant: NCC1Cc2cc3c(cc21)OCO3
Reactant: CCOC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)NCC1Cc2cc3c(cc21)OCO3
Reaction time: 2 h

Procedure:
7.9 g (44.6 mmoles) of (5,6-dihydrocyclobuta[4,5]benzo[1,2-d][1,3]dioxol-5-ylmethyl)amine are dissolved in 80 mL of dichloromethane. 80 mL of water and 6 mL (1.6 equivalents) of (12N) aqueous sodium hydroxide solution are added. Over 15 minutes there are added 3.95 mL (1.1 equivalents) of ethyl chloroformate and stirring is carried out at 25° C. for 2 hours. The mixture is separated and the organic phases is washed with saturated aqueous NaHCO3 solution. Drying over MgSO4, filtration and evaporation to dryness are carried out. The expected product is obtained in the form of a brown solid.
Reaction SMILES: [OH:1][CH:2]1[C:14]2[NH:13][C:12]3[C:7](=[CH:8][CH:9]=[C:10]([C:15]([F:18])([F:17])[F:16])[CH:11]=3)[C:6]=2[CH:5]=[CH:4][NH:3]1>[Pd]>[OH:1][C:2]1[C:14]2[NH:13][C:12]3[C:7](=[CH:8][CH:9]=[C:10]([C:15]([F:18])([F:16])[F:17])[CH:11]=3)[C:6]=2[CH:5]=[CH:4][N:3]=1
Reactant: OC1NC=Cc2c1[nH]c1cc(C(F)(F)F)ccc21
Agent: [Pd]
Product: Oc1nccc2c1[nH]c1cc(C(F)(F)F)ccc12
Temperature: 50 °C
Yield: 16.8 %

Procedure:
A portion of dihydro 1-hydroxy-7-trifluoromethyl-β-carboline (6 mg) in xylenes (1 ml) was treated with Pd/C (10%, 7 mg) and the mixture heated at 50° C. for one week. The reaction was concentrated after filtering it through celite, and the residue was chromatographed (1:1 hexane-ethyl acetate) on silica gel to give 1 mg of 1-hydroxy-7-trifluoromethyl-β-carboline. A portion of dihydro 1-hydroxy-7-trifluoromethyl-β-carboline (25 mg) in THF (1 ml) was treated with a solution of lithium aluminum hydride in THF (1 M, 0.5 ml). The reaction was stirred at 60° C. for 6h before quenching with water (5 ml) and extracting with ethyl acetate (3 times 10 ml). The combined organic layers were dried (MgSO4) and concentrated to provide tetrahydro 7-trifluoro-methyl-β-carboline. This material was taken up in xylenes (5 ml) and treated with Pd/C (10%, 15 mg). The mixture was stirred at 150° C. for 48 h before filtering through celite and concentrating. The residue was chromatographed (ethyl acetate) on silica gel to give 5 mg of 7-tri-fluoromethyl-β-carboline.
Reaction SMILES: [CH3:1][Si:2]([CH3:51])([CH3:50])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:42][O:43][CH2:44][CH2:45][Si:46]([CH3:49])([CH3:48])[CH3:47])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:21][CH:22]=3)=[C:12]2[N:11]=[C:10]([CH:29]2[CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:31][CH2:30]2)[CH:9]=1.C1C(=O)N([Br:59])C(=O)C1>CN(C=O)C.CCOC(C)=O>[CH3:49][Si:46]([CH3:48])([CH3:47])[CH2:45][CH2:44][O:43][CH2:42][N:7]([CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:1])([CH3:50])[CH3:51])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:21][CH:22]=3)=[C:12]2[N:11]=[C:10]([CH:29]2[CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:31][CH2:30]2)[C:9]=1[Br:59]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)OC(=O)N1CCC(c2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3ncc(-c4ccc(-c5ccccc5)nc4)c3n2)CC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(c2nc3c(-c4ccc(-c5ccccc5)nc4)cnn3c(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)c2Br)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 88 %

Procedure:
To a solution of tert-butyl 4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-3-(6-phenylpyridin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)piperidine-1-carboxylate (3.24 g, 4.44 mmol) in DMF (20 mL) was added NBS (750 mg, 4.21 mmol). After stirring at rt for one hour, NBS (75 mg 0.42 mmol) was added and the resulting mixture was stirred for another 40 minutes to complete the reaction. The reaction mixture was diluted with EtOAc (200 mL), washed with water (2×50 mL), brine (20 mL) and dried (MgSO4). After concentration in vacuo the residue was purified on silica gel. Elution with EtOAc/Hexanes (0-40%) gave tert-butyl 4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-6-bromo-3-(6-phenylpyridin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)piperidine-1-carboxylate (3 g, 83%).