Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14](=[O:16])C)[CH:5]=[CH:4][C:3]1=2.Cl[O-].[Na+].[OH-:21].[Na+]>O1CCOCC1>[CH3:1][C:2]1([CH3:17])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[C:6]([C:14]([OH:16])=[O:21])[CH:5]=[CH:4][C:3]1=2
Reactant: [OH-]
Reactant: CC(=O)c1ccc2c(c1)C(C)(C)CCC2(C)C
Agent: [Na+]
Agent: [O-]Cl
Solvent: C1COCCO1
Product: CC1(C)CCC(C)(C)c2cc(C(=O)O)ccc21

Procedure:
A mixture of 3.8 g (16.5 mmol) of 5,5,8,8-tetramethyl-2-acetyl-5,6,7,8-tetrahydronaphthalene from the preceeding Example 3, 70 ml of 5.25% aqueous sodium hypochlorite (49 mmol), 25 ml of aqueous 2N NaOH and 30 ml of dioxane was heated at 60°-70° C. for 2 hours. The mixture was allowed to cool and the oily organic layer removed. Then the aqueous layer was washed with two portions of ether. The aqueous layer was then treated with sodium metabisulfite solution until the solution was negative to the potassium iodide.starch test. The aqueous layer was then cooled and acidified with H2SO4. The resultant white precipitate was collected by filtration and washed with water. This crude product was further purified by recrystallization from an ethanol/water mixture to give the title compound as a white, crystalline solid. PMR (CDCl3): δ 1.31 (6H, s), 1.32 (6H, s), 1.71 (4H, s), 7.40 (1H, d, J~8.8 Hz), 7.85 (1H, dd, J~8.8 Hz, 1.8 Hz), 8.08 (1H, d, J~1.8 Hz).
Reaction SMILES: [CH2:1]([O:5][C:6]([C:8]1[C:9]([OH:19])=[C:10]2[C:17]([CH3:18])=[N:16][S:15][C:11]2=[C:12](Br)[N:13]=1)=[O:7])[CH2:2][CH2:3][CH3:4].[CH3:20][Sn](C)(C)C>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]([O:5][C:6]([C:8]1[C:9]([OH:19])=[C:10]2[C:17]([CH3:18])=[N:16][S:15][C:11]2=[C:12]([CH3:20])[N:13]=1)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: C[Sn](C)(C)C
Reactant: CCCCOC(=O)c1nc(Br)c2snc(C)c2c1O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Product: CCCCOC(=O)c1nc(C)c2snc(C)c2c1O
Temperature: 120 °C
Reaction time: 1 h
Yield: 40.2 %

Procedure:
To a solution of 7-bromo-4-hydroxy-3-methyl-isothiazolo[5,4-c]pyridine-5-carboxylic acid butyl ester (0.338 mmol) in DMF (2.05 mL) was added tetramethyltin (0.67 mmol) and PdCl2(PPh3)2 (0.0338 mmol). The reaction mixture was stirred at 120° C. for 1 h. After cooling to r.t., the mixture was partitioned between water (100 mL) and EtOAc (100 mL). The organic layer was washed with brine and water, then dried over MgSO4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel. Eluting with 0-20% EtOAc/CH2Cl2, gave the title compound (38.1 mg) as a white solid: MS (m/z) 281.2 (M+1).
Reaction SMILES: C(OC([NH:11][C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1)=O)C1C=CC=CC=1.[CH3:21][O:22][C:23](=[O:48])[NH:24][C@H:25]([C:29]([N:31]1[CH2:35][CH2:34][CH2:33][C@H:32]1[C:36]1[NH:37][CH:38]=[C:39]([C:41]2[CH:46]=[CH:45][C:44](Br)=[CH:43][CH:42]=2)[N:40]=1)=[O:30])[CH:26]([CH3:28])[CH3:27].CN(C)C=O.O.C(=O)(O)[O-].[Na+]>CO.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.[OH-].[OH-].[Pd+2]>[CH3:21][O:22][C:23](=[O:48])[NH:24][C@H:25]([C:29]([N:31]1[CH2:35][CH2:34][CH2:33][C@H:32]1[C:36]1[NH:37][CH:38]=[C:39]([C:41]2[CH:42]=[CH:43][C:44]([C:15]3[CH:14]=[CH:13][C:12]([NH2:11])=[CH:17][CH:16]=3)=[CH:45][CH:46]=2)[N:40]=1)=[O:30])[CH:26]([CH3:28])[CH3:27]
Reactant: O=C(Nc1ccc(B(O)O)cc1)OCc1ccccc1
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc(-c2ccc(Br)cc2)c[nH]1)C(C)C
Agent: [Pd+2]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Solvent: CO
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc(-c2ccc(-c3ccc(N)cc3)cc2)c[nH]1)C(C)C
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 38.2 %

Procedure:
To a mixture of 4-(benzyloxycarbonylamino)phenylboronic acid (1.57 g, 5.79 mmol) and ((S)-1-{(S)-2-[4-(4-bromo-phenyl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (1.74 g, 3.86 mmol) in N,N-dimethylformamide (30 mL, 400 mmol) was added water (21.91 mL, 1216 mmol) and sodium bicarbonate (2.43 g, 28.96 mmol). The resulting mixture was purged with nitrogen. Tetrakis(triphenylphosphine)palladium(0) (468 mg, 0.41 mmol) was added. The reaction mixture was purged with nitrogen and then heated at 90° C. overnight. The reaction mixture was cooled to RT, diluted with methanol (10 mL), then filtered. The filtrate was concentrated and the crude product was purified by preparative HPLC to give a white solid. (1.28 g) The crude material was dissolved in methanol (40 mL) and then pumped through a continuous flow hydrogenator at 70° C. using a palladium hydroxide on carbon (20% w/w) cartridge. The resulting solution was concentrated to ˜10 mL, treated with Stratospheres™ PL-CO3 resin and stirred at room temperature for 30 min. The reaction mixture was filtered and the filtrate was concentrated to give the title compound (680 mg).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([CH2:15][CH2:16][NH:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[CH:12]=[CH:13][CH:14]=1)C1C=CC=CC=1.[H][H]>C(O)C.[Pd]>[CH:18]1([NH:17][CH2:16][CH2:15][C:11]2[CH:10]=[C:9]([OH:8])[CH:14]=[CH:13][CH:12]=2)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]1
Reactant: [H][H]
Reactant: c1ccc(COc2cccc(CCNC3CCCCC3)c2)cc1
Agent: [Pd]
Solvent: CCO
Product: Oc1cccc(CCNC2CCCCC2)c1

Procedure:
A stirred solution of the oil isolated in Step D (4.5 g, 14 mmol) and Pd/C (10%, 150 mg) in ethanol (100 mL) was hydrogenated under 1 atm of hydrogen overnight. The catalyst was filtered off, and the solvent was removed in vacuo to yield an oil.
Reaction SMILES: [NH4+:1].[OH-].[C:3]([O:7][C:8]([NH:10][C:11]1[S:12][CH:13]=[C:14](/[C:16](=[N:37]/[O:38][C:39]2([C:42]([O:44][CH:45]([C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=3)[C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)=[O:43])[CH2:41][CH2:40]2)/[C:17]([NH:19][C@@H:20]2[C:23](=[O:24])[NH:22][C@@H:21]2[CH2:25][N:26]2[N:30]=[C:29]([CH2:31]OS(C)(=O)=O)[CH:28]=[N:27]2)=[O:18])[N:15]=1)=[O:9])([CH3:6])([CH3:5])[CH3:4]>CCO.C1COCC1.C(Cl)Cl>[NH2:1][CH2:31][C:29]1[CH:28]=[N:27][N:26]([CH2:25][C@@H:21]2[C@H:20]([NH:19][C:17](=[O:18])/[C:16](=[N:37]\[O:38][C:39]3([C:42]([O:44][CH:45]([C:52]4[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=4)[C:46]4[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=4)=[O:43])[CH2:41][CH2:40]3)/[C:14]3[N:15]=[C:11]([NH:10][C:8]([O:7][C:3]([CH3:5])([CH3:4])[CH3:6])=[O:9])[S:12][CH:13]=3)[C:23](=[O:24])[NH:22]2)[N:30]=1
Reactant: [NH4+]
Reactant: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC2(C(=O)OC(c3ccccc3)c3ccccc3)CC2)C(=O)N[C@@H]2C(=O)N[C@@H]2Cn2ncc(COS(C)(=O)=O)n2)cs1
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC2(C(=O)OC(c3ccccc3)c3ccccc3)CC2)C(=O)N[C@@H]2C(=O)N[C@@H]2Cn2ncc(CN)n2)cs1
Temperature: -5 °C
Reaction time: 12 h
Yield: 49 %

Procedure:
To a solution of aq. NH4OH (2 mL, 28-30% wt) in EtOH (2 mL, ratio:1) and THF (2 mL, ratio:1) was added a solution of benzhydryl 1-(((Z)-(1-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)-2-(((2R,3S)-2-((4-(((methylsulfonyl)oxy)methyl)-2H-1,2,3-triazol-2-yl)methyl)-4-oxoazetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)cyclopropanecarboxylate (190 mg, 0.24 mmol) in THF (1 mL) at −5° C. dropwise. After stirring at −5° C. for 1 h and rt for 12 h, the reaction mixture was diluted with 40 mL of DCM and washed with 10 mL of aq. saturated NaHCO3 (aq), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified via silica gel chromatography (MeOH-DCM, 5-10%) to afford the title compound (120 mg, 49%). LCMS: Rt=0.87 min, m/z=716.4 (M+1) Method 2m_acidic.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-])=O)=[C:6]([N:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)[C:5]([Br:24])=[CH:4][N:3]=1.[CH3:25][N:26]([CH3:35])[C:27]1[CH:34]=[CH:33][C:30]([CH:31]=O)=[CH:29][CH:28]=1.[O-]S(S([O-])=O)=O.[Na+].[Na+]>CCO>[C:20]([O:19][C:17]([N:14]1[CH2:15][CH2:16][N:11]([C:6]2[C:5]([Br:24])=[CH:4][N:3]=[C:2]3[NH:1][C:31]([C:30]4[CH:33]=[CH:34][C:27]([N:26]([CH3:35])[CH3:25])=[CH:28][CH:29]=4)=[N:8][C:7]=23)[CH2:12][CH2:13]1)=[O:18])([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)(C)OC(=O)N1CCN(c2c(Br)cnc(N)c2[N+](=O)[O-])CC1
Reactant: CN(C)c1ccc(C=O)cc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: CN(C)c1ccc(-c2nc3c(N4CCN(C(=O)OC(C)(C)C)CC4)c(Br)cnc3[nH]2)cc1
Temperature: 80 °C
Reaction time: 16 h
Yield: 65.5 %

Procedure:
To tert-butyl 4-(2-amino-5-bromo-3-nitropyridin-4-yl)piperazine-1-carboxylate (0.5 g, 1.2 mmol) in EtOH (20 mL) was added 4-dimethylaminobenzaldehyde (0.241 g, 1.6 mmol), and 1M Na2S2O4 (4.7 mL, 4.7 mmol) The reaction mixture was stirred at 80° C. for 16 h then concentrated in vacuo. The residue was purified by chromatography (100% dichloromethane to dichloromethane/ethyl acetate 1/1, 2% MeOH in dichloromethane/ethyl acetate 1/1, and 2% MeOH in CHCl3). The compound is further triturated in dichloromethane/methanol 9/1, filtered and dried in vacuo to give the title compound as a solid (0.394 g, 63% yield).
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][N:7]([CH3:64])[C@H:8]([C:12]([NH:14][C@H:15]([C:19]([N:21]([C@@H:23]([C@@H:60]([CH3:63])[CH2:61][CH3:62])[C@H:24]([O:58][CH3:59])[CH2:25][C:26]([N:28]1[CH2:32][CH2:31][CH2:30][C@H:29]1[C@H:33]([O:56][CH3:57])[C@@H:34]([CH3:55])[C:35]([NH:37][C@@:38]1([C:47]([N:49]2[CH2:54][CH2:53][CH2:52][CH2:51][O:50]2)=[O:48])[CH2:40][C@@H:39]1[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)=[O:36])=[O:27])[CH3:22])=[O:20])[CH:16]([CH3:18])[CH3:17])=[O:13])[CH:9]([CH3:11])[CH3:10])([OH:3])=O.FC(F)(F)C(O)=O.[O:72]=[C:73]1[CH:77]=[CH:76][C:75](=[O:78])[N:74]1[CH2:79][CH2:80][CH2:81][C:82]([NH:84][CH2:85][CH2:86][NH:87][CH3:88])=[O:83].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[O:72]=[C:73]1[CH:77]=[CH:76][C:75](=[O:78])[N:74]1[CH2:79][CH2:80][CH2:81][C:82]([NH:84][CH2:85][CH2:86][N:87]([CH3:88])[C:1](=[O:3])[CH2:4][CH2:5][CH2:6][N:7]([CH3:64])[C@H:8]([C:12]([NH:14][C@H:15]([C:19]([N:21]([C@@H:23]([C@@H:60]([CH3:63])[CH2:61][CH3:62])[C@H:24]([O:58][CH3:59])[CH2:25][C:26]([N:28]1[CH2:32][CH2:31][CH2:30][C@H:29]1[C@H:33]([O:56][CH3:57])[C@@H:34]([CH3:55])[C:35]([NH:37][C@@:38]1([C:47]([N:49]2[CH2:54][CH2:53][CH2:52][CH2:51][O:50]2)=[O:48])[CH2:40][C@@H:39]1[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)=[O:36])=[O:27])[CH3:22])=[O:20])[CH:16]([CH3:17])[CH3:18])=[O:13])[CH:9]([CH3:10])[CH3:11])=[O:83]
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@]1(C(=O)N2CCCCO2)C[C@@H]1c1ccccc1)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)CCCC(=O)O)C(C)C
Reactant: CNCCNC(=O)CCCN1C(=O)C=CC1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@]1(C(=O)N2CCCCO2)C[C@@H]1c1ccccc1)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)CCCC(=O)N(C)CCNC(=O)CCCN1C(=O)C=CC1=O)C(C)C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
6 mg (7 μmol) of N-(3-carboxypropyl)-N-methyl-L-valyl-N-[(3R,4S,5S)-3-methoxy-1-{(2S)-2-[(1R,2R)-1-methoxy-2-methyl-3-{[(1S,2R)-1-(1,2-oxazinan-2-ylcarbonyl)-2-phenylcyclopropyl]amino}-3-oxopropyl]pyrrolidin-1-yl}-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinamide (Intermediate 61) were combined with 3.1 mg (9 μmol) of 4-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)-N-[2-(methylamino)ethyl]butanamide trifluoroacetate, 10.1 mg (27 μmol) of O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate and 5 μl of N,N-diisopropylethylamine in 2 ml of DMF, and the mixture was stirred at RT for 4 h. Then the solvent was removed under reduced pressure and the remaining residue was purified by means of preparative HPLC. The corresponding fractions were concentrated and, by lyophilization from dioxane, 1 mg (13.4% of theory) of the title compound were obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:20]([CH3:22])[CH3:21])[CH:5]=[C:6]2[C:10]=1[NH:9][C:8]1[C:11]([CH2:17][CH2:18][OH:19])([CH2:15][CH3:16])[O:12][CH2:13][CH2:14][C:7]2=1.[CH3:23][C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[C:28]([CH3:30])[CH:29]=1>>[CH3:23][C:24]1[CH:25]=[C:26]([C:2]2[CH:3]=[C:4]([CH:20]([CH3:22])[CH3:21])[CH:5]=[C:6]3[C:10]=2[NH:9][C:8]2[C:11]([CH2:17][CH2:18][OH:19])([CH2:15][CH3:16])[O:12][CH2:13][CH2:14][C:7]3=2)[CH:27]=[C:28]([CH3:30])[CH:29]=1
Reactant: Cc1cc(C)cc(B(O)O)c1
Reactant: CCC1(CCO)OCCc2c1[nH]c1c(Br)cc(C(C)C)cc21
Product: CCC1(CCO)OCCc2c1[nH]c1c(-c3cc(C)cc(C)c3)cc(C(C)C)cc21

Procedure:
The title compound is prepared in a manner analogous to Example 1, except using 2-(8-bromo-1-ethyl-6-isopropyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-ethanol and 3,5-dimethylphenylboronic acid in step 1.F.
Reaction SMILES: [NH2:1][C:2]1[C:9]([CH2:10]SC)=[C:8]([F:13])[C:7]([F:14])=[CH:6][C:3]=1[C:4]#[N:5].O>C(O)C.[Ni]>[NH2:1][C:2]1[C:9]([CH3:10])=[C:8]([F:13])[C:7]([F:14])=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: CSCc1c(N)c(C#N)cc(F)c1F
Agent: [Ni]
Solvent: O
Solvent: CCO
Product: Cc1c(N)c(C#N)cc(F)c1F
Reaction time: 0.5 h
Yield: 76.4 %

Procedure:
To a solution of 2-amino-4,5-difluoro-3-methylthiomethylbenzonitrile (4.0 g) in ethanol (80 ml) are added Raney nickel (40 ml) with ethanol (80 ml). The mixture is stirred at 40°-50° C. for 30 minutes, and then filterd. To the filtrate is added water, the reaction mixture is extracted with ethyl acetate. The extract is dried over magnesium sulfate and concentrated. The product is recrystallized from n-hexane to give 2-amino-4,5-difluoro-3-methylbenzonitrile (2.4 g), as a white crystal, m.p. 114°-116° C.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7](B(O)O)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].O1C=CC=C1P(C1OC=CC=1)C1OC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br/[C:36](/[C:44]1[N:49]=[C:48]([O:50][CH3:51])[C:47]([Cl:52])=[CH:46][CH:45]=1)=[CH:37]\[CH:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1>O1CCOCC1.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].O>[Cl:52][C:47]1[C:48]([O:50][CH3:51])=[N:49][C:44](/[C:36](/[C:7]2[CH:8]=[CH:9][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:5][CH:6]=2)=[CH:37]/[CH:38]2[CH2:43][CH2:42][O:41][CH2:40][CH2:39]2)=[CH:45][CH:46]=1
Reactant: COc1nc(/C(Br)=C/C2CCOCC2)ccc1Cl
Reactant: CC(C)c1ccc(B(O)O)cc1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: COc1nc(/C(=C/C2CCOCC2)c2ccc(C(C)C)cc2)ccc1Cl
Temperature: 90 °C
Reaction time: 2 h

Procedure:
4-Isopropylphenylboronic acid (103 mg), tris(dibenzylideneacetone)dipalladium (38 mg), tri(2-furyl)phosphine (58 mg), cesium carbonate (273 mg) and water (0.5 mL) were added to a solution of 6-[(Z)-1-bromo-2-(tetrahydro-2H-pyran-4-yl)ethenyl]-3-chloro-2-methoxypyridine (140 mg) in 1,4-dioxane (3 mL), and the mixture was stirred at 90° C. for two hours. The reaction solution was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and filtered. The solvent was then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1→1:1) to give 3-chloro-2-methoxy-6-[(E)-1-[4-(propan-2-yl)phenyl]-2-(tetrahydro-2H-pyran-4-yl)ethenyl]pyridine containing impurities as a yellow oil (170 mg).
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]1[NH:10][C:9]2[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=2[N:7]([C:15]([C:17]23[CH2:26][CH:21]4[CH2:22][CH:23]([CH2:25][CH:19]([CH2:20]4)[CH2:18]2)[CH2:24]3)=[O:16])[CH2:6][CH:5]1[NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29].Br[CH2:36][C:37]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=1[CH3:45])=[O:38]>O1CCCC1>[C:40]1([CH3:45])[C:39]([C:37]([CH2:36][N:10]2[C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[N:7]([C:15]([C:17]34[CH2:26][CH:21]5[CH2:22][CH:23]([CH2:25][CH:19]([CH2:20]5)[CH2:18]3)[CH2:24]4)=[O:16])[CH2:6][CH:5]([NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C:4]2=[O:3])=[O:38])=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: Cc1ccccc1C(=O)CBr
Reactant: CC(C)(C)OC(=O)NC1CN(C(=O)C23CC4CC(CC(C4)C2)C3)c2ccccc2NC1=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccccc1C(=O)CN1C(=O)C(NC(=O)OC(C)(C)C)CN(C(=O)C23CC4CC(CC(C4)C2)C3)c2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 46.6 %

Procedure:
To 60% sodium hydride (128 mg) suspended in anhydrous tetrahydrofuran (30 ml), 2-oxo-3-tert-butoxycarbonylamino-5-(adamantan-1-yl)carbonyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine was added at room temperature under argon atmosphere. The mixture was stirred at room temperature for 30 minutes. Subsequently, 2-bromo-2′-methylacetophenone (375 mg) in anhydrous tetrahydrofuran (10 ml) was added thereto, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure. Ice-water (50 ml) was added to the residue, followed by extraction with chloroform. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. Ethanol was added to the residue for solidification and collection by filtration, to thereby obtain 426 mg of the title compound as a white solid (yield: 46.6%).
Reaction SMILES: CN1CCOCC1.Cl[C:9]([O:11][CH2:12][C:13]#[CH:14])=[O:10].[C:15]([C:17]1[CH:34]=[CH:33][C:20]([O:21][CH2:22][CH:23]([NH:25][C:26](=[O:32])[C@H:27]([CH:29]([CH3:31])[CH3:30])[NH2:28])[CH3:24])=[CH:19][CH:18]=1)#[N:16].O>C(Cl)Cl>[C:15]([C:17]1[CH:18]=[CH:19][C:20]([O:21][CH2:22][CH:23]([NH:25][C:26](=[O:32])[C@H:27]([CH:29]([CH3:30])[CH3:31])[NH:28][C:9]([O:11][CH2:12][C:13]#[CH:14])=[O:10])[CH3:24])=[CH:33][CH:34]=1)#[N:16]
Reactant: C#CCOC(=O)Cl
Reactant: CC(COc1ccc(C#N)cc1)NC(=O)[C@@H](N)C(C)C
Solvent: O
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: C#CCOC(=O)N[C@H](C(=O)NC(C)COc1ccc(C#N)cc1)C(C)C
Temperature: 25 °C
Reaction time: 15 h
Yield: 82.9 %

Procedure:
0.2 g of N-methylmorpholine, and subsequently 0.2 g of propargyl chloroformate were added to a suspension containing 0.5 g of N1 -[2-(4-cyanophenoxy)-1-methylethyl]-L-valinamide suspended in 30 ml of methylene chloride at -15° C. The mixture was allowed to sit and warm naturally to room temperature and stirred for 15 hours at room temperature. Water was subsequently added to the reaction mixture. After the methylene chloride layer was washed with water, the organic layer was dried over anhydrous magnesium sulfate and then the methylene chloride was removed under reduced pressure. The residue was purified by column chromatography on silica gel, thus obtaining 0.5 g of the desired product in the form of white powder (yield: 78%).
Reaction SMILES: N1C2C(=CC=CC=2)C=C1.C([N:17]1[C:29]2[C:28]([O:30][CH2:31][CH2:32][CH2:33]Br)=[C:27]3[N:35](C(OC(C)(C)C)=O)[C:36]4[CH:37]=[CH:38][C:39]([Br:42])=[CH:40][C:41]=4[C:26]3=[CH:25][C:24]=2[C:23]2[C:18]1=[CH:19][CH:20]=[C:21]([Br:50])[CH:22]=2)(OC(C)(C)C)=O.[NH:51]1[CH2:56][CH2:55][O:54][CH2:53][CH2:52]1>>[Br:50][C:21]1[CH:22]=[C:23]2[C:18](=[CH:19][CH:20]=1)[NH:17][C:29]1[C:28]([O:30][CH2:31][CH2:32][CH2:33][N:51]3[CH2:56][CH2:55][O:54][CH2:53][CH2:52]3)=[C:27]3[NH:35][C:36]4[CH:37]=[CH:38][C:39]([Br:42])=[CH:40][C:41]=4[C:26]3=[CH:25][C:24]2=1
Reactant: C1COCCN1
Reactant: CC(C)(C)OC(=O)n1c2ccc(Br)cc2c2cc3c4cc(Br)ccc4n(C(=O)OC(C)(C)C)c3c(OCCCBr)c21
Agent: c1ccc2[nH]ccc2c1
Product: Brc1ccc2[nH]c3c(OCCCN4CCOCC4)c4[nH]c5ccc(Br)cc5c4cc3c2c1

Procedure:
The title compound was prepared in a manner analogous to Example 70 except the starting indole is 5,7-diBOC-2,10-dibromo-6-(3-bromopropoxy)indolo[2,3-b]carbazole and the reagent is morpholine. 1H-NMR (400 MHz, DMSO-d6) δ ppm 11.28 (s, 2H), 8.67 (s, 1H), 8.28 (d, J=2.0 Hz, 2H), 7.51-7.40 (m, 4H), 4.30 (t, J=6.6 Hz, 2H), 3.56 (t, J=4.6 Hz, 4H), 2.52 (t, J=7.2 Hz, 2H), 2.44-2.32 (m, 4H), 2.11-2.00 (m, 2H); MS (ESI) m/z 556.0 (M−H)−
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]([CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:10]=[CH:11][C:12]=1OS(C(F)(F)F)(=O)=O.[N:28]1([C:34]([C:36]2[CH:41]=[CH:40][C:39](B(O)O)=[CH:38][CH:37]=2)=[O:35])[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1.[F-].[Cs+]>C(COC)OC.C(O)C>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]([CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:10]=[CH:11][C:12]=1[C:39]1[CH:38]=[CH:37][C:36]([C:34]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)=[O:35])=[CH:41][CH:40]=1
Reactant: O=C(c1ccc(B(O)O)cc1)N1CCOCC1
Reactant: CCOC(=O)CCc1ccc(OS(=O)(=O)C(F)(F)F)c(OCCCOC)c1
Agent: [Cs+]
Agent: [F-]
Solvent: COCCOC
Solvent: CCO
Product: CCOC(=O)CCc1ccc(-c2ccc(C(=O)N3CCOCC3)cc2)c(OCCCOC)c1
Temperature: 25 °C
Yield: 65.9 %

Procedure:
Ethyl 3-[3-(3-methoxypropoxy)-4-{[(trifluoromethyl)sulfonyl]oxy}phenyl]propanoate (0.8 g, 1.9 mmol) was dissolved in dimethoxyethane (12 mL) and ethanol (1.2 mL). 4-Morpholine-4-carbonylphenylboronic acid (0.50 g, 2.1 mmol) was added and argon: was bubbled in the mixture for 15 minutes. Cesium fluoride (0.6 g, 4.2 mmol) and tetrakistriphenylphosphine palladium (0.11 g, 0.1 mmol) were added and the mixture was brought to reflux under an argon atmosphere for 4 hours. After cooling to room temperature, solvents were evaporated under reduced pressure and the residue was dissolved in ethyl acetate/water (15 mL/15 mL). The organic layer was washed with saturated aqueous sodium bicarbonate and brine, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate, 7/3) to yield 0.57 g (65%) of the desired product as a yellow oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]2[O:8][CH2:9][C:10]([CH2:12][O:13][C:4]=2[CH:3]=1)=[O:11].[CH2:14]([N:16]1[C:28]2[CH:27]=[CH:26][C:25]([CH:29]=O)=[CH:24][C:23]=2[C:22]2[C:17]1=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH3:15]>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]2[O:8][CH2:9][C:10](=[O:11])/[C:12](=[CH:29]/[C:25]3[CH:26]=[CH:27][C:28]4[N:16]([CH2:14][CH3:15])[C:17]5[C:22]([C:23]=4[CH:24]=3)=[CH:21][CH:20]=[CH:19][CH:18]=5)/[O:13][C:4]=2[CH:3]=1
Reactant: CCn1c2ccccc2c2cc(C=O)ccc21
Reactant: Cc1ccc2c(c1)OCC(=O)CO2
Product: CCn1c2ccccc2c2cc(/C=C3\Oc4cc(C)ccc4OCC3=O)ccc21

Procedure:
Calone is reacted with 9-ethylcarbazole-3-carbaldehyde analogously to the reaction conditions of Example 1, giving 7-methyl-4-[1-(9-ethyl-9H-carbazol-3-yl)meth-(Z)-ylidene]benzo[b]-1,4-dioxepin-3-one
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([N:8]2[CH2:12][CH2:11][CH2:10][C@H:9]2[C:13]([CH3:21])([CH3:20])[O:14][SiH2:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH:7]=1.[Cl:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[C:28](=[O:32])[NH:27][CH2:26]2>>[C:16]([SiH2:15][O:14][C:13]([CH3:21])([CH3:20])[C@@H:9]1[CH2:10][CH2:11][CH2:12][N:8]1[C:6]1[CH:7]=[C:2]([N:27]2[CH2:26][C:25]3[C:29](=[CH:30][CH:31]=[C:23]([Cl:22])[CH:24]=3)[C:28]2=[O:32])[CH:3]=[N:4][CH:5]=1)([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)[SiH2]OC(C)(C)[C@@H]1CCCN1c1cncc(Br)c1
Reactant: O=C1NCc2cc(Cl)ccc21
Product: CC(C)(C)[SiH2]OC(C)(C)[C@@H]1CCCN1c1cncc(N2Cc3cc(Cl)ccc3C2=O)c1

Procedure:
In analogy to the procedures described for the preparation of example 135, 3-bromo-5-[(S)-2-(tert-butyl-dimethyl-silanyloxymethyl)-pyrrolidin-1-yl]-pyridine (example 135[B]) has been reacted with 5-chloro-2,3-dihydro-isoindol-1-one to give 2-{5-[(S)-2-(tert-butyl-dimethyl-silanyloxymethyl)-pyrrolidin-1-yl]-pyridin-3-yl}-5-chloro-2,3-dihydro-isoindol-1-one, which was then deprotected with 4M HCl in dioxane to give the title compound as white solid. MS: 344.0 (M+H+).