Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([S:7]([NH:10][C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][C:18]=3[O:20][CH3:21])[N:13](C(OC(C)(C)C)=O)[N:12]=2)(=[O:9])=[O:8])=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[S:6][C:5]([S:7]([NH:10][C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][C:18]=3[O:20][CH3:21])[NH:13][N:12]=2)(=[O:8])=[O:9])=[CH:4][CH:3]=1
Reactant: COc1cccc2c1c(NS(=O)(=O)c1ccc(Cl)s1)nn2C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cccc2[nH]nc(NS(=O)(=O)c3ccc(Cl)s3)c12
Reaction time: 0.5 h

Procedure:
A solution of 1,1-dimethylethyl 3-{[(5-chloro-2-thienyl)sulfonyl]amino}-4-(methyloxy)-1H-indazole-1-carboxylate (for a preparation see Intermediate 6) (155 mg, 0.35 mmol) was dissolved in DCM (0.2 mL) and TFA (0.4 mL) was added. The solution was stood at room temperature for 30 min, and then blown down to dryness under a stream of nitrogen in a Radley's blow down unit to give the title compound (200 mg). LCMS (System D) RT=1.02 min, ES+ve m/z 344 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]([NH2:15])=[O:14])=[C:11]([NH:16][C:17]([NH:19][CH2:20][CH2:21][CH2:22][N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)=[O:18])[S:10][N:9]=2)=[CH:4][CH:3]=1.[F:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][C:31]=1[N:40]=[C:41]=[O:42]>C(N(CC)C(C)C)(C)C>[F:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][C:31]=1[NH:40][C:41]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([C:13]([NH2:15])=[O:14])=[C:11]([NH:16][C:17]([NH:19][CH2:20][CH2:21][CH2:22][N:23]3[CH2:24][CH2:25][O:26][CH2:27][CH2:28]3)=[O:18])[S:10][N:9]=2)=[CH:6][CH:7]=1)=[O:42]
Reactant: O=C=Nc1cc(C(F)(F)F)ccc1F
Reactant: NC(=O)c1c(-c2ccc(N)cc2)nsc1NC(=O)NCCCN1CCOCC1
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)c1c(-c2ccc(NC(=O)Nc3cc(C(F)(F)F)ccc3F)cc2)nsc1NC(=O)NCCCN1CCOCC1
Yield: 60.1 %

Procedure:
In a manner similar to that described for Example 3 (, 3-(4-aminophenyl)-5-(3-(3-morpholinopropyl)ureido)isothiazole-4-carboxamide (12 mg, 0.030 mmol), 3 drops N,N-diisopropylethylamine, and 2-fluoro-5-(trifluoromethyl)phenyl isocyanate (0.0087 mL, 0.060 mmol) was used to give the title compound as a white solid (11 mg, 62%).
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:17]=[C:16]([N:18]2[CH2:23][CH2:22][N:21]([C:24](=[O:31])[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:20][CH2:19]2)[CH:15]=[CH:14][C:10]=1[C:11]([OH:13])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN.C1COCC1.[CH2:39]([N:41](CC)CC)C.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1>C1COCC1>[CH2:1]([NH:8][C:9]1[CH:17]=[C:16]([N:18]2[CH2:19][CH2:20][N:21]([C:24](=[O:31])[C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH2:22][CH2:23]2)[CH:15]=[CH:14][C:10]=1[C:11]([NH:41][CH3:39])=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCN(CC)CC
Reactant: O=C(O)c1ccc(N2CCN(C(=O)c3ccccc3)CC2)cc1NCc1ccccc1
Agent: CN
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: CNC(=O)c1ccc(N2CCN(C(=O)c3ccccc3)CC2)cc1NCc1ccccc1
Yield: 35 %

Procedure:
A solution of 2-(benzylamino)-4-(4-benzoylpiperazin-1-yl)benzoic acid (80 mg, 0.2 mmol), 2 M methylamine THF solution (0.96 ml, 1.9 mmol), triethylamine (0.08 ml, 0.57 mmol) and diphenylphosphoryl azide (0.045 ml, 0.2 mmol) in 15 ml THF was stirred for 16 hours. The run was quenched with 1 ml water and all the solvents were evaporated under vacuum. 2-(benzylamino)-N-methyl-4-(4-benzoylpiperazin-1-yl)benzamide (30 mg, 36%) was obtained by flash column chromatograph (60% ethyl acetate in hexanes). 1H NMR (500 MHz, CDCl3) δ (ppm) 2.97 (d, 3H), 3.14-3.25 (d, br, 4H), 3.65 (s, br, 2H), 3.72 (s, br, 2H), 4.42 (d, 2H), 6.01 (d, J=2.3 Hz, 2H), 6.15 (dd, J=2.3, 8.7 Hz, 1H), 7.26-7.49 (m, 10H), 8.52 (s, 1H). 13C NMR (125 MHz, CDCl3): δ (ppm) 26.9, 47.8, 48.9, 98.3, 103.4, 107.5, 127.5, 127.6, 129.0, 129.1 130.4, 136.0, 139.7, 151.6, 154.3, 170.6, 170.9.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5](Cl)=[C:6]([C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)[C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1.CC#N.[OH2:25]>C(Cl)Cl>[Cl:1][C:2]1[N:3]=[N:4][C:5]([OH:25])=[C:6]([C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)[C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1
Reactant: O
Reactant: Clc1ccc(-c2c(Cl)nnc(Cl)c2-c2ccncc2)cc1
Solvent: CC#N
Solvent: ClCCl
Product: Oc1nnc(Cl)c(-c2ccc(Cl)cc2)c1-c1ccncc1
Temperature: 80 °C
Reaction time: 4 h
Yield: 48 %

Procedure:
To a round bottom flask was added 3,6-dichloro-4-(4-chlorophenyl)-5-(pyridin-4-yl)pyridazine (1.5 gm, 4.464 mmol), CH3CN (5 ml), water (1 ml) and LiOH monohydrate (0.938 gm, 22.32 mmol). The reaction was heated to 80° C. and stirred at this temperature for 4 hrs. After this time, the reaction was colled to rt and concentrated under reduced pressure. The residue was diluted with water (30 ml). The pH of the aqueous solution was adjusted to 7 with 1N HCl. The resulting solution was poured into a separatory funnel and extract with EtOAc (4×20 ml). The combined organic layers were washed with saturated aqueous NaCl (30 ml). The organic layer was then slurried with MgSO4 to remove excess water, filtered and concentrated to give a white solid residue. The residue was stirred in CH2Cl2 (10 ml) for 15 min. The solution was then filter and the solid was collected to give product 6-chloro-5-(4-chlorophenyl)-4-(pyridin-4-yl)pyridazin-3-ol as white solid (0.70 gm, 48% yield). HPLC retention time (method A) 1.332 min.
Reaction SMILES: [O:1]([C:8]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:9]=1[C:10]1[C:11]([CH2:24][O:25][CH3:26])=[C:12]([C:21](O)=[O:22])[N:13]=[CH:14][C:15]=1[NH:16]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(C1NC=CN=1)(C1[NH:30]C=CN=1)=O>O1CCCC1>[O:1]([C:8]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:9]=1[C:10]1[C:11]([CH2:24][O:25][CH3:26])=[C:12]([C:21]([NH2:30])=[O:22])[N:13]=[CH:14][C:15]=1[NH:16]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COCc1c(C(=O)O)ncc2[nH]c3cccc(Oc4ccccc4)c3c12
Reactant: O=S(c1ncc[nH]1)c1ncc[nH]1
Solvent: C1CCOC1
Product: COCc1c(C(N)=O)ncc2[nH]c3cccc(Oc4ccccc4)c3c12
Reaction time: 5 h
Yield: 74.3 %

Procedure:
2.7 g of 5-phenoxy-4-methoxymethyl-beta-carboline-3-carboxylic acid is added to a solution of 30 mmol of thionyldiimidazole in 150 ml of tetrahydrofuran. The reaction mixture is stirred for 5 hours and filtered. The filtrate is mixed with 12 ml of 25% NH3 in water, stirred overnight and concentrated in a vacuum to 50 ml. After addition of 100 ml of water, 2 g of the desired product is obtained as yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:15][CH2:16][C:17]([N:19]2[CH2:24][C@H:23]([CH3:25])[N:22]([CH2:26][C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)[CH2:21][C@H:20]2[CH3:34])=[O:18])=[C:6]([CH:8]([OH:14])[CH2:9][CH2:10][C:11](O)=[O:12])[CH:7]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.C(=O)(O)[O-].[Na+]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:15][CH2:16][C:17]([N:19]2[CH2:24][C@H:23]([CH3:25])[N:22]([CH2:26][C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)[CH2:21][C@H:20]2[CH3:34])=[O:18])=[C:6]([CH:8]2[O:14][C:11](=[O:12])[CH2:10][CH2:9]2)[CH:7]=1
Reactant: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1C(=O)COc1ccc(Cl)cc1C(O)CCC(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1C(=O)COc1ccc(Cl)cc1C1CCC(=O)O1
Yield: 109.5 %

Procedure:
To a solution of 4-(5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1-yl]-2-oxo-ethoxy}-phenyl)-4-hydroxy-butyric acid (0.050 g, 0.10 mmol) in toluene (5 mL) was added p-toluene sulfonic acid (0.040 g) and the reaction was stirred at reflux for 4 hours. The reaction was cooled, diluted with saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. Trituration in diethyl ether/hexanes gave the title compound (0.052 g, LRMS: 475.2, 477.3).
Reaction SMILES: F[C:2]1[C:3]([C:15]#[N:16])=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[CH:9]=[N:10][CH:11]=[CH:12][C:13]=1[CH3:14].[OH:17][NH:18]C(=O)C.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[CH3:14][C:13]1[CH:12]=[CH:11][N:10]=[CH:9][C:8]=1[C:7]1[CH:6]=[CH:5][N:4]=[C:3]2[C:15]([NH2:16])=[N:18][O:17][C:2]=12
Reactant: CC(=O)NO
Reactant: Cc1ccncc1-c1ccnc(C#N)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccncc1-c1ccnc2c(N)noc12
Temperature: 80 °C
Reaction time: 3 h
Yield: 77.2 %

Procedure:
A mixture of 3′-fluoro-4-methyl-3,4′-bipyridine-2′-carbonitrile (0.057 g, 0.267 mmol), N-hydroxyacetamide (0.060 g, 0.802 mmol), and potassium carbonate (0.222 g, 1.604 mmol) in DMF (Ratio: 7.0, Volume: 1.170 ml) and water (Ratio: 1.000, Volume: 0.167 ml) was stirred at 80° C. for 3 hr. The reaction mixture was filtered through a disposable fritted funnel. The filter cake was washed with EtOAc. Layers in the filtrate were separated and the aqueous phase was extracted with EtOAc (3×). The organic phases were combined, dried over Na2SO4, filtered, concentrated, and further dried under high vacuum to afford the title compound as a brown solid (49 mg, 0.206 mmol, 77% yield). ESI MS (M+H)+=227.1.
Reaction SMILES: C1COCC1.Cl[C:7]1[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][N:8]=1.[H-].[Na+].[CH3:20][O:21][N:22]=[C:23]([C:32]1[O:36][N:35]=[C:34]([CH3:37])[CH:33]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH2:30][OH:31]>O>[CH3:20][O:21][N:22]=[C:23]([C:32]1[O:36][N:35]=[C:34]([CH3:37])[CH:33]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH2:30][O:31][C:7]1[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][N:8]=1
Reactant: FC(F)(F)c1cnc(Cl)c(Cl)c1
Reactant: CON=C(c1cc(C)no1)c1ccccc1CO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CON=C(c1cc(C)no1)c1ccccc1COc1ncc(C(F)(F)F)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.4 %

Procedure:
THF (7.5 ml), 2,3-dichloro-5-trifluoromethylpyridine (0.81 g, 3.75 mmol) and 60% sodium hydride (0.12 g, 3.0 mmol) were added to 2-hydroxymethylphenyl 3-methylisoxazol-5-yl ketone O-methyloxime (0.62 g, 2.5 mmol) under ice-cooling, and the mixture was stirred at room temperature overnight. Water (100 ml) was added to the reaction mixture, and the mixture was extracted with ether (150 ml). The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate/n-hexane) to give isomer A (0.29 g, yield: 27.2%) and isomer B (0.76 g, yield: 71.4%) of 2-(3-chloro-5-trifluoromethyl-2-pyridyloxymethyl)phenyl 3-methylisoxazol-5-yl ketone O-methyloxime.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH2:5][C:6]1[N:7]=[C:8]([C:12]([O:14]CC)=O)[S:9][C:10]=1[CH3:11].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.O[NH:43][C:44](=[NH:56])[C:45]1[CH:50]=[CH:49][C:48]([O:51][C:52]([F:55])([F:54])[F:53])=[CH:47][CH:46]=1>CN(C=O)C.CC(O)=O.O.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH2:5][C:6]1[N:7]=[C:8]([C:12]2[O:14][N:56]=[C:44]([C:45]3[CH:46]=[CH:47][C:48]([O:51][C:52]([F:53])([F:54])[F:55])=[CH:49][CH:50]=3)[N:43]=2)[S:9][C:10]=1[CH3:11]
Reactant: N=C(NO)c1ccc(OC(F)(F)F)cc1
Reactant: CCOC(=O)c1nc(Cc2cccc(Br)c2)c(C)s1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: Cc1sc(-c2nc(-c3ccc(OC(F)(F)F)cc3)no2)nc1Cc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 63.8 %

Procedure:
A solution of ethyl 4-(3-bromobenzyl)-5-methylthiazole-2-carboxylate (0.06 mmol, crude from previous step), EDC.HCl (12 mg, 0.1 mmol) and HOBT (10 mg, 0.1 mmol) in DMF (0.4 mL) was stirred at RT for 30 min. N-hydroxy-4-(trifluoromethoxy)benzimidamide (15 mg, 0.07 mmol) was added and the reaction mixture was stirred for 1 h at RT. DMF (2 mL) was added to the mixture with 2 drops of AcOH. The mixture was subsequently heated to 140° C. for additional 2 h and then cooled to RT, diluted with H2O and taken into EtOAc. The organic layer was washed with NaHCO3, concentrated, and purified by silica gel column chromatography(0-45% EtOAc/Hexane) to give the titled compound (19 mg, 68%). MS (ES+) C20H13BrF3N3O2S requires: 495, 497, found: 496, 498 [M+H]+(1:1).
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:12]=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:23])[CH:14]=[CH:15][CH:16]=2)[CH:10]=1)=[O:5])C.[OH-].[K+]>C(O)C>[Cl:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([N:9]2[CH:10]=[C:6]([C:4]([OH:5])=[O:3])[N:7]=[CH:8]2)[CH:12]=1
Reactant: CCOC(=O)c1cn(-c2cccc(-c3ccccc3Cl)c2)cn1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1cn(-c2cccc(-c3ccccc3Cl)c2)cn1

Procedure:
This compound is prepared by hydrolysis of 9e using a 1:1 mixture of aqueous potassium hydroxide (2M) and ethanol.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[N:7]1([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:12][CH2:11][CH:10]([C:13](OC)=[O:14])[CH2:9][CH2:8]1.C(OCC)(=O)C.[O-]S([O-])(=O)=O.[Na+].[Na+]>C1COCC1.O>[OH:14][CH2:13][CH:10]1[CH2:11][CH2:12][N:7]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:8][CH2:9]1
Reactant: COC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(CO)CC1
Temperature: 0 °C

Procedure:
A mixture of 70 g of LiAlH4 in 1500 mL of THF was cooled to 0° C., then 180 g of 1-tert-butyl 4-methyl piperidine-1,4-dicarboxylate in THF was added dropwise. When the reaction was finished, 200 mL of ethyl acetate and solid anhydrous Na2SO4. Water was added until the solution became clear. The mixture was filtered and the filtrate was evaporated to afford the title compound.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH2:22][CH2:23][OH:24])[C:5]1[N:6]=[N:7][C:8]([N:11]2[C:15]([NH2:16])=[C:14]([C:17]([O:19]CC)=O)[CH:13]=[N:12]2)=[CH:9][CH:10]=1.O.[NH2:26][NH2:27]>O1CCOCC1>[OH:24][CH2:23][CH2:22][N:4]([CH2:3][CH2:2][OH:1])[C:5]1[N:6]=[N:7][C:8]([N:11]2[C:15]([NH2:16])=[C:14]([C:17](=[O:19])[NH:26][NH2:27])[CH:13]=[N:12]2)=[CH:9][CH:10]=1
Reactant: CCOC(=O)c1cnn(-c2ccc(N(CCO)CCO)nn2)c1N
Reactant: NN
Solvent: O
Solvent: C1COCCO1
Product: NNC(=O)c1cnn(-c2ccc(N(CCO)CCO)nn2)c1N

Procedure:
A mixture of 6.72 g. (20 mmoles) of 3-[bis(hydroxyethyl)-amino]-6-(4-ethoxycarbonyl-5-amino-1-pyrazolyl)-pyridazine (prepared according to Example 2), 34 ml. of 72% hydrazine hydrate and 34 ml. of dioxane is stirred at reflux temperature for 12 hours. After cooling the separated crystals are filtered, washed with water and ethanol and then recrystallized from 30 ml. of ethanol. Yield: 5.7 g. (88.5%); m.p.: 217°-219° C.
Reaction SMILES: C(O[C@H:5]1[NH:8][C:7](=[O:9])[C@@H:6]1[C@H:10]([O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])[CH3:11])(=O)C.[K].[CH3:21][O:22][CH2:23][C:24]([OH:26])=[S:25]>O1CCOCC1.C(OCC)(=O)C.O.[Br-].[Zn+2].[Br-]>[CH3:21][O:22][CH2:23][C:24]([S:25][C@H:5]1[NH:8][C:7](=[O:9])[C@@H:6]1[C@H:10]([O:12][Si:13]([C:16]([CH3:17])([CH3:18])[CH3:19])([CH3:14])[CH3:15])[CH3:11])=[O:26]
Reactant: CC(=O)O[C@H]1NC(=O)[C@@H]1[C@@H](C)O[Si](C)(C)C(C)(C)C
Reactant: COCC(O)=S
Agent: [Br-]
Agent: [K]
Agent: [Zn+2]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COCC(=O)S[C@H]1NC(=O)[C@@H]1[C@@H](C)O[Si](C)(C)C(C)(C)C
Temperature: 40 °C
Reaction time: 4 h
Yield: 89.8 %

Procedure:
To a solution of 4-(R)acetoxy-3(R)-[1(R)t-butyldimethylsilyloxyethyl]azetidin-2-one (2.87 g) in dioxane (40 ml) the potassium salt of methoxythioacetic acid (1.7 g) was added. Zinc bromide (2.7 g) was added to the resulting suspension and the reaction mixture was stirred for 4 hours at 40° C. The reaction mixture was then cooled at room temperature and poured in a mixture of ethyl acetate and water. The organic layer was separated, washed twice with water, dried over anhydrous sodium sulfate, and evaporated in vacuo. The residue was purified by column chromatography to give 2.99 g of the title product (90% yield). NMR (CDCl3) δ (ppm): 0.1 (6H, s); 0.83 (9H, s); 1.16 (3H, d); 3.13 (1H, dd); 3.42 (3H, s), 4.01 (2H, s) 4.20 (1H, m); 5.22 (1H, d); 6.55 (1H, s)
Reaction SMILES: [Cl:1][C:2]1[N:10](CC=C)[C:9]2[C:8](=[O:14])[N:7]([CH3:15])[C:6](=[O:16])[NH:5][C:4]=2[N:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH2:23](I)[CH3:24].N1CCOCC1>CN(C=O)C.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[NH:10][C:9]2[C:8](=[O:14])[N:7]([CH3:15])[C:6](=[O:16])[N:5]([CH2:23][CH3:24])[C:4]=2[N:3]=1
Reactant: C=CCn1c(Cl)nc2[nH]c(=O)n(C)c(=O)c21
Reactant: CCI
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: C1COCCN1
Product: CCn1c(=O)n(C)c(=O)c2[nH]c(Cl)nc21
Temperature: 25 °C
Reaction time: 90 h
Yield: 69.8 %

Procedure:
To a solution of 8-chloro-1-methyl-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione (100 mg, 0.42 mmol) in anhydrous DMF (3 ml) was added sodium carbonate (58 mg, 0.54 mmol), after 10 minutes stirring ethyl iodide (0.043 ml, 0.54 mmol) was added and the reaction mixture stirred at room temperature under nitrogen for 90 hours. Pd(PPh3)4 (73 mg, 0.063 mmol) was then added and the reaction vessel evacuated and flushed with nitrogen (×3), morpholine (0.37 ml, 4.3 mmol) was added and stirring at room temperature under nitrogen continued for 4 hours. The reaction mixture was diluted with EtOAc (25 ml) and washed with 2M HCl aq. (25 ml). The organic extract was dried (MgSO4) filtered and evaporated. Purification by aminopropyl SPE (5 g) loading the compound and washing with MeOH before eluting the product with 5% AcOH/MeOH afforded the title compound as a white solid (67 mg, 70%). NMR; dH (400 MHz, d6-DMSO) 1.20 (t, 3H, J=7 Hz), 3.22 (s, 3H), 3.97 (q, 2H, J=7 Hz), 14.46 (1H, br s); m/z 227.2[M−H]−.
Reaction SMILES: [C:1]([C:5]1[S:9][C:8]([C:10]2[S:11][C:12](/[C:15](/[O:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=3)=[CH:16]/Cl)=[CH:13][CH:14]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C1C=CC(P(C2C(OC3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=CC=3)=CC=CC=2)C2C=CC=CC=2)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].[F-].[Cs+]>O1CCOCC1.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]>[C:1]([C:5]1[S:9][C:8]([C:10]2[S:11][C:12]([C:15]3[O:18][C:19]4[CH:20]=[C:21]([O:25][CH3:26])[CH:22]=[CH:23][C:24]=4[CH:16]=3)=[CH:13][CH:14]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1cccc(O/C(=C\Cl)c2ccc(-c3ccc(C(C)(C)C)s3)s2)c1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: COc1ccc2cc(-c3ccc(-c4ccc(C(C)(C)C)s4)s3)oc2c1
Temperature: 25 °C

Procedure:
(Z)-5-(tert-butyl)-5′-(2-chloro-1-(3-methoxyphenoxy)vinyl)-2,2′-bithiophene (2.9 g, 7.16 mmol) and DPEphos (0.19 g, 0.36 mmol) were dissolved in anhydrous 1,4-dioxane (40 mL). Cesium carbonate (7.0 g, 21.5 mmol) and cesium fluoride (3.3 g, 21.5 mmol) were added and the reaction mixture was deoxygenated by bubbling argon through it for 1 hour. Tris(dibenzylideneacetone)dipalladium(0) (0.16 g, 0.18 mmol) was added and the reaction mixture was heated to reflux for 20 hours. After cooling to room temperature, the reaction mixture was filtered, poured into water (250 mL), mixed well and separated. The aqueous portion was extracted with ether (2×200 mL) and the combined organics were washed with water (500 mL), dried over MgSO4, filtered and solvent removed by rotary evaporation. The resulting brown solid was redissolved in DCM (250 mL) and deposited onto silica gel. Flash chromatography (combi-flash, hexanes) afforded a yellow, powdery solid, 1.53 g (58%). 1H NMR (600 MHz, CDCl3) δ 7.40 (d, J=8.5 Hz, 1H), 7.29 (d, J=3.8 Hz, 1H), 7.07 (d, J=3.8 Hz, 1H), 7.04 (d, J=1.4 Hz, 1H), 7.01 (d, J=3.6 Hz, 1H), 6.86 (dd, J=8.5, 2.2 Hz, 1H), 6.76 (s, 1H), 6.75 (d, J=3.6 Hz, 1H), 3.87 (s, 3H), 1.41 (s, 9H).
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14]C(=O)OCC)=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[CH3:20][O:21][CH2:22][CH:23]1[CH2:27]O[C:25](=[O:28])[O:24]1.C(=O)([O-])[O-].[K+].[K+].C(Cl)Cl>O>[CH3:20][O:21][CH2:22][CH:23]1[O:24][C:25](=[O:28])[N:14]([C:11]2[CH:12]=[CH:13][C:8]([N:5]3[CH2:4][CH2:3][C:2](=[O:1])[CH2:7][CH2:6]3)=[CH:9][CH:10]=2)[CH2:27]1
Reactant: CCOC(=O)Nc1ccc(N2CCC(=O)CC2)cc1
Reactant: COCC1COC(=O)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: COCC1CN(c2ccc(N3CCC(=O)CC3)cc2)C(=O)O1
Temperature: 160 °C
Yield: 8.6 %

Procedure:
A mixture of 6.0 g of ethyl 4-(4-oxo-piperidin-1-yl)-phenylcarbamate, 5.0 g of 4-methoxymethyl-1,3-dioxolan-2-one and 0.6 g of potassium carbonate was heated to 160° C. under argon for 3 h. The reaction mixture was cooled, treated with methylene chloride and water and the phases were separated. The organic phase was dried with magnesium sulfate and concentrated. The residue (7.8 g) was chromatographed over silica gel 60 using ethyl acetate as the eluent. There was obtained 0.6 g of (RS)-5-methoxymethyl-3-[4-(4-oxo-piperidin-1-yl)-phenyl]-oxazolidin-2-one. 1H-nmr (CDCl3) ppm: 7.46 (d, 2H), 6.98 (d, 2H), 4.76 (m, 1H), 3.99 (t, 1H), 3.88 (t, 1H), 3.64 (d, 2H), 3.57 (t, 4H), 3.44 (s, 3H), 2.56 (t, 4H).
Reaction SMILES: C1(SC2C3C=C4C(C=CC=C4)=CC=3SC=2[Si](C)(C)C)C=CC=CC=1.[C:25]1([Se:31][C:32]2[C:33]3[CH:44]=[CH:43][CH:42]=[CH:41][C:34]=3[S:35][C:36]=2[Si](C)(C)C)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[C:25]1([Se:31][C:32]2[C:33]3[CH:44]=[CH:43][CH:42]=[CH:41][C:34]=3[S:35][CH:36]=2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: C[Si](C)(C)c1sc2ccccc2c1[Se]c1ccccc1
Agent: C[Si](C)(C)c1sc2cc3ccccc3cc2c1Sc1ccccc1
Product: c1ccc([Se]c2csc3ccccc23)cc1

Procedure:
Except that 3-(phenylsulfenyl)-2-trimethylsilylnaphtho[2,3-b]thiophene was replaced with 3-(phenylselenenyl)-2-trimethylsilylbenzo[b]thiophene, the reaction was implemented in the same way as in Example 8. Purification was implemented by column chromatography (silica gel, CHCl3, Rf: 0.9), so that a white solid was quantitatively produced.
Reaction SMILES: [Cl:1][C:2]([Cl:17])=[C:3]([C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=1)[C:4]([OH:6])=O.O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1.C(N(CC)CC)C.[Cl:40][C:41]1[CH:51]=[C:50]([O:52][CH2:53][CH:54]=[C:55]([Cl:57])[Cl:56])[CH:49]=[C:48]([Cl:58])[C:42]=1[O:43][CH2:44][CH2:45][CH2:46][NH2:47]>ClCCl.C(OCC)(=O)C>[Cl:17][C:2]([Cl:1])=[C:3]([C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=1)[C:4]([NH:47][CH2:46][CH2:45][CH2:44][O:43][C:42]1[C:48]([Cl:58])=[CH:49][C:50]([O:52][CH2:53][CH:54]=[C:55]([Cl:57])[Cl:56])=[CH:51][C:41]=1[Cl:40])=[O:6]
Reactant: NCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Reactant: O=C(O)C(=C(Cl)Cl)c1ccc(C(F)(F)F)cc1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: O=C(NCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl)C(=C(Cl)Cl)c1ccc(C(F)(F)F)cc1

Procedure:
74 mg of 3,3-dichloro-2-(4-trifluoromethyl-phenyl)-acrylic acid, 67 mg of bis(2-oxo-3-oxazolidinyl)-phosphinic acid chloride, 53 mg of triethylamine and 100 mg of 3-[2,6-dichloro-4-(3,3-dichloro-allyloxy)-phenoxy]-propylamine are stirred in 2 ml of dichloromethane for 48 hours at 40° C. The reaction mixture is diluted with 16 ml of ethyl acetate and washed twice with aqueous potassium carbonate solution. After concentration of the organic phase and purification over silica gel, the title compound is obtained.
Reaction SMILES: C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[N:8]2[CH:12]=[C:11]([CH2:13][CH2:14][CH2:15]O)[N:10]=[CH:9]2)C=CC=CC=1.[OH:29][C:30]1[CH:35]=[CH:34][C:33]([CH2:36][C:37](=[O:42])[CH2:38][CH2:39][CH2:40][CH3:41])=[CH:32][CH:31]=1>>[NH:8]1[CH:12]=[C:11]([CH2:13][CH2:14][CH2:15][O:29][C:30]2[CH:31]=[CH:32][C:33]([CH2:36][C:37](=[O:42])[CH2:38][CH2:39][CH2:40][CH3:41])=[CH:34][CH:35]=2)[N:10]=[CH:9]1
Reactant: CCCCC(=O)Cc1ccc(O)cc1
Reactant: OCCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Product: CCCCC(=O)Cc1ccc(OCCCc2c[nH]cn2)cc1

Procedure:
5 mmol of 3-(1-triphenylmethyl-1H-imidazol-4-yl)propanol and 6 mmol of (4-hydroxyphenyl)hexanone (prepared from hexanoic acid according to standard methods (Friedel-Crafts acylation)) are treated as described in Example 56.