Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:4]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[O:16][C:17]3[C:25]([F:26])=[CH:24][C:23]([F:27])=[C:22]([NH2:28])[C:18]=3[C:19](=[O:21])[CH:20]=2)=[CH:11][C:10]=1[F:29])[CH2:5][CH2:6][CH2:7]Cl)(=[O:3])[CH3:2].[N-:30]=[N+:31]=[N-:32].[Na+].O>CN(C)C=O>[C:1]([N:4]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[O:16][C:17]3[C:25]([F:26])=[CH:24][C:23]([F:27])=[C:22]([NH2:28])[C:18]=3[C:19](=[O:21])[CH:20]=2)=[CH:11][C:10]=1[F:29])[CH2:5][CH2:6][CH2:7][N:30]=[N+:31]=[N-:32])(=[O:3])[CH3:2]
Reactant: CC(=O)N(CCCCl)c1ccc(-c2cc(=O)c3c(N)c(F)cc(F)c3o2)cc1F
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)N(CCCN=[N+]=[N-])c1ccc(-c2cc(=O)c3c(N)c(F)cc(F)c3o2)cc1F
Temperature: 70 °C
Reaction time: 4 h
Yield: 105.6 %

Procedure:
810 mg (1.91 mmol) of 2-[4-[N-acetyl-N-(3-chloropropyl)amino]-3-fluorophenyl]-5-amino-6,8-difluoro-4H-1-benzopyran-4-one obtained in Example 50 was dissolved in 40 ml of dimethylformamide under argon atmosphere, 622 mg of sodium azide was added at room temperature and the mixture was stirred at 70° C. for 4 hours. Water was added to the reaction solution, the mixture was extracted twice with ethyl acetate, the organic layer was washed once with water and once with an aqueous saturated solution of sodium chloride and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to give 870 mg of 2-[4-[N-acetyl-N-(3-azidopropyl)amino]-3-fluorophenyl]-5-amino-6,8-difluoro-4H-1-benzopyran-4-one.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH2:5][CH:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([O:17][C:18]3[S:19][C:20](Br)=[N:21][N:22]=3)[CH:14]=[C:15]([CH3:16])[C:7]1=2)[CH3:2]>CCO.[Pd]>[CH2:1]([O:3][C:4](=[O:24])[CH2:5][CH:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([O:17][C:18]3[S:19][CH:20]=[N:21][N:22]=3)[CH:14]=[C:15]([CH3:16])[C:7]1=2)[CH3:2]
Reactant: CCOC(=O)CC1OB(O)c2cc(Oc3nnc(Br)s3)cc(C)c21
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CC1OB(O)c2cc(Oc3nncs3)cc(C)c21
Reaction time: 1 h
Yield: 70.1 %

Procedure:
A mixture of [6-(5-bromo-[1,3,4]thiadiazol-2-yloxy)-1-hydroxy-4-methyl-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl]-acetic acid ethyl ester (0.53 g, 1.28 mmol) and Pd/C (0.5 g) in EtOH (15 mL) was hydrogenated at 45 psi for 1 hour. The mixture was filtered through a pad of celite and concentrated in vacuo. The residue was purified by silica gel flash column chromatography (DCM:MeOH 95:5) to give [1-hydroxy-4-methyl-6-([1,3,4]thiadiazol-2-yloxy)-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl]-acetic acid ethyl ester (0.3 g, 70%). 1H NMR (400 MHz, DMSO): δ 9.15 (s, 1H), 7.40 (s, 1H), 7.28 (s, 1H), 5.52 (d, J=8.8 Hz, 1H), 4.00 (q, J=7.2 Hz, 2H), 3.10 (dd, J=4.0, 15.6 Hz, 1H), 2.52-2.45 (m, 1H), 2.30 (s, 3H), 1.10 (t, J=6.8 Hz, 3H). MS (ESI) m/z=335 [M+H]+.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]3[C:13](=[C:14]([C:16]([NH2:18])=[O:17])[CH:15]=2)[NH:12][CH:11]=[C:10]3[CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:25][C:26]1[N:30]([CH3:31])[N:29]=[C:28]([CH3:32])[C:27]=1[S:33](Cl)(=[O:35])=[O:34].C(N(CC)CC)C>>[Cl:25][C:26]1[N:30]([CH3:31])[N:29]=[C:28]([CH3:32])[C:27]=1[S:33]([N:22]1[CH2:23][CH2:24][CH:19]([C:10]2[C:9]3[C:13](=[C:14]([C:16]([NH2:18])=[O:17])[CH:15]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[CH:8]=3)[NH:12][CH:11]=2)[CH2:20][CH2:21]1)(=[O:34])=[O:35]
Reactant: Cc1nn(C)c(Cl)c1S(=O)(=O)Cl
Reactant: NC(=O)c1cc(-c2ccccc2)cc2c(C3CCNCC3)c[nH]c12
Solvent: CCN(CC)CC
Product: Cc1nn(C)c(Cl)c1S(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4ccccc4)cc23)CC1

Procedure:
Following the general procedure in example 267, 5-(phenyl)-3-(4-piperidinyl)-1H-indole-7-carboxamide (32 mg, 0.1 mmol), 5-chloro-1,3-dimethyl-1H-pyrazole-4-sulfonyl chloride (34.5 mg, 0.15 mmol) and triethylamine (0.06 mL, 0.3 mmol) were reacted to form the desired product which was purified by Gilson HPLC (CH3CN/Water, 0.1% TFA) (22 mg, 43%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[C@H:7]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1)[NH:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].O.C(=O)([O-])[O-].[K+].[K+].[C:32]([O:36][C:37](=[O:40])[CH2:38]Br)([CH3:35])([CH3:34])[CH3:33]>O1CCCC1>[C:1]([O:5][C:6](=[O:24])[CH:7]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1)[N:8]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:38][C:37]([O:36][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:40])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CC(C)(C)OC(=O)[C@H](Cc1ccc(O)cc1)NCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CN(Cc1ccccc1)C(Cc1ccc(O)cc1)C(=O)OC(C)(C)C

Procedure:
15.1 g (46.1 mmol) of N-benzyl-tyrosine-tert-butyl ester (Example a) is dissolved in 50 ml of tetrahydrofuran and mixed with 5 ml of water and 9.54 9 (69 mmol) of potassium carbonate. After instillation of 9.89 g (51 mmol) of bromoacetic acid-tert-butyl ester, it is stirred for two days at 65° C. After cooling, it is filtered, concentrated by evaporation in a vacuum and the residue is chromatographed on silica gel with diethyl ether/hexane/triethylamine. The product fractions are concentrated by evaporation in a vacuum and dried.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[Cl:8].C([Mg]Cl)(C)C.[C:14]1(=[O:18])[CH2:17][CH2:16][CH2:15]1>C1COCC1>[Cl:8][C:7]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:14]1([OH:18])[CH2:17][CH2:16][CH2:15]1
Reactant: Clc1ccncc1Br
Reactant: O=C1CCC1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: OC1(c2cnccc2Cl)CCC1
Temperature: -15 °C
Reaction time: 1 h
Yield: 87.1 %

Procedure:
To a solution of 3-bromo-4-chloropyridine (CAN 36953-42-1, 1 g, 5.2 mmol) in dry THF (25.0 ml) cooled down to −15° C. under an argon atmosphere was added isopropyl magnesium chloride, lithium chloride complex 1.3M solution in THF (4.2 ml, 5.46 mmol) and the reaction mixture was stirred at −15° C. for 1 hour. To the reaction mixture at −15° C. was slowly added cyclobutanone (CAN 1191-95-3, 401 mg, 428 μl, 5.72 mmol) and the reaction was stirred at −15° C. for 2 hours. The reaction was then let to warm up to 0° C. and stirred at 0° C. for 2 hours. Reaction was quenched by addition of water and the reaction mixture was concentrated in vacuo. The residue was dissolved in ethylacetate and extraction with an 3.0M aqueous solution of ammonium chloride. The organic phase was dried over sodium sulfate and evaporated down to dryness. The crude material was purified by flash chromatography on silica eluting with a heptane/ethylacetate gradient to yield the title compound (832 mg, 78%) as a yellow oil. MS (ESI, m/z): 184.3 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12](=[O:17])[C:13]([F:16])([F:15])[F:14])[C@@H:7]([CH3:18])[CH2:6][NH:5]2.N1C=CC=CC=1.[CH:25]1([C:28](Cl)=[O:29])[CH2:27][CH2:26]1>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12](=[O:17])[C:13]([F:14])([F:16])[F:15])[C@@H:7]([CH3:18])[CH2:6][N:5]2[C:28]([CH:25]1[CH2:27][CH2:26]1)=[O:29]
Reactant: C[C@H]1CNc2cc(Br)ccc2N1C(=O)C(F)(F)F
Reactant: O=C(Cl)C1CC1
Solvent: c1ccncc1
Solvent: ClCCl
Product: C[C@H]1CN(C(=O)C2CC2)c2cc(Br)ccc2N1C(=O)C(F)(F)F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 97.5 %

Procedure:
A 250-mL, three-necked, round bottomed flask fitted with a nitrogen inlet, magnetic stir bar, and thermocouple was charged with (S)-1-(6-bromo-2-methyl-3,4-dihydroquinoxalin-1(2H)-yl)-2,2,2-trifluoroethanone (7.0 g, 21.66 mmol), dichloromethane (140 mL), and pyridine (2.63 mL, 32.5 mmol). The mixture was cooled to 0° C. and cyclopropanecarbonyl chloride (2.36 mL, 26.0 mmol) was slowly added while maintaining the internal temperature below 7° C. The reaction mixture was stirred cold for 30 min. and then warmed to rt. The reaction mixture was washed with 1 M aqueous HCl solution (25 mL) and water (25 mL), and the combined organic layers were concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (eluting with 4:1 hexanes-ethyl acetate) to afford (S)-1-(6-bromo-4-(cyclopropanecarbonyl)-2-methyl-3,4-dihydroquinoxaline-1(2H)-yl)-2,2,2-trifluoroethanone (8.26 g, 97%) as an off-white solid. MS (ESI, pos. ion) m/z 392 [M+1]+.
Reaction SMILES: [H-].[Na+].[C:3]([NH:6][CH:7]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:8]([O:10][CH2:11][CH3:12])=[O:9])(=[O:5])[CH3:4].Br[CH:19]1[CH2:28][CH2:27][C:26]2[C:21](=[CH:22][CH:23]=[C:24]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[CH:25]=2)[C:20]1=[O:37]>CN(C=O)C>[CH2:11]([O:10][C:8](=[O:9])[C:7]([NH:6][C:3](=[O:5])[CH3:4])([CH:19]1[CH2:28][CH2:27][C:26]2[C:21](=[CH:22][CH:23]=[C:24]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[CH:25]=2)[C:20]1=[O:37])[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH3:12]
Reactant: CCCCCCCCc1ccc2c(c1)CCC(Br)C2=O
Reactant: CCOC(=O)C(NC(C)=O)C(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCCCc1ccc2c(c1)CCC(C(NC(C)=O)(C(=O)OCC)C(=O)OCC)C2=O
Temperature: 0 °C
Reaction time: 3 h
Yield: 74.6 %

Procedure:
Sodium hydride (720 mg, 18.0 mmol) 60% in mineral oil was suspended in dry DMF (10 mL) and a solution of diethyl acetamidomalonate (3.26 g, 15 mmol) in dry DMF (10 mL) was added. The solution was stirred at 0° C. for 3 hours until the anion had formed. A solution of 4 (2.02 g, 6.0 mmol) in dry DMF (10 mL) was added and the solution warmed to room temperature and stirred overnight. The mixture was poured into distilled water (50 mL), in an ice-bath, acidified to pH 3 with 1M hydrochloric acid and extracted with ethyl acetate (3×50 mL). The organic phases were washed with brine (2×30 mL) and dried over magnesium sulfate and concentrated under vacuum. The residue was purified by column chromatography (Silica gel, 40% EtOAc in hexanes) to provide 2.12 g of compound 5 (75%).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH2:8][CH2:9][NH:10]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:13](OC(=O)C)(=[O:15])[CH3:14]>ClCCl>[C:13]([N:10]1[C:11]2[C:7](=[CH:6][CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:12]=2)[CH2:8][CH2:9]1)(=[O:15])[CH3:14]
Reactant: O=[N+]([O-])c1ccc2c(c1)NCC2
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Product: CC(=O)N1CCc2ccc([N+](=O)[O-])cc21
Reaction time: 2 h
Yield: 99.4 %

Procedure:
A stirred solution of 2,3-dihydro-6-nitro-1H-indole (100 g, 0.61 mole) in dichloromethane (1000 ml) at room temperature was treated dropwise over 20 minutes with acetic anhydride (62 ml, 0.66 mole). The reaction mixture was stirred for a further 2 h, then washed with 10% Na2CO3 solution (300 ml) dried (Na2SO4) and concentrated in vacuo to afford the title compound as a yellow solid (125 g, 100%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[CH:28]=[CH:27][C:20]4[CH2:21][CH2:22][CH2:23][CH2:24][C:25](=O)[C:19]=4[CH:18]=3)[CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C[O-].[Na+].Cl.[BH4-].[Na+].[C:35](=O)([O:38]C)[O:36][CH3:37]>C1COCC1.CO.O.CC(C)=O>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[C:23]4[CH2:22][CH2:21][CH2:20][C:27]([C:35]([O:36][CH3:37])=[O:38])=[CH:28][C:24]=4[CH:25]=[CH:19][CH:18]=3)[CH2:13][CH2:12]2)(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)N2CCC(c3ccc4c(c3)C(=O)CCCC4)CC2)cc1
Reactant: COC(=O)OC
Agent: C[O-]
Agent: Cl
Agent: [BH4-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: COC(=O)C1=Cc2cccc(C3CCN(S(=O)(=O)c4ccc(C)cc4)CC3)c2CCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3-[1-(4-methylphenylsulfonyl)piperidin-4-yl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-one (3.25 g) in dimethyl carbonate (50 ml) was added at room temperature sodium methoxide (2.21 g), and the mixture was refluxed for 4.5 hours and cooled to room temperature. To the mixture was added 1N hydrochloric acid (100 ml), and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the mixture was concentrated to give crude product (3.91 g). The resulting crude product was dissolved in THF (150 ml), and to the mixture was added at −40° C. a solution of sodium boro hydride (0.31 g) in methanol (10 ml). The mixture was stirred at −10 to −20° C. for 1 hour. To the mixture was added a solution of sodium boro hydride (0.31 g) in methanol (10 ml), and the mixture was stirred for 1.5 hours. To the mixture was added acetone (2 ml), and the mixture was stirred for 30 minutes. To the mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the mixture was concentrated, and the residue was dissolved in THF (40 ml). To the mixture was added triethylamine (3.42 ml). To the mixture was added at 0° C. methanesulfonyl chloride (0.95 ml), and the mixture was stirred at 0° C. for 30 minutes and then at room temperature for 30 minutes. To the mixture was added 1,8-diazabicyclo[5,4,0]-7-undecene (3.7 ml), and the mixture was stirred for 14 hours. To the mixture was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the mixture was concentrated, and the residue was purified with column chromatography (ethyl acetate/hexane=1:2) to give colorless crystals of methyl 4-[1-(4-methylphenylsulfonyl)piperidin-4-yl]-6,7-dihydro-5H-benzocycloheptene-8-carboxylate (2.01 g).
Reaction SMILES: [OH-].[K+].[CH3:3]C1C=CC(S(N(N=O)C)(=O)=O)=CC=1.C(O)CO.CCOCC.[NH:26]1[C:30]2[CH:31]=[C:32]([N:35]3[CH:39]([C:40]4[CH:45]=[CH:44][C:43]([CH:46]5[CH2:51][CH2:50][CH:49]([N:52]6[CH2:57][CH2:56][O:55][CH2:54][CH2:53]6)[CH2:48][CH2:47]5)=[CH:42][CH:41]=4)[C:38]([CH3:58])=[C:37]([OH:59])[C:36]3=[O:60])[CH:33]=[CH:34][C:29]=2[N:28]=[CH:27]1>CO>[NH:26]1[C:30]2[CH:31]=[C:32]([N:35]3[CH:39]([C:40]4[CH:45]=[CH:44][C:43]([CH:46]5[CH2:47][CH2:48][CH:49]([N:52]6[CH2:53][CH2:54][O:55][CH2:56][CH2:57]6)[CH2:50][CH2:51]5)=[CH:42][CH:41]=4)[C:38]([CH3:58])=[C:37]([O:59][CH3:3])[C:36]3=[O:60])[CH:33]=[CH:34][C:29]=2[N:28]=[CH:27]1
Reactant: CC1=C(O)C(=O)N(c2ccc3nc[nH]c3c2)C1c1ccc(C2CCC(N3CCOCC3)CC2)cc1
Reactant: Cc1ccc(S(=O)(=O)N(C)N=O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: OCCO
Solvent: CO
Solvent: CCOCC
Product: COC1=C(C)C(c2ccc(C3CCC(N4CCOCC4)CC3)cc2)N(c2ccc3nc[nH]c3c2)C1=O

Procedure:
The compound was synthesized starting from KOH (15 eq in water), diazald (8 eq), ethylene glycol/Et2O (1/2 v/v, 30 ml), 1-(1H-Benzo[d]imidazol-6-yl)-3-hydroxy-4-methyl-5-(4-(4-morpholinocyclohexyl)phenyl)-1H-pyrrol-2(5H)-one (0.350 g, 0.74 mmol, 1 eq) and MeOH (10 ml); yield: 0.040 g (11%); MS m/z: 487.2 [M+H]+; 1H-NMR: (400 MHz, CDCl3) δ: 12.34 (s, 1H), 8.13 (d, 1H), 7.70 (d, 1H), 7.45 (d, 2H), 7.17 (d, 5H), 5.75 (s, 1H), 3.95 (s, 3H), 3.56 (d, 4H), 2.35 (d, 4H), 2.1 (d, 1H), 1.90 (d, 2H), 1.69 (d, 5H), 1.4 (d, 4H); HPLC (METHOD [A]): rt 7.84 min (98.72%)
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:12]1[CH:17]2[CH:13]1[CH2:14][O:15][CH2:16]2.C(=O)(O)[O-].[Na+]>ClCCl>[CH2:1]([O:8][CH2:9][CH2:10][O:11][C@@H:17]1[CH2:16][O:15][CH2:14][C@H:13]1[OH:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1OCC2OC12
Reactant: OCCOCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O[C@@H]1COC[C@H]1OCCOCc1ccccc1
Reaction time: 3 h
Yield: 82.5 %

Procedure:
Into dichloromethane (5.0 mL), 2-benzyloxyethanol (7.07 g, 46.5 mmol) and 3,4-epoxytetrahydrofuran (1.0 g, 11.6 mmol) were dissolved, to which a boron trifluoride-diethyl ether complex (0.08 g, 0.58 mmol) was added at room temperature, followed by stirring for three hours. To the resulting reaction liquid, a saturated aqueous solution of sodium bicarbonate was added, followed by extraction with dichloromethane. The resulting organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue thus obtained was purified by silica gel column chromatography (hexane:ethyl acetate, 100:0-0:100, V/V) to give the desired title compound (2.28 g, yield 82%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([CH2:13][CH3:14])([CH3:12])[C:7](=[O:15])[C:6]([C:16]([NH:18][CH2:19][C:20]([O:22]C(C)(C)C)=[O:21])=[O:17])=[C:5]2[OH:27]>C(O)(C(F)(F)F)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([CH2:13][CH3:14])([CH3:12])[C:7](=[O:15])[C:6]([C:16]([NH:18][CH2:19][C:20]([OH:22])=[O:21])=[O:17])=[C:5]2[OH:27]
Reactant: CCC1(C)C(=O)C(C(=O)NCC(=O)OC(C)(C)C)=C(O)c2cc(Cl)ccc21
Solvent: O=C(O)C(F)(F)F
Product: CCC1(C)C(=O)C(C(=O)NCC(=O)O)=C(O)c2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79.9 %

Procedure:
A mixture of 1,1-dimethylethyl N-((6-chloro-1-ethyl-4-hydroxy-1-methyl-2-oxo-naphthalen-3-yl)carbonyl)glycinate (0.4 g, 1 mmol) in 3 mL TFA was stirred at room temperature for 30 minutes, M+1=338, M−1=336. The mixture was concentrated in vacuo and the residue was sonicated in 10 mL heptane. The solid was filtered, washed with 10 mL heptane, and dried under high vacuum to give 0.27 g of the title compound as an off-white solid. MS (m/z)=338 (M+H)+. Calculated for C16H16ClNO5 337.07.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:9]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[C:11](=[O:20])[CH:10]2[CH2:21][CH2:22][CH:23]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[OH:24])[CH:6]=[CH:7][CH:8]=1.[OH:32][CH:33]([CH:58]([OH:65])[CH:59]([OH:64])[CH:60]([OH:63])[CH2:61][OH:62])[C:34](=[O:57])[CH2:35][O:36][CH2:37][CH2:38][O:39][CH2:40][CH2:41][NH:42][C:43]([CH2:45][O:46][CH2:47][CH2:48][O:49][CH2:50][CH2:51][O:52][CH2:53][C:54](O)=[O:55])=[O:44].C(N=C=NC(C)C)(C)C.OC1C2N=NNC=2C=CC=1>CN(C)C=O>[F:19][C:16]1[CH:15]=[CH:14][C:13]([N:12]2[C:11](=[O:20])[CH:10]([CH2:21][CH2:22][CH:23]([C:25]3[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=3)[OH:24])[CH:9]2[C:5]2[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=2)[CH2:2][NH:1][C:54](=[O:55])[CH2:53][O:52][CH2:51][CH2:50][O:49][CH2:48][CH2:47][O:46][CH2:45][C:43](=[O:44])[NH:42][CH2:41][CH2:40][O:39][CH2:38][CH2:37][O:36][CH2:35][C:34](=[O:57])[CH:33]([OH:32])[CH:58]([OH:65])[CH:59]([OH:64])[CH:60]([OH:63])[CH2:61][OH:62])=[CH:18][CH:17]=1
Reactant: O=C(O)COCCOCCOCC(=O)NCCOCCOCC(=O)C(O)C(O)C(O)C(O)CO
Reactant: NCc1cccc(C2C(CCC(O)c3ccc(F)cc3)C(=O)N2c2ccc(F)cc2)c1
Agent: CC(C)N=C=NC(C)C
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Product: O=C(COCCOCCOCC(=O)NCc1cccc(C2C(CCC(O)c3ccc(F)cc3)C(=O)N2c2ccc(F)cc2)c1)NCCOCCOCC(=O)C(O)C(O)C(O)C(O)CO

Procedure:
29 is prepared similarly to 18 starting from 62 mg of 4-(3-aminomethylphenyl)-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]azetidin-2-one 15, 76 mg of {2-[2-({2-[2-(3,4,5,6,7-pentahydroxy-2-oxoheptyloxy)ethoxy]ethylcarbamoyl}methoxy)-ethoxy]ethoxy}acetic acid 26, 57 μl of diisopropylcarbodiimide and 40 mg of hydroxybenzotriazole in 2 ml of dimethylformamide. This gives 29:
Reaction SMILES: [Br:1][C:2]1[N:6]2[N:7]=[C:8](F)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[CH3:12][N:13]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:14][CH2:15][CH2:16][NH2:17].CN(C=O)C>CCOC(C)=O.O>[Br:1][C:2]1[N:6]2[N:7]=[C:8]([NH:17][CH2:16][CH2:15][CH2:14][N:13]([CH3:12])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1
Reactant: CN(CCCN)c1ccccc1
Reactant: Fc1ccc2ncc(Br)n2n1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CN(CCCNc1ccc2ncc(Br)n2n1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.2 %

Procedure:
To 300 mg (1.389 mmol) of the 3-bromo-6-fluoroimidazo[1,2-b]pyridazine, was added N1-methyl-N1-phenylpropane-1,3-diamine (456 mg, 2.778 mmol) Cs2CO3 (903 mg, 2.778 mmol) and 10 mL DMF. This mixture is stirred overnight at rt. It was diluted with 30 mL EtOAc, and 15 mL of water. The organic layer was washed with brine and dried over MgSO4. It was concentrated and purified using silica gel chromatography (ISCO) eluting with 0-10% MeOH/DCM to obtain 301 mg (60%) of product.
Reaction SMILES: [OH-].[Na+].Cl.[NH2:4][C:5]1([C:10]([OH:12])=[O:11])[CH2:9][CH2:8][CH2:7][CH2:6]1.[C:13](Cl)(=[O:18])[CH2:14][CH2:15][CH2:16][CH3:17]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1.O>[C:13]([NH:4][C:5]1([C:10]([OH:12])=[O:11])[CH2:9][CH2:8][CH2:7][CH2:6]1)(=[O:18])[CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: NC1(C(=O)O)CCCC1
Reactant: CCCCC(=O)Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [Br-]
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCC(=O)NC1(C(=O)O)CCCC1
Temperature: 0 °C

Procedure:
In a 3 necked 250 ml round bottom flask equipped with mechanical stirrer, was charged with sodium hydroxide solution (24.1 g dissolved in 100 ml water) and 1-aminocyclopentane carboxylic acid hydrochloride (25 g) and chilled to 0° C. under stirring. Tetra butyl ammonium bromide (0.25 g) was added to the reaction mixture followed by slow addition of a solution of valeroyl chloride (27.5 g) in toluene (20 ml) during one hour at 0-5° C. under stirring. The reaction mass was stirred for 1 hour at 0-5° C. The reaction mixture was diluted with water (100 ml) toluene (20 ml) and stirred for 15 minutes. The two phases were separated. The aqueous phase was washed with toluene (20 ml). Aqueous phase was chilled to 10° C. and acidified with hydrochloric acid and stirred it for 1 hour. The product was filtered and washed with water. The product was dried at 60° C. till constant weight. (Yield: 22 g; 68%).
Reaction SMILES: [N:1]1[N:9]2[C:4]([CH2:5][S:6][CH2:7][CH2:8]2)=[CH:3][C:2]=1[CH2:10][OH:11]>O=[Mn]=O.C(Cl)(Cl)Cl>[N:1]1[N:9]2[C:4]([CH2:5][S:6][CH2:7][CH2:8]2)=[CH:3][C:2]=1[CH:10]=[O:11]
Reactant: OCc1cc2n(n1)CCSC2
Agent: O=[Mn]=O
Solvent: ClC(Cl)Cl
Product: O=Cc1cc2n(n1)CCSC2

Procedure:
MnO2 (activated) (11.46 g) was added to the CHCl3 (135 mL) solution of (6,7-dihydro-4H-pyrazolo[5,1-c][1,4]thiazin-2-yl)methanol (2.31 g) and refluxed for 1 h under a nitrogen atmosphere. The reaction mixture was filtered through a pad of Celite. The filtrate was concentrated under a reduced pressure. The residue was applied to silica gel column chromatography, then the column was eluted with n-hexane-AcOEt (1/1). The titled compound was obtained as pale yellow crystals (1.78 g, 78%).
Reaction SMILES: [Br:1][C:2]1[C:22]([Cl:23])=[CH:21][C:5]2[N:6]([CH2:9][C:10]3[CH:20]=[CH:19][C:13]4[N:14]=[C:15]([S:17][CH3:18])[O:16][C:12]=4[CH:11]=3)[CH:7]=[N:8][C:4]=2[CH:3]=1.C1C=C(Cl)C=C(C(OO)=[O:32])C=1>C(Cl)Cl>[Br:1][C:2]1[C:22]([Cl:23])=[CH:21][C:5]2[N:6]([CH2:9][C:10]3[CH:20]=[CH:19][C:13]4[N:14]=[C:15]([S:17]([CH3:18])=[O:32])[O:16][C:12]=4[CH:11]=3)[CH:7]=[N:8][C:4]=2[CH:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1nc2ccc(Cn3cnc4cc(Br)c(Cl)cc43)cc2o1
Solvent: ClCCl
Product: CS(=O)c1nc2ccc(Cn3cnc4cc(Br)c(Cl)cc43)cc2o1
Yield: 66.7 %

Procedure:
A solution of 6-((5-bromo-6-chloro-1H-benzo[d]imidazol-1-yl)methyl)-2-(methylthio)benzo[d]oxazole (554 mg, 1.80 mmol) and m-CPBA (403 mg, 2.34 mmol) in DCM (18 mL) was stirred at 0° C. for 3 h. The reaction mixture was washed with aqueous Na2S2O3 and brine. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 1:5 petroleum ether/ethyl acetate to give 6-((5-bromo-6-chloro-1H-benzo[d]imidazol-1-yl)methyl)-2-(methylsulfinyl)benzo[d]oxazole (510 mg, 87.5%) as a yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 8.59 (s, 1H), 8.08 (s, 1H), 8.04 (s, 1H), 7.97 (s, 1H), 7.90 (d, J=8.7 Hz, 1H), 7.50 (d, J=9.3 Hz, 1H), 5.69 (s, 2H), 3.18 (s, 3H). LCMS (ESI) m/z 424 (M+H)+.