Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[C@H:2]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1)[CH3:3].C1C=CC(P([N:28]=[N+:29]=[N-:30])(C2C=CC=CC=2)=O)=CC=1.C1CCN2C(=NCCC2)CC1>C1(C)C=CC=CC=1.CCOC(C)=O>[N:28]([C@@H:2]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1)[CH3:3])=[N+:29]=[N-:30]
Reactant: COC(=O)c1ccc([C@H](C)O)cc1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: C1CCC2=NCCCN2CC1
Product: COC(=O)c1ccc([C@@H](C)N=[N+]=[N-])cc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A solution of (S)-methyl 4-(1-hydroxyethyl)benzoate (24.8 g, 138 mmol) in toluene (300 mL) was cooled in ice-salt bath (bath temp: −10° C.). DPPA (36.3 mL, 168 mmol) was then added dropwise over 15 min (Bath temp was kept at −10° C. during addition). After 5 min, DBU (25.3 mL, 169 mmol) was added over 8 min. The ice in the bath was allowed to melt and the reaction mixture was stirred overnight at RT. The reaction mixture was diluted with EtOAc (200 mL), and washed with 0.1 N HCl aq. (300 mL). The aqueous layer was extracted with EtOAc (100 mL×2) and the combined organic phase was further washed with 0.1N HCl aq. (300 mL×2), 5% NaHCO3 (300 mL×2), and saturated NaCl (300 mL×2). The organic layers was dried over Na2SO4 and concentrated under reduced pressure. The crude product was chromatographed on SiO2 (ISCO: hexane/CH2Cl2=3/1→3/7) to yield the title compound. MS (m/z): 206.2 (m+H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:21]3[C:12](=[CH:13][C:14]4[O:19][CH2:18][CH2:17][O:16][C:15]=4[CH:20]=3)[O:11][CH2:10]2)[C:2]1=[O:22].N1C2C(=CC=CC=2)C2(C3C4C(C=CC=3OC2)=NON=4)C1=O.Br[CH2:45][C:46]1[CH:56]=[CH:55][C:49]([C:50]([O:52][CH2:53][CH3:54])=[O:51])=[CH:48][CH:47]=1.C(OC1C=CC(CCl)=NC=1)C1C=CC=CC=1>>[O:22]=[C:2]1[C:3]2([C:21]3[C:12](=[CH:13][C:14]4[O:19][CH2:18][CH2:17][O:16][C:15]=4[CH:20]=3)[O:11][CH2:10]2)[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[N:1]1[CH2:45][C:46]1[CH:56]=[CH:55][C:49]([C:50]([O:52][CH2:53][CH3:54])=[O:51])=[CH:48][CH:47]=1
Reactant: CCOC(=O)c1ccc(CBr)cc1
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCCO3
Agent: ClCc1ccc(OCc2ccccc2)cn1
Agent: O=C1Nc2ccccc2C12COc1ccc3nonc3c12
Product: CCOC(=O)c1ccc(CN2C(=O)C3(COc4cc5c(cc43)OCCO5)c3ccccc32)cc1

Procedure:
Following the procedure as described in EXAMPLE 9.67 and making non-critical variations using 2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one to replace 7H-spiro[benzofuro[4,5-c][1,2,5]oxadiazole-8,3′-indolin]-2′-one, and ethyl 4-(bromomethyl)benzoate to replace 5-(benzyloxy)-2-(chloromethyl)pyridine, ethyl 4-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)methyl]benzoate was obtained (95%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ 8.03 (d, J=8.4 Hz, 2H), 7.39 (d, J=8.1 Hz, 2H), 7.21-7.16 (m, 2H), 7.03 (t, J=7.5 Hz, 1H), 6.72 (d, J=7.5 Hz, 1H), 6.52 (s, 1H), 6.24 (s, 1H), 5.14 (d, J=15.9 Hz, 1H), 4.95 (d, J=9.0 Hz, 1H), 4.87 (d, J=15.9 Hz, 1H), 4.67 (d, J=8.7 Hz, 1H), 4.36 (q, J=7.1 Hz, 2H), 4.22-4.19 (m, 2H), 4.15-4.12 (m, 2H), 1.38 (t, J=7.1 Hz, 3H); MS (ES+) m/z 458.1 (M+1).
Reaction SMILES: [Cs].C(C1C=C(O)C=C2C=1C(=O)NS2(=O)=O)(C)C.C(Br)C1C=CC=CC=1.[CH2:26]([N:33]1[C:43](=[O:44])[C:42]2[C:37](=[CH:38][C:39]([OH:48])=[CH:40][C:41]=2[CH:45]([CH3:47])[CH3:46])[S:34]1(=[O:36])=[O:35])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.[CH2:49]([N:51]([CH2:55][CH3:56])[C:52](Cl)=[S:53])[CH3:50]>CN(C=O)C>[CH2:26]([N:33]1[C:43](=[O:44])[C:42]2[C:37](=[CH:38][C:39]([O:48][C:52](=[S:53])[N:51]([CH2:55][CH3:56])[CH2:49][CH3:50])=[CH:40][C:41]=2[CH:45]([CH3:46])[CH3:47])[S:34]1(=[O:36])=[O:35])[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: CCN(CC)C(=S)Cl
Reactant: CC(C)c1cc(O)cc2c1C(=O)N(Cc1ccccc1)S2(=O)=O
Agent: BrCc1ccccc1
Agent: CC(C)c1cc(O)cc2c1C(=O)NS2(=O)=O
Agent: [Cs]
Solvent: CN(C)C=O
Product: CCN(CC)C(=S)Oc1cc(C(C)C)c2c(c1)S(=O)(=O)N(Cc1ccccc1)C2=O

Procedure:
Selective N-benzylation of the cesium salt of 4-isopropyl-6-hydroxysaccharin (Preparation 19) with benzyl bromide and reaction of the 2-benzyl-4-isopropyl-6-hydroxysaccharin with N,N-diethylthiocarbamyl chloride in DMF using the procedure described above in Preparation 12 affords 2-benzyl-4-isopropyl-6-(N,N-diethylthiocarbamyloxy)saccharin which, on heating, rearranges to 2-benzyl-4-isopropyl-6-(N,N-diethylcarbamyl-thio)saccharin. The latter, on hydrolysis with alkali, affords 2-benzyl-4-isopropyl-6-mercaptosaccharin which on reaction with methyl iodide, and transfer hydrogenolysis affords 4-isopropyl-6-methylthiosaccharin. Oxidation of the latter with one or two molar equivalents of 3-chloroperbenzoic acid affords 4-isopropyl-6-methyl-sulfinylsaccharin and 4-isopropyl-6-methylsulfonylsaccharin.
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[CH:8][C:7]([CH2:18][CH2:19][CH:20]=O)=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[C:22]1([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[CH:8][C:7]([CH2:18][CH2:19][CH2:20][N:31]2[CH2:32][CH2:33][N:28]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:29][CH2:30]2)=[N:6]1)([CH3:3])([CH3:2])[CH3:4]
Reactant: COc1ccc(-c2cc(CCC=O)nn2C(C)(C)C)cc1
Reactant: c1ccc(N2CCNCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(-c2cc(CCCN3CCN(c4ccccc4)CC3)nn2C(C)(C)C)cc1

Procedure:
125 mg (90%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-tert-butyl-5-(4-methoxyphenyl)-1H-pyrazol-3-yl)propanal (85 mg, 0.297 mmol), 1-phenylpiperazine (0.045 mL, 0.297 mmol), DIPEA (0.078 mL, 0.446 mmol) and NaBH(OAc)3 (189 mg, 0.891 mmol).
Reaction SMILES: BrC(C1C=CC=CC=1)CC.[Mg].[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:15]=1[C:22](O)([CH2:24][CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH3:23].C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(O)C=CC=CC=1>CCOCC>[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:15]=1[CH:22]([CH2:24][CH2:25][CH2:26][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[CH3:23]
Reactant: COc1ccc(OC)c(C(C)(O)CCCc2ccccc2)c1
Agent: CCC(Br)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Mg]
Solvent: CCOCC
Solvent: Oc1ccccc1
Product: COc1ccc(OC)c(C(C)CCCc2ccccc2)c1
Temperature: 25 °C

Procedure:
A solution of 1-bromopropylbenzene (51.7 g., 0.26 mole) in ether (225 ml.) is added dropwise over a one hour period to a refluxing mixture of magnesium (7.32 g.) in ether (78 ml.). The reaction mixture is refluxed for 30 minutes longer and then a solution of 2,5-dimethoxy-acetophenone (50 g.) in ether (60 ml.) is added dropwise and heated to reflux for 1.5 hours. The reaction is quenched by addition of saturated ammonium chloride (250 ml.) the ether layer is separated and the aqueous phase extracted with ether (3×200 ml.). The combined ether extracts are dried over magnesium sulfate and concentrated under vacuum to yield 80.3 g. (100%) of 2-(2'5'-dimethyloxyphenyl)-5-phenyl-2-pentanol as an oil. The oil (78.1 g., 0.26 mole), 21.7 g. of p-toluenesulfonic acid and 1250 ml. of phenol are combined and heated at reflux for one hour, while collecting the water (5.5 ml.) evolved in a Dean-Stark apparatus. The mixture is cooled to room temperature, washed with 200 ml. portions of water, saturated sodium bicarbonate and brine, then dried over magnesium sulfate. The filtered phenol layer yields 75.6 g. of 2-(2',5'-dimethoxyphenyl)-5-phenyl-2-pentene as an orange oil upon evaporation.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([OH:11])([CH3:10])[CH3:9])[CH:5]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][C@@H:13]2[CH3:18])[N:3]=1.CC1(C)C(C)(C)OB([C:27]2[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29][CH:28]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.C(Cl)Cl.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:31][C:30]1[CH:32]=[CH:33][C:27]([C:2]2[N:7]=[C:6]([C:8]([OH:11])([CH3:10])[CH3:9])[CH:5]=[C:4]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][C@@H:13]3[CH3:18])[N:3]=2)=[CH:28][CH:29]=1
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Reactant: C[C@H]1COCCN1c1cc(C(C)(C)O)nc(Cl)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: ClCCl
Solvent: O
Product: C[C@H]1COCCN1c1cc(C(C)(C)O)nc(-c2ccc(N)cc2)n1
Temperature: 80 °C
Reaction time: 6 h
Yield: 60.4 %

Procedure:
Dichlorobis(triphenylphosphine)palladium(II) (0.492 g, 0.70 mmol) was added to 2-[2-chloro-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-4-yl]propan-2-ol (3.81 g, 14.02 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (3.38 g, 15.42 mmol) and sodium carbonate (4.46 g, 42.06 mmol) in DME (80 mL) and water (20.00 mL) under nitrogen. The resulting solution was stirred at 80° C. for 6 hours. The reaction mixture was diluted with DCM (200 mL), and washed with water (400 mL) twice. The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 20 to 60% ethyl acetate in isohexane, to give a material which was further purified by ion exchange chromatography using an SCX column, eluting with 2M ammonia in methanol, to give the desired material as a pink gum (2.78 g).
Reaction SMILES: [NH2:1][NH:2][C:3]([NH2:5])=[S:4].[C:6]([C:8]([CH3:13])([CH3:12])[C:9](O)=O)#[N:7].O=P(Cl)(Cl)Cl>O1CCOCC1.Cl.C(Cl)Cl>[NH2:5][C:3]1[S:4][C:9]([C:8]([CH3:13])([CH3:12])[C:6]#[N:7])=[N:1][N:2]=1
Reactant: CC(C)(C#N)C(=O)O
Reactant: NNC(N)=S
Agent: Cl
Solvent: C1COCCO1
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Product: CC(C)(C#N)c1nnc(N)s1
Temperature: 90 °C
Reaction time: 1 h
Yield: 32.7 %

Procedure:
300 mg (3.29 mmol) of thiosemicarbazide and 370 mg (3.27 mmol) of 2-Cyano-2-methylpropanoic acid are dissolved in dioxane (10.0 mL) and heated to 90° C. 300 μL (3.29 mmol) of POCl3 are added dropwise. The reaction is stirred at 90° C. for 1 h, cooled to RT and diluted with 1 N aq. HCl and DCM. The aq. layer is separated, 4 N aq. NaOH is added to reach pH 8 and then extracted with DCM. Then combined organic layer is washed with brine and dried. The solvent is removed under reduced pressure to afford 180 mg of 2-(5-amino[1,3,4]thiadiazol-2-yl)-2-methyl-propionitrile. Yield: 32%; ESI-MS: 169 [M+H]+; HPLC (Rt): 0.24 min (method B)
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#N)=[CH:4][N:3]=1.C1(C)C=CC=CC=1.CC(C[AlH]CC(C)C)C.[OH:26]S(O)(=O)=O>CO>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([CH:6]=[O:26])=[CH:8][CH:9]=1
Reactant: N#Cc1ccc(Cl)nc1
Reactant: O=S(=O)(O)O
Agent: CC(C)C[AlH]CC(C)C
Solvent: CO
Solvent: Cc1ccccc1
Product: O=Cc1ccc(Cl)nc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 62 %

Procedure:
Combine 6-chloro-nicotino-nitrile (1.00 g, 7.21 mmol) and toluene (24 mL). Cool the resulting solution at 0° C. and add DIBAL-H (1.0 M in toluene, 7.58 mL, 7.58 mmol) dropwise. Stir the resulting red solution at 0° C. for 1 h. Then, add methanol (2 mL) followed by H2SO4 (aq. 2.0 M, 6 mL). Stir for 1 h at rt. Add CHCl3:isopropanol (3/1, 15 mL) and wash with Rochelle's salt solution (20 mL), followed by NaHCO3 (20 mL) and brine. Dry the combined organic layers over magnesium sulfate, filter and concentrate. Purify by flash chromatography (EtOAc/hexanes 10%) to give the title compound (530 mg, 62%).
Reaction SMILES: Br[C:2]1[C:3]([O:37][CH3:38])=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[N:6]=[C:5]2[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[CH:31]=1.CC(C)([O-])C.[Na+].C(=[NH:58])(C1C=CC=CC=1)C1C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1.C(OCC)C>[F:36][C:32]1[CH:31]=[C:30]([C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([NH2:58])[C:3]=3[O:37][CH3:38])[N:7]([C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:6]=2)[CH:35]=[CH:34][CH:33]=1
Reactant: COc1c(Br)ccc2c1c(-c1cccc(F)c1)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: N=C(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: COc1c(N)ccc2c1c(-c1cccc(F)c1)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
A total of 810 mg of 5-bromo-3-(3-fluoro-phenyl)-4-methoxy-1-trityl-1H-indazole obtained in Production Example II-18-a was dissolved in 7.2 ml of toluene, 194 mg of sodium t-butoxide, 0.29 ml of benzophenoneimine, 135 mg of 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl and 74.5 mg of tris(dibenzylideneacetone)bispalladium were added, and the mixture was stirred at 80° C. in an atmosphere of nitrogen gas for 8 hours. The reaction mixture was cooled to room temperature, and diethyl ether was added. The mixture was filtrated through Celite, and the filtrate was evaporated. The resulting residue was dissolved in 7.2 ml of tetrahydrofuran and 0.36 ml of 2 N hydrochloric acid was added, followed by stirring at room temperature for 3 hours. Saturated aqueous sodium hydrogencarbonate solution was added to the reaction mixture and the mixture was extracted with diethyl ether, The resulting organic layer was washed with brine, dried over magnesium sulfate and the solvent was evaporated. The residue was purified and separated by silica gel column chromatography (ethyl acetate:hexane=1:3), to give 426 mg of the title compound as reddish brown crystals.
Reaction SMILES: [S:1]1[CH2:6][CH2:5][S:4][CH:3]=[C:2]1[C:7]([OH:9])=O.S(Cl)([Cl:12])=O>>[S:1]1[CH2:6][CH2:5][S:4][CH:3]=[C:2]1[C:7]([Cl:12])=[O:9]
Reactant: O=C(O)C1=CSCCS1
Reactant: O=S(Cl)Cl
Product: O=C(Cl)C1=CSCCS1

Procedure:
A suspension of 5,6-dihydro-1,4-dithiin-2-carboxylic acid (13.1 g) in thionyl chloride (60 cc) is gradually heated to reflux. After 30 minutes under reflux, the solution obtained is concentrated to dryness at 50° C. under reduced pressure (4 kPa) and the oily residue obtained is washed with cyclohexane (2×100 cc). The decanted oil is dried at 50° C. under reduced pressure (4 kPa). 5,6-Dihydro-1,4-dithiin-2-carbonyl chloride (15.8 g) is thereby obtained, and this is used as it is in the following operation.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[Br:9][C:10]1[CH:11]=[C:12]([CH:15]=[C:16](F)[CH:17]=1)[C:13]#[N:14].C([O-])([O-])=O.[K+].[K+]>CN(C)C(=O)C.CCOC(C)=O.O>[Br:9][C:10]1[CH:11]=[C:12]([CH:15]=[C:16]([O:8][C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[CH:17]=1)[C:13]#[N:14]
Reactant: Oc1ccc(F)cc1
Reactant: N#Cc1cc(F)cc(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: N#Cc1cc(Br)cc(Oc2ccc(F)cc2)c1
Temperature: 160 °C

Procedure:
A mixture of 4-fluorophenol (0.3 g, 2.7 mmol), 3-bromo-5-fluorobenzonitrile (0.53 g, 2.7 mmol), K2CO3 (1.1 g, 8.0 mmol) in N,N-dimethylacetamide (3 mL) was heated to 160° C. for 3 hr. The reaction mixture was cooled to room temperature and diluted with EtOAc and water. The organic layer was separated, dried (MgSO4), concentrated, and purified by chromatography on silica gel (EtOAc/hexanes) to afford 3-bromo-5-(4-fluorophenoxy)benzonitrile.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20](O)=[O:21])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][C:24]=1[NH2:33].C(OC(N1CCN(C2C=CC(C(=O)NC3C=CC=C(C(C)(C)C)C=3)=CC=2)CC1)=O)(C)(C)C>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20](=[O:21])[NH:33][C:24]3[CH:25]=[CH:26][C:27]4[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH:23]=3)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(C(=O)O)cc2)CC1
Reactant: Nc1ccc2ccccc2c1
Agent: CC(C)(C)OC(=O)N1CCN(c2ccc(C(=O)Nc3cccc(C(C)(C)C)c3)cc2)CC1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(C(=O)Nc3ccc4ccccc4c3)cc2)CC1

Procedure:
4-[4-(Naphthalen-2-ylcarbamoyl)-phenyl]-piperazine-1-carboxylic acid tert-butyl ester was synthesized from 4-(4-carboxy-phenyl)-piperazine-1-carboxylic acid tert-butyl ester and naphthalen-2-ylamine in a manner similar to the one described in the synthesis of 4-[4-(3-tert-butyl-phenylcarbamoyl)-phenyl]-piperazine-1-carboxylic acid tert-butyl ester, above. LCMS calcd for C26H29N3O3 (m/e) 431, obsd 432 (M+H).
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]2[N:22]=[C:21]([NH:23][C:24]3[CH:32]=[CH:31][C:30]([C@H:33]4[CH2:38][CH2:37][C@H:36]([OH:39])[CH2:35][CH2:34]4)=[C:29]4[C:25]=3[C:26](=[O:41])[N:27]([CH3:40])[CH2:28]4)[C:20]([C:42]([F:45])([F:44])[F:43])=[CH:19][N:18]=2)=[C:12]([O:46][CH3:47])[CH:11]=1)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].[C:48]([O:52][P:53](N(CC)CC)[O:54][C:55]([CH3:58])([CH3:57])[CH3:56])([CH3:51])([CH3:50])[CH3:49].N1C=NN=N1.C1C=C(Cl)C=C(C(OO)=[O:77])C=1>C(Cl)Cl>[CH2:1]([O:3][P:4]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]2[N:22]=[C:21]([NH:23][C:24]3[CH:32]=[CH:31][C:30]([C@H:33]4[CH2:34][CH2:35][C@H:36]([O:39][P:53]([O:52][C:48]([CH3:49])([CH3:50])[CH3:51])([O:54][C:55]([CH3:56])([CH3:57])[CH3:58])=[O:77])[CH2:37][CH2:38]4)=[C:29]4[C:25]=3[C:26](=[O:41])[N:27]([CH3:40])[CH2:28]4)[C:20]([C:42]([F:43])([F:44])[F:45])=[CH:19][N:18]=2)=[C:12]([O:46][CH3:47])[CH:11]=1)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2]
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc([C@H]4CC[C@H](O)CC4)c4c3C(=O)N(C)C4)n2)c(OC)c1)OCC
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCN(CC)P(OC(C)(C)C)OC(C)(C)C
Agent: c1nnn[nH]1
Solvent: ClCCl
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc([C@H]4CC[C@H](OP(=O)(OC(C)(C)C)OC(C)(C)C)CC4)c4c3C(=O)N(C)C4)n2)c(OC)c1)OCC
Temperature: -78 °C
Reaction time: 14 h

Procedure:
A solution of diethyl(4-{[4-{[7-(trans-4-hydroxycyclohexyl)-2-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-yl]amino}-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate (100.0 mg, 0.15 mmol), di(tert-butyl)N,N-diethylphosphoramidite (367.9 mg, 1.48 mmol), and 1H-tetrazole (113.7 mg, 1.62 mmol) in DCM (5 mL) was stirred at rt for 18 h. The mixture was then cooled to −78° C. and mCPBA (43.65 mg, 0.18 mmol) was added. The resulting mixture was allowed to warm to rt during 1 h, and stirred for another 14 h. The mixture was concentrated in vacuo and the residue was purified by silica gel chromatography (5% 7 N ammonia in MeOH in DCM) to afford 38.5 mg of the desired product. 1H NMR (CDCl3, 400 MHz): δ=1.27 (t, J=7.2 Hz, 6H), 1.51 (s, 18H), 1.60-1.71 (m, 4H), 1.90-1.93 (m, 2H), 2.30-2.32 (m, 2H), 2.52 (dt, J=2.4, 7.2 Hz, 1H), 3.18 (d, J=21.60 Hz, 2H), 3.22 (s, 3H), 3.93 (s, 3H), 4.00-4.09 (m, 4H), 4.38 (s, 2H), 6.88 (dt, J=2.0, 8.4 Hz, 1H), 6.95 (t, J=2.0 Hz, 1H), 7.32 (d, J=8.8 Hz, 1H), 7.65 (s, 1H), 8.28 (d, J=7.6 Hz, 1H), 8.39 (s, 1H), 8.64 (d, J=8.8 Hz, 1H), 10.51 (s, 1H). MS (ES+): m/z 870.39 [MH+]. HPLC: tR=4.67 min (ZQ3, polar—5 min).
Reaction SMILES: [CH:1]1([CH2:7][O:8][C:9]([NH:11][C@H:12]([C:21](O)=[O:22])[CH2:13][C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)OCC.C(N(CC)CC)C>O1CCCC1>[CH:1]1([CH2:7][O:8][C:9]([NH:11][C@H:12]([CH2:21][OH:22])[CH2:13][C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(N[C@@H](Cc1ccc(O)cc1)C(=O)O)OCC1CCCCC1
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(N[C@H](CO)Cc1ccc(O)cc1)OCC1CCCCC1
Yield: 75.1 %

Procedure:
In 30 ml of tetrahydrofuran, 3.2 g of N-(cyclohexylmethoxycarbonyl)-tyrosine was dissolved. To the solution were added 1.1 g of ethyl chlorocarbonate and 1.0 g of triethylamine while cooling with ice and stirring. After stirring the mixture for 10 minutes, the precipitate was removed by filtration. The filtrate was added to a suspension of 1.0 g of sodium borohydride and 10 ml of tetrahydrofuran cooled with ice. The mixture was stirred for two hours, then neutralized with hydrochloric acid and concentrated in vacuo. The residue was extracted with ethyl acetate and the extract was washed with water, dried and concentrated to dryness. The residue was crystallized from ethyl acetate-petroleum ether to give 2.3 g of N-(cyclohexylmethoxycarbonyl)-tyrosinol with a melting point of 121°-126° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:17](=[CH:18][C:19]=1[F:20])[C:16]1[C:7](=[C:8]3[C:13](=[CH:14][CH:15]=1)[CH:12]=[C:11]([OH:21])[CH:10]=[CH:9]3)[C:6](OC)([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH2:30][N:31]3[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]3)=[CH:24][CH:23]=1)[O:5]2.C(N(CC)CC)C.FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]2[C:17](=[CH:18][C:19]=1[F:20])[C:16]1[C:7](=[C:8]3[C:13](=[CH:14][CH:15]=1)[CH:12]=[C:11]([OH:21])[CH:10]=[CH:9]3)[CH:6]([C:22]1[CH:23]=[CH:24][C:25]([O:28][CH2:29][CH2:30][N:31]3[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36]3)=[CH:26][CH:27]=1)[O:5]2
Reactant: COC1(c2ccc(OCCN3CCCCC3)cc2)Oc2cc(F)c(F)cc2-c2ccc3cc(O)ccc3c21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: Oc1ccc2c3c(ccc2c1)-c1cc(F)c(F)cc1OC3c1ccc(OCCN2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 18 %

Procedure:
Dissolve 8,9-Difluoro-5-methoxy-5-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-5H-6-oxa-chrysen-2-ol (1.1 gm, 21. mmoles) in 30 ml of methylene chloride and add 2 ml of triethylamine and 2 ml of trifluoroacetic acid. Stir at room temperature for 1 hour, neutralize with sodium bicarbonate solution and separate the organic layer. Wash the water layer with methylene chloride and combine the organic layers. Dry the liquid over sodium sulfate and remove the solvent. Purify as described in Preparation 17 to obtain an 18% yield of the racemic. Obtain the individual enantiomers by chiral chromatography using a Chiralpak AD column eluting with ethanol containing 0.2% dimethylethylamine and monitoring at 225 nm.
Reaction SMILES: [C:1]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:6]=[CH:5][C:4]([CH2:7][O:8][C:9]2[CH:18]=[C:17]3[C:12]([CH2:13][CH:14]([CH2:19][CH2:20][N:21]([CH3:23])[CH3:22])[CH2:15][NH:16]3)=[CH:11][CH:10]=2)=[CH:3][CH:2]=1.[CH3:30][S:31]([Cl:34])(=[O:33])=[O:32]>N1C=CC=CC=1.O>[ClH:34].[C:1]1([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:2]=[CH:3][C:4]([CH2:7][O:8][C:9]2[CH:18]=[C:17]3[C:12]([CH2:13][CH:14]([CH2:19][CH2:20][N:21]([CH3:23])[CH3:22])[CH2:15][N:16]3[S:31]([CH3:30])(=[O:33])=[O:32])=[CH:11][CH:10]=2)=[CH:5][CH:6]=1
Reactant: CS(=O)(=O)Cl
Reactant: CN(C)CCC1CNc2cc(OCc3ccc(-c4ccccc4)cc3)ccc2C1
Solvent: O
Solvent: c1ccncc1
Product: CN(C)CCC1Cc2ccc(OCc3ccc(-c4ccccc4)cc3)cc2N(S(C)(=O)=O)C1
Product: Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 7-(4-biphenylyl)methoxy-3-[2-(N,N-dimethylamino) ethyl]-1,2,3,4-tetrahydroquinoline (110 mg) in pyridine (5 ml) was added methanesulfonyl chloride (0.03 ml) in an ice bath. The reaction mixture was stirred at room temperature for 3 hr. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, dried, and concentrated. The residue was purified by alumina column chromatography (eluent: ethyl acetate: hexane=1:2) and converted into its hydrochloride, which was then recrystallized from ethanol-ethyl acetate to obtain the titled compound (88 mg).