Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:9]=[C:8]([C:10]([OH:12])=O)[CH:7]=[CH:6][C:5]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19].[NH2:20][C:21](=[N:38]O)[C:22]1[CH:36]=[CH:35][C:25]([O:26][CH2:27][CH2:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])=[C:24]([F:37])[CH:23]=1>>[F:37][C:24]1[CH:23]=[C:22]([C:21]2[N:38]=[C:10]([C:8]3[CH:7]=[CH:6][C:5]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=4[CH3:19])=[C:4]([CH2:3][O:2][CH3:1])[CH:9]=3)[O:12][N:20]=2)[CH:36]=[CH:35][C:25]=1[O:26][CH2:27][CH2:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31]
Reactant: COCc1cc(C(=O)O)ccc1-c1ccccc1C
Reactant: CCOC(=O)CCCOc1ccc(C(N)=NO)cc1F
Product: CCOC(=O)CCCOc1ccc(-c2noc(-c3ccc(-c4ccccc4C)c(COC)c3)n2)cc1F

Procedure:
The title compound was prepared following procedure described for example 4, step 1, but starting from Intermediate 28 (192.22 mg; 0.75 mmol) and Intermediate 66 (234.54 mg; 0.83 mmol). The reaction mixture was filtered through a SPE NH2 column (2×2 g) and rinsed with ACN. The filtrate was passed through a SPE SCX column (2×2 g) and rinsed with ACN. After evaporation of the solvents, the crude product was purified by flash chromatography (c-hex/(DCM/EtOAc 1:1) gradient from 1:0 to 1:1), affording the title compound as a colorless oil. 1H NMR (CDCl3) δ 8.41 (d, J=1.4 Hz, 1H), 8.15 (dd, J=7.8, 1.9 Hz, 1H), 7.95-7.90 (m, 2H), 7.36-7.23 (m, 4H), 7.14-7.05 (m, 2H), 4.27-4.13 (m, 6H), 3.33 (s, 3H), 2.57 (t, J=7.2 Hz, 2H), 2.19 (quint., J=6.6 Hz, 2H), 2.08 (s, 3H), 1.27 (t, J=7.2 Hz, 3H). LC/MS (Method B): 505.3 (M+H)+. HPLC (Method A) Rt 6.24 min (Purity: 98.9%).
Reaction SMILES: C([O:3][C:4](=[O:19])[CH:5]([O:16][CH2:17][CH3:18])[CH2:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]=[CH:10]2)C.Cl[CH2:21][C:22]1[N:23]=[C:24]([C:28]2[CH:33]=[C:32]([F:34])[CH:31]=[C:30]([F:35])[CH:29]=2)[O:25][C:26]=1[CH3:27]>>[F:34][C:32]1[CH:33]=[C:28]([C:24]2[O:25][C:26]([CH3:27])=[C:22]([CH2:21][N:12]3[C:13]4[C:9](=[CH:8][C:7]([CH2:6][CH:5]([O:16][CH2:17][CH3:18])[C:4]([OH:3])=[O:19])=[CH:15][CH:14]=4)[CH:10]=[CH:11]3)[N:23]=2)[CH:29]=[C:30]([F:35])[CH:31]=1
Reactant: CCOC(=O)C(Cc1ccc2[nH]ccc2c1)OCC
Reactant: Cc1oc(-c2cc(F)cc(F)c2)nc1CCl
Product: CCOC(Cc1ccc2c(ccn2Cc2nc(-c3cc(F)cc(F)c3)oc2C)c1)C(=O)O
Yield: 20 %

Procedure:
Starting from rac-2-ethoxy-3-(1H-indol-5-yl)-propionic acid ethyl ester and 4-chloromethyl-2-(3,5-difluoro-phenyl)-5-methyl-oxazole, the title compound was obtained in 20% yield as a brown oil. MS: (M+H)+ 441.3.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]([NH:14][C:15]2[C:20]([CH:21]([CH3:23])[CH3:22])=[CH:19][C:18]([OH:24])=[CH:17][C:16]=2[CH:25]([CH3:27])[CH3:26])=[O:13])[CH2:7][CH2:6]1.[CH2:28]([O:30][CH2:31][CH2:32]Br)[CH3:29].[F-].[K+]>CN(C=O)C>[CH:21]([C:20]1[CH:19]=[C:18]([O:24][CH2:29][CH2:28][O:30][CH2:31][CH3:32])[CH:17]=[C:16]([CH:25]([CH3:27])[CH3:26])[C:15]=1[NH:14][C:12](=[O:13])[CH2:11][N:8]1[CH2:7][CH2:6][N:5]([CH2:4][CH2:3][CH2:2][OH:1])[CH2:10][CH2:9]1)([CH3:23])[CH3:22]
Reactant: CC(C)c1cc(O)cc(C(C)C)c1NC(=O)CN1CCN(CCCO)CC1
Reactant: CCOCCBr
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOCCOc1cc(C(C)C)c(NC(=O)CN2CCN(CCCO)CC2)c(C(C)C)c1
Temperature: 25 °C
Reaction time: 120 h
Yield: 78 %

Procedure:
To a solution of this acetamide (500 mg, 1.32 mmol) solution in DMF (12 ml) were added 2-bromoethyl ethyl ether (7 ml) and potassium fluoride 40 wt. % on alumina (40 wt. %, 1.96 g, 13.2 mmol), and the mixture was stirred at room temperature for 5 days. After the catalyst was filtered off, the filtrate was diluted with water and extracted with ethylacetate. The organic layer was washed with a saturated sodium chloride solution and dried over anhydrous sodium sulfate, and the solvent was evaporated therefrom. The resulting residue was purified by a silica gel column chromatography (developing solvent; chloroform:methanol=30:1) to provide 448 mg (yield 78%) of N-[2,6-diisopropyl-4-(2-ethoxyethyloxy)phenyl]-2-[4-(3-hydroxypropyl)piperazin-1-yl]acetamide as colorless powdery crystals.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH:6][C:7]1[CH:14]=[C:13]([F:15])[C:10]([CH:11]=O)=[C:9]([Cl:16])[CH:8]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl>ClCCl.O>[Cl:16][C:9]1[CH:8]=[C:7]([OH:6])[CH:14]=[C:13]([F:15])[C:10]=1[CH2:11][N:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=Cc1c(F)cc(O)cc1Cl
Reactant: C1CCNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: Oc1cc(F)c(CN2CCCC2)c(Cl)c1
Yield: 69.8 %

Procedure:
Pyrrolidine (4.65 mL, 56 mmol) was added to a solution of intermediate 17, 4-hydroxy-2-chloro-6-fluorobenzaldehyde (7.5 g, 43 mmol) in dichloromethane (100 mL). The reaction mixture was cooled on ice bath, and sodium triacetoxyborohydride (13.71 g, 65 mmol) was added in portions under stirring. The reaction mixture was intensively stirred for 24 h at RT. Water (100 mL) and concentrated HCl were added to attain pH˜2. The organic layer was separated. The aqueous one was extracted with CH2Cl2 (2×100 mL), then with EtOAc (100 mL). The organic layers were discarded. The aqueous fraction was alkalized with K2CO3 to pH˜10, the obtained crystals were separated by filtration, dried in vacuo, recrystallized from Et2O/hexane mixture (1:1) to give the title compound (7 g, 71%, 30 mmol). LCMS data: 231 and 230 (M+H)+ (calculated for C11H13ClFNO 229.7). 1H NMR data (DMSO-d6): 10.25 (br.s, 1H, OH), 6.66-6.70 (m, 1H, H—Ar), 6.54 (dd, 1H, J1=2.2 Hz, J2=11.3 Hz, H—Ar), 3.58 (d, 2H, J1=2.4 Hz, Ar—CH2); 2.38-2.46 (m, 4H), 1.58-1.68 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:5]=[CH:4][C:3]=1[OH:12].[I-].C[O:15][C:16]([C:18]1([CH2:28][CH3:29])[CH2:22][C:21]2[CH:23]=[C:24]([OH:27])[CH:25]=[CH:26][C:20]=2[O:19]1)=[O:17].[C:30]1(O)[CH:35]=CC=C[CH:31]=1>>[C:8]([C:6]1[CH:5]=[CH:4][C:3]([O:12][CH2:31][CH2:30][CH2:35][O:27][C:24]2[CH:25]=[CH:26][C:20]3[O:19][C:18]([CH2:28][CH3:29])([C:16]([OH:15])=[O:17])[CH2:22][C:21]=3[CH:23]=2)=[C:2]([Cl:1])[CH:7]=1)([CH3:9])([CH3:11])[CH3:10]
Reactant: CC(C)(C)c1ccc(O)c(Cl)c1
Reactant: Oc1ccccc1
Reactant: CCC1(C(=O)OC)Cc2cc(O)ccc2O1
Agent: [I-]
Product: CCC1(C(=O)O)Cc2cc(OCCCOc3ccc(C(C)(C)C)cc3Cl)ccc2O1

Procedure:
The title compound was prepared following the general procedures described Example 1, Step 3 and Step 4, employing 2-chloro-4-tert-butylphenol instead of 2-chloro-4-(trifluoroethoxy)phenol for the preparation of the iodide and the intermediate prepared in Example 4, Step 1 as the phenol for coupling with the iodide.
Reaction SMILES: C1(P([N:15]=[N+:16]=[N-:17])(C2C=CC=CC=2)=O)C=CC=CC=1.N12CCCN=C1CCCCC2.[CH3:29][C:30]1[O:34][C:33]([C@@H:35]([CH:37]2[CH2:41][CH2:40][CH2:39][O:38]2)O)=[CH:32][CH:31]=1.O>C1(C)C=CC=CC=1>[N:15]([C@H:35]([CH:37]1[CH2:41][CH2:40][CH2:39][O:38]1)[C:33]1[O:34][C:30]([CH3:29])=[CH:31][CH:32]=1)=[N+:16]=[N-:17]
Reactant: Cc1ccc([C@H](O)C2CCCO2)o1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1ccc([C@H](N=[N+]=[N-])C2CCCO2)o1
Temperature: 0 °C
Reaction time: 24 h
Yield: 62.8 %

Procedure:
11.9 ml (55.3 mmol; 1.2 eq) of diphenylphosphoryl azide and then 8.3 ml (55.3 mmol; 1.2 eq) of 1,8-diazabicyclo[5.4.0]undec-7-ene were added dropwise to a solution of 8.40 g (46.1 mmol; 1.0 eq) of (5-methylfuran-2-yl)-(R)-tetrahydrofuran-2-ylmethanol in 300 ml of toluene cooled to 0° C. The mixture was allowed to return to ambient temperature gently and was then stirred for 24 hours. The reaction medium was treated with water and extracted with ethyl acetate, The organic phases were combined, washed with a 1 M sodium dihydrogen phosphate solution, dried over magnesium sulfate, filtered and evaporated. The residue was chromatographed on silica gel (column puriFlash IR-50SI/300G, puriFlash) eluted with heptane/ethyl acetate (90/10). 6.0 g of 2-((R)-azidotetrahydrofuran-2-ylmethyl)-5-methylfuran were obtained (mixture of the 2 diastereoisomers). Yield=63%.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[C:6]1([CH:12]2[CH2:21][C:20]3[NH:19][CH:18]=[CH:17][C:16](=O)[C:15]=3[C:14](=[O:23])[CH2:13]2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>>[Cl:3][C:16]1[C:15]2[C:14](=[O:23])[CH2:13][CH:12]([C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH2:21][C:20]=2[N:19]=[CH:18][CH:17]=1
Reactant: O=C1CC(c2ccccc2)Cc2[nH]ccc(=O)c21
Reactant: O=P(Cl)(Cl)Cl
Product: O=C1CC(c2ccccc2)Cc2nccc(Cl)c21
Temperature: 100 °C
Reaction time: 2 h
Yield: 92.8 %

Procedure:
Under ice-cooling, to phosphorus oxychloride (3.6 g) was added 7-phenyl-1,4,5,6,7,8-hexahydroquinoline-4,5-dione (0.35 g), and the mixture was stirred at 100° C. for 2 hours and cooled. Under reduced pressure, phosphorus oxychloride was evaporated, and to the residue was added 1N sodium hydroxide solution. The mixture was extracted with ethyl acetate, and the organic layer was washed with water and saturated brine, dried with magnesium sulfate and concentrated under reduced pressure to give colorless crystals of 4-chloro-7-phenyl-5,6,7,8-tetrahydroquinolin-5-one (0.35 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH3:9])[C:5]([NH2:8])=[N:6][CH:7]=1.[Cl:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=1)[CH:14]=O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[N+:31]([C:33]([CH3:36])([CH3:35])[CH3:34])#[C-:32]>CO>[Br:1][C:2]1[CH:3]=[C:4]([CH3:9])[C:5]2[N:6]([C:32]([NH:31][C:33]([CH3:36])([CH3:35])[CH3:34])=[C:14]([C:13]3[CH:16]=[CH:17][CH:18]=[C:11]([Cl:10])[CH:12]=3)[N:8]=2)[CH:7]=1
Reactant: Cc1cc(Br)cnc1N
Reactant: O=Cc1cccc(Cl)c1
Reactant: [C-]#[N+]C(C)(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Product: Cc1cc(Br)cn2c(NC(C)(C)C)c(-c3cccc(Cl)c3)nc12
Reaction time: 0.08 h
Yield: 30.9 %

Procedure:
5-bromo-3-methylpyridin-2-amine (200 mg, 1.07 mmol, Eq: 1.00), 3-chlorobenzaldehyde (158 mg, 128 μL, 1.12 mmol, Eq: 1.05) and p-toluenesulfonic acid monohydrate (61.0 mg, 321 μmol, Eq: 0.3) were dissolved in MeOH (1.5 mL) and the intensive yellow solution was stirred for 5 min. To this yellow solution was added dropwise 2-isocyano-2-methylpropane (88.9 mg, 122 μL, 1.07 mmol, Eq: 1.00) and the corresponding yellow solution was stirred for 2 h. The precipitate was filtered off, washed with MeOH (4 mL) and dried under vacuum to give the product as a white solid (130 mg, 31.0%). MS: 394.1 [M+H]+; 1H-NMR (D6-DMSO): δ 8.48 (s, 1H), 8.27 (s, 1H), 8.17 (d, 1H), 7.46 (t, 1H), 7.36 (d, 1H), 7.22 (s, 1H), 4.81 (s, 1H), 3.34 (s, 3H), 1.03 (s, 9H).
Reaction SMILES: [C:1]1([C@H:7]([CH3:11])[C:8](O)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)([Cl:14])=O.CN(C)C1C=CC=CC=1>ClC(Cl)=C(Cl)Cl>[C:1]1([C@H:7]([CH3:11])[C:8]([Cl:14])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(Cl)Cl
Reactant: C[C@H](C(=O)O)c1ccccc1
Solvent: CN(C)c1ccccc1
Solvent: ClC(Cl)=C(Cl)Cl
Product: C[C@H](C(=O)Cl)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 102.4 %

Procedure:
Into a 10 L four-necked flask, 600 g (4.00 mol) of (S)-2-phenylpropionic acid, 2.4 L of tetrachloroethylene, 951 g (8.00 mol) of thionyl chloride and a small amount of dimethyl aniline were added, followed by stirring at room temperature overnight, and excess of thionyl chloride and tetrachloroethylene were distilled off under reduced pressure to obtain 691 g of (S)-2-phenylpropionic chloride.
Reaction SMILES: [I-].[CH3:2][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Li]CCCC.[CH2:27]([N:34]1[CH2:38][CH:37]([C:39]2[CH:44]=[CH:43][C:42]([Cl:45])=[C:41]([Cl:46])[CH:40]=2)[CH:36]([CH:47]=O)[CH2:35]1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C1COCC1>[CH2:27]([N:34]1[CH2:35][CH:36]([CH:47]=[CH2:2])[CH:37]([C:39]2[CH:44]=[CH:43][C:42]([Cl:45])=[C:41]([Cl:46])[CH:40]=2)[CH2:38]1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=CC1CN(Cc2ccccc2)CC1c1ccc(Cl)c(Cl)c1
Reactant: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [I-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C=CC1CN(Cc2ccccc2)CC1c1ccc(Cl)c(Cl)c1
Reaction time: 1 h
Yield: 79.8 %

Procedure:
To a suspension of methyltriphenylphosphonium iodide (5.53 g, 0.0136 mol) in THF (50 mL) was added n-BuLi (1.6N in heptane, 6.5 mL, 0.0104 mol) dropwise at 0° C. and stirred for one hour. To this reaction mixture was added a solution of (3RS,4SR)-1-benzyl-4-(3,4-dichloro-phenyl)-pyrrolidine-3-carbaldehyde 2.68 g (0.008 mol) in THF (15 mL) dropwise at 0° C. and stirred for another one hour. The reaction was quenched by aq. ammonium chloride solution and extracted with ethylacetate. The separated organic layer was dried on anhydrous sodium sulfate and concentrated in vaccuo. The residue was purified by silica gel column chromatography eluted by a mixture of heptane and ethyl acetate (4: 1) yielding 2.12 g (80%) of the title compound as a light yellow oil. ES-MS m/e: 332.1 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([CH:10]=[O:11])[CH:7]=[CH:6][C:5]=1[OH:12].CCN(CC)CC.[O:21](S(C(F)(F)F)(=O)=O)[S:22]([C:25]([F:28])([F:27])[F:26])(=O)=[O:23].[NH4+].[Cl-]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([CH:10]=[O:11])[CH:7]=[CH:6][C:5]=1[O:12][S:22]([C:25]([F:28])([F:27])[F:26])(=[O:23])=[O:21]
Reactant: COC(=O)c1cc(C=O)ccc1O
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: CN(C)c1ccncc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(C=O)ccc1OS(=O)(=O)C(F)(F)F
Temperature: 25 °C
Yield: 74.4 %

Procedure:
To a solution of 5-formyl-2-hydroxy-benzoic acid methyl ester (1.0 g, 5.6 mmol) in CH2Cl2 (10 mL) at −78° C. was added Et3N (0.85 mL, 6.1 mmol) and DMAP (68 mg, 0.56 mmol) followed by dropwise addition of Tf2O (1.03 mL, 6.1 mmol) over 20 min. The reaction mixture was then warmed to room temperature and poured into saturated aqueous NH4Cl and extracted with CH2Cl2 (3×25 mL). The combined extracts were dried (Na2SO4), filtered and concentrated. The residue was purified by flash chromatography (SiO2, 15% EtOAc/hexanes) to afford Example 236A (1.3 g, 76%) as a colorless oil.
Reaction SMILES: [C:1]1([CH3:10])[C:2]([C:7]([OH:9])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1.[I:11]N1C(=O)CCC1=O>CN(C=O)C.O.CCOC(C)=O.CC([O-])=O.CC([O-])=O.[Pd+2]>[I:11][C:3]1[CH:4]=[CH:5][CH:6]=[C:1]([CH3:10])[C:2]=1[C:7]([OH:9])=[O:8]
Reactant: O=C1CCC(=O)N1I
Reactant: Cc1ccccc1C(=O)O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cccc(I)c1C(=O)O
Temperature: 100 °C
Reaction time: 17 h
Yield: 92 %

Procedure:
To a solution of o-toluic acid (2.00 g, 14.7 mmol) in dry DMF (60 mL) under an atmosphere of nitrogen was added N-iodosuccinimide (3.64 g, 16.2 mmol) followed by Pd(OAc)2 (0.330 g, 1.47 mmol). The resulting reaction mixture was heated to 100° C. and stirred for 17 hours. Upon cooling to room temperature the reaction was diluted with water (100 mL) and EtOAc (150 mL), the layers were separated and the aqueous layer was extracted with EtOAc (2×100 mL), the combined organics were washed with water (100 mL), brine (100 mL), water (100 mL), brine (100 mL), dried (MgSO4), filtered and concentrated in vacuo to give the title compound (I57) (3.56 g, 92% yield) as a brown oily solid; 1H NMR (400 MHz, CDCl3) δ 7.69 (d, J=7.9 Hz, 1H), 7.21 (d, J=7.6 Hz, 1H), 7.02 (t, J=7.8 Hz, 1H), 2.44 (s, 3H). LCMS Method C: rt 5.36 min.
Reaction SMILES: CC1(C)[C:30]2[NH:31][C:27](=[C:28](F)[C:29]=2F)[C:26](C)(C)[C:24]2[NH:25][C:21](=[C:22](F)[C:23]=2F)[C:20](C)(C)[C:18]2[NH:19][C:15](=[C:16](F)[C:17]=2F)[C:14](C)(C)[C:12]2[NH:13][C:9](=[C:10](F)[C:11]=2F)[C:8](C)(C)C2NC1=C(F)C=2F.CO.FC1C=CNC=1F.CS(O)(=O)=O>CC(C)=O>[CH2:26]1[C:27]2[NH:31][C:30](=[CH:29][CH:28]=2)[CH2:8][C:9]2[NH:13][C:12](=[CH:11][CH:10]=2)[CH2:14][C:15]2[NH:19][C:18](=[CH:17][CH:16]=2)[CH2:20][C:21]2[NH:25][C:24]1=[CH:23][CH:22]=2
Reactant: CC1(C)c2[nH]c(c(F)c2F)C(C)(C)c2[nH]c(c(F)c2F)C(C)(C)c2[nH]c(c(F)c2F)C(C)(C)c2[nH]c(c(F)c2F)C(C)(C)c2[nH]c1c(F)c2F
Agent: CS(=O)(=O)O
Agent: Fc1cc[nH]c1F
Solvent: CC(C)=O
Solvent: CO
Product: c1cc2[nH]c1Cc1ccc([nH]1)Cc1ccc([nH]1)Cc1ccc([nH]1)C2
Temperature: 25 °C
Reaction time: 48 h
Yield: 52 %

Procedure:
β-Decafluoro-meso-decamethylcalix[5]pyrrole, 46 and β-hexadecafluoro-meso-hexadecamethylcalix[8]pyrrole, 48. To a round bottom flask containing methanol (37.5 mL), difluoropyrrole (773 mg, 7.50 mmol), and acetone (548 μL, 7.50 mmol were added. After dissolution of the reactants, methanesulfonic acid (490 μL, 7.50 mmol) was added and the reaction mixture was allowed to stir at ambient temperature for 2 days. The reaction mixture was then washed with aqueous NaCO3 (200 mL saturated) and taken into dichloromethane (100 mL). The resulting organic layer was then washed with water (2×100 mL), dried (Na2SO4), and the solvent was removed on the rotary evaporator. Purification of the crude reaction mixture, which was found to contain 44, 46 and 48 in appriciable yields as judged by TLC analysis, was effected via flash chromatography, using hexanes-acetone 4/1 v/v as the eluent. This resulted in the isolation of 44 (rf=0.4, 560 mg, 0.98 mmol, 52%), 46 (rf=0.2, 249 mg, 0.35 mmol, 23%), and 48 (rf=0.1, 150 mg, 0.13 mmol, 14%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([CH3:23])[C:17]=1[CH3:24].Cl[C:26](Cl)([O:28][C:29](=[O:35])OC(Cl)(Cl)Cl)Cl.[CH:37]1(CO)[CH2:39][CH2:38]1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:29](=[O:35])[O:28][CH2:26][CH:37]2[CH2:39][CH2:38]2)=[C:18]([CH3:23])[C:17]=1[CH3:24]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: OCC1CC1
Reactant: COc1cc2nccc(Oc3ccc(N)c(C)c3C)c2cc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COc1cc2nccc(Oc3ccc(NC(=O)OCC4CC4)c(C)c3C)c2cc1OC
Yield: 84.5 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,3-dimethylaniline (50 mg) was added to toluene (5 ml), and triethylamine (0.5 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (68 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, cyclopropylmethanol (17 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution, water, and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (55 mg, yield 80%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[C:6]([N+:12]([O-])=O)[CH:5]=1)[CH3:2].[NH2:15][C:16]1[CH:33]=[CH:32][C:19]([O:20][CH2:21][C@@H:22]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH3:23])=[CH:18][C:17]=1[F:34].S([O-])([O-])(=O)=O.[Mg+2]>C(O)C>[CH2:1]([O:3][C:4]1[CH:11]=[CH:10][C:7]2[C:6]([CH:5]=1)=[N:12][N:15]([C:16]1[CH:33]=[CH:32][C:19]([O:20][CH2:21][C@@H:22]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:28])[CH3:29])[CH3:23])=[CH:18][C:17]=1[F:34])[CH:8]=2)[CH3:2]
Reactant: C[C@@H](COc1ccc(N)c(F)c1)NC(=O)OC(C)(C)C
Reactant: CCOc1ccc(C=O)c([N+](=O)[O-])c1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CCO
Product: CCOc1ccc2cn(-c3ccc(OC[C@H](C)NC(=O)OC(C)(C)C)cc3F)nc2c1
Yield: 57.1 %

Procedure:
A mixture of 4-ethoxy-2-nitrobenzaldehyde (5.20 g), tert-butyl [(1S)-2-(4-amino-3-fluorophenoxy)-1-methylethyl]carbamate (7.58 g), magnesium sulfate (3.21 g) and ethanol (60 mL) was stirred under reflux overnight. The reaction mixture was concentrated under reduced pressure, triethyl phosphite (13.7 ml) was added to the residue, and the mixture was stirred at 130° C. for 3 hr. The reaction mixture was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound as a yellow solid (6.53 g).
Reaction SMILES: ClCCN(C1C=CC(C=O)=CC=1)CCCl.[Cl:16][CH2:17][CH2:18][N:19]([C:23]1[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][CH:24]=1)[CH2:20][CH2:21][Cl:22].N[C:32]1[C:39]([NH2:40])=[CH:38][CH:37]=[CH:36][C:33]=1[C:34]#[N:35]>CO>[Cl:16][CH2:17][CH2:18][N:19]([C:23]1[CH:24]=[CH:25][C:26]([C:27]2[NH:40][C:39]3[CH:32]=[C:33]([C:34]#[N:35])[CH:36]=[CH:37][C:38]=3[N:28]=2)=[CH:29][CH:30]=1)[CH2:20][CH2:21][Cl:22]
Reactant: N#Cc1ccc(N(CCCl)CCCl)cc1
Reactant: N#Cc1cccc(N)c1N
Agent: O=Cc1ccc(N(CCCl)CCCl)cc1
Solvent: CO
Product: N#Cc1ccc2nc(-c3ccc(N(CCCl)CCCl)cc3)[nH]c2c1
Yield: 40 %

Procedure:
A solution of 4-(N,N-bis(2-chloroethyl)amino)-benzaldehyde (IX, n=0) [Anker, R. M., Cook, A. H., "Quinoxaline cyanines. Part IV. Some halogenated styryl derivatives", J. Chem. Soc., 1944 489-4927] (1.32 g, 5.4 mmol) in MeOH (25 mL) was added to a stirred solution of 2,3-diaminobenzonitrile (X) [Stephens, F. F., Bower, J. D., "The preparation of benzimindazoles and benzoxazoles from Schiff's bases. Part II.", J. Chem. Soc., 1950 1722-1726] (0.72 g, 5.4 mmol) in aqueous MeOH (25 mL), immediately followed by a 0.05M aqueous solution of cupric acetate (1.1 mol equiv.). The suspension was brought briefly to the boil and filtered hot. The precipitate was washed with aqueous MeOH and redissolved in conc. HCl. This acid solution was treated with an aqueous solution of Na2S (1.5 mol equiv.) and the precipitated CuS removed by filtration. The filtrate was then basified with conc. ammonia, diluted with water and repeatedly extracted with EtOAc. The combined organic extracts were dried (Na2SO4), filtered and concentrated, and the residue was chromatographed on SiO2. Elution with CH2Cl2 /EtOAc (3:1) yielded 2-[4-(N,N-bis(2-chloroethyl)amino)phenyl]-5-cyanobenzimidazole (XI, n=0) [compound 7 of Table 1] (0.80 g, 40% yield), mp (EtOAc/petroleum ether) 80° C. (dec.). 1H NMR ((CD3)2CO) δ 8.15 (d, J2',3' =9.0 Hz, 2 H, H-2',H-6'), 7.94 (d, J4,6 =1.5 Hz, 1 H, H-4), 7.69 (d, J6,7 =8.5 Hz, 1 H, H-7), 7.50 (dd, J6,7 =8.5 Hz and J4,6 =1.5 Hz, 1 H, H-6), 6.99 (d, J2',3' =9.0 Hz, 2 H, H-3',H-5'), 3.94 (br t, J=7.5 Hz, 4 H, NCH2CH2Cl), 3.83 (br t, J=7.5 Hz, 4 H, NCH2CH2Cl). 13C NMR δ 155.98, 149.75, 143.08, 140.50, 129.62, 126.31, 120.58, 120.13, 118.40, 116.15, 112.93, 105.47, 53.52, 41.43. Anal. (C18H16Cl2N4) C,H,N,Cl.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH2:8][OH:9])=[C:6]([CH:10]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:5]=[C:4]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[N:3]=1.C(N(CC)CC)C.Cl[C:48](Cl)([O:50]C(=O)OC(Cl)(Cl)Cl)Cl>C1COCC1>[CH2:33]([O:32][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[C:4]1[CH:5]=[C:6]([CH:10]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:23])([CH3:24])[CH3:22])[CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:7]2[CH2:8][O:9][C:48](=[O:50])[NH:1][C:2]=2[N:3]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC(C)(C)OC(=O)NC(Cc1ccccc1)c1cc(-c2ccccc2OCc2ccccc2)nc(N)c1CO
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC(Cc1ccccc1)c1cc(-c2ccccc2OCc2ccccc2)nc2c1COC(=O)N2
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 154.1 %

Procedure:
To a cold (0° C.) solution of tert-butyl 1-[2-amino-6-[2-(benzyloxy)phenyl]-3-(hydroxymethyl)-4-pyridinyl]-2-phenylethylcarbamate (0.210 g, 0.400 mmol) in THF (3.0 mL) including triethylamine (0.167 mL, 1.199 mmol) was added dropwise a solution of triphosgene (0.059 g, 0.200 mmol) in THF (1.0 mL). After stirred at 0° C. for 45 min, the mixture was allowed to warm to room temperature, and the stirring was continued for 30 min. The reaction mixture was cooled at 0° C., and then quenched with saturated aqueous NaHCO3 solution. The resulting mixture was extracted with ethyl acetate and water. The separated organic phase was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (hexane:ethyl acetate, 2:1) to give tert-butyl 1-{7-[2-(benzyloxy)phenyl]-2-oxo-1,4-dihydro-2H-pyrido[2,3-d][1,3]oxazin-5-yl}-2-phenylethylcarbamate as a colorless oil (0.170 g, yield; 77%).