Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[C:16]([C:38]3[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=3)=[C:17]3[C:22](=[CH:23][CH:24]=2)[CH:21]=[N:20][C:19]([NH:25][C:26]2[CH:31]=[C:30]([O:32][CH3:33])[C:29]([O:34][CH3:35])=[C:28]([O:36][CH3:37])[CH:27]=2)=[CH:18]3)[CH2:10][CH2:9]1)=O)(C)(C)C>C(O)C.Cl>[F:44][C:41]1[CH:42]=[CH:43][C:38]([C:16]2[C:15]([O:14][CH:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)=[CH:24][CH:23]=[C:22]3[C:17]=2[CH:18]=[C:19]([NH:25][C:26]2[CH:27]=[C:28]([O:36][CH3:37])[C:29]([O:34][CH3:35])=[C:30]([O:32][CH3:33])[CH:31]=2)[N:20]=[CH:21]3)=[CH:39][CH:40]=1
Reactant: COc1cc(Nc2cc3c(-c4ccc(F)cc4)c(OC4CCN(C(=O)OC(C)(C)C)CC4)ccc3cn2)cc(OC)c1OC
Agent: Cl
Solvent: CCO
Product: COc1cc(Nc2cc3c(-c4ccc(F)cc4)c(OC4CCNCC4)ccc3cn2)cc(OC)c1OC
Reaction time: 1 h
Yield: 85 %

Procedure:
20 mg of 4-[5-(4-Fluoro-phenyl)-3-(3,4,5-trimethoxy-phenylamino)-isoquinolin-6-yloxy]-piperidine-1-carboxylic acid tert-butyl ester (183) were dissolved in 5 ml of ethanol saturated with HCl (gaseous). The resulting mixture was stirred for 1 h, then the solvent was evaporated and the product collected. Yield: 85%
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH:7]2[CH2:13][C@H:12]3[N:14]([CH2:15][CH2:16][C:17]4([C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=5)[O:22][CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18]4)[C@H:9]([CH2:10][CH2:11]3)[CH2:8]2)[C:5]2[CH:36]=[CH:37][CH:38]=[CH:39][C:4]=2[N:3]=1.[ClH:40]>C(Cl)(Cl)Cl.O1CCOCC1>[ClH:40].[ClH:40].[ClH:40].[CH3:1][C:2]1[N:6]([CH:7]2[CH2:8][C@H:9]3[N:14]([CH2:15][CH2:16][C:17]4([C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=5)[O:22][CH2:21][CH2:20][NH:19][CH2:18]4)[C@H:12]([CH2:11][CH2:10]3)[CH2:13]2)[C:5]2[CH:36]=[CH:37][CH:38]=[CH:39][C:4]=2[N:3]=1
Reactant: Cc1nc2ccccc2n1C1C[C@H]2CC[C@@H](C1)N2CCC1(c2ccccc2)CN(C(=O)OC(C)(C)C)CCO1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: C1COCCO1
Product: Cc1nc2ccccc2n1C1C[C@H]2CC[C@@H](C1)N2CCC1(c2ccccc2)CNCCO1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of tert-butyl 2-{2-[(1R,5S)-3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-2-phenylmorpholine-4-carboxylate (330 mg, 0.62 mmol) in 5 mL CHCl3 was added 0.8 mL of a solution of 4N HCl in dioxane. After stirring at room temperature for 2 h, another 3 mL 4N HCl in dioxane was added and the mixture was heated at 40° C. for 90 min. The solution was then evaporated and dried in vacuo to provide 2-methyl-1-{(1R,5S)-8-[2-(2-phenylmorpholin-2-yl)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}-1H-benzimidazole trihydrochloride, which was used without further purification. ESI-MS 431 (M+H).
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[S:11][C:12]3[CH:18]=[C:17]([OH:19])[CH:16]=[CH:15][C:13]=3[N:14]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].C1N2CN3CN(C2)CN1C3.FC(F)(F)[C:32](O)=[O:33].C([O-])(O)=O.[Na+]>O>[OH:19][C:17]1[CH:16]=[CH:15][C:13]2[N:14]=[C:10]([N:7]3[CH2:6][CH2:5][N:4]([CH:1]([CH3:3])[CH3:2])[CH2:9][CH2:8]3)[S:11][C:12]=2[C:18]=1[CH:32]=[O:33]
Reactant: CC(C)N1CCN(c2nc3ccc(O)cc3s2)CC1
Reactant: O=C(O)C(F)(F)F
Agent: C1N2CN3CN1CN(C2)C3
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CC(C)N1CCN(c2nc3ccc(O)c(C=O)c3s2)CC1
Temperature: 120 °C
Reaction time: 1 h
Yield: 14 %

Procedure:
A mixture of 2-(4-Isopropyl-piperazin-yl)-benzothiazol-6-ol (76 mg, 0.027 mmol), hexamethylenetetramine (153 mg, 1.10 mmol) and trifluoroacetic acid (2 mL) was stirred in a closed vessel under argon atmosphere at 120° C. for 1 h. The mixture was cooled to room temperature then 10 ml, of water was added. The pH of the mixture was adjusted to 8 by portionwise addition of saturated NaHCO3 solution, and extracted with dichloromethane (3×15 mL). After drying (MgSO4), filtration and evaporation of the solvent, the residue was purified by column chromatography (Kieselgel 60) using chloroform-methanol 49:1 as eluent followed by trituration with diethyl ether and n-hexane. The title compound (14 mg, 0.040 mmol, 14%) was obtained as a yellow solid.
Reaction SMILES: Br[C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[C:6]([N:11]2[N:20]=[CH:19][C:18]3[C:13](=[C:14]([F:25])[CH:15]=[C:16]([C:21]([CH3:24])([CH3:23])[CH3:22])[CH:17]=3)[C:12]2=[O:26])[C:3]=1[CH:4]=[O:5].[CH2:27]([C@H:29]1[CH2:34][N:33]([CH:35]2[CH2:38][O:37][CH2:36]2)[CH2:32][CH2:31][N:30]1[C:39]1[CH:40]=[CH:41][C:42]([NH:45][C:46]2[C:47](=[O:62])[N:48]([CH3:61])[CH:49]=[C:50](B3OC(C)(C)C(C)(C)O3)[CH:51]=2)=[N:43][CH:44]=1)[CH3:28].[O-]P([O-])([O-])=O.[K+].[K+].[K+].C([O-])(=O)C.[Na+]>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].O.C(#N)C>[C:21]([C:16]1[CH:17]=[C:18]2[C:13](=[C:14]([F:25])[CH:15]=1)[C:12](=[O:26])[N:11]([C:6]1[CH:7]=[C:8]([F:10])[CH:9]=[C:2]([C:50]3[CH:51]=[C:46]([NH:45][C:42]4[CH:41]=[CH:40][C:39]([N:30]5[CH2:31][CH2:32][N:33]([CH:35]6[CH2:36][O:37][CH2:38]6)[CH2:34][C@@H:29]5[CH2:27][CH3:28])=[CH:44][N:43]=4)[C:47](=[O:62])[N:48]([CH3:61])[CH:49]=3)[C:3]=1[CH:4]=[O:5])[N:20]=[CH:19]2)([CH3:23])([CH3:22])[CH3:24]
Reactant: CC(C)(C)c1cc(F)c2c(=O)n(-c3cc(F)cc(Br)c3C=O)ncc2c1
Reactant: CC[C@H]1CN(C2COC2)CCN1c1ccc(Nc2cc(B3OC(C)(C)C(C)(C)O3)cn(C)c2=O)nc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Solvent: O
Product: CC[C@H]1CN(C2COC2)CCN1c1ccc(Nc2cc(-c3cc(F)cc(-n4ncc5cc(C(C)(C)C)cc(F)c5c4=O)c3C=O)cn(C)c2=O)nc1
Temperature: 25 °C
Yield: 35.2 %

Procedure:
A 25-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 2-bromo-6-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-4-fluorobenzaldehyde 102h (168 mg, 0.40 mmol), 111f (198 mg, 0.40 mmol), Pd(dppf)Cl2 (15 mg, 0.02 mmol), K3PO4 (170 mg, 0.8 mmol), sodium acetate (66 mg, 0.8 mmol), acetonitrile (5 mL), and water (0.8 mL). After three cycles of vacuum/argon flush, the mixture was heated at reflux for 2 h. It was then cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by silica-gel column chromatography eluting with 30:1 dichloromethane/methanol to afford 111g as a white solid (100 mg, 35%). MS: [M+H]+ 710.3
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[O:10][C:9]([CH2:12][CH2:13][NH2:14])=[CH:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.Cl[C:23]([O:25][CH2:26][CH3:27])=[O:24]>C1COCC1>[CH3:1][O:2][C:3]1[C:11]2[O:10][C:9]([CH2:12][CH2:13][NH:14][C:23](=[O:24])[O:25][CH2:26][CH3:27])=[CH:8][C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: COc1cccc2cc(CCN)oc12
Reactant: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)NCCc1cc2cccc(OC)c2o1
Temperature: 25 °C
Reaction time: 5 h
Yield: 21.8 %

Procedure:
2-(7-methoxy-1-benzofuran-2-yl)ethanamine (from step 5) (100 mg, 0.523 mmol) was dissolved in THF (4 ml). To this solution triethylamine (0.211 g, 2.09 mmol) and ethyl chloroformate (0.085 g, 0.784 mmol) was added at 0° C. and then stirred at room temperature for 5 h. THF was evaporated and the residue was purified by column chromatography using 100-200 mesh silica gel and eluted in 5% ethyl acetate-petroleum ether to obtain 30 mg of yellow thick liquid.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[N:17]1[C:30]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[S:24][C:23]2[C:18]1=[CH:19][CH:20]=[CH:21][CH:22]=2.Cl>N1C=CC=CC=1>[C:1]([O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[N:17]1[C:30]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[S:24][C:23]2[C:18]1=[CH:19][CH:20]=[CH:21][CH:22]=2)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Oc1ccccc1N1c2ccccc2Sc2ccccc21
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Solvent: c1ccncc1
Product: O=C(Oc1ccccc1N1c2ccccc2Sc2ccccc21)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
16.0 g (114 mmol) of benzoyl chloride were added dropwise at 0-5° C. with stirring to a solution of 4.00 g (13.7 mmol) of 10-(2-hydroxyphenyl)phenothiazine in 24 ml of pyridine within 30 min. After stirring at room temperature for 2 h, the reaction solution was heated to 60-65° C. and stirred at this temperature for 15 min. After cooling to room temperature, the suspension was then stirred overnight. After adding 300 ml of ice-water, the suspension was admixed slowly with 19 ml of conc. hydrochloric acid (pH 0.9) and stirred for 1 h. The suspension was filtered through a glass frit. The residue was washed to neutrality with 2 l of water and dried at 60° C. under reduced pressure. 2.87 g (53% of theory) of colorless microcrystals having a melting point of 144-148° C. were obtained.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][C:11]3[CH:17]=[CH:16][C:15]([C:18]4[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][CH:19]=4)=[CH:14][C:12]=3[N:13]=2)=[CH:5][CH:4]=1.[F:33][C:34]([F:39])([F:38])[C:35]([OH:37])=[O:36]>C(Cl)Cl>[F:33][C:34]([F:39])([F:38])[C:35]([OH:37])=[O:36].[NH:21]1[CH2:22][CH2:23][CH:18]([C:15]2[CH:16]=[CH:17][C:11]3[O:10][C:9]([C:6]4[CH:5]=[CH:4][C:3]([C:2]([F:31])([F:1])[F:32])=[CH:8][CH:7]=4)=[N:13][C:12]=3[CH:14]=2)[CH2:19][CH2:20]1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ccc3oc(-c4ccc(C(F)(F)F)cc4)nc3c2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: FC(F)(F)c1ccc(-c2nc3cc(C4CCNCC4)ccc3o2)cc1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
Tert-butyl 4-{2-[4-(trifluoromethyl)phenyl]benzo[d]oxazol-5-yl}-5,6-dihydropyridine-1(2H)-carboxylate (80 mg, 0.17 mmol) dissolved in DCM (15 ml), cooled to 0° C., trifluoroacetic acid (0.1 ml) was added and stirred the reaction mixture at rt for 3 h. DCM and trifluoroacetic acid was removed on rotavapour to obtain the crude. Crude was washed with petether to obtain 5-(piperidin-4-yl)-2-(4-(trifluoromethyl)phenyl)benzo[d]oxazole 2,2,2-trifluoroacetate (90 mg) as an off-white solid. 5-(piperidin-4-yl)-2-(4-(trifluoromethyl)phenyl)benzo[d]oxazole 2,2,2-trifluoroacetate (90 mg, 0.19 mmol) dissolved in DCM (15 ml). To this mixture added TEA (0.1 ml, 0.56 mmol) and stirred the reaction mixture at rt for 30 mins. Reaction mixture cooled to 0° C. and added isopropylchloro formate (46 mg, 0.38 mmol). This mixture was stirred at rt for 30 mins. Work up (DCM/H2O) followed by evaporation of the DCM on rotavapour afforded crude. Crude was purified with combiflash using a gradient mixture of ethylacetate and petether (15:85) as eluent to afford the titled compound (30 mg) as an off-white solid. M.P.: 145-148° C. 1H-NMR (δ ppm, CDCl3, 400 MHz): 8.36 (d, J 8.1, 2H), 7.78 (d, J 8.3, 2H), 7.62 (d, J 1.5, 1H), 7.54 (d, J 8.5, 1H), 7.29-7.21 (m, 1H), 4.96 (septet, 6.2, 1H), 4.31 (bs, 2H), 2.95-2.76 (m, 3H), 1.90 (d, J 12.7, 2H), 1.75-1.63 (m, 2H), 1.27 (d, J 6.2, 6H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].C1(N=C=NC2CCCCC2)CCCCC1.[CH3:22][S:23]([C:26]1[CH:34]=[CH:33][C:29]([C:30]([OH:32])=O)=[C:28]([CH3:35])[C:27]=1[CH2:36][O:37][CH3:38])(=[O:25])=[O:24].[C:39]1(=[O:46])[CH2:44][CH2:43][CH2:42][C:41](=[O:45])[CH2:40]1>C(O)(CC)(C)C>[CH3:22][S:23]([C:26]1[CH:34]=[CH:33][C:29]([C:30]([CH:40]2[C:41](=[O:45])[CH2:42][CH2:43][CH2:44][C:39]2=[O:46])=[O:32])=[C:28]([CH3:35])[C:27]=1[CH2:36][O:37][CH3:38])(=[O:24])=[O:25]
Reactant: COCc1c(S(C)(=O)=O)ccc(C(=O)O)c1C
Reactant: O=C1CCCC(=O)C1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)(C)O
Product: COCc1c(S(C)(=O)=O)ccc(C(=O)C2C(=O)CCCC2=O)c1C
Temperature: 80 °C
Reaction time: 11 h
Yield: 7.3 %

Procedure:
1.3 g of potassium carbonate and 3.0 g of N,N'-dicyclohexylcarbodiimide were added to a solution mixture comprising 2.0 g of 4-methanesulfonyl-3-methoxymethyl-2-methylbenzoic acid, 0.9 g of 1,3-cyclohexanedione and 100 ml of t-amyl alcohol. The mixture was stirred at 80° C. for 11 hours. It was concentrated under reduced pressure, and then an aqueous potassium carbonate solution was added. Then, insoluble substances were removed by filtration. The filtrate was washed with chloroform, then acidifed by an addition of concentrated hydrochloric and extracted with chloroform. The chloroform layer was washed with water and with a saturated sodium chloride aqueous solution and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 1.1 g of a crude desired product. This crude product was recrystallized from ethanol to obtain 0.2 g of the desired product. Melting point: 192°-198° C.
Reaction SMILES: ClS(O)(=O)=O.CO[CH:8](OC)[CH2:9][NH:10][CH:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH3:12].C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C>[CH3:12][C:11]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:8]=[CH:9][N:10]=1
Reactant: COC(CNC(C)c1ccccc1)OC
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)Cl
Agent: [K+]
Solvent: CCOC(C)=O
Product: Cc1nccc2ccccc12
Temperature: 25 °C

Procedure:
To cooled chlorosulfonic acid (16 ml, −10° C.) was cautiously added D7 (5 g, 0.024 mol) over a period of 2 h. Reaction was allowed to warm to ambient temperature and stirring continued for 3d. The reaction was then poured into ice-water slurry (500 ml), basified using solid potassium carbonate followed by extraction using DCM. Organic phase was separated, dried over MgSO4, filtered and concentrated under reduced pressure to leave an oil. Chromatography on silica gel eluting with ethyl acetate afforded the title compound as yellow oil.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[C:17]([O:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[CH:22][CH:21]=2)=[O:18])=[CH:11][CH:10]=1.[NH2:32][C:33]1[CH:34]=[C:35]([CH:39]=[C:40]([NH2:42])[CH:41]=1)[C:36]([OH:38])=[O:37]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O>[NH2:32][C:33]1[CH:34]=[C:35]([CH:39]=[C:40]([NH2:42])[CH:41]=1)[C:36]([O:38][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[C:17]([O:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[CH:22][CH:21]=2)=[O:18])=[CH:11][CH:10]=1)=[O:37]
Reactant: Nc1cc(N)cc(C(=O)O)c1
Reactant: CCCCCOc1ccc(OC(=O)/C=C/c2ccc(OCCCCCCCl)cc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CN(C)C=O
Product: CCCCCOc1ccc(OC(=O)/C=C/c2ccc(OCCCCCCOC(=O)c3cc(N)cc(N)c3)cc2)cc1
Temperature: 80 °C
Yield: 69.9 %

Procedure:
7.50 g (16.85 mmol) 4-pentoxyphenyl (2E)-3-{4-(6-chlorohexyloxy)phenyl}acrylate, 2.82 g (18.54 mmol) 3,5-diaminobenzoic acid and 0.62 g (1.69 mmol) tetrabutylammonium iodide were dissolved in 80 ml dimethylformamide. 3.00 ml (20.22 mmol) 1,8-diazabicyclo[5.4.0]undec-7-ene(1,5-5) (DBU) were added dropwise in the course of 10 minutes. The reaction temperature rose to 30° C. The mixture was then heated at 80° C. for 22 h. The reaction mixture was cooled and then partitioned between ethyl acetate and a saturated sodium bicarbonate solution; the organic phase was washed repeatedly with water, dried over sodium sulphate, filtered and concentrated by rotary evaporation. Chromatography of the residue on 1 kg silica gel using cyclohexane:ethyl acetate 1:1 as eluent yielded 6.6 g of 6-{4-[(1E)-3-(4-pentyloxyphenoxy)-3-oxoprop-1-enyl]phenoxy}hexyl 3,5 diamino-benzoate.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([N:5]2[CH2:10][CH2:9][N:8]([C:11]3[N:16]=[CH:15][CH:14]=[CH:13][N:12]=3)[CH2:7][CH2:6]2)[CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[C:50]1([C:59]2[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=2)[CH:55]=[CH:54][C:53]([C:56](O)=[O:57])=[CH:52][CH:51]=1>CN(C=O)C.O>[C:50]1([C:59]2[CH:60]=[CH:61][CH:62]=[CH:63][CH:64]=2)[CH:51]=[CH:52][C:53]([C:56]([N:1]2[CH2:4][CH:3]([N:5]3[CH2:6][CH2:7][N:8]([C:11]4[N:12]=[CH:13][CH:14]=[CH:15][N:16]=4)[CH2:9][CH2:10]3)[CH2:2]2)=[O:57])=[CH:54][CH:55]=1
Reactant: O=C(O)c1ccc(-c2ccccc2)cc1
Reactant: c1cnc(N2CCN(C3CNC3)CC2)nc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1ccc(-c2ccccc2)cc1)N1CC(N2CCN(c3ncccn3)CC2)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-(4-azetidin-3-yl-piperazin-1-yl)-pyrimidine (0.172 g, 0.87 mmol) and HATU (0.347 g, 0.913 mmol) in DMF (4 mL) was added DIPEA (0.607 mL, 3.48 mmol). The mixture was stirred at room temperature for 30 min and then biphenyl-4-carboxylic acid (0.87 mmol) was added. The resulting mixture was stirred at room temperature for 5 h. H2O (8 mL) was added and the resulting mixture extracted with EtOAc (3×). The organic layer was dried over MgSO4 and concentrated. The resulting residue was purified by HPLC to yield biphenyl-4-yl-[3-(4-pyrimidin-2-yl-piperazin-1-yl)-azetidin-1-yl]-methanone.
Reaction SMILES: C([O:3][C:4](=[O:34])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:19]=[C:18]([Cl:20])[CH:17]=[C:16]([O:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][C:23]=3Br)[CH:15]=2)=[CH:9][C:8]=1[CH3:33])C.C([Sn](CCCC)(CCCC)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][N:41]=1)CCC>>[Cl:20][C:18]1[CH:19]=[C:14]([CH:15]=[C:16]([O:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:29])[F:30])=[CH:24][C:23]=2[C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][N:41]=2)[CH:17]=1)[O:13][C:10]1[CH:11]=[CH:12][C:7]([CH2:6][CH2:5][C:4]([OH:3])=[O:34])=[C:8]([CH3:33])[CH:9]=1
Reactant: CCOC(=O)CCc1ccc(Oc2cc(Cl)cc(Oc3ccc(C(F)(F)F)cc3Br)c2)cc1C
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Product: Cc1cc(Oc2cc(Cl)cc(Oc3ccc(C(F)(F)F)cc3-c3ccccn3)c2)ccc1CCC(=O)O

Procedure:
The title compound is prepare by reacting the compound of 3-{4-[3-(2-bromo-4-trifluoromethyl-phenoxy)-5-chloro-phenoxy]-2-methyl-phenyl}-propionic acid ethyl ester with 2-tributylstannyl pyridine as in Example 39 to afford 0.055 g (32%). 1H NMR (400 MHz, CDCl3); HRMS (ES+) m/z exact mass calculated for C28H21NO4F3Cl 528.1190, found 528.1194.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH:9]1[C:15](=[O:20])N(OC)C)=[O:7])([CH3:4])[CH3:3].[O:21]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[CH:23]=[CH:22]1>>[C:2]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH:9]1[C:15]([C:22]1[O:21][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[CH:23]=1)=[O:20])=[O:7])([CH3:1])([CH3:3])[CH3:4]
Reactant: CON(C)C(=O)C1CN(C)CCN1C(=O)OC(C)(C)C
Reactant: c1ccc2occc2c1
Product: CN1CCN(C(=O)OC(C)(C)C)C(C(=O)c2cc3ccccc3o2)C1
Yield: 52 %

Procedure:
The title compound (1.81 g, 52%) was prepared from (RS)-2-(methoxy-methyl-carbamoyl)-4-methyl-piperazine-1-carboxylic acid dimethyl-ethyl ester, D54 (2.9 g, 10.1 mmol) and benzofuran (0.74 g, 10.1 mmol) using the method of Description 2.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[C:8]#[N:9])[CH3:2].[C:13]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])(=[O:16])[CH:14]=[CH2:15]>>[C:8]([C:7]1[CH:6]=[C:5]([CH:12]=[CH:11][CH:10]=1)[CH2:4][N:3]([CH2:1][CH3:2])[CH2:15][CH2:14][C:13]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])#[N:9]
Reactant: C=CC(=O)OC(C)(C)C
Reactant: CCNCc1cccc(C#N)c1
Product: CCN(CCC(=O)OC(C)(C)C)Cc1cccc(C#N)c1
Temperature: 80 °C

Procedure:
A mixture of 3-[(ethylamino)methyl]benzonitrile (5 g, 31 mmol) and tert-butyl acrylate (4.6 mL, 31 mmol) was heated neat at 80° C. for 12 hours. The crude mixture was purified by flash chromatography (silica, pet ether/EtOAc) to afford the title compound as colorless oil. 1H NMR (DMSO-d6, 400 MHz) δ 7.69 (m, 2H), 7.62 (d, J=7.8 Hz, 1H), 7.50 (m, 1H), 3.56 (s, 2H), 2.64 (t, 2H), 2.40 (m, 2H), 2.32 (t, 2H), 1.39 (s, 9H), 0.93 (t, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([C:12]([OH:14])=O)[C:9]([OH:15])=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:16])=[N:7]2.[Cl:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][NH2:23])=[CH:20][CH:19]=1.CCN=C=NCCCN(C)C.Cl.O.OC1C2N=NNC=2C=CC=1>CN(C=O)C.C1(C)C=CC=CC=1.C(Cl)Cl>[Cl:1][C:2]1[CH:11]=[C:10]([C:12]([NH:23][CH2:22][C:21]2[CH:24]=[CH:25][C:18]([Cl:17])=[CH:19][CH:20]=2)=[O:14])[C:9]([OH:15])=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:16])=[N:7]2
Reactant: NCc1ccc(Cl)cc1
Reactant: Cc1ccc2c(Cl)cc(C(=O)O)c(O)c2n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1ccc2c(Cl)cc(C(=O)NCc3ccc(Cl)cc3)c(O)c2n1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 5-chloro-8-hydroxy-2-methyl-7-quinolinecarboxylic acid (0.500 g) and 4-chlorobenzylamine (0.28 mL) in 20 mL DMF is added EDC hydrochloride (0.444 g) and hydroxybenzotriazole hydrate (0.312 g). The reaction is stirred at room temperature for 48 h. The mixture is then partitioned between EtOAc and water. The aqueous layer is extracted with EtOAc (3×). The combined organic layers are washed with brine (1×), dried over sodium sulfate and condensed. The residue is stirred in 20 mL 1:1 THF/1N HCl overnight. The solution is neutralized with saturated aqueous NaHCO3. The reaction is partitioned between EtOAc and water. The aqueous layer is extracted with EtOAc (3×). The combined organic layers are washed with brine (1×), dried and condensed. The crude product is chromatographed on silica, eluting with 3% MeOH/CH2Cl2. Fractions homogeneous by TLC are combined and condensed. The residue taken up in a minimal amount of CH2Cl2. Toluene is added to the solution and the mixture is sonicated while adding hexanes until a white solid formed. The solid is collected and dried to yield 0.310 g of the title product as a white solid.
Reaction SMILES: CC1C=CC(S([O:11][CH2:12][CH2:13][N:14]2[CH2:18][CH2:17][O:16][C:15]2=[O:19])(=O)=O)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].O[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1/[CH:33]=[CH:34]/[CH:35]([CH2:48][C:49]1[CH:54]=[CH:53][C:52]([C:55]([O:57][CH3:58])=[O:56])=[CH:51][CH:50]=1)[CH2:36][CH2:37][C:38]1[CH:47]=[CH:46][C:41]([C:42]([O:44][CH3:45])=[O:43])=[CH:40][CH:39]=1.[Cl-].[NH4+]>C1(C)C=CC=CC=1>[CH3:58][O:57][C:55]([C:52]1[CH:51]=[CH:50][C:49]([CH2:48][CH:35](/[CH:34]=[CH:33]/[C:28]2[CH:27]=[CH:32][CH:31]=[CH:30][C:29]=2[O:11][CH2:12][CH2:13][N:14]2[CH2:18][CH2:17][O:16][C:15]2=[O:19])[CH2:36][CH2:37][C:38]2[CH:47]=[CH:46][C:41]([C:42]([O:44][CH3:45])=[O:43])=[CH:40][CH:39]=2)=[CH:54][CH:53]=1)=[O:56]
Reactant: COC(=O)c1ccc(CCC(/C=C/c2ccccc2O)Cc2ccc(C(=O)OC)cc2)cc1
Reactant: Cc1ccc(S(=O)(=O)OCCN2CCOC2=O)cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(CCC(/C=C/c2ccccc2OCCN2CCOC2=O)Cc2ccc(C(=O)OC)cc2)cc1
Temperature: 60 °C
Reaction time: 18 h

Procedure:
A solution of 82.0 mg (0.288 mmol) of 2-(2-oxo-1,3-oxazolidin-3-yl)ethyl 4-methylbenzenesulfonate [CAS Reg. No. 159974-55-7] is initially charged in 1.5 ml of dry toluene, and 187 mg (0.576 mmol) of cesium carbonate are added. 32 mg (0.072 mmol) of methyl 4-{(4E)-5-(2-hydroxy-phenyl)-3-[4-(methoxycarbonyl)benzyl]pent-4-en-1-yl}benzoate (racemate; Example 18A) are then added. The reaction mixture is stirred at 60° C. for 18 h and then carefully poured into 15 ml of ice-cold 10% strength ammonium chloride solution. The mixture is extracted twice with ethyl acetate. The combined organic phases are dried over sodium sulfate, filtered and concentrated. This gives 39 mg (0.070 mmol, 97% of theory) of a colorless oil which is reacted without further purification
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1.[N:13]12[CH2:20][CH2:19][CH:16]([CH2:17][CH2:18]1)[C:15](=[O:21])[CH2:14]2.CO>CCOCC>[OH:21][C:15]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)[CH:16]2[CH2:19][CH2:20][N:13]([CH2:18][CH2:17]2)[CH2:14]1
Reactant: O=C1CN2CCC1CC2
Reactant: Brc1ccccn1
Agent: [Li]CCCC
Solvent: CO
Solvent: CCOCC
Product: OC1(c2ccccn2)CN2CCC1CC2
Temperature: -70 °C
Yield: 27.7 %

Procedure:
n-Butyl lithium (1.6M in hexanes, 17.4 ml, 27.9 mmol) was added dropwise to a solution of 2-bromopyridine (2.66 ml, 27.9 mmol) in ether (75 ml) cooled to -70° C. After 30 min a solution of 3-quinuclidinone (3.49 g, 27.9 mmol) in ether (25 ml) was added and the reaction mixture allowed to warm to -20° C. over 1 h. Methanol (50 ml) was added and the solution concentrated. The crude product was chromatographed through silica-gel using dichloromethane/methanol/ammonia (89:10:1) as eluent to give 1.58 g of the title compound as a tan solid. The dihydrochloride salt was prepared; m.p. 210°-5° C.; Found C, 51.82; H, 6.50; N, 9.98. C12H18N2Cl2O requires C, 51.99; H, 6.55; N, 10.10; δ(360 MHz, D2O) 8.792 (1H, d, J=5.4 Hz, py-H), 8.528 (1H, dt, J=8.1, 1.5 Hz, py-H), 8.139 (1H, d, J=8.1 Hz, py-H), 7.961 (1H, t, J=6.7 Hz, py-H), 4.177 (1H, d, J=14.3 Hz, H-2ax), 3.661 (1H, d, J=14.3 Hz, H-2eq), 3.54-3.35 (4H, m, H2 -6 and H2 -7) 2.55-1.65 (5H, m, H-4, H2 -5 and H2 -8); m/e 204 (M+).