Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([Cl:30])[CH:5]=[C:6]2[C:11]=1[O:10][C:9](=[O:12])[CH:8]=[C:7]2[NH:13][CH:14]1[CH2:19][CH2:18][N:17]([CH2:20][C:21]2[CH:29]=[CH:28][C:24]3[O:25][CH2:26][O:27][C:23]=3[CH:22]=2)[CH2:16][CH2:15]1.C([O-])([O-])=O.[K+].[K+].[NH:37]1[CH2:41][CH2:40][CH2:39][C:38]1=O.CNCCNC>C1(C)C=CC=CC=1.C(Cl)Cl.[Cu]I>[N:37]1([C:2]2[CH:3]=[C:4]([Cl:30])[CH:5]=[C:6]3[C:11]=2[O:10][C:9](=[O:12])[CH:8]=[C:7]3[NH:13][CH:14]2[CH2:19][CH2:18][N:17]([CH2:20][C:21]3[CH:29]=[CH:28][C:24]4[O:25][CH2:26][O:27][C:23]=4[CH:22]=3)[CH2:16][CH2:15]2)[CH2:41][CH2:40][CH2:39][CH2:38]1
Reactant: O=C1CCCN1
Reactant: O=c1cc(NC2CCN(Cc3ccc4c(c3)OCO4)CC2)c2cc(Cl)cc(Br)c2o1
Agent: [Cu]I
Agent: CNCCNC
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: O=c1cc(NC2CCN(Cc3ccc4c(c3)OCO4)CC2)c2cc(Cl)cc(N3CCCC3)c2o1
Temperature: 25 °C
Reaction time: 16 h
Yield: 20.4 %

Procedure:
A solution of 8-Bromo-6-chloro-4-[1-benzo[1,3]dioxol-5-ylmethyl-piperidin-4-ylamino]chromen-2-one (30 mg, 0.061 mmol) in 0.3 mL toluene under nitrogen was treated with K2CO3 (20 mg, 0.13 mmol), about 3 mg CuI (0.016 mmol), 2-pyrrolidinone (10 uL, 0.13 mmol), followed by N,N′-dimethylethylenediamine (3 uL, 0.025 mmol) and heated to reflux. After 16 hours, the reaction was allowed to cool to room temperature, diluted with CH2Cl2, washed with distilled water, dried (Na2SO4) and concentrated. Purification by reverse phase HPLC (Zorbax C18, 21.2×250 mm column, 15 mL/min, 0 to 60% acetonitrile:water with 0.1% trifluoroacetic acid) followed by extraction into CH2Cl2 after basification with 1 M K2CO3, dried (Na2SO4) and concentrated to give the title compound (6 mg, 20%). 1H NMR (300 MHz, ppm, DMSO-d6) δ 1.6 (m, 2H), 1.8 (m, 2H), 2.1 (m, 4H), 2.7 (m, 2H), 3.4-3.5 (m, 3H), 3.72 (t, J=7 Hz, 2H) 5.23 (s, 1H), 5.92 (s, 2H), 6.68-6.80 (m, 3H), 7.27 (m, 1H), 7.62 (d, J=2.3 Hz, 1H), 8.20 (d, J=2.4 Hz, 1H). MS(ESI) 496 (M+H), 494 (M−H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][C:13]=1[Cl:14])[O:5][CH2:6][C:7](=[NH:10])OC.[NH3:15]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][C:13]=1[Cl:14])[O:5][CH2:6][C:7]([NH2:15])=[NH:10]
Reactant: COC(=N)COc1ccc(Cl)c(Cl)c1
Reactant: N
Solvent: CCO
Product: N=C(N)COc1ccc(Cl)c(Cl)c1

Procedure:
Obtained using the procedure described in section b of Example 2, starting with 28.2 g (0.12 mole) of methyl 2-(3,4-dichlorophenoxy)acetimidate and 10.2 g (0.60 mole) of ammonia in 480 ml of absolute ethanol. Reaction time: 3 hours. Yld: 26.3 g (quantitative).
Reaction SMILES: [F:1][CH:2]([F:27])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:11][CH:12]=[C:13]([CH2:15][CH2:16][C:17]([C:19]3[C:24]([CH3:25])=[CH:23][CH:22]=[CH:21][N:20]=3)=[O:18])[N:14]=2)=[CH:6][C:5]=1[OH:26].N12CCCN=C1CC[CH2:31][CH2:30][CH2:29]2.BrCCC.O>C(O)C.C(OCC)(=O)C>[F:27][CH:2]([F:1])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:11][CH:12]=[C:13]([CH2:15][CH2:16][C:17]([C:19]3[C:24]([CH3:25])=[CH:23][CH:22]=[CH:21][N:20]=3)=[O:18])[N:14]=2)=[CH:6][C:5]=1[O:26][CH2:29][CH2:30][CH3:31]
Reactant: C1CCC2=NCCCN2CC1
Reactant: Cc1cccnc1C(=O)CCc1coc(-c2ccc(OC(F)F)c(O)c2)n1
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCCBr
Product: CCCOc1cc(-c2nc(CCC(=O)c3ncccc3C)co2)ccc1OC(F)F

Procedure:
A 80 mg quantity of the compound obtained in Example 327 and 0.09 ml of 1,8-diazabicyclo[5,4,0]undec-7-ene were dissolved in 2 ml of ethanol, 80 mg of 1-bromopropane was then added to the obtained solution, and heated and refluxed overnight. After cooling, water was added to the obtained reaction mixture, and ethyl acetate extraction was performed. The organic layer was washed twice with water, concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=3:1). The obtained crystals were recrystallized from aqueous 80% ethanol, thereby yielding 25 mg of white powdery 3-[2-(4-difluoromethoxy-3-propoxyphenyl)oxazol-4-yl]-1-(3-methylpyridin-2-yl)propan-1-one.
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[CH:3]=[CH:2]1.C1COCC1.[C:15]1([S:21](Cl)(=[O:23])=[O:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[C:15]1([S:21]([N:1]2[C:9]3[CH:8]=[CH:7][N:6]=[CH:5][C:4]=3[CH:3]=[CH:2]2)(=[O:23])=[O:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: c1cc2[nH]ccc2cn1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: C1CCOC1
Product: O=S(=O)(c1ccccc1)n1ccc2cnccc21
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 59.5 %

Procedure:
A 100 mL round-bottomed flask was charged with a solution of 1H-pyrrolo[3,2-c]pyridine (1.0 g, 8.4 mmol) in anhydrous THF (50 mL) NaH (60% in mineral oil, 0.41 g, 10.2 mmol) was added and the reaction mixture was stirred for 5 min at room temperature. To this solution was added dropwise, at 0° C., benzenesulfonyl chloride (1.35 mL, 10.2 mmol) and the resulting mixture was stirred at room temperature for 2 h. The reaction mixture was quenched with water (30 mL) and extracted with EtOAc (3×100 mL) The organic layers were combined, dried (Na2SO4) and concentrated in vacuo to give the title compound as a white solid (1.29 g, 55%). 1H NMR (DMSO, 300 MHz): δ 8.95 (s, 1 H); 8.49 (d, J=5.8 Hz, 1 H); 8.13-8.05 (m, 2 H); 8.02-7.94 (m, 2 H); 7.79-7.71 (m, 1 H); 7.69-7.59 (m, 2 H); 7.01 (dd, J=3.7, 0.9 Hz, 1 H).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH:9]2[C:13]3=[C:14]([F:22])[CH:15]=[N:16][C:17]4[CH:18]=[CH:19][C:20](=[O:21])[N:11]([C:12]=43)[CH2:10]2)[CH2:4][C@H:3]1[OH:23].[S:24]1[C:32]2[CH:31]=[C:30]([CH:33]=O)[N:29]=[CH:28][C:27]=2[O:26][CH2:25]1.[ClH:35].Cl.C(OCC)C>C(Cl)(Cl)Cl>[ClH:35].[F:22][C:14]1[CH:15]=[N:16][C:17]2[CH:18]=[CH:19][C:20](=[O:21])[N:11]3[CH2:10][CH:9]([CH2:8][N:5]4[CH2:6][CH2:7][C@H:2]([NH:1][CH2:33][C:30]5[N:29]=[CH:28][C:27]6[O:26][CH2:25][S:24][C:32]=6[CH:31]=5)[C@H:3]([OH:23])[CH2:4]4)[C:13]=1[C:12]=23
Reactant: N[C@H]1CCN(CC2Cn3c(=O)ccc4ncc(F)c2c43)C[C@H]1O
Reactant: O=Cc1cc2c(cn1)OCS2
Agent: Cl
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Product: O=c1ccc2ncc(F)c3c2n1CC3CN1CC[C@H](NCc2cc3c(cn2)OCS3)[C@H](O)C1

Procedure:
The free base of the title compound was synthesised from racemic 4-{[(3R,4S)-4-amino-3-hydroxy-1-piperidinyl]methyl}-3-fluoro-4,5-dihydro-7H-pyrrolo[3,2,1-de]-1,5-naphthyridin-7-one and [1,3]oxathiolo[5,4-c]pyridine-6-carbaldehyde (for a synthesis see WO2004058144, Example 61) according to the general method of Example 24(b). The free base of the title compound was converted to the hydrochloride by dissolving in chloroform and adding 1 equivalent of 1M HCl/diethyl ether, then evaporating to dryness. MS as that of free base.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([N:7]2[CH:12]([OH:13])[CH2:11][CH2:10][N:9]([CH3:14])[C:8]2=[O:15])=[N:4][N:3]=1.Cl[C:17]([O:19][CH3:20])=[O:18]>N1C=CC=CC=1>[CH3:1][C:2]1[S:6][C:5]([N:7]2[CH:12]([O:13][C:17]([O:19][CH3:20])=[O:18])[CH2:11][CH2:10][N:9]([CH3:14])[C:8]2=[O:15])=[N:4][N:3]=1
Reactant: Cc1nnc(N2C(=O)N(C)CCC2O)s1
Reactant: COC(=O)Cl
Solvent: c1ccncc1
Product: COC(=O)OC1CCN(C)C(=O)N1c1nnc(C)s1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Tetrahydro-1-(5-methyl-1,3,4-thiadiazol-2-yl)-3-methyl-6-hydroxy-2(1H)-pyrimidinone (0.05 mole) dissolved in pyridine (80 ml) is charged into a glass reaction vessel equipped with a mechanical stirrer and thermometer. The solution is cooled to a temperature of about 10° C. and methyl chloroformate (0.06 mole) dissolved in pyridine (25 ml) is slowly added with stirring over a period of about 15 minutes. After the addition is completed, the reaction mixture is warmed to room temperature and is stirred for an additional period of about 20 minutes to ensure completion of the reaction. After this time the reaction mixture is filtered. The filtrate is then combined with water (100 ml) resulting in the formation of a precipitate. This precipitate is recovered by filtration and is dissolved in ether. The ether solution is washed with dilute aqueous sodium carbonate, is dried over anhydrous magnesium sulfate and is filtered. The filtrate is then stripped of ether to yield the desired product tetrahydro-1-(5-methyl-1,3,4-thiadiazol-2-yl)-3-methyl-6-methoxycarbonyloxy-2(1H)-pyrimidinone as the residue.
Reaction SMILES: Cl[C:2]1[C:10]2[O:9][CH2:8][CH2:7][C:6]=2[C:5]([CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:17])[CH3:16])=[CH:4][CH:3]=1>C(O)C.[Pd]>[O:9]1[C:10]2[CH:2]=[CH:3][CH:4]=[C:5]([CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:17])[CH3:16])[C:6]=2[CH2:7][CH2:8]1
Reactant: CC(=O)NCCCc1ccc(Cl)c2c1CCO2
Agent: [Pd]
Solvent: CCO
Product: CC(=O)NCCCc1cccc2c1CCO2
Yield: 80.1 %

Procedure:
A solution of the N-[3-(7-chloro-2,3-dihydro-benzofuran-4-yl)-propyl]-acetamide, (78 mg) in ethanol (5 ml) was hydrogenated over palladium (10%; 20 mg) over 64 h. The catalyst was filtered off and the filtrate concentrated in vacuo. The residue was purified by column chromatography, eluting with dichloromethane/methanol 50:1 gave the title compound as a colourless solid (54 mg) mp 66-67° C.
Reaction SMILES: [C:1]1([C@@H:7]([N:9]2[C@@H:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C@H:13]3[CH2:20][C@@H:10]2[CH:11]=[CH:12]3)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:21]1CCC=CC=1>>[C:1]1([CH:7]([N:9]2[CH:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:13]3[CH2:12][CH2:11][CH:10]2[CH:20]=[CH:21]3)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)[C@H]1[C@@H]2C=C[C@@H](C2)N1[C@@H](C)c1ccccc1
Reactant: C1=CCCC=C1
Product: CCOC(=O)C1C2C=CC(CC2)N1C(C)c1ccccc1

Procedure:
In the reaction (a) of Example 1, 1,3-cyclohexadiene is used in place of cyclopentadiene to give ethyl 2-(1-phenylethyl)-2-azabicyclo[2.2.2]oct-5-ene-3-carboxylate.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9].[C:13]([C:17]1[CH:18]=[C:19]([C:26]2[CH:27]=[N:28][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:30][CH:31]=2)[C:20]([OH:25])=[C:21]([CH:24]=1)[CH:22]=O)([CH3:16])([CH3:15])[CH3:14].[BH4-].[Na+]>CO>[C:13]([C:17]1[CH:18]=[C:19]([C:26]2[CH:27]=[N:28][C:29]([C:32]([F:35])([F:33])[F:34])=[CH:30][CH:31]=2)[C:20]([OH:25])=[C:21]([CH:24]=1)[CH2:22][NH:1][CH2:2][CH2:3][CH2:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:9])([CH3:11])[CH3:10])([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(C)(C)OC(=O)NCCCN
Reactant: CC(C)(C)c1cc(C=O)c(O)c(-c2ccc(C(F)(F)F)nc2)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)NCCCNCc1cc(C(C)(C)C)cc(-c2ccc(C(F)(F)F)nc2)c1O
Temperature: 25 °C
Reaction time: 4 h
Yield: 101.2 %

Procedure:
tert-Butyl N-(3-aminopropyl)carbamate (0.404 g, 2.32 mmol) was added to a solution of 5-(tert-butyl)-2-hydroxy-3-(6-(trifluoromethyl)pyridin-3-yl)benzaldehyde (from Example 47 Step 1) (0.5 g, 1.55 mmol) in methanol (5 mL) and the reaction mixture stirred at room temperature under nitrogen for 4 hours. Sodium borohydride (234 mg, 6.19 mmol) was then added and the reaction mixture stirred at room temperature for 2.5 hours. The reaction was quenched by the addition of saturated aqueous ammonium chloride solution (5 mL), the mixture stirred vigorously for 10 minutes then partitioned between ethyl acetate (80 mL) and saturated aqueous ammonium chloride solution (80 mL). The organic phase was separated, washed with water (80 mL) and saturated brine (80 mL), dried (MgSO4), filtered and concentrated under reduced pressure to give a yellow syrup. The product was purified using flash chromatography on silica eluting with a solvent gradient of 0 to 6% methanol (containing 1% aqueous ammonium hydroxide) in dichloromethane to give tert-butyl (3-((5-(tert-butyl)-2-hydroxy-3-(6-(trifluoromethyl)pyridin-3-yl)benzyl)amino)propyl)carbamate (0.755 g, 100% yield) as a yellow syrup.
Reaction SMILES: [N+]([O-])([O-])=O.[NH4+].[CH3:6][C:7]([CH3:16])=[CH:8][CH2:9][O:10][CH:11]=[CH:12][C:13]([CH3:15])=[CH2:14]>C1(C)C(C)=CC=CC=1>[CH3:14][C:13]([CH3:15])=[CH:12][CH2:11][O:10][CH:9]([O:10][CH2:9][CH:8]=[C:7]([CH3:16])[CH3:6])[CH:8]=[C:7]([CH3:16])[CH3:6]
Reactant: C=C(C)C=COCC=C(C)C
Agent: O=[N+]([O-])[O-]
Agent: [NH4+]
Solvent: Cc1ccccc1C
Product: CC(C)=CCOC(C=C(C)C)OCC=C(C)C
Temperature: 100 °C

Procedure:
20 Parts of 1,1-di-(3-methyl-2-butenyloxy)-3-methyl-2-butene which was synthesized in Example 1, 43 parts of xylene, and 0.1 part of ammonium nitrate were charged in a flask, and the xylene was distilled off under reduced pressure (20 mmHg). Thereafter the bath temperature was maintained at not higher than 100°C., and the distillate was collected until the reaction was completed. Re-distilling the so obtained distillate, 5.15 parts of a fraction of a distillate boiling at 46.5°C./0.1 mmHg was obtained, which was confirmed to be 1-(3-methyl-2-butenyloxy)-3-methyl-1,3-butadiene from the results of IR, NMR, and high resolving power mass spectrum analyses. The analyses data are shown in Table 9.
Reaction SMILES: Cl.Cl.[NH:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[C:20]4[C:15](=[N:16][CH:17]=[N:18][C:19]=4[NH2:21])[N:14]([CH3:22])[N:13]=3)=[CH:9][CH:10]=2)[CH2:5][CH2:4]1.[CH3:23][O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[CH2:31][C:32](O)=[O:33].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O>[CH3:22][N:14]1[C:15]2=[N:16][CH:17]=[N:18][C:19]([NH2:21])=[C:20]2[C:12]([C:8]2[CH:7]=[C:6]3[C:11](=[CH:10][CH:9]=2)[N:3]([C:32](=[O:33])[CH2:31][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[O:24][CH3:23])[CH2:4][CH2:5]3)=[N:13]1
Reactant: COc1ccccc1CC(=O)O
Reactant: Cn1nc(-c2ccc3c(c2)CCN3)c2c(N)ncnc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccccc1CC(=O)N1CCc2cc(-c3nn(C)c4ncnc(N)c34)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.4 %

Procedure:
In a 20 mL vial with cap, to the solution of 3-(2,3-dihydro-1H-indol-5-yl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine 2HCl (70 mg, 0.206 mmol), [2-(methyloxy)phenyl]acetic acid (34.3 mg, 0.206 mmol), HATU (78 mg, 0.206 mmol) in DMF (2 mL) was added Hunig's base (0.144 mL, 0.825 mmol). The mixture was stirred at room temperature for overnight. LCMS showed reaction was completed. The reaction was poured into water, off-white solid formed. The solid was filtered to give the title compound (78 mg) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 3.28 (m, 2H), 3.78 (s, 3H), 3.80 (s, 2H), 3.94 (s, 3H), 4.22-4.30 (m, 2H), 6.93 (t, J=7.45 Hz, 1H), 7.01 (d, J=7.83 Hz, 1H), 7.20 (dd, J=7.58, 1.52 Hz, 1H), 7.25-7.32 (m, 1H), 7.43 (d, J=8.34 Hz, 1H), 7.51 (s, 1H), 8.16 (d, J=8.34 Hz, 1H), 8.25 (s, 1H).
Reaction SMILES: [CH3:1][CH:2]1[C:7]([C:8]2[CH:17]=[C:16]3[C:11]([C:12](SC)=[N:13][CH:14]=[N:15]3)=[CH:10][CH:9]=2)=[N:6][NH:5][C:4](=[O:20])[CH2:3]1.[CH3:21][N:22](C)[CH:23]=O>C(N(CC)CC)C.CNC>[CH3:1][CH:2]1[C:7]([C:8]2[CH:17]=[C:16]3[C:11]([C:12]([N:22]([CH3:23])[CH3:21])=[N:13][CH:14]=[N:15]3)=[CH:10][CH:9]=2)=[N:6][NH:5][C:4](=[O:20])[CH2:3]1
Reactant: CSc1ncnc2cc(C3=NNC(=O)CC3C)ccc12
Reactant: CN(C)C=O
Agent: CNC
Solvent: CCN(CC)CC
Product: CC1CC(=O)NN=C1c1ccc2c(N(C)C)ncnc2c1
Temperature: 60 °C
Reaction time: 4 h
Yield: 51 %

Procedure:
Compound 57 (0.6 g) obtained in Example 19 was dissolved in a mixture of 10 ml of dimethylformamide, 1 ml of triethylamine and 5ml of aqueous 50% dimethylamine solution. The resulting solution was stirred at 60° C. for 4 hours and then concentrated. Thereafter, water was added to the residue, and the crystals precipitated were collected by filtration and dried to give 0.3 g (51%) of 4,5-dihydro-5-methyl-6-(4-dimethylaminoquinazolin-7-yl)-3(2H)-pyridazinone (Compound 13).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH2:7])[S:5][CH:6]=1.Cl[C:9]1[CH:14]=[C:13]([S:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:22])[CH:12]=[CH:11][N:10]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>[Cl:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[S:15][C:13]1[CH:12]=[CH:11][N:10]=[C:9]([NH:7][C:4]2[S:5][CH:6]=[C:2]([CH3:1])[N:3]=2)[CH:14]=1
Reactant: Cc1csc(N)n1
Reactant: Clc1cc(Sc2ccccc2Cl)ccn1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: Cc1csc(Nc2cc(Sc3ccccc3Cl)ccn2)n1
Yield: 83.6 %

Procedure:
Using the method of Example 3, Step B, 4-methylthiazol-2-amine (7.88 mL, 5.52 mmol), 2-chloro-4-(2-chlorophenylthio)pyridine (1.55 g, 6.07 mmol), potassium phosphate (1.29 g, 6.07 mmol), tris(dibenzylideneacetone)dipalladium (0) (0.126 g, 0.138 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethyl-9H-xanthene (0.0878 g, 0.152 mmol) were reacted in toluene (8 mL) to afford 4-(2-chlorophenylthio)-N-(4-methylthiazol-2-yl)pyridin-2-amine (1.54 g, 82.8% yield) as yellow solid. 1H NMR (CDCl3) δ 8.11 (d, 1H), 7.59 (dd, 1H), 7.53 (dd, 1H), 7.38 (dt, 1H), 7.29 (dt, 1H), 6.56 (dd, 1H), 6.48 (d, 1H), 2.23 (s, 3H); Mass spectrum (esi) m/z 334 (100) (M+H).
Reaction SMILES: [Na].[CH2:2]([OH:16])[C@@H:3]([OH:15])[C@@H:4]([OH:14])[C@H:5]([OH:13])[C@@H:6]([OH:12])[C@@H:7]([OH:11])[C:8]([O-:10])=[O:9].[Na+]>O.O[Mo](O)(=O)=O>[CH2:2]([OH:16])[C@@H:3]([OH:15])[C@@H:4]([OH:14])[C@H:5]([OH:13])[C@@H:6]([OH:12])[C@@H:7]([OH:11])[C:8]([OH:10])=[O:9]
Reactant: O=C([O-])[C@H](O)[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: O=[Mo](=O)(O)O
Agent: [Na+]
Agent: [Na]
Solvent: O
Product: O=C(O)[C@H](O)[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Temperature: 25 °C

Procedure:
The molybdenum ester of glucoheptonic acid was prepared as follows: Approximately 241 grams (1 mol) of the sodium salt of molybdic acid (sodium molybdenate) and 248 grams (1 mol) of sodium glucoheptonate were charged to an esterification vessel containing about 600 ml. of water as a solvent. With stirring, the temperature was maintained at about 25° C. for approximately 30 minutes. The mixture was thereafter diluted to a final volume of one liter with additional water.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([CH:8]([C:17]2[CH:18]=[C:19]([CH:24]=[CH:25][C:26]=2[O:27][CH3:28])[C:20]([O:22][CH3:23])=[O:21])[C:9](=[O:16])[C:10]#[C:11][Si](C)(C)C)=[CH:4][CH:3]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.O.CCOC(C)=O.CN1C(=O)CCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:11]=[CH:10][C:9](=[O:16])[C:8]=2[C:17]2[CH:18]=[C:19]([CH:24]=[CH:25][C:26]=2[O:27][CH3:28])[C:20]([O:22][CH3:23])=[O:21])[N:7]=1
Reactant: COC(=O)c1ccc(OC)c(C(C(=O)C#C[Si](C)(C)C)c2ccc(Cl)nn2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)c1ccc(OC)c(-c2c(=O)ccn3nc(Cl)ccc23)c1
Temperature: 90 °C
Reaction time: 0.17 h

Procedure:
To a solution methyl 3-[1-(6-chloropyridazin-3-yl)-2-oxo-4-(trimethylsilyl)but-3-yn-1-yl]-4methoxybenzoate (5.58 g, 13.4 mmol) in THF (200 mL) was added TBAF (20.0 mL, 20 mmol) at 0° C. After 10 min the reaction was complete by TLC analysis and diluted with H2O/EtOAc (1/1). The organic layer was washed with H2O, brine, dried over MgSO4 and concentrated to yield an oil. The crude material was dissolved in NMP (25 mL) and heated to 90° C. for 0.5 hr. The completed reaction was poured into 500 mL of ice water and the solid precipitate was collected and dried.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[C:5]([N+:10]([O-])=O)[CH:4]=1.[Sn].[Cl-].[OH-].[Na+]>C(O)C>[NH2:10][C:5]1[CH:4]=[C:3]([C:2]([F:1])([F:13])[F:14])[CH:8]=[CH:7][C:6]=1[OH:9]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1O
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Nc1cc(C(F)(F)F)ccc1O
Temperature: 80 °C
Reaction time: 2 h
Yield: 83.3 %

Procedure:
A mixture of 4-trifluoromethyl-2-nitrophenol (1.0 g, 4.8 mmol) and tin (It) chloride (5.4 g, 24.2 mmol) in ethanol (150 mL) was heated at 80° C. under argon. After 2 hours, the starting material had disappeared and the solution was allowed to cool down and then poured into ice. The pH was made slightly basic (pH7-8), by addition of solid NaOH, before being extracted with ethyl acetate. The organic phase was washed with brine, dried over MgSO4 and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (4%MeOH/CH2Cl2) gave the desired product (708 mg, 83%). 1H NMR (CD3OD): d 6.87 (s, 1H), 6.80 (d, 1H), 6.69 (d, 1H).
Reaction SMILES: [C:1]([C:3]1([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1)#[N:2].C(C1(C2C=CC(OC)=C(C=2)[CH:27]=[O:28])CC1)#N>>[C:1]([C:3]1([C:9]2[CH:10]=[CH:11][C:12]([O:15][CH3:16])=[C:13]([CH:14]=2)[CH:27]=[O:28])[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1)#[N:2]
Reactant: COc1ccc(C2(C#N)CCOCC2)cc1
Reactant: COc1ccc(C2(C#N)CC2)cc1C=O
Product: COc1ccc(C2(C#N)CCOCC2)cc1C=O

Procedure:
This compound was prepared from Compound 88 in the same manner of Compound 2.
Reaction SMILES: C(OC(=O)C(OCC)CC1C=CC(O)=C(C)C=1)C1C=CC=CC=1.CC1OC(C2C=CC=CC=2)=NC=1CC(O)=O.[CH2:40]([O:47][C:48](=[O:83])[CH:49]([O:80][CH2:81][CH3:82])[CH2:50][C:51]1[CH:56]=[CH:55][C:54]([O:57][C:58](=[O:72])[CH2:59][C:60]2[N:61]=[C:62]([C:66]3[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=3)[O:63][C:64]=2[CH3:65])=[C:53]([CH2:73]C2C=CC=CC=2)[CH:52]=1)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>>[CH2:40]([O:47][C:48](=[O:83])[CH:49]([O:80][CH2:81][CH3:82])[CH2:50][C:51]1[CH:56]=[CH:55][C:54]([O:57][C:58](=[O:72])[CH2:59][C:60]2[N:61]=[C:62]([C:66]3[CH:67]=[CH:68][CH:69]=[CH:70][CH:71]=3)[O:63][C:64]=2[CH3:65])=[C:53]([CH3:73])[CH:52]=1)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: CCOC(Cc1ccc(OC(=O)Cc2nc(-c3ccccc3)oc2C)c(Cc2ccccc2)c1)C(=O)OCc1ccccc1
Agent: CCOC(Cc1ccc(O)c(C)c1)C(=O)OCc1ccccc1
Agent: Cc1oc(-c2ccccc2)nc1CC(=O)O
Product: CCOC(Cc1ccc(OC(=O)Cc2nc(-c3ccccc3)oc2C)c(C)c1)C(=O)OCc1ccccc1

Procedure:
The title compound was prepared from 2-ethoxy-3-(4-hydroxy-3-methyl-phenyl)-propionic acid benzyl ester (311 mg, 0.98 mmol) and (5-methyl-2-phenyl-oxazol-4-yl)-acetic acid (215 mg, 0.98 mmol) in the same manner as described for 3-{3-benzyl-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-acetoxy]-phenyl}-2-ethoxy-propionic acid benzyl ester. The crude product was purified by column chromatography using DCM/iPrOH (95:5) as the eluent to afford the pure product as a solid (480 mg, 94.5%). 1H NMR (400 MHz, CDCl3): δ 7.98-8.02 (m, 2H), 7.26-7.44 (m, 8H), 6.91-7.05 (m, 3H), 5.12 (s, 2H), 4.01-4.05 (t, 1H), 3.82 (s, 2H), 3.56-3.59 (m, 1H), 3.34-3.37 (m, 1H), 2.95-2.97 (d, 2H), 2.43 (s, 3H), 2.11 (s, 3H), 1.12-1.17 (t, 3H).
Reaction SMILES: [H-].[Na+].[C:3]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:8]=1[OH:17])([CH3:6])([CH3:5])[CH3:4].[CH2:18]([N:30]1[C:34](=[O:35])[CH:33]=[CH:32][C:31]1=[O:36])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]>C(O)(C)(C)C>[C:13]([C:9]1[CH:10]=[C:11]([CH:33]2[CH2:32][C:31](=[O:36])[N:30]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[C:34]2=[O:35])[CH:12]=[C:7]([C:3]([CH3:6])([CH3:5])[CH3:4])[C:8]=1[OH:17])([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)c1cccc(C(C)(C)C)c1O
Reactant: CCCCCCCCCCCCN1C(=O)C=CC1=O
Agent: [H-]
Agent: [Na+]
Solvent: CC(C)(C)O
Product: CCCCCCCCCCCCN1C(=O)CC(c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)C1=O
Yield: 17.3 %

Procedure:
This compound is prepared by the procedure of Example 1 from 2.40 g (0.1 mol) of sodium hydride, 20.63 g (0.1 mol) of 2,6-di-tert-butylphenol, and 26.54 g (0.1 mol) of N-n-dodecylmaleimide in tert-butyl alcohol. The reaction mixture is concentrated in vacuo and the residue is dissolved in 800 ml of toluene. The toluene solution is extracted sequentially with 1M sodium hydroxide (2×100 ml) and water (6×200 ml). The organic phase is dried over anhydrous sodium sulfate. The solvent is removed in vacuo and the residue purified by flash chromatography (8:2 heptane: ethyl acetate eluent) followed by recrystallization from petroleum ether to give 8.15 g (17%) of a white solid: mp 66°-70° C.