Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[CH3:9][O:10][C:11](=[O:21])[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=1.I[CH2:23][CH:24]1[CH2:28][CH2:27][CH2:26][CH:25]1[O:29][CH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][O:31]1>O1CCCC1.CN1CCCN(C)C1=O.CN1CCCN(C)C1=O>[CH3:9][O:10][C:11](=[O:21])[CH:12]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=1)[CH2:23][CH:24]1[CH2:28][CH2:27][CH2:26][CH:25]1[O:29][CH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][O:31]1
Reactant: ICC1CCCC1OC1CCCCO1
Reactant: COC(=O)Cc1ccc(Cl)c(Cl)c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CN1CCCN(C)C1=O
Solvent: C1CCOC1
Product: COC(=O)C(CC1CCCC1OC1CCCCO1)c1ccc(Cl)c(Cl)c1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 74.8 %

Procedure:
A solution of freshly prepared lithium diisopropylamide (10.4 mL of a 0.31M stock solution, 3.22 mmol) cooled to −78° C. was treated with 3,4-dichlorophenylacetic acid methyl ester (prepared as in Example 1, 642 mg 2.93 mmol) in tetrahydrofuran/1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (7.33 mL, 3:1). The resulting solution was stirred at −78° C. for 45 min. A solution of 2-(2-iodomethyl-cyclopentyloxy)-tetrahydropyran (1.0 g, 3.22 mmol) in 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (1 mL) was then added. The reaction mixture was stirred at −78° C. for 2 h. The reaction was then warmed to 25° C. and was stirred at 25° C. for 16 h. The reaction mixture was then quenched by the dropwise addition of a saturated aqueous ammonium chloride solution (10 mL). This mixture was poured into water (100 mL) and extracted with methylene chloride (3×50 mL). The organics were dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 90/10 hexanes/ethyl acetate) afforded 2-(3,4-dichloro-phenyl)-3-[2-(tetrahydro-pyran-2-yloxy)-cyclopentyl]-propionic acid methyl ester (880 mg, 74.8%) as a pale yellow oil: EI-HRMS m/e calcd for C20H26Cl2O4 (M+) 400.1208 found 400.1203.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[CH:4][C:3]=1[C:18]([F:21])([F:20])[F:19].C(B(CC)[C:25]1[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=1)C.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>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].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>[CH3:17][O:16][C:13]1[CH:14]=[CH:15][C:10]([CH2:9][NH:8][C:5]2[CH:4]=[C:3]([C:18]([F:21])([F:20])[F:19])[C:2]([C:25]3[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=3)=[N:7][CH:6]=2)=[CH:11][CH:12]=1
Reactant: CCB(CC)c1cccnc1
Reactant: COc1ccc(CNc2cnc(Cl)c(C(F)(F)F)c2)cc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: COc1ccc(CNc2cnc(-c3cccnc3)c(C(F)(F)F)c2)cc1
Temperature: 105 °C
Yield: 73.2 %

Procedure:
To a solution of 6-chloro-N-(4-methoxybenzyl)-5-(trifluoromethyl)pyridin-3-amine (Intermediate 1, Step 3, 1.2 g, 3.8 mmol) and 3-(diethylboryl)pyridine (0.613 g, 4.17 mmol) in 1,4-dioxane (100 mL) was added K3PO4(2.52 g, 9.48 mmol). The mixture was degassed then flushed with nitrogen before Pd2(dba)3 (173 mg, 0.02 mmol) and Xantphos (0.218 mg, 0.04 mmol) were added. The mixture was heated at 105° C. overnight. The reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated in vacuo and the residue was purified by column chromatography on silica gel using EtOAc/PE=1/to afford 1 g of N-(4-methoxybenzyl)-3-(trifluoromethyl)-[2,3′-bipyridin]-5-amine.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([N:8]2[C:16](=[O:17])[C:15]3[CH:14]4[C:18]([CH3:20])([CH3:19])[C:11]([CH3:21])([CH2:12][CH2:13]4)[C:10]=3[N:9]2[CH3:22])[CH:5]=[CH:6][CH:7]=1.[CH3:23][O:24][C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][CH:30]=1.C(=O)([O-])[O-].[K+].[K+]>C(COC)OC.ClCCl.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:23][O:24][C:25]1[CH:30]=[C:29]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([N:8]3[C:16](=[O:17])[C:15]4[C@@H:14]5[C:18]([CH3:19])([CH3:20])[C@@:11]([CH3:21])([CH2:12][CH2:13]5)[C:10]=4[N:9]3[CH3:22])[CH:3]=2)[CH:28]=[CH:27][CH:26]=1
Reactant: COc1cccc(B(O)O)c1
Reactant: Cn1c2c(c(=O)n1-c1cccc(I)c1)C1CCC2(C)C1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: ClCCl
Product: COc1cccc(-c2cccc(-n3c(=O)c4c(n3C)[C@]3(C)CC[C@H]4C3(C)C)c2)c1

Procedure:
A mixture of 2-(3-iodo-phenyl)-1,7,8,8-tetramethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Example 23; 80 mg, 0.2 mmol), 3-methoxy-phenyl-boronic acid (46 mg, 0.29 mmol), potassium carbonate (66 mg, 0.47 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (10 mg, 0.014 mmol) in dimethoxyethane (4 mL) was sealed under argon and heated at 80 degrees overnight and then at 90 degrees over the weekend. The reaction mixture was diluted with dichloromethane, filtered through a cotton plug and frit, evaporated, and purified using an Analogix Intelliflash 280 system (Analogix, Inc., Burlington, Wis.) with an RS-12 column, eluting with 0-60% ethyl acetate/hexanes to give (4S,7R)-2-(3′-methoxy-biphenyl-3-yl)-1,7,8,8-tetramethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one and unreacted starting material (54 mg, 67%). The product was further purified by preparative HPLC (Gilson 215 collector, Shimadzu prep HPLC system, Leap autoinjector. Solvent (A) 0.05% TFA/H2O (B) 0.035% TFA/ACN, using a linear gradient of 20-80% solvent B in 10 minutes, with a C-18 column, 2.0×10 cm eluting at 20 ml/min and UV-directed collection) followed by lyophilization to give (4S,7R)-2-(3′-methoxy-biphenyl-3-yl)-1,7,8,8-tetramethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (13 mg, 17%) as a white solid. ES(+)-MS (M+H) 389.
Reaction SMILES: [CH2:1]([C:3]1([CH2:18][CH2:19][OH:20])[C:8]2[NH:9][C:10]3[C:15]([C:7]=2[CH2:6][CH2:5][O:4]1)=[CH:14][CH:13]=[CH:12][C:11]=3[CH2:16][CH3:17])[CH3:2].CS(C)=O.[CH3:25][C:26](OC(C)=O)=[O:27]>O>[CH2:1]([C:3]1([CH2:18][CH2:19][O:20][C:26](=[O:27])[CH3:25])[C:8]2[NH:9][C:10]3[C:15]([C:7]=2[CH2:6][CH2:5][O:4]1)=[CH:14][CH:13]=[CH:12][C:11]=3[CH2:16][CH3:17])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CCc1cccc2c3c([nH]c12)C(CC)(CCO)OCC3
Solvent: O
Solvent: CS(C)=O
Product: CCc1cccc2c3c([nH]c12)C(CC)(CCOC(C)=O)OCC3
Yield: 78 %

Procedure:
A solution of compound 1 (273 mg, 1.0 mmol), dry DMSO (3 mL), dry Ac2O (2 mL), and dry TEA (1 mL) was stirred overnight at room temperature. The reaction mixture was then diluted with water and extracted three times with EtOAc. The combined organic phases were washed with saturated NaHCO3 and brine, dried with Na2SO4, concentrated, and purified by column chromatography using 10:90:EtOAc:Hexane to give a yellow solid (245 mg, 78%): mp 126–127° C. 1HNMR (CDCl3, δ TMS): 0.91 (t, 3H), 1.38 (t, 3H), 1.88 (s, 3H), 1.90 (m, 2H), 2.21 (t, 2H), 2.78 (m, 2H), 2.87 (q, 2H), 4.01 (t, 2H), 4.14 (m, 2H), 7.02–7.37 (m 3H, Ar—H), 7.71 (br, 1H, NH). MS−: m/z 350 (MCl−), 314 ([M−H]−). Anal. (C19H25NO3): C, H, N.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].S(=O)(=O)(O)O.[F:12][C:13]1[CH:33]=[CH:32][C:16]([CH2:17][NH:18][CH:19]([CH2:23][O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:20][C:21]#[N:22])=[CH:15][CH:14]=1.N>C(OCC)C>[F:12][C:13]1[CH:33]=[CH:32][C:16]([CH2:17][NH:18][CH:19]([CH2:23][O:24][CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:20][CH2:21][NH2:22])=[CH:15][CH:14]=1
Reactant: N#CCC(COCc1ccccc1)NCc1ccc(F)cc1
Agent: N
Agent: O=S(=O)(O)O
Agent: [Al+3]
Solvent: CCOCC
Product: NCCC(COCc1ccccc1)NCc1ccc(F)cc1
Reaction time: 0.5 h
Yield: 82 %

Procedure:
To a suspension of lithium aluminum hydride (136 mg, 3.58 mmol) in diethyl ether (10 ml) was added under ice-cooling conc. sulfuric acid (0.15 ml, 1.5 mmol) and, after stirring for 0.5 hour, a solution of 3-(p-fluorobenzylamino)-6-phenyl-5-oxahexanenitrile (300 mg, 1.01 mmol) in diethyl ether (5 ml) was added dropwise and the mixture was heated under reflux for one hour. After cooling, aqueous ammonia (2 ml) was added under ice-cooling to the reaction mixture and stirred for 2 hours. The reaction mixture was filtered with Celite and the filtrate was distilled off under reduced pressure. The residue was chromatographed using silica gel column to give the title compound as a colorless oily substance from the fraction from methanol-chloroform-aqueous ammonia (90/10/0.5). Yield=82%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][C:10]([C:17]3[CH:22]=[C:21]([Cl:23])[CH:20]=[C:19]([Cl:24])[CH:18]=3)([C:13]([F:16])([F:15])[F:14])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[CH2:25][NH2:26].C(N(CC)CC)C.[C:34](Cl)(=[O:36])[CH3:35]>O1CCCC1.C(OC)(C)(C)C>[Cl:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][C:10]([C:17]3[CH:18]=[C:19]([Cl:24])[CH:20]=[C:21]([Cl:23])[CH:22]=3)([C:13]([F:15])([F:14])[F:16])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[CH2:25][NH:26][C:34](=[O:36])[CH3:35]
Reactant: CC(=O)Cl
Reactant: NCc1ccc(N2CCC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: COC(C)(C)C
Product: CC(=O)NCc1ccc(N2CCC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.3 %

Procedure:
To the solution of 1-{2-chloro-4-[3-(3,5-dichlorophenyl)-3-(trifluoromethyl)pyrrolidin-1-yl]phenyl}methanamine (0.12 g) and triethylamine (0.04 g) in tetrahydrofuran was added dropwise acetyl chloride (0.02 g), and the mixture was stirred for one hour at room temperature. The reaction solution was diluted with t-butylmethylether and then washed with water and brine. The organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled away under the reduced pressure, and the residue was then purified by silica gel chromatography to yield N-{2-chloro-4-[3-(3,5-dichlorophenyl)-3-(trifluoromethyl)pyrrolidin-1-yl]benzyl}acetamide (0.1 g). 1H-NMR (CDCl3) δ: 1.98-2.01 (3H, m), 2.50-2.58 (1H, m), 2.82-2.87 (1H, m), 3.45-3.51 (2H, m), 3.74 (1H, d), 4.02 (1H, d), 4.41 (2H), 6.43-6.46 (1H, m), 6.58-6.59 (1H, m), 7.26-7.38 (4H, m)
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH2:8][C@@H:7]([NH:13][S:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)(=[O:16])=[O:15])[CH2:6]2)#[N:2].C(O)(=O)C.C1COCC1.I([Cl:35])(=O)=O.I(Cl)(=O)=O.I(Cl)(=O)=O.I(Cl)(=O)=O.C([N+](C)(C)C)C1C=CC=CC=1>C(Cl)Cl>[Cl:35][C:11]1[CH:12]=[C:3]([C:1]#[N:2])[CH:4]=[C:5]2[C:10]=1[NH:9][CH2:8][CH:7]([NH:13][S:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)(=[O:16])=[O:15])[CH2:6]2
Reactant: O=I(=O)Cl
Reactant: N#Cc1ccc2c(c1)C[C@H](NS(=O)(=O)c1ccccc1)CN2
Agent: C[N+](C)(C)Cc1ccccc1
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: C1CCOC1
Product: N#Cc1cc(Cl)c2c(c1)CC(NS(=O)(=O)c1ccccc1)CN2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 58.7 %

Procedure:
To a suspension of racemate 1G (313.4 mg, 1 mmol) in a mixed solvent of acetic acid (3 mL), THF (3 mL) and CH2Cl2 (3 mL) at RT was added benzyltrimethyl-ammonium tetrachloroiodate (419 mg, 1 mmol). After addition, the mixture was stirred at RT for 30 min to become a clear yellow solution which was concentrated in vacuo. The residue was triturated with CH2Cl2 and H2O and the resultant solid filtered and washed with CH2Cl2 and H2O, dried in vacuo to give the title compound as an off-white solid (204 mg, 59%).
Reaction SMILES: CON(C)[C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[N:10][C:11]([CH3:18])=[C:12]([CH3:17])[CH:13]=2)[N:8]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[N:21]=2)[CH:7]=1)=[O:5].[CH3:28][O:29][C:30]1[CH:35]=[CH:34][C:33]([Mg]Br)=[CH:32][C:31]=1[CH3:38]>C1COCC1>[CH3:28][O:29][C:30]1[CH:35]=[CH:34][C:33]([C:4]([C:6]2[C:15](=[O:16])[C:14]3[C:9](=[N:10][C:11]([CH3:18])=[C:12]([CH3:17])[CH:13]=3)[N:8]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[N:21]=3)[CH:7]=2)=[O:5])=[CH:32][C:31]=1[CH3:38]
Reactant: COc1ccc([Mg]Br)cc1C
Reactant: CON(C)C(=O)c1cn(Cc2cccc(C)n2)c2nc(C)c(C)cc2c1=O
Solvent: C1CCOC1
Product: COc1ccc(C(=O)c2cn(Cc3cccc(C)n3)c3nc(C)c(C)cc3c2=O)cc1C
Yield: 34.4 %

Procedure:
Experimental conditions analogous to those described for Step 6 of Example 60 were used with 100 mg (0.273 mmol) of 6,7-Dimethyl-1-(6-methyl-pyridin-2-ylmethyl)-4-oxo-1,4-dihydro-[1,8]naphthyridine-3-carboxylic acid methoxy-methyl amide, 1.2 mL (0.60 mmol, 0.5 M in tetrahydrofuran) of 4-methoxy-3-methylphenylmagnesium bromide and 1.2 mL of THF. The crude product was purified by flash column chromatography using 20-100% ethyl acetate in hexane and further purified on the reverse phase HPLC with a C18 column, gradient of 20-70% acetonitrile—0.1% TFA to give 40.1 mg of 3-(4-Methoxy-3-methyl-benzoyl)-6,7-dimethyl-1-(6-methyl-pyridin-2-ylmethyl)-1H-[1,8]naphthyridin-4-one. LC-MSD, m/z for C26H25N3O3 [M+H]: 428.19 LC retention time on HPLC, C18 column gradient 20-95% acetonitrile with 0.1% TFA in 4 minutes: 2.2 min.
Reaction SMILES: Cl.[C:2]1([C:8]([CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[O:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24]>C1COCC1.C(OCC)(=O)C>[C:8]([CH:10]1[CH2:15][CH2:14][N:13]([C:23]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:24])[CH2:12][CH2:11]1)(=[O:9])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: O=C(c1ccccc1)C1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(c1ccccc1)C1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirring suspension of phenyl(piperidin-4-yl)methanone hydrochloride 86 (1.97 g, 8.73 mmol) and potassium carbonate (3.62 g, 26.2 mmol) in THF (40 mL) at 0° C. was added benzyl chloroformate (1.433 mL, 10.04 mmol) and the reaction mixture was allowed to slowly warm to room temperature and stirred for 2 h. The mixture was diluted with ethyl acetate, washed with brine, water, dried over Na2SO4, filtered and concentrated to afford compound 87 quantitative yield. LRMS (ESI): (calc) 323.39 (found) 324.31 (MH)+
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]2[C@H:8]3[C@H:19]([CH2:20][CH2:21][C@:3]12[CH3:4])[C@:16]1([CH2:17][OH:18])[C:11]([CH2:12][C:13](=[O:23])[CH2:14][C@@H:15]1[CH3:22])=[CH:10][CH2:9]3.[H-].[Al+3].[Li+].[H-].[H-].[H-].C(C(C(C([O-])=O)O)O)([O-])=O.[K+].[Na+]>O1CCCC1>[CH3:22][C@@H:15]1[C@@:16]2([CH2:17][OH:18])[C:11](=[CH:10][CH2:9][C@@H:8]3[C@@H:19]2[CH2:20][CH2:21][C@@:3]2([CH3:4])[C@H:5]3[CH2:6][CH2:7][C@@H:2]2[OH:1])[CH2:12][C@@H:13]([OH:23])[CH2:14]1
Reactant: C[C@H]1CC(=O)CC2=CC[C@H]3[C@@H]4CC[C@H](O)[C@@]4(C)CC[C@@H]3[C@]21CO
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: C[C@H]1C[C@H](O)CC2=CC[C@H]3[C@@H]4CC[C@H](O)[C@@]4(C)CC[C@@H]3[C@]21CO

Procedure:
A solution of 17β,19-dihydroxy-1α-methyl-5-androsten-3-one in tetrahydrofuran is added to a suspension of lithium aluminum hydride in tetrahydrofuran. After stirring overnight at room temperature an aqueous solution of sodium potassium tartrate is added until a readily filtered granular precipitate forms. This precipitate is removed by filtration and washed well with ether. The filtrate and ether washings are combined, washed with water, dried over magnesium sulfate and concentrated under vacuum. Crystallization of the residue yields 1α-methyl-5-androstene-3β,17β,19-triol.
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[C:30]([O:32]C)[CH:29]=[CH:28][C:3]=1[O:4][C:5]1[S:6][C:7]([C:10]2[CH:14]=[C:13]([CH:15]([N:17]3[C:25](=[O:26])[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[C:18]3=[O:27])[CH3:16])[O:12][N:11]=2)=[CH:8][N:9]=1.B(Br)(Br)Br.CO>ClCCl>[Cl:1][C:2]1[CH:31]=[C:30]([OH:32])[CH:29]=[CH:28][C:3]=1[O:4][C:5]1[S:6][C:7]([C:10]2[CH:14]=[C:13]([CH:15]([N:17]3[C:25](=[O:26])[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[C:18]3=[O:27])[CH3:16])[O:12][N:11]=2)=[CH:8][N:9]=1
Reactant: COc1ccc(Oc2ncc(-c3cc(C(C)N4C(=O)c5ccccc5C4=O)on3)s2)c(Cl)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CO
Product: CC(c1cc(-c2cnc(Oc3ccc(O)cc3Cl)s2)no1)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 76.9 %

Procedure:
To a solution of Example 30E (1.2 g, 2.5 mmol) in dichloromethane (20 mL) was added boron tribromide (0.95 mL, 10 mmol) at −78° C. Upon addition, the mixture was allowed to stir at 25° C. for 16 hours. The reaction was then cooled to 0° C., treated with methanol (5 mL) and diluted with dichloromethane (80 mL). The resulting mixture was washed with water (120 mL) and brine (150 mL). The organic layer was dried (MgSO4), filtered and concentrated. The concentrate was purified by flash chromatography on silica gel eluting with a solvent gradient from 20% to 60% ethyl acetate in hexanes to yield 900 mg of the title compound (77%) as a off-white solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.81 (d, J=6.99 Hz, 3H) 5.55-5.70 (m, 1H) 6.84 (dd, J=8.82, 2.94 Hz, 1H) 6.99 (d, J=2.57 Hz, 1H) 7.17 (s, 1H) 7.42 (d, J=8.82 Hz, 1H) 7.80-7.98 (m, 5H); MS (ESI) m/z 468.0 (M+H)+, 500.0 (M+Na)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1B(O)O.Br[C:15]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][C:16]=1[C:17]([O:19][CH3:20])=[O:18].C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>CN(C)C=O.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O.C(OCC)C>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[C:15]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][C:16]=1[C:17]([O:19][CH3:20])=[O:18]
Reactant: COc1ccc(B(O)O)c(OC)c1
Reactant: COC(=O)c1cc([N+](=O)[O-])ccc1Br
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1cc([N+](=O)[O-])ccc1-c1ccc(OC)cc1OC
Temperature: 80 °C
Reaction time: 8 h

Procedure:
A mixture of 2,4-dimethoxyphenylboronic acid (25.0 g, 137 mmol), methyl 2-bromo-5-nitrobenzoate (35.7 g, 137 mmol), cesium carbonate (89.4 g, 274 mmol) and bis(triphenylphosphine)palladium (II) dichloride (4.81 g, 6.85 mmol) was suspended in N,N-dimethylformamide (450 mL), and then the suspension was stirred under argon atmosphere at 80° C. overnight. After cooling down, ethyl acetate (200 mL), diethylether (400 mL) and water (1000 mL) were added thereto and the mixture was separated into a water phase and an organic layer. The water layer was extracted with a mixed solvent of ethyl acetate (150 mL)-diethylether (150 mL) (twice). The combined organic layer was washed with water (500 mL, 3 times) and saturated brine (500 mL) successively, dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure to give the titled reference compound as a brown oil. (Quantitative)
Reaction SMILES: [CH3:1][C@@:2]1([CH2:9][S:10](Cl)(=[O:12])=[O:11])[C:6](=[O:7])[NH:5][C:4](=[O:8])[NH:3]1.Cl.[F:15][C:16]([F:36])([C:32]([F:35])([F:34])[F:33])[CH2:17][O:18][C:19]1[CH:31]=[CH:30][C:22]([O:23][CH:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[CH:21][CH:20]=1>ClCCl.C(N(CC)CC)C>[CH3:1][C@:2]1([CH2:9][S:10]([N:27]2[CH2:28][CH2:29][CH:24]([O:23][C:22]3[CH:21]=[CH:20][C:19]([O:18][CH2:17][C:16]([F:15])([F:36])[C:32]([F:34])([F:35])[F:33])=[CH:31][CH:30]=3)[CH2:25][CH2:26]2)(=[O:12])=[O:11])[NH:3][C:4](=[O:8])[NH:5][C:6]1=[O:7]
Reactant: FC(F)(F)C(F)(F)COc1ccc(OC2CCNCC2)cc1
Reactant: C[C@]1(CS(=O)(=O)Cl)NC(=O)NC1=O
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@]1(CS(=O)(=O)N2CCC(Oc3ccc(OCC(F)(F)C(F)(F)F)cc3)CC2)NC(=O)NC1=O
Reaction time: 16 h
Yield: 17.8 %

Procedure:
[(4S)-4-methyl-2,5-dioxoimidazolidin-4-yl]methanesulphonyl chloride (0.188 g) was added to a solution of 4-{4-(2,2,3,3,3-pentafluoropropoxy)phenoxy]-piperidine hydrochloride (0.30 g) in dichloromethane (10 ml) and triethylamine (0.70 ml) at ambient temperature. Stirred for 16 hours and evaporated to dryness. The residue was purified by prep HPLC (using λ230 nm as the detecting wavelength) eluting with 0-95% acetonitrile, H2O, +0.2% trifluoroacetic acid. Yielded a solid product, which was dried under vacuum at 50° C. to give the title compound (0.076 g). NMR: (DMSOd6) δ 10.7 (s, 1H), 8.0 (s, 1H), 7.0 (m, 4H), 4.75 (t, 2H), 4.45 (m, 1H), 3.5 (d, 1H), 3.3 (m, 3H), 3.1 (m, 2H), 1.95 (m, 2H), 1.7 (m, 2H), 1.35 (s, 3H). Mass Spectrum: M−H− 513.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[C:5]([NH:16][CH2:17][CH2:18][NH:19][C:20](=[O:22])[CH3:21])=[N:6][C:7]2[C:12]([CH:13]=1)=[CH:11][C:10]([O:14][CH3:15])=[CH:9][CH:8]=2.[CH3:23][O:24][C:25]1[CH:26]=[C:27]2[C:32](=[CH:33][C:34]=1[O:35][CH3:36])[C:31]([CH3:37])=[N:30][C:29]([OH:38])=[CH:28]2.[Li+].[OH-]>C1COCC1.C(Cl)Cl>[OH:38][C:29]1[N:30]=[C:31]([CH3:37])[C:32]2[C:27]([C:28]=1[CH2:3][C:4]1[C:5]([NH:16][CH2:17][CH2:18][NH:19][C:20](=[O:22])[CH3:21])=[N:6][C:7]3[C:12]([CH:13]=1)=[CH:11][C:10]([O:14][CH3:15])=[CH:9][CH:8]=3)=[CH:26][C:25]([O:24][CH3:23])=[C:34]([O:35][CH3:36])[CH:33]=2
Reactant: COc1ccc2nc(NCCNC(C)=O)c(CCl)cc2c1
Reactant: COc1cc2cc(O)nc(C)c2cc1OC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: ClCCl
Solvent: C1CCOC1
Product: COc1ccc2nc(NCCNC(C)=O)c(Cc3c(O)nc(C)c4cc(OC)c(OC)cc34)cc2c1
Temperature: 160 °C
Reaction time: 1.5 h

Procedure:
To a stirred solution of N-(2-(3-(chloromethyl)-6-methoxyquinolin-2-ylamino)ethyl)acetamide hydrochloride SLA 41176 (115 mg, 0.33 mmol) in THF (10 mL) in a 20 mL microwave vial equipped with a magnetic stirrer was added 6,7-dimethoxy-1-methylisoquinolin-3-ol CCH18060 (73 mg, 0.33 mmol) followed by a 2 N aq. LiOH solution (0.33 mL, 0.66 mmol) and the mixture was stirred at 160° C. for 1.5 h under microwave irradiation. After cooling to RT, the mixture was diluted with CH2Cl2:MeOH=9:1 (150 mL), washed with brine (20 mL), dried over Na2SO4, filtered and concentrated at 40° C. under vacuum. Purification by column chromatography (SiO2, eluent CH2Cl2:MeOH=100:0 to 90:10) provided N-(2-(3-((3-hydroxy-6,7-dimethoxy-1-methylisoquinolin-4-yl)methyl)-6-methoxyquinolin-2-ylamino)ethyl)acetamide. This free base was dissolved in CH2Cl2 (2 mL) in a 10 mL round-bottomed flask equipped with a magnetic stirrer before addition of 0.49 M HCl in MeOH (2 mL) and the solution was stirred for 5 min at RT then concentrated at 40° C. under vacuum to afforded N-(2-(3-((3-hydroxy-6,7-dimethoxy-1-methylisoquinolin-4-yl)methyl)-6-methoxyquinolin-2-ylamino)ethyl)acetamide dihydrochloride 73 as a yellow solid (19.5 mg, 10% yield).
Reaction SMILES: [CH:1]1[C:2]([CH2:19][C:20]([OH:22])=[O:21])=[CH:3][C:4]([I:18])=[C:5]([O:8][C:9]2[CH:10]=[C:11]([I:17])[C:12]([OH:16])=[C:13]([I:15])[CH:14]=2)[C:6]=1[I:7].[CH2:23](OC(Cl)=O)C1C=CC=CC=1>CO>[CH3:23][O:21][C:20](=[O:22])[CH2:19][C:2]1[CH:1]=[C:6]([I:7])[C:5]([O:8][C:9]2[CH:10]=[C:11]([I:17])[C:12]([OH:16])=[C:13]([I:15])[CH:14]=2)=[C:4]([I:18])[CH:3]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: O=C(O)Cc1cc(I)c(Oc2cc(I)c(O)c(I)c2)c(I)c1
Solvent: CO
Product: COC(=O)Cc1cc(I)c(Oc2cc(I)c(O)c(I)c2)c(I)c1
Reaction time: 0.5 h
Yield: 100 %

Procedure:
In anhydrous conditions, Tetrac (5.0 g, 6.7 mmol, 1.0 eq.) was dissolved in anhydrous methanol (200 mL). To the solution was then added dropwise SOCl2 (485 μL, 6.7 mmol, 1.0 eq.). The reaction was set to reflux for 2 days. Water was then added to the reaction medium (200 mL) and then the solution was concentrated to yield a precipitate. The precipitate was then collected by vacuum filtration and then recrystallized to give orange crystals (3.10 g, 4.0 mmol) of methyl-2-(4-(4-hydroxy-3,5-diiodophenoxy)-3,5-diiodophenyl)acetate in 61% yield. Method B: In anhydrous conditions, Tetrac (1.0 g, 1.3 mmol, 1.0 eq.) was suspended in MeOH (20 mL). TEA (181.4 μL, 1.3 mmol, 1.0 eq.) was then added dropwise followed by benzylchloroformate (184.8 μL, 1.3 mmol, 1.0 eq.). After stirring for 30 minutes, the solution was filtered, the solvent was removed from the residue and the product was separated by silica gel chromatography (eluent=DCM). The collected fractions were then evaporated to give a white powder which was recrystallized to give orange crystals (990 mg, 1.3 mmol) of methyl-2-(4-(4-hydroxy-3,5-diiodophenoxy)-3,5-diiodophenyl)acetate in a quantitative yield.