Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([F:11])[C:3]=1[N:12]1[CH2:21][CH2:20][C:15]2(OCC[O:16]2)[CH2:14][CH2:13]1.O.Cl>CC(C)=O>[F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([F:11])[C:3]=1[N:12]1[CH2:21][CH2:20][C:15](=[O:16])[CH2:14][CH2:13]1
Reactant: O=[N+]([O-])c1cc(F)c(N2CCC3(CC2)OCCO3)c(F)c1
Agent: Cl
Solvent: O
Solvent: CC(C)=O
Product: O=C1CCN(c2c(F)cc([N+](=O)[O-])cc2F)CC1
Temperature: 50 °C
Reaction time: 8 h
Yield: 81 %

Procedure:
The crude 8-(2,6-difluoro-4-nitrophenyl)-1,4-dioxa-8-azaspiro[4.5]decane from the preceding procedure was dissolved in 4:1 acetone:water (100 mL). Concentrated HCl (5 mL) was added, and the resulting mixture was stirred at 50° C. for 8 hours and then cooled to room temperature. The mixture was concentrated in vacuo to approximately 20 mL, which was carefully added to concentrated aq. NaHCO3 (100 mL) and extracted with EtOAc (2×100 mL). The combined organic extracts were dried over Na2SO4, filtered and concentrated in vacuo. The crude product was triturated with Et2O and hexanes to give a bright-yellow solid that was collected and dried to provide the title compound (7.13 g, 81%).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C:2]1=[O:6].C1(C)C=CC=CC=1.[OH-].[Na+].[CH2:16]([O:19][C:20](Cl)=[O:21])[CH:17]=[CH2:18]>O1CCCC1.O>[O:6]=[C:2]1[CH2:3][CH2:4][CH2:5][N:1]1[C:20]([O:19][CH2:16][CH:17]=[CH2:18])=[O:21]
Reactant: O=C1CCCN1
Reactant: C=CCOC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: O
Product: C=CCOC(=O)N1CCCC1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 57 %

Procedure:
Into a 500 mL four neck flask were added 2-pyrrolidone (17.02 g) [mw. 85.10, 200 mmol] and toluene (340 mL), and the mixture was dissolved. Powder sodium hydroxide (8.00 g) [mw. 40.00, 200 mmol] was added thereto, Dean-Stark trap was set, and the mixture was subjected to dehydration reflux for 4 hr. After cooling to 0° C., allyloxycarbonyl chloride (20.10 g) [mw. 120.53, 167 mmol] was added at not more than 30° C., and the mixture was stirred at 25° C. for 30 min. Water (85 mL) and tetrahydrofuran (85 mL) were added to allow for partitioning. The organic layer was washed with 5 w/w aqueous potassium hydrogen sulfate solution (85 mL), and further washed twice with water (85 mL). The organic layer was concentrated under reduced pressure, and the solvent was replaced with tetrahydrofuran. Pale-yellow oil, 19.28 g, yield 57.0%, 1H-NMR (500 MHz, CDCl3, TMS) δ 2.09 (quin, J=7.7 Hz, 2H), 2.54 (t, J=8.2 Hz, 2H), 3.80-3.86 (m, 2H), 4.70-4.77 (m, 2H), 5.25-5.38 (m, 1H), 5.38-5.45 (m, 1H), 5.88-6.04 (m, 1H). 13C-NMR (125 MHz, CDCl3, CDCl3) δ 17.57, 32.78, 46.42, 66.87, 118.76, 131.57, 151.38, 173.98.
Reaction SMILES: CN(C)CCCN=C=NCC.[NH2:12][C:13]1[C:14]([O:28][CH2:29][CH:30]2[CH2:35][CH2:34][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:32][CH2:31]2)=[CH:15][C:16]([NH:19][C:20]2[CH:25]=[N:24][C:23]([C:26]#[N:27])=[CH:22][N:21]=2)=[N:17][CH:18]=1.[CH3:43][N:44]([CH3:49])[CH2:45][C:46](O)=[O:47].O.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C>CN(C=O)C>[C:26]([C:23]1[N:24]=[CH:25][C:20]([NH:19][C:16]2[CH:15]=[C:14]([O:28][CH2:29][CH:30]3[CH2:35][CH2:34][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:32][CH2:31]3)[C:13]([NH:12][C:46](=[O:47])[CH2:45][N:44]([CH3:49])[CH3:43])=[CH:18][N:17]=2)=[N:21][CH:22]=1)#[N:27]
Reactant: CC(C)(C)OC(=O)N1CCC(COc2cc(Nc3cnc(C#N)cn3)ncc2N)CC1
Reactant: CN(C)CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)CC(=O)Nc1cnc(Nc2cnc(C#N)cn2)cc1OCC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 14.2 %

Procedure:
1-[3-(Dimethylamino)propyl]-3-ethylcarbodiimide (95 mg, 0.49 mmol) was added to a solution of tert-butyl 4-((5-amino-2-(5-cyanopyrazin-2-ylamino)pyridin-4-yloxy)methyl)piperidine-1-carboxylate (140 mg, 0.33 mmol), N,N-dimethylglycine (51 mg, 0.49 mmol), 1-hydroxybenzotriazole hydrate (76 mg, 0.49 mmol) and N-ethyldiisopropylamine (86 μL, 0.49 mmol) in DMF (4 mL). The mixture was stirred overnight at room temperature then partitioned between ethyl acetate and water. The organic phase was washed sequentially with water, dilute sodium bicarbonate solution and brine, then dried (Na2SO4) and concentrated. Preparative HPLC gave tert-butyl 4-((2-(5-cyanopyrazin-2-ylamino)-5-(2-(dimethylamino)acetamido)pyridin-4-yloxy)methyl)piperidine-1-carboxylate (24 mg, 14%) as an off-white powder.
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]1[C:9]2([CH2:15][O:14][CH2:13][CH2:12][O:11][CH2:10]2)[N:8]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:7][C@@H:6]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[NH:5]1.Br[CH2:30][C:31]([O:33][CH3:34])=[O:32]>CN(C=O)C>[CH3:34][O:33][C:31](=[O:32])[CH2:30][N:5]1[C:4](=[O:3])[C:9]2([CH2:15][O:14][CH2:13][CH2:12][O:11][CH2:10]2)[N:8]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:7][C@H:6]1[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](c2ccccc2)NC(=O)C12COCCOC2
Reactant: COC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)CN1C(=O)C2(COCCOC2)N(C(=O)OC(C)(C)C)C[C@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
24 mg (0.55 mmol) sodium hydride were added to 0.18 g (0.5 mmol) (3R)-tert-butyl 5-oxo-3-phenyl-8,11-dioxa-1,4-diazaspiro[5.6]dodecane-1-carboxylate in 3 ml DMF. After 5 min at RT 54 μl (0.91 mmol) methyl bromoacetate were added and then the reaction mixture was stirred for 1 h at RT. The reaction was poured onto ice water and extracted with ethyl acetate. The organic phase was washed with water, dried and evaporated down.
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH2:5][CH2:6][CH:7]2OC.CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Br:1][CH2:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH2:5][CH:6]=[CH:7]2
Reactant: COC1CCc2c(CBr)cccc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: BrCc1cccc2c1CC=C2

Procedure:
To a hot (110° C.) solution of 2.41 g (10.0 mmol) of 4-(bromomethyl)-1-methoxyindane in 40 ml of toluene 0.20 g of TsOH was added. This mixture was refluxed for 2 hours using a Dean-Stark head. The resulting mixture was passed through short column (4 cm) with silica gel 60 (40-63 μm), the silica gel layer was additionally washed by 20 ml of toluene. The combined elute was evaporated to dryness, the product was isolated by flash chromatography on silica gel 60 (40-63 μm, eluent: hexanes). Yield 1.98 g (95%) of the title material. Anal. calc. for C10H9Br: C, 57.44; H, 4.34. Found: C, 57.32; H, 4.41. 1H NMR (CDCl3): δ 7.40 (m, 1H, 4-H), 7.29 (m, 1H, 5-H), 7.22 (m, 1H, 6-H), 6.92 (m, 1H, 3-H), 6.63 (m, 1H, 2-H), 4.62 (s, 2H, CH2Br), 3.48 (m, 2H, 1,1′-H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.[NH2:18][CH:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[N:21]([CH3:35])[C:20]1=[O:36]>>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([NH:18][CH:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[N:21]([CH3:35])[C:20]2=[O:36])=[O:17])[CH3:14])=[O:11])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: CN1C(=O)C(N)c2ccccc2C1c1ccccc1
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Product: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)NC1C(=O)N(C)C(c2ccccc2)c2ccccc21

Procedure:
Following General Procedure D above using N-(3,5-difluorophenylacetyl)-1H-alanine (Example B) and 4-amino-2-methyl-1-phenyl-1,2,3,4-tetrahydroisoquinoline-3-one (General Procedure 5-D), the title compound was prepared as a solid having a melting point of 115° C.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[CH3:12][N:13]([CH3:23])[C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1>>[CH3:12][N:13]([CH3:23])[C:14]1[CH:19]=[CH:18][C:17]([C:2]2[CH:11]=[C:10]3[C:5]([CH:6]=[CH:7][CH:8]=[N:9]3)=[CH:4][CH:3]=2)=[CH:16][CH:15]=1
Reactant: CN(C)c1ccc(B(O)O)cc1
Reactant: Brc1ccc2cccnc2c1
Product: CN(C)c1ccc(-c2ccc3cccnc3c2)cc1

Procedure:
N,N-Dimethyl-4-(quinolin-7-yl)aniline T504 was prepared using general procedure A from 7-bromoquinoline (52 mg, 0.25 mmol) and (4-(dimethylamino)phenyl)boronic acid (41 mg, 0.25 mmol). The product T504 was obtained as a yellow solid (52 mg, 83%). 1H NMR (400 MHz, CDCl3): δ 8.89 (dd, J=4.4, 1.6 Hz, 1H), 8.28 (m, 1H), 8.12 (dq, J=8.4, 0.8 Hz, 1H), 7.81 (d, J=1.2 Hz, 2H), 7.68 (m, 2H), 7.33 (dd, J=8.4, 4.4 Hz, 1H), 6.84 (m, 2H), 3.00 (s, 3H); MS (ESI): 249 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][OH:18])[CH2:11][CH2:10]1.O=CCCCNC(=O)C1C=CC=CC=1>>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][CH:17]=[O:18])[CH2:13][CH2:14]1
Reactant: OCCCN1CCN(c2cccc(Cl)c2Cl)CC1
Agent: O=CCCCNC(=O)c1ccccc1
Product: O=CCCN1CCN(c2cccc(Cl)c2Cl)CC1

Procedure:
3-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-propionaldehyde (36B) is prepared from 36A as described for 1E.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:10])[C:5]([NH2:9])=[CH:6][C:7]=1I.[Cl:11][C:12]1[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([NH2:10])[C:5]([NH2:9])=[CH:6][C:7]=1[C:16]1[CH:15]=[CH:14][CH:13]=[C:12]([Cl:11])[C:17]=1[Cl:18]
Reactant: Nc1cc(Cl)c(I)cc1N
Reactant: OB(O)c1cccc(Cl)c1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Nc1cc(Cl)c(-c2cccc(Cl)c2Cl)cc1N
Temperature: 100 °C
Reaction time: 8 h

Procedure:
To a solution of 4-chloro-5-iodobenzene-1,2-diamine (100 mg, 0.37 mmol) in dioxane (15 ml) and water (5 ml) was added (2,3-dichlorophenyl)boronic acid (141.3 mg, 0.74 mmol), sodium carbonate (118.2 mg, 1.10 mmol) and Pd(PPh3)4 (42.9 mg, 0.04 mmol). The resulting solution was stirred overnight at 100° C. within an inert atmosphere of nitrogen. The resulting solution was concentrated under vacuum and dissolved in water (100 ml) and extracted with ethyl acetate (4×30 ml). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum to give a residue, which was purified by a silica gel column with between 5% to 25% ethyl acetate in petroleum ether to afford 4-chloro-5-(2,3-dichlorophenyl)benzene-1,2-diamine as a brown solid (92 mg, crude). Finally, the solution of 4-chloro-5-(2,3-dichlorophenyl)benzene-1,2-diamine (100 mg, 0.35 mmol) in pentafluoropropionic acid (35 ml) and hydrochloric acid (conc, 7 ml) was stirred overnight at 100° C. and then concentrated under vacuum. The residue was dissolved in water (100 ml) and extracted with ethyl acetate (4×30 ml), dried over anhydrous sodium sulfate and concentrated. The crude product (500 mg) was purified by Prep-HPLC to afford 5-chloro-6-(2,3-dichlorophenyl)-2-(pentafluoroethyl)-1H-1,3-benzodiazole. TFA salt as a white solid (42 mg).
Reaction SMILES: O=[C:2]1[N:25]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]([OH:36])=[O:35])[C:6]2=[N:7][C:8]([C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=3)=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=3)[N:10]=[C:5]2[CH2:4][CH2:3]1.N1([BH3-])CCCC1.[Li+]>C1COCC1>[C:14]1([CH3:17])[CH:13]=[CH:12][C:11]([C:9]2[N:10]=[C:5]3[CH2:4][CH2:3][CH2:2][N:25]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]([OH:36])=[O:35])[C:6]3=[N:7][C:8]=2[C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)=[CH:16][CH:15]=1
Reactant: Cc1ccc(-c2nc3c(nc2-c2ccc(C)cc2)N(CCCCCCCCC(=O)O)C(=O)CC3)cc1
Agent: [BH3-]N1CCCC1
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1ccc(-c2nc3c(nc2-c2ccc(C)cc2)N(CCCCCCCCC(=O)O)CCC3)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
9-(6-Oxo-2,3-di-p-tolyl-7,8-dihydropyrido[2,3-b]pyrazin-5(6H)-yl)nonanoic acid (Example 8) (200 mg, 0.412 mmol) in THF (10 ml) was stirred under N2 for 10 mins. Lithium pyrrolidinoborohydride (1M in THF) (2.059 ml, 2.059 mmol) was added carefully and the resulting mixture was stirred at RT for 1.5 hours. The reaction was quenched with 1M HCl and the mixture was concentrated under reduced pressure. The resulting mixture was extracted with DCM and the organic extracts were passed through a phase separating column. The organics were concentrated under reduced pressure and purification of the crude product by chromatography on silica eluting with 0-100% EtOAc in iso-hexane afforded the titled compound;
Reaction SMILES: [CH:1](/[N:14]=[CH:15]/[C:16]1[O:20][N:19]=[C:18]([CH3:21])[C:17]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[C:28]([C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=1)=[O:29])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)Cl.[Si]([C:44]#[N:45])(C)(C)C>C([O-])(O)=O.[Na+]>[CH:1]([NH:14][CH:15]([C:16]1[O:20][N:19]=[C:18]([CH3:21])[C:17]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[C:28](=[O:29])[C:30]1[CH:31]=[CH:32][C:33]([Cl:36])=[CH:34][CH:35]=1)[C:44]#[N:45])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: C[Si](C)(C)C#N
Reactant: Cc1noc(/C=N/C(c2ccccc2)c2ccccc2)c1-c1ccccc1C(=O)c1ccc(Cl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1noc(C(C#N)NC(c2ccccc2)c2ccccc2)c1-c1ccccc1C(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.8 %

Procedure:
To a round bottomed flask was added (E)-(2-(5-((benzhydrylimino)methyl)-3-methylisoxazol-4-yl)phenyl)(4-chlorophenyl)methanone (320 mg, 0.652 mmol), DCM (4.5 mL), and Yt(OTf)3 (40.4 mg, 0.065 mmol). To this solution was added TMS-CN (175 μl, 1.304 mmol) and the reaction was stirred overnight at room temperature. This solution was diluted with saturated aqueous NaHCO3. The layers were separated and the aqueous phase was extracted with DCM. The combined organic layers were dried over Na2SO4, filtered, and concentrated. The crude residue was purified via Biotage (EtOAc/hex) to afford the titled compound (300 mg, 0.579 mmol). LC/MS m/z 518 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]([N:5]1[CH2:11][C@@H:10]([CH3:12])[C:9]2[CH:13]=[C:14]([Cl:17])[CH:15]=[CH:16][C:8]=2[CH2:7][CH2:6]1)=[O:4].[Br:20]N1C(=O)CCC1=O.FC(F)(F)S(O)(=O)=O>ClC(Cl)C.C(OCC)(=O)C>[F:19][C:2]([F:18])([F:1])[C:3]([N:5]1[CH2:11][C@@H:10]([CH3:12])[C:9]2[C:13]([Br:20])=[C:14]([Cl:17])[CH:15]=[CH:16][C:8]=2[CH2:7][CH2:6]1)=[O:4]
Reactant: O=C1CCC(=O)N1Br
Reactant: C[C@@H]1CN(C(=O)C(F)(F)F)CCc2ccc(Cl)cc21
Agent: O=S(=O)(O)C(F)(F)F
Solvent: CC(Cl)Cl
Solvent: CCOC(C)=O
Product: C[C@@H]1CN(C(=O)C(F)(F)F)CCc2ccc(Cl)c(Br)c21
Temperature: 75 °C
Reaction time: 16 h
Yield: 16.7 %

Procedure:
A solution of (S)—N-Trifluoroacetyl-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (0.875 g, 3.0 mmol) in dichloroethane (7 mL) was treated with N-bromosuccinimide (0.284 g, 2.1 mmol) and trifluoromethanesulfonic acid (0.639 g, 4.2 mmol). The reaction was stirred for 16 h at 75° C., diluted with ethyl acetate (20 mL) and extracted with water (2×10 mL). The organics were dried with MgSO4, filtered and concentrated. Flash chromatography (5% EtOAc in hexanes, silica) resulted in 0.13 g of a clear oil. MS calculated for C13H12BrClF3NO+H: 370, observed: 370.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH2:18][C:17]3[C:16]4[N:15]=[CH:14][CH:13]=[CH:12][C:11]=4[O:10][C:9]=3[C:8]([CH3:20])([CH3:19])[C:7]=2[CH:21]=1.Cl([O-])=[O:23].[Na+].ON1C(=O)C2=CC=CC=C2C1=O>CC#N.O.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:18](=[O:23])[C:17]3[C:16]4[N:15]=[CH:14][CH:13]=[CH:12][C:11]=4[O:10][C:9]=3[C:8]([CH3:19])([CH3:20])[C:7]=2[CH:21]=1
Reactant: [O-][Cl+][O-]
Reactant: COc1ccc2c(c1)C(C)(C)c1oc3cccnc3c1C2
Agent: O=C1c2ccccc2C(=O)N1O
Agent: [Na+]
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccc2c(c1)C(C)(C)c1oc3cccnc3c1C2=O
Temperature: 40 °C
Reaction time: 1 h
Yield: 69.3 %

Procedure:
8-Methoxy-10,10-dimethyl-5,10-dihydro-11-oxa-4-aza-benzo[b]fluorene (Compound GT15-3, 22 mg) was dissolved in MeCN (0.26 ml) and water (0.13 ml), added with sodium chlorite (14 mg) and N-hydroxyphthalimide (2.6 mg), and the mixture was stirred at 40° C. for 1 hr. The reaction mixture was diluted with ethyl acetate. The organic layer was washed with saturated aqueous solution of sodium bicarbonate and saturated brine, and then concentrated under reduced pressure. The resulting residues were purified by silica gel column (ethyl acetate/hexane) to obtain the title compound (16 mg, 70%).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([Br:9])[CH:3]=1.[CH3:10][O:11][C:12](=[O:23])[CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][C:16]=1[CH3:22].CC(C)(C(=O)CC(=O)C(C)(C)C)C.C([O-])([O-])=O.[Cs+].[Cs+]>CN1C(=O)CCC1.CCOCC.Cl[Cu]>[CH3:10][O:11][C:12](=[O:23])[CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][C:2]2[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([Br:9])[CH:3]=2)=[CH:17][C:16]=1[CH3:22]
Reactant: COC(=O)CCc1ccc(O)cc1C
Reactant: Cc1cc(Br)cc(Br)c1
Agent: Cl[Cu]
Agent: CC(C)(C)C(=O)CC(=O)C(C)(C)C
Agent: O=C([O-])[O-]
Solvent: CN1CCCC1=O
Solvent: CCOCC
Product: COC(=O)CCc1ccc(Oc2cc(C)cc(Br)c2)cc1C
Temperature: 120 °C
Yield: 59 %

Procedure:
The mixture of 1,3-dibromo-5-methyl-benzene (15 g, 0.06 mol), 3-(4-hydroxy-2-methyl-phenyl)-propionic acid methyl ester (3.9 g, 0.02 mol), CuCl (1 g, 0.01 mol), 2,2,6,6-tetramethyl-heptane-3,5-dione (0.92 g, 0.005 mol) and Cs2CO3 (7.8 g, 0.024 mol) in 40 mL of dry NMP is heated to 120° C. for overnight. The mixture is cooled to rt and diluted with Et2O and filtered through a pad of celite. Organic layer is washed with 1N HCl, H2O and brine, and then dried over Na2SO4, filtered and concentrated. Crude material is purified by chromatography (hexanes/acetone=20:1) to afford the title compound (59%) as a yellow oil. Rf=0.29 (20/1 hexanes/acetone). 1H NMR (400 MHz, CDCl3).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][CH:2]1[CH2:11]O.CC1C=CC(S([O-])(=O)=O)=CC=1.[CH3:24][C:25]1([CH:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[O:29][CH2:28][CH2:27][O:26]1.C(=O)([O-])[O-].[Na+].[Na+].CN(C)C(=O)C>O>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][CH:2]1[CH2:11][N:33]1[CH2:32][CH2:31][CH:30]([C:25]2([CH3:24])[O:26][CH2:27][CH2:28][O:29]2)[CH2:35][CH2:34]1
Reactant: CC1(C2CCNCC2)OCCO1
Reactant: OCC1COc2ccccc2O1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CC1(C2CCN(CC3COc4ccccc4O3)CC2)OCCO1
Temperature: 75 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
A mixture of 22.5 parts of 2,3-dihydro-1,4-benzodioxin-2-methanol 4-methylbenzenesulfonate (ester), 11.1 parts of 4-(2-methyl-1,3-dioxolan-2-yl)piperidine, 15 parts of sodium carbonate and 135 parts of N,N-dimethylacetamide was stirred overnight at 75° C. Water was added. The product was extracted with 4-methyl-2-pentanone. The extract was dried, filtered and evaporated, yielding 20.6 parts (100%) of 1-[(2,3-dihydro-1,4-benzodioxin-2-yl)methyl]-4-(2-methyl-1,3-dioxolan-2-yl)piperidine as an oily residue (intermediate 86).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][C:18]3[CH:20]=[CH:21][C:22]([O:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[CH:23][C:17]=3[S:16](=[O:32])(=[O:31])[CH2:15][CH2:14]2)[CH:3]=1.[NH2:33][CH2:34][C:35]1([N:39]([CH2:47][C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH2:38][O:37][CH2:36]1.CC(C)([O-])C.[Na+]>O1CCOCC1.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[CH2:47]([N:39]([CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C:35]1([CH2:34][NH:33][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=3)[N:5]=[C:4]([N:13]3[CH2:19][C:18]4[CH:20]=[CH:21][C:22]([O:24][C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)=[CH:23][C:17]=4[S:16](=[O:32])(=[O:31])[CH2:15][CH2:14]3)[CH:3]=2)[CH2:36][O:37][CH2:38]1)[C:48]1[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=1
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4cc(Oc5ccccc5)ccc4C3)cc(Cl)c2c1
Reactant: NCC1(N(Cc2ccccc2)Cc2ccccc2)COC1
Agent: [Fe+2]
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4cc(Oc5ccccc5)ccc4C3)cc(NCC3(N(Cc4ccccc4)Cc4ccccc4)COC3)c2c1
Temperature: 120 °C
Reaction time: 2 h
Yield: 52.6 %

Procedure:
A mixture solution of 4-(4-chloro-6-methylquinolin-2-yl)-8-phenoxy-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (167.0 mg, 0.36 mmol), (3-(aminomethyl)-N,N-dibenzyloxetan-3-amine (609.0 mg, 2.16 mmol), 1,1′-bis(diphenylphosphino)-ferrocenedichloropalladium(II) (15.0 mg, 0.02 mmol), 1,1′-bis(diphenylphosphino)-ferrocene (11.2 mg, 0.02 mmol) and sodium tert-butoxide (75.0 mg, 0.72 mmol) in 1,4-dioxane (2.0 mL) was heated with stirring at 120° C. for 2 hours under microwave irridiation. After being cooled to room temperature, the reaction mixture was extracted with ethyl acetate (100 mL). The organic layer was washed with brine (50 mL×2), dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by ISCO combi-flash chromatography (gradient elution, 20-60% ethyl acetate in petroleum ether) to afford 134.6 mg of the desired product as a light yellow solid (yield was 52.6%). MS obsd. (ESI+) [(M+H)+] 711.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:19])[N:14]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:13]([CH2:24]Cl)=[C:12]2[C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:33]1(=[O:43])[NH:37][C:36](=[O:38])[C:35]2=[CH:39][CH:40]=[CH:41][CH:42]=[C:34]12.[K].O>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:19])[N:14]([CH2:20][CH:21]([CH3:22])[CH3:23])[C:13]([CH2:24][N:37]1[C:33](=[O:43])[C:34]3[C:35](=[CH:39][CH:40]=[CH:41][CH:42]=3)[C:36]1=[O:38])=[C:12]2[C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CC(C)Cn1c(CCl)c(-c2ccc(Cl)cc2)c2cc(OCc3ccccc3)ccc2c1=O
Agent: [K]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)Cn1c(CN2C(=O)c3ccccc3C2=O)c(-c2ccc(Cl)cc2)c2cc(OCc3ccccc3)ccc2c1=O
Yield: 96.2 %

Procedure:
A solution of 6-benzyloxy-3-chloromethyl-4-(4-chlorophenyl)-2-isobutyl-1(2H)-isoquinolinone (3.96 g, 8.5 mmol) and potassium phthalimide (2.37 g, 12.8 mmol) in N,N-dimethylformamide (40 ml) was stirred at room temperature for 6 h. The reaction mixture was poured into water and extracted with ethyl acetate. After washing the extract with water, the extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 2-[[6-benzyloxy-4-(4-chlorophenyl)-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinyl]methyl]-1H-isoindole-1,3(2H)-dione (4.72 g, 96.3%) as crystals.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1/[CH:11]=[CH:12]/[C:13](Cl)=[O:14].[NH2:16][C:17]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:18]=1[C:19]([OH:21])=[O:20].C(N(CC)CC)C>O1CCCC1>[C:19]([C:18]1[CH:22]=[C:23]([F:26])[CH:24]=[CH:25][C:17]=1[NH:16][C:13](=[O:14])/[CH:12]=[CH:11]/[C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]=1)([OH:21])=[O:20]
Reactant: O=C(Cl)/C=C/c1ccc2ccccc2c1
Reactant: Nc1ccc(F)cc1C(=O)O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(/C=C/c1ccc2ccccc2c1)Nc1ccc(F)cc1C(=O)O

Procedure:
Prepared analogously to Example 31 from trans-3-(naphth-2-yl)-acrylic acid chloride and 2-amino-5-fluoro-benzoic acid in tetrahydrofuran with the addition of triethylamine.