Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])O.[Na+].[Br:6][C:7]1[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][C:8]=1[F:14].Cl[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17]>CC(C)=O>[CH2:19]([O:18][C:16](=[O:17])[NH:11][C:10]1[CH:12]=[CH:13][C:7]([Br:6])=[C:8]([F:14])[CH:9]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Nc1ccc(Br)c(F)c1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Product: O=C(Nc1ccc(Br)c(F)c1)OCc1ccccc1
Temperature: 15 °C
Reaction time: 1.5 h

Procedure:
Sodium hydrogen carbonate (27.63 g, 0.329 mol, 1.25 eq) and a saturated solution of sodium hydrogen carbonate (333 ml) were added to a stirred solution of 4-bromo-3-fluoroaniline (50.0 g, 0.263 mol, 1 eq) in acetone (660 ml). The resulting mixture was cooled to 15° C. and benzyl chloroformate (39 ml, 0.276 mol, 1.05 eq) was added gradually, taking care that the reaction temperature did not exceed 22° C. The mixture was stirred over 90 mins at room temperature and the acetone was removed under vacuum. The aqueous layer was then extracted with ethyl acetate (3×150 ml). The combined organic layers were then washed with a saturated sodium chloride solution, and dried over MgSO4. After filtration, the solvent was removed, and n-hexane added. The mixture was stirred during 30 min at room temperature, the crystals were filtrated and washed with hexane to give the first crop of solid. The filtrate was evaporated, and the solid mixed with heptane at 0° C. and stirred during 30 min. The product was again filtered, to give the second crop of solid. The two crops were then combined, to give the product (85.3 g, quantitative) as of solid.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[C:7]([NH2:10])[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[Br:11]Br.O>C(O)(=O)C>[Br:11][C:6]1[C:5]2[S:1][CH:2]=[N:3][C:4]=2[CH:9]=[CH:8][C:7]=1[NH2:10]
Reactant: BrBr
Reactant: Nc1ccc2ncsc2c1
Solvent: CC(=O)O
Solvent: O
Product: Nc1ccc2ncsc2c1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 67 %

Procedure:
To a solution of benzothiazol-6-ylamine (6.4 g, 42.6 mmol) in glacial acetic acid (40 mL) was added bromine (2.18 mL) in glacial acetic acid (10 mL) dropwise. The reaction mixture was stirred at RT for 1 h. Water (160 mL) was added to the reaction mixture and the solid formed was extracted with ethyl acetate (3×40 mL). The combined organic fractions were washed with saturated aqueous sodium bicarbonate solution (200 mL), water (100 mL), and brine (20 mL), dried over anhydrous sodium sulfate, and concentrated. Purification of the residue by column chromatography (20% ethyl acetate:hexanes) afforded 6.5 g (67%) of the title compound as a yellow solid. 1H NMR (300 MHz, CDCl3): δ 4.31 (br. s, 2H), 7.02 (d, J=8.4 Hz, 1H), 7.92 (d, J=8.4 Hz, 1H), 8.80 (s, 1H).
Reaction SMILES: [C:1](=[O:13])([O:7][CH:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1)[O:2][CH:3](Cl)[CH2:4][CH3:5].[I-:14].[Na+].CCOCC.O>C(#N)C>[C:1](=[O:13])([O:7][CH:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1)[O:2][CH:3]([I:14])[CH2:4][CH3:5]
Reactant: [I-]
Reactant: CCC(Cl)OC(=O)OC1CCCC1
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Solvent: CC#N
Product: CCC(I)OC(=O)OC1CCCC1

Procedure:
A solution of 3.11 g of 1-chloropropyl cyclopentyl carbonate and 6 g of sodium iodide in 40 ml of acetonitrile is stirred at 60° C. for 60 minutes and then concentrated under reduced pressure. The residue obtained is distributed with 100 ml of ether and 100 ml of water. The ether layer is separated, washed serially with 50 ml of 5% sodium thiosulfate and 100 ml of saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure to give the title compound as oily material.
Reaction SMILES: S(=O)(=O)(O)[OH:2].[CH3:6][C:7]1[CH:13]=[C:12]([CH3:14])[CH:11]=[C:9]([OH:10])[C:8]=1O>>[CH3:6][C:7]1[CH:8]=[C:9]([OH:10])[CH:11]=[C:12]([CH3:14])[C:13]=1[OH:2]
Reactant: O=S(=O)(O)O
Reactant: Cc1cc(C)c(O)c(O)c1
Product: Cc1cc(O)cc(C)c1O
Reaction time: 0.5 h

Procedure:
By following in the same manner as in Example 53, except that the amount of sulfuric acid was reduced from 0.01 g. to 0.001 g., and the reaction time was 30 minutes, 3.16 g, (22.9 m. moles) of 3,5-dimethylcatechol and 2.13 g. (15.4 m. moles) of 2,6-dimethylhydroquinone were obtained. The yield of dihydric alkylphenols was 75.4 percent.
Reaction SMILES: Cl.C(OCC)(=[O:4])C.[Cl:8][C:9]1[CH:28]=[CH:27][C:12]2[O:13][C:14]3[CH:26]=[CH:25][CH:24]=[CH:23][C:15]=3[C@H:16]3[CH2:20][N:19]([CH3:21])[C:18](=[O:22])[C@@H:17]3[C:11]=2[CH:10]=1>C1(C)C(C)=CC=CC=1>[ClH:8].[Cl:8][C:9]1[CH:28]=[CH:27][C:12]2[O:13][C:14]3[CH:26]=[CH:25][CH:24]=[CH:23][C:15]=3[C@@H:16]([CH2:20][NH:19][CH3:21])[C@H:17]([C:18]([OH:22])=[O:4])[C:11]=2[CH:10]=1
Reactant: CCOC(C)=O
Reactant: CN1C[C@@H]2c3ccccc3Oc3ccc(Cl)cc3[C@H]2C1=O
Agent: Cl
Solvent: Cc1ccccc1C
Product: CNC[C@@H]1c2ccccc2Oc2ccc(Cl)cc2[C@H]1C(=O)O
Temperature: 65 °C

Procedure:
HCl (55.5 g) and silica gel (55 g) were suspended in xylene (550 mL). The suspension was heated to reflux for 1 night. The reaction mixture was cooled to 65° C. and ethyl acetate (550 mL) was added. The silica gel was filtered off and washed with ethyl acetate (550 mL). The organic phase was evaporated. The crude product was dissolved in methanol (750 mL). The methanol was partly evaporated upon which crystallization of the product takes place. After cooling to 5° C. for 3 hours, the product was obtained by filtration. This yielded trans-11-chloro-2,3,3a,12b-tetrahydro-2-methyl-1H-dibenz[2,3:6,7]oxepino[4,5-c]pyrrol-1-one (IV) (47.8 g, 86%); mp 150.6° C.; 1H-NMR (400.13 MHz in CDCl3 relative to TMS) δ 3.03 (d, 3H), 4.03 (m, 1H), 3.53-3.65 (m, 2H), 3.82 (m, 1H), 7.01-7.28 (m, 6H), 7.87 (dd, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][CH2:14][CH3:15])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN=C=NC[CH2:22][CH2:23][N:24]([CH3:26])C.Cl.CN1CCOCC1.N1CCC1>C(Cl)Cl>[N:24]1([C:10](=[O:12])[C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:13][CH2:14][CH3:15])[CH2:23][CH2:22][CH2:26]1
Reactant: CCN=C=NCCCN(C)C
Reactant: CCC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: C1CNC1
Agent: Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CCC[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCC1
Temperature: 0 °C
Yield: 59.8 %

Procedure:
(S)-2-(Tert-butoxycarbonylamino)pentanoic acid (17.0 g, 78.25 mmol), which is commercially available, and EDC hydrochloride (18.00 g, 93.90 mmol) was mixed in DCM (300 mL). To the mixture was NMM (20.65 mL, 187.79 mmol) added. The mixture was cooled to 0° C. and azetidine (6.33 mL, 93.90 mmol) was added. The resultant mixture was stirred at 0° C. for 30 min. and at rt over night. The reaction mixture was washed with NaHCO3 (saturated, 2×300 mL) and brine (300 mL), filtered through a phase separator and concentrated under reduced pressure. The residue was purified via Biotage (gradient; DCM/iso-propanol, 99:1 to 90:10, KP-SIL 340 g column). The solvent was removed under reduced pressure to give the title compound (12.0 g, 60%). 1H NMR (400 MHz, CD3OD) δ 0.92, 1.20-1.76, 2.30, 3.89-4.26, 4.26-4.46, 5.16. LCMS (M+H)+: 257.
Reaction SMILES: [C:1]1(=[O:36])[N:5]([CH2:6][CH2:7][CH2:8][N:9]([S:21]([C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=2)(=[O:23])=[O:22])[CH2:10][C:11]([F:20])([F:19])[CH2:12]COS(C)(=O)=O)[C:4](=[O:31])[C:3]2=[CH:32][CH:33]=[CH:34][CH:35]=[C:2]12.[C:37]1(=[O:47])[NH:41][C:40](=[O:42])[C:39]2=[CH:43][CH:44]=[CH:45][CH:46]=[C:38]12.[K].[CH3:49]N(C=O)C>O>[C:1]1(=[O:36])[N:5]([CH2:6][CH2:7][CH2:8][N:9]([S:21]([C:24]2[CH:25]=[CH:26][C:27]([CH3:30])=[CH:28][CH:29]=2)(=[O:23])=[O:22])[CH2:10][C:11]([F:20])([F:19])[CH2:12][CH2:49][N:41]2[C:37](=[O:47])[C:38]3=[CH:46][CH:45]=[CH:44][CH:43]=[C:39]3[C:40]2=[O:42])[C:4](=[O:31])[C:3]2=[CH:32][CH:33]=[CH:34][CH:35]=[C:2]12
Reactant: O=C1NC(=O)c2ccccc21
Reactant: Cc1ccc(S(=O)(=O)N(CCCN2C(=O)c3ccccc3C2=O)CC(F)(F)CCOS(C)(=O)=O)cc1
Reactant: CN(C)C=O
Agent: [K]
Solvent: O
Product: Cc1ccc(S(=O)(=O)N(CCCN2C(=O)c3ccccc3C2=O)CC(F)(F)CCN2C(=O)c3ccccc3C2=O)cc1
Temperature: 90 °C

Procedure:
Under an atmosphere of nitrogen, a mixture of 1-phthalimido-4-p-toluenesulfonyl-6,6-difluoro-8-methanesulfonyloxy-4-aza-octane, (7.6 g, 14 mM), potassium phthalimide (2.85 g, 10% excess) and dry DMF (20 mL) is stirred and heated at 90° C. for 20 hours. Following the addition of water (approximately 100 mL), the reaction is extracted with dichloromethane, washed with 1N KOH (twice), and dried (Na2SO4). The solvents are removed by evaporation to yield and oil (8.7 g) which is flash-chromatographed on silica (300 g, eluent: ethyl acetate/petroleum ether/50--50) with 100 mL fractions being taken. Fractions 15-29 are pooled and the solvent is evaporated to yield 1,8-diphthalimido-4-p-toluenesulfonyl-6,6-difluoro-4-aza-octane, which crystallizes on standing: 6.62 g (80%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17]1[CH2:16][CH2:15][CH:14]([NH2:22])[CH2:13][C:12]2=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].I[CH2:30][CH3:31]>C(#N)C>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17]1[CH2:16][CH2:15][CH:14]([NH:22][CH2:30][CH3:31])[CH2:13][C:12]2=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1.[OH:8][C:9]1[CH:10]=[C:11]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17]1[CH2:16][CH2:15][CH:14]([NH:22][CH2:30][CH3:31])[CH2:13][C:12]2=1
Reactant: CCI
Reactant: NC1CCc2[nH]c3ccc(OCc4ccccc4)cc3c2C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCNC1CCc2[nH]c3ccc(O)cc3c2C1
Product: CCNC1CCc2[nH]c3ccc(OCc4ccccc4)cc3c2C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 21.2 %

Procedure:
To a solution of 0.225 gm (0.77 mMol) 6-benzyloxy-3-amino-1,2,3,4-tetrahydro-9H-carbazole in 20 mL acetonitrile were added 0.223 gm (1.617 mMol) potassium carbonate followed by 130 μL (1.617 mMol) iodoethane and the reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was then heated at 60° C. for 4 hours and then at 50°-45° C. for 3 hours. The reaction mixture was then concentrated under reduced pressure and the residue partitioned between dichloromethane and water. The organic phase was then dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to radial chromatography (silica gel, 2 mm), eluting with 97:3:1 dichloromethane:methanol:ammonium hydroxide. Fractions shown to contain the desired compound were concentrated under reduced pressure to give 0.045 gm (6%) of the desired compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[N:16]=[CH:15][C:14]([C@H:17]([N:19]3[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][C@@H:20]3[CH3:32])[CH3:18])=[CH:13][C:12]=2[C:33]2[N:41]=[C:40]([CH3:42])[N:39]=[C:38]3[C:34]=2[N:35]=[CH:36][N:37]3C2CCCCO2)[CH:5]=[N:6][C:7]=1[O:8][CH3:9].FC(F)(F)C(O)=O.F[C:57](F)(F)[S:58](O)(=[O:60])=[O:59].CS(Cl)(=O)=O>C(Cl)Cl.O.[Cl-].[Na+].O>[F:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[C:12]([C:33]3[N:41]=[C:40]([CH3:42])[N:39]=[C:38]4[C:34]=3[N:35]=[CH:36][NH:37]4)=[CH:13][C:14]([C@H:17]([N:19]3[CH2:24][CH2:23][N:22]([S:58]([CH3:57])(=[O:60])=[O:59])[CH2:21][C@@H:20]3[CH3:32])[CH3:18])=[CH:15][N:16]=2)[CH:5]=[N:6][C:7]=1[O:8][CH3:9]
Reactant: COc1ncc(Nc2ncc([C@@H](C)N3CCN(C(=O)OC(C)(C)C)C[C@@H]3C)cc2-c2nc(C)nc3c2ncn3C2CCCCO2)cc1F
Reactant: O=S(=O)(O)C(F)(F)F
Agent: CS(=O)(=O)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: O
Product: COc1ncc(Nc2ncc([C@@H](C)N3CCN(S(C)(=O)=O)C[C@@H]3C)cc2-c2nc(C)nc3[nH]cnc23)cc1F
Reaction time: 1 h
Yield: 4.63 %

Procedure:
A mixture of (3S)-tert-butyl 4-((1R)-1-(6-(5-fluoro-6-methoxypyridin-3-ylamino)-5-(2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-3-yl)ethyl)-3-methylpiperazine-1-carboxylate (0.180 g, 0.272 mmol) and trifluoroacetic acid (0.314 mL, 4.08 mmol) in DCM (10 mL) was treated with trifluoromethanesulfonic acid (0.01 mL) and allowed to stir under inert atmosphere for 1 h. The mixture was concentrated in vacuo, then THF (10 mL) was added to the residue and stirred 5 min. Then sodium carbonate (0.500 g) was added to the mixture and allowed to stir under inert atmosphere an additional 5 min. Then methanesulfonyl chloride (0.064 mL, 0.816 mmol) was added slowly via syringe into the mixture. The mixture was allowed to stir under inert atmosphere overnight. The mixture was diluted with DCM (20 mL),water (20 mL) and brine solution (10 mL). The organic layer was extracted with DCM (3×15 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was recrystallized from methanol and dichloromethane to give N-(5-fluoro-6-methoxypyridin-3-yl)-5-((R)-1-((S)-2-methyl-4-(methylsulfonyl)piperazin-1-yl)ethyl)-3-(2-methyl-9H-purin-6-yl)pyridin-2-amine (0.007 g, 0.013 mmol, 4.63% yield) as a tan solid. 1H NMR (400 MHz, CDCl3) δ 12.69 (s, 1H) 9.84 (s, 1H) 8.38 (dd, J=12.42, 2.05 Hz, 1H) 8.28 (d, J=2.15 Hz, 1H) 8.22 (s, 1H) 8.11 (d, J=2.15 Hz, 1H) 7.26 (s, 8H) 4.16 (dq, J=14.18, 6.94 Hz, 1H) 4.04 (s, 3H) 3.30 (s, 2H) 3.14-3.21 (m, 1H) 2.93-3.06 (m, 4H) 2.85 (dd, J=10.76, 7.24 Hz, 1H) 2.69-2.78 (m, 4H) 2.55-2.64 (m, 1H) 1.54 (d, J=6.85 Hz, 3H) 1.13-1.32 (m, 3H). m/z (ESI, +ve ion) 556.1 (M+H)+.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]#[N:8].Br[CH2:10][CH2:11]Br>>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1([CH2:7][NH2:8])[CH2:11][CH2:10]1
Reactant: N#CCc1cccs1
Reactant: BrCCBr
Product: NCC1(c2cccs2)CC1

Procedure:
(1-Thien-2-ylcyclopropyl)methylamine is prepared from 2-thienyl acetonitrile and 1,2-dibromoethane as described in Example 1 in 57% overall yield.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[NH:4][N:3]=1.[O:13]1[CH2:18][CH:17]=[C:16](B2OC(C)(C)C(C)(C)O2)[CH2:15][CH2:14]1.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.O.CCOC(C)=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>[O:13]1[CH2:14][CH:15]=[C:16]([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5](=[O:12])[NH:4][N:3]=2)[CH2:17][CH2:18]1
Reactant: O=c1[nH]nc(Cl)c2ccccc12
Reactant: CC1(C)OB(C2=CCOCC2)OC1(C)C
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: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=c1[nH]nc(C2=CCOCC2)c2ccccc12
Temperature: 180 °C

Procedure:
A mixture of 4-chlorophthalazin-1(2H)-one (150 mg, 0.831 mmol), 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (174 mg, 0.831 mmol), Na2CO3 (164 mg, 2.49 mmol) and Pd(PPh3)4 (47.8 mg, 0.042 mmol) in DMF (3 mL) and H2O (1 mL) was heated at 180° C. under microwave condition for 20 minutes. The mixture was diluted with EtOAc and washed with saturated aqueous NaHCO3, dried (Na2SO4), filtered, and concentrated to afford the title compound: MS (APCI) M/Z 229 (M+H)+.
Reaction SMILES: CS([Cl:5])(=O)=O.[CH3:6][S:7]([C:10]1[CH:34]=[CH:33][C:13]2[N:14]([CH:17]3[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][CH:25]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)O)[CH2:19][CH2:18]3)[CH:15]=[N:16][C:12]=2[CH:11]=1)(=[O:9])=[O:8].C(N(CC)CC)C>ClCCl>[Cl:5][CH:25]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:24][CH2:23][N:20]1[CH2:21][CH2:22][CH:17]([N:14]2[C:13]3[CH:33]=[CH:34][C:10]([S:7]([CH3:6])(=[O:9])=[O:8])=[CH:11][C:12]=3[N:16]=[CH:15]2)[CH2:18][CH2:19]1
Reactant: CS(=O)(=O)c1ccc2c(c1)ncn2C1CCN(CCC(O)c2ccccc2)CC1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)c1ccc2c(c1)ncn2C1CCN(CCC(Cl)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Methanesulphonyl chloride (0.46 ml) was added to a solution of 3-{4-[5-(methylsulfonyl)-1H-benzimidazol-1-yl]piperidin-1-yl}-1-phenylpropan-1-ol (2.1 g) and triethylamine (0.9 ml) in dichloromethane (30 ml) at 0° C. The mixture was allowed to warm to room temperature and stirring was continued for 16 hours. The reaction mixture was washed with water (15 ml) and brine (15 ml) and dried. Removal of the solvent gave the title compound as an orange foam, yield 1.85 g, M+H 432.
Reaction SMILES: Br[C:2]1[CH:8]=[C:7]([F:9])[C:5]([NH2:6])=[C:4]([F:10])[CH:3]=1.[Cu][C:12]#[N:13].CN1CCCC1=O.Cl>[Fe](Cl)(Cl)Cl.O>[C:12]([C:2]1[CH:8]=[C:7]([F:9])[C:5]([NH2:6])=[C:4]([F:10])[CH:3]=1)#[N:13]
Reactant: N#C[Cu]
Reactant: Nc1c(F)cc(Br)cc1F
Agent: Cl[Fe](Cl)Cl
Agent: Cl
Solvent: O
Solvent: CN1CCCC1=O
Product: N#Cc1cc(F)c(N)c(F)c1
Yield: 57.2 %

Procedure:
21 g of 4-bromo-2,6-difluoroaniline, 11 g of copper (I) cyanide, and 70 ml of N-methyl-2-pyrrolidone were placed in a flask for three hours to form a reaction mixture. The reaction mixture was poured into a solution of 41 g of iron (III) chloride mixed with 13 ml of concentrated hydrochloric acid and 50 ml of water. The mixture was extracted with chloroform and washed with water and 10% potassium hydroxide and the chloroform was removed by distillation. The residue was distilled under reduced pressure (bp 90° to 110° C. at 4 mmHg) and recrystallized with a mixture of hexane and chloroform to yield 8.9 g of 4-cyano-2,6-difluoroaniline.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][N:2]1[C:11]1[N:16]=[C:15]([O:17][CH3:18])[C:14]([NH2:19])=[C:13]([O:20][CH3:21])[N:12]=1.N1C=CC=CC=1.[C:28]([CH2:32][C:33](Cl)=[O:34])([CH3:31])([CH3:30])[CH3:29]>ClCCl>[CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][N:2]1[C:11]1[N:16]=[C:15]([O:17][CH3:18])[C:14]([NH:19][C:33](=[O:34])[CH2:32][C:28]([CH3:31])([CH3:30])[CH3:29])=[C:13]([O:20][CH3:21])[N:12]=1
Reactant: CC(C)(C)CC(=O)Cl
Reactant: COc1nc(N2CCc3ccccc3C2)nc(OC)c1N
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1nc(N2CCc3ccccc3C2)nc(OC)c1NC(=O)CC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.1 %

Procedure:
To a mixture of 4c (0.219 g, 0.76 mmol) and pyridine (0.06 g, 0.76 mmol) in dichloromethane (5 ml) was added tert-butylacetyl chloride (0.102 g, 0.76 mmol). The mixture was stirred at room temperature for 1 hour. The mixture was washed with brine and extracted with ethyl acetate. The organic layer was dried over MgSO4, concentrated and chromatographed to yield the title compound (0.262 g, 0.73 mmol, 96%). 1H NMR (CDCl3, 400 MHz) δ 1.10 (s, 9H), 2.20 (s, 2H), 2.90 (t, J=5.8 Hz, 2H), 3.92 (s, 6H), 4.01 (t, J=5.8 Hz, 2H), 4.87 (s, 2H), 6.14 (s, 1H), 7.15-7.19 (m, 4H).
Reaction SMILES: C(OC([NH:8][C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([C:26]2[CH:27]=[CH:28][C:29](OS([C:44]([F:47])([F:46])[F:45])(=O)=O)=[C:30]([C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([O:38][CH3:39])[CH:33]=3)[CH:31]=2)([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)[N:10]=1)=O)(C)(C)C.P([O-])([O-])([O-])=O.[K+].[K+].[K+].COCC[O:60][CH3:61].O.C([OH:65])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>[F:47][C:44]([F:45])([F:46])[C:61]([OH:60])=[O:65].[CH3:39][O:38][C:34]1[CH:33]=[C:32]([C:30]2[CH:29]=[CH:28][CH:27]=[C:26]([C:11]3([C:18]4[CH:19]=[CH:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=4)[C:12]4[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=4)[C:9]([NH2:8])=[N:10]3)[CH:31]=2)[CH:37]=[CH:36][CH:35]=1
Reactant: COc1ccc(C2(c3ccc(OS(=O)(=O)C(F)(F)F)c(-c4cccc(OC)c4)c3)N=C(NC(=O)OC(C)(C)C)c3ccccc32)cc1
Reactant: CCO
Reactant: COCCOC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Product: COc1ccc(C2(c3cccc(-c4cccc(OC)c4)c3)N=C(N)c3ccccc32)cc1
Product: O=C(O)C(F)(F)F
Temperature: 125 °C
Reaction time: 0.25 h

Procedure:
To trifluoro-methanesulfonic acid 5-[3-tert-butoxycarbonylamino-1-(4-methoxy-phenyl)-1H-isoindol-1-yl]-3′-methoxy-biphenyl-2-yl ester (Scheme #2, G) (50 mg, 0.075 mmol) was added potassium phosphate (32 mg, 0.15 mmol), dichlorobis(triphenylphosphine)palladium(II) (16 mg, 0.022 mmol), and 1,2-dimethoxyethane: water:ethanol (7:3:2, 2.0 mL). The reaction was heated in a microwave at 125° C. for 15 minutes, more dichlorobis(triphenylphosphine)palladium(II) (16 mg, 0.022 mmol) was added, and the reaction reheated at 125° C. for 15 minutes. The solvent was removed under reduced pressure and the crude material dissolved in acetonitrile/water with trifluoroacetic acid (75:25:0.1, 1.0 mL), the insoluble material was filtered off and the filtrate was purified using RP-HPLC AG1 (tR=21.2 min). The combined purified fractions were lyophilized to give the title compound (9.0 mg). 1H NMR (300 MHz, DMSO-d6/TFA-d) δ 8.33 (d, J=7.7 Hz, 1 H) 7.87 (m, 2 H), 7.22-7.13 (m, 4 H), 7.76-7.64 (m, 2 H), 7.59-7.47 (m, 2 H), 7.40-7.29 (m, 2 H), 6.97 (d, J=8.8 Hz, 3 H), 3.81 (s, 3 H), 3.76 (s, 3 H); MS (ES+) m/z 421 [M+1]+; tR=2.08 min.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:11](=[C:12](OS(C(F)(F)F)(=O)=O)[N:13]([CH:18]([CH2:21][CH3:22])[CH2:19][CH3:20])[N:14]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[F:31][C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][CH:37]=1>>[CH2:21]([CH:18]([N:13]1[C:12]([C:35]2[CH:34]=[CH:33][C:32]([F:31])=[CH:37][CH:36]=2)=[C:11]2[C:15]([CH2:16][CH2:17][NH:8][CH2:9][CH2:10]2)=[N:14]1)[CH2:19][CH3:20])[CH3:22]
Reactant: CCC(CC)n1nc2c(c1OS(=O)(=O)C(F)(F)F)CCN(C(=O)OC(C)(C)C)CC2
Reactant: OB(O)c1cccc(F)c1
Product: CCC(CC)n1nc2c(c1-c1ccc(F)cc1)CCNCC2
Yield: 93.7 %

Procedure:
The title compound (93 mg) was prepared as in Example 177, Steps C and D, using 150 mg of 2-(1-ethyl-propyl)-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 183, Step A) and 138 mg of 3-fluorophenylboronic acid. MS (ESI): exact mass calculated for C18H24FN3, 301.20; found, m/z 302.5 [M+H]+. 1H NMR (500 MHz, CDCl3): 7.44-7.30 (m, 4H), 3.92-3.85 (m, 1H), 3.51-3.43 (m, 2H), 3.38-3.33 (m, 2H), 3.30-3.24 (m, 2H), 2.86-2.78 (m, 2H), 1.98-1.85 (m, 2H), 1.84-1.73 (m, 2H), 0.73 (t, J=7.4 Hz, 3H).
Reaction SMILES: O[C:2]1[CH:16]=[CH:15][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.Br[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39].[C:40](=[O:43])([O-])[O-].[K+].[K+].Cl>O.CN(C=O)C>[CH2:18]([O:14][C:11]1[CH:12]=[CH:13][C:8]([C:6]([C:5]2[CH:15]=[CH:16][C:2]([O:43][CH2:40][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH3:18])=[CH:3][CH:4]=2)=[O:7])=[CH:9][CH:10]=1)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39]
Reactant: O=C(c1ccc(O)cc1)c1ccc(O)cc1
Reactant: CCCCCCCCCCCCCCCCCCCCCCBr
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCCCCCCCCCOc1ccc(C(=O)c2ccc(OCCCCCCCCCCCCCCCCCCCCCC)cc2)cc1
Temperature: 80 °C
Reaction time: 6.5 h
Yield: 89 %

Procedure:
To 4,4′-dihydroxy-benzophenone (8.2 g, 38.3 mmol) and 1-bromodocosane (31.3 g, 80.4 mmol) were added DMF (300 mL) and potassium carbonate (15.9 g, 115 mmol) and the mixture was stirred at 80° C. for 6.5 hr. After confirmation of disappearance of monoalkylated form, the reaction mixture was ice-cooled and 1N hydrochloric acid (300 mL) and water (150 mL) were slowly added with sufficient stirring. The slurry was filtered, and the obtained crystals were washed with water and methanol to give 4,4′-didocosoxy-benzophenone (28.3 g, 34.1 mmol, 89%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:12][CH3:13])[C:9]=1[O:10][CH3:11])[CH:5]=[O:6].C[Mg+].[Br-].[CH3:17]COC(C)=O>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]([OH:6])[CH3:17])[CH:7]=[C:8]([O:12][CH3:13])[C:9]=1[O:10][CH3:11]
Reactant: CCOC(C)=O
Reactant: COc1cc(C=O)cc(Br)c1OC
Agent: C[Mg+]
Agent: [Br-]
Solvent: C1CCOC1
Product: COc1cc(C(C)O)cc(Br)c1OC
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
Under nitrogen, a solution of the 3-bromo-4,5-dimethoxybenzaldehyde (2.45 g; 10 mmol) in dry THF (10 ml) was added via syringe through a septum to a cold (ice-bath) solution of MeMgBr (15 mmol; 5.0 ml of 3.0 M Et2O solution) diluted with 10 ml dry THF. After the addition, the mixture was stirred for 10 minutes at 0° C., then for 1 hour at room temperatures. TLC (Hex:EtOAc=3:1) indicated complete disappearance of the reactant and a new product spot with lower Rf (0.25 vs 0.5).