Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:30]/[O:31][CH2:32][C:33](=[O:36])[NH:34][CH3:35])/[C:27](O)=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1.[NH2:62][C@@H:63]1[C:81](=[O:82])[N:65]2[C:66]([C:78]([OH:80])=[O:79])=[C:67]([CH2:70][S:71][C:72]3[N:76]([NH2:77])[N:75]=[N:74][N:73]=3)[CH2:68][S:69][C@H:64]12.C(N(CC)CC)C.NC1C(CSC2N(NC(C)C)N=NN=2)=C(C(O)=O)N2C(=O)C[C@H]2S1>CC(N(C)C)=O.O>[C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:30]/[O:31][CH2:32][C:33](=[O:36])[NH:34][CH3:35])/[C:27]([NH:62][C@@H:63]2[C:81](=[O:82])[N:65]3[C:66]([C:78]([OH:80])=[O:79])=[C:67]([CH2:70][S:71][C:72]4[N:76]([NH2:77])[N:75]=[N:74][N:73]=4)[CH2:68][S:69][C@H:64]23)=[O:28])[N:25]=1)([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CNC(=O)CO/N=C(\C(=O)O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: N[C@@H]1C(=O)N2C(C(=O)O)=C(CSc3nnnn3N)CS[C@H]12
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CC(C)Nn1nnnc1SCC1=C(C(=O)O)N2C(=O)C[C@H]2SC1N
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CC(=O)N(C)C
Solvent: O
Product: CNC(=O)CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(CSc3nnnn3N)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 17 h
Yield: 77.7 %

Procedure:
A solution of 2-(2-tritylaminothiazol-4-yl)-(Z)-2-(N-methylcarbamoyl)methoxyiminoacetic acid (3.25 g, 6.5 mmol), 1-hydroxybenzotriazole (0.97 g, 7.15 mmol) and N,N'-dicyclohexylcarbodiimide (1.41 g, 6.83 mmol) in dimethylacetamide (34 ml) was stirred at room temperature for 4 hours. To the solution was added a solution of 7β-amino-3-[(1-amino-1H-tetrazol-5-yl)thiomethyl]-3-cephem-4-carboxylic acid (2.57 g, 7.8 mmol) and triethylamine (1.73 g, 17.2 mmol) in dimethylacetamide (20 ml) and water (2.4 ml) and the mixture was stirred at room temperature for 17 hours. Then the mixture was treated in a manner similar to that described in Example 6, (c) to give pale brown powder of 7β-[2-(2-tritylaminothiazol-4-yl)-(Z)-2-(N-methylcarbamoyl)methoxyiminoacetamido]-3-[(1-amino-1H-tetrazol-5-yl)thiomethyl]-3-cephem-4-carboxylic acid (4.1 g, 78%).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][Si:6]([CH:13]([CH3:15])[CH3:14])([CH:10]([CH3:12])[CH3:11])[CH:7]([CH3:9])[CH3:8].[CH2:16]([O:18][C:19]([C:21]1[NH:29][C:28]2[CH:27]=[CH:26][N:25]=[CH:24][C:23]=2[C:22]=1[NH:30][C:31]1[CH:36]=[CH:35][C:34]([I:37])=[CH:33][C:32]=1[F:38])=[O:20])[CH3:17].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[CH2:16]([O:18][C:19]([C:21]1[N:29]([CH2:2][CH2:3][CH2:4][O:5][Si:6]([CH:13]([CH3:15])[CH3:14])([CH:10]([CH3:12])[CH3:11])[CH:7]([CH3:9])[CH3:8])[C:28]2[CH:27]=[CH:26][N:25]=[CH:24][C:23]=2[C:22]=1[NH:30][C:31]1[CH:36]=[CH:35][C:34]([I:37])=[CH:33][C:32]=1[F:38])=[O:20])[CH3:17]
Reactant: CC(C)[Si](OCCCBr)(C(C)C)C(C)C
Reactant: CCOC(=O)c1[nH]c2ccncc2c1Nc1ccc(I)cc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(Nc2ccc(I)cc2F)c2cnccc2n1CCCO[Si](C(C)C)(C(C)C)C(C)C
Temperature: 80 °C
Yield: 28.9 %

Procedure:
(3-Bromo-propoxy)-triisopropyl-silane (209 mg, 0.71 mmol) was dissolved in DMF (5 ml) and 3-(2-fluoro-4-iodophenylamino)-1H-pyrrolo[3,2-c]pyridine-2-carboxylic acid ethyl ester (250 mg, 0.59 mmol) was added, followed by cesium carbonate (250 mg, 0.77 mmol). The mixture was heated at 80° C. under nitrogen for 3 hours, then allowed to cool, diluted with water and extracted with dichloromethane (×2). The combined organic layers were washed with 20% aqueous lithium chloride solution, dried over magnesium sulfate then concentrated in vacuo. Purification of the resultant residue by flash chromatography (Si-PPC, dichloromethane:methanol gradient 1:0 to 99:1) gave the title compound as a yellow oil (109 mg, 44%). LCMS (method B): RT 3.41, M+H+ 640.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:10])=[C:4]([CH:7]=[CH:8][CH:9]=1)[NH:5][CH3:6].C(N(C(C)C)CC)(C)C.ClCCCl.[C:24]12([C:34](Cl)=[O:35])[CH2:33][CH:28]3[CH2:29][CH:30]([CH2:32][CH:26]([CH2:27]3)[CH2:25]1)[CH2:31]2>C(OCC)(=O)C>[Br:1][C:2]1[C:3]([CH3:10])=[C:4]([N:5]([CH3:6])[C:34]([C:24]23[CH2:33][CH:28]4[CH2:29][CH:30]([CH2:32][CH:26]([CH2:27]4)[CH2:25]2)[CH2:31]3)=[O:35])[CH:7]=[CH:8][CH:9]=1
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Reactant: CNc1cccc(Br)c1C
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: Cc1c(Br)cccc1N(C)C(=O)C12CC3CC(CC(C3)C1)C2
Temperature: 50 °C

Procedure:
3-Bromo-N,2-dimethylaniline (300 mg) and diisopropylethylamine (581 mg) were added to 1,2-dichloroethane (5 mL). 1-Adamantanecarbonyl chloride (328 mg) was added and the solution was heated at 50° C. for three days. The solution was diluted with 70% ethyl acetate (hexanes), washed three times with 1M aqueous HCl, washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude material was purified by flash column chromatography on silica gel using 10% ethyl acetate (hexanes) to yield the title compound.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][C:11]3[N:20]4[N:21]=[C:22]([NH2:24])[N:23]=[C:19]4[C:18]4[CH:17]=[CH:16][C:15](F)=[CH:14][C:13]=4[N:12]=3)=[CH:9][C:4]=2[O:3][CH2:2]1.[NH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][C:11]3[N:20]4[N:21]=[C:22]([NH2:24])[N:23]=[C:19]4[C:18]4[CH:17]=[CH:16][C:15]([N:26]5[CH2:31][CH2:30][O:29][CH2:28][CH2:27]5)=[CH:14][C:13]=4[N:12]=3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: Nc1nc2c3ccc(F)cc3nc(Cc3ccc4c(c3)OCO4)n2n1
Reactant: C1COCCN1
Product: Nc1nc2c3ccc(N4CCOCC4)cc3nc(Cc3ccc4c(c3)OCO4)n2n1
Temperature: 140 °C
Yield: 50 %

Procedure:
To 5-benzo[1,3]dioxol-5-ylmethyl-8-fluoro-[1,2,4]triazolo[1,5-c]quinazolin-2-ylamine (0.05 g, 0.15 mmol), prepared as described in Example 21, morpholine (1 mL) was added and the mixture was heated at 140° C. for 2 h. The reaction was cooled at room temperature, the solid precipitated was filtered and washed with a mixture MeOH/H2O 9:1, to provide the title compound (0.03 g, 50% yield).
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([C:7]2[C:12]([F:13])=[CH:11][CH:10]=[CH:9][C:8]=2[OH:14])=[CH:5][N:6]=1.CS([C:19]1[N:24]=[C:23]([O:25][CH3:26])[CH:22]=[C:21]([O:27][CH3:28])[N:20]=1)(=O)=O.C(=O)([O-])[O-]>CN(C=O)C>[CH3:1][C:2]1[O:3][C:4]([C:7]2[C:8]([O:14][C:19]3[N:24]=[C:23]([O:25][CH3:26])[CH:22]=[C:21]([O:27][CH3:28])[N:20]=3)=[CH:9][CH:10]=[CH:11][C:12]=2[F:13])=[CH:5][N:6]=1
Reactant: COc1cc(OC)nc(S(C)(=O)=O)n1
Reactant: Cc1ncc(-c2c(O)cccc2F)o1
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: COc1cc(OC)nc(Oc2cccc(F)c2-c2cnc(C)o2)n1
Temperature: 50 °C
Reaction time: 14 h

Procedure:
4 ml DMF solution containing 0.12 g 2-(2-methyloxazole-5-yl) -3-fluorophenol, 0.12 g 2-methanesulfonyl-4,6-dimethoxypyrimidine and 0.18 g pottasium carbonate was stirred for 14 hours at 50° C. After completing the reaction, the solution reacted was poured into ice water and then extracted with ethyl acetate. The organic layer obtained was washed with water and then dried by using anhydrous magnesium sulfate. After filtration, the solvent used was removed by distillation under reduced pressure, and the residue obtained was treated with petroleum ether, affording the objective substance in an amount of 0.1 g.
Reaction SMILES: B(O)O.[C:4]([O:8][C:9](=[O:20])[NH:10][CH2:11][C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1[NH2:19])([CH3:7])([CH3:6])[CH3:5].CC[N:23]([CH2:26][CH3:27])[CH2:24][CH3:25]>C(Cl)Cl.CC([O-])=O.CC([O-])=O.[Cu+2]>[C:4]([O:8][C:9](=[O:20])[NH:10][CH2:11][C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1[NH:19][C:14]1[CH:13]=[C:12]2[C:26](=[CH:27][CH:15]=1)[N:23]([CH2:24][CH:25]1[CH2:6][CH2:4][CH2:5]1)[N:10]=[CH:11]2)([CH3:7])([CH3:5])[CH3:6]
Reactant: CC(C)(C)OC(=O)NCc1cc(F)ccc1N
Reactant: CCN(CC)CC
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: OBO
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCc1cc(F)ccc1Nc1ccc2c(cnn2CC2CCC2)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 61.8 %

Procedure:
To a flask containing boronic acid (0.175 g, 0.76 mmol), amine (6q) (0.22 g, 0.915 mmol), Cu(OAc)2 (0.135 g, 0.76 mmol) and 4 Å sieves (0.2 g) in DCM, Et3N (0.52 mL, 3.7 mmol) was slowly added. The mixture was stirred at room temperature for 3 days. DCM was added to the reaction mixture and filtered. The filtrate was washed with H2O (2×), brine and dried over Na2SO4. After concentration, the residue was purified by chromatography (Sep-Pak; 10 g) with hexane/Et2O (3:1). The fractions containing the product were combined to afford (7q-2) (0.12 g, 37% yield). 1HNMR (400 MHz, CDCl3) δ 7.82 (s, 1H), 7.34 (d, J=8.6 Hz, 1H), 7.24 (br s, 1H), 7.13 (d, J=8.6 Hz, 1H), 6.94-6.84 (m, 3H), 5.02 (br s, NH), 4.35 (d, J=7.8 Hz, 2H), 4.29 (d, J=6.2 Hz, 2H), 2.98-2.85 (m, 1H), 2.10-1.98 (m, 2H), 1.95-1.79 (m, 4H), 1.44 (s, 9H); MS (APCI+) m/z 425 (M+H) was detected.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10]P(OC)(OC)=O)=[CH:6][CH:5]=1.C([N-]C(C)C)(C)C.[Li+].[O:26]([C:31]([N:33]1[CH2:38][CH2:37][C:36](=O)[CH2:35][CH2:34]1)=[O:32])[C:27]([CH3:30])([CH3:29])[CH3:28].O>C1COCC1.C(OCC)(=O)C>[C:27]([O:26][C:31]([N:33]1[CH2:38][CH2:37][C:36](=[CH:10][C:7]2[CH:6]=[CH:5][C:4]([C:3]([O:2][CH3:1])=[O:17])=[CH:9][CH:8]=2)[CH2:35][CH2:34]1)=[O:32])([CH3:30])([CH3:28])[CH3:29]
Reactant: COC(=O)c1ccc(CP(=O)(OC)OC)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(C=C2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: -78 °C
Reaction time: 12 h
Yield: 35 %

Procedure:
The crude product (compound 48) was dissolved in dry THF (200 mL) under N2 and cooled to −78° C. Lithium diisopropylamide (32.7 mL 1.5 M in hexanes, 49 mmol) was added dropwise. The solution was allowed to warm to room temperature. A solution of compound 46 (9.76 g, 49 mmol in 100 mL dry THF) was added to the reaction dropwise and was stirred under N2 for 12 hrs. Water (300 mL) and ethyl acetate (300 mL) were added to the reaction mixture and extracted. The aqueous phase was washed with ethyl acetate (2×300 mL). The combined ethyl acetate was dried over MgSO4 and evaporated to give a crude product, which was purified by silica gel chromatography (0-33% ethyl acetate in hexanes) to provide compound 49 as a white solid (5.64 g, 35%).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:10]=[C:11]([CH:17]=[CH:18][CH:19]=2)[O:12][CH2:13][CH2:14][CH2:15][NH2:16])[CH2:4][CH2:3]1.Cl.[Cl-].[C:22](O)(=[O:30])[C:23]1[CH:28]=[CH:27][CH:26]=[N+:25]([O-:29])[CH:24]=1>N1C=CC=CC=1>[CH3:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:10]=[C:11]([CH:17]=[CH:18][CH:19]=2)[O:12][CH2:13][CH2:14][CH2:15][NH:16][C:22]([C:23]2[CH:24]=[N+:25]([O-:29])[CH:26]=[CH:27][CH:28]=2)=[O:30])[CH2:4][CH2:3]1
Reactant: CC1CCN(Cc2cccc(OCCCN)c2)CC1
Reactant: O=C(O)c1ccc[n+]([O-])c1
Agent: Cl
Agent: [Cl-]
Solvent: c1ccncc1
Product: CC1CCN(Cc2cccc(OCCCNC(=O)c3ccc[n+]([O-])c3)c2)CC1
Temperature: 0 °C
Yield: 30.6 %

Procedure:
To a mixture of 0.023 mol of 3-[3-(4-methylpiperidinomethyl)phenoxy]propylamine and 30 ml of pyridine, stirred at 0° C., 0.047 mol of nicotinic acid 1-oxide chloride hydrochloride is added, portionwise; then the mixture is stirred for 1 hour at room temperature and the solvent is evaporated under reduced pressure. The residue is taken up with N hydrochloric acid and the salts thus obtained are eliminated by filtration, then the mixture is extracted 3 times with 100 ml of ethyl acetate and sodium hydroxide is added thereto to basic pH. The mixture is extracted with ethyl acetate containing 10% ethanol, the organic phase is dried over anhydrous sodium sulfate and the solvent is evaporated under reduced pressure. An oil which crystallizes slowly is obtained. The product is triturated in diethyl ether and filtered to give 4.5 g of crude product which is chromatographed on silica in a mixture methanol: chloroforme 15:35 and crystallized from ethyl acetate. Thus 2.7 g of N-[3-[3-(4-methylpiperidinomethyl)phenoxy] propyl]-3-pyridinecarboxamide 1-oxide are obtained, SR 58037, m.p. 109°-111° C.; yield: 35% of the theoretical value.
Reaction SMILES: Cl[CH2:2][CH2:3][S:4](Cl)(=[O:6])=[O:5].[H-].[Na+].[CH:10](/[C:18]1[CH:23]=[CH:22][C:21]([C:24]2[C:25]([NH2:30])=[N:26][CH:27]=[CH:28][CH:29]=2)=[CH:20][CH:19]=1)=[CH:11]\[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C1COCC1>[C:12]1(/[CH:11]=[CH:10]/[C:18]2[CH:23]=[CH:22][C:21]([C:24]3[C:25]4=[N:30][S:4](=[O:6])(=[O:5])[CH2:3][CH2:2][N:26]4[CH:27]=[CH:28][CH:29]=3)=[CH:20][CH:19]=2)[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: Nc1ncccc1-c1ccc(/C=C/c2ccccc2)cc1
Reactant: O=S(=O)(Cl)CCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=S1(=O)CCN2C=CC=C(c3ccc(/C=C/c4ccccc4)cc3)C2=N1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
2-Chloroethanesulfonyl chloride (0.410 mL) was added to a mixture of NaH (60%, 390 mg) in THF (dry) (8 mL) at 0° C. under nitrogen flow. The mixture was stirred at 0° C. for 5 min. The mixture of (E)-3-(4-styrylphenyl)pyridin-2-amine (531 mg) in THF (dry) (20 mL) was added dropwise and the mixture was stirred at room temperature under atmosphere overnight. The mixture was quenched with water at 0° C., and water, EtOAc and THF were added. The insoluble material was collected by filtration and crystallized from DMSO-EtOH to give the title compound (340 mg) as slightly pale yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[CH:3]=1.[OH:20][C@@H:21]1[CH2:25][CH2:24][NH:23][CH2:22]1>>[ClH:1].[CH3:19][O:18][C:15]1[CH:16]=[CH:17][C:12]([C:4]2[CH:3]=[C:2]([N:23]3[CH2:24][CH2:25][C@@H:21]([OH:20])[CH2:22]3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=2)=[CH:13][CH:14]=1
Reactant: COc1ccc(-c2cc(Cl)c3ccccc3n2)cc1
Reactant: O[C@@H]1CCNC1
Product: COc1ccc(-c2cc(N3CC[C@@H](O)C3)c3ccccc3n2)cc1
Product: Cl

Procedure:
The title compound, m.p. 266-267° C., and MS: m/e=321.3 (M+H+), was prepared from 4-chloro-2-(4-methoxy-phenyl)-quinoline and (R)-3-hydroxypyrrolidine.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([CH:16]([CH3:18])[CH3:17])[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.Cl[C:20]1[CH:28]=[CH:27][C:23](C(O)=O)=[CH:22][N:21]=1.[CH:29]([N:32]1CCNCC1)(C)[CH3:30].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.CN1CCOCC1>C(Cl)Cl.[OH-].[Na+]>[NH3:7].[CH:16]([N:13]1[CH2:14][CH2:15][N:10]([C:8]([C:5]2[CH:6]=[N:7][C:2]([NH:32][CH2:29][CH2:30][N:21]3[CH2:20][CH2:28][CH2:27][CH2:23][CH2:22]3)=[CH:3][CH:4]=2)=[O:9])[CH2:11][CH2:12]1)([CH3:18])[CH3:17]
Reactant: CC(C)N1CCN(C(=O)c2ccc(Cl)nc2)CC1
Reactant: CC(C)N1CCNCC1
Reactant: O=C(O)c1ccc(Cl)nc1
Agent: On1nnc2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: ClCCCl
Solvent: CN1CCOCC1
Product: CC(C)N1CCN(C(=O)c2ccc(NCCN3CCCCC3)nc2)CC1
Product: N
Yield: 56 %
Yield: 2 %

Procedure:
(6-Chloro-pyridin-3-yl)-(4-isopropyl-piperazin-1-yl)-methanone. To a solution of 6-chloronicotinic acid (0.985 g, 6.25 mmol) and 1-isopropyl-piperazine (1.50 g, 7.50 mmol) in DCM (100 mL) was added HOBt (1.20 g, 9.40 mmol), EDC (1.80 g, 9.40 mmol), and N-methyl morpholine (3.4 mL, 31.3 mmol). After 18 h the reaction was diluted with 1 N NaOH (50 mL) and extracted with DCM (3×50 mL). The organic extracts were combined, dried (Na2SO4), and concentrated. Chromatography of the residue (SiO2: 2-4% 2 M NH3 in MeOH/DCM) gave the title compound as a solid (0.934 g, 56%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[C:10](=[O:18])[NH:11][NH:12][C:13]=2[C:14]([F:17])([F:16])[F:15])=[CH:4][CH:3]=1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27]2[C:28]([O:36][C@@H:37]3[O:54][C@H:53]([CH2:55][O:56][C:57](=[O:59])[CH3:58])[C@@H:48]([O:49][C:50](=[O:52])[CH3:51])[C@H:43]([O:44][C:45](=[O:47])[CH3:46])[C@H:38]3[O:39][C:40](=[O:42])[CH3:41])=[N:29][NH:30][C:31]=2[C:32]([F:35])([F:34])[F:33])=[CH:22][CH:21]=1>>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27]2[C:28]([O:36][C@@H:37]3[O:54][C@H:53]([CH2:55][O:56][C:57](=[O:59])[CH3:58])[C@@H:48]([O:49][C:50](=[O:52])[CH3:51])[C@H:43]([O:44][C:45](=[O:47])[CH3:46])[C@H:38]3[O:39][C:40](=[O:42])[CH3:41])=[N:29][NH:30][C:31]=2[C:32]([F:34])([F:33])[F:35])=[CH:22][CH:21]=1.[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[C:10]([O:18][C@@H:37]3[O:54][C@H:53]([CH2:55][OH:56])[C@@H:48]([OH:49])[C@H:43]([OH:44])[C@H:38]3[OH:39])=[N:11][NH:12][C:13]=2[C:14]([F:16])([F:15])[F:17])=[CH:4][CH:3]=1
Reactant: O=c1[nH][nH]c(C(F)(F)F)c1Cc1ccc(Cl)cc1
Agent: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(F)(F)F)c2Cc2ccc(Cl)cc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Product: OC[C@H]1O[C@@H](Oc2n[nH]c(C(F)(F)F)c2Cc2ccc(Cl)cc2)[C@H](O)[C@@H](O)[C@@H]1O

Procedure:
4-[(4-Chlorophenyl)methyl]-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-5-trifluoromethyl-1H-pyrazole was prepared in a similar manner to that described in Example 26 using 4-[(4-chlorophenyl)methyl]-1,2-dihydro-5-trifluoromethyl-3H-pyrazol-3-one instead of 1,2-dihydro-4-[(4-methylthiophenyl)methyl]-5-trifluoromethyl-3H-pyrazol-3-one. Then, the title compound was prepared in a similar manner to that described in Example 35 using 4-[(4-chlorophenyl)methyl]-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-5-trifluoromethyl-1H-pyrazole instead of 4-[(4-isopropoxyphenyl)methyl]-5-methyl-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-1H-pyrazole.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[Cl:22])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:23]([OH:26])[CH2:24][CH3:25])=[CH:4][CH:3]=1.[CH3:27][O:28][CH2:29][C:30](O)=[O:31].C(N(CC)CC)C.Cl.C(N=C=NCCCN(C)C)C>CN(C)C1C=CN=CC=1.O1CCCC1.O>[CH3:27][O:28][CH2:29][C:30]([O:26][CH:23]([C:5]1[C:6]2[N:7]3[CH2:14][CH2:13][CH2:12][N:11]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[Cl:22])[C:8]3=[N:9][C:10]=2[C:2]([Cl:1])=[CH:3][CH:4]=1)[CH2:24][CH3:25])=[O:31]
Reactant: COCC(=O)O
Reactant: CCC(O)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: CCC(OC(=O)COC)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 24 h
Yield: 55.9 %

Procedure:
To a solution of 1-[9-chloro-1-(2,4-dichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]propan-1-ol (150 mg, 0.365 mmol), methoxyacetic acid (0.0453 mL, 0.59 mmol), triethylamine (0.25 mL, 1.79 mmol) and 4-dimethylaminopyridine (48.0 mg, 0.39 mmol) in tetrahydrofuran (5.0 mL) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (170 mg, 0.887 mmol) at room temperature. The mixture was stirred at room temperature for 24 hr. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with a 25-80% ethyl acetate/n-hexane gradient mixture and recrystallization from 2-propanol/diisopropyl ether to give the title compound (98.4 mg, 0.204 mmol, 56%) as colorless crystals.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][S:4][N:3]=1.C([Li])CCC.[CH2:12]([Sn:16]([CH2:22][CH2:23][CH2:24][CH3:25])([CH2:18][CH2:19][CH2:20][CH3:21])Cl)[CH2:13][CH2:14][CH3:15].C([O-])(O)=O.[Na+]>C1COCC1>[CH3:1][C:2]1[CH:6]=[C:5]([Sn:16]([CH2:18][CH2:19][CH2:20][CH3:21])([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:12][CH2:13][CH2:14][CH3:15])[S:4][N:3]=1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: Cc1ccsn1
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1cc(C)ns1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a cold (−78° C.) solution of 3-methylisothiazole (100 mg, 1.0 mmol) in anhydrous THF (2.0 mL) was added n-butyllithium (0.693 mL, 1.1 mmol) dropwise. After stirring for 60 min at −78° C., a solution of tributylchlorostannane (0.326 mL, 1.210 mmol) in anhydrous THF (0.5 mL) was added to the reaction mixture. The reaction mixture was stirred for 30 min at −78° C. and then allowed to warm to RT over a 2 to 3 h period. Saturated aq NaHCO3 was added and the aqueous phase was extracted with EtOAc (3×50 mL). The combined organic phase was dried over anhydrous Na2SO4, filtered, and evaporated in vacuo. The residue was purified by silica gel column chromatography (9:1 Hexane/EtOAc, Flash 60 column) to give the title compound. 1H NMR (500 MHz, CDCl3) δ ppm 0.86-0.94 (m, 9H), 1.05-1.21 (m, 6H), 1.26-1.38 (m, 6H), 1.44-1.65 (m, 6H), 2.56 (s, 3H), 6.97-7.04 (m, 1H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[C:11]2\[O:12][C:13]3[C:20]([CH2:21][N:22]4[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH2:23]4)=[C:19]([O:35][CH2:36][CH2:37][C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)[CH:18]=[CH:17][C:14]=3[C:15]\2=[O:16])=[N:2]1.FC(F)(F)C(O)=O.C(=O)([O-])O.[Na+]>C(Cl)Cl.O>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[C:11]2\[O:12][C:13]3[C:20]([CH2:21][N:22]4[CH2:23][CH2:24][NH:25][CH2:26][CH2:27]4)=[C:19]([O:35][CH2:36][CH2:37][C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)[CH:18]=[CH:17][C:14]=3[C:15]\2=[O:16])=[N:2]1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2c(OCCc3ccccc3)ccc3c2O/C(=C\c2n[nH]c4ccccc24)C3=O)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: O
Product: O=C1/C(=C/c2n[nH]c3ccccc23)Oc2c1ccc(OCCc1ccccc1)c2CN1CCNCC1
Reaction time: 8 h
Yield: 34.8 %

Procedure:
A solution of tert-butyl (Z)-4-({2-[(1H-indazol-3-yl)methylene]-3-oxo-6-phenethoxy-2,3-dihydrobenzofuran-7-yl}methyl)piperazine-1-carboxylate (0.0730 g, 0.126 mmol) in methylene chloride (3 mL) was added with trifluoroacetic acid (3 mL) at room temperature, and the mixture was stirred overnight. The reaction mixture was concentrated, added with methanol (8 mL) and a 5% solution of hydrogen chloride in methanol (2 mL), and thereby made basic, and then the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated, and then the residue was suspended in acetonitrile and thereby washed to obtain an orange solid. This solid was suspended in water (4 mL) and saturated aqueous sodium hydrogencarbonate (4 mL), and the suspension was stirred for 1 hour. The reaction mixture was filtered, and then the resulting solid was washed with water to obtain the objective (Z)-2-[(1H-indazol-3-yl)methylene]-6-phenethoxy-7-(piperazin-1-ylmethyl)benzofuran-3(2H)-one (0.0211 g, 34%).
Reaction SMILES: [C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[N:18]=[C:17]([CH3:22])[CH:16]=[C:15]3C(F)(F)F)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[Br:27]C1C2C(=CC=C(O)C=2)N=C(C)C=1>>[Br:27][C:15]1[C:14]2[C:19](=[CH:20][CH:21]=[C:12]([O:11][C@H:8]3[CH2:9][CH2:10][C@H:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:6][CH2:7]3)[CH:13]=2)[N:18]=[C:17]([CH3:22])[CH:16]=1
Reactant: Cc1cc(C(F)(F)F)c2cc(O[C@H]3CC[C@H](C(C)(C)C)CC3)ccc2n1
Reactant: Cc1cc(Br)c2cc(O)ccc2n1
Product: Cc1cc(Br)c2cc(O[C@H]3CC[C@H](C(C)(C)C)CC3)ccc2n1

Procedure:
Synthesized as per 6-(trans-4-tert-Butyl-cyclohexyloxy)-2-methyl-4-trifluoromethyl-quinoline using 4-Bromo-2-methyl-quinolin-6-ol as starting material. ESI-MS(M+H+): 378.1.
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][C:5]2[S:6][C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[C:4]=2[CH:3]=1.C(N(CC)CC)C.[C:22](Cl)(=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24]>C(Cl)Cl>[C:23]([C:22]([NH:1][C:2]1[CH:14]=[CH:13][C:5]2[S:6][C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[C:4]=2[CH:3]=1)=[O:27])([CH3:26])([CH3:25])[CH3:24]
Reactant: Nc1ccc2sc3ccccc3c2c1
Reactant: CC(C)(C)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)C(=O)Nc1ccc2sc3ccccc3c2c1
Yield: 65.3 %

Procedure:
2-Aminodibenzthiophene (Bull. Soc. Chim. Fr. (1996), 133 (6), 597-610; 2.0 g, 10 mmol) and triethylamine (1.11 g, 11 mmol) were dissolved in DCM (50 ml) and cooled in an ice bath. A solution of pivaloyl chloride (1.21 g, 10 mmol) in DCM (10 ml) was added slowly and the resultant solution was stirred at ambient temperature for 16 hours then evaporated in vacuo. The residue was triturated with methanol to leave the product as a colourless solid (1.85 g). NMR: 9.40 (s, 1H), 8.59 (s, 1H), 8.17 (m, 1H), 7.98 (d, 1H), 7.90 (d, 1H), 7.73 (dd, 1H), 7.46 (m, 2H), 1.15 (s, 9H); m/z 284.