Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[C:7]([F:8])=[C:6]([Cl:9])[C:5]([N+:10]([O-:12])=[O:11])=[C:4]([F:13])[C:3]=1[CH3:14].C(O)C.[CH3:18][N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>O.C(N(CC)CC)C>[CH3:18][N:19]1[CH2:24][CH2:23][N:22]([C:2]2[C:7]([F:8])=[C:6]([Cl:9])[C:5]([N+:10]([O-:12])=[O:11])=[C:4]([F:13])[C:3]=2[CH3:14])[CH2:21][CH2:20]1
Reactant: CN1CCNCC1
Reactant: Cc1c(F)c(F)c(Cl)c([N+](=O)[O-])c1F
Solvent: CCN(CC)CC
Solvent: CCO
Solvent: O
Product: Cc1c(F)c([N+](=O)[O-])c(Cl)c(F)c1N1CCN(C)CC1

Procedure:
To 2,3,6-trifluoro-4-chloro-5-nitrotoluene (0.17 g) are added ethanol (3.3 ml), water (0.5 ml), N-methyl-piperazine (0.45 ml) and triethylamine (0.56 ml) and the mixture is refluxed for 24 hours. After the reaction is completed, water is added to the reaction mixture and the mixture is extracted with diethyl ether, and the extract is washed with water and dried. The solvent is distilled off under reduced pressure and the residue is purified by silica-gel column-chromatography (eluent; dichloromethane: methanol =20:1) to give 2-(4-methyl-1-piperazinyl)-3,6-difluoro-4-chloro-5-nitrotoluene (0.13 g).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:31]=[CH:30][C:8]([CH2:9][O:10][C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[N:16]2[CH2:20][CH2:21][CH2:22][CH:23]([CH2:24][C:25]([O:27]CC)=[O:26])[C:15]2=[CH:14]3)=[CH:7][C:6]=1[C:32]([F:35])([F:34])[F:33])([CH3:3])[CH3:2].[Li+].[OH-].C(O)(=O)CC(CC(O)=O)(C(O)=O)O.C(Cl)Cl>O1CCOCC1.CCOC(C)=O>[CH:1]([O:4][C:5]1[CH:31]=[CH:30][C:8]([CH2:9][O:10][C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[N:16]2[CH2:20][CH2:21][CH2:22][CH:23]([CH2:24][C:25]([OH:27])=[O:26])[C:15]2=[CH:14]3)=[CH:7][C:6]=1[C:32]([F:35])([F:33])[F:34])([CH3:3])[CH3:2]
Reactant: CCOC(=O)CC1CCCn2c1cc1cc(OCc3ccc(OC(C)C)c(C(F)(F)F)c3)ccc12
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)Oc1ccc(COc2ccc3c(c2)cc2n3CCCC2CC(=O)O)cc1C(F)(F)F
Temperature: 50 °C
Yield: 106.2 %

Procedure:
Ethyl 2-(2-(4-isopropoxy-3-(trifluoromethyl)benzyloxy)-6,7,8,9-tetrahydropyrido[1,2-a]indol-9-yl)acetate (0.147 g, 0.3 mmol) was dissolved in 1,4-dioxane (4.5 mL). LiOH (1.0 M, 1.501 mL) was added at 25° C. to give a slightly turbid solution. The reaction was heated at 50° C. for 2 h, cooled to 24° C., and acidified with 0.5 M citric acid (6.01 mL, 3.00 mmol). The mixture was diluted with EtOAc (50 mL), washed with water (2×10 mL), brine (10 mL), and dried over MgSO4. The solvent was evaporated in vacuo to give an oil which was coevaporated with DCM and hexanes (excess) at 25° C. to give the title compound as an off-white solid (147 mg). LCMS m/z=462.1 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.28 (d, J=6.06 Hz, 6H), 1.39-1.57 (m, 1H), 1.83-2.20 (m, 3H), 2.40-2.48 (m, 2H), 2.84 (dd, J=15.85, 5.62 Hz, 1H), 3.73-3.86 (m, 1H), 4.11 (m, 1H), 4.78 (dt, J=12.16, 6.11 Hz, 1H), 5.06 (s, 2H), 6.15 (s, 1H), 6.78 (dd, J=8.72, 2.40 Hz, 1H), 7.05 (d, J=2.40 Hz, 1H), 7.23 (d, J=8.72 Hz, 1H), 7.29 (d, J=9.22 Hz, 1H), 7.63-7.70 (m, 2H), 12.27 (bs, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][C:18]([O:26]C)=[C:19]([O:24][CH3:25])[CH:20]=3)[C:15]=2[CH:28]=O)[C:6]([N+:11]([O-])=O)=[CH:7][C:8]=1[O:9][CH3:10]>C(Cl)(Cl)Cl>[CH2:25]1[O:26][C:18]2[C:19](=[CH:20][C:21]3[CH:22]=[CH:23][C:14]4[C:5]5[CH:4]=[C:3]([O:2][CH3:1])[C:8]([O:9][CH3:10])=[CH:7][C:6]=5[N:11]=[CH:28][C:15]=4[C:16]=3[CH:17]=2)[O:24]1
Reactant: COc1cc(-c2ccc3cc(OC)c(OC)cc3c2C=O)c([N+](=O)[O-])cc1OC
Solvent: ClC(Cl)Cl
Product: COc1cc2ncc3c4cc5c(cc4ccc3c2cc1OC)OCO5
Yield: 60 %

Procedure:
Using a procedure similar to that described in Example 1, except replacing the compound 17 used therein with compound 18, the title compound was prepared in 60% yield; mp >250° C.; IR (Nujol) 1680; UV (CHCl3) 285, 360, 380 nm (log ε=3.01, 2.21, 2.47); 1H NMR δ 4.10 (3H, s), 4.14 (3H, s), 6.15 (2H, s), 7.28 (1H, s), 7.68 (1H, s), 7.83 (1H, s), 7.97 (1H, d, J=9.2), 8.16 (1H, s), 8.28 (1H, d, J=9.2), 9.85 (1H, s); 13C NMR δ 56.7, 100.3, 102.1, 102.2, 106.1, 109.2, 118.4, 127.5, 128.9, 131.2, 131.7, 140.8, 145.6, 145.7, 148.4, 149.9, 150.4, 151.7, 176.1; HRMS calcd for C20H15NO4 : 333.1001; found: 333.0999.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:9])=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].Br[CH2:11][CH2:12][CH2:13][CH2:14][C:15](Cl)=[O:16].[H-].[Na+]>C(Cl)Cl.C1COCC1>[Br:1][C:2]1[C:3]([CH3:9])=[C:4]([N:5]2[CH2:11][CH2:12][CH2:13][CH2:14][C:15]2=[O:16])[CH:6]=[CH:7][CH:8]=1
Reactant: Cc1c(N)cccc1Br
Reactant: O=C(Cl)CCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cc1c(Br)cccc1N1CCCCC1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.2 %

Procedure:
A solution of 3-bromo-2-methylaniline (1 g, 5.37 mmol) in DCM (15 mL) was treated with TEA (0.749 mL, 5.37 mmol) and then dropwise with a solution of 5-bromopentanoyl chloride (1.072 g, 5.37 mmol) in DCM (4 mL). The mixture was stirred at rt for 30 min, then was diluted with DCM, washed with water and brine, and dried and concentrated. The residue was dissolved in THF (100 mL) and added to a suspension of sodium hydride (60% oil dispersion, pre-washed with hexane, 0.430 g, 10.75 mmol) in THF (50 mL). The resulting mixture was stirred overnight at rt. The mixture was concentrated and the residue was acidified with 1 M hydrochloric acid. The mixture was extracted with DCM and the organic phase was washed with water, dried and concentrated to give 1-(3-bromo-2-methylphenyl)piperidin-2-one as a tan oil (1.4 g, 97%). 1H NMR (400 MHz, chloroform-d) δ 7.49-7.54 (1H, m), 7.07-7.13 (2H, m), 3.38-3.60 (2H, m), 2.54-2.59 (2H, m), 2.26 (3H, s), 1.91-2.02 (4H, m). Mass spectrum m/z 268, 270 (M+H)+.
Reaction SMILES: [CH2:1]([N:3]([CH2:10][CH2:11][OH:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:2].C(N(CC)CC)C.[C:20](Cl)(=[O:22])[CH3:21].O>CC(C)=O>[C:20]([O:12][CH2:11][CH2:10][N:3]([CH2:1][CH3:2])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)(=[O:22])[CH3:21]
Reactant: CCN(CCO)c1ccccc1
Reactant: CC(=O)Cl
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: CCN(CCOC(C)=O)c1ccccc1
Temperature: 0 °C
Yield: 99.9 %

Procedure:
51.8 g of 2-(N-ethylanilino)ethanol and 31.7 g of triethylamine were dissolved in 300 ml of acetone. To this were slowly added 25 g of acetyl chloride while cooling the reaction solution with ice water, and this was caused to react for 6 hours at room temperature while stirring. 200 ml of water were poured in. An organic layer was extracted with ethyl acetate and dried with sodium sulfate. Then the solvent was boiled off under reduced pressure to yield 64.9 g of 2-(N-ethylanilino)ethyl acetate.
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][C:5]2[C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[O:9][C:4]=2[CH:3]=1.[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH2:15]([O:1][C:2]1[CH:14]=[CH:13][C:5]2[C:6](=[O:12])[O:7][C:8]([CH3:10])([CH3:11])[O:9][C:4]=2[CH:3]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: BrCc1ccccc1
Reactant: CC1(C)OC(=O)c2ccc(O)cc2O1
Product: CC1(C)OC(=O)c2ccc(OCc3ccccc3)cc2O1

Procedure:
7-Benzyloxy-2,2-dimethyl-benzo[1,3]dioxin-4-one was prepared from 7-hydroxy-2,2-dimethyl-benzo[1,3]dioxin-4-one and benzyl bromide under conditions analogous to example 47-a. 1H NMR (200 MHz, CDCl3): δ (ppm)=7.85 (d, J=8.5 Hz, 1H), 7.39 (m, 5H), 6.71 (dd, J=8.7, 2.3 Hz, 1H), 6.48 (d, J=2.3 Hz, 1H), 5.09 (s, 2H), 1.72 (s, 6H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.[OH:9][CH:10]([CH:14]([CH3:16])[CH3:15])[C:11](O)=[O:12].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C>C(Cl)Cl>[OH:9][CH:10]([CH:14]([CH3:16])[CH3:15])[C:11]([NH:8][C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][N:6]=1)=[O:12]
Reactant: Cc1ccc(N)nc1
Reactant: CC(C)C(O)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(NC(=O)C(O)C(C)C)nc1
Temperature: 25 °C
Reaction time: 70 h
Yield: 14.2 %

Procedure:
5-Methylpyridin-2-amine (CAS 1603-41-4) (2.014 g, 18.6 mmol) was added in one portion to 2-hydroxy-3-methylbutanoic acid (CAS 4026-18-0) (2.0 g, 16.9 mmol), 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (7.08 g, 18.6 mmol) and N-ethyl-N-isopropylpropan-2-amine (5.80 mL, 33.9 mmol) in DCM (40 mL). The resulting suspension was stirred at ambient temperature for 70 hours. The reaction mixture was concentrated, diluted with EtOAc (150 mL) and washed sequentially with water (150 mL) and saturated brine (75 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 20 to 50% EtOAc in isohexane to afford 2-hydroxy-3-methyl-N-(5-methylpyridin-2-yl)butanamide (500 mg).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]([CH3:16])([C:9]1[CH:14]=[CH:13][C:12](C)=[CH:11][CH:10]=1)[CH2:7][OH:8].BrCCCCC(C)(C1C=CC=CC=1)C(OCC)=O.[Li+].[BH4-].CO>C(Cl)Cl>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]([CH3:16])([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[CH2:7][OH:8]
Reactant: Cc1ccc(C(C)(CO)CCCCBr)cc1
Agent: CCOC(=O)C(C)(CCCCBr)c1ccccc1
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Solvent: ClCCl
Product: CC(CO)(CCCCBr)c1ccccc1
Yield: 84 %

Procedure:
According to the procedure given for the synthesis of 206e, 205d (52.0 g, 166.0 mmol) was reacted with LiBH4 (5.4 g, 247.9 mmol) and methanol (8.2 g, 255.9 mmol) in CH2Cl2 (180 mL) to afford 206d (38.0 g, 84%) as an oil. 1H NMR (CDCl3): δ 7.5-7.1 (m, 5 H), 3.60 (d, 1 H, J=10.8), 3.53 (d, 1 H, J=10.8), 3.34 (t, 2 H, J=7.0), 1.90-1.78 (m, 3 H), 1.62-1.26 (m, 3 H), 1.35 (s, 3 H), 1.14 (m, 1 H). 13C NMR (CDCl3): δ 144.4, 128.4, 126.5, 126.1, 72.4, 43.2, 37.4, 33.5, 33.3, 22.5, 21.4.
Reaction SMILES: [CH2:1]([C:3]1[N:4]([CH2:23][C:24]([OH:27])([CH3:26])[CH3:25])[C:5]2[C:14]3[CH:13]=[CH:12][C:11]([CH:15]=[CH:16][C:17]([N:19]([CH3:21])[CH3:20])=[O:18])=[CH:10][C:9]=3[N:8]=[CH:7][C:6]=2[N:22]=1)[CH3:2]>[Pd].CO>[CH2:1]([C:3]1[N:4]([CH2:23][C:24]([OH:27])([CH3:26])[CH3:25])[C:5]2[C:14]3[CH:13]=[CH:12][C:11]([CH2:15][CH2:16][C:17]([N:19]([CH3:21])[CH3:20])=[O:18])=[CH:10][C:9]=3[N:8]=[CH:7][C:6]=2[N:22]=1)[CH3:2]
Reactant: CCc1nc2cnc3cc(C=CC(=O)N(C)C)ccc3c2n1CC(C)(C)O
Agent: [Pd]
Solvent: CO
Product: CCc1nc2cnc3cc(CCC(=O)N(C)C)ccc3c2n1CC(C)(C)O
Temperature: 50 °C
Reaction time: 19 h

Procedure:
A glass Parr vessel was charged with 10% palladium on carbon (0.14 g), methanol (50 mL) and 3-[2-ethyl-1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-7-yl]-N,N-dimethylprop-2-enamide (1.20 g, 3.27 mmol). The vessel was evacuated and charged with hydrogen gas (40 psi, 2.8×105 Pa). The reaction was shaken at 50° C. for approximately 19 hours. After cooling to ambient temperature, the reaction mixture was filtered and the filtrate concentrated to dryness to provide crude 3-[2-ethyl-1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-7-yl]-N,N-dimethylpropanamide as a white semi-solid. MS (APCI) m/z 369 (M+H)+.
Reaction SMILES: [CH:1]1([O:6][C:7](=[O:26])[C@@H:8]([NH:15]C(OCC2C=CC=CC=2)=O)[CH2:9][O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:5][CH2:4][CH2:3][CH2:2]1>CCO.[OH-].[Pd+2].[OH-]>[CH:1]1([O:6][C:7](=[O:26])[C@@H:8]([NH2:15])[CH2:9][O:10][C:11]([CH3:12])([CH3:13])[CH3:14])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC(C)(C)OC[C@H](NC(=O)OCc1ccccc1)C(=O)OC1CCCC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)OC[C@H](N)C(=O)OC1CCCC1
Reaction time: 4 h
Yield: 95.5 %

Procedure:
(S)-2-Benzyloxycarbonylamino-3-tert-butoxy-propionic acid cyclopentyl ester (3.82 g, 0.011 mol) was dissolved in EtOH (50 ml). 20% wt. Palladium hydroxide (wet) was added cautiously to the solution. The system was evacuated and put under a hydrogen atmosphere for 4 hours. The system was evacuated and the palladium residues filtered off through Celite. The Celite was thoroughly washed with EtOH (3×5 ml). The solvent of the filtrate was removed in vacuo to give the product as a colourless oil (2.41 g, 100% yield). 1H NMR (300 MHz, CDCl3), δ: 1.15 (9H, s, CH3×3), 1.50-1.90 (10H, m, CH2×4, NH2), 3.50-3.70 (3H, m, CH2, CH), 5.22 (1H, s, CH).
Reaction SMILES: Cl.C(N=C=NCCCN(C)C)C.[CH:13]1[C:25]2[CH:24]([CH2:26][O:27][C:28]([NH:30][C@@H:31]([CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[C:32]([OH:34])=[O:33])=[O:29])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]=2[CH:16]=[CH:15][CH:14]=1.ON1C(=O)CCC1=O.[C:50]([S:54][S:55][CH2:56][CH:57](O)[C:58]([OH:60])=[O:59])([CH3:53])([CH3:52])[CH3:51]>CN(C)C=O.CN(C)C1C=CN=CC=1.C(O)=O>[CH:13]1[C:25]2[CH:24]([CH2:26][O:27][C:28]([NH:30][C@@H:31]([CH2:35][C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=3)[C:32]([O:34][CH:57]([CH2:56][S:55][S:54][C:50]([CH3:53])([CH3:52])[CH3:51])[C:58]([OH:60])=[O:59])=[O:33])=[O:29])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]=2[CH:16]=[CH:15][CH:14]=1
Reactant: CC(C)(C)SSCC(O)C(=O)O
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)O)OCC1c2ccccc2-c2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: O=CO
Product: CC(C)(C)SSCC(OC(=O)[C@H](Cc1ccccc1)NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Reaction time: 18 h
Yield: 39.9 %

Procedure:
1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI.HCl) (247 mg, 1.29 mmol) was added to a solution of (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-phenylpropanoic acid (Fmoc-Phe-OH) (500 mg, 1.29 mmol) and N-hydroxysuccinimide (HOSu) (149 mg, 1.29 mmol) in dimethylformamide (DMF) (4.5 ml) at room temperature under a nitrogen atmosphere, and the mixture was stirred at the same temperature for 18 hours. 3-(tert-Butyldisulfanyl)-2-hydroxypropanoic acid (Compound SP666) (100 mg, 0.475 mmol) and 4-dimethylaminopyridine (DMAP) (58.1 mg, 0.475 mmol) were added to the reaction solution (1.7 ml) at room temperature, and the mixture was stirred at the same temperature for 5 hours. Formic acid (18 μl) was added to the reaction solution, and the mixture was purified by reverse-phase silica gel chromatography (0.1% aqueous formic acid solution/0.1% formic acid-acetonitrile solution) to afford 2-(((S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-phenylpropanoyl)oxy)-3-(tert-butyldisulfanyl)propanoic acid (Fmoc-Phe-tBuSSlac-OH) (Compound SP667) (110 mg, 40%).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([C:23]2[O:24][C:25]([C:28]3[CH:33]=[CH:32][C:31]([CH2:34][Br:35])=[CH:30][CH:29]=3)=[N:26][N:27]=2)[C:5]([N:8]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[N:6][CH:7]=1.CC1(C)C(C)(C)OB([C:44]2[CH2:45][CH2:46][N:47]([C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])[CH2:48][CH:49]=2)O1.C(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)(C)C.C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1.Cl[Pd]Cl.O>[C:11]([O:10][C:9]([N:8]([C:16]([O:18][C:19]([CH3:21])([CH3:20])[CH3:22])=[O:17])[C:5]1[N:6]=[CH:7][C:2]([C:44]2[CH2:49][CH2:48][N:47]([C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])[CH2:46][CH:45]=2)=[N:3][C:4]=1[C:23]1[O:24][C:25]([C:28]2[CH:33]=[CH:32][C:31]([CH2:34][Br:35])=[CH:30][CH:29]=2)=[N:26][N:27]=1)=[O:15])([CH3:13])([CH3:14])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1ncc(Br)nc1-c1nnc(-c2ccc(CBr)cc2)o1
Agent: Cl[Pd]Cl
Agent: CN(C)c1ccc(P(C(C)(C)C)C(C)(C)C)cc1
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(C)OC(=O)N1CC=C(c2cnc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c(-c3nnc(-c4ccc(CBr)cc4)o3)n2)CC1
Temperature: 60 °C
Yield: 59.8 %

Procedure:
To a solution of tert-butyl N-[5-bromo-3-[5-[4-(bromomethyl)phenyl]-1,3,4-oxadiazol-2-yl]pyrazin-2-yl]-N-tert-butoxycarbonyl-carbamate (500 mg, 0.82 mmol) in toluene (4.4 mL)/water (484 μL) was added tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (304 mg, 1.0 mmol) followed by the addition of 4-ditert-butylphosphanyl-N,N-dimethyl-aniline; dichloropalladium (58 mg, 0.082 mmol) and K2CO3 (226 mg, 1.6 mmol). The reaction mixture was heated at 60° C. for 3 h. The reaction mixture was partitioned between DCM and saturated aqueous NaHCO3, the layers were separated and the aqueous layer was extracted with DCM. The combined organics were dried over Na2SO4, filtered and concentrated to brown oil. The crude material was purified by silica gel column chromatography using 0-20% EtOAc in hexanes to yield tert-butyl 4-[5-[bis(tert-butoxycarbonyl)amino]-6-[5-[4-(bromomethyl)phenyl]-1,3,4-oxadiazol-2-yl]pyrazin-2-yl]-3,6-dihydro-2H-pyridine-1-carboxylate (350 mg, 60%). 1HNMR (400 MHz, CDCl3) δ 8.74 (s, 1H), 8.22 (d, J=33.8 Hz, 2H), 7.59 (d, J=8.2 Hz, 2H), 6.92 (s, 1H), 4.54 (s, 2H), 4.24 (s, 2H), 3.73 (t, J=5.5 Hz, 2H), 2.79 (d, J=0.8 Hz, 2H), 1.37 (s, 18H), 1.24 (s, 9H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([N+:12]([O-:14])=[O:13])[C:3]=1[I:15].C1C(=O)N([Br:23])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[Br:23][CH2:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:9])[F:10])[CH:5]=[C:4]([N+:12]([O-:14])=[O:13])[C:3]=1[I:15]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc(C(F)(F)F)cc([N+](=O)[O-])c1I
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: O=[N+]([O-])c1cc(C(F)(F)F)cc(CBr)c1I

Procedure:
A mixture of the title compound from Step C (0.38 g, 1.15 mmol), NBS (0.24 g, 1.38 mmol) and catalytic amount of AIBN in carbon tetrachloride (5 ml) was heated to reflux for 3 days. During the period more AIBN was added daily. The mixture was cooled and concentrated. The title compound was obtained after flash column using hexane as the eluant. 1H NMR (CDCl3, 500 MHz): δ 7.91 (s, 1H), 7.80 (s, 1H), 4.75 (s, 2H).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[C:6]([CH2:11]O)[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.[BrH:13]>CC(O)=O>[BrH:13].[Br:13][CH2:11][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:5]=1[CH:4]=[CH:3][N:2]=[CH:1]2
Reactant: OCc1cccc2cnccc12
Agent: Br
Solvent: CC(=O)O
Product: BrCc1cccc2cnccc12
Temperature: 25 °C

Procedure:
To a solution of isoquinolin-5-ylmethanol (0.63 g, 3.9 mmol) in AcOH (3.3 mL) was added HBr (6.6 mL, a 30% w/w solution in AcOH, 24 mmol), and the reaction mixture was stirred at 75° C. for 45 min. The reaction mixture was cooled to room temperature, and the precipitate was collected to provide the 5-bromomethylisoquinoline hydrobromide acid salt as a brown solid (1.1 g, 87%): 1H NMR (300 MHz, CDCl3) δ 9.22 (s, 1H), 8.58 (d, J=6 Hz, 1H), 7.95-7.89 (m, 2H), 7.76 (d, J=9 Hz, 1H), 7.59 (dd, J=9, 6 Hz, 1H), 5.16 (s, 2H).
Reaction SMILES: [CH2:1]([C:5]1[N:10]=[C:9]([CH3:11])[N:8]([C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)[C:7](=[O:19])[C:6]=1[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[C:33]2[NH:37][C:36](=[O:38])[O:35][N:34]=2)=[CH:23][CH:22]=1)[CH2:2][CH2:3][CH3:4].[Si]([O:46][CH:47]1[CH2:52][CH2:51][CH:50](O)[CH2:49][CH2:48]1)(C(C)(C)C)(C)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1.O>[CH2:1]([C:5]1[N:10]=[C:9]([CH3:11])[N:8]([C:12]2[CH:17]=[CH:16][C:15]([O:18][C@H:50]3[CH2:51][CH2:52][C@H:47]([OH:46])[CH2:48][CH2:49]3)=[CH:14][CH:13]=2)[C:7](=[O:19])[C:6]=1[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[C:33]2[NH:37][C:36](=[O:38])[O:35][N:34]=2)=[CH:23][CH:22]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(C)n(-c2ccc(O)cc2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Reactant: CC(C)(C)[Si](C)(C)OC1CCC(O)CC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CCCCc1nc(C)n(-c2ccc(O[C@H]3CC[C@H](O)CC3)cc2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Reaction time: 2 h

Procedure:
To a solution of 6-butyl-3-(4-hydroxyphenyl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one (1.2 g), 4-{[tert-butyl(dimethyl)silyl]oxy}cyclohexanol (1.2 g) and triphenylphosphine (1.4 g) in tetrahydrofuran (12 mL) was added dropwise diisopropyl azodicarboxylate (1.9 M toluene solution, 2.8 mL). After stirring for 2 hr, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and a mixture of the residue, hydroxylammonium chloride (0.87 g), sodium hydrogen carbonate (1.3 g) and dimethyl sulfoxide (9 mL) was stirred overnight at 90° C. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (9 mL). N,N′-carbonyldiimidazole (0.3 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.28 mL) were added, and the mixture was stirred at room temperature for 30 min. Tetrabutylammonium fluoride (1.0 M tetrahydrofuran solution, 2.5 mL) was added, and the mixture was stirred overnight at 50° C. The reaction mixture was diluted with ethyl acetate, washed with 5% aqueous potassium hydrogen sulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound (0.45 g, 33%) as an amorphous solid.
Reaction SMILES: [CH3:1][N:2]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH:4]=1.[Li:18]CCCC>CCCCCC>[CH3:1][N:2]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]([Li:18])[CH:4]=1
Reactant: [Li]CCCC
Reactant: CN(C1=CCc2ccccc21)c1ccccc1
Solvent: CCCCCC
Product: [Li]C1C=C(N(C)c2ccccc2)c2ccccc21
Reaction time: 8 h
Yield: 89 %

Procedure:
N-Methyl-N-phenyl-1H-inden-3-amine(6.8g, 30.7 mmol) was dissolved in 100 mL of hexane and 10 12.3 mL of 2.5 M n-BuLi (0.936 eq) was added dropwise via syringe over a 15 minute period. The solution developed a yellow precipitate upon the addition of n-BuLi and the slurry was allowed to stir overnight. After this time the solid was filtered, washed with 50 mL of hexane and allowed to dry in Vacuo overnight to afford the desired anion as a yellow-orange solid (5.83 g, 25.6 mmol) in 89 percent yield based upon the lithio reagent.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].C(N(CC)CC)C.[CH3:14][O:15][C:16]([C:18]1[C:27]2[CH2:26][CH2:25][CH2:24][CH2:23][C:22]=2[CH:21]=[CH:20][C:19]=1OS(C(F)(F)F)(=O)=O)=[O:17].[C:36](=[NH:49])([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>[CH3:14][O:15][C:16]([C:18]1[C:27]2[CH2:26][CH2:25][CH2:24][CH2:23][C:22]=2[CH:21]=[CH:20][C:19]=1[N:49]=[C:36]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)=[O:17]
Reactant: N=C(c1ccccc1)c1ccccc1
Reactant: COC(=O)c1c(OS(=O)(=O)C(F)(F)F)ccc2c1CCCC2
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: COC(=O)c1c(N=C(c2ccccc2)c2ccccc2)ccc2c1CCCC2
Temperature: 100 °C

Procedure:
Cesium carbonate (12.4 g), palladium (II) acetate (0.12 g), triethylamine (0.12 mL) and Xantphos (0.474 g) were suspended in dioxane (50 mL) under nitrogen. 2-Trifluoromethanesulfonyloxy-5,6,7,8-tetrahydronaphthalene-1-carboxylic acid methyl ester (Intermediate 7, 4.2 g) and benzhydrylidenamine (5.5 mL) in dioxane (35 mL) were added and the mixture was heated at 100° C. for 3.5 hours. The resulting mixture was partitioned between ethyl acetate and water. The organic solution was washed with water and concentrated under vacuum. The residue was recrystallised from methanol to give the title compound as an off-white solid (8.2 g).