Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1([CH3:17])[CH2:8][CH2:7][C:6]2[C:9]([CH3:16])=[C:10]([OH:15])[C:11]([CH3:14])=[C:12]([CH3:13])[C:5]=2[O:4]1)#[CH:2].Br[C:19]1[C:24]([OH:25])=[CH:23][CH:22]=[CH:21][N:20]=1>C(N(CC)CC)C>[O:25]1[C:24]2[C:19](=[N:20][CH:21]=[CH:22][CH:23]=2)[CH:2]=[C:1]1[C:3]1([CH3:17])[CH2:8][CH2:7][C:6]2[C:9]([CH3:16])=[C:10]([OH:15])[C:11]([CH3:14])=[C:12]([CH3:13])[C:5]=2[O:4]1
Reactant: Oc1cccnc1Br
Reactant: C#CC1(C)CCc2c(C)c(O)c(C)c(C)c2O1
Solvent: CCN(CC)CC
Product: Cc1c(C)c2c(c(C)c1O)CCC(C)(c1cc3ncccc3o1)O2

Procedure:
This compound was prepared by reacting rac-3,4-dihydro-2-ethynyl-2,5,7,8-tetramethyl-2H-1-benzopyran-6-ol with 2-bromo-3-hydroxypyridine under the conditions described in Example 26, but using twice as much triethylamine and lengthening the reaction time to 3 days. Chromatography of the crude product over the 40-fold amount of silica gel using 10 % (V/V) of ethyl acetate in methylene chloride followed by crystallization from ether/hexane and recrystallization from ethyl acetate/hexane gave off-white crystals with m.p. 168°-169°.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=2)[CH:3]=1.[CH2:17]([CH2:19][NH2:20])[OH:18].CCN(C(C)C)C(C)C>CCCCO>[CH3:16][O:15][C:11]1[CH:10]=[C:9]([NH:8][C:4]2[N:5]=[CH:6][N:7]=[C:2]([NH:20][CH2:19][CH2:17][OH:18])[CH:3]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: NCCO
Reactant: COc1cccc(Nc2cc(Cl)ncn2)c1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: COc1cccc(Nc2cc(NCCO)ncn2)c1
Temperature: 200 °C
Yield: 84 %

Procedure:
100 mg of 6-chloro-N-(3-methoxyphenyl)pyrimidin-4-amine, 27 mg of ethanolamine and 119 mg of DIPEA were dissolved in 2 mL of n-BuOH and the mixture obtained was charged into a microwave vial and the vial obtained was heated to 200° C. for 45 minutes under microwave irradiation. Progress of the reaction was monitored by TLC. Upon termination of the reaction n-BuOH was evaporated off and to the evaporation residue obtained 5 mL of water were added. The mixture obtained was extracted with EtOAc, the phases were separated and the organic phase obtained was dried and subjected to evaporation. 2-(6-(3-Methoxyphenylamino)pyrimidin-4-ylamino)ethan-1-ol was obtained in the form of a yellow oil.
Reaction SMILES: [CH2:1]([N:4]([CH2:8][CH2:9][OH:10])[CH2:5][CH2:6][OH:7])[CH:2]=C.S(C1C=CC(C)=CC=1)([O:14][CH2:15][CH2:16][O:17][CH2:18]COC)(=O)=O>>[CH3:18][O:17][CH2:16][CH2:15][O:14][CH2:2][CH2:1][N:4]([CH2:8][CH2:9][OH:10])[CH2:5][CH2:6][OH:7]
Reactant: C=CCN(CCO)CCO
Reactant: COCCOCCOS(=O)(=O)c1ccc(C)cc1
Product: COCCOCCN(CCO)CCO

Procedure:
The title compound was prepared as described above for N-allyldiethanolamine in Example 1 except that 2-methoxyethoxyethyl tosylate was used (0.55 mol, 150.9 g) in a 0.5 mol preparation. The pure diol whose formula is shown below was obtained (49.8 g, 48%) on fractional distillation at 129°-131° C. (0.04 mm):
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6](=[O:14])[NH:7][C:8]3[C:13]([C:4]=2[CH:3]=1)=[CH:12][CH:11]=[CH:10][N:9]=3.Br[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[Cl:25]>>[Cl:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[CH2:18][NH:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6](=[O:14])[NH:7][C:8]3[C:13]([C:4]=2[CH:3]=1)=[CH:12][CH:11]=[CH:10][N:9]=3
Reactant: Clc1ccccc1CBr
Reactant: Nc1ccc2c(=O)[nH]c3ncccc3c2c1
Product: O=c1[nH]c2ncccc2c2cc(NCc3ccccc3Cl)ccc12
Yield: 6.3 %

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 458 using 70 (139 mg, 0.66 mmol) and 1-(bromo-methyl)-2-chlorobenzene (162 mg, 0.79 mmol) to provide 470 (14 mg, 6% yield) as a white powder. LC-MS (M+H=337, obsd.=337). 1H NMR (400 MHz, DMSO-D6) δ 11.51 (s, 1H), 8.56 (d, J=6.8, 1H), 8.42 (dd, J=1.6, 4.7, 1H), 8.01 (d, J=8.8, 1H), 7.44 (m, 2H), 7.39 (d, J=2.1, 1H), 7.29 (m, 2H), 7.18 (m, 2H), 6.95 (dd, J=2.1, 8.8, 1H), 4.58 (d, J=5.9, 2H).
Reaction SMILES: [CH2:1]1[NH:5][CH2:4][CH:3]2[CH2:6][O:7][CH2:8][CH2:9][CH:2]12.C([O-])([O-])=O.[K+].[K+].[Cl:16][CH2:17][CH2:18][CH2:19]Br>CC(C)=O>[Cl:16][CH2:17][CH2:18][CH2:19][N:5]1[CH2:1][CH:2]2[CH2:9][CH2:8][O:7][CH2:6][CH:3]2[CH2:4]1
Reactant: C1CC2CNCC2CO1
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: ClCCCN1CC2CCOCC2C1
Yield: 16.9 %

Procedure:
To a solution of octahydropyrano[3,4-c]pyrrole (0.14 g) in acetone (30 mL) was added K2CO3 (0.76 g) followed by 1-chloro-3-bromopropane (0.57 g, 2.0 eq). The reaction mixture was heated to reflux for 12 h and filtered. The filtrate was concentrated in vacuo, and the residue was dissolved in EtOAc (100 mL). The solution was washed with water (100 mL×2) followed by brine (100 mL), dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was chromatographed with a silica gel column (eluting agent: 20:1 (v/v) EA/CH3OH) to give the title compound (38 mg, 16.96%). The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 204.7 (M+1).
Reaction SMILES: C[O:2][C:3](=O)[C:4]([CH3:16])([CH3:15])[CH2:5][O:6][C:7]1[C:8]([NH2:14])=[N:9][CH:10]=[C:11]([Br:13])[CH:12]=1.[H-].[Na+]>CS(C)=O.O>[Br:13][C:11]1[CH:10]=[N:9][C:8]2[NH:14][C:3](=[O:2])[C:4]([CH3:16])([CH3:15])[CH2:5][O:6][C:7]=2[CH:12]=1
Reactant: COC(=O)C(C)(C)COc1cc(Br)cnc1N
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CC1(C)COc2cc(Br)cnc2NC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.3 %

Procedure:
To a solution of 3-(2-amino-5-bromo-pyridin-3-yloxy)-2,2-dimethylpropionic acid methyl ester (880 mg, 2.90 mmol) in DMSO (40 mL) was added NaH (60% in oil, 139 mg, 3.48 mmol), and the mixture was stirred overnight at room temperature. The mixture was diluted with water (100 mL), and further stirred for 15 min. The resulting precipitate was collected by filtration to give the title compound (600 mg, 76%) as a white solid: 1H NMR (300 MHz, CDCl3) δ 8.34 (br s, 1H), 8.11 (d, J=1.8 Hz, 1H), 7.46 (d, J=1.8 Hz, 1H), 4.01 (s, 2H), 1.32 (s, 6H); ESI MS m/e 271 (M+H)+.
Reaction SMILES: Br[CH:2]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:3]1[CH:8]=[CH:7][C:6]([Cl:9])=[C:5]([N+:10]([O-:12])=[O:11])[CH:4]=1.[CH3:19][C:20]1[N:21]=[CH:22][NH:23][CH:24]=1>C(#N)C>[Cl:9][C:6]1[CH:7]=[CH:8][C:3]([CH:2]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:23]2[CH:24]=[C:20]([CH3:19])[N:21]=[CH:22]2)=[CH:4][C:5]=1[N+:10]([O-:12])=[O:11]
Reactant: O=[N+]([O-])c1cc(C(Br)c2ccccc2)ccc1Cl
Reactant: Cc1c[nH]cn1
Solvent: CC#N
Product: Cc1cn(C(c2ccccc2)c2ccc(Cl)c([N+](=O)[O-])c2)cn1
Reaction time: 24 h
Yield: 54.5 %

Procedure:
A mixture of 31.9 parts of 4-(bromophenylmethyl)-1-chloro-2-nitrobenzene, 49.3 parts of 4-methyl-1H-imidazole and 120 parts of acetonitrile was stirred for 24 hours at reflux temperature. The reaction mixture was concentrated and the concentrate was taken up in 150 parts of water. The product was extracted with dichloromethane. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane, methanol and methanol, saturated with ammonia, (98:1:1 by volume) as eluent. The desired fractions were collected and the eluent was evaporated. The residue was converted into the ethanedioate salt in 80 parts of 2-propanol. The salt was filtered off, washed with 2-propanol and dried, yielding 22.8 parts (54.5%) of 1-[(4-chloro-3-nitrophenyl)phenylmethyl]-4-methyl-1H-imidazole ethanediotate(1:1); mp. 105° C. (int. 133).
Reaction SMILES: [N:1]([C:4]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[CH:8]=1)([CH3:6])[CH3:5])=[C:2]=[O:3].O>ClCCCl>[CH3:14][O:13][C:9]1[CH:8]=[C:7]2[C:12](=[CH:11][CH:10]=1)[C:2](=[O:3])[NH:1][C:4]2([CH3:6])[CH3:5]
Reactant: COc1cccc(C(C)(C)N=C=O)c1
Solvent: ClCCCl
Solvent: O
Product: COc1ccc2c(c1)C(C)(C)NC2=O
Temperature: 0 °C

Procedure:
To an ice-cold slurry of FeCl3 (35.69 g, 220 mmol) in dry DCE (800 mL) is added a solution of isocyanate 56 (19.12 g, 100.0 mmol) in the same solvent (100 mL) over 45 min. After completion of the addition, GC analysis of an aliquot indicates complete reaction. Water (600 mL) is added and the resulting mixture is stirred vigorously. The layers are separated, and the organic phase is washed 2×1 L with 1 M tartaric acid solution and once with brine. The solution is dried (MgSO4), filtered and evaporated to a dark liquid. This is purified by FC (1:4 hexane/EtOAc, then EtOAc) to provide the 5-methoxy isoindolone 57 as a pale yellow solid, mp 146-147° C., 7.38 g (39%), and the regioisomeric 7-methoxy isoindolone 61 as a yellow solid, mp 155-158° C., 2.85 g (15%). For 57: 1H NMR (CDCl3) 7.74 (d, 1, J=8.5), 7.00-6.95 (m, 1), 6.85 (d, 1, J=2.2), 3.89 (s, 3), 1.54 (s, 6); 13C NMR (CDCl3) 169.57, 163.19, 155.44, 125.31, 123.14, 114.18, 105.92, 58.64, 55.61, 27.81; MS (MW=191.2, EI, eE=70 eV) m/z 191 (M+), 176 (base peak), 161, 133, 118, 88, 77, 63, 42.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[CH:10](N(CC)C(C)C)([CH3:12])[CH3:11].C(Br)C#C>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1.FC(F)(F)S([O-])(=O)=O.[Zn+2].FC(F)(F)S([O-])(=O)=O>[CH2:12]([C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][CH:2]=1)[C:10]#[CH:11]
Reactant: CCN(C(C)C)C(C)C
Reactant: c1ccc2[nH]ccc2c1
Agent: C#CCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: Cc1ccccc1
Product: C#CCc1c[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of indole (0.50 g, 4.67 mmol), zinc trifluoromethanesulfonate (1.02 g, 2.8 mmol) and tetrabutylammonium iodide (0.86 g, 2.34 mmol) in toluene (14 mL) was added N,N-diisopropylethylamine (0.89 mL, 5.14 mmol) and the mixture was stirred at room temperature for about 15 min. Propargyl bromide (0.26 mL, 2.34 mmol) was added and the solution was stirred at room temperature for about 4 hours. The solution was quenched by addition of aqueous ammonium chloride and the mixture was extracted with diethyl ether. The combined organic extracts were dried (MgSO4), filtered and concentrated under vacuum, the residue was purified by flash column chromatography on silica gel using hexanes/ethyl acetate (8:1) as the mobile phase to provide Example 650. 1H NMR (300 MHz, CDCl3) δ 2.13 (t, J=2.7 Hz, 1H), 3.70 (d, J=2.7 Hz, 2H), 6.55 (s, 1H), 7.37 (m, 2H), 7.64 (m, 2H), 7.98 (br s, 1H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]([O:10][Si](C)(C)C)[C:8]#N)[CH:2]=1.[CH3:15][O:16][C:17]([C:19]1[CH:24]=[CH:23][C:22](CBr)=[CH:21][CH:20]=1)=[O:18].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Cl-].[Na+]>O1CCCC1>[O:10]=[C:7]([C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)[CH2:8][C:22]1[CH:23]=[CH:24][C:19]([C:17]([O:16][CH3:15])=[O:18])=[CH:20][CH:21]=1
Reactant: C[Si](C)(C)OC(C#N)c1cccnc1
Reactant: COC(=O)c1ccc(CBr)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(CC(=O)c2cccnc2)cc1
Reaction time: 0.5 h

Procedure:
A solution of diisopropylamine (4.5 g) in dry tetrahydrofuran (60 ml) was cooled to -35 to 31 40 ° C., followed by addition of 1.5M n-butyl lithium in 30 ml of hexane in solution, and stirred for 30 minutes, to produce lithium diisopropylamide. To the solution was added a solution of 2-(3-pyridyl)-2-(trimethylsiloxy)acetonitrile in dry tetrahydrofuran at -78 ° C., and stirred at the same temperature for 30 minutes. After the addition of a solution of methyl 4-bromomethyl benzoate in dry tetrahydrofuran at - 78 ° C., stirring was effected overnight at -78 ° C. to room temperature. To the reaction mixture obtained was added 1.0 M tetra-n-butylammonium fluoride in 40 ml of dry tetrahydrofuran in solution and stirred at room temperature for 3.5 hours. The reaction solution was poured into saturated aqueous sodium chloride solution, and after separation of the organic phase, the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed in saturated aqueous sodium chloride solution, followed by drying over magnesium sulfate and distillation of the solvent. The residue was subjected to chromatography on a silica gel column. A fraction eluted with chloroform-methanol (50:1 v/v) was recrystallized in n-hexane chloroform to produce 3.0 g of methyl 4-[2-oxo-2-(3-pyridyl)ethyl]benzoate.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][C:3]1=O.P(Cl)(Cl)(Cl)=O.[NH:13]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([C:22]([O:24][CH3:25])=[O:23])[CH:20]=2)[CH:15]=[CH:14]1.C([O-])([O-])=O.[Na+].[Na+]>ClCCCl.O>[CH3:25][O:24][C:22]([C:19]1[CH:20]=[C:21]2[C:16](/[C:15](=[C:3]3/[N:2]([CH3:1])[CH2:6][CH2:5][CH2:4]/3)/[CH:14]=[N:13]2)=[CH:17][CH:18]=1)=[O:23]
Reactant: CN1CCCC1=O
Reactant: COC(=O)c1ccc2cc[nH]c2c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCCl
Solvent: O
Product: COC(=O)c1ccc2c(c1)N=C/C2=C1/CCCN1C
Reaction time: 0.25 h
Yield: 56.6 %

Procedure:
A mixture of 1.6 mL (16 mmol) 1-methyl-2-pyrrolidone and 10 mL phosphoryl chloride (POCl3) in 10 mL 1,2-dichloroethane was stirred for 15 min and 1.75 g (10 mmol) methyl indole-6-carboxylate and 1.6 mL (16 mmol) 1-methyl-2-pyrrolidone in 10 mL 1,2-dichloroethane was added. The mixture was heated to reflux for 2 h. Water and Na2CO3 aq. was added to adjust to pH=9. Subsequently the mixture was extracted with DCM and the combined organic layers were washed with water, dried with Na2SO4 and evaporated to dryness. Trituration with acetone provided 1.45 g (57%) of the title compound as light brown solid. MS (m/e): 257.2 (MH+).
Reaction SMILES: [OH:1][NH2:2].C([O:5][C:6](=O)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]([C:20]1[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[CH:22][N:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)C>CN(C=O)C.CO>[OH:1][NH:2][C:6](=[O:5])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]([C:20]1[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[CH:22][N:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1
Reactant: CCOC(=O)CCCCCCN(c1ccccn1)c1cc(OC)ccn1
Reactant: NO
Solvent: CO
Solvent: CN(C)C=O
Product: COc1ccnc(N(CCCCCCC(=O)NO)c2ccccn2)c1
Reaction time: 17 h
Yield: 84 %

Procedure:
HONH2 (50% aqueous, 2 mL) was added to III (10 mg, 0.028 mmol) in DMF (0.5 mL) and MeOH (2 mL) at rt. The reaction mixture was stirred for 17 h, after which the solvents were evaporated under reduced pressure. The resulting residue was dissolved and co-evaporated with toluene (2×2 mL) then was purified by silica gel column chromatography eluting with CH2Cl2/MeOH (100:3 to 100:10) to furnish IV as a colourless oil (8 mg, 84%).
Reaction SMILES: [BH4-].[Na+].[O:3]=[C:4]([CH2:10][CH2:11][CH:12]=[C:13]([CH3:25])[CH2:14][CH2:15][CH:16]=[C:17]([CH3:24])[CH2:18][CH2:19][CH:20]=[C:21]([CH3:23])[CH3:22])[CH2:5][C:6]([O:8][CH3:9])=[O:7].[NH4+].[Cl-]>CO>[OH:3][CH:4]([CH2:10][CH2:11][CH:12]=[C:13]([CH3:25])[CH2:14][CH2:15][CH:16]=[C:17]([CH3:24])[CH2:18][CH2:19][CH:20]=[C:21]([CH3:23])[CH3:22])[CH2:5][C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)CC(=O)CCC=C(C)CCC=C(C)CCC=C(C)C
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Product: COC(=O)CC(O)CCC=C(C)CCC=C(C)CCC=C(C)C
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Powdered sodium borohydride (38 mg, 1.0 mmol) was added at 0° C. to a stirred solution of methyl 3-oxo-7,11,15-trimethylhexadeca-6,10,14-trienoate (580 mg, 1.8 mmol) in methanol (5 mL) in one portion. The resulting mixture was stirred at 0° C. for 15 minutes, then treated with a saturated aqueous solution of NH4Cl (2 mL). The resulting mixture was extracted with diethyl ether. This extract was washed with water, dried, filtered and evaporated to give the crude product which was purified by flash chromatography. Elution of the column with hexane:ethyl acetate (10:1/v:v) afforded the title compound as a colorless gum.
Reaction SMILES: [ClH:1].Cl.Cl.C([C:6]1[CH:7]=[CH:8][C:9]2[N:15]([CH2:16][C:17]3[N:18]=[CH:19][NH:20][CH:21]=3)[CH2:14][C@@H:13]([CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[NH:12][CH2:11][C:10]=2[CH:29]=1)#N.[CH:30](=O)[CH2:31][CH2:32][CH3:33].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>CC(O)=O.C(Cl)Cl>[ClH:1].[ClH:1].[ClH:1].[CH2:30]([N:12]1[CH2:11][C:10]2[CH:29]=[CH:6][CH:7]=[CH:8][C:9]=2[N:15]([CH2:16][C:17]2[N:18]=[CH:19][NH:20][CH:21]=2)[CH2:14][CH:13]1[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:31][CH2:32][CH3:33]
Reactant: CCCC=O
Reactant: N#Cc1ccc2c(c1)CN[C@H](Cc1ccccc1)CN2Cc1c[nH]cn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCCCN1Cc2ccccc2N(Cc2c[nH]cn2)CC1Cc1ccccc1
Reaction time: 14 h
Yield: 354.3 %

Procedure:
A solution of Example 391 (0.23 g, 0.7 mmol) and butyraldehyde (1 g, 14 mmol) in 1:4 AcOH/CH2Cl2 (25 mL) was stirred at rt for 1 hr. NaBH(OAc)3 (3.0 g, 14 mmol) was added and stirring was continued for 14 hrs. The reaction was quenched with conc. NH4OH and diluted with 10% iPrOH in CH2Cl2 (50 mL). The organic phase was washed with 1 N NaOH (2×20 mL), dried over Na2SO4 and evaporated to give a yellow solid (0.4 g) which was purified by reverse phase preparative HPLC (gradient of aqueous methanol with 0.1% TFA) and converted to the HCl salt by lyophilizing with 1 N HCl to give Example 392 as a yellow solid (45 mg, 12%). MS (M+H)+ 400.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[CH2:5].C[O-].[Na+].[CH3:17][CH:18]([SH:20])[CH3:19].Cl>CO.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:13])[CH:4]([CH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)[CH2:5][S:20][CH:18]([CH3:19])[CH3:17]
Reactant: C=C(Cc1ccccc1)C(=O)OC
Reactant: CC(C)S
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)C(CSC(C)C)Cc1ccccc1
Reaction time: 0.5 h

Procedure:
To a solution of methyl-2-benzylacrylate (20 gm, 0.113 mol) in methanol (100 ml) at room temperature was added a solution of sodium methoxide (2N, 17 ml) followed by isopropylthiol (12.56 ml). TLC (4:1, Hexanes: ethyl acetate) showed reaction to be complete after 30 min. The reaction mixture was made acidic with 1N HCl and extracted three times with ethyl acetate. The combined organic fractions were dried over NaSO4, filtered and evaporated in vacuo. The crude product was purified by chromatography (silica 4:1, hexanes: ethyl acetate to give methyl-3-isopropylthio-2-benzylpropionate.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.CCCCCC.[F:19][C:20]1[CH:25]=[C:24]([CH3:26])[CH:23]=[CH:22][N:21]=1.[Cl-].[NH4+].[O:29]1CCC[CH2:30]1>>[F:19][C:20]1[CH:25]=[C:24]([CH2:26][CH2:30][OH:29])[CH:23]=[CH:22][N:21]=1
Reactant: Cc1ccnc(F)c1
Reactant: C1CCOC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Product: OCCc1ccnc(F)c1
Temperature: -80 °C
Reaction time: 1 h
Yield: 57 %

Procedure:
To a solution of anhydrous diisopropylamine (18.5 mL, 0.13 mol) in anhydrous tetrahydrofuran (160 mL) was added dropwise at −80° C., under argon, a 1.3 M n-butyllithium solution in hexane (100 mL, 0.13 mol). The mixture was stirred at −80° C. for 1 h before addition dropwise of a solution of 2-fluoro-4-picoline (41) (9.00 g, 6.30 mmol) in anhydrous tetrahydrofuran (60 mL). The mixture was stirred at −80° C. for 1 h once again before addition dropwise of a p-formaldehyde (16.6 g, 0.55 mol) suspension in anhydrous tetrahydrofuran (100 mL). The mixture was stirred at −80° C. for 1 h and then at room temperature for 12 h. A saturated aqueous ammonium chloride solution (450 mL) was added to the mixture. The solution was decanted and the aqueous layer was extracted with dichloromethane (4×200 mL). The organic layers were combined, dried on magnesium sulfate, filtered and evaporated under vacuum. The residue obtained was chromatographed (Al2O3, CH2Cl2/EtOH, 99/1, v/v) to give compound 42 (7.25 g, 51.4 mmol) as an orange-coloured oil. Yield 57%; Rf (Al2O3, CH2Cl2/EtOH, 99/1, v/v) 0.32; IR (CCl4) ν 1046, 1149, 1278, 1413, 1613, 2800-3000, 3100-3600, 3634 cm−1; 1H NMR (200 MHz, CDCl3) δ 2.87 (t, 2H, J=6.3 Hz), 3.87 (t, 2H, J=6.3 Hz), 6.82 (s, 1H), 7.07 (d, 1H, J=5.2 Hz), 8.01 (d, 1H, J=5.2 Hz); MS m/z 141 (M+, 23), 111 (100), 91 (34), 83 (14), 64 (10), 57 (12).
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([S:30]([N:33]([C:40]2[CH:45]=[C:44]([Cl:46])[CH:43]=[CH:42][C:41]=2[Cl:47])[C@H:34]([CH3:39])[CH2:35][CH2:36][CH2:37][OH:38])(=[O:32])=[O:31])=[CH:26][CH:25]=1>ClCCl>[Cl:23][C:24]1[CH:25]=[CH:26][C:27]([S:30]([N:33]([C:40]2[CH:45]=[C:44]([Cl:46])[CH:43]=[CH:42][C:41]=2[Cl:47])[C@H:34]([CH3:39])[CH2:35][CH2:36][CH:37]=[O:38])(=[O:32])=[O:31])=[CH:28][CH:29]=1
Reactant: C[C@H](CCCO)N(c1cc(Cl)ccc1Cl)S(=O)(=O)c1ccc(Cl)cc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: C[C@H](CCC=O)N(c1cc(Cl)ccc1Cl)S(=O)(=O)c1ccc(Cl)cc1
Reaction time: 18 h
Yield: 51 %

Procedure:
To a solution of Dess-Martin periodinane (4.24 g, 10.0 mmol) in dichloromethane (100 mL) at 0° C. was added dropwise 4-chloro-N-(2,5-dichlorophenyl)-N-(1R)(4-hydroxy-1-methylbutyl)benzenesulfonamide (3.60 g, 8.8 mmol) in dichloromethane (50 mL). The reaction was allowed to slowly come to room temperature with stirring over 18 h. The reaction was then quenched with a saturated solution of 1:1 NaHCO3/NaHSO3 (25 mL) and diluted with EtOAc. The organic phase was washed with H2O and brine, dried over MgSO4, filtered, and concentrated in vacuo. Flash silica gel chromatography (silica gel, 20% EtOAc/hexanes) of the concentrate afforded the title compound as a white wax (1.85 g, 51% yield): 1H NMR (CDCl3) δ 9.70 (s, 1H), 7.68–7.75 (m, 2H), 6.98–7.49 (m, 5H), 4.80–4.85 (m, 1H), 2.36–3.00 (m, 2H), 1.17–1.36 (m, 3H).
Reaction SMILES: Cl.Br[C:3]1[C:4]([O:9][C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)=[CH:12][CH:11]=2)=[N:5][CH:6]=[CH:7][CH:8]=1.C1(N(C)C2CCCCC2)CCCCC1.[O:37]1[CH:42]=[CH:41][CH2:40][CH2:39][CH2:38]1>[Pd].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.O1CCOCC1>[O:37]1[CH:38]=[CH:39][CH2:40][CH2:41][CH:42]1[C:3]1[C:4]([O:9][C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)=[CH:12][CH:11]=2)=[N:5][CH:6]=[CH:7][CH:8]=1
Reactant: Brc1cccnc1Oc1ccc(Nc2ccccn2)cc1
Reactant: C1=COCCC1
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: CN(C1CCCCC1)C1CCCCC1
Solvent: C1COCCO1
Product: C1=COC(c2cccnc2Oc2ccc(Nc3ccccn3)cc2)CC1
Temperature: 105 °C

Procedure:
To a 25 mL microwave vial was added Bis(tri-tert-butylphosphine) palladium (0) (101 mg, 0.198 mmol) and N-(4-(3-bromopyridin-2-yloxy)phenyl)pyridin-2-amine hydrochloride (750 mg, 1.981 mmol) before evacuating and backfilling with nitrogen (2×). After addition of Dioxane (5.659 ml), N-cyclohexyl-N-methylcyclohexanamine (0.840 ml, 3.96 mmol), and 3,4-dihydro-2H-pyran (666 mg, 7.92 mmol) was added and the mixture was heated to 105° C. Following complete consumption of the starting material, the reaction mixture was cooled to room temperature and the volatiles were removed under reduced pressure. Following silica gel chromatography, the title compound was obtained as a racemic mixture. MS (ESI, pos. ion) m/z: 346.0. IC50 (uM) 0.064.
Reaction SMILES: Br[CH:2]([CH3:4])[CH3:3].[CH3:5][C:6]1([CH3:17])[CH2:10][C:9]2[CH:11]=[CH:12][C:13]([CH:15]=[O:16])=[CH:14][C:8]=2[O:7]1.[Cl-].[NH4+].Cl>O1CCCC1>[CH3:5][C:6]1([CH3:17])[CH2:10][C:9]2[CH:11]=[CH:12][C:13]([CH:15]([CH:2]([CH3:4])[CH3:3])[OH:16])=[CH:14][C:8]=2[O:7]1
Reactant: CC1(C)Cc2ccc(C=O)cc2O1
Reactant: CC(C)Br
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)C(O)c1ccc2c(c1)OC(C)(C)C2
Yield: 67.8 %

Procedure:
18.7 g of 2-bromopropane in 30 ml of absolute tetrahydrofuran are added dropwise to 3.6 g of Mg filings in 15 ml of absolute tetrahydrofuran. The mixture is stirred under reflux for 1 hour and is then cooled to 5°-10° C. At this temperature, 23 g of 2,2-dimethyl-2,3-dihydrobenzofuran-6-aldehyde in 100 ml of absolute tetrahydrofuran are added dropwise. The reaction mixture is stirred overnight and is then cautiously decomposed with a cold saturated ammonium chloride solution and a few milliliters of 10% strength hydrochloric acid, sufficient to dissolve the precipitate. The mixture is then extracted three times by shaking with ether and the combined ether extracts are washed with sodium bisulfate solution, sodium bicarbonate solution and water, dried over sodium sulfate and concentrated under reduced pressure. 19.5 g of 2,2-dimethyl-2,3-dihydrobenzofuran-6-yl-(α-isopropyl)-carbinol are obtained in the form of a yellowish oil, which is sufficiently pure for the subsequent reactions. (Yield 68%).