Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH2:5][N:6]1[C:14](=[O:15])[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([N+:16]([O-])=O)[CH:12]=2)[C:7]1=[O:19])[CH3:2]>C(O)(=O)C.[Pd]>[CH2:1]([O:3][C:4](=[O:20])[CH2:5][N:6]1[C:14](=[O:15])[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([NH2:16])[CH:12]=2)[C:7]1=[O:19])[CH3:2]
Reactant: CCOC(=O)CN1C(=O)c2ccc([N+](=O)[O-])cc2C1=O
Agent: [Pd]
Solvent: CC(=O)O
Product: CCOC(=O)CN1C(=O)c2ccc(N)cc2C1=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 78.5 %

Procedure:
10% Palladium/C (50% wet) solid (2.0 g) was added to a solution mixture of (5-nitro-1,3-dioxo-1,3-dihydro-isoindol-2-yl)-acetic acid ethyl ester (10.0 g) in glacial acetic acid (150 ml). Stirred vigorously under H2 (balloon pressure) at room temperature overnight (18 h). Catalyst was filtered off through a pad of celite and rinsed with methylene chloride. Filtrate was concentrated to give the title compound (7.0 g). 1H NMR (200 MHz, CDCl3) δ 7.59 (d, J=8.2 Hz, 1H), 7.02 (d, J=2.0 Hz, 1H), 6.81 (dd, J=8.2, 2.0 Hz, 1H), 4.38 (br S, 2H), 4.36 (s, 2H), 4.20 (q, J=7.0 Hz, 2H), 1.27 (t, J=7.0 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C@@H:7]2[O:19][C@H:18]([CH2:20][O:21]C(=O)C)[C@@H:13]([O:14]C(=O)C)[C@H:8]2[O:9]C(=O)C)[C:5]2[CH:25]=[CH:26][CH:27]=[CH:28][C:4]=2[N:3]=1.C([O:32][CH2:33][CH2:34][CH2:35][CH2:36][O:37][C:38]1[CH:39]=[C:40]([CH:43]=[C:44]([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[CH:45]=1)[CH:41]=O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O>O1CCCC1>[OH:32][CH2:33][CH2:34][CH2:35][CH2:36][O:37][C:38]1[CH:39]=[C:40]([CH:43]=[C:44]([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[CH:45]=1)[CH2:41][NH:1][C:2]1[N:6]([C@@H:7]2[O:19][C@H:18]([CH2:20][OH:21])[C@@H:13]([OH:14])[C@H:8]2[OH:9])[C:5]2[CH:25]=[CH:26][CH:27]=[CH:28][C:4]=2[N:3]=1
Reactant: CC(=O)OC[C@H]1O[C@@H](n2c(N)nc3ccccc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: CC(=O)OCCCCOc1cc(C=O)cc(-c2ccccc2)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: OCCCCOc1cc(CNc2nc3ccccc3n2[C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)cc(-c2ccccc2)c1
Temperature: 25 °C
Reaction time: 13 h
Yield: 30.1 %

Procedure:
2-Amino-1-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)-1H-benzimidazole (0.20 g) and 3-(4-acetoxybutoxy)-5-phenylbenzaldehyde (0.19 g) were suspended in tetrahydrofuran (3 mL), and the mixture was stirred at room temperature for 13 hours. To the reaction mixture was added sodium triacetoxyborohydride (0.21 g), and the mixture was stirred at room temperature for 24 hours. After adding water to the reaction mixture, the mixture was concentrated under reduced pressure. The obtained residue was dissolved in methanol (2 mL). To the reaction mixture was added 5 mol/L aqueous sodium hydroxide solution (0.5 mL), and the mixture was stirred at room temperature for 1 hour. To the reaction mixture was added acetic acid (1 mL), and the mixture was concentrated under reduced pressure. The obtained residue was purified by preparative reverse phase column chromatography (Shiseido CAPSELL PAC C18UG80, 5 μm, 20×50 mm, flow rate 30 mL/minutes linear gradient, water/methanol=70/30-10/90) to give the title compound (0.08 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9]Cl)=[CH:4][CH:3]=1.[CH2:11]([O:13][P:14]([O:18]CC)[O:15][CH2:16][CH3:17])[CH3:12]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][P:14](=[O:18])([O:15][CH2:16][CH3:17])[O:13][CH2:11][CH3:12])=[CH:4][CH:3]=1
Reactant: CCOP(OCC)OCC
Reactant: Fc1ccc(SCCl)cc1
Product: CCOP(=O)(CSc1ccc(F)cc1)OCC
Yield: 94.5 %

Procedure:
This compound was prepared in the manner of Example 3.B., using 59.3 grams (0.34 mole) of 4-fluorophenylthiomethyl chloride and 71.3 grams (0.43 mole) of triethylphosphite. The residue was distilled under reduced pressure to give 89.4 grams (95.7%) of diethyl 4-fluorophenylthiomethylphosphonate; b.p. 147° C./0.6 mm.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:17])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[CH2:18](O)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[OH:1][C:2]1[CH:7]=[C:6]([O:8][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:5]=[CH:4][C:3]=1[C:9](=[O:17])[CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: OCc1ccccc1
Reactant: O=C(Cc1ccccc1)c1ccc(O)cc1O
Product: O=C(Cc1ccccc1)c1ccc(OCc2ccccc2)cc1O
Yield: 87.3 %

Procedure:
Using the previous procedure and starting from 1-(2,4-dihydroxyphenyl)-2-phenylethanone (7.08 g, 31.0 mmol) and benzyl alcohol (3.37 mL, 32.55 mmol), 8.62 g (87%) of the title compound was obtained as a white solid: mp 106-108° C. (lit. 104-105° C.); IR (KBr) 1620, 1572, 1500; 1389, 1352, 1270, 1230, 1192, 1134, 1000, 974, 830, 760, 729, 697, 628, 561 cm−1; 1H NMR (400 MHz, CDCl3) δ 12.69 (br s, 1H), 7.48 (d, J=8.7 Hz, 1H), 7.25-7.39 (m, 10H), 6.49-6.51 (m, 2H), 5.07 (s, 2H), 4.20 (s, 2H); 13C NMR (100 MHz, CDCl3) δ 202.41, 166.20, 16.5.68, 136.22, 134.79, 132.53, 129.76, 129.17, 129.14, 128.76, 127.95, 127.51, 113.77, 108.75, 102.47, 70.66, 45.28; HRMS calculated for C21H18NaO3 (M+Na)+ 341.1154; found 341.1136.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[CH3:11][N:12]([CH3:31])[CH:13]([CH3:30])[CH2:14][C:15]([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:16]#N.CC[O:34]CC>C1(C)C=CC=CC=1.C1COCC1>[CH3:11][N:12]([CH3:31])[CH:13]([CH3:30])[CH2:14][C:15]([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)[CH:16]=[O:34]
Reactant: CC(CC(C#N)(c1ccccc1)c1ccccc1)N(C)C
Reactant: CCOCC
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(CC(C=O)(c1ccccc1)c1ccccc1)N(C)C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of 1.5M diisobutylaluminum hydride in toluene (7.5 ml) was added to a stirring solution of 4-dimethylamino-2,2-diphenylpentanenitrile (3 g) in THF (7.5 ml), at -78° C. under nitrogen. The resultant mixture was then removed from the dry ice-acetone bath and allowed to warm to room temperature. Stirring was continued at room temperature for 1 day. Saturated ammonium chloride solution was added, and the resultant mixture was extracted with ethyl acetate (3×). The combined extracts were washed with brine and dried (MgSO4). An equal volume of 10% sulfuric acid was added, and the mixture was stirred at room temperature for 3 hours. Water was added, and the aqueous mixture was again extracted with ethyl acetate (3×). The combined extracts were washed with water and dried (MgSO4). Rotary evaporation of the solution gave a crude product which was treated with anhydrous ether. The separated solid material was filtered off, and the filtrate was again rotary-evaporated to yield 1.4 g of 4-dimethylamino-2,2-diphenylpentanal, as a viscous residue which solidified upon standing.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:30]=[CH:31][CH:32]=2)[O:11][CH2:12][CH2:13][CH2:14][C:15]2[NH:20][C:19](=[O:21])[C:18]([O:22]CC3C=CC=CC=3)=[CH:17][N:16]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>Cl>[N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:30]=[CH:31][CH:32]=2)[O:11][CH2:12][CH2:13][CH2:14][C:15]2[NH:20][C:19](=[O:21])[C:18]([OH:22])=[CH:17][N:16]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=c1[nH]c(CCCOc2cccc(CN3CCCCC3)c2)ncc1OCc1ccccc1
Agent: Cl
Product: O=c1[nH]c(CCCOc2cccc(CN3CCCCC3)c2)ncc1O

Procedure:
2-[3-[3-(Piperidinomethyl)phenoxy]propyl]-5-benzyloxypyrimidin-4-one (0.68 g) was stirred under reduced pressure and taken to pH 8 with hours in lN hydrochloric acid (20 ml). The mixture was concentrated under reduced pressure and taken to pH 8 with aqueous sodium bicarbonate. This mixture was extracted with n-butanol (3×20 ml); these extracts were combined, washed with water (2'5 ml), dried (MgSO4) and evaporated under reduced pressure to give the title compound. This was dissolved in methanol containing ethanolic HCl, excess solvent was evaporated under reduced pressure and the residue crystallised from isopropanol-acetone to give 2-[3-[3-(piperidinomethyl)phenoxy]propyl]-5-hydroxypyrimidin -4-one dihydrochloride (0.24 g), m.p. 192°-4° C.
Reaction SMILES: [Cl:1][C:2]1[CH:32]=[CH:31][C:30]([CH2:33][NH:34][C:35](=[O:40])[C:36]([F:39])([F:38])[F:37])=[CH:29][C:3]=1[C:4]([NH:6][C:7]([N:9]([C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[C:20]([O:27][CH3:28])[CH:19]=1)[NH:10]C(OC(C)(C)C)=O)=[O:8])=O.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:32]=[CH:31][C:30]([CH2:33][NH:34][C:35](=[O:40])[C:36]([F:39])([F:38])[F:37])=[CH:29][C:3]=1[C:4]1[NH:6][C:7](=[O:8])[N:9]([C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[C:20]([O:27][CH3:28])[CH:19]=2)[N:10]=1
Reactant: COc1cc(N(NC(=O)OC(C)(C)C)C(=O)NC(=O)c2cc(CNC(=O)C(F)(F)F)ccc2Cl)ccc1[N+](=O)[O-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(-n2nc(-c3cc(CNC(=O)C(F)(F)F)ccc3Cl)[nH]c2=O)ccc1[N+](=O)[O-]
Yield: 65.1 %

Procedure:
The title compound was prepared according to the procedure described in step-2 of Intermediate-9 by using tert-butyl 2-((2-chloro-5-((2,2,2-trifluoroacetamido)methyl)benzoyl)carbamoyl)-2-(3-methoxy-4-nitrophenyl)hydrazinecarboxylate (2.0 g, 4.23 mmol), TFA (30 mL) and DCM (5 mL) to afford 1.300 g of the desired product. NMR (300 MHz, DMSO d6): δ 3.96 (s, 3H), 4.47 (d, J=5.4 Hz, 2H), 7.54 (d, J=8.7 Hz, 1H), 7.67-7.74 (m, 3H), 7.93 (s, 1H), 8.10 (d, J=9.0 Hz, 1H), 10.11 (m, 1H), 12.86 (br s, 1H); MS (m/z): 471.88 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[S:15][C:14]([S:16]([NH2:19])(=[O:18])=[O:17])=[CH:13][CH:12]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl.[CH3:28][C:29]([CH3:37])([CH2:33][N:34]([CH3:36])[CH3:35])[C:30](Cl)=[O:31]>CC(C)=O>[CH3:28][C:29]([CH3:37])([CH2:33][N:34]([CH3:36])[CH3:35])[C:30]([O:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[S:15][C:14]([S:16](=[O:17])(=[O:18])[NH2:19])=[CH:13][CH:12]=2)(=[O:9])=[O:10])=[CH:4][CH:3]=1)=[O:31]
Reactant: NS(=O)(=O)c1ccc(S(=O)(=O)c2ccc(O)cc2)s1
Reactant: CN(C)CC(C)(C)C(=O)Cl
Agent: Cl
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: CN(C)CC(C)(C)C(=O)Oc1ccc(S(=O)(=O)c2ccc(S(N)(=O)=O)s2)cc1
Reaction time: 72 h

Procedure:
A solution of 5-[(4-hydroxyphenyl)sulfonyl]thiophene-2-sulfonamide (3.19 g. 0.01 mole) in acetone (60 ml) at -10° was treated with triethylamine (1.11 g, 0.011 mole). Then 2,2-dimethyl-3-dimethylaminopropionyl chloride hydrochloride (2.20 g, 0.011 mole) was added portionwise, during 15 minutes at -10°. The cooling bath was removed and stirring was continued. After 72 hours at room temperature, the reaction mixture was heated on a steam bath for 4 hours. The reaction mixture was cooled and treated with triethylamine (1.11 g, 0.011 mole) and heated on a steam bath for 1 hour.
Reaction SMILES: [Br:1][C:2]1[N:6]2[C:7](Br)=[CH:8][N:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[CH2:12]([CH2:14][NH2:15])[OH:13]>O1CCOCC1.CC(O)C.C(Cl)Cl.O>[Br:1][C:2]1[N:6]2[CH:7]=[CH:8][N:9]=[C:10]([NH:15][CH2:14][CH2:12][OH:13])[C:5]2=[N:4][CH:3]=1
Reactant: NCCO
Reactant: Brc1cncc2ncc(Br)n12
Solvent: O
Solvent: ClCCl
Solvent: CC(C)O
Product: OCCNc1nccn2c(Br)cnc12
Temperature: 80 °C
Yield: 33.5 %

Procedure:
To a solution of 3,5-dibromo-imidazo[1,2-a]pyrazine (D) (400 mg, 1.44 mmol) in dioxane (2 ml) was added ethanolamine (0.436 ml, 7.22 mmol). The mixture was heated at 80° C. in sealed tube for 5 hr. The mixture was then cooled to rt, diluted with 20% IPA/DCM and water. The organic layer was washed with brine, dried and concentrated. The residue was purified on a silica gel column to give 124 mg (yield 33%) of the title compound.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:25][O:26][C@:27]1([C:36]2[CH:41]=[CH:40][C:39]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=3[CH:48]=[CH2:49])=[CH:38][CH:37]=2)[CH2:31][NH:30][C@H:29]([C:32]([O:34][CH3:35])=[O:33])[CH2:28]1.[CH2:50]([O:57][C:58]([NH:60][C@@H:61]([C:65]([CH3:68])([CH3:67])[CH3:66])[C:62](O)=[O:63])=[O:59])[CH2:51][CH2:52][CH2:53][CH2:54][CH:55]=[CH2:56].CCN(C(C)C)C(C)C>C(Cl)Cl>[CH2:50]([O:57][C:58]([NH:60][C@@H:61]([C:65]([CH3:68])([CH3:67])[CH3:66])[C:62]([N:30]1[CH2:31][C@:27]([O:26][CH3:25])([C:36]2[CH:41]=[CH:40][C:39]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=3[CH:48]=[CH2:49])=[CH:38][CH:37]=2)[CH2:28][C@H:29]1[C:32]([O:34][CH3:35])=[O:33])=[O:63])=[O:59])[CH2:51][CH2:52][CH2:53][CH2:54][CH:55]=[CH2:56]
Reactant: C=Cc1ccccc1-c1ccc([C@@]2(OC)CN[C@H](C(=O)OC)C2)cc1
Reactant: C=CCCCCCOC(=O)N[C@H](C(=O)O)C(C)(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CCCCCCOC(=O)N[C@H](C(=O)N1C[C@](OC)(c2ccc(-c3ccccc3C=C)cc2)C[C@H]1C(=O)OC)C(C)(C)C
Temperature: 25 °C
Yield: 74.2 %

Procedure:
HATU (248 mg, 0.652 mmol) was added to a solution of (2S,4R)-methyl 4-methoxy-4-(2′-vinylbiphenyl-4-yl)pyrrolidine-2-carboxylate (200 mg, 0.593 mmol), (S)-2-((hept-6-enyloxy)carbonylamino)-3,3-dimethylbutanoic acid (201 mg, 0.741 mmol) and DIEA (0.311 mL, 1.778 mmol) in DCM (8 mL) and stirred at r.t. 60 hours. The reaction was evaporated and purified on the Biotage (10-40% EtOAc:Hex) to give (2S,4R)-methyl 1-((S)-2-((hept-6-enyloxy)carbonylamino)-3,3-dimethylbutanoyl)-4-methoxy-4-(2′-vinylbiphenyl-4-yl)pyrrolidine-2-carboxylate (260 mg, 0.440 mmol, 74% yield) as a white solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.96-1.00 (m, 1H) 1.06-1.10 (m, 1H) 1.11-1.19 (m, 7H) 1.30-1.47 (m, 4H) 1.55-1.64 (m, 2H) 1.99-2.10 (m, 2H) 2.49-2.55 (m, 1H) 2.89 (d, J=13.05 Hz, 1H) 2.93-3.04 (m, 3H) 3.73-3.80 (m, 3H) 3.92-4.10 (m, 3H) 4.11-4.20 (m, 1H) 4.31-4.41 (m, 1H) 4.87-5.05 (m, 3H) 5.23 (dd, J=10.92, 1.13 Hz, 1H) 5.38-5.42 (m, 1H) 5.68-5.75 (m, 1H) 5.75-5.86 (m, 1H) 6.62-6.76 (m, 1H) 7.28-7.43 (m, 7H) 7.63-7.69 (m, 1H). LCMS: r.t.=2.25 min., [M+H]+=591 Phenomenex Luna S10 (3×50 mm); Solvent A=95% water—5% methanol—10 mM ammonium acetate, Solvent B=5% water—95% methanol—10 mM ammonium acetate; gradient=0% to 100% solvent B over 2 min. and then hold for 1 min.; 4 ml/min; inj. vol.=10 ul; wavelength=220 nm.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[Br:9][CH2:10][CH2:11][CH2:12]Br.C([O-])([O-])=O.[Cs+].[Cs+]>C(#N)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:12][CH2:11][CH2:10][Br:9])=[CH:4][CH:3]=1
Reactant: Oc1ccc(F)cc1
Reactant: BrCCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: Fc1ccc(OCCCBr)cc1
Reaction time: 24 h
Yield: 14.7 %

Procedure:
To a solution of 4-fluorophenol (0.0567 g, 0.506 mmol) in acetonitrile (4 mL) was added 1,3-dibromopropane (0.520 mL, 5.12 mmol) followed by Cs2CO3 (0.252 g, 0.774 mmol). The reaction mixture was stirred for 24 h and then concentrated under vacuum. The resulting residue was treated with H2O (4 mL) and extracted with DCM (8 mL). The organic layer was dried through a phase separator and concentrated under vacuum. The residue was taken up in DMSO and purified by preparatory HPLC (without TFA) to give the title compound (0.0173 g, 14.7%). ELMS Rt (2.25 min).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]1(=[O:30])[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22](=[O:29])[NH:21]1.[CH3:31][C:32]1([CH3:39])[CH2:37][CH2:36][CH:35](O)[CH:34]=[CH:33]1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[CH3:31][C:32]1([CH3:39])[CH2:37][CH2:36][CH:35]([N:21]2[C:22](=[O:29])[C:23]3[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:20]2=[O:30])[CH:34]=[CH:33]1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CC1(C)C=CC(O)CC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC1(C)C=CC(N2C(=O)c3ccccc3C2=O)CC1
Temperature: 0 °C
Yield: 42.8 %

Procedure:
Resin supported triphenylphosphine (32.7 g, 106 mmol), isoindoline-1,3-dione (17.19 g, 117 mmol), and 4,4-dimethylcyclohex-2-enol (13.4 g, 106 mmol) were combined and THF (197 mL) was added. The mixture was stirred and cooled to 0° C., then diisopropyl azodicarboxylate (21.09 mL, 107 mmol) was added drop-wise over 2 min. The reaction was stirred and allowed to warm slowly to ambient temperature overnight. The reaction mixture was filtered and then concentrated to a yellow solid under reduced pressure. Ethyl acetate (200 mL) was added and the resulting solids were filtered off again. The ethyl acetate filtrate was washed with water (100 mL), the aqueous layer extracted with ethyl acetate (100 mL), the combined organic layers were dried over anhydrous magnesium sulfate, filtered, and concentrated to an oil that was purified by silica gel chromatography (0-20% ethyl acetate/hexane) to afford 2-(4,4-dimethylcyclohex-2-enyl)isoindoline-1,3-dione (11.59 g, 45.4 mmol, 42.8% yield) as an oil. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.84 (s, 4H), 5.51-5.62 (m, 1H), 5.43 (d, J=10.15 Hz, 1H), 4.59-4.74 (m, 1H), 2.14-2.30 (m, 1H), 1.67-1.81 (m, 1H), 1.44-1.68 (m, 2H), 1.09 (s, 3H), 1.01 (s, 3H); MS (ESI) m/z 256.2 [M+1]+.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=2[C:11]([OH:13])=O)=[N:7][CH:8]=1.[CH2:20]([O:22][C:23]([C:25]1[CH:26]=[N:27][C:28]2[C:33]([CH:34]=1)=[CH:32][CH:31]=[C:30]([NH2:35])[CH:29]=2)=[O:24])[CH3:21].C(N(C(C)C)CC)(C)C>S(Cl)(Cl)=O.ClCCCl>[CH2:20]([O:22][C:23]([C:25]1[CH:26]=[N:27][C:28]2[C:33]([CH:34]=1)=[CH:32][CH:31]=[C:30]([NH:35][C:11](=[O:13])[C:10]1[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=1[C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:19])[F:18])=[CH:8][N:7]=1)[CH:29]=2)=[O:24])[CH3:21]
Reactant: CCOC(=O)c1cnc2cc(N)ccc2c1
Reactant: O=C(O)c1ccccc1-c1ccc(C(F)(F)F)cn1
Solvent: ClCCCl
Solvent: O=S(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cnc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cn3)ccc2c1
Reaction time: 4 h
Yield: 84.1 %

Procedure:
2-(5-Trifluoromethyl-pyridin-2-yl)-benzoic acid (325 mg, 1.05 mmol) was dissolved in 15 ml of thionyl chloride, and the mixture heated at 60 C. After 4 h, the volatiles were removed under vacuum, the residue combined with 7-amino-quinoline-3-carboxylic acid ethyl ester (100 mg, 0.46 mmol), dissolved in 1,2-dichloroethane (15 ml), and diisopropylethylamine (300 mg, 2.31 mmol) added. After heating at reflux for 48 h, the reaction mixture was washed with 1N HCl, dried (magnesium sulfate), filtered, and concentrated under vacuum. The resulting residue was purified by silica gel chromatography eluting with 50% ethyl acetate in hexanes to provide 180 mg (85%) of the title compound.
Reaction SMILES: C(O[C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]=1[CH:17]=[O:18])CC(C)C.[OH:19][C:20]1C2C(=CC=CC=2)C(C=O)=[CH:22][CH:21]=1.BrCCC>>[CH2:20]([O:19][C:15]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([CH:17]=[O:18])=[CH:7][CH:16]=1)[CH2:21][CH3:22]
Reactant: CC(C)CCOc1ccc2ccccc2c1C=O
Reactant: O=Cc1ccc(O)c2ccccc12
Solvent: CCCBr
Product: CCCOc1ccc(C=O)c2ccccc12

Procedure:
Prepared according to the Procedure for 2-(isopentyloxy)-1-naphthaldehyde using 4-hydroxy-1-naphthaldehyde and 1-bromopropane.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][N:3]=1.Br[C:10]1[C:11](=[O:18])[N:12]([CH3:17])[N:13]=[C:14]([Cl:16])[CH:15]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Cs+].[Cs+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[Cl:16][C:14]1[CH:15]=[C:10]([NH:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[N:7]=2)[C:11](=[O:18])[N:12]([CH3:17])[N:13]=1
Reactant: Cc1nccc(N)n1
Reactant: Cn1nc(Cl)cc(Br)c1=O
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: Cc1nccc(Nc2cc(Cl)nn(C)c2=O)n1
Temperature: 100 °C
Yield: 73.4 %

Procedure:
A 100-mL single-neck round-bottomed flask equipped with a reflux condenser was charged with 2-methylpyrimidin-4-amine (330 mg, 3.03 mmol), 4-bromo-6-chloro-2-methylpyridazin-3(2H)-one (675 mg, 3.03 mmol), Pd2(dba)3 (274 mg, 0.30 mmol), XantPhos (143 mg, 0.30 mmol), Cs2CO3 (2960 mg, 9.09 mmol), and dioxane (40 mL). After three cycles of vacuum/argon flush, the mixture was heated at 100° C. for overnight. It was then filtered and the filtrate was evaporated in vacuo. The residue was purified by silica-gel column chromatography eluting with 1:20 methanol/dichloromethane to afford 225a as a yellow solid (560 mg, 73%). MS-ESI: [M+H]+ 252.1
Reaction SMILES: [CH2:1]([O:8][P:9]([O:19][CH2:20][O:21][C:22](=[O:39])[N:23]([CH:36]1[CH2:38][CH2:37]1)[C:24](=[O:35])[C:25]1[CH:30]=[CH:29][C:28]([CH3:31])=[C:27]([N+:32]([O-])=O)[CH:26]=1)([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[NH4+]>CO.C1COCC1.[Zn]>[CH2:12]([O:11][P:9]([O:19][CH2:20][O:21][C:22](=[O:39])[N:23]([C:24](=[O:35])[C:25]1[CH:30]=[CH:29][C:28]([CH3:31])=[C:27]([NH2:32])[CH:26]=1)[CH:36]1[CH2:38][CH2:37]1)([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: Cc1ccc(C(=O)N(C(=O)OCOP(=O)(OCc2ccccc2)OCc2ccccc2)C2CC2)cc1[N+](=O)[O-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccc(C(=O)N(C(=O)OCOP(=O)(OCc2ccccc2)OCc2ccccc2)C2CC2)cc1N
Reaction time: 3 h
Yield: 97.2 %

Procedure:
To a solution of (bis(benzyloxy)phosphoryloxy)methyl-cyclopropyl(4-methyl-3-nitrobenzoyl)carbamate (0.53 g, 1.0 mmol) in MeOH/THF (1:1, 50 mL) under nitrogen were added ammonium chloride (0.79 g, 14.8 mmol) and zinc (0.75 g, 11.5 mmol). After 3 h, the precipitate was filtered, and the filtrate was concentrated in vacuo, diluted with EtOAc and washed with water (2×), brine successively, dried over Na2SO4, filtered, and concentrated in vacuo to give the title compound as a colorless oil (0.51 g, 100% yield). (M+H)+=525.19.
Reaction SMILES: [CH3:1][N:2]1[CH2:8][CH2:7][CH2:6][C:5](=[O:9])[CH2:4][CH2:3]1.Br[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]1[O:18][CH2:19][C:20]([CH3:23])([CH3:22])[N:21]=1>>[CH3:22][C:20]1([CH3:23])[CH2:19][O:18][C:17]([C:12]2[CH:11]=[CH:16][CH:15]=[CH:14][C:13]=2[C:5]2([OH:9])[CH2:6][CH2:7][CH2:8][N:2]([CH3:1])[CH2:3][CH2:4]2)=[N:21]1
Reactant: CN1CCCC(=O)CC1
Reactant: CC1(C)COC(c2ccccc2Br)=N1
Product: CN1CCCC(O)(c2ccccc2C2=NC(C)(C)CO2)CC1

Procedure:
Reaction of 2,3,4,5,6,7-hexahydro-1-methylazepin-4-one and 2-(2-bromophenyl)-4,4-dimethyl-2-oxazoline by the method described in Example 1c provides 4-[2-(4,4-dimethyl-2-oxazolin-2-yl)phenyl]-2,3,4,5,6,7-hexahydro-4-hydroxy-1-methylazepine.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:15]#[N:16])[CH:11]=2)[CH:6]=1)=[O:4].[Li+].[OH-]>C1COCC1.ClCCl.O>[C:15]([C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][CH:9]=1)[CH:6]=[C:5]([C:3]([OH:4])=[O:2])[CH:14]=[CH:13]2)#[N:16]
Reactant: COC(=O)c1ccc2cc(C#N)ccc2c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: O
Product: N#Cc1ccc2cc(C(=O)O)ccc2c1
Yield: 86.2 %

Procedure:
A solution of 6-cyano-naphthalene-2-carboxylic acid methyl ester from Example 96 (2.00 g, 9.47 mmol) in THF (19 mL) and 1M aqueous LiOH (18.94 mL, 18,94 mmol) was vigorously stirred at room temperature for 3 hours. The reaction mixture was then diluted with 150 mL of 1:1 dichloromethane/water, and the organics were discarded. The aqueous material was acidified to pH 2 with 1N HC1, extracted with EtOAc (2×150 mL), extracts dried over MgSO4, and concentrated to provide the desired compound as a white solid (1.61 g, 86%).