Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([CH:22](C(C)(C)C(C)C)[O:23][SiH](C)C)=[C:14]([CH:33]=[CH:34]O[Si](C(C)(C)C)(C)C)[CH:13]=3)[CH2:9]1)=O)(C)(C)C.[F-].[NH4+]>>[NH3:8].[CH3:21][C@@H:19]1[CH2:20][NH:8][CH2:9][C@@H:10]2[N:18]1[C:17]1[N:16]=[C:15]3[CH2:22][O:23][CH2:34][CH2:33][C:14]3=[CH:13][C:12]=1[CH2:11]2
Reactant: CC(C)C(C)(C)C(O[SiH](C)C)c1nc2c(cc1C=CO[Si](C)(C)C(C)(C)C)C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@@H](C)N21
Agent: [F-]
Agent: [NH4+]
Product: C[C@@H]1CNC[C@H]2Cc3cc4c(nc3N21)COCC4
Product: N
Temperature: 0 °C
Reaction time: 2 h
Yield: 15.4 %

Procedure:
A solution of 0.154 g (4R,9aR)-7-[2-(tert-Butyl-dimethyl-silanyloxy)-vinyl]-6-[dimethyl-(1,1,2-trimethyl-propyl)-silanyloxymethyl]-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylic acid tert-butyl ester in and 0.154 g ammonium fluoride in 3.00 ml was heated to reflux for 4 h. The reaction mixture was partitioned between water and ethyl acetate. The phases were separated and the organic phase was washed with brine dried over sodium sulfate and evaporated. To as solution of the residue in 3.00 ml dichloromethane was added at 0° C. 0.14 ml triethylsilane and 0.14 ml trifluoroacetic acid and the mixture was stirred at 0° C. for 2 h. To the resulting solution was added 0.7 ml trifluoroacetic acid and the mixture was allowed to thaw to room temperature over 17 h. The solvent was evaporated and the residue was partitioned between water and ethyl acetate. The phases were separated and the pH of the aqueous phase was adjusted to 12.00 by addition of 2N aqueous sodium hydroxide and the product was extracted with methylenechloride and purified by chromatography on silica gel with dichloromethane:methanol:ammonia=90:10:1 to yield 0.0047 g of the title compound as slightly yellow oil. (MS: 246.3 (M+H+))
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5]([OH:7])=O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[CH2:33]([NH:36][CH2:37][CH2:38][CH3:39])[CH2:34][CH3:35].C(N(CC)CC)C>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5]([N:36]([CH2:37][CH2:38][CH3:39])[CH2:33][CH2:34][CH3:35])=[O:7]
Reactant: CCCNCCC
Reactant: O=C(O)c1ccnc(Cl)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCN(CCC)C(=O)c1ccnc(Cl)c1
Yield: 76.5 %

Procedure:
Stir a solution of 2-chloroisonicotinic acid (1.0 g, 6.3 mmol), 1-hydroxybenzotriazole (850 mg, 6.3 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.21 g, 6.3 mmol), dipropyl amine (862 μL, 6.3 mmol), and triethylamine (1.75 mL, 12.6 mmol) in dichloromethane (63 mL) at room temperature over the weekend. Wash the solution with 0.1 N citric acid (2×50 mL), saturated aqueous sodium bicarbonate (50 mL), saturated aqueous sodium chloride (50 mL), dry (sodium sulfate), concentrate and purify (silica gel chromatography, eluting with 10:90 to 20:80 ethyl acetate:hexanes) to give the title compound (1.16 g, 76%).
Reaction SMILES: Cl.[F:2][C:3]1[S:7][C:6]([NH2:8])=[N:5][CH:4]=1.N1C=CN=C1.[S:14](Cl)(Cl)(=[O:16])=[O:15].[CH3:19][C:20]1[N:21]=[CH:22][N:23]([C:25]2[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[CH:27][C:26]=2[C:35]2[CH:44]=[CH:43][CH:42]=[C:41]3[C:36]=2[CH2:37][CH2:38][NH:39][CH2:40]3)[CH:24]=1.CCN(C(C)C)C(C)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(Cl)Cl.CCCCCCC>[F:2][C:3]1[S:7][C:6]([NH:8][S:14]([N:39]2[CH2:38][CH2:37][C:36]3[C:41](=[CH:42][CH:43]=[CH:44][C:35]=3[C:26]3[CH:27]=[CH:28][C:29]([C:31]([F:32])([F:33])[F:34])=[CH:30][C:25]=3[N:23]3[CH:24]=[C:20]([CH3:19])[N:21]=[CH:22]3)[CH2:40]2)(=[O:16])=[O:15])=[N:5][CH:4]=1
Reactant: Cc1cn(-c2cc(C(F)(F)F)ccc2-c2cccc3c2CCNC3)cn1
Reactant: O=S(=O)(Cl)Cl
Reactant: Nc1ncc(F)s1
Agent: Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: c1c[nH]cn1
Solvent: CCCCCCC
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cn(-c2cc(C(F)(F)F)ccc2-c2cccc3c2CCN(S(=O)(=O)Nc2ncc(F)s2)C3)cn1
Temperature: 80 °C
Reaction time: 0.17 h
Yield: 0.4 %

Procedure:
A solution of 5-fluorothiazol-2-amine hydrochloride (Milestone Pharmatech, Brunswick, N.J., 0.692 g, 4.48 mmol) and imidazole (1.219 g, 17.91 mmol) in 10 mL DCM was cooled to −78° C. and was treated with sulfuryl chloride (0.364 ml, 4.48 mmol). After stirring for 10 minutes, the reaction mixture was placed in a 0° C. bath and was allowed to stir for one hour at which point about 3 mL heptane was added, and the organics were decanted off. The resulting solid was treated with a solution of 5-(2-(4-methyl-1H-imidazol-1-yl)-4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline (0.800 g, 2.239 mmol) in 15 mL DCM followed by DIPEA (4.69 ml, 26.9 mmol) and was heated to 80° C. for 30 minutes. The reaction mixture was poured into 1N citric acid solution and was extracted with EtOAc. The organics were concentrated then purified directly by reverse phase column chromatography [RediSep Gold C18 150 g, 10 to 100% (0.1% NH4OH in MeOH)/(0.1% NH4OH in water)] yielding N-(5-fluorothiazol-2-yl)-5-(2-(4-methyl-1H-imidazol-1-yl)-4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide (0.005 g, 9.30 μmol). [M+H]+=538.0 1H NMR (400 MHz, Acetone-d6) δ ppm: 7.93 (s, 1H), 7.88 (d, J=8.0 Hz, 1H), 7.67 (d, J=8.0 Hz, 1H), 7.28 (s, 1H), 7.23 (s, 1H), 7.09-7.20 (m, 2H), 7.02 (d, J=7.0 Hz, 1H), 6.99 (d, J=0.7 Hz, 1H), 4.25-4.43 (m, 2H), 3.78-3.83 (m, 1H), 3.18-3.28 (m, 1H), 2.45-2.55 (m, 1H), 2.33-2.42 (m, 1H), 2.14 (s, 3H)
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]([OH:8])[CH2:5][O:6][CH3:7].I[CH2:10][C:11]([O-:13])=[O:12].[Na+].[H-].[Na+].O>O1CCCC1>[CH3:1][O:2][CH2:3][CH:4]([O:8][CH2:10][C:11]([OH:13])=[O:12])[CH2:5][O:6][CH3:7]
Reactant: O=C([O-])CI
Reactant: COCC(O)COC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COCC(COC)OCC(=O)O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 38.6 %

Procedure:
A solution of 1,3-dimethoxy-2-propanol (361.5 mg, Tyger) in tetrahydrofuran (4 ml) was added with sodium iodoacetate (624.6 mg, Spectrum), and successively added with sodium hydride (198 mg, Wako Pure Chemical Industries) as several portions at 0° C., and the mixture was stirred at the same temperature for 30 minutes, and then further stirred at room temperature for 15.5 hours. The reaction mixture was cooled again to 0° C., and then carefully added with water and then with chloroform, and the organic layer was separated. The aqueous layer was acidified (pH 4) with 1 N hydrochloric acid, and extracted three times with chloroform, and the combined organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. Then, the solvent was evaporated under reduced pressure to obtain the title compound (206.5 mg).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]([C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)=[CH:11][CH:10]=1)([OH:8])[C:4]([F:7])([F:6])[F:5].[Br:23]Br.CCN(C(C)C)C(C)C.[S:34]1[CH:38]=[CH:37][CH:36]=[C:35]1[S:39](Cl)(=[O:41])=[O:40]>C(O)(=O)C>[Br:23][C:13]1[CH:14]=[C:9]([C:3]([OH:8])([C:4]([F:7])([F:6])[F:5])[C:2]([F:1])([F:21])[F:22])[CH:10]=[CH:11][C:12]=1[N:15]1[CH2:20][CH2:19][N:18]([S:39]([C:35]2[S:34][CH:38]=[CH:37][CH:36]=2)(=[O:41])=[O:40])[CH2:17][CH2:16]1
Reactant: BrBr
Reactant: OC(c1ccc(N2CCNCC2)cc1)(C(F)(F)F)C(F)(F)F
Reactant: O=S(=O)(Cl)c1cccs1
Solvent: CC(=O)O
Solvent: CCN(C(C)C)C(C)C
Product: O=S(=O)(c1cccs1)N1CCN(c2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2Br)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
1,1,1,3,3,3-hexafluoro-2-(4-(1-piperazinyl)phenyl)-2-propanol (1.9 g, 5.8 mmol, published PCT patent application no. WO 2006/094842) was dissolved in acetic acid (10 mL). Bromine (1.9 g, 12 mmol) was added drop wise. The reaction was allowed to stir at room temperature until a solid precipitated. The solid was filtered, dissolved in EtOAc (100 mL) and washed with 1 N NaOH (3×50 mL). The organic layer was separated and washed with water (100 mL), brine (50 mL), dried (Na2SO4), filtered, and concentrated. The residue was dissolved in CH2Cl2 (20 mL). To this was added Hünig's base (1.0 mL) and 2-thiophenesulfonyl chloride (1.1 g, 5.8 mmol, Sigma-Aldrich, St. Louis, Mo.) at room temperature. After 3 h, the mixture was purified via column chromatography (40 g of silica, 10% EtOAc in hexanes) to afford 2-(3-bromo-4-(4-(thiophenylsulfonyl)piperazinyl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol (1.5 g).
Reaction SMILES: [CH:1]1([N:7]=[C:8]=[N:9][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(CC(O)=O)(=[O:18])N.C(C1CN1)#N>O1CCCC1>[C:8]([NH:7][CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1)([NH:9][CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)=[O:18]
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: NC(=O)CC(=O)O
Agent: N#CC1CN1
Solvent: C1CCOC1
Product: O=C(NC1CCCCC1)NC1CCCCC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
2.15 g. Dicyclohexylcarbodiimide are introduced portionwise at 0° to 5° C. into a suspension of 1.03 g. carbamoylacetic acid and 0.68 g. 2-cyanoaziridine in 18 ml. tetrahydrofuran. The reaction mixture is stirred for 1 hour at 0° C. and then for 2 hours at ambient temperature. It is then filtered with suction and the solid material is washed with tetrahydrofuran and diethyl ether into the filtrate, 2.2 g. dicyclohexylurea (m.p. 226°-228° C.) being obtained. The filtrate is evaporated in a vacuum and the evaporation residue is triturated with ether to give 1.3 g. 1-carbamoylacetyl-2-cyanoaziridine; m.p. 115°-119° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH2:23][CH:24]4[O:29][CH2:28][CH2:27][NH:26][CH2:25]4)=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH2:30]=O>C(O)=O.O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH2:23][CH:24]4[O:29][CH2:28][CH2:27][N:26]([CH3:30])[CH2:25]4)=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COc1cc2c(Nc3ccc(Cl)c(Cl)c3)ncnc2cc1OCC1CNCCO1
Reactant: C=O
Solvent: O=CO
Solvent: O
Product: COc1cc2c(Nc3ccc(Cl)c(Cl)c3)ncnc2cc1OCC1CN(C)CCO1
Temperature: 95 °C
Yield: 91 %

Procedure:
To a solution of N-(3,4-dichlorophenyl)-6-(methyloxy)-7-[(morpholin-2-ylmethyl)oxy]quinazolin-4-amine (3.32 g, 7.7 mmol) in formic acid (33.2 mL) was added a 37 wt % solution of formaldehyde in water (3.32 mL), and the reaction mixture was heated at 95° C. for 2.5 h. After cooling to room temperature, the reaction mixture was concentrated. The residue was dissolved in methanol and treated with Bio-Rad AG®1-X8 hydroxide form resin until pH 8. Filtration and concentration in vacuo afforded 3.11 g (91%) of the title compound as a yellow-brown solid. 1H NMR (400 MHz, d4-MeOH): 8.46 (s, 1H), 8.14 (d, 1H), 7.73 (dd, 1H), 7.68 (s, 1H), 7.48 (d, 1H), 7.13 (s, 1H), 4.21-4.09 (m, 2H), 4.02 (s, 3H), 4.01-3.91 (m, 3H), 2.96 (m, 1H), 2.75 (m, 1H), 2.35 (s, 3H), 2.22 (m, 1H), 2.11 (t, 1H); MS (EI) for C21H22N4O3Cl2: 449 (MH+).
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.O.C(O)(=O)C.[Si]([O:41][CH2:42][CH2:43][CH:44]([C:53]1[C:57]([CH:58]2[CH2:60][CH2:59]2)=[C:56]([CH:61]2[CH2:64][CH:63]([CH2:65][CH:66]([CH2:69][CH3:70])[CH2:67][CH3:68])[CH2:62]2)[O:55][N:54]=1)[CH2:45][C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1>O1CCCC1>[CH:58]1([C:57]2[C:53]([CH:44]([CH2:43][CH2:42][OH:41])[CH2:45][C:46]([O:48][C:49]([CH3:51])([CH3:50])[CH3:52])=[O:47])=[N:54][O:55][C:56]=2[CH:61]2[CH2:62][CH:63]([CH2:65][CH:66]([CH2:69][CH3:70])[CH2:67][CH3:68])[CH2:64]2)[CH2:59][CH2:60]1
Reactant: CCC(CC)CC1CC(c2onc(C(CCO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)CC(=O)OC(C)(C)C)c2C2CC2)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: O
Product: CCC(CC)CC1CC(c2onc(C(CCO)CC(=O)OC(C)(C)C)c2C2CC2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.7 %

Procedure:
To tetrabutylammonium fluoride (1 M in tetrahydrofuran) (6.26 mL) were added water (0.0725 mL), acetic acid (0.29 mL) and a solution of tert-butyl 5-(tert-butyldiphenylsilanyloxy)-3-{4-cyclopropyl-5-[3-(2-ethylbutyl)cyclobutyl]isoxazol-3-yl}valerate (2.76 g) in tetrahydrofuran (20 mL) at ice temperature. The mixture was stirred at RT overnight. The reaction mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography (Eluent: ethyl acetate/hexane=1/6→1/4→1/2) to give the title compound (1.72 g).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:11]=[C:10]([NH2:12])[O:9][N:8]=2)[CH2:3][CH2:2]1.C(C1C=C(N[C:22](=[O:30])[O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)ON=1)(C)C>>[O:1]1[CH2:2][CH2:3][CH:4]([C:7]2[CH:11]=[C:10]([NH:12][C:22](=[O:30])[O:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[O:9][N:8]=2)[CH2:5][CH2:6]1
Reactant: CC(C)c1cc(NC(=O)Oc2ccccc2)on1
Reactant: Nc1cc(C2CCOCC2)no1
Product: O=C(Nc1cc(C2CCOCC2)no1)Oc1ccccc1
Yield: 56 %

Procedure:
Prepared from 3-(tetrahydro-2H-pyran-4-yl)isoxazol-5-amine (170 mg, 1.01 mmol) according to the method described for phenyl 3-isopropylisoxazol-5-ylcarbamate in Example 122A Step 3, to afford phenyl 3-(tetrahydro-2H-pyran-4-yl)isoxazol-5-ylcarbamate as a colorless solid (164 mg, 56%). 1H NMR (300 MHz, CDCl3) δ 7.93 (brs, 1H), 7.39-7.45 (m, 2H), 7.18-7.32 (m, 3H), 6.09 (s, 1H), 4.02-4.08 (m, 2H), 3.48-3.57 (m, 2H), 2.96 (m, 1H), 1.78-1.89 (m, 4H); LC-MS (ESI) m/z 289 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[NH:9][CH:8]=[CH:7][C:6]2=[O:15].[H-].[Na+].[CH3:18][O:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24]Br)=[CH:22][CH:21]=1.O>CN(C)C=O.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]([CH2:24][C:23]1[CH:26]=[CH:27][C:20]([O:19][CH3:18])=[CH:21][CH:22]=1)[CH:8]=[CH:7][C:6]2=[O:15]
Reactant: COc1ccc(CBr)cc1
Reactant: COc1cc2[nH]ccc(=O)c2cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(Cn2ccc(=O)c3cc(OC)c(OC)cc32)cc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
6,7-Dimethoxy-4(1H)-quinolone (0.5 g) was dissolved in dimethylformamide (10 ml). 60% Sodium hydride (130 mg) and 4-methoxybenzyl bromide (0.42 ml) were added to the solution, and the mixture was stirred at room temperature for 15 hours. Water was added to the mixture, and extraction was conducted with ethyl acetate. The extract was washed with water and dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (Wako Gel C-200, 30 g). Elution with a mixed solvent of chloroform (90 parts) and methanol (10 parts) gave 6,7-dimethoxy-1-(4-methoxybenzyl)-4(1H)-quinolone (compound 17, 0.39 g).
Reaction SMILES: C(OC([N:8]1[CH2:38][CH2:37][C:11]2([O:15][C:14](=[O:16])[N:13]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH:26]([CH3:28])[CH3:27])=[CH:20][CH:19]=3)[CH:12]2[CH2:29][C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(=O)([O-])[O-].[K+].[K+].[CH2:45](Br)[CH3:46].[ClH:48]>CN(C=O)C.C(OCC)C>[ClH:48].[F:36][C:33]1[CH:32]=[CH:31][C:30]([CH2:29][CH:12]2[C:11]3([CH2:37][CH2:38][N:8]([CH2:45][CH3:46])[CH2:9][CH2:10]3)[O:15][C:14](=[O:16])[N:13]2[CH2:17][C:18]2[CH:19]=[CH:20][C:21]([O:24][CH2:25][CH:26]([CH3:28])[CH3:27])=[CH:22][CH:23]=2)=[CH:35][CH:34]=1
Reactant: CC(C)COc1ccc(CN2C(=O)OC3(CCN(C(=O)OC(C)(C)C)CC3)C2Cc2ccc(F)cc2)cc1
Reactant: CCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCN1CCC2(CC1)OC(=O)N(Cc1ccc(OCC(C)C)cc1)C2Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
69NLS77 (190 mg, 0.45 mmol) was N-BOC deprotected as described in the preparation of 69NLS79-II and dissolved in DMF (3 mL). Potassium carbonate (250 mg, 1.80 mmol) was added, followed by ethylbromide (50 μL, 0.45 mmol)) and the mixture stirred overnight at rt. Workup was carried out as for 69NLS79-II. The residue was purified by silica gel column chromatography, eluting with a stepwise gradient of 0-6% methanol in dichloromethane, followed by repurification of the compound by acidic ion-exchange SPE cartridge, to give 38-PH20 (77 mg, 38%) as a colourless oil. The compound was converted to its hydrochloride form by treatment with 2M HCl in diethylether as described above, giving the salt as a colorless powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:9]([C@@H:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[N:14]2[CH2:23][CH3:24])[CH2:10][CH:11]=O)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:25][S:26]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[CH:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1)=[O:27]>>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:9]([C@@H:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[N:14]2[CH2:23][CH3:24])[CH2:10][CH2:11][N:37]2[CH2:38][CH2:39][CH:34]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=3[S:26]([CH3:25])=[O:27])[CH2:35][CH2:36]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CS(=O)c1ccccc1C1CCNCC1
Reactant: CCN1C(=O)c2ccccc2[C@H]1[C@@H](CC=O)c1ccc(Cl)c(Cl)c1
Product: CCN1C(=O)c2ccccc2[C@H]1[C@@H](CCN1CCC(c2ccccc2S(C)=O)CC1)c1ccc(Cl)c(Cl)c1
Product: Cl
Yield: 74.7 %

Procedure:
(3S)-3-(3,4-Dichlorophenyl)-3-[(1R)-2-ethyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl]propionaldehyde (0.4 g) was coupled to 4-(2-methylsulfinylphenyl)piperidine (0.36 g) using a method similar to that described in Example 1, to afford the title compound (0.25 g); mp 120°-125° C.
Reaction SMILES: C(O[C:4]([C:6]1[S:10][C:9]2[CH:11]=[CH:12][CH:13]=[C:14]([N:15]3[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][C:23]4[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=4)[CH2:17][CH2:16]3)[C:8]=2[CH:7]=1)=O)C.[Cl-:30].[NH4+:31].C[Al](C)C>C1(C)C=CC=CC=1>[ClH:30].[CH3:29][C:26]1[CH:25]=[CH:24][C:23]([CH2:22][CH2:21][N:18]2[CH2:17][CH2:16][N:15]([C:14]3[C:8]4[CH:7]=[C:6]([C:4]#[N:31])[S:10][C:9]=4[CH:11]=[CH:12][CH:13]=3)[CH2:20][CH2:19]2)=[CH:28][CH:27]=1
Reactant: [NH4+]
Reactant: [Cl-]
Reactant: CCOC(=O)c1cc2c(N3CCN(CCc4ccc(C)cc4)CC3)cccc2s1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: Cc1ccc(CCN2CCN(c3cccc4sc(C#N)cc34)CC2)cc1
Product: Cl
Yield: 22.1 %

Procedure:
In an analogous manner to example 3, the title compound (0.28 g) as a white solid, mp 260.5°-264.0° C., is prepared from ethyl-4-[4-[2-(4-methylphenyl)ethyl]-1-piperazinyl]-benzo[b]thiophene-2-carboxylate (1.30 g, 3.18 mmol, prepared in example 26), dry ammonium chloride ( 0.51 g, 9.6 mmol) and trimethyl aluminum (4.8 mL of a 2M solution in toluene, 9.6 mmol). The free base of the title compound is isolated by flash chromatography (ethyl acetate:hexane, 40:60 , TLC Rf =0.4); 1H NMR (DMSO-d6) δ11.48 (1H, bs), 8.51 (1H, s), 7.82 (1H, d, J=8.2 Hz), 7.56 (1H, t, J=7.9 Hz), 7.19 (4H, m), 7.10 (1H, d, J=7.6 Hz), 3.65 (4H, m), 3.45 (6 H, m), 3.11 (2H, m), 2.29 (3H, s),; 13C NMR (DMSO-d6) δ148.03, 142.47, 135.82, 134.78, 133.93, 131.41, 129.17, 128.52, 117.51, 114.72, 113.96, 107.09, 56.20, 51.03, 48.47, 28.83, 20.59; IR (KBr) 2539, 2448, 1564, 1458, 959 cm-1 ; CI/MS (CH4) 362(100%).
Reaction SMILES: C(O[C:4](=[O:9])[CH2:5][C:6](=O)[CH3:7])C.[C:10]1([CH3:23])[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[NH:16][C:17]([NH:19][C:20]([NH2:22])=[NH:21])=[NH:18]>C(O)C>[CH3:7][C:6]1[N:21]=[C:20]([NH:19][C:17]([NH:16][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH3:23])=[NH:18])[NH:22][C:4](=[O:9])[CH:5]=1
Reactant: CCOC(=O)CC(C)=O
Reactant: Cc1ccccc1NC(=N)NC(=N)N
Solvent: CCO
Product: Cc1cc(=O)[nH]c(NC(=N)Nc2ccccc2C)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 68 %

Procedure:
In a 50 milliliter round-bottom flask, 3-oxobutyric acid ethyl ester (2.6 grams, 0.020 mol; obtained from Aldrich Chemical Co., Milwaukee, Wis.) was added at room temperature to a solution of 1-(o-tolyl)biguanide (3.8 grams, 0.020 mol; obtained from Aldrich Chemical Co.) in anhydrous ethanol (20 milliliters). The mixture was heated at reflux and stirred for 4 hours. After a few minutes, all the components dissolved. Cooling the resulting yellow solution mixture to room temperature gave a colorless precipitate. The precipitate was isolated by filtration and thoroughly washed with cold ethanol (0° C.). The solid was then recrystallized from anhydrous ethanol, recovered by filtration, and dried under reduced pressure to give the targeted N-(4-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)-N′-o-tolylguanidine as a colorless solid (3.50 grams, 68 percent yield): mp=260° C.; Exact mass calculated for C13H15N5O=257.1277. Measured Low Resolution Mass Spectrum (MAB/LR/N2)=257.1.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[C:7]([O:11][C:12](=[O:30])[NH:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][N:21]2[CH2:26][CH2:25][NH:24][C:23](=O)[C:22]2([CH3:29])[CH3:28])=[CH:16][N:15]=1)([CH3:10])([CH3:9])[CH3:8]>C1COCC1>[C:7]([O:11][C:12](=[O:30])[NH:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][N:21]2[CH2:26][CH2:25][NH:24][CH2:23][C:22]2([CH3:29])[CH3:28])=[CH:16][N:15]=1)([CH3:10])([CH3:8])[CH3:9]
Reactant: CC(C)(C)OC(=O)Nc1ccc(CN2CCNC(=O)C2(C)C)cn1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1ccc(CN2CCNCC2(C)C)cn1
Temperature: 50 °C
Reaction time: 3 h
Yield: 58 %

Procedure:
LiAlH4 (1M in THF, 78 mL, 78 mmol, 2 equiv) was added to a solution of [5-(2,2-dimethyl-3-oxo-piperazin-1-ylmethyl)-pyridin-2-yl]-carbamic acid tert-butyl ester (Step 109.4) (13 g, 39 mmol) in THF (150 mL) at 50° C., under an argon atmosphere. The resulting mixture was stirred for 3 h at 50° C., cooled to 0° C., quenched by addition of acetone, filtered through a pad of celite and the filtrate was concentrated. The residue was purified by silica gel column chromatography (DCM/MeOH/NH3aq, 97.5:1.5:1) to afford 7.25 g of the title compound as a white solid. Title compound: ESI-MS: 321.3 [M+H]+; tR=1.91 min (System 1); TLC: Rf=0.11 (DCM/MeOH, 9:1).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:20])[N:5]([CH:12]1[CH2:17][CH2:16][C:15](=[O:18])[NH:14][C:13]1=[O:19])[C:6]2=[O:11].[O:21]1[CH:25]=[CH:24][CH:23]=[C:22]1[CH:26]=O.[BH4-].[Na+]>C(O)(=O)C>[O:19]=[C:13]1[CH:12]([N:5]2[C:4](=[O:20])[C:3]3[C:7](=[CH:8][CH:9]=[CH:10][C:2]=3[NH:1][CH2:26][C:22]3[O:21][CH:25]=[CH:24][CH:23]=3)[C:6]2=[O:11])[CH2:17][CH2:16][C:15](=[O:18])[NH:14]1
Reactant: Nc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: O=Cc1ccco1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C1CCC(N2C(=O)c3cccc(NCc4ccco4)c3C2=O)C(=O)N1
Temperature: 25 °C
Reaction time: 24 h
Yield: 35.4 %

Procedure:
To a suspension of 4-amino-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione (0.55 g, 2 mmol) in acetic acid (20 ml) was added furan-2-carbaldehyde (0.20 g, 2.05 mmol). The mixture was heated to reflux for 5 hours and allowed to cool at room temperature. Sodium borohydride (80 mg, 2 mmol) was added to the reaction mixture. The reaction mixture was stirred for 24 hours. The solvent was evaporated in vacuo and the residue was dissolved in ethyl acetate (100 ml), washed with H2O (3×100 ml), saturated aqueous NaHCO3 (2×100 ml), brine (1×100 ml), and dried. The solvent was evaporated and the residue was purified by chromatography (ethyl acetate/hexane, 1:1) to give 0.25 g (35%) of product as a yellow solid: mp 171–173° C.; 1H NMR (DMSO-d6) δ 11.10 (s, 1H), 7.58 (t, J=7.1 Hz, 2H), 7.18 (d, J=8.6 Hz, 1H), 7.08–6.97 (m, 2H), 6.39–6.36 (m, 2H), 5.06 (dd, J=5.2 and 12.4 Hz, 1H), 4.57 (d, J=6.0 Hz, 2H), 2.96–2.82 (m, 1H), 2.63–2.46 (m, 2H), 2.06–2.02 (m, 1H; 13C NMR (DMSO-d6) δ 172.76, 170.01, 168.75, 167.21, 151.97, 145.81, 142.42, 136.05, 132.09, 117.60, 111.04, 110.42, 109.73, 107.38, 48.57,30.95,22.10; Anal. Calcd. For C18H15N3O5: C, 61.19; H, 4.28; N, 11.89. Found: C, 61.02; H, 4.24; N, 11.81.