Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][SH:8])=[CH:5][CH:4]=1.C[O-].[Na+].Cl[C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][C:16]=1[C:25]#[N:26]>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][S:8][C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:22])([F:24])[F:23])=[CH:17][C:16]=2[C:25]#[N:26])=[CH:5][CH:4]=1
Reactant: N#Cc1cc(C(F)(F)F)ccc1Cl
Reactant: COc1ccc(CS)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(CSc2ccc(C(F)(F)F)cc2C#N)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of p-methoxybenzylmercaptan (20.0 g, 0.13 mol) and sodium methoxide (7.0 g) in N,N-dimethylformamide (55 ml) was added dropwise with stirring under a nitrogen atmosphere to a solution of 4-chloro-3-cyanobenzotrifluoride (26.7 g, 0.13 mol) in N,N-dimethylformamide (35 ml) cooled in an ice bath. After stirring for 2 hours at room temperature, the reaction mixture was poured into ice-water and extracted several times with dichloromethane. The combined organic extracts were dried (sodium sulfate) and evaporated to afford in essentially quantitative yield, 2-(4'-methoxybenzylthio)-5-trifluoromethylbenzonitrile as an oil; 60 MHZ NMR spectrum in chloroform-d was in accord with the desired structure. A mixture of the crude product in ethanol (110 ml) and 20% aqueous sodium hydroxide (450 ml) was heated at reflux temperature with stirring for 24 hours. The cooled hydrolysis mixture was concentrated, the resulting solid filtered, and washed with ether. The mother liquors were partitioned and the ethereal layer evaporated. The filtered solid was dissolved in methanol and added to the residue from the mother liquor work-up. The solution was evaporated, the resulting oil suspended in water and the aqueous mixture acidified with 6N hydrochloric acid. The precipitated solid was filtered and dried in vacuo over phosphorous pentoxide; yield 41 g (92%).
Reaction SMILES: C([Mg]Cl)(C)C.O1CCCC1.I[C:12]1[N:13]=[C:14]2[C:20]3[CH:21]=[CH:22][C:23]([C:25]([O:27][CH3:28])=[O:26])=[CH:24][C:19]=3[O:18][CH2:17][CH2:16][N:15]2[CH:29]=1.[CH2:30]([Sn:34](Cl)([CH2:39][CH2:40][CH2:41][CH3:42])[CH2:35][CH2:36][CH2:37][CH3:38])[CH2:31][CH2:32][CH3:33].[NH4+].[Cl-]>>[CH2:39]([Sn:34]([CH2:30][CH2:31][CH2:32][CH3:33])([CH2:35][CH2:36][CH2:37][CH3:38])[C:12]1[N:13]=[C:14]2[C:20]3[CH:21]=[CH:22][C:23]([C:25]([O:27][CH3:28])=[O:26])=[CH:24][C:19]=3[O:18][CH2:17][CH2:16][N:15]2[CH:29]=1)[CH2:40][CH2:41][CH3:42]
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: COC(=O)c1ccc2c(c1)OCCn1cc(I)nc1-2
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1cn2c(n1)-c1ccc(C(=O)OC)cc1OCC2
Reaction time: 2.5 h

Procedure:
Isopropylmagnesium chloride in tetrahydrofuran (2.0 M, 1.5 mL, 3.00 mmol) was added dropwise to a solution of methyl 2-iodo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-9-carboxylate (740 mg, 2.00 mmol) in Tetrahydrofuran (12 mL, 150 mmol) at room temperature. The mixture was stirred for 2.5 hours. Tributyltin chloride (0.8138 mL, 3.000 mmol) was added and the mixture was stirred for 18 hours. The mixture was mixed with sat aq. NH4Cl and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4 and purified on 25 g silica column eluting with 15-20% ethyl acetate in heptane. Yield 160 mg (15%). MS(ESI+): 535.2
Reaction SMILES: FC(F)(F)C(O)=O.C([O:10][C:11](=[O:37])[C:12]1[CH:17]=[CH:16][C:15]([C:18]2[N:19]=[C:20]3[N:24]([CH:25]=2)[N:23]=[C:22]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH2:33][CH2:34][CH2:35][CH3:36])=[CH:28][CH:27]=2)[S:21]3)=[CH:14][CH:13]=1)C.CO.[OH-].[Na+].Cl>O1CCCC1>[CH2:33]([O:32][C:29]1[CH:28]=[CH:27][C:26]([C:22]2[S:21][C:20]3=[N:19][C:18]([C:15]4[CH:16]=[CH:17][C:12]([C:11]([OH:37])=[O:10])=[CH:13][CH:14]=4)=[CH:25][N:24]3[N:23]=2)=[CH:31][CH:30]=1)[CH2:34][CH2:35][CH3:36]
Reactant: CCCCOc1ccc(-c2nn3cc(-c4ccc(C(=O)OCC)cc4)nc3s2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: CCCCOc1ccc(-c2nn3cc(-c4ccc(C(=O)O)cc4)nc3s2)cc1
Yield: 102.5 %

Procedure:
To a solution of 4-[2-(4-butyloxyphenyl)imidazo[2,1-b]-[1,3,4]thiadiazol-6-yl]benzoic acid ethyl ester trifluoroacetic acid salt (2.05 g) in the mixture of methanol (41 ml) and tetrahydrofuran (20.5 ml) was added 2N NaOH aq. (19.1 ml) and refluxed for 17 hours. The reaction mixture was adjusted to pH 1-2 with 1N HCl and the resulting precipitate was collected by filtration to give 4-[2-(4-butyloxyphenyl)imidazo[2,1-b][1,3,4]thiadiazol-6-yl]benzoic acid (1.544 g).
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[OH:16])=[CH:3]1>CO.[Pd]>[CH3:1][C:2]1([CH3:17])[CH2:7][C:6]([CH3:8])([CH3:9])[CH2:5][CH:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[OH:16])[CH2:3]1
Reactant: CC1(C)C=C(c2ccccc2O)CC(C)(C)C1
Agent: [Pd]
Solvent: CO
Product: CC1(C)CC(c2ccccc2O)CC(C)(C)C1
Temperature: 25 °C
Reaction time: 27 h
Yield: 98.9 %

Procedure:
To a solution of 2-(3,3,5,5-tetramethylcyclohex-1-enyl)phenol (1.7 g, 7.4 mmol) produced in Example (102a) in methanol (30 mL) was added 10% palladium on carbon (0.5 g, wet), followed by stirring for 27 hours at room temperature and atmospheric pressure under a hydrogen atmosphere. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure to give 1.7 g of a crude product of the title compound as a light yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[CH:5][C:4]=1[NH2:9].[C:10]([CH2:12][C:13](O)=[O:14])#[N:11].Cl.C(N=C=NCCCN(C)C)C>C1COCC1.CN(C1C=CN=CC=1)C>[C:10]([CH2:12][C:13]([NH:9][C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:3]=1[O:2][CH3:1])=[O:14])#[N:11]
Reactant: COc1ccncc1N
Reactant: N#CCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: C1CCOC1
Product: COc1ccncc1NC(=O)CC#N
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.9 %

Procedure:
4-Methoxypyridin-3-amine (22 g, 177.2 mmol) and 2-cyanoacetic acid (19.60 g, 230.4 mmol) were slurried in THF (1 L). The mixture was cooled in an ice bath and DMAP (28.15 g, 230.4 mmol) was added followed by 3-(ethyliminomethyleneamino)-N,N-dimethyl-propan-1-amine hydrochloride (50.95 g, 265.8 mmol). The mixture was allowed to warm to ambient temperature and stirred overnight. The mixture was partially concentrated, then diluted with ethyl acetate/water. The organic phase was isolated and washed with saturated NaHCO3, then brine, dried (MgSO4), filtered and concentrated. The residue was slurried in ether/petrol to give 2-cyano-N-(4-methoxypyridin-3-yl)acetamide 8 as a yellow solid (26.4 g, 78%). LC-MS (M+H)+ 192.0; 1H NMR (500 MHz, DMSO-d6) δ 9.81 (s, 1H), 8.86 (s, 1H), 8.28 (d, 1H), 7.15 (d, 1H), 4.00 (s, 2H), 3.92 (s, 3H).
Reaction SMILES: [O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5][C:4]([C:12]2[N:17]=[C:16]([CH2:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][C:24]([O:26]C(C)(C)C)=[O:25])[CH:15]=[CH:14][CH:13]=2)=[N:3]1.C(OC(C)C)(C)C>FC(F)(F)C(O)=O>[O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5][C:4]([C:12]2[N:17]=[C:16]([CH2:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][C:24]([OH:26])=[O:25])[CH:15]=[CH:14][CH:13]=2)=[N:3]1
Reactant: CC(C)(C)OC(=O)CCOCCCc1cccc(-c2nc(=O)c3ccccc3s2)n1
Solvent: O=C(O)C(F)(F)F
Solvent: CC(C)OC(C)C
Product: O=C(O)CCOCCCc1cccc(-c2nc(=O)c3ccccc3s2)n1
Temperature: 0 °C
Reaction time: 5 h
Yield: 38.5 %

Procedure:
tert-Butyl 3-{3-[6-(4-oxo-4H-1,3-benzothiazin-2-yl)-2-pyridyl]propoxy}propanoate (1.70 g, 4.0 mmol) was dissolved in trifluoroacetic acid (15 ml) under ice cooling, and the mixture was stirred at 0° C. for 5 hrs. The reaction mixture was combined with isopropylether (50 ml) and stirred for 30 minutes. The precipitated crystals were collected by filtration. The crystals were recrystallized from ethanol-hexane to give the titled compound (0.57 g, 39%) as white crystals.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([S:8][CH3:9])[N:5]=[C:4]([NH:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[CH:14]=2)[CH:3]=1.[CH2:23]([O:25][C:26](=[O:34])[C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([OH:33])[CH:28]=1)[CH3:24].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.O>[CH2:23]([O:25][C:26](=[O:34])[C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([O:33][C:2]2[CH:3]=[C:4]([NH:10][CH2:11][CH2:12][C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[CH:14]=3)[N:5]=[C:6]([S:8][CH3:9])[N:7]=2)[CH:28]=1)[CH3:24]
Reactant: COc1ccc(CCNc2cc(Cl)nc(SC)n2)cc1OC
Reactant: CCOC(=O)c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cccc(Oc2cc(NCCc3ccc(OC)c(OC)c3)nc(SC)n2)c1
Temperature: 90 °C
Yield: 83.5 %

Procedure:
A mixture of (6-dhloro-2-methylsulfanyl-pyrimidin-4-yl)-[2-(3,4-dimethoxy-phenyl)-ethyl]-amine [250 mg, 0.74 mmol, Intermediate (31)], 3-hydroxy-benzoic acid ethyl ester (0.18 g, 1.1 mmol), and Cs2CO3 (0.48 g, 1.48 mmol) in DMF (4 mL) is heated to 90° C. for 15 h. The mixture is diluted with water, and extracted with EtOAc. The extracts are washed (water), dried (MgSO4), filtered, concentrated, and chromatographed (silica gel, 30% EtOAc in Heptane) to afford 3-{6-[2-(3,4-dimethoxy-phenyl)-ethylamino]-2-methylsulfanyl-pyrimidin-4-yloxy}-benzoic acid ethyl ester [0.29 g 83%, Intermediate (71)]. LCMS: RT=3.7 minutes, MS: 470 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH3:15][CH:16]([CH3:32])[CH2:17][NH:18][CH:19]1[CH2:24][CH2:23][CH2:22][N:21]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:20]1.P(C#N)(=O)(OCC)OCC.O>ClCCCl>[NH2:1][C:2]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:3]=1[C:4]([N:18]([CH2:17][CH:16]([CH3:32])[CH3:15])[CH:19]1[CH2:24][CH2:23][CH2:22][N:21]([C:25]([O:27][C:28]([CH3:29])([CH3:30])[CH3:31])=[O:26])[CH2:20]1)=[O:6]
Reactant: CC(C)CNC1CCCN(C(=O)OC(C)(C)C)C1
Reactant: Nc1cc(C(F)(F)F)ccc1C(=O)O
Agent: CCOP(=O)(C#N)OCC
Solvent: O
Solvent: ClCCCl
Product: CC(C)CN(C(=O)c1ccc(C(F)(F)F)cc1N)C1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 70 °C
Reaction time: 8 h
Yield: 47.7 %

Procedure:
2-amino-4-(trifluoromethyl)benzoic acid (0.32 g) and tert-butyl 3-[(2-methylpropyl)amino]piperidine-1-carboxylate (0.4 g) were dissolved in 1,2-dichloroethane (20 ml), diethyl phosphorocyanidate (0.31 g) was added and the mixture was stirred at 70° C. overnight. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (0:10-1:1) was concentrated under reduced pressure to give the object compound (0.33 g).
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:8]=[CH:9][C:10]([O:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[N:11][CH:12]=1.[B:20](OC(C)C)([O:25]C(C)C)[O:21]C(C)C.[OH-].[Na+]>O.C1COCC1>[CH:14]1([O:13][C:10]2[N:11]=[CH:12][C:7]([B:20]([OH:25])[OH:21])=[CH:8][CH:9]=2)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: Brc1ccc(OC2CCCCC2)nc1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: OB(O)c1ccc(OC2CCCCC2)nc1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 85.2 %

Procedure:
n-Butyllithium (1.6 M in hexane) (20.5 mL) was dropwised to a mixture of 5-bromo-2-(cyclohexyloxy)pyridine (7.00 g) and THF (dry) (75 mL) at −78° C. and the mixture was stirred at the same temperature under nitrogen for 40 min. Triisopropyl borate (7.71 g) was dropwised to the mixture at −78° C. and the mixture was stirred at the same temperature for 5 min. Then the mixture was warmed up to room temperature and stirred for additional 30 min. The mixture was poured into 1N NaOH aq. (75 mL)/water (120 mL) and stirred for 1 hr. The organic layer was separated and the aqueous phase was washed with Et2O (100 mL×2) and neutralized by 1N HCl aq. The mixture was extracted with EtOAc, dried over anhydrous sodium sulfate and concentrated in vacuo to give [6-(cyclohexyloxy)pyridin-3-yl]boronic acid (5.15 g) as pale yellow solid. Tetrakis(triphenylphosphine)palladium(0) (107 mg) was added to a suspension of 3-bromo-5-chloropyridin-2-amine (640 mg), [6-(cyclohexyloxy)pyridin-3-yl]boronic acid (750 mg) and sodium carbonate (654 mg) in DME (15 mL) and water (3 mL) and the mixture was stirred at 100° C. under nitrogen for 2.5 hr. Water and EtOAc were added and the organic layer was separated, washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with EtOAc in hexane) to give the title compound (846 mg) as colorless gum.
Reaction SMILES: C([Mg]Cl)(C)C.[CH2:6]([SnH:10]([CH2:15][CH2:16][CH2:17][CH3:18])[CH2:11][CH2:12][CH2:13][CH3:14])[CH2:7][CH2:8][CH3:9].[CH:19](=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(OCC)C>[Sn:10]([CH:19]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[OH:26])([CH2:6][CH2:7][CH2:8][CH3:9])([CH2:11][CH2:12][CH2:13][CH3:14])[CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCC[SnH](CCCC)CCCC
Reactant: O=Cc1ccccc1
Agent: CC(C)[Mg]Cl
Solvent: CCOCC
Product: CCCC[Sn](CCCC)(CCCC)C(O)c1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 28.9 %

Procedure:
This example demonstrates the synthesis and purification of the alpha-hydroxystannane complex Bu3SnCH(OH)Ph. Under nitrogen, a dry 250 mL round bottom flask was charged with 2.0 M isopropyl magnesium chloride in diethyl ether (20.6 mL, 41.2 mmol). An additional 15 mL of diethyl ether was then added. To this stirred solution was added tributyl tin hydride (10.0 g, 34.4 mmol) dropwise over a period of 10-15 min. The resulting reaction mixture was heated to reflux, stirred for 1 h, and then cooled down to about 0° C. Benzaldehyde (4.0 g, 37.8 mmol) was then added dropwise over a period of approximately 10 min while maintaining the temperature at about 0° C. The resulting reaction mixture was then heated to reflux and stirred for 1 h before cooling back down to room temperature. The reaction was then quenched by addition of approximately 15 mL aqueous ammonium chloride under nitrogen. The resulting mixture was filtered through a glass frit and the solids were extracted with diethyl ether. The combined organic extracts were concentrated under vacuum and filtered through Florisil™. The Florisil™ pad was washed further with hexane. The combined organic extracts were concentrated under vacuum to afford an oil. Chromatography on silica gel using 95/5 hexane/ethyl acetate as the eluent afforded 3.95 g of Bu3SnCH(OH)Ph as a pale yellow oil. 1H NMR (CDCl3) δ 7.2 (t, 2H, Hmeta), 7.1 d (d, 1 2H, Hora)), 7.0 (t, 1H, Hpara), 5.1 [d, 1H, CH(OH)], 1.7 [d, 1H, CH(OH)], 1.4-0.7 (m, 27H, Bu's); 119Sn NMR (CDCl3) δ −25.0 relative to SnMe4; 13C NMR (CDCl3) δ 147.8 (Cispo), 128.4 (Cortho, or Cmeta), 124.6 (Cpara), 122.9 Cortho or Cmeta), 71.3 [CH(OH)], 28.9 and 27.4 (CH2's), 13.6 (CH3), 9.1 (CH2).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]([NH:17][C:18](=[O:27])[C@H:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH3:20])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH:12]([CH3:16])[CH2:13][CH2:14][CH3:15])=[CH:6][CH:5]=1.[CH:28]1([CH:31]=O)[CH2:30][CH2:29]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>C(#N)C>[CH:28]1([CH2:31][NH:1][CH2:2][C@H:3]([NH:17][C:18](=[O:27])[C@H:19]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH3:20])[C:4]2[CH:5]=[CH:6][C:7]([O:10][CH2:11][CH:12]([CH3:16])[CH2:13][CH2:14][CH3:15])=[CH:8][CH:9]=2)[CH2:30][CH2:29]1
Reactant: O=CC1CC1
Reactant: CCCC(C)COc1ccc([C@H](CN)NC(=O)[C@@H](C)c2ccccc2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: CCCC(C)COc1ccc([C@H](CNCC2CC2)NC(=O)[C@@H](C)c2ccccc2)cc1
Reaction time: 0.25 h
Yield: 43.5 %

Procedure:
To a stirred solution of (2S)-N-((1R)-2-amino-1-(4-(2-methylpentyloxy)phenyl)ethyl)-2-phenylpropanamide (50 mg, 0.136 mmol), prepared according to the procedure described in example 5, in acetonitrile (3 mL), was added cyclopropanecarboxaldehyde (10.23 μL, 0.136 mmol) and stirring was continued for 15 min. To this mixture, sodium triacetoxyborohydride (57.5 mg, 0.271 mmol) was added and the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was transferred to a separatory funnel containing saturated aqueous NaHCO3 solution (10 mL). The aqueous layer was extracted with ethyl acetate (2×20 mL). The combined organic layers washed with brine, dried over MgSO4, filtered and concentrated. The residue was purified by reverse phase HPLC (acetonitrile/water with 0.1% TFA). The organic solvent was removed on the rotovapor and the aqueous mixture was frozen and placed on the lyophilizer. The product was transferred to a separatory funnel containing saturated aqueous NaHCO3 solution (10 mL). The aqueous layer was extracted with ethyl acetate (2×20 mL). The combined organic layers were dried over MgSO4, filtered and concentrated to afford (2S)-N-((1R)-2-(cyclopropylmethylamino)-1-(4-(2-methylpentyloxy)phenyl)ethyl)-2-phenylpropanamide (25 mg, 43.6% yield) as a colorless oil: 1H NMR (400 MHz, CDCl3) δ 7.20-7.36 (m, 5H), 6.92 (d, J=8.6 Hz, 2H), 6.73 (d, J=8.6 Hz, 2H), 6.50 (d, J=6.8 Hz, 1H), 4.99 (q, J=6.3 Hz, 1H), 3.74 (dd, J=8.8, 5.8 Hz, 1H), 3.59-3.68 (m, 2H), 2.95 (dd, J=12.2, 6.4 Hz, 1H), 2.82 (dd, J=12.2, 4.9 Hz, 1H), 2.33-2.47 (m, 2H), 2.08-2.31 (m, 1H), 1.83-1.95 (m, 1H), 1.49 (d, J=7.1 Hz, 3H), 1.26-1.48 (m, 3H), 1.13-1.25 (m, 1H), 0.97 (d, J=6.8 Hz, 3H), 0.90 (t, J=7.1 Hz, 3H), 0.75-0.84 (m, 1H), 0.37-0.46 (m, 2H), −0.02-0.08 (m, 2H); LRMS (ESI) m/e 423.4 [(M+H)+, calcd for C27H39N2O2 423.3].
Reaction SMILES: [ClH:1].[Cl:2][CH2:3][C:4]1[C:5]([NH:16][CH2:17][CH3:18])=[N:6][C:7]2[C:12]([CH:13]=1)=[CH:11][C:10]([O:14][CH3:15])=[CH:9][CH:8]=2.[CH:19]([C:22]1[C:31]2[C:26](=[CH:27][C:28]([O:34][CH3:35])=[C:29]([O:32][CH3:33])[CH:30]=2)[CH:25]=[C:24]([OH:36])[N:23]=1)([CH3:21])[CH3:20].[Li+].[OH-]>C1COCC1.C(Cl)Cl>[ClH:2].[ClH:1].[CH2:17]([NH:16][C:5]1[C:4]([CH2:3][C:25]2[C:26]3[C:31](=[CH:30][C:29]([O:32][CH3:33])=[C:28]([O:34][CH3:35])[CH:27]=3)[C:22]([CH:19]([CH3:20])[CH3:21])=[N:23][C:24]=2[OH:36])=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:14][CH3:15])[CH:11]=2)[N:6]=1)[CH3:18]
Reactant: CCNc1nc2ccc(OC)cc2cc1CCl
Reactant: COc1cc2cc(O)nc(C(C)C)c2cc1OC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCNc1nc2ccc(OC)cc2cc1Cc1c(O)nc(C(C)C)c2cc(OC)c(OC)cc12
Temperature: 150 °C
Reaction time: 1.5 h
Yield: 5 %

Procedure:
To a stirred solution of 3-(chloromethyl)-N-ethyl-6-methoxyquinolin-2-amine hydrochloride (250 mg, 0.87 mmol) in THF (10 mL) in a 20 mL microwave vial equipped with a magnetic stirrer was added 1-isopropyl-6,7-dimethoxyisoquinolin-3-ol SIL 32164 (215 mg, 0.87 mmol) followed by a 2 N aq. LiOH solution (0.87 mL, 1.74 mmol) and the mixture was stirred at 150° 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 cyclohexane:EtOAc=100:0 to 0:100) followed by a second purification by column chromatography (SiO2, eluent CH2Cl2:MeOH=100:0 to 95:5) provided, after evaporation and drying, 38 mg of 4-((2-(ethylamino)-6-methoxyquinolin-3-yl)methyl)-1-isopropyl-6,7-dimethoxyisoquinolin-3-ol as a brown solid. This free base was dissolved in CH2Cl2 (2 mL) in a 10 mL round-bottomed flask equipped with a magnetic stirrer before addition of a 0.49 M HCl solution in MeOH (0.70 mL). The reaction mixture was stirred for 5 min at RT then concentrated at 40° C. under vacuum to afford 4-((2-(ethylamino)-6-methoxyquinolin-3-yl)methyl)-1-isopropyl-6,7-dimethoxyisoquinolin-3-ol dihydrochloride 47 as a yellow solid (24 mg, 5% yield).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N.[CH3:21][C:22]1[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[C:24]([O:32][CH3:33])[CH:23]=1.S([O-])([O-])=O.[Na+].[Na+]>C(Cl)(Cl)(Cl)Cl>[Br:1][CH2:21][C:22]1[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[C:24]([O:32][CH3:33])[CH:23]=1
Reactant: COC(=O)c1ccc(C)cc1OC
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1ccc(CBr)cc1OC
Temperature: 70 °C
Reaction time: 1 h

Procedure:
9.07 g (51.0 mmol) of N-bromosuccinimide and 120 mg of azobis(isobutyronitrile) were added to a solution of 7.64 g (42.4 mmol) of methyl 4-methyl-2-methoxybenzoate in 140 ml of carbon tetrachloride under a stream of nitrogen, and the resulting mixture was stirred at 70° C. for 1 hour. A further 200 mg of azobis(isobutyronitrile) were then added, making a total addition of 320 mg (1.95 mmol). The reaction mixture was then stirred for 1 hour, after which an aqueous solution of sodium sulfite was added to the mixture to decompose any excess of the reagent. The organic phase was concentrated by evaporation under reduced pressure to one-fourth of its original volume. The concentrate was diluted with ethyl acetate, and the diluted solution was washed with a saturated aqueous solution of sodium hydrogencarbonate, with water and with a saturated aqueous solution of sodium chloride, in that order, after which it was dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, giving 11.26 of crude methyl 4-bromomethyl-2-methoxybenzoate as a residue.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)[N:6]=[C:5]([C:20]([OH:22])=O)[CH:4]=1.S(Cl)(Cl)=O.Cl.[OH:28][NH2:29].C(N(CC)CC)C>C(OCC)(=O)C.CN(C=O)C.C1C=CC=CC=1>[OH:28][NH:29][C:20]([C:5]1[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=[C:7]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)[N:6]=1)=[O:22]
Reactant: COc1cc(Oc2cccc(C(F)(F)F)c2)nc(C(=O)O)c1
Reactant: NO
Agent: Cl
Solvent: c1ccccc1
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: COc1cc(Oc2cccc(C(F)(F)F)c2)nc(C(=O)NO)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3.0 g (0.0096 mol) of 4-methoxy-6-(3-(trifluoromethyl)phenoxy}-2-pyridine carboxylic acid was mixed with 2.25 g (0.0096×2.0 mol) of thionyl chloride and then with about 50 ml of benzene and a small amount of DMF, followed by treating the obtained mixture under reflux for about 30 minutes. The reaction solution was concentrated and mixed with methylene chloride and then with 1.32 g (0.0096×2.0 mol) of hydroxyl amine hydrochloride and 2.42 g (0.0096×2.5 mol) of triethyl amine, followed by stirring at room temperature for about one hour. The reaction solution was distributed in ethyl acetate-saturated sodium bicarbonate water, and washed with saturated brine. The organic phase of the solution was dried with anhydrous sodium sulfate, concentrated and purified by silica gel column chromatography (eluting solution: ethyl acetate/hexane), thereby obtaining an aimed product.