Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC(=O)[CH:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH3:23])C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[C:49]([O:52][CH2:53][CH3:54])(=[O:51])C.CCCCCC>>[CH2:53]([O:52][C:49](=[O:51])[CH:23]=[C:22]([N:14]1[C:15]2[C:11](=[CH:10][C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:17][CH:16]=2)[CH:12]=[CH:13]1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[CH3:54]
Reactant: CCOC(=O)C(C)c1ccccc1
Reactant: CCOC(C)=O
Reactant: c1ccc(COc2ccc3[nH]ccc3c2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCCCCC
Product: CCOC(=O)C=C(c1ccccc1)n1ccc2cc(OCc3ccccc3)ccc21
Reaction time: 72 h
Yield: 68 %

Procedure:
A mixture of 5-benzyloxy-1H-indole (4.46 g, 20.0 mmol), phenyl-propionic acid ethyl ester (7.00 g, 40.0 mmol), and tetrabutylammonium fluoride [1.0 M in THF] (36.0 mL, 50.0 mmol) was stirred for 3 days. After removal of solvent, the crude reaction mixture was submitted to flash chromatography on silica gel with ethyl acetate/hexane (1:4) to give the title compound (5.42 g, 68% yield) as an E/Z isomeric mixture. Mass Spectrum (LCMS, ESI) calculated for C26H24NO3 398.2 (M+H); found 398.2.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][CH2:15][CH:16]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:18][CH:19]1[CH2:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][CH2:15][CH2:16][NH:18][CH:19]1[CH2:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=CCCC1CCCCN1Cc1ccccc1
Reactant: NC1Cc2ccccc2C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: c1ccc(CN2CCCCC2CCCNC2Cc3ccccc3C2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of compound 23 (820 mg, 3.55 mmol) in DCM (15 mL) was added 2-amino-indane (472 mg, 3.55 mmol) drop-wise at ice cold conditions. Acetic acid (0.2 mL) was added to the reaction mixture, followed by sodium triacetoxy borohydride (2.2 g, 10.65 mmol) portion-wise at ice cold conditions. The reaction mixture was stirred at rt for 16 hours. The reaction mixture was diluted with DCM, washed with saturated NaHCO3 solution and brine. The organic layer was dried over Na2SO4, filtered and concentrated. The crude material was purified by 230-400 silica gel column chromatography using 1-3% MeOH-DCM as eluent to yield compound 24.
Reaction SMILES: [OH:1][C:2]1[C:7]([CH2:8]N(CC)CC)=[CH:6][C:5]([CH3:14])=[CH:4][C:3]=1[N:15]1[N:19]=[C:18]2[CH:20]=[CH:21][CH:22]=[CH:23][C:17]2=[N:16]1.[OH:24][C:25]1[CH:38]=[C:37]([O:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])[CH:36]=[CH:35][C:26]=1[C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:28].C[O-].[Na+]>>[N:16]1[N:15]([C:3]2[CH:4]=[C:5]([CH3:14])[CH:6]=[C:7]([CH2:8][C:38]3[C:37]([O:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])=[CH:36][CH:35]=[C:26]([C:27](=[O:28])[C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[C:25]=3[OH:24])[C:2]=2[OH:1])[N:19]=[C:18]2[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=12
Reactant: CCCCCCCCOc1ccc(C(=O)c2ccccc2)c(O)c1
Reactant: CCN(CC)Cc1cc(C)cc(-n2nc3ccccc3n2)c1O
Agent: C[O-]
Agent: [Na+]
Product: CCCCCCCCOc1ccc(C(=O)c2ccccc2)c(O)c1Cc1cc(C)cc(-n2nc3ccccc3n2)c1O
Temperature: 25 °C
Yield: 33.1 %

Procedure:
2-(2-Hydroxy-3-diethylaminomethyl-5-methylphenyl)-2H-benzotriazole (21.0 g, 0.067 mol), 2-hydroxy-4-n-octyloxybenzophenone (22.0 g, 0.067 mol), and p-cumene (80 g) are charged to a reaction flask. The mixture is heated to dissolve, and sodium methoxide (1.0 g, 25% in methanol) is added as catalyst. The solution is heated with agitation under a nitrogen flow at reflux (176°-178° C.) for 24 hours. After cooling to room temperature, the solution is filtered, and the black filtered solid (~1 g) is discarded. The product is then precipitated with methanol. The yellow solid (12.5 g) obtained is vacuum filtered, and identified using thin layer chromatography, with toluene:acetone (1:1 ) as the mobile phase. To remove the yellow color, the solid product is dissolved in hot toluene, and silica gel is introduced. The silica gel is gravity filtered hot. The toluene is removed by vacuum distillation, yielding 8.2 g of the title compound as an off-white solid, m.p. 124°-126° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([N+:12]([O-:14])=[O:13])=[C:7](OC)[CH:6]=[CH:5]2.[CH:17]1([NH2:23])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([N+:12]([O-:14])=[O:13])=[C:7]([NH:23][CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)[CH:6]=[CH:5]2
Reactant: COc1ccc2cc(Br)ccc2c1[N+](=O)[O-]
Reactant: NC1CCCCC1
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1c(NC2CCCCC2)ccc2cc(Br)ccc12
Temperature: 120 °C
Reaction time: 17 h
Yield: 84 %

Procedure:
A solution of 6-bromo-2-methoxy-1-nitronaphthalene (10.0 g, 35.6 mmol) and 8 ml of cyclohexylamine in 50 ml of dry N,N-dimethylformamide was heated with stirring at 120° C. for 17 h. The mixture was evaporated to dryness and the residue was triturated with 50 ml of ethanol at 0° C. The solid was isolated by filtration and washed with light petroleum to give 10.4 g (84%) of 6-bromo-2-cyclohexylamino-1-nitronaphthalene. The crude product was suspended in 150 ml of 96% ethanol and hydrogenated at room temperature and 40 psi over Ni/Raney. After the hydrogen uptake was completed, the reaction mixture was filtered into 50 ml of 4M hydrochloric acid and concentrated to dryness. Crude 1-amino-6-bromo-2-cyclohexylaminonaphthalene hydrochloride (9.8 g, 27.6 mmol) was taken up in 80 ml of dry tetrahydrofuran. Dry triethylamine (7.7 ml, 55.3 mmol) was added, followed by the dropwise addition of ethyloxalyl chloride (3.1 ml, 27.7 mmol) with stirring at 0° C. The mixture was stirred over night at room temperature and finally at reflux for 4 h. The cooled mixture was filtered and the solid was washed with water and ethanol affording 5.2 g (51%) of the title compound. M.p. 347.0° C. (N,N-dimethylformamide, DSC); IR (KBr): 1700 cm-1 ; 1H-NMR (DMSO-d6) 1.13-2.93 (m, 10H, 5CH2), 4.33-4.90 (m, 1H, NCH), 7.47-8.67 (m, 5H, ArH), 12.1 (broad s, 1H, NH); MS (m/z): 372 (M+, 17%).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]2[CH:14]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[CH:12]=[N:11][C:10]=12)=[O:5])C.[OH-].[Na+].Cl>C(O)CCC>[CH3:22][O:21][C:18]1[CH:17]=[CH:16][C:15]([C:13]2[CH:12]=[N:11][C:10]3[N:9]([N:8]=[CH:7][C:6]=3[C:4]([OH:5])=[O:3])[CH:14]=2)=[CH:20][CH:19]=1
Reactant: CCOC(=O)c1cnn2cc(-c3ccc(OC)cc3)cnc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCO
Product: COc1ccc(-c2cnc3c(C(=O)O)cnn3c2)cc1

Procedure:
A solution of 6-(4-methoxy-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid ethyl ester (1-1, 660 mg, 2.2 mmol, 1 equiv) and aquoeus sodium hydroxide solution (1N, 11.1 mL, 11.1 mmol, 5.00 equiv) in-BuOH (45 mL) was stirred for 24 hours at 100° C. The yellow solution was poured directly into aqueous 1N HCl solution (500 mL), and the resulting aqueous mixture was extracted with chloroform (3×300 mL). The combined organic layers were dried over sodium sulfate and concentrated to afford 6-(4-methoxy-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (1-2) as a white solid. 1H NMR (400 MHz, DMSO) δ 12.38 (br s, 1H), 9.54 (m, 1H), 9.16 (m, 1H), 8.60 (s, 1H), 7.84 (d, 2H, J=8 Hz), 7.12 (d, 2H, J=8 Hz), 3.85 (s, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]([CH2:17][CH:18]([C:26]1[CH:31]=[CH:30][C:29]([O:32]COC)=[CH:28][CH:27]=1)[CH2:19][C:20]1[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=1)[S:7]([C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1)(=[O:9])=[O:8])=[O:5])[CH3:2].Cl.O.C(=O)([O-])O.[Na+]>O1CCOCC1.C(Cl)Cl>[CH2:1]([O:3][C:4]([N:6]([CH2:17][CH:18]([C:26]1[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=1)[CH2:19][C:20]1[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=1)[S:7]([C:10]1[CH:11]=[CH:12][C:13]([Cl:16])=[CH:14][CH:15]=1)(=[O:9])=[O:8])=[O:5])[CH3:2]
Reactant: CCOC(=O)N(CC(Cc1cccnc1)c1ccc(OCOC)cc1)S(=O)(=O)c1ccc(Cl)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Solvent: ClCCl
Product: CCOC(=O)N(CC(Cc1cccnc1)c1ccc(O)cc1)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 7 h
Yield: 94.1 %

Procedure:
To the solution of 8 ml of the solution of 1.11 g of N-ethoxycarbonyl-N-[2-(4-methoxymethyloxyphenyl)-3-(3-pyridyl)propyl]-4-chlorobenzenesulfonamide in dioxane was added 2 ml of aqueous 6N hydrogen chloride solution, and stirred at room temperature for 7 hours. To the reaction mixture were added water and methylene chloride, followed by further addition of sodium hydrogen carbonate. The organic phase was separated, which was then extracted with ethyl acetate from aqueous phase. The organic phases were combined and washed in saturated aqueous sodium chloride, followed by drying over magnesium sulfate to distill off the solvent under reduced pressure. The obtained residue was subjected to chromatography on a silica gel column, and from the fraction eluted with methanol-methylene chloride (1:99 v/v) was obtained 956 mg of N-ethoxycarbonyl-N-[2-(4-hydroxyphenyl)-3-(3-pyridyl)propyl]-4-chlorobenzenesulfonamide.
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[CH2:8][C:9]([OH:11])=O.C(Cl)(=O)C(Cl)=O.[NH4+:18].[OH-]>C(Cl)Cl.CN(C=O)C.C1COCC1>[CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[CH2:8][C:9]([NH2:18])=[O:11]
Reactant: [NH4+]
Reactant: O=C(O)CC1CC2CCC1C2
Agent: O=C(Cl)C(=O)Cl
Agent: [OH-]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: NC(=O)CC1CC2CCC1C2
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.7 %

Procedure:
A solution of 2-(bicyclo[2.2.1]heptan-2-yl)acetic acid (0.50 g, 3.24 mmol) in DCM (30 mL) was treated with oxalyl chloride (0.426 mL, 4.86 mmol), followed by a catalytic amount of DMF (1 drop) and stirred at RT for 2 h. A solution of NH4OH (˜15M, 2 mL, ˜30 mmol) in THF (5 mL) was added drop wise and the mixture stirred at RT overnight. The mixture was concentrated to dryness and the residue was dissolved in EtOAc, washed with brine, dried over MgSO4 and concentrated to dryness to afford 2-(bicyclo[2.2.1]heptan-2-yl)acetamide (480 mg, 97%). 1H NMR (400 MHz, DMSO-d6): δ 7.19 (s, 1H), 6.65 (s, 1H), 2.14 (s, 1H), 1.91 (m, 3H), 1.75 (m, 1H), 1.35 (m, 4H), 1.11 (m, 4H); MS (ESI) m/z: 154.2 (M+H+).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]([CH:14]=[CH:15][CH:16]=1)[C:10]([O:12][CH3:13])=[O:11].C(N(CC)C(C)C)(C)C.Cl[C:27]1[O:28][C:29]2[CH:35]=[CH:34][CH:33]=[CH:32][C:30]=2[N:31]=1.O>O1CCCC1>[O:28]1[C:29]2[CH:35]=[CH:34][CH:33]=[CH:32][C:30]=2[N:31]=[C:27]1[NH:1][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]([CH:14]=[CH:15][CH:16]=1)[C:10]([O:12][CH3:13])=[O:11]
Reactant: Clc1nc2ccccc2o1
Reactant: COC(=O)c1cccc(OCCCCN)c1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COC(=O)c1cccc(OCCCCNc2nc3ccccc3o2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methyl 3-(4-aminobutoxy)benzoate (4.81 g) was dissolved in 50.0 mL of tetrahydrofuran and N,N-diisopropylethylamine (2.90 g, 22.4 mmol) was added. Under cooling, 2-chlorobenzoxazole (3.44 g, 22.4 mmol) was added dropwise thereto and stirred overnight at room temperature. Following the addition of water, the resulting mixture was extracted with ethyl acetate. The organic layer was washed with brine. The organic layer was dried with sodium sulfate and then concentrated under reduced pressure, followed by purification by silica gel column chromatography (hexane:ethyl acetate=4:1) to give a compound of interest (3.22 g, 50.7%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:16][CH3:17])=[CH:4][C:5]2[CH2:11][N:10]([CH2:12][CH3:13])[CH2:9][C:8](=[O:14])[NH:7][C:6]=2[CH:15]=1.Cl[C:19]1[N:24]=[C:23]([NH:25][C@@H:26]2[CH2:31][CH2:30][CH2:29][CH2:28][C@H:27]2[NH:32][S:33]([CH3:36])(=[O:35])=[O:34])[C:22]([Cl:37])=[CH:21][N:20]=1.[NH4+].[OH-]>C(Cl)Cl.CO>[Cl:37][C:22]1[C:23]([NH:25][C@@H:26]2[CH2:31][CH2:30][CH2:29][CH2:28][C@H:27]2[NH:32][S:33]([CH3:36])(=[O:35])=[O:34])=[N:24][C:19]([NH:1][C:2]2[C:3]([O:16][CH3:17])=[CH:4][C:5]3[CH2:11][N:10]([CH2:12][CH3:13])[CH2:9][C:8](=[O:14])[NH:7][C:6]=3[CH:15]=2)=[N:20][CH:21]=1
Reactant: CS(=O)(=O)N[C@@H]1CCCC[C@H]1Nc1nc(Cl)ncc1Cl
Reactant: CCN1CC(=O)Nc2cc(N)c(OC)cc2C1
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: CCN1CC(=O)Nc2cc(Nc3ncc(Cl)c(N[C@@H]4CCCC[C@H]4NS(C)(=O)=O)n3)c(OC)cc2C1
Yield: 24.8 %

Procedure:
In an analogous manner to procedure 1656g, 8-amino-4-ethyl-7-methoxy-1,3,4,5-tetrahydro-benzo[e][1,4]diazepin-2-one (70 mg, 0.30 mmol) and N-[(1R,2R)-2-(2,5-dichloro-pyrimidin-4-ylamino)-cyclohexyl]-methanesulfonamide (101 mg, 0.30 mmol) were coupled to provide N-{(1R,2R)-2-[5-chloro-2-(4-ethyl-7-methoxy-2-oxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-8-ylamino)-pyrimidin-4-ylamino]-cyclohexyl}-methane-sulfonamide (40 mg, 20%) as a mustard yellow solid following preparative tlc (DCM/MeOH/c.NH4OH=90/9/1); 1H NMR (400 MHz, CDCl3) δ 8.15 (s, 1H), 8.00 (s, 1H), 7.49 (s, 1H), 7.46 (s, 1H), 6.82 (s, 1H), 5.53 (d, J=7 Hz, 1H), 5.31 (d, J=7 Hz, 1H), 3.94 (s, 3H), 3.74 (s, 2H), 3.40 (s, 2H), 3.29 (m, 1H), 2.87 (s, 3H), 2.77 (q, J=7 Hz, 2H), 2.23 (m, 2H), 1.84 (m, 2H), 1.38 (m, 2H), 1.27 (m, 2H), 1.20 (t, J=7 Hz, 3H); MS (m/e) 538 (M+1); mp 216° C. (dec.).
Reaction SMILES: C(N(CC)CC)C.[NH2:8][CH:9]1[C:19](=[O:20])[N:11]2[CH:12]([C:17]#[N:18])[C:13]([CH3:16])([CH3:15])[S:14][C@H:10]12.[CH3:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[C:28](Cl)([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[CH3:41])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C(Cl)Cl>[CH3:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[C:28]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[CH3:41])([NH:8][CH:9]1[C:19](=[O:20])[N:11]2[CH:12]([C:17]#[N:18])[C:13]([CH3:15])([CH3:16])[S:14][C@H:10]12)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: Cc1ccccc1C(Cl)(c1ccccc1)c1ccccc1C
Reactant: CC1(C)S[C@@H]2C(N)C(=O)N2C1C#N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccccc1C(NC1C(=O)N2C(C#N)C(C)(C)S[C@H]12)(c1ccccc1)c1ccccc1C
Temperature: -10 °C
Reaction time: 1 h

Procedure:
Triethylamine (444 mg., 4.4 mmole) is added to a suspension of 6-amino-2,2-dimethyl-3-cyanopenam (468 mg., 2 mmole) in methylene chloride (20 ml.) and the resulting mixture cooled to -10° C. A solution of α,α-di(2-methylphenyl)benzyl chloride (614 mg., 2 mmole) in methylene chloride (12 ml.) is added over a ten minute period and the resulting yellow solution stirred for one hour at -10° C. The cooling bath is removed and the mixture stirred and allowed to warm to room temperature. It is stirred for two hours at room temperature and is then concentrated under reduced pressure to a brown sludge. The sludge is chromatographed on a silica gel column (70-23- mesh., 380 × 20 mm. column) using chloroform as eluent. Fractions (15 ml. each) are collected. Fractions 13-19 are combined and concentrated in vacuo to dryness to give 155 mg. of product as a foam.
Reaction SMILES: [CH:1]1[C:14]2[CH2:13][CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[Al+3].[Cl-].[Cl-].[Cl-].[C:19](Cl)(=[O:21])[CH3:20].Cl>C(Cl)Cl>[C:19]([C:9]1[CH:8]=[CH:7][C:6]2[C:5]3[C:14](=[CH:1][CH:2]=[CH:3][CH:4]=3)[CH2:13][CH2:12][C:11]=2[CH:10]=1)(=[O:21])[CH3:20]
Reactant: c1ccc2c(c1)CCc1ccccc1-2
Reactant: CC(=O)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(=O)c1ccc2c(c1)CCc1ccccc1-2
Reaction time: 2 h

Procedure:
To a solution of 18 g (0.1 mole) 9,10-dihydrophenanthrene in 200 mL of dry CH2Cl2, cooled in ice, 20 g (0.15 mole) of anh. AlCl3 was added. To this solution 9.42 g (0.12 mmole) of acetyl chloride in 50 mL of dry CH2Cl2 was added in 17 mins. Stirring was continued for 30 mins in ice and 2 h at room temperature. The solution was poured on ice and 25 mL of concentrated HCl and stirred for 15 mins. The yellow organic layer was separated, washed with NaHCO3 solution, and dried. The solvent was removed and the residue distilled at 0.15 mm pressure. The distillate, 15.28 g, crystallized from ethanol-hexane, m.p. 58°-60°°.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13](=[O:14])[N:12]3[C:15]([CH3:19])=[CH:16][CH:17]=[CH:18][C:11]3=[N:10][C:9]=2[CH2:20]O)[CH:5]=[CH:6][CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:41]1(=[O:51])[NH:45][C:44](=[O:46])[C:43]2=[CH:47][CH:48]=[CH:49][CH:50]=[C:42]12.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13](=[O:14])[N:12]3[C:15]([CH3:19])=[CH:16][CH:17]=[CH:18][C:11]3=[N:10][C:9]=2[CH2:20][N:45]2[C:41](=[O:51])[C:42]3[C:43](=[CH:47][CH:48]=[CH:49][CH:50]=3)[C:44]2=[O:46])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccc2nc(CO)c(-c3cccc(F)c3)c(=O)n12
Reactant: O=C1NC(=O)c2ccccc21
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1cccc2nc(CN3C(=O)c4ccccc4C3=O)c(-c3cccc(F)c3)c(=O)n12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 3-(3-fluorophenyl)-2-(hydroxymethyl)-6-methyl-4H-pyrido[1,2-a]pyrimidin-4-one (0.05110 g, 0.180 mmol) in THF (3.00 mL) was added triphenylphosphine (0.141 g, 0.539 mmol), phthalimide (0.0793 g, 0.539 mmol), and diisopropyl azodicarboxylate (0.106 mL, 0.539 mmol). The reaction mixture was stirred at rt. After 3 h, the mixture was concd under reduced pressure and partitioned between EtOAc (100 mL) and brine (100 mL). The organic layer was dried over Na2SO4, filtered, and concd under reduced pressure. The residue was purified by silica gel column chromatography on a 40 g Redi-Sep™ column using 0 to 50% gradient of EtOAc in hexane over 14 min and 50% isocratic of EtOAc for 15 min as eluent to give 2-((3-(3-fluorophenyl)-6-methyl-4-oxo-4H-pyrido-[1,2-a]pyrimidin-2-yl)methyl)isoindoline-1,3-dione as a solid: Mass Spectrum (ESI) m/e=414.1 (M+1).
Reaction SMILES: [CH:1]([Mg]Br)=[CH2:2].[Br:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]([CH3:14])[CH3:13])=[C:8]([N+:15]([O-])=O)[CH:7]=1.[NH4+].[Cl-]>C1COCC1>[Br:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]([CH3:14])[CH3:13])=[C:8]2[C:7]=1[CH:1]=[CH:2][NH:15]2
Reactant: CC(C)c1ccc(Br)cc1[N+](=O)[O-]
Reactant: C=C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)c1ccc(Br)c2cc[nH]c12
Reaction time: 1 h

Procedure:
Vinyl magnesium bromide (1 M in THF) (98 mL, 98 mmol) was added to 4-bromo-1-isopropyl-2-nitrobenzene (4 g, 16.39 mmol) in THF (60 mL) at −40° C. The reaction mixture was stirred for 1 h, then poured into saturated aqueous NH4Cl and extracted with ether. The combined ethereal extracts were dried (MgSO4) and concentrated. Chromatography over silica eluting with 1-20% EtOAc/hexanes afforded the title compound. LC-MS: calculated for C11H12BrN 237,02, observed m/e 238.2 (M+H)+ Rt (1.96/4 min.).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=2)[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[CH3:19][O:20][CH2:21]Cl.O>CN(C=O)C>[CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[CH:8][C:9]([O:12][CH2:19][O:20][CH3:21])=[CH:10][N:11]=2)[CH2:2][CH2:3]1
Reactant: Oc1ccc(OCC2CC2)nc1
Reactant: COCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COCOc1ccc(OCC2CC2)nc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of 6-(cyclopropylmethoxy)pyridin-3-ol (855 mg) and potassium carbonate (1.44 g) in DMF (15 mL) was added chloromethyl methyl ether (0.635 mL), and the mixture was stirred at room temperature for 1 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed twice with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (789 mg) as an oil.
Reaction SMILES: C(OC([N:6]1[CH2:12][CH2:11][C:10]2[C:13]([CH3:17])=[C:14](Br)[S:15][C:9]=2[CH2:8][CH2:7]1)=O)C.C([Li])CCC.[CH3:23][C:24]([CH3:29])([CH3:28])[C:25](Cl)=[O:26]>C1COCC1>[CH3:23][C:24]([CH3:29])([CH3:28])[C:25]([C:14]1[S:15][C:9]2[CH2:8][CH2:7][NH:6][CH2:12][CH2:11][C:10]=2[C:13]=1[CH3:17])=[O:26]
Reactant: CCOC(=O)N1CCc2sc(Br)c(C)c2CC1
Reactant: CC(C)(C)C(=O)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1c(C(=O)C(C)(C)C)sc2c1CCNCC2
Temperature: -78 °C
Reaction time: 0.08 h

Procedure:
The product of step (h) (60 mg, 0.19 mmol) was dissolve in 2 mL THF and cooled to −78° C. Butyl lithium (0.15 mL of 1.6M) was added and the reaction was stirred for 5 minutes. Trimethylacetyl chloride (36 μL, 0.3 mmol) was added and the reaction was warmed to room temperature. The reaction was quenched with water (5 mL) and the product was extracted into DCM (2×). The extracts were concentrated to dryness and treated with 4 mL of 1:1 EtOH:40% KOH (aq) and heated to 100° C. for 14 hours. The reaction was cooled and diluted with water. The product was extracted into DCM (2×5 mL). The extracts were concentrated and the title compound was purified by preparative HPLC-MS. 1H NMR (CD3OD) δ 3.38-3.31 (m, 4H), 3.23 (t, J=5.1 Hz, 2H), 3.04 (t, J=5.2 Hz, 2H), 2.30 (s, 3H), 1.32 (s, 9H);
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].Br[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O.CCCCCC>[CH2:11]([O:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: O=Cc1ccccc1O
Reactant: CCCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCCCCOc1ccccc1C=O
Temperature: 80 °C
Yield: 97.3 %

Procedure:
2-Hydroxybenzaldehyde (110 g), was alkylated by mixing this compound with 1-bromononane (180 g), anhydrous potassium carbonate and dimethylformamide (800 mL). This mixture was heated at 80° C. for 14 hours. Hexane and water were then added and the hexane extract was concentrated and the residue was distilled to yield the 2-nonyloxybenzaldehyde (210 g), bp 121° C. (0.3 mm Hg). A solution of 2-nonyloxybenzaldehyde prepared above (100 g) in ethanol (1000 mL) at 10° C. was reduced by treating with an excess of sodium borohydride (6 g) and after stirring the mixture for a further 15-20 min. at room temperature, the compound 2-nonyloxybenzylalcohol was isolated by extraction into hexane. Removal of the hexane in vacuo yielded the crude 2-nonyloxybenzylalcohol (98 g). The resulting 2-nonyloxybenzylalcohol was added to a mixture of triphenylphosphine hydrobromide (144 g) in acetonitrile (500 mL) and the resultant solution was heated at reflux for 14 hours. Removal of the solvents in vacuo and crystallization of the residue from a tetrahydrofuran/ethyl ether mixture gave the pure [[2-(nonyloxy)phenyl]methyl]triphenylphosphonium bromide (208 g).