Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[NH:2]N.[Br:4][C:5]1[CH:6]=[C:7]([CH3:21])[C:8]2[S:13][CH2:12][C:11](=[CH:14][N:15](C)[CH3:16])[C:10](=O)[C:9]=2[C:19]=1[CH3:20]>C(O)C>[Br:4][C:5]1[CH:6]=[C:7]([CH3:21])[C:8]2[S:13][CH2:12][C:11]3[C:10](=[N:2][N:15]([CH3:16])[CH:14]=3)[C:9]=2[C:19]=1[CH3:20]
Reactant: CNN
Reactant: Cc1cc(Br)c(C)c2c1SCC(=CN(C)C)C2=O
Solvent: CCO
Product: Cc1cc(Br)c(C)c2c1SCc1cn(C)nc1-2
Yield: 72.1 %

Procedure:
4.53 mL (0.085 mol) of methyl hydrazine (purchased from Aldrich Chemical Company) was added dropwise to a mixture of 21.54 g (0.066 mol) of the title compound of Step D in 115 mL of ethanol. The mixture was stirred at reflux under nitrogen for 5 hr and was then evaporated to dryness. The crude product was chromatographed over silica gel eluting with a mixture of (1:9) ethyl acetate:hexane to yield two components. Concentration of the major fraction yielded 14.72 g of the title compound of Step E as an oil; 1H NMR (CDCl3): δ2.3 (s,3H), 2.82 (s,3H), 3.76 (s,2H), 3.9 (s,3H), 7.2 (s, 1H), 7.3 (s,1H). Concentration of the minor fraction yielded 3.87 g of the isomer 8-bromo-1,4-dihydro-1,6,9-trimethyl[1]benzothiopyrano[4,3-c]pyrazole as an oil; 1H NMR (CDCl3): δ2.3 (s,3H), 2.46 (s,3H), 3.75 (s,3H), 3.59 and 3.81 (2d,2H), 7.4 (s,1H), 7.45 (s,1H).
Reaction SMILES: C(OC([N:8]1[C:12]2=[N:13][CH:14]=[C:15]([O:17][CH:18]3[CH2:23][CH2:22][N:21]([CH:24]4[CH2:26][CH2:25]4)[CH2:20][CH2:19]3)[CH:16]=[C:11]2[CH:10]=[C:9]1[C:27]([N:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1)=[O:28])=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH:24]1([N:21]2[CH2:22][CH2:23][CH:18]([O:17][C:15]3[CH:16]=[C:11]4[CH:10]=[C:9]([C:27]([N:29]5[CH2:34][CH2:33][O:32][CH2:31][CH2:30]5)=[O:28])[NH:8][C:12]4=[N:13][CH:14]=3)[CH2:19][CH2:20]2)[CH2:25][CH2:26]1
Reactant: CC(C)(C)OC(=O)n1c(C(=O)N2CCOCC2)cc2cc(OC3CCN(C4CC4)CC3)cnc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(c1cc2cc(OC3CCN(C4CC4)CC3)cnc2[nH]1)N1CCOCC1
Yield: 79.4 %

Procedure:
The solution of 0.16 g (0.34 mmol) 5-(1-cyclopropyl-piperidin-4-yloxy)-2-(morpholine-4-carbonyl)-pyrrolo[2,3-b]pyridine-1-carboxylic acid tert-butyl ester in 2 ml dichloromethane was cooled down to 0° C. and treated with 0.52 ml (0.8 g, 6.8 mmol) trifluoroacetic acid. The cooling bath was removed and after 1 hour at room temperature the solution was evaporated and the residue was flash-chromatographed on silica gel with dichloromethane:methanol:ammonia (9:1:0.1 v/v) as eluant to give 0.1 g (83%) of the desired compound as a colorless solid.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH:15]=[C:14]([CH:19]([CH3:23])[C:20](O)=O)[CH:13]=[CH:12]2.Cl.[NH:25]1[CH2:30][CH2:29][S:28][CH2:27][CH2:26]1.C(N1CCOCC1)C.B>C1C=CC=CC=1.C(Cl)Cl.O1CCCC1.O>[N:25]1([CH2:20][CH:19]([C:14]2[CH:13]=[CH:12][C:11]3[C:16](=[CH:17][CH:18]=[C:9]([O:8][CH3:7])[CH:10]=3)[CH:15]=2)[CH3:23])[CH2:30][CH2:29][S:28][CH2:27][CH2:26]1
Reactant: C1CSCCN1
Reactant: COc1ccc2cc(C(C)C(=O)O)ccc2c1
Agent: B
Agent: CCN1CCOCC1
Agent: Cl
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: c1ccccc1
Product: COc1ccc2cc(C(C)CN3CCSCC3)ccc2c1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Oxalyl chloride (10 ml) is added dropwise to a suspension of 2-(6-methoxynaphth-2-yl)-propionic acid (17.4 g, 75.6 mmols) in benzene (200 ml). After refluxing for 2 hours, the benzene is evaporated off under reduced pressure and the residue is taken up in alcohol-free methylene chloride (100 ml). This solution is added dropwise, in the course of 30 minutes, to a cooled suspension (0° C.) of thiamorpholine hydrochloride (11.6 g, 83.16 mmols) and N-ethylmorpholine (19.12 g, 166 mmols) in methylene chloride (100 ml). After standing overnight, the reaction medium is washed successively with water, hydrochloric acid (10% strength), water, aqueous sodium bicarbonate solution (saturated) and water and then dried (Na2SO4) and evaporated. This yields a solid which is the intermediate (IV). A solution of this amide (5.60 g, 17.78 mmols) in tetrahydrofuran (50 ml) is added dropwise to a stirred solution of borane (55 mmols) in tetrahydrofuran (50 ml), which has been cooled to 0° C. The solution is then heated at the reflux temperature for 2 hours and again cooled to 0° C. Water is then added cautiously in order to destroy the excess borane, and dilute hydrochloric acid is added.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([N:13]=[N+]=[N-])[CH2:10][C@H:9]1[CH2:16][OH:17])=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([NH2:13])[CH2:10][C@H:9]1[CH2:16][OH:17])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1C[C@@H](N=[N+]=[N-])C[C@H]1CO
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1C[C@@H](N)C[C@H]1CO
Yield: 98 %

Procedure:
Dissolve (2S,4S)-4-azido-2-hydroxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (32 g) in methanol (150 mL). Add 10% palladium on carbon (3.2 g) and hydrogenate (1 atm) at room temperature for 16 h. Filter off the catalyst through a plug of diatomaceous earth and concentrate under vacuum to obtain the title compound (28 g, crude) as a thick, yellow oil.
Reaction SMILES: [N+]([O-])(O)=O.N([O-])=O.[Na+].[CH:9]1([CH2:12][N:13]2[C:17]([CH2:18][OH:19])=[CH:16][N:15]=[C:14]2S)[CH2:11][CH2:10]1.C(=O)([O-])[O-].[K+].[K+]>O>[CH:9]1([CH2:12][N:13]2[C:17]([CH2:18][OH:19])=[CH:16][N:15]=[CH:14]2)[CH2:10][CH2:11]1
Reactant: OCc1cnc(S)n1CC1CC1
Agent: O=C([O-])[O-]
Agent: O=N[O-]
Agent: [K+]
Solvent: O=[N+]([O-])O
Solvent: O
Product: OCc1cncn1CC1CC1
Reaction time: 2 h
Yield: 64.8 %

Procedure:
To 5.0M nitric acid (44 ml) was added sodium nitrite (135 mg), and 1-cyclopropylmethyl-5-hydroxymethyl-2-mercaptoimidazole (9.0 g) was added by portions at 0° C. The mixture was allowed to be at room temperature and the mixture was stirred for 2 hours, and water (50 ml) was added to the mixture. The mixture was neutralized with potassium carbonate at 0° C., and the solvent was distilled off under reduced pressure. Ethanol was added to the mixture, and the insolubles were filtered off, and the solvent was distilled off under reduced pressure. To the obtained residue was added methanol-ethyl acetate, and basic silica gel was added to the mixture. This mixture was purified by basic silica gel column chromatography (methanol-ethyl acetate=1:8), to obtain solids, which was recrystallized from diisopropyl ether-ethyl acetate, to give 1-cyclopropylmethyl-5-hydroxymethylimidazole (4.82 g) as brown crystals.
Reaction SMILES: Br[C:2](=[C:6]([OH:8])[CH3:7])[C:3](=O)C.[C:9]([NH2:12])(=[S:11])[CH3:10]>CC(C)=O>[C:6]([C:2]1[S:11][C:9]([CH3:10])=[N:12][CH:3]=1)(=[O:8])[CH3:7]
Reactant: CC(N)=S
Reactant: CC(=O)C(Br)=C(C)O
Solvent: CC(C)=O
Product: CC(=O)c1cnc(C)s1
Reaction time: 8 h

Procedure:
To a solution of the product of Example 151B (14.5 g, 88 mmol) in acetone (220 mL) was added thioacetamide (6.6 g, 88 mmol) and stirred overnight. The solid was filtered to give the title compound as the hydrogen bromide salt. 1H NMR (300 MHz, DMSO-d6) δ ppm 2.54 (s, 3 H) 2.71 (s, 3 H) 8.46 (s, 1 H). MS (DCI) m/z 142 (M+H)+.
Reaction SMILES: [CH3:1][N:2]([CH2:8][C:9]1[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=1)[C:3](=[O:7])[C:4]([O-])=[O:5].[NH2:15][NH2:16]>CCO>[NH:15]([C:4](=[O:5])[C:3]([N:2]([CH3:1])[CH2:8][C:9]1[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=1)=[O:7])[NH2:16]
Reactant: NN
Reactant: CN(Cc1ccncc1)C(=O)C(=O)[O-]
Solvent: CCO
Product: CN(Cc1ccncc1)C(=O)C(=O)NN
Temperature: 80 °C
Reaction time: 18 h

Procedure:
A mixture of 2-(methyl(pyridin-4-ylmethyl)amino)-2-oxoacetate (77) (0.96 g, 4.61 mmol) and hydrazine (0.21 mL, 5.82 mmol) in EtOH (15 mL) was stirred at 80° C. for 18 h. The solvent was removed in vacuo to provide 2-hydrazinyl-N-methyl-2-oxo-N-(pyridin-4-ylmethyl)acetamide (78) as a pale yellow solid. This product was directly used in the next step reaction without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12][N:13]2[CH:17]=[CH:16][N:15]=[CH:14]2)=[CH:6][CH:5]=1)([O-])=O.[Cl-].[Ca+2].[Cl-]>C(O)C>[N:13]1([CH2:12][CH2:11][CH2:10][C:7]2[CH:8]=[CH:9][C:4]([NH2:1])=[CH:5][CH:6]=2)[CH:17]=[CH:16][N:15]=[CH:14]1
Reactant: O=[N+]([O-])c1ccc(CCCn2ccnc2)cc1
Agent: [Ca+2]
Agent: [Cl-]
Solvent: CCO
Product: Nc1ccc(CCCn2ccnc2)cc1
Temperature: 25 °C
Yield: 73.7 %

Procedure:
1-[3-(4-nitrophenyl)propyl]imidazole (1.2 g) was dissolved in 85% ethanol solution (37 ml), calcium chloride (0.30 g) and reduced iron (1.5 g) were added to the mixture, and the mixture was heated to reflux for 4 hours. After cooling to room temperature, the mixture was filtered with Celite, and washed with ethyl acetate. The solvent was removed under reduced pressure, and water was added to the obtained residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography, to give 4-[3-(imidazol-1-yl)propyl]aniline (0.77 g).
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:14]=[C:13]2[S:15][C:16]([N:18]=[C:19](SC)SC)=[N:17][C:12]2=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.Cl.[NH2:26][CH2:27][C@@:28]1([OH:36])[CH:33]2[CH2:34][CH2:35][N:30]([CH2:31][CH2:32]2)[CH2:29]1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[CH2:1]([O:8][C:9]1[N:14]=[C:13]2[S:15][C:16]([NH:18][C:19]3[O:36][C@:28]4([CH2:27][N:26]=3)[CH:33]3[CH2:34][CH2:35][N:30]([CH2:31][CH2:32]3)[CH2:29]4)=[N:17][C:12]2=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CSC(=Nc1nc2ccc(OCc3ccccc3)nc2s1)SC
Reactant: NC[C@]1(O)CN2CCC1CC2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: c1ccc(COc2ccc3nc(NC4=NC[C@@]5(CN6CCC5CC6)O4)sc3n2)cc1
Temperature: 100 °C
Yield: 67 %

Procedure:
A mixture of dimethyl 5-(benzyloxy)thiazolo[5,4-b]pyridin-2-ylcarbonimidodithioate (500 mg, 1.38 mmol), (S)-3-(aminomethyl)quinuclidin-3-ol dihydrochloride (317 mg, 1.38 mmol) and cesium carbonate (1.0 g, 3.07 mmol) in DMF (7 mL) was heated to 100° C. for 2 hours. The reaction mixture was cooled to ambient temperature, poured into water and extracted with chloroform (4×). The combined organics were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The mixture was purified by silica gel chromatography (2-20% [9:1 methanol:ammonium hydroxide]-chloroform) to afford (R)—N-(5-(benzyloxy)thiazolo[5,4-b]pyridin-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine (390 mg, 67% yield). 1H NMR (500 MHz, CDCl3) δ ppm 9.18 (br. s., 1H) 7.76 (d, J=8.85 Hz, 1H) 7.50 (d, J=7.32 Hz, 2H) 7.41 (t, J=7.32 Hz, 2H) 7.32-7.37 (m, 1H) 5.42 (s, 2H) 4.02 (d, J=9.46 Hz, 1H) 3.68 (d, J=9.46 Hz, 1H) 3.37-3.44 (m, 1H) 2.75-3.06 (m, 5H) 2.13-2.25 (m, 2H) 1.73-1.82 (m, 1H) 1.49-1.70 (m, 3H). MS (LC/MS) R.T.=1.69; [M+H]+=421.98.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH:11]=O)=[CH:3][CH:2]=1.[CH2:13]([O:15][C:16](=[O:19])[NH:17][NH2:18])[CH3:14]>C(O)C>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH:11]=[N:18][NH:17][C:16]([O:15][CH2:13][CH3:14])=[O:19])=[CH:3][CH:2]=1
Reactant: CCOC(=O)NN
Reactant: O=Cc1ccnc2ccccc12
Solvent: CCO
Product: CCOC(=O)NN=Cc1ccnc2ccccc12
Yield: 52.3 %

Procedure:
A mixture of 4.72 gm (0.03 mole) of 4-quinolinecarboxaldehyde, 3.12 gm (0.03 mole) of ethylcarbazate and 100 ml of absolute ethanol is refluxed 9 hr. The solvent is evaporated. The solid is crystallized from ethyl acetate/Skellysolve B to give 3.82 gm (53%) of the title compound having a melting point of 161.2° C.
Reaction SMILES: [C:1]([CH2:3][C:4]([OH:6])=O)#[N:2].[N:7]1([CH2:13][C:14]2[CH:28]=[CH:27][C:17]3[NH:18][C:19]([C:21]4[C:25]([NH2:26])=[CH:24][NH:23][N:22]=4)=[N:20][C:16]=3[CH:15]=2)[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[C:1]([CH2:3][C:4]([NH:26][C:25]1[C:21]([C:19]2[NH:18][C:17]3[CH:27]=[CH:28][C:14]([CH2:13][N:7]4[CH2:8][CH2:9][O:10][CH2:11][CH2:12]4)=[CH:15][C:16]=3[N:20]=2)=[N:22][NH:23][CH:24]=1)=[O:6])#[N:2]
Reactant: Nc1c[nH]nc1-c1nc2cc(CN3CCOCC3)ccc2[nH]1
Reactant: N#CCC(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: N#CCC(=O)Nc1c[nH]nc1-c1nc2cc(CN3CCOCC3)ccc2[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.3 %

Procedure:
A mixture of cyano-acetic acid (23 mg, 0.28 mmol), 3-(5-morpholin-4-ylmethyl-1H-benzimidazol-2-yl)-1H-pyrazol-4-ylamine (70%, 100 mg, 0.23 mmol), TBTU (89 mg, 0.28 mmol) and DMF (2 ml) was stirred at 25° C. overnight. The mixture was then evaporated in vacuo. Flash chromatography, eluting with DCM-6% MeOH/DCM afforded 2-cyano-N-[3-(5-morpholin-4-ylmethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-acetamide as a yellow solid (65 mg, 77%). (LC/MS (acidic method/final compound): Rt 4.61, [M+H]+ 366).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([N:9]=[C:10]=[O:11])[CH:6]=[CH:7][CH:8]=1)#[N:2].[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([NH:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)(=[O:21])=[O:20])=[CH:15][CH:14]=1>C(Cl)Cl>[CH2:23]([NH:22][S:19]([C:16]1[CH:15]=[CH:14][C:13]([NH:12][C:10]([NH:9][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:1]#[N:2])[CH:4]=2)=[O:11])=[CH:18][CH:17]=1)(=[O:21])=[O:20])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: Nc1ccc(S(=O)(=O)NCc2ccccc2)cc1
Reactant: N#Cc1cccc(N=C=O)c1
Solvent: ClCCl
Product: N#Cc1cccc(NC(=O)Nc2ccc(S(=O)(=O)NCc3ccccc3)cc2)c1
Reaction time: 1 h

Procedure:
A solution of 3-cyanophenylisocyanate (6.4 g, 1 eq) in DCM (100 ml), was added to 4-amino-N-benzylbenzenesulfonamide (10.4 g, 1 eq), dissolved in DCM (100 ml), at 4° C. in small portions, stirred for 1 h. Afterwards the mixture was stirred at rt for 16 h. The solvent was removed in vacuo and the residue was recrystallized from ethanol/water (1/1). The product was filtered, washed 2 times with ethanol/water (1/1) at 4° C., and dried in vacuo to give N-benzyl-4-[3-(3-cyanophenyl)-ureido]-benzenesulfonamide. Yield 90% N-benzyl-4-[3-(3-cyanophenyl)-ureido]-benzenesulfonamide (22 g, 1 eq) was dissolved in ethanol (150 ml). Hydrochloric acid was bubbled through the solution for 2 h at 4° C. Then the solution was stirred for 1 h at rt. The solvent was removed in vacuo. The product was washed with ethanol/water (1/1) at 4° C., and dried in vacuo to give 3-[3-(4-benzylsulfamoylphenyl)-ureido]-benzimidic acid ethyl ester. Yield 75%.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][C:3]=1[N+:11]([O-])=O>C(O)C.[Pd]>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][C:3]=1[NH2:11]
Reactant: N#CCc1ccc(N)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCO
Product: N#CCc1ccc(N)c(N)c1

Procedure:
A solution of 1-amino-2-nitro-4-cyanomethylbenzene (6 g.) in ethanol (100 ml.) was hydrogenated for 1.5 hour at atmospheric pressure in presence of 3.6 g. of 10% w/w Pd/C. The catalyst was removed and the solvent was evaporated to give 1,2-diamino-4-cyanomethylbenzene which was used without further purification.
Reaction SMILES: CO[C:3]([C@@H:5]1[CH2:19][C@H:18]2[C@@H:8]([CH2:9][C:10]3[C:20]4[C:13](=[CH:14][CH:15]=[CH:16][C:17]2=4)[NH:12][C:11]=3[CH3:21])[N:7]([CH2:22][CH2:23][CH3:24])[CH2:6]1)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+].[CH3:33][S-:34].[Na+]>O1CCOCC1.O>[CH3:21][C:11]1[NH:12][C:13]2[C:20]3[C:10]=1[CH2:9][C@@H:8]1[C@@H:18]([C:17]=3[CH:16]=[CH:15][CH:14]=2)[CH2:19][C@@H:5]([CH2:3][S:34][CH3:33])[CH2:6][N:7]1[CH2:22][CH2:23][CH3:24]
Reactant: CCCN1C[C@H](C(=O)OC)C[C@@H]2c3cccc4[nH]c(C)c(c34)C[C@H]21
Reactant: C[S-]
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1COCCO1
Solvent: O
Product: CCCN1C[C@H](CSC)C[C@@H]2c3cccc4[nH]c(C)c(c34)C[C@H]21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
345 mg of 2-methyl-6-n-propyl-8beta-ergoline-carboxylic acid methyl ester (1.06 mmol) is dissolved in 10 ml of anhydrous dioxane and heated with 150 mg of lithium aluminum hydride for 90 minutes to 80° C. After the cooling, 0.15 ml of water, 0.15 ml of 15% sodium hydroxide solution and 0.45 ml of water are added in succession, the precipitate is filtered off and the filtrate is concentrated by evaporation, quantitative yield. The crude alcohol is dissolved in 5 ml of pyridine and stirred with 0.25 ml of methanesulfonyl chloride for one hour at room temperature. Ice is added, it is stirred for another 30 minutes, and it is made alkaline with ammonia. The mixture is extracted with dichloromethane, the organic phase is dried and concentrated by evaporation. The residue of 388 mg is dissolved in 5 ml of N,N-dimethylacetamide and 720 mg of sodium methyl mercaptide (10 mmol) is stirred for an hour at room temperature. Ice is added to the mixture and it is extracted with dichloromethane. The organic phases are dried and concentrated by evaporation. 175 mg is crystallized from methanol, yield 50% [α]D =-80° (0.5% in chloroform).
Reaction SMILES: [OH:1][CH:2]([C:13]1[S:14][CH:15]=[CH:16][CH:17]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9]([NH2:12])(=[O:11])=[O:10].C1([O:24][C:25](=O)[NH:26][C:27]2[N:32]=[C:31]([O:33][CH3:34])[CH:30]=[C:29]([O:35][CH3:36])[N:28]=2)C=CC=CC=1.C1CCN2C(=NCCC2)CC1.CCCCCl>O1CCOCC1.Cl.C(Cl)Cl>[CH3:34][O:33][C:31]1[CH:30]=[C:29]([O:35][CH3:36])[N:28]=[C:27]([NH:26][C:25]([NH:12][S:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[CH:2]([OH:1])[C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)(=[O:10])=[O:11])=[O:24])[N:32]=1
Reactant: NS(=O)(=O)c1ccccc1C(O)c1cccs1
Reactant: COc1cc(OC)nc(NC(=O)Oc2ccccc2)n1
Agent: Cl
Solvent: CCCCCl
Solvent: C1COCCO1
Solvent: C1CCC2=NCCCN2CC1
Product: COc1cc(OC)nc(NC(=O)NS(=O)(=O)c2ccccc2C(O)c2cccs2)n1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 35.9 %

Procedure:
To 0.5 g of the product of Example 6, dissolved in 30 mL of p-dioxane, was added 0.51 g of phenyl(4,6-dimethoxypyrimidin-2-yl)carbamate followed by 0.27 mL of "DBU". The reaction was stirred for 1.5 hours, diluted with 45 mL of ice-water and acidified with 10 drops of concentrated hydrochloric acid to obtain an oily precipitate. The water was decanted from the oil and the oily residue was dissolved in methylene chloride, washed with water and brine, and finally dried (MgSO4). Filtration and concentration of the filtrate, in vacuo, yielded an oil. Trituration with a 10:1 mixture of n-chlorbutane and methylene chloride provided 0.3 g of the subject compound as an off-white solid, m.p. 152°-54°.
Reaction SMILES: [F:1][C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[CH:4][CH:3]=1.Cl.[CH3:11][NH:12][O:13][CH3:14].O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(C(C)C)CC)(C)C>O1CCCC1.O>[F:1][C:2]1[S:6][C:5]([C:7]([N:12]([O:13][CH3:14])[CH3:11])=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(F)s1
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: O
Product: CON(C)C(=O)c1ccc(F)s1
Temperature: 25 °C
Yield: 87.1 %

Procedure:
To a stirred solution of 5-fluorothiophene-2-carboxylic acid (33.95 g, 232.3 mmol) in tetrahydrofuran (465 mL) at 0° C. under nitrogen is added N,O-dimethylhydroxylamine hydrochloride (45.32 g, 464.6 mmol), 1-hydroxybenzotriazole monohydrate (53.36 g, 348.5 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (89.1 g, 464.6 mmol), and diisopropylethylamine (162 mL, 929 mmol). The mixture is allowed to warm to room temperature over 18 hours. The mixture is diluted with water (500 mL) and extracted with ethyl acetate (500 mL). The aqueous phase is re-extracted twice with ethyl acetate (300 mL). The combined organic extracts are dried over sodium sulfate, filtered, and concentrated under reduced pressure. The liquid residue is purified by silica gel chromatography eluting with hexanes/ethyl acetate (3:1) to give the title compound (38.28 g, 87%) as a pale yellow liquid. ES/MS (m/e): 190 (M+H).
Reaction SMILES: COC(=O)C=CCCCC.[CH3:11][O:12][C:13](=[O:38])[CH2:14][CH2:15][CH2:16]/[CH:17]=[CH:18]\[CH2:19][C@H:20]1[C@H:24]([Cl:25])[CH2:23][C@@H:22]([OH:26])[C@@H:21]1/[CH:27]=[CH:28]/[C:29](=[O:37])[C:30]([CH3:36])([CH3:35])[CH2:31][CH2:32][CH2:33][CH3:34].[Cl-].[Ce+3].[Cl-].[Cl-].[BH4-].[Na+].C(O)(=O)C>CO>[CH3:11][O:12][C:13](=[O:38])[CH2:14][CH2:15][CH2:16]/[CH:17]=[CH:18]\[CH2:19][C@H:20]1[C@H:24]([Cl:25])[CH2:23][C@@H:22]([OH:26])[C@@H:21]1/[CH:27]=[CH:28]/[C@@H:29]([OH:37])[C:30]([CH3:36])([CH3:35])[CH2:31][CH2:32][CH2:33][CH3:34]
Reactant: CCCCC(C)(C)C(=O)/C=C/[C@@H]1[C@@H](C/C=C\CCCC(=O)OC)[C@H](Cl)C[C@H]1O
Agent: CCCCC=CC(=O)OC
Agent: [BH4-]
Agent: [Ce+3]
Solvent: CO
Solvent: CC(=O)O
Product: CCCCC(C)(C)[C@H](O)/C=C/[C@@H]1[C@@H](C/C=C\CCCC(=O)OC)[C@H](Cl)C[C@H]1O
Reaction time: 1 h

Procedure:
A solution of 600 mg of IX in 25 ml of methanol is mixed with 60 mg of cerium(III) chloride with stirring and then 500 mg of sodium borohydride is added at -40° C. After 1 hour, thin-film chromatography checking shows a complete reduction. It is installed with 1 ml of glacial acetic acid, concentrated by evaporation in a vacuum, diluted with water and extracted several times with dichloromethane. The combined organic phases are washed with sodium bicarbonate solution and salt water, dried over magnesium sulfate and concentrated by evaporation in a vacuum. The residue is chromatographed on silica gel with dichloromethane/1-10% acetane. First 280 mg of XI is eluted as nonpolar component and then 295 mg of the desired epimer X, both as colorless oils.
Reaction SMILES: CC1N=CC2C(C=1)=CC=CC=2.C(Br)C1C=CC=CC=1.FC(F)(F)C1C=CC([Mg]Br)=CC=1.[CH2:32]([N:39]1[C:48]([CH3:49])=[CH:47][C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[CH:40]1[C:50]1[CH:55]=[CH:54][C:53]([C:56]([F:59])([F:58])[F:57])=[CH:52][CH:51]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.C([N+]1C(C)=CC2C(=CC=CC=2)C=1C1C=CC(C(F)(F)F)=CC=1)C1C=CC=CC=1.[BH4-].[Na+].[OH-].[Na+]>C1COCC1.C(O)(=O)C>[CH2:32]([N:39]1[CH:48]([CH3:49])[CH2:47][C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[CH:40]1[C:50]1[CH:51]=[CH:52][C:53]([C:56]([F:58])([F:59])[F:57])=[CH:54][CH:55]=1)[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: CC1=Cc2ccccc2C(c2ccc(C(F)(F)F)cc2)N1Cc1ccccc1
Agent: BrCc1ccccc1
Agent: Cc1cc2ccccc2c(-c2ccc(C(F)(F)F)cc2)[n+]1Cc1ccccc1
Agent: Cc1cc2ccccc2cn1
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC1Cc2ccccc2C(c2ccc(C(F)(F)F)cc2)N1Cc1ccccc1
Temperature: 70 °C
Reaction time: 16 h

Procedure:
To a solution of 3-methylisoquinoline (1.0 g, 6.98 mmol) in THF (6 mL) was added benzyl bromide (0.78 mL, 6.63 mmol). After the addition was completed, the mixture was heated at 70° C. under N2 for 16 h. The mixture was cooled down to RT and THF (10 mL). Then, the mixture was cooled to 0° C. and (4-(trifluoromethyl)phenyl)magnesium bromide was added, and then stirred at RT for 16 h. After quenching with saturated ammonium chloride solution, the mixture was extracted several times with EtOAc. The combined organic extracts were dried over MgSO4 and concentrated. The residue was mixed with silica gel and the solid mixture was purified by silica gel flash column chromatography (30%-100% EtOAc/hexane, then 20% MeOH in DCM) to give a mixture of 2-benzyl-3-methyl-1-(4-(trifluoromethyl)phenyl)-1,2-dihydroisoquinoline & 2-benzyl-3-methyl-1-(4-(trifluoromethyl)phenyl)-isoquinolinium, which was used without further purification. This mixture was dissolved in THF (45 mL) and sodium borohydride (2.6 g, 68.9 mmol) was added. The resulting mixture was stirred at RT 15 min, and then glacial acetic acid (1 mL) was added. The mixture was stirred at RT for 2 h, and then at 55° C. for an additional 2 h. After cooling down to RT, it was basified with NaOH (10 N) (to pH>12). The organic layer was collected and the aqueous layer was extracted several times with EtOAc. The combined organic extracts were then dried over MgSO4 and concentrated. The residue was dissolved MeOH (5 mL) and the solution mixture was purified by preparative HPLC (0% MeCN 0.1% TFA/H2O 0.1% TFA). All fractions of the product were combined and MeCN was removed in vacuo. The aqueous phase was basified with NaHCO3 and extracted with EtOAc. The combined organic extracts were dried over MgSO4, concentrated, and dried to give the title compound as a yellow oil.