Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](N)[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.S(=O)(=O)(O)O.N([O-])=O.[Na+].[I-:25].[Na+]>COCCOC.O>[F:1][C:2]1[CH:3]=[C:4]([I:25])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Nc1ccc(Oc2ccccc2)c(F)c1
Reactant: [I-]
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Fc1cc(I)ccc1Oc1ccccc1
Temperature: -5 °C
Reaction time: 0.5 h
Yield: 96.6 %

Procedure:
To a stirred solution of 3-fluoro-4-phenoxybenzenamine (2.6 g, 12.79 mmol, 1.00 equiv) in ethylene glycol dimethyl ether (35 mL) at room temperature was added a solution of 50% sulfuric acid (5 mL) in water (25 mL) dropwise. The reaction was cooled to −5° C. and a solution of sodium nitrite (1.33 g, 19.28 mmol, 1.51 equiv) in water (9 mL) was then added dropwise within 20 min. The resulting solution was stirred for 30 min at −5-0° C. A solution of sodium iodide (9.6 g, 64.00 mmol, 5.00 equiv) in water (25 mL) was added dropwise into the reaction mixture at −5° C. The resulting solution was stirred at −5-0° C. for 30 min then extracted with 3×100 mL of ethyl acetate. The combined organic layers was washed with 3×200 mL of saturated sodium sulfite solution, dried over anhydrous sodium sulfate and concentrated under vacuum to give 3.88 g (97%) of 2-fluoro-4-iodo-1-phenoxybenzene as a yellow oil. 1H-NMR (400 MHz, CDCl3): δ 7.53-7.49 (m, 1H), 7.42-7.30 (m, 2H), 7.13-7.08 (m, 1H), 6.99-6.96 (m, 2H), 6.78 (t, J=8.4 Hz, 2H) ppm.
Reaction SMILES: [CH:1]([S:5][C:6]1[C:11]([C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:10][CH:9]=[CH:8][C:7]=1Br)=[C:2]([CH3:4])[CH3:3].[PH2](O)=O.C(N(CC)CC)C.Cl>O1CCOCC1.[Cl-].[Na+].O>[CH3:3][C:2]1([CH3:4])[CH2:1][S:5][C:6]2[C:11]([C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:10][CH:9]=[CH:8][C:7]1=2
Reactant: CC(C)=CSc1c(Br)cccc1C(C)(C)C
Agent: Cl
Agent: O=[PH2]O
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)c1cccc2c1SCC2(C)C
Temperature: 24 °C

Procedure:
A solution of 2-bromo-6-tert-butylphenyl isobutenyl thioether (600 mg, 2.07 mmol), 90% hypophosphorous acid (4.4 g, 60 mmol), and triethylamine (8.4 mL, 60 mmol) in dioxane (30 mL) is deoxygenated by bubbling with N2 for 20 min. The solution is then heated under N2 to reflux, and a solution of azo-bis-isobutyrylnitrile (205 mg, 1.04 mmol) in deoxygenated dioxane (2 mL) is added in 0.2-mL portions over 3 h. The reaction is allowed to cool to 24° C., and 1N HCl (40 mL) and brine (30 mL) are added. The mixture is extracted with Et2O (3×50 mL), and the ethereal layers are back extracted with 1N NaOH (40 mL). The organic phase is dried (MgSO4), filtered and evaporated to a yellow oil. Kugelrohr distillation provides 3,3-dimethyl-7-tert-butyl-2,3-dihydrobenzo[b]thiophene as a colorless oil.
Reaction SMILES: [CH2:1]([S:5][C:6]1[N:10]=[CH:9][NH:8][N:7]=1)[CH2:2][CH2:3][CH3:4].[CH2:11]([N:14]([CH2:18][CH:19]=[CH2:20])[C:15](Cl)=[O:16])[CH:12]=[CH2:13].O1CCCC1>C(N(CC)CC)C>[CH2:11]([N:14]([CH2:18][CH:19]=[CH2:20])[C:15]([N:8]1[CH:9]=[N:10][C:6]([S:5][CH2:1][CH2:2][CH2:3][CH3:4])=[N:7]1)=[O:16])[CH:12]=[CH2:13]
Reactant: C=CCN(CC=C)C(=O)Cl
Reactant: CCCCSc1nc[nH]n1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C=CCN(CC=C)C(=O)n1cnc(SCCCC)n1

Procedure:
A mixture of 6.3 g. 3-n-butylthio-1,2,4-triazole, 6.8 g. diallylcarbamoyl chloride, 25 ml. tetrahydrofuran and 8 ml. dry triethylamine was refluxed under anhydrous conditions for 4 hours. The reaction mixture was worked up as described in Example1 to produce an oil which was distilled under reduced pressure to give 1-diallylcarbamoyl-3-n-butylthio-1,2,4-triazole, b.p. 157°C./0.6 mm. (95.0% 1-isomer by GLC assay). Elemental analysis satisfactory.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][C:25]=1[Cl:26])[CH2:5][N:6]([CH3:22])[C:7]([C:9]1[CH2:10][N:11]([CH2:16][CH:17](OC)OC)[C:12](=[O:15])[C:13]=1[OH:14])=[O:8].[CH3:27][CH:28]1[O:33][CH:32]([CH3:34])[CH2:31][NH:30][CH2:29]1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][C:25]=1[Cl:26])[CH2:5][N:6]([CH3:22])[C:7]([C:9]1[CH2:10][N:11]([CH2:16][CH2:17][N:30]2[CH2:29][CH:28]([CH3:27])[O:33][CH:32]([CH3:34])[CH2:31]2)[C:12](=[O:15])[C:13]=1[OH:14])=[O:8]
Reactant: COC(CN1CC(C(=O)N(C)Cc2ccc(Cl)c(Cl)c2)=C(O)C1=O)OC
Reactant: CC1CNCC(C)O1
Product: CC1CN(CCN2CC(C(=O)N(C)Cc3ccc(Cl)c(Cl)c3)=C(O)C2=O)CC(C)O1

Procedure:
Compound 750 was prepared from 1-(2,2-dimethoxy-ethyl)-4-hydroxy-5-oxo-2,5-dihydro-1H-pyrrole-3-carboxylic acid (3,4-dichloro-benzyl)-methyl-amide and 2,6-dimethyl-morpholine using the method described for compound 747. The title compound was isolated as a pale yellow powder (0.014 g, 14% yield). HRMS (M+H) calcd for C21H28N3Cl2O4: 456.14570. found: 456.1472.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:11]([OH:13])=O)[CH3:10])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1.[CH2:45]([O:47][C:48](=[O:73])[CH2:49][CH2:50][C:51]1[O:52][C:53]2[CH:72]=[CH:71][CH:70]=[CH:69][C:54]=2[C:55]=1[CH2:56][CH:57]1[CH2:61][CH2:60][CH2:59][N:58]1[C:62](=[O:68])[CH:63]([NH2:67])[CH:64]([CH3:66])[CH3:65])[CH3:46]>CN1C(=O)CCC1.C(OCC)C>[CH2:45]([O:47][C:48](=[O:73])[CH2:49][CH2:50][C:51]1[O:52][C:53]2[CH:72]=[CH:71][CH:70]=[CH:69][C:54]=2[C:55]=1[CH2:56][CH:57]1[CH2:61][CH2:60][CH2:59][N:58]1[C:62](=[O:68])[CH:63]([NH:67][C:11](=[O:13])[CH:9]([NH:8][C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2])[CH3:10])[CH:64]([CH3:66])[CH3:65])[CH3:46]
Reactant: CCOC(=O)CCc1oc2ccccc2c1CC1CCCN1C(=O)C(N)C(C)C
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CCOCC
Solvent: CN1CCCC1=O
Product: CCOC(=O)CCc1oc2ccccc2c1CC1CCCN1C(=O)C(NC(=O)C(C)NC(=O)OC(C)(C)C)C(C)C
Reaction time: 0.17 h

Procedure:
A solution containing Boc-L-alanine (69 mg, 0.37 mmol) in NMP (3 mL) was treated with HATU (131 mg, 0.34 mmol) followed by NMM (0.1 mL, 0.9 mmol) at ambient temperature. After 10 min, amine 50 (111 mg, 0.28 mmol) in NMP (5 mL) was added in a dropwise fashion. After 5 h, the reaction mixture was diluted with diethyl ether and washed successively with NaHCO3, 1 M HCl, water, and brine. The organic extract was dried over anhydrous Na2SO4, filtered and concentrated to afford 160 mg (quant.) of 51 which was used without further purification. 1H NMR (CDCl3, 300 MHz) δ7.81-7.78 (m, 1H), 7.38-7.36 (m, 1H), 7.28-7.21 (m, 3H), 6.86 (d, J=8.7 Hz, 1H), 5.04 (d, J=6.9 Hz, 1H), 4.61 (dd, J=6.3, 8.7 Hz, 1H), 4.48-4.42 (m, 1H), 4.22 (m, 1H), 4.13 (q, J=6.9 Hz, 2H), 3.73-3.62 (m, 2H), 3.41-3.36 (m, 2H), 3.28 (dd, J=3.0, 13.5 Hz, 1H), 3.11 (app t, J=6.9 Hz, 2H), 2.85-2.73 (m, 4H), 2.38 (app t, J=8.1 Hz, 2H), 2.13-1.98 (m, 2H), 1.80-1.64 (m, 1H), 1.45 (s, 9H), 1.37 (d, J=6.9 Hz, 3H), 1.26 (t, J=7.5 Hz, 3H), 1.03-0.95 (m, 6H) ppm. Mass spectrum: m/z 572 [M+H]+; and, 594 [M+Na]+.
Reaction SMILES: [C:1]1([C:7]2[O:11][N:10]=[C:9]([C:12]3[O:16][N:15]=[C:14]4[C:17]5[C:22]([CH2:23][CH2:24][C:13]=34)=[CH:21][C:20]([CH:25]([OH:27])[CH3:26])=[CH:19][CH:18]=5)[C:8]=2[C:28]([F:31])([F:30])[F:29])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.S([O-])([O-])(=O)=S.[Na+].[Na+].C(=O)(O)[O-]>ClCCl>[C:1]1([C:7]2[O:11][N:10]=[C:9]([C:12]3[O:16][N:15]=[C:14]4[C:17]5[C:22]([CH2:23][CH2:24][C:13]=34)=[CH:21][C:20]([C:25](=[O:27])[CH3:26])=[CH:19][CH:18]=5)[C:8]=2[C:28]([F:29])([F:30])[F:31])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(O)c1ccc2c(c1)CCc1c-2noc1-c1noc(-c2ccccc2)c1C(F)(F)F
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: ClCCl
Product: CC(=O)c1ccc2c(c1)CCc1c-2noc1-c1noc(-c2ccccc2)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 94.8 %

Procedure:
To 1-(3-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-yl)ethanol (Preparation 125A 0.44 g, 1.032 mmol) in dichloromethane (5 mL) was added Dess-Martin Periodinane (0.481 g, 1.135 mmol) in batches, over 2 min. at room temperature. The reaction mixture was stirred at room temperature for 1.5 h. A 1:1 mixture of saturated aqueous sodium thiosulfate and saturated aqueous bicarbonate (3.6 mL) was added slowly to the reaction mixture at room temperature and the contents stirred for 15 min. The organic layer was separated and the aqueous layer was extracted with dichloromethane (2×10 mL). The combined organic layers were dried over sodium sulfate, filtered through a pad of Celite and concentrated under reduce pressure to yield 1-(3-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-yl)ethanone (0.415 g, 0.978 mmol, 95% yield) as a tan colored solid. LC/MS M+1=425.
Reaction SMILES: [OH:1][C@H:2]1[C@H:7]([OH:8])[C@@H:6]([OH:9])[C@H:5]([OH:10])[O:4][C@@H:3]1[C:11]([OH:13])=[O:12].CCCC[N+](CCCC)(CCCC)CCCC.[F-].C1COCC1.Br[CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>CN(C=O)C.CC(O)C.C(Cl)Cl>[OH:1][C@H:2]1[C@H:7]([OH:8])[C@@H:6]([OH:9])[C@H:5]([OH:10])[O:4][C@@H:3]1[C:11]([O:13][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=[O:12]
Reactant: O=C(O)[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O
Reactant: BrCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CC(C)O
Product: O=C(OCc1ccccc1)[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 17 h
Yield: 64.9 %

Procedure:
To a solution of (2S,3S,4S,5R,6R)-3,4,5,6-tetrahydroxytetrahydro-2H-pyran-2-carboxylic acid (1 g, 5.15 mmol) and TBAF in THF (6.18 mL, 6.18 mmol) in DMF (7 mL) was slowly added (bromomethyl)benzene (0.925 g, 5.41 mmol) at 0° C. The clear solution was warmed up to room temperature slowly and let it stir for 17 hours. TLC indicated the reaction was completed (20% iPrOH/CH2Cl2). The solvent was removed and the reaction residue was purified by silica gel chromatography with 10-20% iPrOH/CH2Cl2 to provide the desired product as a colorless oil (950 mg, 65%). LCMS: m/e 283.31 (M−H)−, 2.55 min (method 10).
Reaction SMILES: COC(=O)[CH:4]([O:41][CH:42]1[CH2:47][CH2:46][CH2:45][CH2:44][O:43]1)[C:5](=[O:40])[CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][C@H:12]1[C@@H:16]([O:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)[CH2:15][C@@H:14]([O:24][CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][O:26]2)[C@@H:13]1[CH2:31][O:32][Si:33]([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34].[Li+].[OH-]>C1COCC1>[Si:33]([O:32][CH2:31][C@H:13]1[C@H:14]([O:24][CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][O:26]2)[CH2:15][C@H:16]([O:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)[C@@H:12]1[CH2:11]/[CH:10]=[CH:9]\[CH2:8][CH2:7][CH2:6][C:5](=[O:40])[CH2:4][O:41][CH:42]1[CH2:47][CH2:46][CH2:45][CH2:44][O:43]1)([C:36]([CH3:39])([CH3:37])[CH3:38])([CH3:34])[CH3:35]
Reactant: COC(=O)C(OC1CCCCO1)C(=O)CCC/C=C\C[C@@H]1[C@@H](CO[Si](C)(C)C(C)(C)C)[C@H](OC2CCCCO2)C[C@@H]1OC1CCCCO1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OC[C@@H]1[C@@H](C/C=C\CCCC(=O)COC2CCCCO2)[C@@H](OC2CCCCO2)C[C@H]1OC1CCCCO1
Yield: 85.5 %

Procedure:
Ketone of example 51 (60 mg, 0.086 mmol), THF (3 mL), and LiOH (0.3 mL, 1M in H2O, 0.34 mmol;) were combined and refluxed under N2 for 2 h. The THF was evaporated, the aqueous phase was extracted with CH2Cl2 (2×), and the combined organics were washed with brine and dried (Na2SO4) filtered and concentrated in vacuo. FCC (silica gel 1:4, EtOAc/hex) afforded the desired ketone (47 mg).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].I[CH2:11][CH3:12].C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O.[Cl-].[Na+].O>[CH2:11]([O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6])[CH3:12]
Reactant: CCI
Reactant: O=Cc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: CCOc1cccc(C=O)c1

Procedure:
Combine 3-hydroxybenzaldehyde (5.6 g, 46 mmol) and 1-iodoethane (10.7 g, 69 mmol) in DMSO (25 mL) and warm to 80° C. Treat with of cesium carbonate (22.4 g, 69 mmol) in portions. During the addition the temperature begin to rise so the bath is removed. Stir the reaction at 80° C. for 1 hour, pour into 200 mL brine and extract twice with 150 mL diethyl ether. Wash the combine extracts twice with 200 mL brine, dry over MgSO4 and concentrate under vacuum to give an oil. Purification by chromatography (SiO2; 2.5% EtOAc in hexanes) affords 5.73 g (38 mmol; 83%) of the title compound as an oil: 1H NMR (CDCl3) 9.94 (s, 1H), 7.42-7.41 (m, 2H), 7.36-7.35 (m, 1H), 7.16-7.13 (m, 1H), 4.10-4.04 (q, 2H), 1.64-1.40 (t, 3H).
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]([C:30]([F:33])([F:32])[F:31])=[C:10]([C:12]([NH:14][C:15]3[CH:16]=[CH:17][C:18]([C:21]4[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[CH:23][CH:22]=4)=[N:19][CH:20]=3)=[O:13])[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[C:35]([O:39][C:40](=[O:46])[C@H:41]1[CH2:45][CH2:44][CH2:43][NH:42]1)([CH3:38])([CH3:37])[CH3:36].C(N(CC)CC)C.ON1C2N=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>ClCCl.CN(C)C=O>[C:35]([O:39][C:40]([C@H:41]1[CH2:45][CH2:44][CH2:43][N:42]1[C:25](=[O:26])[C:24]1[CH:28]=[CH:29][C:21]([C:18]2[CH:17]=[CH:16][C:15]([NH:14][C:12]([C:10]3[N:11]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[O:8][C:9]=3[C:30]([F:33])([F:32])[F:31])=[O:13])=[CH:20][N:19]=2)=[CH:22][CH:23]=1)=[O:46])([CH3:38])([CH3:36])[CH3:37]
Reactant: CC(C)(C)OC(=O)[C@H]1CCCN1
Reactant: O=C(O)c1ccc(-c2ccc(NC(=O)c3nc(-c4ccccc4)oc3C(F)(F)F)cn2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)[C@H]1CCCN1C(=O)c1ccc(-c2ccc(NC(=O)c3nc(-c4ccccc4)oc3C(F)(F)F)cn2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.1 %

Procedure:
A mixture of 4-{5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-yl}-benzoic acid (45 mg, 0.1 mmol), D-proline t-butyl ester hydrochloride (31 mg, 0.15 mmol), triethylamine (50 μL, 0.3 mmol), 1-hydroxy-7-azabenzotriazole (HOAT) (20 mg, 0.15 mmol), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (30 mg, 0.15 mmol) in anhydrous dichloromethane (5 mL) and N,N-dimethylformamide (1.5 mL) was stirred at room temperature overnight. The reaction mixture was concentrated and purified by flash chromatography (Merck silica gel 60, 230-400 mesh, 0%-100% ethyl acetate in hexane) to give (R)-1-(4-{5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-yl}-benzoyl)-pyrrolidine-2-carboxylic acid tert-butyl ester (51 mg, 84%) as a white solid.
Reaction SMILES: [CH2:1]([N:8]([CH2:16][CH3:17])[CH2:9][CH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:19]([O:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]2[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][N:30]=2)=[CH:24][CH:23]=1)=[O:20].C1(O)C=CC=CC=1>ClCCl>[F:37][C:35]([F:36])([F:38])[C:32]1[CH:33]=[CH:34][C:29]([O:28][C:25]2[CH:26]=[CH:27][C:22]([O:21][C:19]([N:13]3[CH2:12][CH2:11][CH:10]([CH2:9][N:8]([CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[CH2:16][CH3:17])[CH2:15][CH2:14]3)=[O:20])=[CH:23][CH:24]=2)=[N:30][CH:31]=1
Reactant: O=C(Cl)Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Reactant: CCN(Cc1ccccc1)CC1CCNCC1
Solvent: ClCCl
Solvent: Oc1ccccc1
Product: CCN(Cc1ccccc1)CC1CCN(C(=O)Oc2ccc(Oc3ccc(C(F)(F)F)cn3)cc2)CC1
Reaction time: 8 h

Procedure:
Benzyl-ethyl-piperidin-4-ylmethyl-amine (1.42 mmol) was dissolved in dichloromethane. 4-(5-Trifluoromethyl-pyridin-2-yloxy)-phenyl chloroformate (1.42 mmol, 0.451 g) (prepared from the corresponding phenol by conventional methods) was added at room temperature. The reaction mixture was stirred overnight and evaporated to dryness. The crude product was subjected to column chromatography, ethyl acetate/heptane (1:3)→Triethylamine/ethyl acetate 1:9). The fractions containing the title product, was evaporated to dryness and HCl (g) in ethyl acetate was added and stirred for 16 hours. The solution was evaporated to dryness and dryed in vacoum for 16 h. to give the title product. (58%, light yellow crystals). HPLC-MS m/z=514.1 (M+1), Rt: 3.27 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:15])[C:7]3[N:8]([CH2:11][CH2:12][CH2:13][N:14]=3)[C:9]=2[CH:10]=1.[N+:16]([O-])([OH:18])=[O:17]>OS(O)(=O)=O>[Cl:1][C:2]1[C:3]([N+:16]([O-:18])=[O:17])=[CH:4][C:5]2[C:6](=[O:15])[C:7]3[N:8]([CH2:11][CH2:12][CH2:13][N:14]=3)[C:9]=2[CH:10]=1
Reactant: O=C1C2=NCCCN2c2cc(Cl)ccc21
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=C1C2=NCCCN2c2cc(Cl)c([N+](=O)[O-])cc21
Temperature: -10 °C
Reaction time: 1 h
Yield: 78.7 %

Procedure:
To a cold mixture of 7-chloro-3,4-dihydropyrimido[1,2-a]indole-10(2H)-one (0.221 g, 1.00 mmol ) in concentrated H2SO4 (1 mL), was added fuming nitric acid (0.042 mL, 1.00 mmol ) drop-wise with cooling in a ice/brine bath (−10° C.). After stirring for 10 minutes the ice bath was removed and stirring continued for 1 hour at room temperature. Controlling the temperature with an ice bath, fresh fuming HNO3 (0.021 mL) was added. After stirring for an additional hour the mixture was added to ice and basified with concentrated NH4OH. The resulting yellow solid was filtered, dissolved in CH2Cl2 and filtered again. The filtrate was washed with H2O and the organic layer was separated and concentrated to give the title compound as a bright yellow solid (0.209 g, 79% yield). Anal. Calc'd for C11H8ClN3O3+0.2H2O: C, 47.60; H, 3.00; N, 14.87. Found: C, 47.58; H, 3.02; N, 14.85. NMR (300 Mz, DMSO-d6): consistent. MS: (ES+) m/z 266 [M+H] one chlorine pattern observed. m.p.: 152-165° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([C:13]([OH:15])=O)=[N:10][C:9]=2[C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=2[Cl:23])=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[CH:33]1[CH:38]=[N:37][C:36]2N(O)N=N[C:35]=2[CH:34]=1.F[P-](F)(F)(F)(F)F.ClC1N(C)CC[NH+]1C.C(N)CCCC>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([C:13]([NH:37][CH2:36][CH2:35][CH2:34][CH2:33][CH3:38])=[O:15])=[N:10][C:9]=2[C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=2[Cl:23])=[CH:4][CH:3]=1
Reactant: O=C(O)c1nc(-c2ccc(Cl)cc2Cl)c(-c2ccc(Br)cc2)s1
Reactant: On1nnc2cccnc21
Agent: CN1CC[NH+](C)C1Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCCN
Product: CCCCCNC(=O)c1nc(-c2ccc(Cl)cc2Cl)c(-c2ccc(Br)cc2)s1
Temperature: 0 °C
Reaction time: 8 h
Yield: 69.4 %

Procedure:
Part B: 5-(4-Bromophenyl)-4-(2,4-dichlorophenyl)thiazole-2-carboxylic acid (0.50 gram, 1.17 mmol) and diisopropylethylamine (DIPEA) (1.02 mL, 5.85 mmol) are dissolved in dichloromethane (5 mL) and cooled to 0° C. 7-Aza-1-hydroxybenzotriazole (HOAt) (0.11 gram, 0.81 mmol) and 2-chloro-1,3-dimethylimidazolinium hexafluorophosphate (CIP) (0.50 gram, 1.76 mmol) are added, followed by addition of n-pentylamine (0.15 gram, 1.76 mmol) and the resulting mixture is stirred at room temperature overnight. Flash chromatographic purification (dichloromethane) gives 5-(4-bromophenyl)-4-(2,4-dichlorophenyl)-N-(n-pentyl)thiazole-2-carboxamide as an amorphous solid (0.28 gram, 48% yield).
Reaction SMILES: C([Li])CCC.[C:6]1([CH2:12][CH2:13][CH2:14][C:15]#[CH:16])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH3:17][O:18][C:19]1[CH2:26][CH2:25][C:22]2([O:24][CH2:23]2)[C:21](=[O:27])[CH:20]=1.[Cl-].[NH4+]>C(OCC)C.C1(C)C=CC=CC=1>[OH:27][C:21]1([CH:16]=[CH:15][CH2:14][CH2:13][CH2:12][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH:20]=[C:19]([O:18][CH3:17])[CH2:26][CH2:25][C:22]21[O:24][CH2:23]2
Reactant: COC1=CC(=O)C2(CC1)CO2
Reactant: C#CCCCc1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: COC1=CC(O)(C=CCCCc2ccccc2)C2(CC1)CO2
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 103.7 %

Procedure:
74 ml (0.118 mol) of n-butyllithium (1.6 molar in hexane) are added dropwise, under a nitrogen atmosphere, to a solution, cooled to -78° C., of 25 ml (0.157 mol) of 5-phenylpentyne in 400 ml of anhydrous diethyl ether. The whole is stirred at -78° C. for 15 minutes and then at 0° C. for 75 minutes. There is then added dropwise to that solution a solution, cooled to -78° C., of 6-methoxy-1-oxa-spiro[2.5]oct-5-en-4-one (11 g; 71.33 mmol) in 80 ml of anhydrous toluene. After 1 hour's stirring at -78° C., the reaction mixture is poured into an aqueous 10% ammonium chloride solution (1000 ml). Conventional treatment of the organic phase yields 22 g (74 mmol) of 4-hydroxy-6-methoxy-4-(5-phenylpenten-1-yl)-1-oxa-spiro[2.5]octene (2 isomers) in the form of an oily residue which is used in the following step without being purified. Hydrogenation of a solution of 22 g (74 mmol) of that mixture of isomers in 610 ml of benzene in the presence of 10 g of Lindlar catalyst for a period of 7 hours results, after filtration and evaporation, in 22 g (73 mmol) of 4-hydroxy-6methoxy-4-(5-phenylpentyl)-1-oxa-spiro[2.5]oct-5-ene in the form of an oily residue which is used in the following step without being purified.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([C:14]3[C:15]([O:28][CH2:29][CH3:30])=[C:16](/[CH:22]=[CH:23]/[C:24]([O:26][CH3:27])=[O:25])[C:17]([CH3:21])=[C:18]([Cl:20])[CH:19]=3)[CH3:13])[N:9]=[C:10]([CH3:11])[C:3]=12.N12CCCN=C1CCCCC2.[N+:42]([CH3:45])([O-:44])=[O:43]>>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([C:14]3[C:15]([O:28][CH2:29][CH3:30])=[C:16]([CH:22]([CH2:45][N+:42]([O-:44])=[O:43])[CH2:23][C:24]([O:26][CH3:27])=[O:25])[C:17]([CH3:21])=[C:18]([Cl:20])[CH:19]=3)[CH3:13])[N:9]=[C:10]([CH3:11])[C:3]=12
Reactant: CCOc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C)c1/C=C/C(=O)OC
Reactant: C[N+](=O)[O-]
Solvent: C1CCC2=NCCCN2CC1
Product: CCOc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C)c1C(CC(=O)OC)C[N+](=O)[O-]
Temperature: 90 °C
Reaction time: 22 h
Yield: 48 %

Procedure:
A solution of methyl (2E)-3-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-ethoxy-6-methylphenyl}acrylate (0.40 g, 0.93 mmol) in nitromethane (6.3 mL) was treated with 1,8-diazabicyclo[5.4.0]undec-7-ene (0.14 mL, 0.93 mmol) and stirred at 90° C. for 22 h. The reaction mixture was concentrated, diluted with methanol, and purified by preparative LCMS (XBridge C18 Column, eluting with a gradient of acetonitrile in water with 0.1% trifluoroacetic acid, at flow rate of 60 mL/min). The LCMS fractions were concentrated to remove acetonitrile, treated with solid sodium bicarbonate, and extracted into ethyl acetate. The ethyl acetate was concentrated to give the desired product (0.22 g, 48%) as a mixture of diastereoisomers. LCMS for C22H28ClN6O5 (M+H)+: m/z=491.2; Found: 491.2.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:20]Br.[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]([CH3:36])([CH3:35])[C:30]([F:34])=[CH:31][CH2:32]O)=[CH:25][CH:24]=1.C(OCC)(=O)C.CCCCCC>C(Cl)(Cl)(Cl)Cl>[Br:20][CH2:32][CH:31]=[C:30]([F:34])[C:29]([C:26]1[CH:27]=[CH:28][C:23]([Cl:22])=[CH:24][CH:25]=1)([CH3:36])[CH3:35]
Reactant: CC(C)(C(F)=CCO)c1ccc(Cl)cc1
Reactant: BrBr
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CC(C)(C(F)=CCBr)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.6 %

Procedure:
A solution of triphenyl phosphine (12.58 g, 55.6 mmol) in carbon tetrachloride at -5° C. to 5° C. is treated dropwise with a solution of bromine (8.89 g, 55.6 mmol) in carbon tetrachloride over 50 minutes under nitrogen, stirred at room temperature for one hour, treated with a solution of 4-(p-chlorophenyl)-3-fluoro-4-methyl-2-penten-1-ol, (Z)- (10.6 g, 46.3 mmol) in carbon tetrachloride over 15 minutes, refluxed for 2.5 hours, cooled to room temperature, and poured into petroleum ether. The resultant mixture is filtered through diatomaceous earth and concentrated in vacuo to obtain a residue. Flash chromatography of the residue using silica gel and a 1:9 ethyl acetate/hexane solution gives the title product as an oil (12.5 g, 92.6% yield).