Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:17]([O:19][CH3:20])=[O:18])[C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH:15]=O)=[CH:11][C:12]=3[C:13]=2[N:14]=1.[NH:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>CN(C=O)C.C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([C:17]([O:19][CH3:20])=[O:18])[C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH2:15][N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)=[CH:11][C:12]=3[C:13]=2[N:14]=1
Reactant: C1COCCN1
Reactant: COC(=O)c1cc(Br)nc2c1[nH]c1ccc(C=O)cc12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: COC(=O)c1cc(Br)nc2c1[nH]c1ccc(CN3CCOCC3)cc12
Reaction time: 0.08 h
Yield: 59 %

Procedure:
A suspension of methyl 2-bromo-8-formyl-5H-pyrido[3,2-b]indole-4-carboxylate (200 mg, 0.600 mmol) in DMF (1 mL) was stirred for 5 min and then diluted with DCM (10 mL). Morpholine (0.063 mL, 0.720 mmol) was added and the suspension was cooled in an ice bath. Sodium triacetoxyborohydride (344 mg, 1.62 mmol) was added and the suspension was left stirring for 0.5 hr. Acetic acid (0.069 mL, 1.20 mmol) was then added and the bath removed. The reaction was left stirring at RT overnight. It was diluted with DCM and washed with sat. aq. NaHCO3 solution followed by water (2×). After drying with sodium sulfate, the solvent was removed and radial chromatography (step gradient elution with DCM containing 0 to 3% MeOH) afforded methyl 2-bromo-8-(morpholinomethyl)-5H-pyrido[3,2-b]indole-4-carboxylate (143 mg, 0.354 mmol, 59% yield) as dark green solid. MS (ESI) m/z 436.10 (M+H). 1H NMR (400 MHz, chloroform-d) δ ppm 9.55 (1H, br. s.), 8.27 (1H, s), 7.94 (1H, s), 7.56 (1H, dd, J=8.31, 1.51 Hz), 7.45 (1H, d, J=8.31 Hz), 4.04 (3H, s), 3.66-3.74 (4H, m), 3.64 (2H, s), 2.46 (4H, br. s.).
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][C@H:8]1CC(=C)C[O:10][C@@H:9]1[C:15]1[CH:20]=[C:19]([F:21])[C:18]([F:22])=[CH:17][C:16]=1[F:23])([CH3:4])([CH3:3])[CH3:2].C[N+]1([O-])CC[O:29]CC1.S(=O)(=O)(O)[O-].[Na+].C(OCC)(=O)C.[C:45]([OH:49])([CH3:48])([CH3:47])[CH3:46]>CC(C)=O.O.[Os](=O)(=O)(=O)=O>[OH:49][C:45]1([CH2:48][OH:29])[CH2:47][O:10][C@H:9]([C:15]2[CH:20]=[C:19]([F:21])[C:18]([F:22])=[CH:17][C:16]=2[F:23])[C@@H:8]([NH:7][C:6](=[O:24])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:46]1
Reactant: C=C1CO[C@H](c2cc(F)c(F)cc2F)[C@@H](NC(=O)OC(C)(C)C)C1
Reactant: C[N+]1([O-])CCOCC1
Reactant: CC(C)(C)O
Agent: O=[Os](=O)(=O)=O
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@H]1CC(O)(CO)CO[C@@H]1c1cc(F)c(F)cc1F
Reaction time: 48 h

Procedure:
To a solution of tert-butyl[(2R,3S)-5-methylene-2-(2,4,5-trifluorophenyl)tetrahydro-2H-pyran-3-yl]carbamate (203 mg, 0.59 mmol) in tert-butyl alcohol (6 mL), acetone (3 mL) and water (1.5 mL) was added osmium tetroxide (0.113 mL of 2.5% solution in tert-butyl alcohol, 0.009 mmol). The resultant mixture was stirred at room temperature for 10 minutes and then treated with N-methylmorpholine N-oxide (92 mg, 0.79 mmol) and stirred. After two days, the reaction mixture was treated with aqueous sodium bisulfate solution (5 mL, 2.0N) followed after 10 min by ethyl acetate. The organic layer was washed successively with 2N hydrochloric acid and saturated aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate, filtered and evaporated to yield tert-butyl [(2R,3S)-5-hydroxy-5-(hydroxymethyl)-2-(2,4,5-trifluorophenyl)tetrahydro-2H-pyran-3-yl]carbamate which was used in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C@H:6]([C:11]([OH:13])=O)[CH2:7][C@H:8]([OH:10])[CH:9]=1)=[O:4].[C:14]([O:18][C:19]([C@@:21]1([NH2:26])[CH2:23][C@H:22]1[CH:24]=[CH2:25])=[O:20])([CH3:17])([CH3:16])[CH3:15].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[CH:6]([C:11](=[O:13])[NH:26][C@:21]2([C:19]([O:18][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:20])[CH2:23][C@H:22]2[CH:24]=[CH2:25])[CH2:7][CH:8]([OH:10])[CH:9]=1)=[O:4]
Reactant: COC(=O)C1=C[C@@H](O)C[C@H]1C(=O)O
Reactant: C=C[C@@H]1C[C@]1(N)C(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C=C[C@@H]1C[C@]1(NC(=O)C1CC(O)C=C1C(=O)OC)C(=O)OC(C)(C)C
Temperature: 0 °C

Procedure:
To an ice cooled solution of 28 (50 mg, 37 mmol) and (1R,2S)-1-amino-2-vinyl-cyclopropane carboxylic acid tert-butyl ester in DMF (5 mL), DIPEA (47 mmol) and HATU (47 mmol) were added. After two hours the solution was concentrated and purified using column chromatography (toluene/ethyl acetate 3:1). This gave the title compound as a slightly yellow oil (50 mg, 38%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:41])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][C:24]([C:27](=[O:31])[NH:28][O:29][CH3:30])([CH3:26])[CH3:25])[CH2:14][C:13](=O)[NH:12][CH:11]3[C:33]3[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:34]=3[CH3:40])[C:5]2=[CH:4][CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:51])=CC=1>C1COCC1.C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:41])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][C:24]([C:27](=[O:31])[NH:28][O:29][CH3:30])([CH3:26])[CH3:25])[CH2:14][C:13](=[S:51])[NH:12][CH:11]3[C:33]3[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:34]=3[CH3:40])[C:5]2=[CH:4][CH:3]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CONC(=O)C(C)(C)Oc1ccc(Cl)cc1C1CC(=O)NC(c2cc(F)ccc2C)C12C(=O)Nc1cc(Cl)ccc12
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CONC(=O)C(C)(C)Oc1ccc(Cl)cc1C1CC(=S)NC(c2cc(F)ccc2C)C12C(=O)Nc1cc(Cl)ccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 38.6 %

Procedure:
A mixture of racemic (2′S, 3S, 4′R)-6-chloro-4′-[5-chloro-2-(1-methoxycarbamoyl-1-methyl-ethoxy)-phenyl]-2′-(5-fluoro-2-methyl-phenyl) spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (25 mg, 0.042 mmol) and Lawesson's reagent (33 mg, 0.084 mmol) in THF (1 mL) was stirred at room temperature for 1 h, and then diluted with toluene (10 mL). The mixture was concentrated and the residue was washed with DCM twice. The DCM solutions were combined and concentrated. The residue was purified by flash column to give the title compound as white solid (10 mg).
Reaction SMILES: I[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([NH:12][C:13]([CH:15]3[CH2:17][CH2:16]3)=[O:14])[N:8]=[CH:9]2)=[CH:4][CH:3]=1.N1C2C(=CC=C3C=2N=CC=C3)[CH:21]=[CH:20][CH:19]=1.C(=O)([O-])[O-:33].[Cs+].[Cs+]>C(O)(C)C.ClCCl.[Cu]I>[CH:20]([O:33][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([NH:12][C:13]([CH:15]3[CH2:17][CH2:16]3)=[O:14])[N:8]=[CH:9]2)=[CH:4][CH:3]=1)([CH3:21])[CH3:19]
Reactant: c1cnc2c(c1)ccc1cccnc12
Reactant: O=C(Nc1cc2ccc(I)cc2cn1)C1CC1
Reactant: O=C([O-])[O-]
Agent: [Cu]I
Agent: [Cs+]
Solvent: ClCCl
Solvent: CC(C)O
Product: CC(C)Oc1ccc2cc(NC(=O)C3CC3)ncc2c1
Temperature: 210 °C
Reaction time: 5 h
Yield: 7 %

Procedure:
A mixture of N-(7-iodoisoquinolin-3-yl)cyclopropanecarboxamide (338 mg, 1.0 mmol), 1,10-phenanthroline (180 mg, 1.0 mmol), copper(I) iodide (190 mg, 1.0 mmol) and cesium carbonate (422.5 mg, 1.3 mmol) in isopropanol (25 mL) were stirred at 210° C. for 5 hours under nitrogen in a sealed stainless container. After being cooled to room temperature, the mixture was diluted with dichloromethane and filtered through a pad of Celite and filter cake was washed with dichloromethane. The combined filtrates were concentrated and purified by prep-HPLC to give product (18.9 mg, 26%). LCMS (ESI): RT (min)=0.967, M+H+=271.1, method=A. 1H NMR (400 MHz, CDCl3) δ 8.80 (s, 1H), 8.45 (s, 1H), 8.28 (s, 1H), 7.68 (d, J=9.2 Hz, 1H), 8.02 (t, J=0.8 Hz, 1H), 7.84 (d, J=8.8 Hz, 1H), 7.53 (dd, J=1.6, 8.4 Hz, 1H), 7.38-7.31 (m, 5H), 2.09-1.99 (m, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][CH:7]=1)=[O:5])[CH3:2].[H-].[Na+].[CH3:19][O:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25]Cl)=[CH:23][CH:22]=1>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([CH2:25][C:24]2[CH:27]=[CH:28][C:21]([O:20][CH3:19])=[CH:22][CH:23]=2)[CH:7]=1)=[O:5])[CH3:2]
Reactant: COc1ccc(CCl)cc1
Reactant: CCOC(=O)c1c[nH]c2ccccc2c1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(Cc2ccc(OC)cc2)c2ccccc2c1=O
Yield: 66.6 %

Procedure:
Experimental conditions analogous to those described for Step 3 of Example 1, from 03.00 g (13.8 mmol) of 4-oxo-1,4-dihydro-quinoline-3-carboxylic acid ethyl ester, 0.66 g (16.6 mmol) of 60% sodium hydride, 2.60 g (16.6 mmol) of 4-methoxybenzyl chloride in 30 mL DMF to give 3.10 g of the product as an off-white solid.
Reaction SMILES: O[C:2]1[CH:7]=C(O)[N:5]=[C:4]([CH3:9])[N:3]=1.P(Cl)(Cl)([Cl:12])=O.Cl[CH2:16][Cl:17]>>[Cl:12][C:2]1[CH:7]=[C:16]([Cl:17])[N:5]=[C:4]([CH3:9])[N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: ClCCl
Reactant: Cc1nc(O)cc(O)n1
Product: Cc1nc(Cl)cc(Cl)n1
Temperature: 95 °C

Procedure:
4,6-Dihydroxy-2-methylpyrimidine 21 (1.03 g, 8.1 mmol) is suspended in 2.5 mL phosphorus oxychloride (27.3 mmol). The mixture is heated to 95° C. for 18 hours. Upon cooling, the mixture is diluted with dichloromethane (100 mL) and filtered. It is then washed with water, saturated aqueous sodium bicarbonate and brine, then concentrated to yield 4,6-dichloro-2-methylpyrimidine 22 as a white powder. 1H-NMR (400 MHz, CDCl3) δ=7.45 (s, 1H), 2.77 (s, 3H). MS calculated for C5H5Cl2N2 (M+H+) 162.99. found 163.2.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[CH:10]([Mg]Cl)([CH3:12])[CH3:11].C(=O)C1C=CC=CC=1>C1COCC1>[CH2:12]([C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1)[CH:10]=[CH2:11]
Reactant: CC(C)[Mg]Cl
Reactant: N#Cc1ccc(Br)cc1
Solvent: O=Cc1ccccc1
Solvent: C1CCOC1
Product: C=CCc1ccc(C#N)cc1
Yield: 81 %

Procedure:
Highly substituted chloro and methoxy aryl bromides can readily be converted into the desired Grignard reagents 3i, j. After the reaction with ClPPh2 and oxidative work-up, the phosphine oxides 2ia, ja are obtained in good yields (entry 15, 16). This type of compound is of interest in relation with P-ligands for asymmetric catalysis.[5] Also functions like a cyano group are tolerated. Thus, the reaction of 4-bromobenzonitrile in THF at −7° C. leads to the desired arylmagnesium reagent (3d) in only 50% conversion using i-PrMgCl whereas over 90% is observed with i-PrMgCl•LiCl (Scheme 3). The addition of benzaldehyde provides the alcohol 2da in 81% yield whereas allylation of arylmagnesium reagent (3d) with allyl bromide leads to the corresponding 4-allylbenzonitrile in 92% yield (entry 5,6 of Table 1). See FIG. 3 for additional information.
Reaction SMILES: [C:1]([Si:5]([CH3:14])([CH3:13])[O:6][C@H:7]1[CH2:11][CH2:10][C@H:9](O)[CH2:8]1)([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.[Cl:48][C:49]1[CH:50]=[C:51]2[C:56](=[O:57])[NH:55][C:53](=[O:54])[C:52]2=[CH:58][C:59]=1[Cl:60]>CC1CCCO1>[C:1]([Si:5]([CH3:14])([CH3:13])[O:6][C@@H:7]1[CH2:11][CH2:10][C@H:9]([N:55]2[C:56](=[O:57])[C:51]3[C:52](=[CH:58][C:59]([Cl:60])=[C:49]([Cl:48])[CH:50]=3)[C:53]2=[O:54])[CH2:8]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C1NC(=O)c2cc(Cl)c(Cl)cc21
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@H](O)C1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC1CCCO1
Product: CC(C)(C)[Si](C)(C)O[C@@H]1CC[C@H](N2C(=O)c3cc(Cl)c(Cl)cc3C2=O)C1
Reaction time: 8 h

Procedure:
To a round bottomed flask was added trans 3-(tert-butyl-dimethyl-silanyloxy)-cyclopentanol (1.0 g, 4.62 mmol, prepared from WO2008065021), triphenylphosphine (1.52 g, 5.76 mmol) and 2-methyltetrahydrofuran (120 mL). Diisopropyl azodicarboxylate (1.23 mL, 6.25 mmol) was added over two minutes via syringe followed by 4,5-dichlorophthalimide (1.35 g, 6.25 mmol). The reaction was stirred overnight and evaporated. The reaction was repeated and the combined material was purified by column chromatography (160 g SiO2, EtOAc in hexane) to give cis 2-[3-(tert-butyl-dimethyl-silanyloxy)-cyclopentyl]-5,6-dichloro-isoindole-1,3-dione, a yellowish solid (2.0 gm, 52% yield)
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[C:11]1(C(C)C)[CH:16]=CC=C[CH:12]=1>>[CH:11]([C:9]1[C:10]2[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=2)[CH:6]=[CH:7][CH:8]=1)([CH3:16])[CH3:12]
Reactant: CC(C)c1ccccc1
Reactant: c1ccc2ccccc2c1
Product: CC(C)c1cccc2ccccc12

Procedure:
Reaction was carried out as in Example 4, but by reacting naphthalene with cumene in a molar ratio of 1 to 0.8 for 4 hours. Yield of isopropylnaphthalene obtained was 37%%, with an isomer distribution of 92% β- and 8% α.
Reaction SMILES: [NH2:1][CH:2]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[O:37][CH:38]([F:40])[F:39])[C:3]1[N:7]2[CH:8]=[C:9]([C:12]3[CH:13]=[N:14][C:15]([N:18]4[CH2:23][CH2:22][C:21]([CH3:29])([C:24]([O:26]CC)=[O:25])[CH2:20][CH2:19]4)=[N:16][CH:17]=3)[CH:10]=[CH:11][C:6]2=[N:5][C:4]=1[CH3:30].[OH-].[Na+:42]>C1COCC1.CO>[NH2:1][CH:2]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[O:37][CH:38]([F:39])[F:40])[C:3]1[N:7]2[CH:8]=[C:9]([C:12]3[CH:13]=[N:14][C:15]([N:18]4[CH2:19][CH2:20][C:21]([CH3:29])([C:24]([O-:26])=[O:25])[CH2:22][CH2:23]4)=[N:16][CH:17]=3)[CH:10]=[CH:11][C:6]2=[N:5][C:4]=1[CH3:30].[Na+:42]
Reactant: CCOC(=O)C1(C)CCN(c2ncc(-c3ccc4nc(C)c(C(N)c5ccccc5OC(F)F)n4c3)cn2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1nc2ccc(-c3cnc(N4CCC(C)(C(=O)[O-])CC4)nc3)cn2c1C(N)c1ccccc1OC(F)F
Temperature: 60 °C
Yield: 90.5 %

Procedure:
To a suspension of Example 300 (0.155 g, 0.2815 mmol) in THF (1 mL) and methanol (1 mL) was added 1.0M aqueous sodium hydroxide solution (0.27 mL, 0.28 mmol) and the mixture was heated at 60° C. for a total of 18 h. The mixture was concentrated in vacuo and re-dissolved in water (10 mL), then frozen and freeze-dried, to afford the title compound (0.138 g, 90%) as an off white solid. δH (400 MHz, DMSO-d6) 8.62 (d, 1H, J 0.2 Hz), 8.54 (s, 2H), 8.04 (m, 1H), 7.42 (m, 3H), 7.11 (m, 1H), 5.87 (m, 1H), 4.32 (m, 2H), 3.25 (m, 2H), 2.42 (d, 2H, J 5.6 Hz), 2.20 (s, 3H), 2.08 (m, 2H), 1.10 (m, 2H), 0.99 (s, 3H). LCMS (pH 3): MH+ 523.8, RT 1.48 minutes.
Reaction SMILES: [C:1]([NH:8][CH:9]([CH2:21][OH:22])[CH:10]=[CH:11][CH:12]1[C:16]([CH3:18])([CH3:17])[CH2:15][CH2:14][C:13]1([CH3:20])[CH3:19])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH3:23]OS(OC)(=O)=O.O>C(Cl)Cl>[C:1]([NH:8][CH:9]([CH2:21][O:22][CH3:23])[CH:10]=[CH:11][CH:12]1[C:13]([CH3:20])([CH3:19])[CH2:14][CH2:15][C:16]1([CH3:18])[CH3:17])([O:3][C:4]([CH3:6])([CH3:5])[CH3:7])=[O:2]
Reactant: CC(C)(C)OC(=O)NC(C=CC1C(C)(C)CCC1(C)C)CO
Reactant: COS(=O)(=O)OC
Solvent: O
Solvent: ClCCl
Product: COCC(C=CC1C(C)(C)CCC1(C)C)NC(=O)OC(C)(C)C

Procedure:
A solution of 2,2,5,5-tetramethylcyclopentylmethyl bromide in ether is added slowly to magnesium turnings until the Grignard begins to form. The remainder of the alkyl bromide is then added and the mixture stirred until all the magnesium dissolved. At 0° C. a solution of N-Boc-0-methyl-D-serinal is quenched with 1M HCl, and extracted with ether, and the extracts are evaporated. The residue is dissolved in dioxane and 2M H2SO4 is added. The mixture is heated until the alcohol is dehydrated as shown by thin layer chromatography. Water is added and the mixture is extracted with ether. The organic layer is dried over MgSO4 and is evaporated to give N-Boc-3-amino-4-methoxy-1-(2,2,5,5-tetramethylcyclopentyl)--butene and some N-Boc-3-amino-4-hydroxy-1-(2,2,5,5-tetramethylcyclopentyl)-1-butene. This mixture is dissolved in methylene chloride and is methylated with dimethylsulfate. Water is added and the mixture is extracted with ether. The organic layer is dried over MgSO4 and is evaporated to give N-Boc-3-amino-4-methoxy-1-(2,2,5,5-tetramethylcyclopentyl)-1-butene.
Reaction SMILES: [Cl-].[CH3:2][O:3][CH3:4].[C:5]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(C)([O-])C.[K+].[Br:30][CH:31]1[C:36]2([C:39]3[CH:44]=[CH:43][C:42]([Cl:45])=[CH:41][CH:40]=3)[CH2:37][CH2:38][C:33](C=O)([CH2:34][O:35]2)[CH2:32]1>O1CCCC1>[Br:30][CH:31]1[C:36]2([C:39]3[CH:44]=[CH:43][C:42]([Cl:45])=[CH:41][CH:40]=3)[CH2:37][CH2:38][C:33]([CH:5]=[CH:2][O:3][CH3:4])([CH2:34][O:35]2)[CH2:32]1
Reactant: COC
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: O=CC12CCC(c3ccc(Cl)cc3)(OC1)C(Br)C2
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC=CC12CCC(c3ccc(Cl)cc3)(OC1)C(Br)C2
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 95 %

Procedure:
To a solution of triphenylphosphine methoxymethane chloride (3.51 g, 10.24 mmol) in tetrahydrofuran (20 ml) under nitrogen at room temperature, was added potassium t-butoxide (1.149 g, 10.24 mmol). The reddish solution was stirred at room temperature for 90 minutes. Then a solution of 6-bromo-1-(4-chloro-phenyl)-2-oxa-bicyclo[2.2.2]octane-4-carbaldehyde (2.25 g, 6.83 mmol) in tetrahydrofuran (6 ml) was added to the reaction mixture. The reaction mixture was stirred at room temperature for 10 minutes and then quenched with water (2 ml). The mixture was partitioned between brine (15 ml) and ethyl acetate (60 ml). The aqueous layer was extracted with ethyl acetate (2×30 ml) and the combined organic extracts were washed with brine, dried over Na2SO4, and concentrated. The residue was purified by flash chromatography (heptanes/acetone 2/1) to afford the cis and trans mixtures of 6-bromo-1-(4-chloro-phenyl)-4-(2-methoxy-vinyl)-2-oxa-bicyclo[2.2.2]octane (2.32 g, 95%) as colorless oil. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.74-2.99 (m, 6H) 3.54 (3.89 (m, 4H) 3.91-6.36 (m, 5H) 7.28-7.43 (m, 4H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C@H:19]([CH3:21])[NH2:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[O:28]1[CH:32]=[CH:31][CH:30]=[C:29]1[CH2:33][N:34]=[C:35]=[S:36].O>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[C@@H:19]([NH:20][C:35]([NH:34][CH2:33][C:29]4[O:28][CH:32]=[CH:31][CH:30]=4)=[S:36])[CH3:21])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: S=C=NCc1ccco1
Reactant: C[C@H](N)[C@H](Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccccc1
Solvent: ClCCl
Solvent: O
Product: C[C@H](NC(=S)NCc1ccco1)[C@H](Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccccc1
Yield: 76.8 %

Procedure:
(αS,βR)-β-{[1-(4-Fluorophenyl)-1H-indazole-5-yl]oxy}-α-methylbenzeneethanamine (50 mg, 0.14 mmol), as described in Example 1, is dissolved in 0.89 mL dichloromethane and furylmethylisothiocyanate (19.3 mg, 0.14 mmol) is dropwise added. After stirring for 90 min at r.t. water (5 mL) is added and the reaction mixture extracted once with ethyl acetate (50 mL). The organic phase is washed with water (10 mL) and dried over Na2SO4. After filtration the solvent is removed and the residue purified by chromatography (silicagel, eluents: hexane/ethylacetate). 53.8 mg (77.7%) of the title compound are obtained.
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)(=O)CCCCCCCCCCCCC.N1C(C)=CC=CC=1C.[C:34]([C:42]1[CH:43]=[N:44][C:45]2[C:50]([C:51]=1[C:52]1[CH:53]=[C:54]([NH:58]CC3C=CC(CC([O-])=O)=CC=3)[CH:55]=[CH:56][CH:57]=1)=[CH:49][CH:48]=[CH:47][C:46]=2[C:70]([F:73])([F:72])[F:71])(=[O:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>C(OCC)(=O)C.CC([O-])=O.CC([O-])=O.[Cu+2].C1(C)C=CC=CC=1>[NH:58]([C:54]1[CH:53]=[C:52]([C:51]2[C:50]3[C:45](=[C:46]([C:70]([F:73])([F:71])[F:72])[CH:47]=[CH:48][CH:49]=3)[N:44]=[CH:43][C:42]=2[C:34]([C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)=[O:41])[CH:57]=[CH:56][CH:55]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OB(O)c1ccccc1
Reactant: O=C([O-])Cc1ccc(CNc2cccc(-c3c(C(=O)c4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: CCCCCCCCCCCCCC(=O)O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: Cc1cccc(C)n1
Product: O=C(c1ccccc1)c1cnc2c(C(F)(F)F)cccc2c1-c1cccc(Nc2ccccc2)c1
Reaction time: 24 h
Yield: 118.6 %

Procedure:
Phenylboronic acid (0.12 g, 1.0 mmol), Cu(OAc)2 (0.036 g, 0.2 mmol), and myristic acid (0.046 g, 0.2 mmol) were combined in a 100-mL round-bottom flask with a large stir bar. A rubber septum was attached, and dry toluene (2 mL), 2,6-lutidine (0.116 mL, 1.0 mmol), and {4-[({3-[3-benzoyl-8-(trifluoromethyl)quinolin-4-yl]phenyl}amino)methyl]phenyl}acetate (0.045 g, 0.09 mmol) were successively added. The resulting mixture was stirred at a high rate for 24 h, diluted with ethyl acetate (10 mL), filtered through a plug of silica gel, and then purified by semi-preparative HPLC (Column: Phenomenex C18 Luna 21.6 mm×60 mm, 5 μM; Solvent A: Water (0.1% TFA buffer); Solvent B: Acetonitrile (0.1% TFA buffer); Solvent Gradient: Time 0: 0% B; 10 min: 100% B; Hold 100% B 5 min. Flow Rate: 22.5 mL/min). The product was collected based on UV absorption and concentrated to give the title compound as a yellow solid (0.05 g, 94%). MS (ESI) m/z 469; MS (ESI) m/z 467; HRMS: calcd for C29H19F3N2O, 468.1449; found (ESI, [M−H]−), 467.1362; Anal. Calcd for C29H19F3N2O: C, 74.35; H, 4.09; N, 5.98. Found: C, 74.27; H, 3.72; N, 5.82.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5](I)=[CH:4][N:3]=1.CC1(C)C(C)(C)OB([C:18]2[S:19][CH:20]=[CH:21][CH:22]=2)O1.[CH3:24][O:25][CH2:26][CH2:27][OH:28]>>[Cl:1][C:2]1[N:7]=[C:6]([O:28][CH2:27][CH2:26][O:25][CH3:24])[C:5]([C:20]2[S:19][CH:18]=[CH:22][CH:21]=2)=[CH:4][N:3]=1
Reactant: COCCO
Reactant: Clc1ncc(I)c(Cl)n1
Reactant: CC1(C)OB(c2cccs2)OC1(C)C
Product: COCCOc1nc(Cl)ncc1-c1cccs1

Procedure:
Preparation according to procedures 4b and 3 with the use of 2,4-dichloro-5-iodopyrimidine, 2-methoxy-ethanol and 4,4,5,5-tetramethyl-2-(2-thienyl)-1,3,2-dioxaborolane.
Reaction SMILES: Br.[Br-].[CH3:3][NH:4][CH2:5][CH2:6][CH2:7][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C([Li])CCC.[CH:32]1[C:42]2[C:41](=O)[C:40]3[CH:44]=[CH:45][CH:46]=[CH:47][C:39]=3[CH2:38][O:37][C:36]=2[CH:35]=[CH:34][CH:33]=1.O>O1CCCC1.CCCCCCC>[CH3:3][NH:4][CH2:5][CH2:6]/[CH:7]=[C:41]1\[C:40]2[C:39]([CH2:38][O:37][C:36]3[C:42]\1=[CH:32][CH:33]=[CH:34][CH:35]=3)=[CH:47][CH:46]=[CH:45][CH:44]=2
Reactant: CNCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C1c2ccccc2COc2ccccc21
Agent: Br
Agent: [Br-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCCC
Solvent: O
Product: CNCC/C=C1\c2ccccc2COc2ccccc21
Reaction time: 0.5 h

Procedure:
Desmethyldoxepin is prepared according to the following method. Anhydrous 3-methylaminopropyltriphenylphosphonium bromide hydrobromide (1530 g) prepared as in U.S. Pat. No. 3,509,175, is suspended in 4.5 L dry tetrahydrofuran and 6.0 moles of butyl lithium in heptane is added during 1 hour. After an additional 30 minutes, 483 g of 6,11-dihydrodibenz[b,e]oxepin-11-one, is added to the deep red solution and the reaction is maintained at reflux for 10 hours. Water, 500 mL, is added at room temperature and the solvent is removed in vacuo. The crude residue is treated with 10% hydrochloric acid until acidic (pH 2) and then 1.5 L benzene is added. After stirring, the mixture separates into three phases (an insoluble hydrochloride salt product phase, an aqueous phase and an organic phase). The benzene layer is removed by decantation and the remaining mixture is rendered basic with 10% sodium hydroxide solution and is extracted with 3×1500 mL portions of benzene. The benzene extracts are washed, then dried with anhydrous sodium sulfate and concentrated in a vacuum leaving a solid residue of desmethyldoxepin.
Reaction SMILES: [SH:1][C:2]1[S:3][C:4]2[CH2:14][CH2:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][C:11]=3[O:15][CH2:16][C:17]([O:19]CC)=[O:18])[C:5]=2[N:6]=1.[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH2:22]([S:1][C:2]1[S:3][C:4]2[CH2:14][CH2:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][C:11]=3[O:15][CH2:16][C:17]([OH:19])=[O:18])[C:5]=2[N:6]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)COc1cccc2c1CCc1sc(S)nc1-2
Product: O=C(O)COc1cccc2c1CCc1sc(SCc3ccccc3)nc1-2
Yield: 44 %

Procedure:
Using ethyl [(2-mercapto-4,5-dihydronaphtho[1,2-d]thiazol-6-yl)oxy]acetate and benzyl bromide, the procedure of Example 1 was otherwise repeated to synthesize the title compound. Yield 44%.