Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[N:12]([CH2:13][CH:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)[C:11]3[CH:20]=[C:21]([F:25])[C:22]([F:24])=[CH:23][C:10]=3[N:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[Cl:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[CH2:33][OH:34]>>[Cl:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[CH2:33][O:34][C:2]1[C:7]([C:8]2[N:12]([CH2:13][CH:14]3[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]3)[C:11]3[CH:20]=[C:21]([F:25])[C:22]([F:24])=[CH:23][C:10]=3[N:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Fc1cc2nc(-c3cccnc3Cl)n(CC3CCCCC3)c2cc1F
Reactant: OCc1ccccc1Cl
Product: Fc1cc2nc(-c3cccnc3OCc3ccccc3Cl)n(CC3CCCCC3)c2cc1F

Procedure:
The title compound was prepared in analogy to Example 1, from 2-(2-chloro-pyridin-3-yl)-1-cyclohexylmethyl-5,6-difluoro-1H-benzoimidazole (Ex. 1, intermediate a) and (2-chloro-phenyl)-methanol (CAS Reg. No. 17849-38-6). Light yellow solid (48%). MS (Turbo Spray): m/z=468.2 (M+H).
Reaction SMILES: [O-]Cl=O.[Na+].[CH3:5][O:6][C:7](=[O:17])[C:8]1[CH:13]=[CH:12][C:11]([CH:14]=[O:15])=[C:10]([F:16])[CH:9]=1.S(=O)(=O)([OH:20])N.[O-]S([O-])=O.[Na+].[Na+].Cl>O.CC#N>[CH3:5][O:6][C:7](=[O:17])[C:8]1[CH:13]=[CH:12][C:11]([C:14]([OH:20])=[O:15])=[C:10]([F:16])[CH:9]=1
Reactant: NS(=O)(=O)O
Reactant: COC(=O)c1ccc(C=O)c(F)c1
Agent: Cl
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: COC(=O)c1ccc(C(=O)O)c(F)c1
Reaction time: 1 h

Procedure:
A solution of 80% NaClO2 (0.13 mol) in H2O (50 mL) is added dropwise to a solution of crude 3-fluoro-4-formyl benzoic acid methyl ester (4, 0.12 mol) and sulfamic acid (0.13 mol) in H2O (50 mL) and CH3CN (100 mL). After stirring for 1 h, the reaction mixture is poured into saturated Na2SO3 aqueous solution and 1 N HCl, and extracted three times with EtOAc. The combined organic layers are washed with brine, dried over MgSO4, and evaporated in vacuo. The crystals are collected by filtration and washed with ether/hexane (1:1) to give 2-fluoroterephthalic acid 4-methyl ester (5) as white solid.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH2:15][CH:14]2[CH2:16][CH:7]([C:8]3[C:13]2=[CH:12][C:11]([N+:17]([O-])=O)=[CH:10][CH:9]=3)[CH2:6]1.[H][H]>CCO.C(Cl)Cl.[Pd]>[CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH2:15][CH:14]2[CH2:16][CH:7]([C:8]3[C:13]2=[CH:12][C:11]([NH2:17])=[CH:10][CH:9]=3)[CH2:6]1
Reactant: COCCN1CC2CC(C1)c1cc([N+](=O)[O-])ccc12
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: ClCCl
Product: COCCN1CC2CC(C1)c1cc(N)ccc12
Yield: 142 %

Procedure:
10-(2-Methoxy-ethyl)-4-nitro-10-aza-tricyclo[6.3.1.0*2,7*]dodeca-2,4,6-triene (75 mg, 0.30 mmol) in 8 ml EtOH and 2 ml methylene chloride in a Parr bottle was treated with 50 mg 10% Pd/C and subjected to hydrogen (g) at 40 psi for 2 h. The suspension was filtered and the solvent removed under reduced pressure to yield 10-(2-methoxy-ethyl)-10-aza-tricyclo[6.3.1.0*2,7*]dodeca-2,4,6-trien-4-ylamine (99 mg, 85%). LC/MS (ESI+): 233 (M+H)
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-])=[O:21])=[CH:16][CH:15]=2)=[CH:12][CH:11]=[N:10]1.[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30]C#N)=[CH:26][CH:25]=1>>[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[O:21][N:20]=[C:17]3[CH:18]=[CH:19][C:14]([C:13]4[N:9]([C:3]5[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=5[F:1])[N:10]=[CH:11][CH:12]=4)=[CH:15][C:16]=23)=[CH:26][CH:25]=1
Reactant: O=[N+]([O-])c1ccc(-c2ccnn2-c2ccc(F)cc2F)cc1
Reactant: N#CCc1ccc(Cl)cc1
Product: Fc1ccc(-n2nccc2-c2ccc3noc(-c4ccc(Cl)cc4)c3c2)c(F)c1

Procedure:
The title compound, light green solid (71 mg, 53%), MS (ISP) m/z=408.2 [(M+H)+], mp 155° C., was prepared in accordance with the general method of example 1 from 1-(2,4-difluoro-phenyl)-5-(4-nitro-phenyl)-1H-pyrazole (intermediate I) (100 mg, 353 μmol) and commercially available 2-(4-chloro-phenyl)-acetonitrile.
Reaction SMILES: COC([CH:5]1[CH2:10][C:9]([C:18]#[N:19])([C:11]2[CH:12]=[N:13][C:14]([Cl:17])=[CH:15][CH:16]=2)[CH2:8][CH2:7][C:6]1=[O:20])=O.[Li+].[Cl-]>CS(C)=O.O>[Cl:17][C:14]1[N:13]=[CH:12][C:11]([C:9]2([C:18]#[N:19])[CH2:8][CH2:7][C:6](=[O:20])[CH2:5][CH2:10]2)=[CH:16][CH:15]=1
Reactant: COC(=O)C1CC(C#N)(c2ccc(Cl)nc2)CCC1=O
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Solvent: CS(C)=O
Product: N#CC1(c2ccc(Cl)nc2)CCC(=O)CC1
Temperature: 120 °C

Procedure:
A mixture of 5-cyano-5-(6-chloropyridin-3-yl)-2-oxocyclohexanecarboxylic acid methyl ester (10.6 mmol) and LiCl (21.1 mmol) in 15 mL wet DMSO was heated to 120° C. under microwave conditions for 2 h. The reaction mixture was diluted with water and extracted 3 times with EtOAc. The combined organic layers were washed with brine, dried over MgSO4 and concentrated in vacuo. Purification with CC (KP-SIL™ from Biotage) using Hept/EtOAc (95/5 to 20/80) gives the desired compound as yellow solid.
Reaction SMILES: [C:1]([CH2:4][C@@H:5]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7])([OH:3])=O.[NH:20]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.Cl>C(Cl)Cl>[N:20]1([C:1]([CH2:4][C@@H:5]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])=[O:3])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: CC(C)C[C@H](CC(=O)O)C(=O)OCc1ccccc1
Reactant: C1CCCNCC1
Agent: Cl
Solvent: ClCCl
Product: CC(C)C[C@H](CC(=O)N1CCCCCC1)C(=O)OCc1ccccc1
Yield: 93.5 %

Procedure:
Benzyl (2R)-2-carboxymethyl-4-methylvalerate (1.35 g), hexahydro-1H-azepine (0.610 g) and WSCD.HCl (1.18 g) were reacted in methylene chloride (30 ml) in a similar manner to that of Preparation 1-1) to give benzyl (2R)-2-(hexahydro-1H-azepin-1-ylcarbonylmethyl)-4-methylvalerate (1.65 g).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C:14]([C:15]#[N:16])=[C:13]([CH3:17])[N:12]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=3)[C:11](=[O:28])[NH:10]2)=[C:5]([S:29]([CH3:32])(=[O:31])=[O:30])[CH:4]=1)#[N:2].[H-].[Na+].[C:35]1([CH3:45])[CH:40]=[CH:39][C:38]([S:41](Cl)(=[O:43])=[O:42])=[CH:37][CH:36]=1>C1COCC1>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C:14]([C:15]#[N:16])=[C:13]([CH3:17])[N:12]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=3)[C:11](=[O:28])[N:10]2[S:41]([C:38]2[CH:39]=[CH:40][C:35]([CH3:45])=[CH:36][CH:37]=2)(=[O:43])=[O:42])=[C:5]([S:29]([CH3:32])(=[O:31])=[O:30])[CH:4]=1)#[N:2]
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2S(C)(=O)=O)NC(=O)N1c1cccc(C(F)(F)F)c1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2S(C)(=O)=O)N(S(=O)(=O)c2ccc(C)cc2)C(=O)N1c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 96.4 %

Procedure:
The reaction was carried out under argon. (4S)-4-[4-Cyano-2-(methylsulfonyl)phenyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carbonitrile (278 mg, 604 μmol) was initially charged in dry THF (6 ml), and sodium hydride (60% in mineral oil; 34 mg, 845 μmol; 1.4 eq.) was added at 0° C. The mixture was warmed to RT and stirred for 20 min. A solution of p-toluenesulfonyl chloride (161 mg, 845 μmol; 1.4 eq.) in THF (˜2 ml) was then slowly added dropwise. After a reaction time of 16 h, the reaction mixture was concentrated and the crude product was purified by preparative HPLC (column: Gromsil C-18 10 μm; mobile phase: acetonitrile/water+0.1% TFA 10:90→90:10). This gave the title compound as a colorless solid (358 mg, 96% of theory).
Reaction SMILES: BrBr.[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH:9]=[C:8]2[CH3:14].[NH:15]1[CH:19]=[CH:18][N:17]=[CH:16]1>O1CCOCC1.CCOCC>[N:15]1([C:9]2[NH:10][C:11]3[C:7]([C:8]=2[CH3:14])=[CH:6][C:5]([O:4][CH3:3])=[CH:13][CH:12]=3)[CH:19]=[CH:18][N:17]=[CH:16]1
Reactant: c1c[nH]cn1
Reactant: COc1ccc2[nH]cc(C)c2c1
Agent: BrBr
Solvent: C1COCCO1
Solvent: CCOCC
Product: COc1ccc2[nH]c(-n3ccnc3)c(C)c2c1

Procedure:
A solution of bromine (0.62 ml) in dioxane (25 ml) is added dropwise over a period of 2 hours to a mixture of 5-methoxy-3-methylindole (2.00 g) and imidazole (4.08 g) in dioxane (50 ml) while stirring at 10°. Upon complete addition cooling bath is removed and the suspension is stirred two days at room temperature. The mixture is concentrated in vacuo and the oil obtained is suspended in ether (100 ml) and extracted into 1N hydrochloric acid (2×50 ml). The acid extract is first washed with ether (1×50 ml), the pH is adjusted to pH 6 with 3N sodium hydroxide (38 ml), and the aqueous mixture is then extracted with ether (8×50 ml). This extract is dried over magnesium sulfate, filtered, and concentrated in vacuo to give an oil. This oil is purified by flash chromatography on silica gel (eluent: 95% methylene chloride, 5% methanol) to give 2-(1-imidazolyl)-5-methoxy-3-methylindole as a crystalline solid; NMR (CDCl3): δ10.4 (s, 1H), 7.67 (s, 1H), 3.88 (s, 3H), 2.22 (s, 3H).
Reaction SMILES: O[C:2]1([C:11]2[S:12][CH:13]=[CH:14][N:15]=2)[CH2:7][CH:6]2[CH2:8][CH2:9][CH:3]1[CH2:4][C:5]2=[O:10]>C1COCC1>[S:12]1[CH:13]=[CH:14][N:15]=[C:11]1[C:2]1[CH:3]2[CH2:9][CH2:8][CH:6]([CH:7]=1)[C:5](=[O:10])[CH2:4]2
Reactant: O=C1CC2CCC1CC2(O)c1nccs1
Solvent: C1CCOC1
Product: O=C1CC2CCC1C=C2c1nccs1
Temperature: 25 °C
Reaction time: 4 h
Yield: 55.6 %

Procedure:
806 mg of 5-hydroxy-5-thiazol-2-yl-bicyclo[2.2.2]octan-2-one were dissolved in THF (7.2 mL) and 2.58 g of the Burgess'reagent was added portionwise at 0° C. The ice bath was removed and the reaction mixture was stirred at rt for 4 h, then quenched with cold water and extracted with DCM. The organic phase was washed with water and brine, dried over anh. Na2SO4, filtered and concentrated in vacuo. The crude material was purified by CC using EtOAc/heptane (1/2) as eluant to yield 412 mg of rac-(1R*,4R*)-5-thiazol-2-yl-bicyclo[2.2.2]oct-5-en-2-one as a yellowish oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH2:4][CH2:5][C:6](=[O:14])[C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=1.S(Cl)([Cl:19])(=O)=O.[OH-].[Na+]>C(Cl)Cl.CO>[CH3:1][O:2][C:3](=[O:15])[CH2:4][CH:5]([Cl:19])[C:6](=[O:14])[C:7]1[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][CH:12]=1
Reactant: O=S(=O)(Cl)Cl
Reactant: COC(=O)CCC(=O)c1ccc(C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: COC(=O)CC(Cl)C(=O)c1ccc(C)cc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A stirred solution of 152.6 g (0.74 mole) of 3-(4-methylbenzoyl)propionic methyl ester in 225 mL of methylene chloride was cooled to -5° C. in methanol:ice bath. A solution of 109.9 g (66 mL, 0.81 mole) of sulfuryl chloride (97%) in 65 mL of methylene chloride was added dropwise at a rate which maintained the temperature at 0° C. The reaction mixture was allowed to warm to ambient temperature and stirred overnight. The reaction mixture was cooled to 0° C. in an ice bath and treated with 3N sodium hydroxide until just basic. The organic portion was separated, dried over magnesium sulfate and concentrated in vacuo (172.9 g). The oil was distilled at 125° C. (150 mm Hg) in 4 fractions. A sample of fraction 2 was sent for elemental analysis.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[N:4]=[CH:5][C:6]([NH:9][CH2:10][C@@H:11]2[CH2:17][C@H:16]3[C@H:14]([CH2:15]3)[CH2:13][N:12]2C(OC(C)(C)C)=O)=[N:7][CH:8]=1.C(Cl)Cl>>[C@H:14]12[CH2:15][C@H:16]1[CH2:17][C@@H:11]([CH2:10][NH:9][C:6]1[CH:5]=[N:4][C:3]([C:2]([F:26])([F:25])[F:1])=[CH:8][N:7]=1)[NH:12][CH2:13]2
Reactant: CC(C)(C)OC(=O)N1C[C@H]2C[C@H]2C[C@H]1CNc1cnc(C(F)(F)F)cn1
Solvent: ClCCl
Product: FC(F)(F)c1cnc(NC[C@@H]2C[C@@H]3C[C@@H]3CN2)cn1
Reaction time: 2 h

Procedure:
To a solution of 1,1-dimethylethyl (1S,4S,6S)-4-({[5-(trifluoromethyl)-2-pyrazinyl]amino}methyl)-3-azabicyclo[4.1.0]heptane-3-carboxylate D30 (100 mg) in DCM (4 ml) TFA (2 ml, 26.0 mmol) was added dropwise. The mixture was left reacting at room temperature for 2 hours. Solvent was evaporated in vacuum and the crude was purified by SCX chromatography using MeOH 100% to MeOH/NH3 2M. It was recovered the title compound D31 (57 mg). UPLC: (Acid Final_QC): rt=0.48 minutes, peaks observed: 273 (M+1). C12H15F3N4 requires 272. 1H NMR (400 MHz, CDCl3). δ ppm 0.22-0.29 (m, 1 H) 0.67-0.76 (m, 1 H) 0.82-0.92 (m, 1 H) 1.02-1.13 (m, 1 H) 1.24-1.35 (m, 1 H) 2.01-2.12 (m, 1 H) 2.63-2.72 (m, 1 H) 2.95-3.06 (m, 1 H) 3.17 (dd, 1 H) 3.26 (d, 1 H) 3.53-3.63 (m, 1 H) 5.96 (br. s., 1 H) 7.91-7.96 (m, 1 H) 8.26-8.31 (m, 1 H).
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][C:10]([O:13][C:14]([F:17])([F:16])[F:15])=[CH:9][CH:8]=2)[C:3]=1[C:18](O)=[O:19].Cl.C(N=C=NCCCN(C)C)C.OC1C2N=NNC=2C=CC=1.[N:43]1([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][C:50]=2[OH:55])[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]1>>[NH2:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][C:10]([O:13][C:14]([F:15])([F:17])[F:16])=[CH:9][CH:8]=2)[C:3]=1[C:18]([N:46]1[CH2:45][CH2:44][N:43]([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][C:50]=2[OH:55])[CH2:48][CH2:47]1)=[O:19]
Reactant: Oc1ccccc1N1CCNCC1
Reactant: Nc1onc(-c2ccc(OC(F)(F)F)cc2)c1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Product: Nc1onc(-c2ccc(OC(F)(F)F)cc2)c1C(=O)N1CCN(c2ccccc2O)CC1
Yield: 71.7 %

Procedure:
In a similar manner as described in Example 1, by using dimethylformimide (15 mL), 5-amino-3-(4-(trifluoromethoxy)phenyl)isoxazol-4-carboxylic acid (530 mg, 1.84 mmol), 1-ethyl-3-(dimethylaminopropyl)carbodiimide hydrochloride (388 mg, 2.02 mmol), hydroxybenzotriazole (299 mg, 2.21 mmol) and 2-(piperazine-1-yl)phenol (328 mg, 1.84 mmol), a white solid required compound (591 mg, 1.32 mmol, 72%) was obtained.
Reaction SMILES: B(F)(F)F.CCOCC.[Cl:10][C:11]1[CH:20]=[C:19]2[C:14]([C:15](=[O:27])[C:16]([C:22](OCC)=[O:23])=[CH:17][N:18]2[CH3:21])=[CH:13][CH:12]=1.[CH3:28][NH2:29]>>[Cl:10][C:11]1[CH:20]=[C:19]2[C:14]([C:15](=[O:27])[C:16]([C:22]([NH:29][CH3:28])=[O:23])=[CH:17][N:18]2[CH3:21])=[CH:13][CH:12]=1
Reactant: CN
Reactant: CCOC(=O)c1cn(C)c2cc(Cl)ccc2c1=O
Agent: FB(F)F
Solvent: CCOCC
Product: CNC(=O)c1cn(C)c2cc(Cl)ccc2c1=O
Reaction time: 16 h

Procedure:
Boron trifluoride etherate (5 ml) was added cautiously to a mixture of ethyl 7-chloro-1-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylate (5 g) and a solution of methylamine in IMS (32%; 35 ml) and the mixture was boiled under reflux for 8 hours. The same quantities of boron trifluoride etherate and methylamine in IMS were added and the mixture was boiled under reflux for 24 hours. The same quantities of boron trifluoride etherate and methylamine in IMS were added and the mixture was boiled under reflux for 8 hours. The mixture was kept at ambient temperature for 16 hours and then filtered. The residue was washed with IMS, dried and recrystallised from aqueous IMS to give the novel compound 7-chloro-1,N-dimethyl-4-oxo-1,4-dihydroquinoline-3-carboxamide, m.p. 260°-263°.
Reaction SMILES: CN(C=O)C.[NH:6]1[CH:10]=[CH:9][N:8]=[CH:7]1.[CH2:11]([O:13][N:14]=[C:15](Cl)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[S:22][CH2:23][C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=1)[CH3:12]>CCOCC>[CH2:11]([O:13][N:14]=[C:15]([N:6]1[CH:10]=[CH:9][N:8]=[CH:7]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[S:22][CH2:23][C:24]1[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][CH:29]=1)[CH3:12]
Reactant: CCON=C(Cl)c1ccccc1SCc1ccc(Cl)cc1
Reactant: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCON=C(c1ccccc1SCc1ccc(Cl)cc1)n1ccnc1
Temperature: 170 °C
Reaction time: 21 h
Yield: 14.8 %

Procedure:
DMF (3 ml) and imidazole (0.41 g) were added to α-chloro-2-(4-chlorobenzylthio)benzaldehyde O-ethyloxime (0.68 g), and the mixture was stirred at 170° C. for 21 hours. After completion of the reaction, ether (100 ml) was added, and the mixture was washed with brine (80 ml) twice, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting crude product was purified by silica gel chromatography and recrystallized from ethyl acetate/n-hexane to give 2-(4-chlorobenzylthio)-α-(1-imidazolyl)benzaldehyde O-ethyloxime (0.11 g) as colorless crystals. mp. 96.5°-97.5° C.
Reaction SMILES: [O:1]=[CH:2][C@H:3]([C@@H:5]([C@@H:7]([C@H:9]([CH3:11])[OH:10])[OH:8])[OH:6])[OH:4].C(O[C:16](=[O:18])[CH3:17])(=O)C>N1C=CC=CC=1>[C:2]([O:4][C@@H:3]([C@@H:5]([C@@H:7]([C@H:9]([CH3:11])[O:10][C:16](=[O:18])[CH3:17])[O:8][C:9](=[O:10])[CH3:11])[O:6][C:5](=[O:6])[CH3:7])[CH:2]=[O:1])(=[O:1])[CH3:3]
Reactant: CC(=O)OC(C)=O
Reactant: C[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)C=O
Solvent: c1ccncc1
Product: CC(=O)O[C@H]([C@H](OC(C)=O)[C@H](C)OC(C)=O)[C@@H](C=O)OC(C)=O
Temperature: 25 °C
Reaction time: 36 h

Procedure:
To a suspension of 10 grams of L-fucose in 50 milliliters of pyridine is slowly added 50 milliliters of acetic anhydride. The mixture is stirred for 1 to 2 days at room temperature and then poured into a separatory funnel containing ice water. The resulting mixture is extracted 3 to 4 times with 50 milliliter portions of chloroform. The organic extracts are washed with water, aqueous sodium bicarbonate, and dried over magnesium sulfate. The mixture is filtered and the solvent removed under reduced pressure to give a residue of crude fucose tetraacetate. The crude tetraacetate is co-evaporated several times with toluene to remove any remaining pyridine or acetic acid. The fucose tetraacetate is then treated with 32% hydrogen bromide and acetic acid for 2 hours, and the mixture is then worked up similarly to that just described for the tetraacetate, i.e., chloroform extraction from an ice water mixture. The resultant crude product is 2,3,4-tri-O-acetyl-L-fucopyranosyl bromide.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.C([O:13][C:14]([CH:16]1[CH2:25][CH2:24][C:19]2([O:23][CH2:22][CH2:21][O:20]2)[CH2:18][CH2:17]1)=O)C>C1(C)C=CC=CC=1>[O:20]1[C:19]2([CH2:24][CH2:25][CH:16]([CH:14]=[O:13])[CH2:17][CH2:18]2)[O:23][CH2:22][CH2:21]1
Reactant: CCOC(=O)C1CCC2(CC1)OCCO2
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Product: O=CC1CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Diisobutyl aluminium hydride (1.5 M solution in toluene, 102 ml, 153 mmole) was added dropwise at −70° to −65° C. under argon to a solution of 1,4-dioxaspior[4.5]decane-8-carboxylic acid ethyl ester 4 (32.13 g, 150 mmole) in absolute toluene (160 ml), and stirred for 30 minutes. The reaction mixture was then quenched at −70° to −60° C. by adding methanol (80 ml). The reaction solution was heated to RT, saturated sodium chloride solution (100 ml) was added, and the reaction solution was suction filtered through diatomaceous earth. The diatomaceous earth was washed twice with ethyl acetate, and the aqueous solution was separated and extracted twice with ethyl acetate. The combined organic extracts were washed with saturated sodium chloride solution, dried over sodium sulfate, and concentrated by evaporation in vacuo.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[NH:10][C:9](=S)[CH:8]3[CH2:13][CH2:14][CH2:15][CH:7]3[C:6]=2[CH:5]=[C:4]([Cl:16])[CH:3]=1.[NH3:17]>>[NH2:17][C:9]1[CH:8]2[CH2:13][CH2:14][CH2:15][CH:7]2[C:6]2[CH:5]=[C:4]([Cl:16])[CH:3]=[C:2]([Cl:1])[C:11]=2[N:10]=1
Reactant: N
Reactant: S=C1Nc2c(Cl)cc(Cl)cc2C2CCCC12
Product: NC1=Nc2c(Cl)cc(Cl)cc2C2CCCC12
Yield: 74 %

Procedure:
Analogously to Example 4, 6,8-dichloro-1,2,3,3a,5,9b-hexahydrocyclopenta[c]quinoline-4-thione (100 mg, 0.37 mmol) is reacted with 7N methanolic ammonia solution (20 ml) to form 70 mg (74%) of product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[C:13]3[N:30]=[CH:29][S:28][C:14]=3[N:15]=[C:16]([N:18]3[CH2:23][CH2:22][CH2:21][CH:20]([C:24]([O:26]C)=[O:25])[CH2:19]3)[N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[OH-].[Na+]>C1COCC1.CO.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[C:13]3[N:30]=[CH:29][S:28][C:14]=3[N:15]=[C:16]([N:18]3[CH2:23][CH2:22][CH2:21][CH:20]([C:24]([OH:26])=[O:25])[CH2:19]3)[N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COC(=O)C1CCCN(c2nc(Nc3ccc(OC)c(OC)c3)c3ncsc3n2)C1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(Nc2nc(N3CCCC(C(=O)O)C3)nc3scnc23)cc1OC
Reaction time: 24 h
Yield: 98.7 %

Procedure:
To a stirred solution of methyl 1-(7-(3,4-dimethoxyphenylamino)thiazolo[5,4-d]pyrimidin-5-yl)piperidine-3-carboxylate (0.06 g, 0.139 mmol) in 5 mL of THF and 5 mL of methanol was added a solution of NaOH (0.056 g, 1.39 mmol) in 1 mL of water at room temperature. After the addition, the reaction was stirred at this temperature for 24 hours. The solvent was evaporated and the residue was suspended in 10 mL of THF, then treated by HCl until pH=2. The solvent was evaporated and then dissolved in 30 mL of THF, filtered. The filtrate was evaporated to give 1-(7-(3,4-dimethoxyphenylamino)thiazolo[5,4-d]pyrimidin-5-yl)piperidine-3-carboxylic acid (0.057 g, 98%) as a solid. LC-MS: 416.1 [M+H]+, tR=1.57 min.
Reaction SMILES: [Li+].[BH4-].C[O:4][C:5]([C:7]1[CH:11]=[C:10]([C:12]2[S:13][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([S:23]([CH3:26])(=[O:25])=[O:24])[CH:18]=3)=[CH:15][CH:16]=2)[N:9]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[Cl:33])[N:8]=1)=O.CC(C)=O.O>C1COCC1>[Cl:33][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[N:9]1[C:10]([C:12]2[S:13][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([S:23]([CH3:26])(=[O:24])=[O:25])[CH:18]=3)=[CH:15][CH:16]=2)=[CH:11][C:7]([CH2:5][OH:4])=[N:8]1
Reactant: COC(=O)c1cc(-c2ccc(-c3cccc(S(C)(=O)=O)c3)s2)n(-c2ccccc2Cl)n1
Agent: [BH4-]
Agent: [Li+]
Solvent: CC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CS(=O)(=O)c1cccc(-c2ccc(-c3cc(CO)nn3-c3ccccc3Cl)s2)c1
Yield: 75.2 %

Procedure:
LiBH4 (1.0M in THF, 14 mL, 28 mmol) was added dropwise at rt to a stirred solution of 1-(2-chloro-phenyl)-5-[5-(3-methanesulfonyl-phenyl)-thiophen-2-yl]-1H-pyrazole-3-carboxylic acid methyl ester (4.38 g, 9.26 mmol) in anhydrous THF (100 mL) under N2, and the resulting mixture was stirred at rt for 3d. Acetone (2 mL) and water (2 mL) was added successively at 0° C. and the solid was filtered off. The filtrate was concentrated in vacuo. The residue was taken up in EtOAc (200 mL), washed with water and brine, dried over Na2SO4 and evaporated in vacuo. The crude product was purified by flash chromatography (0-90% EtOAc/hexanes) to give the title compound as a white solid (3.1 g, 75%). 1HNMR (CDCl3): δ 8.04 (m, 1H), 7.84-7.81 (m, 1H), 7.74-7.72 (m, 1H), 7.58-7.44 (m, 5H), 7.21 (d, 1H), 6.76 (d, 1H), 6.69 (s, 1H), 4.80 (s, 2H), 3.07 (s, 3H), 1.65 (brs, 1H). MS(ES): 445 [M+H]+.
Reaction SMILES: Br[C:2]1[S:6][C:5]([CH:7]=[O:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[C:15]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])(=[O:18])[CH:16]=[CH2:17]>CN(C=O)C>[CH:7]([C:5]1[S:6][C:2](/[CH:17]=[CH:16]/[C:15]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[CH:3][CH:4]=1)=[O:8]
Reactant: O=Cc1ccc(Br)s1
Reactant: C=CC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)/C=C/c1ccc(C=O)s1
Temperature: 137.5 °C
Yield: 56 %

Procedure:
A mixture of 5-bromothiophene-2-carboxaldehyde (2.41 g, 12.6 mmol), DMF (40 mL), potassium carbonate (1.75 g, 12.6 mmol), tert-butyl acrylate (8 mL, 56.5 mmol), and CombiPhos-Pd6 (200 mg, CombiPhos Catalysts, Inc., P.O. Box 220, Princeton, N.J. 08542) was heated in a 135 to 140° C. oil bath overnight. The solvent was evaporated, the residue stirred in DCM, and the mixture filtered through a pad of diatomaceous earth. The solvent was evaporated and the residue purified by flash chromatography on silica gel eluting with 20% EtOAc/hexane to give an orange solid (1.68 g), m/e=239 (M+1). 1H NMR (CDCl3) ppm: 1.54 (9H, s), 6.36 (1H, d), 7.28 (1H, d), 7.64 (1H, d), 7.68 (1H, d), 9.9 (1H, s).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([CH:14]2[CH2:19][CH2:18][CH:17]([CH2:20][CH2:21][N:22]([CH3:24])[CH3:23])[CH2:16][CH2:15]2)[CH2:10][CH2:9]1)C1C=CC=CC=1>C(O)C.[Pd]>[CH3:24][N:22]([CH3:23])[CH2:21][CH2:20][CH:17]1[CH2:16][CH2:15][CH:14]([N:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)[CH2:19][CH2:18]1
Reactant: CN(C)CCC1CCC(N2CCN(Cc3ccccc3)CC2)CC1
Agent: [Pd]
Solvent: CCO
Product: CN(C)CCC1CCC(N2CCNCC2)CC1
Temperature: 50 °C
Reaction time: 16 h
Yield: 85.9 %

Procedure:
2-(4-(4-benzylpiperazin-1-yl)cyclohexyl)-N,N-dimethylethanamine (660 mg) is dissolved in ethanol (20 ml). Palladium on carbon (100 mg) is added and the mixture is stirred for 16 hours at 50° C. under an atmosphere of hydrogen (50 psi). The catalyst is removed by filtration and the filtrate concentrated under reduced pressure to give N,N-dimethyl-2-(4-(piperazin-1-yl)cyclohexyl)ethanamine (412 mg). m/z(+) 240 (M+H+).