Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH2:9][C:10]([N:12]([CH:21]([CH3:23])[CH3:22])[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[O:11])[C:7]2[CH:24]=[CH:25][CH:26]=[CH:27][C:6]=2[N:5]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:4](=[O:34])[CH2:3]1.[CH2:35]([N:42]1[C:50]2[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=2)[C:44]([CH2:51]Br)=[N:43]1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>CN(C=O)C.C1(C)C=CC=CC=1>[CH2:35]([N:42]1[C:50]2[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=2)[C:44]([CH2:51][CH:3]2[C:2](=[O:1])[N:8]([CH2:9][C:10]([N:12]([CH:21]([CH3:23])[CH3:22])[C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)=[O:11])[C:7]3[CH:24]=[CH:25][CH:26]=[CH:27][C:6]=3[N:5]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:4]2=[O:34])=[N:43]1)[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: COc1ccc(N(C(=O)CN2C(=O)CC(=O)N(c3ccccc3)c3ccccc32)C(C)C)cc1
Reactant: BrCc1nn(Cc2ccccc2)c2ccccc12
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: COc1ccc(N(C(=O)CN2C(=O)C(Cc3nn(Cc4ccccc4)c4ccccc34)C(=O)N(c3ccccc3)c3ccccc32)C(C)C)cc1
Reaction time: 0.17 h
Yield: 84.7 %

Procedure:
To a stirring solution of 490 mg (1.08 mmol) of 2-(2,4-Dioxo-5-phenyl-2,3,4,5-tetrahydro-benzo[b][1,4]diazepin-1-yl)-N-isopropyl-N-(4-methoxy-phenyl) acetamide, prepared as in Intermediate 4, in 12 mL DMF at 0° C. is added dropwise over 5 min 2.35 mL (1.18 mmol, 1.1 equiv) of a 0.5M solution of KN(TMS)2 in toluene. The resulting solution is stirred 10 min, then a solution of 355 mg (1.18 mmol, 1.1 equiv) of 1-Benzyl-3-bromomethyl-1H-indazole in 3 mL DMF is added. The resulting solution is stirred 4.5 h at RT and then quenched with 5 mL of H2O. The reaction mixture is then poured into 50 mL of EtOAc and extracted with H2O (2×50 mL). The organic layer is separated, dried (MgSO4), and the solvents removed in vacuo. Purification of the material by silica gel flash column chromatography using hexane/EtOAc 3/2 as eluent followed by lyophilization in acetonitrile/H2O afforded 620 mg of the title compound as a white amorphous solid: 1H NMR (CDCl3, 300 MHz) δ7.86 (d, 1H, J=8.1), 7.40 (d, 1H, J=7.9), 7.33-6.88 (m, 20H), 5.43 (s, 2H), 5.00 (m, 1H), 4.25 (m, 3H), 3.85 (m,4H), 3.58 (dd, 1H, J=5.1, 16.0), 1.06 (d, 6H, J=6.6); low resolution MS (FAB)m/e 678 (MH+), 677 (M+),
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N+:4]([O-])[CH:5]=[CH:6][C:7]=1[N+:8]([O-])=O.[CH2:12](OC(OCC)N(C)C)C.[H][H]>CN(C=O)C.C(O)C.C(O)(=O)C.[Pd]>[NH:8]1[C:7]2[C:2](=[CH:3][N:4]=[CH:5][CH:6]=2)[CH:1]=[CH:12]1
Reactant: Cc1c[n+]([O-])ccc1[N+](=O)[O-]
Reactant: [H][H]
Reactant: CCOC(OCC)N(C)C
Agent: [Pd]
Solvent: CCO
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: c1cc2[nH]ccc2cn1
Reaction time: 1.25 h
Yield: 51 %

Procedure:
This compound is prepared in a procedure similar to that described by J. R. Dormoy and A. Heymes in Tetrahedron, 1993, 49(14), 2885-2914. A stirred solution of 3-methyl-4-nitropyridine N-oxide (10.0 g, 65.0 mmol) and N,N-dimethylformamide diethyl acetal (14.5 g, 99 mmol) in DMF is placed in a preheated bath (90° C.) for 1.25 h, cooled and filtered. The filtercake is rinsed with a small amount of methanol and air-dried to give a purple-brown solid, 12.1 g. A portion of this solid (2.09 g, 10.0 mmol) is dissolved in ethanol (50 mL) and acetic acid (2 mL), treated with 10% palladium on carbon placed under 54 psi of hydrogen on a Parr shaker for 16 h and filtered through Celite. The filtrate is concentrated in vacuo and the concentrate is chromatographed (silica gel, 20:80 ethanol:EtOAc), followed by 50:50 ethanol:EtOAc as eluent) to afford the title 5-azaindole compound as a pink solid, 0.601 g (51% yield), identified by comparison of the NMR to literature (Can. J. Chem., 1969, 47, 3257).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:16]([CH2:17][C:18]([OH:20])=O)[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:33]([NH:36][CH2:37][CH2:38][CH3:39])[CH2:34][CH3:35]>O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:16]([CH2:17][C:18]([N:36]([CH2:37][CH2:38][CH3:39])[CH2:33][CH2:34][CH3:35])=[O:20])[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)Cn1c(-c2ccc(Br)cc2)nc2cccnc21
Reactant: CCCNCCC
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CCCN(CCC)C(=O)Cn1c(-c2ccc(Br)cc2)nc2cccnc21
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Under nitrogen bubbling, a mixture of 2-(4-bromophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (13.28 g, 0.04 mole) and 1,1' carbonyldiimidazole (7.14 g, 0.044 mole) in 300 ml of tetrahydrofuran was stirred at room temperature for 6 hrs. Then, under nitrogen atmosphere, dipropylamine (12.12 g, 0.12 mole) was added and the reaction mixture was heated at reflux for 3 hrs. The reaction mixture was filtered and the filtrate was evaporated to dryness. The solid was dried under high vacuum overnight and was recrystallized from isopropyl alcohol-water. The crystalline solid was collected by filtration, washed with water, and dried under high vacuum over the weekend to give 9.0 g (54%), mp 153°-55° C.
Reaction SMILES: [OH-].[Na+].CO.C([O:7][C:8]([C:10]1[C:14]([C:15]2[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][CH:16]=2)=[CH:13][S:12][C:11]=1[N:22]1[C:30](=[O:31])[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]1=[O:32])=[O:9])C.Cl>O>[Br:21][C:18]1[CH:19]=[CH:20][C:15]([C:14]2[C:10]([C:8]([OH:9])=[O:7])=[C:11]([N:22]3[C:30](=[O:31])[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[C:23]3=[O:32])[S:12][CH:13]=2)=[CH:16][CH:17]=1
Reactant: CCOC(=O)c1c(-c2ccc(Br)cc2)csc1N1C(=O)c2ccccc2C1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1c(-c2ccc(Br)cc2)csc1N1C(=O)c2ccccc2C1=O

Procedure:
To a solution of NaOH (1.4 mmol) in a 1:1 mixture of methanol:H2O (6 mL) is added 4-(4-bromophenyl)-2-(1,3-dioxo-1,3-dihydroisoindol-2-yl)-thiophene-3-carboxylic acid ethyl ester (0.7 mmol, Example 21, Part C). The mixture is heated to reflux for 90 min, then diluted with water (12 mL), chilled in an ice bath, and acidified with concentrated HCl. The product that precipitates is collected by filtration, washed with water, and dried, affording the desired compound.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].FC(F)(F)C(O)=O.[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([CH:38]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[C:30]([NH2:37])[CH:29]=3.[F:39][C:40]1[CH:45]=[CH:44][CH:43]=[C:42]([N:46]=[C:47]=[O:48])[CH:41]=1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([CH:38]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[C:30]([NH:37][C:47]([NH:46][C:42]1[CH:43]=[CH:44][CH:45]=[C:40]([F:39])[CH:41]=1)=[O:48])[CH:29]=3
Reactant: Nc1cc2cc(c1)Nc1nc(ncc1Cl)Nc1cccc(c1)CC2
Reactant: O=C=Nc1cccc(F)c1
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1cccc(F)c1)Nc1cc2cc(c1)Nc1nc(ncc1Cl)Nc1cccc(c1)CC2
Yield: 49 %

Procedure:
The desired compound was prepared according to the procedure of Example B83, using 6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-11-amine bis(trifluoroacetate) and 1-fluoro-3-isocyanatobenzene as the starting materials in 49% yield. LCMS for C25H21ClFN6O (M+H)+: m/z=475.2. 1H NMR (400 MHz, DMSO-d6): δ 9.56 (s, 1H), 9.47 (s, 1H), 9.03 (m, 1H), 8.81 (m, 1H), 8.12 (s, 1H), 7.86 (m, 1H), 7.40 (m, 1H), 7.31 (m, 1H), 7.24 (m, 2H), 7.05 (m, 3H), 6.84 (m, 2H), 6.68 (m, 1H), 2.82 (m, 4H).
Reaction SMILES: ICCCOC/C=C/C1C=CC2OCC[O:16][C:11]=2C=1.[NH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.[C:25](=[O:28])([O-:27])[O-].[Na+].[Na+].CS(C)=[O:33]>>[NH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.[C:11]([O-:16])(=[O:33])[C:25]([O-:27])=[O:28]
Reactant: CS(C)=O
Reactant: ICCCOC/C=C/c1ccc2c(c1)OCCO2
Reactant: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCNCC1
Product: O=C([O-])C(=O)[O-]

Procedure:
A Following the procedure described in example 7§B, but starting from trans-2,3-dihydro-6-[3-(3-iodopropoxy)prop-1-en-1-yl]benzo[1,4]dioxine (200 mg), piperidine (165 μL) and sodium carbonate (294 mg) in dimethylsulfoxide (1.8 mL) affords 172 mg of 1-{3-[3-(2,3-dihydrobenzo[1,4]dioxin-6-yl)allyl]oxy}propyl)piperidine, oxalate melting at 120° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][C:14]=2[O:22][CH3:23])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CO.C1(C)C=CC=CC=1>C1COCC1.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][C:14]=2[O:22][CH3:23])[CH2:11]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1cc([N+](=O)[O-])ccc1OC1CN(C(=O)OC(C)(C)C)C1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COc1cc(N)ccc1OC1CN(C(=O)OC(C)(C)C)C1
Yield: 101 %

Procedure:
Dissolve 3-(2-methoxy-4-nitro-phenoxy)-azetidine-1-carboxylic acid tert-butyl ester (210 g, 639 mmol) in THF (630 mL) and transfer with MeOH (1680 mL) to a stainless steel tank containing 10% palladium on carbon pre-wet with toluene. Hydrogenate the mixture on a Parr shaker for 2.5 h. Remove the catalyst by filtration through diatomaceous earth and rinse the solids with MeOH. Concentrate the filtrate in vacuo, and then co-evaporate the residue three times with heptane (500 mL each time) to obtain 190 g (99%) of the title compound as a tan solid which is used immediately in the next reaction. 1H NMR (300 MHz, CDCl3) δ: 6.48 (d, 1H, J=8.5), 6.30 (d, 1H, J=2.6), 6.17 (dd, 1H, J=2.4, 8.5), 4.77 (m, 1H), 4.19 (m, 2H), 4.04 (m, 2H), 3.81 (s, 3H), 3.59 (br s, 2H), 1.42 (s, 9H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[NH:15][C:14]4[CH:16]=[C:17]([O:20][CH3:21])[CH:18]=[CH:19][C:13]=4[N:12]=3)=[N:9][NH:8][C:5]2=[N:6][CH:7]=1.[H-].[Na+].[CH3:24][Si:25]([CH2:28][CH2:29][O:30][CH2:31]Cl)([CH3:27])[CH3:26]>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:15]([CH2:31][O:30][CH2:29][CH2:28][Si:25]([CH3:27])([CH3:26])[CH3:24])[C:14]4[CH:16]=[C:17]([O:20][CH3:21])[CH:18]=[CH:19][C:13]=4[N:12]=3)=[N:9][N:8]([CH2:31][O:30][CH2:29][CH2:28][Si:25]([CH3:27])([CH3:26])[CH3:24])[C:5]2=[N:6][CH:7]=1
Reactant: COc1ccc2nc(-c3n[nH]c4ncc(Br)cc34)[nH]c2c1
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc2nc(-c3nn(COCC[Si](C)(C)C)c4ncc(Br)cc34)n(COCC[Si](C)(C)C)c2c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
5-bromo-3-(6-methoxy-1H-benzoimidazol-2-yl)-1H-pyrazolo[3,4-b]pyridine Compound 19c (HOAc salt, 50 mg, 0.145 mmol) was added to a suspension of NaH (60% in mineral oil, 23 mg, 0.581 mmol) in DMF (5 mL). The mixture was stirred at r.t. for 5 mins, then SEMCl (97 mg, 0.581 mmol) was added. The mixture was stirred at r.t. for 12 hrs, then diluted with AcOEt (60 mL) and washed with water. The solvent was evaporated to dryness and the residue was purified by chromatography to provide 5-bromo-3-[6-methoxy-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazol-2-yl]-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-b]pyridine Compound 20a (60 mg, 78% yield) as a sticky oil.
Reaction SMILES: O=[C:2]([CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:3]([OH:5])=[O:4].C(OC(N[NH:25][CH:26]([C:28]([N:30]1[CH2:37][CH2:36][CH2:35][C@H:31]1[C:32]([OH:34])=[O:33])=[O:29])[CH3:27])=O)C1C=CC=CC=1.C([BH3-])#[N:39].[Na+]>>[C:3]([CH:2]([NH:25][CH:26]([C:28]([N:30]1[CH2:37][CH2:36][CH2:35][C@H:31]1[C:32]([OH:34])=[O:33])=[O:29])[CH2:27][NH2:39])[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([OH:5])=[O:4]
Reactant: [BH3-]C#N
Reactant: O=C(O)C(=O)CCc1ccccc1
Reactant: CC(NNC(=O)OCc1ccccc1)C(=O)N1CCC[C@H]1C(=O)O
Agent: [Na+]
Product: NCC(NC(CCc1ccccc1)C(=O)O)C(=O)N1CCC[C@H]1C(=O)O

Procedure:
Under basic conditions, DL-α,β-diaminopropionic acid is reacted with excess benzyloxycarbonyl chloride to yield upon acidification D,L-α,β-bis(benzyloxycarbonylamino)-propionic acid (mp=123.5°-124° C. ). Phosphorous pentachloride is added to a chloroform solution containing the di-Cbz product to yield on workup D,L-4-(benzyloxycarbonylaminomethyl)-oxazolidin-2,5-dione. A solution of L-proline t-butyl ester in methylene chloride is added to the N-carboxyanhydride in tetrahydrofuran at -60° C. After overnight freezer storage, the mixture is stripped to dryness affording crude product. Trifluoroacetic acid effectively cleaves the t-butyl ester in 2 hours at room temperature resulting in a gross mixture of L-proline and β-benzyloxycarbonylamino-D,L-alanyl-L-proline. Gel filtration chromatography (LH-20) results in pure dipeptide. 2-Oxo-4-phenylbutyric acid and benzyloxycarbonylamino-D,L-alanyl-L-proline are condensed in the presence of sodium cyanoborohydride. Removal of the protecting group from the resulting product yields N-(1-carboxy-3-phenylpropyl)-β-amino-D,L-alanyl-L-proline. The nmr in D2O showed aromatic protons at 7.4δ, methine protons at 4.2δ and multiplets at 3.7, 3.2, 2.9 and 2.1δ.
Reaction SMILES: C(N(CC)CC)C.[F:8][C:9]1[CH:17]=[CH:16][C:12]([C:13](Cl)=[O:14])=[CH:11][CH:10]=1.[NH2:18][C:19]1[CH:31]=[C:30]([C:32]2[O:33][C:34]3[CH:40]=[CH:39][CH:38]=[CH:37][C:35]=3[CH:36]=2)[CH:29]=[CH:28][C:20]=1[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22].C(=O)([O-])O.[Na+]>C(Cl)Cl>[O:33]1[C:34]2[CH:40]=[CH:39][CH:38]=[CH:37][C:35]=2[CH:36]=[C:32]1[C:30]1[CH:29]=[CH:28][C:20]([C:21]([O:23][C:24]([CH3:27])([CH3:25])[CH3:26])=[O:22])=[C:19]([NH:18][C:13](=[O:14])[C:12]2[CH:16]=[CH:17][C:9]([F:8])=[CH:10][CH:11]=2)[CH:31]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)c1ccc(-c2cc3ccccc3o2)cc1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)c1ccc(-c2cc3ccccc3o2)cc1NC(=O)c1ccc(F)cc1
Reaction time: 5 h

Procedure:
0.054 mL of triethylamine and 0.035 mL of 4-fluorobenzoyl chloride were added to 3.5 mL of methylene chloride solution containing 60 mg of tert-butyl 2-amino-4-(benzofuran-2-yl)benzoate at room temperature sequentially and stirred at the same temperature for 5 hours. A saturated sodium hydrogen carbonate aqueous solution was added to the reaction mixture, and the organic layer was separated, and the solvent was evaporated under reduced pressure. The obtained residue was purified with silica gel column chromatography [Flash Tube 2008 manufactured by Trikonex Company, eluent; hexane:ethyl acetate=4:1]to obtain tert-butyl 4-(benzofuran-2-yl)-2-(4-fluorobenzamido)benzoate.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][C:14]1[N:15]=[N:16][CH:17]=[CH:18][CH:19]=1.[CH:20](=[O:22])[CH3:21].[Cl-].[NH4+]>O1CCCC1.CCCCCC>[N:16]1[CH:17]=[CH:18][CH:19]=[C:14]([CH2:13][CH:20]([OH:22])[CH3:21])[N:15]=1
Reactant: CC=O
Reactant: Cc1cccnn1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC(O)Cc1cccnn1
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 18.7 %

Procedure:
Diisopropylamine (8.52 ml) was dissolved in tetrahydrofuran (100 ml). To the solution was added dropwise, at 0° C., n-butyl lithium (a 1.64M hexane solution, 36.6 ml). The mixture was stirred for 30 minutes at the same temperature. The reaction mixture was cooled to −70° C., to which was added dropwise a solution of 3-methyl pyridazine (4.71 g) in tetrahydrofuran (10 ml). The mixture was stirred for 30 minutes at the same temperature, to which then added acetaldehyde (2.45 g). The mixture was wormed up to room temperature over 30 minutes, which was stirred for 6 hours at the same temperature. To the reaction mixture was added a saturated aqueous solution of ammonium chloride (10 ml). The mixture was concentrated under reduced pressure. The concentrate was purified by means of a silica gel chromatography (developing solvent: ethyl acetate-methanol 1:0→9:1) to afford the title compound (1.29 g).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[C:9]2=[O:12])=[CH:4][C:3]=1[F:22].C([O-])([O-])=O.[K+].[K+].[C:29]1(B(O)O)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C1(C)C=CC=CC=1>[F:22][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:2]=1[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:9](=[O:12])[N:8]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)[CH:7]=[CH:6]2
Reactant: OB(O)c1ccccc1
Reactant: COc1ccc(Cn2ccc3cc(F)c(Br)cc3c2=O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: COc1ccc(Cn2ccc3cc(F)c(-c4ccccc4)cc3c2=O)cc1
Temperature: 100 °C

Procedure:
453 mg (1.25 mmol) 7-bromo-6-fluoro-2-(4-methoxy-benzyl)-2H-isoquinolin-1-one (313), 432 mg (3.125 mmol) K2CO3 and 190.5 mg (1.56 mmol) phenylboronic acid were dissolved in 12.5 mL toluene. Under Argon, 72 mg (0.062 mmol) Pd(Ph3)4 were added and the solution was stirred at 100° C. After complete conversion, the solvent is removed i. vac. and saturated sodium bicarbonate solution is added. The aqueous solution is extracted three times with dichloromethane and the organic layers are dried with MgSO4. After evaporation, the crude product is purified by preparative HPLC. Rt=1.80 min (Method C). Detected mass: 360.4 (M+H+).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[N:13]([CH2:16][C:17]([O:19]C)=O)[C:12](S(C)(=O)=O)=[N:11][C:10]=1[C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.Cl.[CH3:32][NH:33][NH:34][CH3:35].C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH2:1]([O:8][C:9]1[C:14](=[O:15])[N:13]2[C:12]([N:33]([CH3:32])[N:34]([CH3:35])[C:17](=[O:19])[CH2:16]2)=[N:11][C:10]=1[C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CNNC
Reactant: CCOC(=O)c1nc(S(C)(=O)=O)n(CC(=O)OC)c(=O)c1OCc1ccccc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1nc2n(c(=O)c1OCc1ccccc1)CC(=O)N(C)N2C
Temperature: 22 °C
Reaction time: 4 h
Yield: 68.7 %

Procedure:
A mixture of intermediate 3, ethyl 5-benzyloxy-1-(methoxycarbonylmethyl)-2-(methylsulfonyl)-6-oxo-1,6-dihydropyrimidine-4-carboxylate, (0.487 g, 1.15 mmol) in N,N-dimethylformamide (25 ml) was treated with 1,2-dimethylhydrazine dihydrochloride (1.56 g, 11.7 mmol) followed by N,N-diisopropylethylamine (4.1 ml, 11.7 mmol) and the resulting mixture stirred at 22° C. for 4 h. The solvent was then removed in vacuo and the residue diluted with ethyl acetate, washed successively with saturated sodium bicarbonate and brine then dried over anhydrous magnesium sulfate. Evaporation of the solvent followed by chromatography on silica gel (elution with a gradient of ethyl acetate 0–50% in toluene) gave 0.294 g (69% yield) of the title ester as a clear syrup.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([N+:9]([O-:11])=[O:10])[C:3]=1[O:12][CH2:13][CH:14]([OH:16])[CH3:15].[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1.C(OCC)(=O)C.Cl>N1C=CC=CC=1>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([N+:9]([O-:11])=[O:10])[C:3]=1[O:12][CH2:13][CH:14]([O:16][S:23]([C:20]1[CH:21]=[CH:22][C:17]([CH3:27])=[CH:18][CH:19]=1)(=[O:25])=[O:24])[CH3:15]
Reactant: CC(O)COc1c([N+](=O)[O-])ccc(F)c1F
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)OC(C)COc2c([N+](=O)[O-])ccc(F)c2F)cc1
Reaction time: 4 h
Yield: 87.2 %

Procedure:
To a solution of 4.5 g of the compound obtained in Example 5 in 8.6 ml of pyridine was added 4.36 g of p-toluenesulfonyl chloride and the mixture was stirred under cooling with ice for 4 hours, and then at room temperature for 4 hours. To the mixture were added ethyl acetate and 1 N hydrochloric acid. The mixture was shaken, and the organic layer was separated. The organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure. The residue was purified through silica gel column chromatography to yield 6.52 g of the titled compound.
Reaction SMILES: CC1C=[C:12]2[O:14]C=1C[C@H](C(C)=C)CCC1C(=O)O[C@@H]([C@H]2C(C)=C)C=1.[C:24]([O:28][C:29](=[O:43])[N:30]([CH2:32][C@H:33]1[CH2:38][CH2:37][C@H:36]([CH:39]=[C:40](Br)Br)[CH2:35][CH2:34]1)[CH3:31])([CH3:27])([CH3:26])[CH3:25].[Li]CCCC.C=O>C1COCC1>[C:24]([O:28][C:29](=[O:43])[N:30]([CH2:32][C@H:33]1[CH2:38][CH2:37][C@H:36]([C:39]#[C:40][CH2:12][OH:14])[CH2:35][CH2:34]1)[CH3:31])([CH3:27])([CH3:26])[CH3:25]
Reactant: C=C(C)[C@@H]1CCC2=C[C@@H](OC2=O)[C@@H](C(=C)C)c2cc(C)c(o2)C1
Reactant: CN(C[C@H]1CC[C@H](C=C(Br)Br)CC1)C(=O)OC(C)(C)C
Agent: C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CN(C[C@H]1CC[C@H](C#CCO)CC1)C(=O)OC(C)(C)C
Temperature: 25 °C

Procedure:
The following reaction was performed in analogy to the reaction described in: Marshall, James A.; Bartley, Gary S.; Wallace, Eli M. Total Synthesis of the Pseudopterane (−)-Kallolide B, the Enantiomer of Natural (+)-Kallolide B. J. Org. Chem. (1996), 61(17), 5729–5735 and Baker, Raymond; Boyes, Alastair L.; Swain, Christopher J. Synthesis of talaromycins A, B, C, and E. J. Chem. Soc., Perkin Trans. 1 (1990), (5), 1415–21.). A solution of 32.9 g (80 mmol) of trans-[4-(2,2-Dibromo-vinyl)-cyclohexylmethyl]-methyl-carbamic acid tert-butyl ester in 640 ml THF was treated at −78° C. with 105 ml (168 mmol) of BuLi (ca 1.6 M in hexane). After 2 h at this temperature 24 g (800 mmol) of paraformaldehyde were added. The reaction mixture was warmed up to RT for 3 h and after 0.5 h at this temperature extracted with water/Et2O (3×). The organic phases were washed with aqueous 10% NaCl, dried over Na2SO4 and evaporated. Purification by flash-chromatography on silica gel (hexane/EtOAc 9:1 to 2:1) yielded 12.1 g (54%) of trans-[4-(3-Hydroxy-prop-1-ynyl)-cyclohexylmethyl]-methyl-carbamic acid tert-butyl ester, MS: 282 (MH+).
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1.[C:15]([N:22]1[CH:26]=[CH:25]N=[CH:23]1)(N1C=CN=C1)=[O:16].[Cl:27][C:28]1[CH:36]=C2[C:31](CCN2)=[CH:30][C:29]=1[CH3:37]>ClCCl.CN(C)C=O>[Cl:27][C:28]1[CH:36]=[C:23]2[C:31]([CH2:25][CH2:26][N:22]2[C:15](=[O:16])[NH:6][C:5]2[CH:7]=[CH:8][C:2]([CH3:1])=[C:3]([C:9]3[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=3)[CH:4]=2)=[CH:30][C:29]=1[CH3:37]
Reactant: Cc1cc2c(cc1Cl)NCC2
Reactant: Cc1ccc(N)cc1-c1cccnc1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1cc2c(cc1Cl)N(C(=O)Nc1ccc(C)c(-c3cccnc3)c1)CC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 57 %

Procedure:
4-Methyl-3-(pyrid-3-yl) aniline (0.30 g, 0.0016 mole) in dry dichloromethane (20 ml) was added, under argon, to 1,1'-carbonyldiimidazole in dry dichloromethane (10 ml) (0.30 g, 0.0018 mole) and stirred at ambient temperature for 1 hour. The solvent was removed in vacuo and the residue dissolved in dry dimethylformamide (30 ml). 6-Chloro-5-methylindoline (see WO 95/01976) (0.27 g, 0.0016 mole) in dry dimethylformamide (10 ml) was added and the mixture heated to 100° C. for 1 hour. After cooling to ambient temperature, the solvent was removed in vacuo and the residue diluted with deionised water (15 ml), extracted into dichloromethane (2×20 ml), dried (Na2SO4) and evaporated in vacuo. The residue was purified by flash column chromatography on silica gel, eluting with 3% methanol/dichloromethane and the resulting solid recrystallised from ethyl acetate/methanol/60-80° petroleum ether to afford the title compound (0.31 g, 57%) as a cream solid (mp 202-203° C.).