Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[CH3:24])[O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])[N:14]=2)[N:11]=1.[CH3:25][N:26]1[C:30]([C:31](Cl)=[O:32])=[CH:29][C:28]([CH3:34])=[N:27]1.C(N(CC)CC)C>O1CCCC1.C(=O)([O-])O.[Na+]>[CH:18]1([C:16]([NH:15][C:13]2[N:14]=[C:9]3[CH:8]=[CH:7][C:6]([O:5][C:4]4[CH:21]=[CH:22][C:23]([CH3:24])=[C:2]([NH:1][C:31]([C:30]5[N:26]([CH3:25])[N:27]=[C:28]([CH3:34])[CH:29]=5)=[O:32])[CH:3]=4)=[N:11][N:10]3[CH:12]=2)=[O:17])[CH2:20][CH2:19]1
Reactant: Cc1cc(C(=O)Cl)n(C)n1
Reactant: Cc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)cc1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1cc(C(=O)Nc2cc(Oc3ccc4nc(NC(=O)C5CC5)cn4n3)ccc2C)n(C)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.6 %

Procedure:
To a solution of N-[6-(3-amino-4-methylphenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (213 mg, 0.659 mmol) in tetrahydrofuran (10 mL) were added a solution of 1,3-dimethyl-1H-pyrazole-5-carbonyl chloride (136 mg, 0.856 mmol) in tetrahydrofuran (0.5 mL) and triethylamine (200 mg, 1.98 mmol) under ice-cooling, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was diluted with saturated aqueous sodium hydrogencarbonate solution, and extracted three times with ethyl acetate, and the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtrated. The solvent was evaporated under reduced pressure, and the residue was filtrated and washed with ethyl acetate/hexane to give the title compound (222 mg, 77%) as a white powder. melting point 223° C.
Reaction SMILES: CS([O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][N:17]=[N+:18]=[N-:19])(=O)=O.C([O-])([O-])=O.[Cs+].[Cs+].O[C:27]1[CH:32]=[CH:31][C:30]([C:33]2[NH:34][C:35](=[O:45])[C:36]3[C:41]([CH:42]=2)=[CH:40][CH:39]=[C:38]([O:43][CH3:44])[CH:37]=3)=[CH:29][CH:28]=1.O>CN(C=O)C>[N:17]([CH2:16][CH2:15][O:14][CH2:13][CH2:12][O:11][CH2:10][CH2:9][O:8][CH2:7][CH2:6][O:5][C:27]1[CH:28]=[CH:29][C:30]([C:33]2[NH:34][C:35](=[O:45])[C:36]3[C:41]([CH:42]=2)=[CH:40][CH:39]=[C:38]([O:43][CH3:44])[CH:37]=3)=[CH:31][CH:32]=1)=[N+:18]=[N-:19]
Reactant: COc1ccc2cc(-c3ccc(O)cc3)[nH]c(=O)c2c1
Reactant: CS(=O)(=O)OCCOCCOCCOCCN=[N+]=[N-]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc2cc(-c3ccc(OCCOCCOCCOCCN=[N+]=[N-])cc3)[nH]c(=O)c2c1
Temperature: 80 °C
Yield: 23.1 %

Procedure:
2-(2-(2-(2-azidoethoxy)ethoxy)ethoxy)ethyl methanesulphonate (175 mg, 0.58 mmol) and Cs2CO3 (190 mg, 0.58 mmol) are added to the mixture of 3-(4-hydroxyphenyl)-7-methoxyisoquinolin-1(2H)-one (compound 45) (130 mg, 0.48 mmol) in DMF (6 mL). The reaction mixture is heated at 80° C. for 24 hours. Then the solvent is evaporated off, the reaction crude is added to water (100 mL) and extracted with CH2Cl2 (3×100 mL). The organic phase is dried over MgSO4, filtered and concentrated under reduced pressure. The residue obtained is purified by silica column chromatography using a gradient of EtOH (1 to 3%) in CH2Cl2 as eluents. Intermediate 3-(4-(2-(2-(2-(2-azidoethoxy)ethoxy)ethoxy)ethoxy)phenyl)-7-methoxyisoquinolin-1(2H)-one (52 mg, 23%) is obtained, which is used directly in the following stage.
Reaction SMILES: [C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:30]/[O:31][C:32]([C:35](=[O:37])[NH2:36])([CH3:34])[CH3:33])/[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.[NH2:63][C@@H:64]1[C:82](=[O:83])[N:66]2[C:67]([C:79]([OH:81])=[O:80])=[C:68]([CH2:71][S:72][C:73]3[N:77]([NH2:78])[N:76]=[N:75][N:74]=3)[CH2:69][S:70][C@H:65]12.C(N(CC)CC)C.NC1SC=C(/C(=N/OCCCC)/C(N[C@@H]2C(=O)N3C(C(O)=O)=C(CSC4N(N)N=NN=4)CS[C@H]23)=O)N=1>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][C:32]([C:35](=[O:37])[NH2:36])([CH3:34])[CH3:33])/[C:27]([NH:63][C@@H:64]2[C:82](=[O:83])[N:66]3[C:67]([C:79]([OH:81])=[O:80])=[C:68]([CH2:71][S:72][C:73]4[N:77]([NH2:78])[N:76]=[N:75][N:74]=4)[CH2:69][S:70][C@H:65]23)=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CC(C)(O/N=C(\C(=O)O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1)C(N)=O
Reactant: N[C@@H]1C(=O)N2C(C(=O)O)=C(CSc3nnnn3N)CS[C@H]12
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CCCCO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(CSc3nnnn3N)CS[C@H]12)c1csc(N)n1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Solvent: CC(=O)N(C)C
Product: CC(C)(O/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)C(N)=O
Yield: 70.5 %

Procedure:
A solution of 2-(2-tritylaminothiazol-4-yl)-(Z)-2-(2-carbamoyl-2-propyloxyimino)acetic acid (2.00 g, 3.9 mmol), 1-hydroxybenzotriazole (0.560 g, 4.29 mmol) and N,N'-dicyclohexylcarbodiimide (0.840 g, 4.10 mmol) in dimethylacetamide (24 ml) was stirred at room temperature for 4 hours. To this solution was added a solution of 7β-amino-3-[(1-amino-1H-tetrazol-5-yl)thiomethyl]-3-cephem-4-carboxylic acid (1.41 g, 4.29 mmol) and triethylamine (0.790 g, 8.58 mmol) in dimethylacetamide (10 ml) and water (1.4 ml) and the mixture was allowed to react 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 yellow powder of 7β-[2-(2-tritylaminothiazol-4-yl)-(Z)-2-(2-carbamoyl-2-propyloxyimino)acetamido]-3-[(1-amino-1H-tetrazol-5-yl)thiomethyl]-3-cephem-4-carboxylic acid (2.27 g, 70.5%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[C:5]([O:8][C:9]1[CH:18]=[C:17]([OH:19])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=1)([CH3:7])[CH3:6])[CH3:2].[CH3:21][C:22]1[C:27]([CH2:28]O)=[CH:26][CH:25]=[C:24]([C:30]2[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][CH:31]=2)[N:23]=1>>[CH2:1]([O:3][C:4](=[O:20])[C:5]([CH3:7])([O:8][C:9]1[CH:18]=[C:17]([O:19][CH2:28][C:27]2[C:22]([CH3:21])=[N:23][C:24]([C:30]3[CH:31]=[CH:32][C:33]([C:36]([F:39])([F:37])[F:38])=[CH:34][CH:35]=3)=[CH:25][CH:26]=2)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=1)[CH3:6])[CH3:2]
Reactant: CCOC(=O)C(C)(C)Oc1cc(O)c2ccccc2c1
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)ccc1CO
Product: CCOC(=O)C(C)(C)Oc1cc(OCc2ccc(-c3ccc(C(F)(F)F)cc3)nc2C)c2ccccc2c1

Procedure:
In analogy to the procedures described in example 4D] and 4E], 2-(4-hydroxy-naphthalen-2-yloxy)-2-methyl-propionic acid ethyl ester (example 17D]) was reacted with [2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-methanol (example 1I]) to give 2-methyl-2-{4-[2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-ylmethoxy]-naphthalen-2-yloxy}-propionic acid ethyl ester, which was subsequently saponified to yield the title compound as yellow solid.
Reaction SMILES: [I:1][CH2:2][C:3]1([CH3:19])[O:18][C:6]2=[C:7]([CH3:17])[C:8]3[CH2:9][CH2:10][N:11](C=O)[C:12]=3[C:13]([CH3:14])=[C:5]2[CH2:4]1.Cl.C(=O)([O-])O.[Na+]>CO.O>[I:1][CH2:2][C:3]1([CH3:19])[O:18][C:6]2=[C:7]([CH3:17])[C:8]3[CH2:9][CH2:10][NH:11][C:12]=3[C:13]([CH3:14])=[C:5]2[CH2:4]1
Reactant: Cc1c2c(c(C)c3c1OC(C)(CI)C3)N(C=O)CC2
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Cc1c2c(c(C)c3c1NCC3)OC(C)(CI)C2
Temperature: 60 °C
Reaction time: 2 h
Yield: 98.2 %

Procedure:
3,5,6,7-Tetrahydro-2-(iodomethyl)-2,4,8-trimethyl-2H-furo[2,3-f]indole-5-carbaldehyde (3.71 g, 10 mmol) was dissolved in methanol (37 ml). To the solution was added concentrated hydrochloric acid, and stirred for 2 hours at 60° C. under argon atmosphere. The mixture was cooled to 0° C., made weakly basic with a saturated aqueous solution of sodium hydrogen carbonate, diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate, and the solvent was removed under reduced pressure, and this was subjected to chromatography on a small amount of silica gel with eluting with ethyl acetate. The resultant oil was crystallized from hexane to obtain 3.37 g of the title compound.
Reaction SMILES: [F:1][C:2]([F:39])([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH2:3][NH:4][C:5]1[C:6]([F:32])=[C:7]([CH2:12][C:13]([NH:15][CH2:16][C:17]2[C:18]([CH3:31])=[N:19][C:20]([NH:23]C(OC(C)(C)C)=O)=[CH:21][CH:22]=2)=[O:14])[C:8]([Cl:11])=[CH:9][CH:10]=1.Cl.O1CCOCC1>>[ClH:11].[NH2:23][C:20]1[N:19]=[C:18]([CH3:31])[C:17]([CH2:16][NH:15][C:13](=[O:14])[CH2:12][C:7]2[C:8]([Cl:11])=[CH:9][CH:10]=[C:5]([NH:4][CH2:3][C:2]([F:1])([F:39])[C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)[C:6]=2[F:32])=[CH:22][CH:21]=1
Reactant: Cc1nc(NC(=O)OC(C)(C)C)ccc1CNC(=O)Cc1c(Cl)ccc(NCC(F)(F)c2ccccc2)c1F
Agent: Cl
Solvent: C1COCCO1
Product: Cc1nc(N)ccc1CNC(=O)Cc1c(Cl)ccc(NCC(F)(F)c2ccccc2)c1F
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 181.3 %

Procedure:
To a flask charged with 2-{3-[(2,2-difluoro-2-phenylethyl)amino]-6-chloro-2-fluorophenyl}-N-({6-[(tert-butoxy)carbonylamino]-2-methyl(3-pyridyl)}methyl)acetamide (770 mg, 1.37 mmol), as prepared in the preceding step, was added a solution of HCl in 1,4-dioxane (5 mL, 20 mmol, 4.0 M). After stirring at ambient temperature for 1.5 hours, some solid precipitated. A solution of MeOH (1 mL) in DCM (3 mL) was added to dissolve the solid, and the mixture was stirred for additional 4 hours. The solvents were removed, and the resulting residue was washed with DCM (5 mL×2), ether (8 mL×2), and dried in high vacuum to give the title compound (620 mg, 91% yield) as a pale brown solid. 1H-NMR (400 MHz, CD3OD) δ 7.81 (d, J=9.1 Hz, 1H), 7.54-7.51 (m, 2H), 7.45-7.42 (m, 3H), 6.94 (dd, J=8.9, 1.6 Hz, 1H), 6.80 (d, J=9.1 Hz, 1H), 6.65 (t, J=9.1 Hz, 1H), 4.25 (s, 2H), 3.81 (t, J=13.8 Hz, 2H), 3.70 (d, J=1.8 Hz, 2H), 2.50 (s, 3H). Mass spectrum (LCMS, ESI) calcd for C23H23ClF3N4O (M+H): 463.1. Found: 463.7.
Reaction SMILES: [C:1]([NH:4][CH2:5][CH:6]([C:16]1[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][CH:17]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:8])(=[O:3])[CH3:2].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[NH2:46][C:47]1[CH:52]=[C:51]([C:53]2[CH:57]=[CH:56][S:55][CH:54]=2)[CH:50]=[CH:49][C:48]=1[NH:58][C:59](=[O:65])[O:60][C:61]([CH3:64])([CH3:63])[CH3:62]>CN(C=O)C.O>[C:61]([O:60][C:59](=[O:65])[NH:58][C:48]1[CH:49]=[CH:50][C:51]([C:53]2[CH:57]=[CH:56][S:55][CH:54]=2)=[CH:52][C:47]=1[NH:46][C:20](=[O:21])[C:19]1[CH:23]=[CH:24][C:16]([CH:6]([CH2:5][NH:4][C:1](=[O:3])[CH3:2])[C:7]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:8])=[CH:17][CH:18]=1)([CH3:62])([CH3:64])[CH3:63]
Reactant: CC(=O)NCC(C(=O)Nc1ccccc1)c1ccc(C(=O)O)cc1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccsc2)cc1N
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)NCC(C(=O)Nc1ccccc1)c1ccc(C(=O)Nc2cc(-c3ccsc3)ccc2NC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
4-{1-[(Acetylamino)methyl]-2-anilino-2-oxoethyl}benzoic acid (232 mg, 0.71 mmol), EDCI (176 mg, 0.92 mmol), and HOBT (124 mg, 0.92 mmol) were combined in DMF (8 mL) and stirred for 10 minutes before adding tert-butyl [2-amino-4-(3-thienyl)phenyl]carbamate (227 mg, 0.78 mmol). The reaction was then stirred at 60° C. for 24 h. The solution was cooled to room temperature, poured into water (40 mL), and filtered to collect an orange solid. The crude solid was dissolved in CH2Cl2 (25 mL) and hexanes (20 mL), concentrated to half volume, and filtered to give tert-butyl[2-[(4-{1-[(acetylamino)methyl]-2-anilino-2-oxoethyl}benzoyl)amino]-4-(3-thienyl)phenyl]carbamate as a white solid. MS (ESI) calcd [M+H]+ 599.2, found 599.1.
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[K].Cl[CH2:14][CH2:15][CH2:16][C:17](=[O:19])[CH3:18]>CN(C=O)C>[O:19]=[C:17]([CH3:18])[CH2:16][CH2:15][CH2:14][N:5]1[C:1](=[O:11])[C:2]2[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4]1=[O:6]
Reactant: CC(=O)CCCCl
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Product: CC(=O)CCCN1C(=O)c2ccccc2C1=O
Temperature: 60 °C
Reaction time: 30 h
Yield: 34.1 %

Procedure:
24.59 g (132.8 mmol) of potassium phthalimide are added to a solution of 14.3 ml (124.4 mmol) of 5-chloro-2-pentanone in 100 ml of DMF and the mixture is left to stir at room temperature for 3 h and at 60° C. for 30 h. After filtering, the filtrate is partitioned between water and dichloromethane. The phases are separated and the organic phase is washed successively with water, twice with an 0.2N solution of NaOH and water and then dried over sodium sulfate. After filtering, the solvent is removed in vacuo and the residue is chromatographed through silica gel using heptane/ethyl acetate=6/4. 9.8 g (34%) of (14.1) are obtained after concentrating the product fractions.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([NH2:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.F[C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1[N+:19]([O-:21])=[O:20].C(N(CC)C(C)C)(C)C>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([NH:10][C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=2[N+:19]([O-:21])=[O:20])[CH3:9])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(N)c1cccc(Cl)c1
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(Nc1cc(F)ccc1[N+](=O)[O-])c1cccc(Cl)c1
Yield: 57.3 %

Procedure:
1-(3-Chlorophenyl)ethanamine (553 mg, 3.55 mmol), 2,4-difluoronitrobenzene (565 mg, 3.55 mmol) and N,N-diisopropylethylamine (918 mg, 7.10 mmol) were stirred at room temperature in dry acetonitrile (20 mL) for 6 h. The solvent was evaporated and the residue was dissolved in dichloromethane and washed with water. The dichloromethane was evaporated to collect the title compound (600 mg, 57% yield). 1H NMR (400 MHz, CDCl3): δ 8.49 (s, 1H), 8.23 (m, 1H), 7.04 (m, 4H), 6.36 (t, 1H), 6.22 (d, 1H), 4.56 (m, 1H), 1.64 (d, 3H); MS (ESI) m/z: Calculated for C14H13ClFN2O2: 295.06; Observed: 295.0 (M++1).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C@:12]1([CH3:18])[CH2:16][O:15][C:14](=[O:17])[NH:13]1)[CH:6]=[CH:5]2.C(=O)([O-])[O-].[Cs+].[Cs+].CS(O[C@H:30]1[CH2:35][CH2:34][C@@H:33]([C:36]([F:39])([F:38])[CH3:37])[CH2:32][CH2:31]1)(=O)=O.O>CC(O)(C)C.CC(=O)CC>[F:38][C:36]([C@H:33]1[CH2:34][CH2:35][C@H:30]([O:1][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[CH:8]=[C:7]([C@:12]2([CH3:18])[CH2:16][O:15][C:14](=[O:17])[NH:13]2)[CH:6]=[CH:5]3)[CH2:31][CH2:32]1)([F:39])[CH3:37]
Reactant: CC(F)(F)[C@H]1CC[C@@H](OS(C)(=O)=O)CC1
Reactant: C[C@@]1(c2ccc3cc(O)ccc3c2)COC(=O)N1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)(C)O
Solvent: O
Solvent: CCC(C)=O
Product: CC(F)(F)[C@H]1CC[C@H](Oc2ccc3cc([C@]4(C)COC(=O)N4)ccc3c2)CC1
Temperature: 110 °C
Reaction time: 0.17 h

Procedure:
(R)-4-(6-Hydroxynaphthalen-2-yl)-4-methyloxazolidin-2-one (121 mg, 0.5 mmol, 0.9 eq.) and cesium carbonate (407 mg, 1.25 mmol, 2.5 eq.) were dissolved in t-BuOH/2-butanone (10 mL/5 mL). The mixture was stirred at 110° C. for 10 min, then cis-4-(1,1-difluoroethyl)cyclohexyl methanesulfonate(145 mg, 0.6 mmol, 1.1 eq.) was added to the mixture and the mixture was stirred at 110° C. for 15 h. Water was added to the mixture and the mixture was extracted with EtOAc. The organic layer was concentrated and purified by is silica gel column chromatography using petroleum ether/ethyl acetate (1/1) as eluent to give product (203 mg, 58%) as a slight yellow solid. EDI-MS (M+1): 390.1. 1H NMR (400 MHz, CDCl3) δ 7.75-7.72 (m, 3H), 7.42 (dd, 1H), 7.16-7.14 (m, 2H), 6.14 (s, 1H), 4.42 (s, 2H), 4.34-4.30 (m, 1H), 2.31-2.29 (m, 2H), 2.04-2.01 (m, 2H), 1.84 (s, 3H), 1.64-1.22 (m, 8H).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][C:6](Cl)=[O:7].C([O-])([O-])=O.[K+].[K+].[CH3:15][NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[SH:23][C:24]1[N:28]([CH2:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[C:27]2[CH:37]=[CH:38][CH:39]=[CH:40][C:26]=2[N:25]=1>C(#N)C>[CH3:15][N:16]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:6]([CH2:5][CH2:4][CH2:3][CH2:2][S:23][C:24]1[N:28]([CH2:29][C:30]([O:32][C:33]([CH3:35])([CH3:36])[CH3:34])=[O:31])[C:27]2[CH:37]=[CH:38][CH:39]=[CH:40][C:26]=2[N:25]=1)=[O:7]
Reactant: CC(C)(C)OC(=O)Cn1c(S)nc2ccccc21
Reactant: CNc1ccccc1
Reactant: O=C(Cl)CCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CN(C(=O)CCCCSc1nc2ccccc2n1CC(=O)OC(C)(C)C)c1ccccc1
Reaction time: 1 h
Yield: 77 %

Procedure:
To a suspension of 5-bromovaleryl chloride (24.8 mg, 16.6 μl, 0.12 mmol) and K2CO3 (31.2 mg, 0.23 mmol) in acetonitrile (3 ml) is added N-methylaniline (14.5 mg, 14.7 μl, 0.14 mmol). After 1 h of stirring, tert-butyl (2-mercapto-benzoimidazol-1-yl)-acetate (Intermediate 3-I, 30 mg, 0.11 mmol) is added and the resulting mixture is refluxed overnight. The crude suspension is filtered over a fritted funnel and the solvent evaporated in vacuo. The crude yellow oil is purified by flash-chromatography on silica gel (AcOEt/heptane, 2:1 containing 3% of Et3N), yielding the title compound (38.4 mg) in 75% as a yellowish oil: tR=6.84 min (LC-1), ESI-MS (pos.): m/z 455.46 [M+H]+, ESI-MS (neg.): m/z 452.19 [M−H]+; 1H-NMR (DMSO-d6): δ (ppm) 1.38 (s, 9H, tBu), 1.56 (m, 4H, CH2CH2), 2.03 (m, 2H, CH2C═O), 3.17 (m, 2H, SCH2), 3.31 (s, 3H, NMe), 4.92 (s, 2H, CH2CO2), 7.12-7.16 (m, 2Harom), 7.26-7.30 (m, 3Harom), 7.36-7.46 (m, 3Harom), 7.51 (m, 1Harom).
Reaction SMILES: [I:1][C:2]1[N:3]=[CH:4][N:5]([CH2:7][C:8]([CH3:11])([OH:10])[CH3:9])[CH:6]=1.O([Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])S(C(F)(F)F)(=O)=O>N1C(C)=CC=CC=1C>[Si:20]([O:10][C:8]([CH3:11])([CH3:9])[CH2:7][N:5]1[CH:6]=[C:2]([I:1])[N:3]=[CH:4]1)([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21]
Reactant: CC(C)(O)Cn1cnc(I)c1
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: Cc1cccc(C)n1
Product: CC(C)(Cn1cnc(I)c1)O[Si](C)(C)C(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 74 %

Procedure:
1-(4-iodo-1H-imidazol-1-yl)-2-methylpropan-2-ol was dissolved in DCm and lutidine was added dropwise at 0° C. The mixture was stirred at 0° C. for 30 min then tert-butyldimethylsilyl triflate (TBSOTf) was added dropwise. The mixture was warmed to room temperature and sat for about an hour, then quenched with 30% acetic acid, extracted ethylacetate, dried, and concentrated to give 1-(2-(tert-butyldimethylsilyloxy)-2-methylpropyl)-4-iodo-1H-imidazole (Yield=74%). LC-MS: m/z=381 [M+H+]
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([NH:8][CH:9]([CH2:12][OH:13])[CH2:10][OH:11])=[N:6][CH:7]=1.[C:14]([O:19][CH2:20][CH3:21])(=[O:18])[C:15]([CH3:17])=O.B(F)(F)F.CCOCC>C(#N)C>[Br:1][C:2]1[CH:7]=[N:6][C:5]([NH:8][CH:9]2[CH2:10][O:11][C:15]([CH3:17])([C:14]([O:19][CH2:20][CH3:21])=[O:18])[O:13][CH2:12]2)=[N:4][CH:3]=1
Reactant: OCC(CO)Nc1ncc(Br)cn1
Reactant: CCOC(=O)C(C)=O
Agent: FB(F)F
Solvent: CCOCC
Solvent: CC#N
Product: CCOC(=O)C1(C)OCC(Nc2ncc(Br)cn2)CO1
Reaction time: 24 h
Yield: 75.8 %

Procedure:
2-[(5-bromopyrimidin-2-yl)amino]propane-1,3-diol (100 mg, 0.40 mmol), ethyl pyruvate (80 μL, 0.72 mmol) and acetonitrile (2 mL) were combined at rt. An aliquot of borontrifluoride etherate (100 μL, 0.80 mmol) was added to the reaction mixture and stirring was continued at rt for 24 hrs. A further portion of borontrifluoride etherate (100 μL, 0.80 mmol) was added to the reaction mixture, which was stirred at rt for a further 24 hrs. The reaction mixture was loaded directly onto a column for flash chromatography (12 g silica column), eluting with 0-100% EtOAc gradient in n-heptane, to give desired product (105 mg, light brown oil). m/z 345.9/347.9 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2/[CH:11]=[C:12]1\[O:13][C:14]2[C:21]([CH2:22][N:23]3[CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25][CH2:24]3)=[C:20]([O:36][CH3:37])[CH:19]=[CH:18][C:15]=2[C:16]\1=[O:17].FC(F)(F)C(O)=O>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2/[CH:11]=[C:12]1\[O:13][C:14]2[C:21]([CH2:22][N:23]3[CH2:24][CH2:25][NH:26][CH2:27][CH2:28]3)=[C:20]([O:36][CH3:37])[CH:19]=[CH:18][C:15]=2[C:16]\1=[O:17]
Reactant: COc1ccc2c(c1CN1CCN(C(=O)OC(C)(C)C)CC1)O/C(=C\c1n[nH]c3ccc(Br)cc13)C2=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc2c(c1CN1CCNCC1)O/C(=C\c1n[nH]c3ccc(Br)cc13)C2=O
Reaction time: 8 h
Yield: 65.2 %

Procedure:
A solution of tert-butyl (Z)-4-({2-[(5-bromo-1H-indazol-3-yl)methylene]-6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl}methyl)piperazine-1-carboxylate (0.160 g, 0.281 mmol) in methylene chloride (4 mL) was added with trifluoroacetic acid (4 mL) at room temperature, and the mixture was stirred overnight. The reaction mixture was concentrated, and then added with water (10 mL) and saturated aqueous sodium hydrogencarbonate (10 mL), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was filtered, and then the resulting solid was washed with water to obtain the objective (Z)-2-[(5-bromo-1H-indazol-3-yl)methylene]-6-methoxy-7-(piperazin-1-ylmethyl)benzofuran-3(2H)-one (0.0860 g, 65%).
Reaction SMILES: [CH2:1]([S:8][C@H:9]1[NH:12][C:11](=[O:13])[C@@H:10]1[Br:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:15]1([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][NH:27][C:28](=[O:31])[CH2:29]Br)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[OH-].[K+].[OH-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[C:15]1([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][NH:27][C:28](=[O:31])[CH2:29][N:12]2[C@H:9]([S:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C@@H:10]([Br:14])[C:11]2=[O:13])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C1N[C@H](SCc2ccccc2)[C@H]1Br
Reactant: O=C(CBr)NCCCCCCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(CN1C(=O)[C@H](Br)[C@H]1SCc1ccccc1)NCCCCCCc1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 49.5 %

Procedure:
A solution of (3S, 4R)-4-benzylthio-3-bromoazetidin-2-one (0.7 g, 2.6 mmol) in dry THF (25 ml) was treated with N-(6-phenylhexyl)bromoacetamide (0.8 g, 2.6 mmol), powdered potassium hydroxide (0.2 g 3 mmol) and tetrabutylammonium hydroxide (0.1 g, 0.3 mmol). The mixture was stirred at room temperature for 4 h and partitioned between ether and brine. The organic layer was separated, dried (MgSO4) and evaporated. The residue was purified by flash chromatography using 3:1 ether:pentane as the eluting solvent. Evaporation of the appropriate fractions gave the title compound as an oil (0.63 g, 53%). 1H NMR δ (CDCl3) 1.21-1.66 (8H, m, (CH2)4), 2.59 (2H, t, J=7.4 Hz, CH2), 3.48,3.82 (each 1H, d, J=16 Hz, NCH2), 3.21 (2H, h, J=6.00 Hz, CH2), 3.37 (1H, dd, J=5.15 Hz, H3b), 3.83 (2H, s, SCH2), 4.59 (1H, d, J=1.6 Hz, H4), 4.89 (1H, d, J=1.6 Hz, H3), 6.04 (1H, bt, NH), 7.14-7.36 (10H, m, Ph--H).
Reaction SMILES: [Br:1][C:2]1[C:10]([O:11][CH2:12][CH3:13])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[O:14][CH2:15][CH3:16].C1N=CN(C(N2C=NC=C2)=O)C=1.[CH3:29][C:30](O)([CH3:32])[CH3:31].C1CCN2C(=NCCC2)CC1>CN(C=O)C>[Br:1][C:2]1[C:10]([O:11][CH2:12][CH3:13])=[CH:9][C:5]([C:6]([O:8][C:30]([CH3:32])([CH3:31])[CH3:29])=[O:7])=[CH:4][C:3]=1[O:14][CH2:15][CH3:16]
Reactant: CC(C)(C)O
Reactant: CCOc1cc(C(=O)O)cc(OCC)c1Br
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: CCOc1cc(C(=O)OC(C)(C)C)cc(OCC)c1Br
Temperature: 40 °C
Reaction time: 2 h

Procedure:
To a mixture of 4-Bromo-3,5-diethoxybenzoic acid (2.8 g) in DMF (25 ml) was added CDI (1.8 g) at room temperature and the mixture was stirred at 40° C. for 2 h. To the reaction mixture, t-BuOH (1.85 ml) and DBU (1.75 ml) were added and further stirred at 40° C. overnight. After cooling to room temperature, the mixture was poured into ice-H2O and extracted with EtOAc. The organic layer was washed with H2O, brine and dried over sodium sulfate. After filtration and concentration, the residue was purified by silica gel column chromatography (hexane/EtOAc) to give the intended compound as a colorless solid.