Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:3]2[NH:22][N:21]=[C:20]([C:23]3[CH:28]=[CH:27][N:26]=[C:25]([CH3:29])[CH:24]=3)[C:4]=2[CH:5]=[N:6][C:7]=1[NH:8][C:9]([NH:11][C@@H:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH3:13])=[O:10].F[B-](F)(F)F.[CH:35]1([PH+](C2CCCCC2)C2CCCCC2)CCCCC1.C[Zn]C.C1(C)C=CC=CC=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CN1C(=O)CCC1.O1CCOCC1>[CH3:35][C:2]1[C:3]2[NH:22][N:21]=[C:20]([C:23]3[CH:28]=[CH:27][N:26]=[C:25]([CH3:29])[CH:24]=3)[C:4]=2[CH:5]=[N:6][C:7]=1[NH:8][C:9]([NH:11][C@@H:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH3:13])=[O:10]
Reactant: Cc1cc(-c2n[nH]c3c(Cl)c(NC(=O)N[C@H](C)c4ccccc4)ncc23)ccn1
Reactant: C1CCC([PH+](C2CCCCC2)C2CCCCC2)CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: C[Zn]C
Solvent: CN1CCCC1=O
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: Cc1cc(-c2n[nH]c3c(C)c(NC(=O)N[C@H](C)c4ccccc4)ncc23)ccn1
Temperature: 100 °C
Yield: 71.4 %

Procedure:
An oven-dried, nitrogen cooled 5 ml microwave vial was charged with (R)-1-(7-chloro-3-(2-methylpyridin-4-yl)-1H-pyrazolo[4,3-c]pyridin-6-yl)-3-(1-phenylethyl)urea (Example 571, 78.7 mg, 0.193 mmol), palladium (II) acetate (8.5 mg, 0.038 mmol) and tricyclohexylphosphonium tetrafluoroborate (36 mg, 0.098 mmol), sealed under a nitrogen atmosphere and charged with Dioxane (1.0 ml) and NMP (0.25 ml) followed by dropwise addition of dimethylzinc in toluene (1.6 ml, 1.920 mmol). Heated to 100° C. for 17 hr. Quenched with TFA until gas evolution ceased, and then poured into saturated aqueous sodium bicarbonate. Extracted 3× with DCM and filtered aqueous layer to remove precipitate. Extracted precipitate with DCM/MeOH. Concentrated combined organic extracts in vacuo and purified via flash chromatography (0-20% MeOH/DCM) followed by mass-triggered reverse-phase HPLC. Obtained (R)-1-(7-methyl-3-(2-methylpyridin-4-yl)-1H-pyrazolo[4,3-c]pyridin-6-yl)-3-(1-phenylethyl)urea (26.9 mg, 0.070 mmol, 36.0% yield) as a white solid. MS ESI calc'd for C22H22N6O [M+H]+=387, found 387. 1H NMR (500 MHz, DMSO-d6) δ 936 (br s, 1H), 9.16 (s, 1H), 8.52 (d, J=5.1 Hz, 1H), 8.27 (s, 1H), 7.89 (s, 1H), 7.82 (d, J=5.1 Hz, 1H), 7.37 (m, 4H), 7.21 (m, 1H), 4.97 (m, 1H), 2.56 (s, 3H), 2.48 (s, 1H), 1.45 (d, J=7.1 Hz, 3H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.F[C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1.O>CS(C)=O>[N+:14]([C:11]1[CH:12]=[CH:13][C:8]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)=[CH:9][CH:10]=1)([O-:16])=[O:15]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: C1COCCN1
Solvent: CS(C)=O
Solvent: O
Product: O=[N+]([O-])c1ccc(N2CCOCC2)cc1
Temperature: 100 °C

Procedure:
A mixture of 24.5 g morpholine and 13.3 g 1-Fluoro-4-nitro-benzene in 30 ml DMSO was heated to 100° C. for 4 h. This solution was poured on to 300 ml of water and the resulting precipitate was collected by filtration to yield a bright yellow crystalline product, which was dried in vacuo.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9].C(O)(=O)C.[H][H]>[Pd].C(O)C>[NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: [H][H]
Reactant: CCOC(=O)Cc1ccccn1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)CC1CCCCN1

Procedure:
50 ml of ethyl 2-(2-pyridyl)acetate, 18.7 ml of acetic acid, 5 g of Pd—C (water-containing product) and 200 ml of ethanol were charged in an auto clave, and the mixture was stirred at 70° C. for 9 hours at a hydrogen pressure of 56 kg/cm2. The Pd—C was filtered off and ethanol was evaporated, to give 72.3 g of white crystals.
Reaction SMILES: N1C=CN=C1.[Br:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][OH:15].[C:16]([Si:20](Cl)([CH3:22])[CH3:21])([CH3:19])([CH3:18])[CH3:17]>CN(C)C=O.O1CCCC1>[Br:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][O:15][Si:20]([CH3:22])([CH3:21])[C:16]([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCCCCCCCCBr
Agent: c1c[nH]cn1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCCCCCCCBr
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 88 %

Procedure:
1.55 g of imidazole were added to a solution fo 3.97 g of 8-bromo octanol in 19 ml of dimethylformamide, and over 10 minutes, 3.32 g of terbutyl chloro dimethyl silane in solution in 4.7 ml of tetrahydrofuran were added. The mixture was stirred for one hour at ambient temperature and the insoluble part was filtered off. The filtrate was evaporated to dryness under reduced pressure and the residue was chromatographed on silica (eluant:cyclohexane-toluene 8-2) to obtain 5.4 g of the expected product.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][C:12]=2[OH:17])O)=[CH:5][CH:4]=1)[CH3:2]>[Pd].C(O)(=O)C>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:11]2[CH:16]=[CH:15][N:14]=[CH:13][C:12]=2[OH:17])=[CH:5][CH:4]=1)[CH3:2]
Reactant: CCc1ccc(C(O)c2ccncc2O)cc1
Agent: [Pd]
Solvent: CC(=O)O
Product: CCc1ccc(Cc2ccncc2O)cc1
Temperature: 25 °C
Reaction time: 7 h
Yield: 39.9 %

Procedure:
Next, to a mixture of (4-ethylphenyl)-(3-hydroxypyridin-4-yl)-methanol (10.54 g, 46.0 mmol) and acetic acid (100 ml), 5% palladium/carbon (5.0 g) was added and stirred under a hydrogen atmosphere at room temperature for 7 hours. After filtration to remove the insoluble materials, the filtrate was concentrated under reduced pressure and the resulting residue was recrystallized (ethyl acetate) to give the titled compound (3.91 g, 40%) as a colorless powder. Moreover, the mother liquor was purified by NH silica gel column chromatography (chloroform:methanol=20:1) to give 4-(4-ethylbenzyl)-3-hydroxypyridine (4.55 g, 46%) as a light-brown powder.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:19]([OH:21])=O)[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].FC1C(O)=C(F)C(F)=C(F)C=1F.[CH3:34][N:35]1CCOCC1.C(O)C>C(Cl)Cl>[CH3:34][NH:35][C:19](=[O:21])[C@H:9]([CH2:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]#[N:18])=[CH:15][CH:16]=1)[NH:8][C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2]
Reactant: CN1CCOCC1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(C#N)cc1)C(=O)O
Agent: Oc1c(F)c(F)c(F)c(F)c1F
Solvent: CCO
Solvent: ClCCl
Product: CNC(=O)[C@H](Cc1ccc(C#N)cc1)NC(=O)OC(C)(C)C
Reaction time: 3 h
Yield: 91.9 %

Procedure:
A solution of N-Boc-4-cyanophenylalanine (1.92 g, 6.6 mmol) and pentafluorophenol (2.43 g, 13.2 mmol) in CH2Cl2 (30 ml) at 0° C. was treated with 4-methylmorpholine (0.74 g, 7.3 mmol). After stirring the reaction mixture for 3 hours, 8M methylazine in ethanol (15 ml, 19.8 mmol) was added and the reaction mixture left to stir at room temperature for 16 hours. The solvent was removed under pressure, the residue dissolved in CH2Cl2 (50 ml) and washed with saturated sodium bicarbonate (2×50 ml) , 1M citric acid (2×50 ml) and brine (50 ml). The CH2Cl2 layer was dried over MgSO4 and the solvent removed under pressure to yield the title compound as a white solid (1.84 g, 92%).
Reaction SMILES: [C:1]1([C:7]2[N:11]3[N:12]=[C:13](Br)[CH:14]=[C:15](Br)[C:10]3=[N:9][C:8]=2[C:18]2[CH:23]=[CH:22][C:21]([C:24]3([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:27][CH2:26][CH2:25]3)=[CH:20][CH:19]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:36][C:37]1[CH:42]=[CH:41][C:40](B(O)O)=[CH:39][CH:38]=1.C(=O)([O-])[O-].[Na+].[Na+]>O.O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:36][C:37]1[CH:42]=[CH:41][C:40]([C:13]2[CH:14]=[C:15]([C:40]3[CH:41]=[CH:42][C:37]([F:36])=[CH:38][CH:39]=3)[C:10]3[N:11]([C:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)=[C:8]([C:18]4[CH:23]=[CH:22][C:21]([C:24]5([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:25][CH2:26][CH2:27]5)=[CH:20][CH:19]=4)[N:9]=3)[N:12]=2)=[CH:39][CH:38]=1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(Br)cc(Br)nn4c3-c3ccccc3)cc2)CCC1
Reactant: OB(O)c1ccc(F)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(-c5ccc(F)cc5)cc(-c5ccc(F)cc5)nn4c3-c3ccccc3)cc2)CCC1

Procedure:
A mixture of tert-butyl (1-{4-[3-phenyl-6,8-dibromoimidazo[1,2-b]pyridazin-2-yl]phenyl}cyclobutyl)carbamate that was prepared in a manner analgous to that described for Intermediate Example Int-6 (0.25 g, 0.42 mmol), (4-fluorophenyl)boronic acid (0.12 g, 0.84 mmol, 2.0 equiv.), 1,1′-bis(diphenylphosphino)ferrocenepalladium(II) dichloride (0.034 g, 0.042 mmol, 0.1 equiv.) and sodium carbonate (0.13 g, 1.25 mmol, 3.0 equiv) in a mixture of water (0.6 mL) and dioxane (4.5 mL) was irradiated in a microwave apparatus at 110° C. for 60 min. The resulting reaction mixture was added to water (25 mL). The aqueous mixture was extracted with DCM (3×25 mL). The combined organic phases were washed with an aqueous NaOH solution (2 N), dried (Na2SO4 anh.) and concentrated under reduced pressure to give impure tert-butyl (1-{4-[6,8-bis(4-fluorophenyl)-3-phenylimidazo[1,2-b]pyridazin-2-yl]phenyl}cyclobutyl)carbamate (0.39 g) which was used without further purification:
Reaction SMILES: [CH:1]1([CH:7]([C:9]2[C:10]([CH2:22][O:23][CH3:24])=[N:11][N:12]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[CH:13]=2)O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]([NH:34][CH2:35][CH2:36][C:37]([O:39]CC)=[O:38])=[O:33])=[CH:28][CH:27]=1>>[CH:1]1([CH:7]([NH:25][C:26]2[CH:27]=[CH:28][C:29]([C:32]([NH:34][CH2:35][CH2:36][C:37]([OH:39])=[O:38])=[O:33])=[CH:30][CH:31]=2)[C:9]2[C:10]([CH2:22][O:23][CH3:24])=[N:11][N:12]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[CH:13]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CCNC(=O)c1ccc(N)cc1
Reactant: COCc1nn(-c2ccc(OC)cc2)cc1C(O)C1CCCCC1
Product: COCc1nn(-c2ccc(OC)cc2)cc1C(Nc1ccc(C(=O)NCCC(=O)O)cc1)C1CCCCC1
Yield: 33 %

Procedure:
Using cyclohexyl[3-(methoxymethyl)-1-(4-methoxyphenyl)-1H-pyrazol-4-yl]methanol (0.75 g) synthesized above and ethyl 3-{[(4-aminophenyl)carbonyl]amino}propanoate (0.54 g) synthesized in Example 1(2) and in the same manner as in Example 1(7), the title object compound (0.39 g, 33%) was obtained as a white solid.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4](=[O:7])[NH:5][CH:6]=1.[Cl-].[Al+3].[Cl-].[Cl-].[O:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[C:17](Cl)=[O:18]>[N+](C1C=CC=CC=1)([O-])=O>[O:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[C:17]([C:6]1[NH:5][C:4](=[O:7])[NH:3][C:2]=1[CH3:1])=[O:18]
Reactant: Cc1c[nH]c(=O)[nH]1
Reactant: O=C(Cl)c1ccco1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=[N+]([O-])c1ccccc1
Product: Cc1[nH]c(=O)[nH]c1C(=O)c1ccco1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
To a slurry of 8.9 g of 1,3-dihydro-4-methyl-2H-imidazol-2-one and 24.0 g of aluminum chloride in 135 ml of nitrobenzene is added 12.9 g of furanoyl chloride in a dropwise manner. The mixture is stirred at 60° C. for 3 hours, cooled and poured over ice water. The solid is then filtered and recrystallized twice from methyl alcohol to afford the title compound. M.P. 214°-216° C.
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:13]=[CH:12][C:6]2[O:7][CH2:8][C:9](=[O:11])[NH:10][C:5]=2[CH:4]=1.C1COCC1>[O-2].[O-2].[Mn+4].ClCCCl>[O:11]=[C:9]1[CH2:8][O:7][C:6]2[CH:12]=[N:13][C:3]([CH:2]=[O:1])=[CH:4][C:5]=2[NH:10]1
Reactant: O=C1COc2cnc(CO)cc2N1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCCl
Solvent: C1CCOC1
Product: O=Cc1cc2c(cn1)OCC(=O)N2
Temperature: 60 °C

Procedure:
A mixture of the hydroxymethyloxazinone (h) (584 mg), manganese dioxide (2.3 g), THF (50 ml) and 1,2-dichloroethane (50 ml) was heated at 60° C. under argon for 20 hours. Filtration through kieselguhr and evaporation of solvent gave a solid which was triturated under EtOAc/hexane 1:3, filtered off and dried (383 mg).
Reaction SMILES: [F:1][C:2]1([F:39])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:14]([NH:16][C:17]4[CH:22]=[CH:21][C:20]([CH3:23])=[C:19]([C:24]5[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH2:31][C@@H:32]6[CH2:36][O:35]C(C)(C)[O:33]6)[CH:25]=5)[N:18]=4)=[O:15])[CH2:13][CH2:12]3)=[CH:10][C:4]=2[O:3]1.CC1C=CC(S(O)(=O)=O)=CC=1>CO.O>[F:39][C:2]1([F:1])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:14]([NH:16][C:17]4[CH:22]=[CH:21][C:20]([CH3:23])=[C:19]([C:24]5[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH2:31][C@@H:32]([OH:33])[CH2:36][OH:35])[CH:25]=5)[N:18]=4)=[O:15])[CH2:13][CH2:12]3)=[CH:10][C:4]=2[O:3]1
Reactant: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)nc1-c1cccc(OC[C@@H]2COC(C)(C)O2)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Product: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)nc1-c1cccc(OC[C@@H](O)CO)c1
Temperature: 80 °C

Procedure:
To a solution of (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(6-(3-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)phenyl)-5-methylpyridin-2-yl)cyclopropane-carboxamide (54 mg, 0.10 mmol) in methanol (2 mL) and water (0.2 mL) was added 4-methylbenzenesulfonic acid (2 mg, 0.01 mmol). The mixture was heated at 80° C. for 1 hour. The reaction mixture was partitioned between ethyl acetate and water, and the aqueous layer was extracted with ethyl acetate (2×). The combined organic layers were washed with sat. NaHCO3 and brine before being dried over MgSO4. After the removal of solvent, the residue was purified by preparative LC/MS to afford (S)-1-(2,2-difluorobenzo[d][1,3]-dioxol-5-yl)-N-(6-(3-(2,3-dihydroxypropoxy)phenyl)-5-methylpyridin-2-yl)cyclo-propanecarboxamide. 1H NMR (400 MHz, CDCl3) δ 8.01 (d, J=8.4 Hz, 1H), 7.65 (s, 1H), 7.50 (d, J=8.4 Hz, 1H), 7.25 (t, J=7.8 Hz, 1H), 7.13 (td, J=8.7, 1.7 Hz, 2H), 6.99 (d, J=8.2 Hz, 1H), 6.92 (d, J=7.6 Hz, 1H), 6.87-6.83 (m, 2H), 4.00-3.91 (m, 3H), 3.71 (dd, J=11.4, 3.2 Hz, 1H), 3.62 (dd, J=11.3, 5.0 Hz, 1H), 2.17 (s, 3H), 1.67 (q, J=3.6 Hz, 2H), 1.08 (q, J=3.6 Hz, 2H). MS (ESI) m/e (M+H+) 499.3.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([O:13][C@@H:14]([C@@H:16]2[CH2:20][C:19](=[O:21])[N:18]([C@@H:22]([C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=3)[CH3:23])[CH2:17]2)[CH3:15])[C:5]2[N:6]([N:8]=[CH:9][C:10]=2[CH:11]=O)[CH:7]=1.Cl.[NH2:33][OH:34].C(=O)(O)[O-].[Na+]>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]([O:13][C@@H:14]([C@@H:16]2[CH2:20][C:19](=[O:21])[N:18]([C@@H:22]([C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=3)[CH3:23])[CH2:17]2)[CH3:15])[C:5]2[N:6]([N:8]=[CH:9][C:10]=2/[CH:11]=[N:33]/[OH:34])[CH:7]=1
Reactant: COc1ccc([C@@H](C)N2C[C@H]([C@@H](C)Oc3cc(Br)cn4ncc(C=O)c34)CC2=O)cc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: COc1ccc([C@@H](C)N2C[C@H]([C@@H](C)Oc3cc(Br)cn4ncc(/C=N/O)c34)CC2=O)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A 100 mL round bottom flask was charged with 6-bromo-4-((R)-1-((R)-1-((R)-1-(4-methoxyphenyl)ethyl)-5-oxopyrrolidin-3-yl)ethoxy)pyrazolo[1,5-a]pyridine-3-carbaldehyde (466 mg, 0.958 mmol), hydroxylamine hydrochloride (79.9 mg, 1.15 mmol), sodium bicarbonate (96.6 mg, 1.15 mmol) and ethanol (8.0 mL). The mixture was stirred at room temperature for 3 h. The reaction was concentrated under reduced pressure to afford (E)-6-bromo-4-((R)-1-((R)-1-((R)-1-(4-methoxyphenyl)ethyl)-5-oxopyrrolidin-3-yl)ethoxy)pyrazolo[1,5-a]pyridine-3-carbaldehyde oxime without further purification.
Reaction SMILES: [CH2:1]=[C:2]1[C@H:9]([CH3:10])[O:8][C@@H:5]([O:6]C)[CH2:4][C@@H:3]1[NH:11][C:12](=[O:17])[C:13]([F:16])([F:15])[F:14]>C(O)(=O)C.O>[CH2:1]=[C:2]1[C@H:9]([CH3:10])[O:8][CH:5]([OH:6])[CH2:4][C@@H:3]1[NH:11][C:12](=[O:17])[C:13]([F:16])([F:15])[F:14]
Reactant: C=C1[C@@H](NC(=O)C(F)(F)F)C[C@H](OC)O[C@H]1C
Solvent: O
Solvent: CC(=O)O
Product: C=C1[C@@H](NC(=O)C(F)(F)F)CC(O)O[C@H]1C
Yield: 98.2 %

Procedure:
A solution of 0.51 g (2 mmol) of the intermediate VIII in 10 ml of acetic acid and 40 ml of water was heated at 100° C. for two hours, then evaporated to dryness to give 2,3,4,6-tetradeoxy-4-C-methylene-3-trifluoroacetamido-L-threo-hexopyranose (IX, 0.47 g, 99%) as a white solid: m.p. 168°-170° C., [α]D20° -160° (c=0.5, CHCl3). Treatment of IX (0.36 g, 1.5 mmol) in 25 ml of dry methylene dichloride with 4 ml of trifluoroacetic anhydride for 2 hours at 0° C. and 1 hour at 20° C. gave, after evaporation, the 1-0-trifluoroacetate (X), which was directly used for the preparation of the corresponding 1-chloro-derivative by treatment with dry hydrogen chloride in anhydrous diethyl ether at 0° C. After standing at 0° C. overnight, the reaction mixture was evaporated to dryness to give 2,3,4,6-tetradeoxy-4-C-methylene-3-trifluoroacetamido-L-threo-hexopyranosyl chloride (III-A, 0.35 g, 90%), suitable for the subsequent coupling reaction without further purification.
Reaction SMILES: [CH3:1][CH:2]([CH3:23])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][C:7]=1[C:13]1[CH:18]=[CH:17][N:16]=[C:15]([S:19](C)(=O)=O)[N:14]=1)=[O:4].S.[K].O.Cl>C(O)C>[SH:19][C:15]1[N:14]=[C:13]([C:7]2[CH:8]=[C:9]([CH3:12])[CH:10]=[CH:11][C:6]=2[NH:5][C:3](=[O:4])[CH:2]([CH3:1])[CH3:23])[CH:18]=[CH:17][N:16]=1
Reactant: Cc1ccc(NC(=O)C(C)C)c(-c2ccnc(S(C)(=O)=O)n2)c1
Agent: Cl
Agent: S
Agent: [K]
Solvent: O
Solvent: CCO
Product: Cc1ccc(NC(=O)C(C)C)c(-c2ccnc(S)n2)c1
Yield: 75.9 %

Procedure:
3.3 g (0.01 mol) 2-methyl-N-[4-methyl-2-[2-(methylsulfonyl)-4-pyrimidinyl]phenyl]propanamide was dissolved in 35 mL absolute ethanol and 3 g potassium hydrogen sulfide was added to this solution with stirring. The reaction mixture was stirred overnight at room temperature. 50 mL water was added and the volume reduced under vacuum to 40 mL. An additional 40 mL water was added and the solution thus obtained was made acidic with concentrated hydrochloric acid. The yellow precipitate was collected by filtration, washed with a little water, then dissolved in 50 mL 1N sodium hydroxide and treated with charcoal. The charcoal was filtered off and the filtrate was made acidic with concentrated hydrochloric acid. The bright yellow precipitate was collected by filtration, washed with water, then dried in a vacuum oven to yield 2.18 g of N-[2-(2-mercapto-4-pyrimidyl)-4-methylphenyl]-2-methylpropanamide. 1H NMR (CDCl3): δ 1.21 (d,6H), 2.40 (s,3H), 2.75 (m,1H), 7.40-8.60 (5H), 11.4(s,1H,NH), 11.9(s,1H,SH).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:12]=[C:13]([Br:17])[C:14]=1[O:15][CH3:16])[CH:6]=[C:7]([C:10]#[N:11])[C:8]#[N:9].[C:18]1([OH:28])[C:27]2[CH2:26][CH2:25][CH2:24][CH2:23][C:22]=2[CH:21]=[CH:20][CH:19]=1.N1CCCCC1>C(O)C>[NH2:9][C:8]1[O:28][C:18]2[C:27]3[CH2:26][CH2:25][CH2:24][CH2:23][C:22]=3[CH:21]=[CH:20][C:19]=2[CH:6]([C:5]2[CH:4]=[C:3]([O:2][CH3:1])[C:14]([O:15][CH3:16])=[C:13]([Br:17])[CH:12]=2)[C:7]=1[C:10]#[N:11]
Reactant: COc1cc(C=C(C#N)C#N)cc(Br)c1OC
Reactant: Oc1cccc2c1CCCC2
Solvent: CCO
Solvent: C1CCNCC1
Product: COc1cc(C2C(C#N)=C(N)Oc3c2ccc2c3CCCC2)cc(Br)c1OC
Yield: 1.4 %

Procedure:
To a stirred suspension of 3,4-dimethoxy-5-bromobenzylidenemalononitrile (293 mg, 1 mmol) and 5,6,7,8-Tetrahydro-1-naphthol (148 mg, 1 mmol) in ethanol (4 ml) was added piperidine (0.1 ml, 1 mmol), and the mixture was refluxed for 2 h. The solvent was evaporated and the residue was purified by column chromatography (EtOAc/Hexane, 1:2), yielding the title compound (6 mg, 1.4%). 1H NMR (CDCl3): 7.89 (d, J=2.0, 1H), 6.80-6.69 (m, 3H), 4.63 (s, 3H), 3.86 (s, 3H), 3.83 (s, 3H), 2.72 (m, 4H), 1.8 (m, 4H).
Reaction SMILES: [CH:1]1([C:4]2[O:8][N:7]=[CH:6][C:5]=2[C:9](=[O:28])[C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][C:11]=2[S:20][C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)[CH2:3][CH2:2]1.ClC1C=C(C=CC=1)C(OO)=[O:34]>ClCCl>[CH:1]1([C:4]2[O:8][N:7]=[CH:6][C:5]=2[C:9](=[O:28])[C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][C:11]=2[S:20]([C:21]2[CH:22]=[CH:23][C:24]([Cl:27])=[CH:25][CH:26]=2)=[O:34])[CH2:3][CH2:2]1
Reactant: O=C(c1ccc(C(F)(F)F)cc1Sc1ccc(Cl)cc1)c1cnoc1C1CC1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: O=C(c1ccc(C(F)(F)F)cc1S(=O)c1ccc(Cl)cc1)c1cnoc1C1CC1
Temperature: -12 °C
Reaction time: 0.25 h
Yield: 72.7 %

Procedure:
A mixture of 5-cyclopropyl-4-[2-(4-chlorophenylsulphenyl)-4-trifluoromethylbenzoyl]isoxazole (1.14 g) and 3-chloroperoxybenzoic acid (0.84 g) in dichloromethane was stirred at -12° C. for 15 minutes. The precipitate was filtered and the filtrate was washed with aqueous sodium metabisulphite, aqueous sodium bicarbonate and a solution of brine and ammonium chloride, dried over anhydrous sodium sulphate and filtered. The dichloromethane was evaporated and the residue was crystallised from ethanol to give 5-cyclopropyl-4-[2-(4-chlorophenylsulphinyl)-4-trifluoromethylbenzoyl]isoxazole (compound 9, 0.86 g) as white crystals, m.p. 151° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH:5]([S:7]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=1)(=[O:9])=[O:8])[CH3:6])[CH3:2].Cl.[N:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH2:26]Cl)[CH:21]=1>[Cl-].C([N+](CC)(CC)CC1C=CC=CC=1)C.C(Cl)Cl.[OH-].[Na+]>[CH2:1]([O:3][C:4](=[O:18])[C:5]([S:7]([C:10]1[CH:11]=[CH:12][C:13]([O:16][CH3:17])=[CH:14][CH:15]=1)(=[O:8])=[O:9])([CH3:6])[CH2:26][C:22]1[CH:21]=[N:20][CH:25]=[CH:24][CH:23]=1)[CH3:2]
Reactant: CCOC(=O)C(C)S(=O)(=O)c1ccc(OC)cc1
Reactant: ClCc1cccnc1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: Cl
Agent: [Cl-]
Solvent: ClCCl
Product: CCOC(=O)C(C)(Cc1cccnc1)S(=O)(=O)c1ccc(OC)cc1
Reaction time: 48 h

Procedure:
To a stirred solution of 2-(4-methoxy-benzenesulfonyl)propionic acid ethyl ester (2.7 gm, 10 mmol), 3-picolyl chloride hydrochloride (3.2 g, 20 mmol). and triethyl benzylammonium chloride (1 g) in methylene chloride (400 ml), 10N NaOH ( 30 ml) was added. The reaction was continued at room temp for 48 hours. At the end, the organic layer was separated and washed well with water. The organic layer was dried, filtered and concentrated. The crude product obtained was purified by silica-gel column chromatography. The column was eluted with 50% ethyl acetate: hexane. 2-(4-Methoxy-benzensulfonyl)-2-methyl-3-pyridin-3-yl-propionic acid ethyl ester was isolated as brown oil. Yield 3.0 g, 82%; Brown oil; MS: 364 (M+H)+.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[C:10]=1[CH2:17][N:18]1[C:23]2[CH:24]=[CH:25][CH:26]=[N:27][C:22]=2[N:21]2[CH2:28][CH2:29][CH2:30][CH:20]2[C:19]1=O.O1CCCC1>CCOCC>[CH3:16][O:15][C:11]1[CH:12]=[CH:13][CH:14]=[C:9]([O:8][CH3:7])[C:10]=1[CH2:17][N:18]1[C:23]2[CH:24]=[CH:25][CH:26]=[N:27][C:22]=2[N:21]2[CH2:28][CH2:29][CH2:30][CH:20]2[CH2:19]1
Reactant: COc1cccc(OC)c1CN1C(=O)C2CCCN2c2ncccc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1cccc(OC)c1CN1CC2CCCN2c2ncccc21
Yield: 67 %

Procedure:
Lithium aluminum hydride (1 g.) was dissolved in 100 ml. of anhydrous diethyl ether. To the stirred solution was added over a period of fifteen minutes a solution of 6a,7,8,9-tetrahydro-5-[(2,6-dimethoxyphenyl)methyl]pyrido[3,2-e]pyrrolo[1,2-a]pyrazin-6(5H)-one (1 g., 0.003 mole) in 50 ml. of dry tetrahydrofuran. The reaction mixture was refluxed for eighteen hours and was worked up by adding wet ether, filtering, drying and evaporating in vacuo. The residue (m.p. 110°-112° C.) was dissolved in ethanol and treated with diethyl ether saturated with hydrogen chloride. The separated solid was recrystallized from methanol to afford 0.7 g. (67% yield) of the title compound as the hydrochloride salt, m.p. 211°-213° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23].O>ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([S:22]([CH3:21])(=[O:24])=[O:23])[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: Brc1ccc(N2CCNCC2)cc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CS(=O)(=O)N1CCN(c2ccc(Br)cc2)CC1
Yield: 99.9 %

Procedure:
1-(4-Bromophenyl)piperazine (5 g, 20.7 mmol) is placed in 104 ml of dichloromethane and then triethylamine (4.34 ml, 31.1 mmol) is added, followed, dropwise, by methanesulfonyl chloride (1.93 ml, 24.9 mmol). Stirring is maintained for 16 h. After the addition of 30 ml of water and stirring, the organic phase is washed with a saturated aqueous sodium chloride solution, dried over MgSO4 and concentrated. 6.6 g of expected 1-(4-bromophenyl)-4-methanesulfonylpiperazine are obtained.