Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]([C:8]([O:10][CH3:11])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1.[CH2:12]([Sn](CCCC)(CCCC)CCCC)[CH:13]=[CH2:14]>CN(C=O)C>[CH2:14]([C:2]1[C:3]([C:8]([O:10][CH3:11])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1)[CH:13]=[CH2:12]
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Reactant: COC(=O)c1ncccc1Br
Solvent: CN(C)C=O
Product: C=CCc1cccnc1C(=O)OC
Temperature: 90 °C
Reaction time: 17 h
Yield: 111.7 %

Procedure:
A mixture of methyl 3-bromo-pyridine-2-carboxylate (11.06 g; 51.2 mmol) Pd[PPh3 ]2Cl2 (1.09 g; 1.55 mmol), and allyl-tributyltin (20.34 g; 61.44 mmol) in DMF under nitrogen was heated at 90° C. for 9.5 hours and then stirred at room temperature overnight (17 hours) . The mixture was poured into ice/water (450 ml) and extracted with ether (4x) . The organic layer was washed with brine, dried over sodium sulfate, and concentrated in vacuo. The resulting residue (yellow oil) was purified by flash chromatography (20%-40% ethyl acetate in hexane) to afford 10.13 g of methyl 3-allyl-pyridine-2-carboxylate as an oil, which was converted into the corresponding HCl salt, m.p. 116°-119° C.
Reaction SMILES: C1(=O)[N:5]([CH2:6][CH2:7][CH2:8][C:9]2[CH:10]=[C:11]([CH:23]=[CH:24][CH:25]=2)[O:12][C:13]([CH3:22])([CH3:21])[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])C(=O)C2=CC=CC=C12.O.NN>C(O)C>[NH2:5][CH2:6][CH2:7][CH2:8][C:9]1[CH:10]=[C:11]([CH:23]=[CH:24][CH:25]=1)[O:12][C:13]([CH3:22])([CH3:21])[C:14]([O:16][C:17]([CH3:19])([CH3:20])[CH3:18])=[O:15]
Reactant: CC(C)(C)OC(=O)C(C)(C)Oc1cccc(CCCN2C(=O)c3ccccc3C2=O)c1
Agent: NN
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)C(C)(C)Oc1cccc(CCCN)c1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
tert-Butyl 2-[3-(3-phthalimidopropyl)phenoxy]-2-methylpropionate (1.87 g, 4.41 mmol) was dissolved in ethanol (10.0 mL) Subsequently, hydrazine monohydrate (184 mg, 5.74 mmol) was added dropwise, and the mixture was stirred overnight at 80° C. Thereafter, the temperature of the mixture was returned to room temperature, and the mixture was subjected to filtration. The resultant filtrate was subjected to drying over sodium sulfate, concentration under reduced pressure, and purification by silica gel chromatography (chloroform/methanol (saturated with ammonia)=20/1), whereby the target compound was obtained (560 mg, 43%).
Reaction SMILES: [CH:1]([C:3]1[C:7]([CH3:8])=[C:6]([CH3:9])[NH:5][C:4]=1[C:10]([O:12][CH3:13])=[O:11])=[O:2].Br[CH2:15][CH:16]=[CH2:17]>>[CH:1]([C:3]1[C:7]([CH3:8])=[C:6]([CH3:9])[N:5]([CH2:17][CH:16]=[CH2:15])[C:4]=1[C:10]([O:12][CH3:13])=[O:11])=[O:2]
Reactant: C=CCBr
Reactant: COC(=O)c1[nH]c(C)c(C)c1C=O
Product: C=CCn1c(C)c(C)c(C=O)c1C(=O)OC

Procedure:
The title compound was prepared as a yellow solid in 95.1% yeild in a similar procedure to that described in Referential Example 9 by using methyl 3-formyl-4,5-dimethylpyrrole-2-carboxylate and 3-bromo-1-propene.
Reaction SMILES: S(=O)(=O)(O)O.[N+:6]([O-:9])(O)=[O:7].[Cl:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[C:12]=1[CH2:18][C:19]([NH:21][C:22]([NH2:24])=[NH:23])=[O:20].[OH-].[Na+]>Cl>[Cl:10][C:11]1[C:16]([N+:6]([O-:9])=[O:7])=[CH:15][CH:14]=[C:13]([Cl:17])[C:12]=1[CH2:18][C:19]([NH:21][C:22]([NH2:24])=[NH:23])=[O:20]
Reactant: O=[N+]([O-])O
Reactant: N=C(N)NC(=O)Cc1c(Cl)cccc1Cl
Agent: Cl
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: N=C(N)NC(=O)Cc1c(Cl)ccc([N+](=O)[O-])c1Cl
Reaction time: 2.5 h

Procedure:
Concentrated sulphuric acid (25 cm3) was added dropwise to cooled concentrated nitric acid (25 cm3), followed by (2,6-dichlorophenylacetyl)-guanidine (2.5 g 8.9 mmol) and the mixture stirred at 0° to 5° C. for 2.5 h. After pouring onto ice (600 g) the mixture was neutralised with sodium hydroxide solution and the precipitated cream solid collected and recrystallised from aqueous methanol affording pale yellow plates of (2,6-dichloro-3-nitrophenylacetyl)-guanidine (2.1 g) m.p. 198°-9° C. (dec). The corresponding hydrochloride was prepared by dissolving the base in hot ethanolic hydrogen chloride. The cooled solution yielded the hydrochloride as a white solid.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][C:8]1[CH:9]=[CH:10][C:11]([S:14]([NH2:17])(=[O:16])=[O:15])=[CH:12][CH:13]=1.Br[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]>CN(C)C=O.CCOCC>[CH2:19]([N:17]([CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH3:19])[S:14]([C:11]1[CH:10]=[CH:9][C:8]([CH3:7])=[CH:13][CH:12]=1)(=[O:16])=[O:15])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]
Reactant: CCCCCCCCCCCCCCBr
Reactant: Cc1ccc(S(N)(=O)=O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCCCCCCCCCCCCCN(CCCCCCCCCCCCCC)S(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 96.3 %

Procedure:
Potassium carbonate (20.18 g; 146.00 mmol) is added to a solution of p-toluenesulfonamide (5.00 g; 29.20 mmol) and 1-bromotetradecane (21.70 ml; 73.00 mmol) in dimethylformamide (75 ml). The suspension is stirred for 20 h at reflux; the reaction medium is then cooled to room temperature, diluted with ether (100 ml) and filtered. The filtrate is washed with water (50 ml) and the aqueous phase is extracted with ether (100 ml). The combined organic phases are dried over sodium sulfate, filtered and concentrated under reduced pressure to give a white solid which is purified by chromatography on a column of silica gel (eluent: 40/60 dichloromethane/hexane) to give N,N-ditetradecyl-p-toluenesulfonamide (15.86 g; 96%) in the form of a white solid.
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][CH:3]=[CH2:4].N1C=CC=CC=1.[Si:12](Cl)([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13]>C(Cl)Cl>[Si:12]([O:5][CH2:1][CH2:2][CH:3]=[CH2:4])([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C=CCCO
Solvent: c1ccncc1
Solvent: ClCCl
Product: C=CCCO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 56.2 %

Procedure:
Under a nitrogen atmosphere, to a cold (0° C.), stirring solution of 3-buten-1-ol (2.16 g, 30.0 mmol), pyridine (9 mL), and methylene chloride (30 mL) was added tert-butyldimethylsilyl chloride (4.53 g, 30.1 mmol) purchased from Aldrich Chemical Company. The ice-bath was removed and the mixture was allowed to stir 1 h at room temperature. The mixture, containing a white precipitate, was poured into water (60 mL) and shaken. The methylene chloride layer was separated from the aqueous layer, and the aqueous layer extracted with methylene chloride (30 mL). The two resulting organic extracts were combined, washed twice with water, dried (Na2SO4), filtered, and evaporated to give 8.94 g of crude product. Vacuum distillation afforded several fractions, the fraction with bp 80°-82° C. at 35 mm Hg was collected to give 3.14 g (56.3%) of product as an oil. 1H NMR (CDCl3): δ 5.86-5.73 (m, 1H), 5.08-4.98 (m, 2H), 3.64 (t, 2H), 2.29-2.22 (m, 2H), 0.87 (s, 9H), 0.03 (s, 6H).
Reaction SMILES: Br[CH2:2][C:3]([O:5]C(C)(C)C)=[O:4].[NH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1>O1CCCC1>[O:13]1[CH2:14][CH2:15][N:10]([CH2:2][C:3]([OH:5])=[O:4])[CH2:11][CH2:12]1
Reactant: C1COCCN1
Reactant: CC(C)(C)OC(=O)CBr
Solvent: C1CCOC1
Product: O=C(O)CN1CCOCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
Dissolve t-butyl bromoacetate (1 eq) in tetrahydrofuran and add morpholine (2.2 eq) via syringe. Stir the reaction mixture at room temperature for 2 hours, filter and wash the filter cake with ethyl acetate. Combine the organic filtrates and wash with saturated sodium bicarbonate (2×), water (2×) and brine. Dry (Na2SO4), filter and evaporate the solvent in vacuo. Take up the oily residue in ethyl acetate, cool in ice and bubble hydrogen chloride gas into the solution. Stir at room temperature overnight, cool and filter to give morpholinoacetic acid (85%); mp 169°-170° C.; 1H NMR (D2O) δ3.75-4.29 (br m, 6), 3.59 (br s, 2), 3.28 (br s, 2).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])[C@@:12]3([C@H:18]([C:19]4[CH:24]=[CH:23][C:22]([C:25]5[CH:26]=[N:27][CH:28]=[N:29][CH:30]=5)=[CH:21][CH:20]=4)[CH2:17][NH:16][CH2:15]3)[N:11]([CH3:31])[C:10]2=[O:32])[CH:5]=[C:6]([Cl:8])[CH:7]=1.I[CH:34]([CH3:36])[CH3:35].C([O-])([O-])=O.[K+].[K+]>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])[C@@:12]3([C@H:18]([C:19]4[CH:20]=[CH:21][C:22]([C:25]5[CH:30]=[N:29][CH:28]=[N:27][CH:26]=5)=[CH:23][CH:24]=4)[CH2:17][N:16]([CH:34]([CH3:36])[CH3:35])[CH2:15]3)[N:11]([CH3:31])[C:10]2=[O:32])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CC(C)I
Reactant: CN1C(=O)N(c2cc(Cl)cc(Cl)c2)C(=O)[C@]12CNC[C@H]2c1ccc(-c2cncnc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)N1C[C@@H](c2ccc(-c3cncnc3)cc2)[C@]2(C1)C(=O)N(c1cc(Cl)cc(Cl)c1)C(=O)N2C
Temperature: 25 °C
Yield: 67.9 %

Procedure:
A mixture of Example 67 (49.7 mg, 0.11 mmol), 2-iodo propane (26 μl, 0.26 mmol) and K2CO3 (36 mg, 0.26 mmol) was heated at 80° C. for 25 h in acetonitrile (2 ml). After cooling to room temperature, the insoluble salts were removed and the filtrate concentrated to dryness. The residue was partitioned between DCM/water. The organic layer was concentrated in vacuo and chromatographed over silica gel (eluent: DCM/MeOH 95/5) to yield the above-titled compound as an amorphous white solid (38.1 mg). 1H NMR (CDCl3): 9.21 (1H, s), 8.92 (2H, s), 7.56 (2H, d, J=8.0 Hz), 7.33 (2H, d, J=8.0 Hz), 7.20 (1H, m), 6.61 (2H, d, J=1.5 Hz), 3.90 (1H, dd, J1=12 Hz , J2=6 Hz), 3.4-3.5 (2H, m), 3.2-3.4 (1H, m), 3.28 (3H, s), 3.09 (1H, d, J=11 Hz), 2.79 (1H, m), 1.23 (6H, m).
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:21]=3I)[C@H:14]2[CH3:31])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[F:34][C:35]1[C:40]([CH:41]([CH3:43])[CH3:42])=[CH:39][C:38](B(O)O)=[C:37]([O:47][CH3:48])[CH:36]=1.C(=O)([O-])[O-].[K+].[K+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CC(C)=O.O>[F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:21]=3[C:38]3[CH:39]=[C:40]([CH:41]([CH3:43])[CH3:42])[C:35]([F:34])=[CH:36][C:37]=3[O:47][CH3:48])[C@H:14]2[CH3:31])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: COc1cc(F)c(C(C)C)cc1B(O)O
Reactant: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1cc(C(F)(F)F)ccc1I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CC(C)=O
Product: COc1cc(F)c(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C

Procedure:
A mixture of (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-iodo-5-(trifluoromethyl)benzyl]-4-methyl-1,3-oxazolidin-2-one (50 mg; 0.084 mmol), (4-fluoro-5-isopropyl-2-methoxyphenyl)boronic acid (EXAMPLE 78, 22 mg; 0.105 mmol), palladium acetate (6 mg; 0.0103 mmol), and potassium carbonate (29 mg; 0.257 mmol) in 5:1 acetone/water (6 mL) was heated at reflux for 1 h. Acetone was removed in vacuo and the residue was diluted with H2O (10 mL) and extracted with CH2Cl2 (3×10 mL). The combined extracts were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (0-25% EtOAc/hexanes gradient) to afford (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[4′-fluoro-5′isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-one as a clear glass. This product can also be made by the method provided in Example 372.
Reaction SMILES: [Cl:1][C:2]1[C:8](I)=[CH:7][C:5]([NH2:6])=[C:4]([O:10][CH3:11])[CH:3]=1.[CH:12]1(B(O)O)[CH2:14][CH2:13]1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>C1(C)C=CC=CC=1.O.CC([O-])=O.CC([O-])=O.[Pd+2]>[Cl:1][C:2]1[C:8]([CH:12]2[CH2:14][CH2:13]2)=[CH:7][C:5]([NH2:6])=[C:4]([O:10][CH3:11])[CH:3]=1
Reactant: COc1cc(Cl)c(I)cc1N
Reactant: OB(O)C1CC1
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: COc1cc(Cl)c(C2CC2)cc1N
Temperature: 80 °C
Reaction time: 16 h
Yield: 89.1 %

Procedure:
A mixture of 4-chloro-5-iodo-2-methoxyaniline (5.0 g, 17.6 mmol), cyclopropylboronic acid (1.8 g, 21.1 mmol), Pd(OAc)2 (314 mg, 1.4 mmol), tricyclohexylphosphine (500 mg, 17.6 mmol), K3PO4.3H2O (16.4 g, 61.6 mmol) in toluene (62.5 mL) and H2O (3 mL) was stirred at 80° C. under argon for 16 h. The mixture was allowed to cool to RT, and then partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (petroleum ether/ethyl acetate=10:1) to afford the desired product (3.1 g, 88.5% yield). ESI-MS m/z: 198.2[M+H]+.
Reaction SMILES: [OH:1][N:2]=[CH:3][C:4]1[N:5]=[C:6]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)[S:7][CH:8]=1.[CH:22]1([CH2:28][O:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[CH:36]=[CH2:37])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1.C(=O)([O-])O.[K+].ClN1C(=O)CCC1=O>C(OCC)(=O)C.O>[CH:22]1([CH2:28][O:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[CH:36]2[O:1][N:2]=[C:3]([C:4]3[N:5]=[C:6]([CH:9]4[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:13][CH2:14]4)[S:7][CH:8]=3)[CH2:37]2)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]1
Reactant: C=Cc1ccccc1OCC1CCCCC1
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(C=NO)cs2)CC1
Agent: O=C([O-])O
Agent: O=C1CCC(=O)N1Cl
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(c2nc(C3=NOC(c4ccccc4OCC4CCCCC4)C3)cs2)CC1
Temperature: 60 °C
Reaction time: 6 h

Procedure:
To a solution of tert-butyl 4-{4-[(hydroxyimino)methyl]-1,3-thiazol-2-yl}piperidine-1-carboxylate (2.90 g) and 1-(cyclohexylmethoxy)-2-vinylbenzene (2.40 g) in ethyl acetate (300 ml) were added, at room temperature, potassium hydrogencarbonate (4.60 g) and N-chlorosuccinimide (1.48 g), and then one drop of water. The reaction mixture was stirred at 60° C. for 6 h, then admixed with ethyl acetate and water and extracted with ethyl acetate. The organic extracts were dried over sodium sulphate and concentrated under reduced pressure. The residue was purified by chromatography. This gave tert-butyl 4-(4-{5-[2-(cyclohexylmethoxy)phenyl]-4,5-dihydro-1,2-oxazol-3-yl}-1,3-thiazol-2-yl)piperidine-1-carboxylate (3.40 g).
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[C@@H:11]2[CH2:12][CH2:13][CH2:14][C@@H:10]2[C:9](=[O:15])[N:8]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([NH:23][C:24]([NH:26][CH2:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[O:25])=[CH:19][CH:18]=2)[C:7]2[CH:35]=[CH:36][CH:37]=[CH:38][C:6]1=2)=[O:4].[C:39]1(=[O:49])[NH:43][C:42](=[O:44])[C:41]2=[CH:45][CH:46]=[CH:47][CH:48]=[C:40]12.[K]>CN(C=O)C.C(OCC)(=O)C.O>[C:29]1([CH2:28][CH2:27][NH:26][C:24](=[O:25])[NH:23][C:20]2[CH:19]=[CH:18][C:17]([CH2:16][N:8]3[C:9](=[O:15])[C@H:10]4[CH2:14][CH2:13][CH2:12][C@H:11]4[N:5]([C:3](=[O:4])[CH2:2][N:43]4[C:42](=[O:44])[C:41]5=[CH:45][CH:46]=[CH:47][CH:48]=[C:40]5[C:39]4=[O:49])[C:6]4[CH:38]=[CH:37][CH:36]=[CH:35][C:7]3=4)=[CH:22][CH:21]=2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: O=C(NCCc1ccccc1)Nc1ccc(CN2C(=O)[C@H]3CCC[C@H]3N(C(=O)CCl)c3ccccc32)cc1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(NCCc1ccccc1)Nc1ccc(CN2C(=O)[C@H]3CCC[C@H]3N(C(=O)CN3C(=O)c4ccccc4C3=O)c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 23.4 %

Procedure:
To a solution of (3aR*,10aS*)-4-(chloroacetyl)-9-[4-[3-(2-phenylethyl)ureido]benzyl]-2,3,3a,4,9,10a-hexahydrobenzo[b]cyclopenta[e][1,4]diazepin-10(1H)-one (53 mg, 0.1 mmol) in DMF (1 mL) was added potassium phthalimide (20 mg, 0.11 mmol) and the mixture was stirred at room temperature for 24 hours. This reaction mixture was diluted with ethyl acetate and water and the aqueous layer was extracted with ethyl acetate. The pooled organic layer was washed with water and saturated aqueous NaCl solution, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was crystallized from ethanol-diethyl ether to provide 15 mg (yield 23%) of the title compound. m.p. 145°-147° C.
Reaction SMILES: Cl.[C:2]1([CH3:12])[CH:7]=[CH:6][C:5]([S:8]([O-:11])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[Na+]>O.CC(C)=O>[OH2:9].[OH2:9].[S:8]([C:5]1[CH:6]=[CH:7][C:2]([CH3:12])=[CH:3][CH:4]=1)([OH:11])(=[O:10])=[O:9]
Reactant: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: Cc1ccc(S(=O)(=O)O)cc1

Procedure:
VD 1827 hydrochloride (6.3 g, 10 mmole) was dissolved in a mixture of water (40 ml) and acetone (10 ml). A solution of sodium 4-toluenesulfonate (1.94 g, 10 mmole in water (10 ml) was added dropwise with stirring. After stirring for 1 hour at room temperature and 2 hours at 5° C., the crystalline precipitate was collected, washed with water (2×10 ml) and dried in vacuo to yield the title compound as colourless crystals with melting point 141°-148° C. dec.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([CH3:12])[N:6]=[CH:7]2.[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=1[CH2:21][N:22]=[C:23]=[O:24]>C1(C)C=CC=CC=1>[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=1[CH2:21][NH:22][C:23]([NH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([CH3:12])[N:6]=[CH:7]2)=[O:24]
Reactant: O=C=NCc1ccc(Cl)cc1Cl
Reactant: Cc1cc2c(N)cccc2cn1
Solvent: Cc1ccccc1
Product: Cc1cc2c(NC(=O)NCc3ccc(Cl)cc3Cl)cccc2cn1
Temperature: 25 °C

Procedure:
5-Amino-3-methylisoquinoline (390 mg, 2.47 mmol) and the product from Example 195A (0.36 mL, 2.47 mmol) were heated in toluene (10 mL) at 80° for 2.5 hours. Upon cooling to room temperature, a precipitate formed, which was collected by filtration, washed with toluene, and air-dried. Remaining impurities were removed by slurrying the solid in 9:1 CH2Cl2:CH3OH and then filtering the mixture to provide the title compound. The corresponding hydrochloride salt was formed by treatment of the free base with methanolic HCl. 1H NMR (300 MHz, DMSO-d6) δ 9.17 (s, 1H), 8.78 (s, 1H), 8.21 (dd, 1H, J=7.4 Hz, 1.0 Hz), 7.77 (s, 1H), 7.70 (d, 1H, J=8.1 Hz), 7.64 (m, 1H), 7.44-7.52 (m, 3H), 7.14 (t, 1H, J=6.1 Hz), 4.38 (d, 2H, J=6.0 Hz), 2.65 (s, 3H); MS (ESI+) m/z 360/362 (M+H, 35Cl/37 Cl).
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][CH3:15])[N:13]=2)[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.Br.BrCC1[CH:47]=[N:48][CH:49]=[C:50]([Cl:55])[C:51]=1[N:52]([CH3:54])[CH3:53]>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][C:15]3[CH:47]=[N:48][CH:49]=[C:50]([Cl:55])[C:51]=3[N:52]([CH3:54])[CH3:53])[N:13]=2)[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCn1nc2nc(C(C)(C)C)nc(N3CCC(F)(F)C3)c2n1
Reactant: CN(C)c1c(Cl)cncc1CBr
Agent: Br
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Product: CN(C)c1c(Cl)cncc1Cn1nc2nc(C(C)(C)C)nc(N3CCC(F)(F)C3)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-2-ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 3-(bromomethyl)-5-chloro-N,N-dimethylpyridin-4-amine hydrobromide and isolated as light yellow gum. MS (m/e): 451.4 (MH+).
Reaction SMILES: [CH3:1][C:2]1([CH3:7])[O:4][CH:3]1[CH2:5][OH:6].[NH2:8][CH:9]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[OH-].[Na+]>ClCCl.[Cl-].[Na+].O.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[CH:9]([NH:8][C:2]([CH3:7])([CH3:1])[CH:3]([OH:4])[CH2:5][OH:6])([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: NC(c1ccccc1)c1ccccc1
Reactant: CC1(C)OC1CO
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: CC(C)(NC(c1ccccc1)c1ccccc1)C(O)CO
Reaction time: 12 h
Yield: 18.2 %

Procedure:
A solution of (3,3-dimethyloxiranyl)methanol (10 g, 98 mmol) in dichloromethane (735 mL) was combined with a solution of titanium isopropoxide (50mL, 169.4mmol) in dichloromethane (100 mL) and a solution of aminodiphenyl-methane (40.6 mL, 235 mmol) in dichloromethane (100 mL), and the reaction mixture was stirred at room temperature for 48 hours. A solution of 10% sodium hydroxide in brine was added and the suspension stirred for an additional 12 hours, filtered and washed with 0.2M hydrochloric acid. The layers were separated, and the organic layer was dried over magnesium sulfate, filtered, concentrated. The residue was purified by column chromatography using 4:1 hexane/ethyl acetate as eluant to give 5.1 g of 3-(benzhydryl-amino)-3-methylbutane-1,2-diol.
Reaction SMILES: [C:1](=[C:4]1[CH2:9][CH2:8][O:7][C:5]1=[O:6])([CH3:3])[CH3:2].[H][H]>C(O)C.[Pd]>[CH:1]([CH:4]1[CH2:9][CH2:8][O:7][C:5]1=[O:6])([CH3:3])[CH3:2]
Reactant: CC(C)=C1CCOC1=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CC(C)C1CCOC1=O
Yield: 90.9 %

Procedure:
In a 250 mL autoclave a mixture of 2-isopropylidene-γ-butyrolactone (10.5 g) and Pd-catalyst (10 wt. % Pd on carbon, 0.050 g) in ethanol (10 mL) was treated with hydrogen (6 bar) at 60° C. for 18 h. Upon completion of the hydrogenation, the mixture was filtered and concentrated on a rotary evaporator to give 9.70 g (91%) of the title compound.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[CH:9]=[CH:8][C:7]([SH:10])=[CH:6][CH:5]=1.[Cl:11][C:12]1[N:17]=[C:16](Cl)[CH:15]=[CH:14][N:13]=1>O1CCCC1.C(OCC)(=O)C>[Cl:11][C:12]1[N:17]=[C:16]([S:10][C:7]2[CH:8]=[CH:9][C:4]([NH2:3])=[CH:5][CH:6]=2)[CH:15]=[CH:14][N:13]=1
Reactant: Nc1ccc(S)cc1
Reactant: Clc1ccnc(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Nc1ccc(Sc2ccnc(Cl)n2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75.7 %

Procedure:
To a suspension of sodium hydride (60% dispensed in mineral oil, 0.97 g, 24 mmol) in anhydrous tetrahydrofuran (80 mL), was added 4-aminobenzenethiol (2.77 g, 22 mmol) dissolved in tetrahydrofuran (20 mL) over 5 minutes. The mixture was stirred at room temperature for 30 minutes, to this was added a solution of 2,4-dichloropyrimidine (3.00 g, 20 mmol) dissolved in tetrahydrofuran (20 mL) over 5 minutes. The resulting mixture was stirred at room temperature for 64 hours, diluted with ethyl acetate (100 mL), washed with water and brine. After being dried (Na2SO4), the organic solution was concentrated in vacuo. The residue was flash chromatographed on silica gel using 5% of acetone in dichloromethane as eluant to give the product (3.60 g, 75%).