Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)S([O:6][CH2:7][C:8]([F:22])([F:21])[C:9]([F:20])([F:19])[C:10]([F:18])([F:17])[CH2:11][O:12][CH2:13][CH2:14][CH2:15][CH3:16])(=O)=O.FC(F)(F)S(O[CH2:31][C:32](F)(F)[C:33](F)(F)[C:34](F)(F)[CH2:35][O:36]CC)(=O)=O>>[CH2:13]([O:12][CH2:11][C:10]([F:17])([F:18])[C:9]([F:19])([F:20])[C:8]([F:21])([F:22])[CH2:7][O:6][C:7]1[CH:8]=[C:9]2[C:33](=[CH:32][CH:31]=1)[CH:34]=[C:35]([OH:36])[CH:11]=[CH:10]2)[CH2:14][CH2:15][CH3:16]
Reactant: CCOCC(F)(F)C(F)(F)C(F)(F)COS(=O)(=O)C(F)(F)F
Reactant: CCCCOCC(F)(F)C(F)(F)C(F)(F)COS(=O)(=O)C(F)(F)F
Product: CCCCOCC(F)(F)C(F)(F)C(F)(F)COc1ccc2cc(O)ccc2c1

Procedure:
In this example, a compound was prepared in essentially the same manner as that described in Example 7, except that 4.0 g (0.010 moles) of 5-butoxy-2,2,3,3,4,4-hexafluoropentyl trifluoromethanesulfonate (prepared essentially as in Example 2) was substituted for the 5-ethoxy-2,2,3,3,4,4-hexafluoropentyl trifluoromethanesulfonate to provide 2.82 g of 6-(5-butoxy-2,2,3,3,4,4-hexafluoropentoxy)-2-hydroxynapthalene product.
Reaction SMILES: [F:1][C:2]1[CH:7]=C(C)[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[K+].[K+].S(=O)(=O)(O)O.[C:28]([OH:31])(=[O:30])[CH3:29]>>[F:1][C:2]1[CH:7]=[C:29]([CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10])[C:28]([OH:31])=[O:30]
Reactant: CC(=O)O
Reactant: Cc1ccc([N+](=O)[O-])c(F)c1
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=C(O)c1ccc([N+](=O)[O-])c(F)c1
Temperature: 120 °C
Yield: 83 %

Procedure:
2-Fluoro-4-methyl-1-nitro-benzene (1.0 g, 12.9 mmol) was added portion-wise to a suspension of potassium dichromate (5.04 g, 17.16 mmol) in glacial acetic acid (8 mL) follow by concentrated sulfuric acid (3.6 mL). The reaction mixture was heated to 120° C. for 2 h and then allowed to cool to ambient temperature. The reaction was quenched with crushed ice and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to afford 3-fluoro-4-nitro-benzoic acid (1.9 g, 83%) as a white solid.
Reaction SMILES: CC([O-])(C)C.[K+].C1COCC1.[CH2:12]([O:15][C:16]1[CH:25]=[CH:24][C:23]2[C:18](=[CH:19][C:20]([O:26][CH2:27][C:28]#[CH:29])=[CH:21][CH:22]=2)[CH:17]=1)[C:13]#[CH:14]>O>[CH:27]([O:26][C:20]1[CH:21]=[CH:22][C:23]2[C:18](=[CH:17][C:16]([O:15][CH:12]=[C:13]=[CH2:14])=[CH:25][CH:24]=2)[CH:19]=1)=[C:28]=[CH2:29]
Reactant: C#CCOc1ccc2ccc(OCC#C)cc2c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: C=C=COc1ccc2ccc(OC=C=C)cc2c1
Yield: 45.3 %

Procedure:
Into a similar reaction vessel, as used in the abovementioned reaction, were placed 2.316 parts of t-BuOK and 13.108 parts of THF and to this, a mixture of 10,000 parts of 2,7-dipropargyloxynaphthalene and 23.333 parts of THF was added dropwise. The content was reacted at 50° C. for 60 minutes and then a deionized water was added to stop the reaction. THF layer and water layer were removed off by using an evaporator, and the residue was subjected to a column chromatography (silica gel 200 mesh) to obtain a purified 2,7-diallenyloxy naphthalene as white rystals (M.P. 80.5°-83.5° C.)
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:8][C:9]2[CH:10]=[CH:11][C:12]3[N:13]([CH:15]=[C:16]([NH:18][C:19]([CH:21]4[CH2:23][CH2:22]4)=[O:20])[N:17]=3)[N:14]=2)[CH:5]=[N:6][CH:7]=1.[F:24][C:25]([F:36])([F:35])[C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][CH:34]=1)[C:29]([NH2:31])=[O:30].N[C@@H]1CCCC[C@H]1N.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O1CCCC1.C(OCC)(=O)C.[Cu]I>[CH:21]1([C:19]([NH:18][C:16]2[N:17]=[C:12]3[CH:11]=[CH:10][C:9]([O:8][C:4]4[CH:3]=[C:2]([NH:31][C:29](=[O:30])[C:28]5[CH:32]=[CH:33][CH:34]=[C:26]([C:25]([F:35])([F:36])[F:24])[CH:27]=5)[CH:7]=[N:6][CH:5]=4)=[N:14][N:13]3[CH:15]=2)=[O:20])[CH2:23][CH2:22]1
Reactant: O=C(Nc1cn2nc(Oc3cncc(Br)c3)ccc2n1)C1CC1
Reactant: NC(=O)c1cccc(C(F)(F)F)c1
Agent: [Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: O=C(Nc1cncc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c1)c1cccc(C(F)(F)F)c1
Temperature: 110 °C
Reaction time: 60 h
Yield: 43 %

Procedure:
To a solution of N-{6-[(5-bromopyridin-3-yl)oxy]imidazo[1,2-b]pyridazin-2-yl}cyclopropanecarboxamide (200 mg, 0.53 mmol), 3-(trifluoromethyl)benzamide (160 mg, 0.91 mmol), trans-1,2-diaminocyclohexane (15 mg, 0.13 mmol) and potassium carbonate (220 mg, 1.6 mmol) in 1,4-dioxane (3.0 mL) was added copper (I) iodide (25 mg, 0.13 mmol) under argon atmosphere, and the mixture was stirred at 110° C. for 60 hr. The reaction mixture was cooled, and diluted with 20% tetrahydrofuran/ethyl acetate. The mixture was washed with water, 5% aqueous sodium hydrogencarbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and filtrated. The solvent was evaporated under reduced pressure, and the residue was purified by NH silica gel column chromatography (ethyl acetate/hexane=60/40→100/0) and precipitated from ethyl acetate/hexane to give the title compound (110 mg, 42%) as a white powder.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:34](O)=[O:35])[CH2:13][CH2:14][CH2:15][NH:16][C:17]([N:19]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[NH:18])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(N)CCCCC1.[C:44]([O:48][C:49](=[O:56])[NH:50][CH2:51][CH:52]([OH:55])[CH2:53][NH2:54])([CH3:47])([CH3:46])[CH3:45].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C)C=O>[C:23]([O:22][C:20]([N:19]([C:17](=[NH:18])[NH:16][CH2:15][CH2:14][CH2:13][C@H:12]([NH:11][C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:10])[C:34](=[O:35])[NH:54][CH2:53][CH:52]([OH:55])[CH2:51][NH:50][C:49](=[O:56])[O:48][C:44]([CH3:47])([CH3:45])[CH3:46])[C:27]([O:29][C:30]([CH3:32])([CH3:33])[CH3:31])=[O:28])=[O:21])([CH3:24])([CH3:25])[CH3:26]
Reactant: CC(C)(C)OC(=O)N(C(=N)NCCC[C@H](NC(=O)OCc1ccccc1)C(=O)O)C(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)NCC(O)CN
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: NC1CCCCC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCC(O)CNC(=O)[C@H](CCCNC(=N)N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Under argon, 0.30 g (0.49 mmol) of N2-[(benzyloxy)carbonyl]-N5-[[bis(tert-butoxycarbonyl)amino](imino)methyl]-L-ornithine-cyclohexanamine (1:1) and 0.12 g (0.64 mmol) of tert-butyl(3-amino-2-hydroxypropyl)carbamate are dissolved in 6 ml of dimethylformamide. Then, at 0° C. (ice bath), 0.123 g (0.64 mmol) of EDC and 0.02 g (0.15 mmol) of HOBt are added. The mixture is slowly warmed to RT and stirred at RT for 12 h. The solution is concentrated in vacuo and the residue is taken up with ethyl acetate. The organic phase is washed successively with saturated sodium bicarbonate and sodium chloride solutions, dried over magnesium sulfate and evaporated in vacuo. The remaining solid is purified by preparative HPLC (Kromasil, mobile phase acetonitrile/0.25% aqueous trifluoroacetic acid 5:95→95:5).
Reaction SMILES: [O:1]1[CH2:4][CH:3]([OH:5])[CH2:2]1.CC(C)([O-])C.[K+].Cl[C:13]1[N:17]([CH3:18])[N:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[C:14]=1[CH:23]=[O:24]>C1COCC1>[CH3:18][N:17]1[C:13]([O:5][CH:3]2[CH2:4][O:1][CH2:2]2)=[C:14]([CH:23]=[O:24])[C:15]([C:19]([F:20])([F:21])[F:22])=[N:16]1
Reactant: OC1COC1
Reactant: Cn1nc(C(F)(F)F)c(C=O)c1Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Cn1nc(C(F)(F)F)c(C=O)c1OC1COC1
Yield: 99.9 %

Procedure:
Oxetane-3-ol (6.12 g, 82.7 mmol) was added dropwise to potassium tert-butoxide (1M in THF) (69.6 ml, 69.6 mmol) at room temperature. 5-Chloro-1-methyl-3-trifluoromethyl-1H-pyrazole-4-carbaldehyde (9.86 g, 46.4 mmol) was dissolved in THF (40 ml) and added slowly to the solution. After 25 minutes the mixture was concentrated and the residue partitioned between ethyl acetate and water. The two phases were separated and the aqueous phase was extracted several times with ethyl acetate. The combined organic phases were washed with brine, dried over magnesium sulfate and concentrated to yield the product as brown oil (11.6 g) which was used in the next step without further purification.
Reaction SMILES: O[CH:2]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([C:11]([O:13][CH3:14])=[O:12])[C:5]=2[CH2:4][CH2:3]1.S(Cl)([Cl:17])=O>>[Cl:17][CH:2]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([C:11]([O:13][CH3:14])=[O:12])[C:5]=2[CH2:4][CH2:3]1
Reactant: O=S(Cl)Cl
Reactant: COC(=O)c1cccc2c1CCC2O
Product: COC(=O)c1cccc2c1CCC2Cl

Procedure:
In 6 ml. of chllroform is dissolved 5.7 g. of methyl 1-hydroxyindan-4-carboxylate and, under cooling with ice, the solution is stirred. Then, 3 ml. of thionyl chloride is added dropwise and, after the dropwise addition has been completed, the mixture is further stirred under cooling with ice for one hour. Then, the solvent and the excess thionyl chloride are distilled off under reduced pressure. The residue obtained is purified by column chromatography on silica gel (500 g. silica gel; eluant: chloroform). The procedure gives methyl 1-chloroindan-4-carboxylate as an oily product.
Reaction SMILES: [OH-].[Na+].[C:3]([O:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18]CCCCCC)[CH:13]=1)(=O)[C:4]1C=[CH:8][CH:7]=[CH:6][CH:5]=1.Br[CH2:26][CH2:27][CH2:28][CH2:29][CH:30]([O:33][CH3:34])[O:31][CH3:32]>[N+](CCCC)(CCCC)(CCCC)CCCC.[I-].O>[CH3:32][O:31][CH:30]([O:33][CH3:34])[CH2:29][CH2:28][CH2:27][CH2:26][O:18][C:14]1[CH:15]=[CH:16][CH:17]=[C:12]([O:11][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[CH:13]=1
Reactant: COC(CCCCBr)OC
Reactant: CCCCCCOc1cccc(OC(=O)c2ccccc2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Agent: [Na+]
Solvent: O
Product: CCCCCCOc1cccc(OCCCCC(OC)OC)c1
Temperature: 90 °C
Reaction time: 8 h
Yield: 58.4 %

Procedure:
A mixture of NaOH (100 mg, 2.5 mmol), n-Bu4NI (37 mg, 0.1 mmol), 3-(hexyloxy)phenyl benzoate (ref. Prasad K. et al. Org. Proc. Res. Dev., 2003, 7 (5), 743-749) (200 mg, 0.67 mmol) in H2O (3 mL) was evacuated and refilled with Ar three times. The reaction mix was heated with stirring to 90° C. under Ar and treated with 5-bromo-1,1-dimethoxypentane (0.24 g, 1.2 mmol), added dropwise over 30 min at 95° C. Stirring was continued at 95° C. overnight. Later, the reaction mixture was cooled to rt and extracted with Et2O (2×). The organic extracts were washed (2 M aq NaOH, brine), concentrated under reduced pressure and purified by flash chromatography on silica gel using 0-7% EtOAc/hexanes as the eluent to afford the title compound as a colorless oil (127 mg, 59%). 1H NMR (400 MHz, CDCl3) δ ppm 7.15 (t, J=8.08 Hz, 1 H), 6.43-6.52 (m, 3 H), 4.89 (t, J=4.67 Hz, 1 H), 3.82-4.03 (m, 10 H), 1.20-1.92 (m, 14 H), 0.91 (t, J=6.82 Hz, 3 H).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([N:10]3[C:18]4[C:17]5[CH:19]=[C:20]([NH:23][C:24]([C:26]6[C:27]([NH:32]CC7C=CC(OC)=CC=7)=[N:28][CH:29]=[CH:30][CH:31]=6)=[O:25])[CH:21]=[CH:22][C:16]=5[CH2:15][CH2:14][C:13]=4[C:12]([C:42]([NH2:44])=[O:43])=[N:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.C(O)(C(F)(F)F)=O.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[NH2:32][C:27]1[C:26]([C:24]([NH:23][C:20]2[CH:21]=[CH:22][C:16]3[CH2:15][CH2:14][C:13]4[C:12]([C:42]([NH2:44])=[O:43])=[N:11][N:10]([C:8]5[CH:7]=[CH:6][C:5]6[O:1][CH2:2][O:3][C:4]=6[CH:9]=5)[C:18]=4[C:17]=3[CH:19]=2)=[O:25])=[CH:31][CH:30]=[CH:29][N:28]=1
Reactant: COc1ccc(CNc2ncccc2C(=O)Nc2ccc3c(c2)-c2c(c(C(N)=O)nn2-c2ccc4c(c2)OCO4)CC3)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)c1nn(-c2ccc3c(c2)OCO3)c2c1CCc1ccc(NC(=O)c3cccnc3N)cc1-2
Yield: 32.5 %

Procedure:
The title compound of Example 209 (1.96 g, 0.0033 mol) was dissolved in 6 mL CH2Cl2 and reacted with 5 mL TFA at room temperature for 36 h. The crude reaction mixture was diluted with CH2Cl2 and basified with a saturated aqueous solution of Na2CO3. The layers were separated and the organic layer was dried over MgSO4. The residue obtained after removal of the solvent under vacuum was triturated with EtOH to afford 0.503 g of title compound (yield: 32%). Mp: 265–267° C. 1H NMR (300 MHz, d6-DMSO): δ 2.88–2.95 (m, 4H), 6.12 (s, 2H), 5.58–6.62 (dd, 1H, J=7.6 Hz, 4.7 Hz), 6.97–7.08 (m, 4H), 7.17 (d, 1H, J=1.9 Hz), 7.28 (s, 1H), 7.32 (s, 2H), 7.55 (s, 2H), 7.95–7.98 (dd, 1H, J=7.7 Hz, 1.7 Hz), 8.11–8.13 (dd, 1H, J=4.7 Hz, 1.7 Hz), 9.99 (s, 1H). M+1=469.
Reaction SMILES: [CH3:1][C:2]1([CH3:41])[C:14]2[CH:13]=[C:12]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4[CH:23]=[CH:24][C:25]5[N:26]([C:35]6[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=6)[C:27]6[C:32]([C:33]=5[CH:34]=4)=[CH:31][CH:30]=[CH:29][CH:28]=6)=[CH:18][CH:17]=3)[CH:11]=[CH:10][C:9]=2[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2.[Br:42][C:43]1[CH:48]=[CH:47][C:46]([C:49]2[CH:54]=[CH:53][C:52](I)=[CH:51][CH:50]=2)=[CH:45][CH:44]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1>[Br:42][C:43]1[CH:44]=[CH:45][C:46]([C:49]2[CH:54]=[CH:53][C:52]([N:15]([C:12]3[CH:11]=[CH:10][C:9]4[C:8]5[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=5)[C:2]([CH3:41])([CH3:1])[C:14]=4[CH:13]=3)[C:16]3[CH:17]=[CH:18][C:19]([C:22]4[CH:23]=[CH:24][C:25]5[N:26]([C:35]6[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=6)[C:27]6[C:32]([C:33]=5[CH:34]=4)=[CH:31][CH:30]=[CH:29][CH:28]=6)=[CH:20][CH:21]=3)=[CH:51][CH:50]=2)=[CH:47][CH:48]=1
Reactant: Brc1ccc(-c2ccc(I)cc2)cc1
Reactant: CC1(C)c2ccccc2-c2ccc(Nc3ccc(-c4ccc5c(c4)c4ccccc4n5-c4ccccc4)cc3)cc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC1(C)c2ccccc2-c2ccc(N(c3ccc(-c4ccc(Br)cc4)cc3)c3ccc(-c4ccc5c(c4)c4ccccc4n5-c4ccccc4)cc3)cc21
Temperature: 25 °C
Yield: 66.7 %

Procedure:
30 g (57 mmol) (9,9-dimethyl-9H-fluoren-2-yl)-[4-(9-phenyl-9H-carbazol-3-yl)-phenyl]-amine and 20 g (57 mmol) 4-bromo-4′-iodo-biphenyl [105946-82-5] are dissolved in 200 ml toluene and treated with 100 ml of a 2 M solution of sodium carbonate. The reaction mixture is carefully degassed and 200 mg tetrakistriphenylphosphine palladiume are added and refluxed for 20 h. The reaction mixture is then cooled to room temperature and 250 ml water is added. The layers are separated. The water phase is then extracted three times with toluene. The organic layers are then washed twice with water, dried over magnesium sulphate, filtrated and the solvent is then removed under vacuum. The residue is recrystallized from butanole/toluene, to yield 29 g (38 mmol) (67%) of a white solid with a purity of 99.3%.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH2:16][CH2:17]O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:38]1(=[O:48])[NH:42][C:41](=[O:43])[C:40]2=[CH:44][CH:45]=[CH:46][CH:47]=[C:39]12.C(OC(N=NC(OCC)=O)=O)C>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([CH2:14][CH2:15][CH2:16][CH2:17][N:42]2[C:38](=[O:48])[C:39]3[C:40](=[CH:44][CH:45]=[CH:46][CH:47]=3)[C:41]2=[O:43])[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCC(CCCCO)CC1
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(CCCCN2C(=O)c3ccccc3C2=O)CC1
Temperature: 15 °C
Reaction time: 8 h

Procedure:
136.0 g (<528 mmol) 4-(1-tert-butoxycarbonylpiperidin-4-yl)-butan-1-ol (crude product), 135.3 g (516 mmol) triphenylphosphine and 75.9 g (516 mmol) phthalimide are suspended in THF and 89.9 g (516 mmol) azodicarboxylic acid diethyl ester are added dropwise within 3 hours under protective atmosphere and light cooling (ca. 15° C.). The mixture is left to stand at RT overnight without further cooling. Subsequently, the solvent is removed under vacuum and the oily residue is dissolved in 500 ml acetic acid ethyl ester and held overnight at 0° C. The sedimented precipitate is filtered and discarded. The solution is concentrated under vacuum and the oily residue is chromatographically purified over silica gel with CHCl3 and crystallized from 200 ml isopropanol after drawing off the solvent. Colorless crystals with a MP of 100-102° C. were recovered; yield: 108.5g (57%).
Reaction SMILES: [CH:1]1([CH2:4][C@H:5]([N:18]2[CH2:26][C:25]3[C:20](=[CH:21][CH:22]=[C:23]([C:27]4[N:31]([CH3:32])[N:30]=[CH:29][CH:28]=4)[CH:24]=3)[C:19]2=[O:33])[CH2:6][N:7]2C(=O)C3C(=CC=CC=3)C2=O)[CH2:3][CH2:2]1.NN>CO>[NH2:7][CH2:6][C@@H:5]([N:18]1[CH2:26][C:25]2[C:20](=[CH:21][CH:22]=[C:23]([C:27]3[N:31]([CH3:32])[N:30]=[CH:29][CH:28]=3)[CH:24]=2)[C:19]1=[O:33])[CH2:4][CH:1]1[CH2:2][CH2:3]1
Reactant: Cn1nccc1-c1ccc2c(c1)CN([C@@H](CC1CC1)CN1C(=O)c3ccccc3C1=O)C2=O
Agent: NN
Solvent: CO
Product: Cn1nccc1-c1ccc2c(c1)CN([C@H](CN)CC1CC1)C2=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 37.2 %

Procedure:
2-{(2S)-3-Cyclopropyl-2-[5-(1-methyl-1H-pyrazol-5-yl)-1-oxo-1,3-dihydro-2H-isoindol-2-yl]propyl}-1H-isoindole-1,3(2H)-dione (56 mg, 0.13 mmol) was dissolved in hydrazine (1 mL, 30 mmol) and methanol (5 mL). The resulting solution was stirred at room temperature for 2 h. Direct purification on prep.HPLC afforded 15 mg (37% yield) of the final desired product. LC-MS found: 311 (M+H)+.
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2.[C:15]1([CH2:21][CH2:22][CH2:23][CH:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[C:30]([OH:35])(=[O:34])[C:31]([OH:33])=[O:32].CO>C(OCC)(=O)C>[C:30]([OH:35])(=[O:34])[C:31]([OH:33])=[O:32].[NH:10]1[C:11]2[C:7](=[C:6]([O:5][CH2:4][C@@H:2]([OH:1])[CH2:3][N:27]3[CH2:28][CH2:29][CH:24]([CH2:23][CH2:22][CH2:21][C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=4)[CH2:25][CH2:26]3)[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9]1
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Reactant: c1ccc(CCCC2CCNCC2)cc1
Agent: O=C(O)C(=O)O
Solvent: CO
Solvent: CCOC(C)=O
Product: O[C@H](COc1cccc2[nH]ccc12)CN1CCC(CCCc2ccccc2)CC1

Procedure:
The title compound was prepared in similar fashion from (S)-(+)-4-(oxiranylmethoxy)-1H-indole and 4-(3-phenylpropyl)piperidine. The resulting free base was dissolved in ethyl acetate, and precipitated with one equivalent of oxalic acid in ethyl acetate in 73% overall yield. FDMS m/e=392 (M+ of free base). α[D]589 =-13.53 (c=0.58, methanol).
Reaction SMILES: I[C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8]([CH2:15][CH2:16][CH3:17])=[CH:9][CH:10]=3)[CH2:5][C:4]=2[CH:3]=1.[C:18]([C:20]1[CH:25]=[CH:24][C:23]([F:26])=[C:22]([F:27])[CH:21]=1)#[CH:19]>CN(C)C=O.C(N(CC)CC)C.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>[CH2:15]([C:8]1[CH:9]=[CH:10][C:11]2[C:12]3[C:4](=[CH:3][C:2]([C:19]#[C:18][C:20]4[CH:25]=[CH:24][C:23]([F:26])=[C:22]([F:27])[CH:21]=4)=[CH:14][CH:13]=3)[CH2:5][C:6]=2[CH:7]=1)[CH2:16][CH3:17]
Reactant: C#Cc1ccc(F)c(F)c1
Reactant: CCCc1ccc2c(c1)Cc1cc(I)ccc1-2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCc1ccc2c(c1)Cc1cc(C#Cc3ccc(F)c(F)c3)ccc1-2

Procedure:
2-iodo-7-propyl-fluorene in dimethylformamide and triethylamine was reacted with 4-ethynyl-1,2-difluorobenzene in the presence of tetrakis(triphenylphosphine)palladium (0), and the product was purified by silica gel column chromatography (hexane) and then recrystallized from ethanol to yield 2-propyl-7-(3,4-difluorophenylethynyl)fluorene.
Reaction SMILES: Br[C:2]1[S:22][C:5]2=[N:6][C:7]([CH3:21])=[CH:8][C:9]([NH:10][S:11]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=3)(=[O:13])=[O:12])=[C:4]2[C:3]=1[CH3:23].[CH:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27](B(O)O)=[CH:26][N:25]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.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>[Cl:20][C:16]1[CH:15]=[C:14]([S:11]([NH:10][C:9]2[CH:8]=[C:7]([CH3:21])[N:6]=[C:5]3[S:22][C:2]([C:27]4[C:28]5[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=5)[CH:24]=[N:25][CH:26]=4)=[C:3]([CH3:23])[C:4]=23)(=[O:13])=[O:12])[CH:19]=[CH:18][CH:17]=1
Reactant: Cc1cc(NS(=O)(=O)c2cccc(Cl)c2)c2c(C)c(Br)sc2n1
Reactant: OB(O)c1cncc2ccccc12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc(NS(=O)(=O)c2cccc(Cl)c2)c2c(C)c(-c3cncc4ccccc34)sc2n1
Temperature: 100 °C
Yield: 37.2 %

Procedure:
To a solution of N-(2-bromo-3,6-dimethylthieno[2,3-b]pyridin-4-yl)-3-chlorobenzenesulfonamide (Example 77) (100 mg, 0.232 mmol) in 1,4-dioxane (2 mL) and water (1 mL) was added 4-isoquinolinylboronic acid (40.1 mg, 0.232 mmol), bis(triphenylphosphine)palladium(II) chloride (16.26 mg, 0.023 mmol) and potassium carbonate (112 mg, 0.811 mmol) and the mixture heated at 100° C. for 1 h using a microwave reactor. The mixture was then filtered through celite, washing with ethyl acetate (30 mL) and the filtrate evaporated to dryness. The residue was then purified by MDAP (acidic conditions), to afford the title compound (41.45 mg). LCMS (A) m/z: 480 [M+1]+, Rt 1.13 min (acidic).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([C:11]#[C:12][CH2:13][OH:14])[CH:2]=1.CC(C)([O-])C.[K+].[CH:21]([N:24]([CH:28]([CH3:30])[CH3:29])[C:25](Cl)=[O:26])([CH3:23])[CH3:22].[NH4+].[Cl-]>C1COCC1.CC(OC)(C)C>[CH:21]([N:24]([CH:28]([CH3:30])[CH3:29])[C:25]([O:14][CH2:13][C:12]#[C:11][C:3]1[CH:2]=[N:1][C:10]2[C:5]([CH:4]=1)=[CH:6][CH:7]=[CH:8][CH:9]=2)=[O:26])([CH3:23])[CH3:22]
Reactant: OCC#Cc1cnc2ccccc2c1
Reactant: CC(C)N(C(=O)Cl)C(C)C
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: COC(C)(C)C
Product: CC(C)N(C(=O)OCC#Cc1cnc2ccccc2c1)C(C)C
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a dry three-necked round-bottom flask equipped with nitrogen inlet and overhead stirrer was charged 3-(3-quinolyl)-2-propyn-1-ol (2 g, 10.8 mmol) (Scheme 1, Compound (3) in THF (20 ml) and the solution was cooled to 0° C. Potassium t-butoxide (1.34 g, 11.9 mmol) was then added followed by diisopropylcarbamoyl chloride (1.65 g, 11.9 mmol). The mixture was stirred for 2 h at 0° C. and then allowed to warm up to room temperature over a period of 6 hours, by which time the reaction was determined to be complete. The reaction mixture was worked up with MTBE (50 ml) and 10% NH4Cl (25 ml) and was concentrated to an orange oil. Yield=3.3 g (100%)
Reaction SMILES: C(N(CC)CC)C.[C:8]([SiH:12]([CH3:14])[CH3:13])([CH3:11])([CH3:10])[CH3:9].[CH3:15][O:16][C:17](=[O:29])[C@H:18]([CH:26]([CH3:28])[CH3:27])[NH:19][C:20]([O:22]CC=C)=[O:21].[Cl-].[NH4+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.ClCCl>[CH3:15][O:16][C:17](=[O:29])[C@H:18]([CH:26]([CH3:27])[CH3:28])[NH:19][C:20]([O:22][Si:12]([C:8]([CH3:11])([CH3:10])[CH3:9])([CH3:14])[CH3:13])=[O:21]
Reactant: C=CCOC(=O)N[C@H](C(=O)OC)C(C)C
Reactant: C[SiH](C)C(C)(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H](NC(=O)O[Si](C)(C)C(C)(C)C)C(C)C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a dichloromethane solution (1.0 ml) of palladium (II) acetate (8.0 mg, 0.04 mmol) and triethylamine (15 μl, 0.11 mmol), t-butyldimethylsilane (179 μl, 1.1 mmol) was added and the mixture was stirred for 15 minutes at room temperature. To the resulting black suspension, a dichloromethane solution (1.0 ml) of N-allyloxycarbonylvaline methyl ester (154 mg, 0.72 mmol) was added and the mixture was stirred for an additional 15 hours. After a saturated aqueous solution of ammonium chloride was added to quench the reaction, extraction with ether was conducted and the ether layer was dried over anhydrous magnesium sulfate and filtered. By distilling off the solvent, N-t-butyldimethylsilyloxycarbonylvaline methyl ester was obtained in an amount of 207 mg (yield, 100%). The physical data for this compound were in agreement with those reported in Examples 4 and 9.